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Human in-vivo cardiac phosphorus NMR spectroscopy at 3.0 Tesla

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Title:
Human in-vivo cardiac phosphorus NMR spectroscopy at 3.0 Tesla
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Bruner, Angela Properzio
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English
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xvii, 282 leaves : ill. ; 29 cm.

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Subjects / Keywords:
Heart ( jstor )
Imaging ( jstor )
Ischemia ( jstor )
Magnetic spectroscopy ( jstor )
Magnetism ( jstor )
Phosphorus ( jstor )
Signals ( jstor )
Spectral line width ( jstor )
Spectroscopy ( jstor )
Supernova remnants ( jstor )
Dissertations, Academic -- Nuclear and Radiological Engineering -- UF ( lcsh )
Nuclear and Radiological Engineering thesis, Ph.D ( lcsh )
Nuclear magnetic resonance spectroscopy ( lcsh )
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bibliography ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph.D.)--University of Florida, 1999.
Bibliography:
Includes bibliographical references (leaves 260-280).
General Note:
Typescript.
General Note:
Vita.
Statement of Responsibility:
by Angela Properzio Bruner.

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University of Florida
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University of Florida
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Copyright [name of dissertation author]. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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HUMAN IN-VIVO CARDIAC PHOSPHORUS NMR SPECTROSCOPY AT 3.0 TESLA


By


ANGELA PROPERZIO BRUNER


















A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY




UNIVERSITY OF FLORIDA

1999








































Copyright 1999

by

Angela Properzio Bruner






































This work is dedicated to my loving husband, Thom Bruner, and my
parents, Sharon and Bill Properzio, without whom I would not have had
the loving support I needed to complete this work.

















ACKNOWLEDGMENTS


I would like to thank the following individuals for their

assistance and for making this work possible. The greatest thanks go to

my advisor and mentor, Dr. Kate Scott, who encouraged and advised me

through this project. Thanks also goes to Dr. Hee-Won Kim, who taught

me the basics of the ISIS pulse sequence, shared experiences in working

on the General Electric (GE) Signa", and offered valuable pulse

programming support. Credit must be given to David Peterson and Bryan

Wolverton, under the direction of Dr. Fitzsimmons, who built the coils

that were used in this study. Thanks also go to the combined efforts of

Dr. Scott, Dr. Fitzsimmons, Dr. Ballinger, Shands at UF, the VA

Hospital, and the Brain Institute for their efforts in getting a 3.0 T

whole body magnet to the University of Florida. Thanks are also well

deserved for Jim Scott who taught me the chemistry for the phantom

preparations.

After starting this project, I was lucky to begin collaborative

work with a number of individuals in cardiology both here at the

University of Florida (UF) and at the University of Alabama at

Birmingham (UAB). Great appreciation goes to Dr. Carl Pepine, currently

the division chief of cardiology, Shands at UF, who fully supported my

efforts and encouraged greater work. Also, countless thanks and

appreciation are well deserved for Alice Boyette, the Women's Ischemic

Syndrome Evaluation (WISE) research cardiology technologist. Alice not


IV











only attended all the WISE meetings and scheduled the cardiac patient

studies on the 1.5 and 3.0 T, but also provided patient handholding and

technical support during the studies. In addition, WISE research nurse

Eileen Handberg-Thurmond was very supportive and made sure that all

financial issues were under control and the necessary equipment

purchased. It was through the efforts of cardiology at UF that the

Dinamap" vital signs monitor was purchased and that all patient studies

were financially compensated. I was also fortunate to have my protocol

and my study results analyzed by a group at UAB who already had a

published history in doing cardiac phosphorus spectroscopy as well as

some experience with higher Tesla whole body systems (a 4.1 Tesla). The

expertise, careful analysis, and approval of my data by Dr. Steven

Buchthal, Dr. Jan den Hollander, and Dr. Gerald Pohost provided

excellent feedback that I was on the right track and succeeding in my

methodology.

I would especially like to thank all of the members of my

committee, Dr. Katherine Scott (Chair), Dr. Jeffrey Fitzsimmons, Dr. J

Ray Ballinger, Dr. Richard Briggs, Dr. Christine Stopka and Dr. David

Hintenlang. These individuals took time out of their busy scheduled to

review my work and support my efforts.

I would also like to sincerely thank those who believed in me and

helped me achieve my doctorate through their continuous moral support.

This includes a long list of family members (Thom Bruner, Sharon

Properzio, Bill Properzio, Tom Bruner Sr, Jess Bruner, Dee Dee Haun,

Carter Haun) and friends (Manuel Arreola, Libby Brateman, Lynn Rill,

Michelle Werner, Cathy Carruthers, Mark Knudsen, Beth Knudsen, Sheila

Marks).


















TABLE OF CONTENTS

page

ACKNOWLEDGMENTS ................... ................... .................iv

LIST OF TABLES. ... .. ....................... ........................ix

LIST OF FIGURES ........... ...... ....................................xi

ABSTRACT ....................................... ....................... xvi

CHAPTERS

1 INTRODUCTION ...................................... .................1

Statement of Problem ................................................. 2
Spectroscopy's Contribution to Diagnosing Myocardial
Ischemia ...................................................... 3
Research Hypotheses ................................................. 4
Specific Objectives .................................... ............. 5
Assumptions.......................................................... 6
Scope of the Project .................................................7
Significance .................... ..................................... 8

2 REVIEW OF LITERATURE ................. .............................. 10

P-31 Spectroscopy Pulse Sequence Options for the Heart............. 13
Slice Localization Techniques ............. ....................... 14
Multi-Voxel Localization Techniques..............................15
Single Voxel Localization Techniques ............................17
Cardiac P-31 Spectroscopy Results in the Literature ................22
Animal studies ..................................... .............. 22
Human Studies................................... .................24
Post-Processing Calculations and Corrections.......................48
Skeletal Muscle Contamination .................................49
Blood Contamination ..............................................49
Relaxation Corrections............................................ 52
Calculation of pH...................................... ..........56

3 PHANTOM P-31 SPECTROSCOPY ACQUISITION TECHNIQUES ................... 60

Phantom Design................... .................................. 61
Gate-able and Depth Phantoms ................................... 61
Slice Profile Phantom .. ........... ..............................64
GE Phosphoric Acid Phantom ......................................64
Radio Frequency Coil Design..................................... ... 65
3.0 Tesla Square Proton Coil Paired with Quadrature
Phosphorus Coil ...............................................65
3.0 Tesla Phosphorus Single-Turn Coil ...........................66






vii



3.0 Tesla Coil Comparisons. ......................................67
1.5 Tesla Coils.................................................. 69
Coil Ideas for Future Cardiac Spectroscopy Studies ..............70
Imaging .................. ............................. ......... .... 70
Spectroscopy ...... ..... .......................... .. .....................71
Localized Proton Spectroscopy. .................................... 72
Localized Phosphorus Spectroscopy................... .............73
Phosphorus STEAMCSI and PRESSCSI............................... 74
Phosphorus ECHOCSI ............................................... 74
Phosphorus SPINECHO ...................................... ........ 75
Phosphorus ISISCSI ............................................... 76
Phosphorus FIDCSI ................................................78
1.5 Tesla to 3.0 Tesla Phosphorus Spectroscopy Comparisons...... 82
Phantom Results ................................. ... ............... 84

4 HUMAN CARDIAC P-31 SPECTROSCOPY ACQUISITION TECHNIQUES .............112

Imaging.................... ................................. ........ 113
Spin-Echo Imaging...............................................113
Gradient-Echo Imaging ............ .... .........................114
Human Positioning..................................................... 114
Gating .. ................ ................. ........ ........... 116
Shimming with Localized Proton Spectroscopy.......................119
Cardiac Phosphorus Spectroscopy In-Vivo Acquisition ...............120
Localized P-31 Multivoxel CSI ...................................120
Localized P-31 ISISCSI. .........................................121
Slice Localized P-31 FIDCSI (DRESS) ............................122
Single Turn versus Quadrature Surface P-31 Coil at 3.0 T.......123
Human Test Participants..................................... ........123
In-Magnet Exercise ................................................. 128
Spectroscopy Post-Processing..................................... 129
Post-Processing Software ................... ................. ...130
Skeletal Muscle ................ .................... ............136
Blood Contamination ......................... ....................136
Ti Relaxation Corrections ........................................ 137
Calculations of pH ..............................................139
Analysis .......... ............................................... 140

5 HUMAN DATA REPRODUCIBILITY. ................. ...................... 156

T, Relaxation Corrections ................... .......................157
Overall Reproducibility of the Oblique DRESS Method.................159
Adequacy of the Hydraulic, In-Magnet, Handgrip Exerciser.......... 165
Reproducibility of the Hydraulic Handgrip ......................... 167
No Drop in [PCr]/[ATP] During Exercise with Reference Volunteer...168
Drop in [PCr]/[ATP] Seen with the Handgrip Exerciser with
Ischemia ................ ......................... ............... 170
Myocardial pH Measured at 3.0 T. ....................................171

6 SUMMARY AND CONCLUSIONS ........................................... 174

Implications for Future Research .................................. 176

APPENDICES

A IRBS AND SCREENING FORMS .......................................... 180






viii



B FIGURE ACQUISITION PARAMETERS ..... ................................. 193

C HYDRAULIC HANDGRIP................................................. 224

D 3.0 T CARDIAC ACQUISITION PROTOCOL................... ...........228

E SPECTROSCOPY POST-PROCESSING INSTRUCTIONS.........................236

F HUMAN Ti RELAXATION DATA .......................................... 256

G T, RELAXATION RATES OF DEPTH PHANTOM .............................. 259

REFERENCES ..................................... ......................... 260

BIOGRAPHICAL SKETCH............... .... ................................. 281

















LIST OF TABLES


Table page

1. Nuclear Spin Parameters ................... ..................... .. 13

2. Research Published on Human, In-Vivo Cardiac P-31
NMR Spectroscopy of Studies on Normal-Controls or
Patients and Related Work ...................................... 26

3. Cardiac [PCr]/[ATP] Ratio of Healthy Volunteers
(Normal Controls) at Rest and During Stress .................... 36

4. Cardiac [PCr]/[ATP] Ratio of Patients with Myocardial
Infarction at Rest and During Stress ........................... 38

5. Cardiac [PCr] and [ATP] Amounts at Rest in Patients with
Myocardial Infarction, Ischemia and in Normal Controls ......... 39

6. Cardiac [PCr]/[ATP] at Rest and Stress in Patients with
Myocardial Ischemia.............................................. 43

7. Cardiac [PCr]/[ATP] at Rest and Stress in Patients with
Myocardial Ischemia with Some Type of Intervention ............. 44

8. Literature Review of In-Magnet Handgrip Exercise Response .......48

9. Published Spin-Lattice Relaxation Times of Myocardial PCr
and ATP ......................................................... 55

10. Myocardial pH in the Literature as Measured by Human,
In-vivo Phosphorus NMR Spectroscopy ............................ 57

11. Gate-able and Depth Phantom Compartment Sizes and
Concentrations ........... .... ............ .................... 62

12. A Comparison of 3.0 Tesla Coil Parameters. ..................... 67

13. Comparison of 1.5 Tesla Coil Parameters ....................... 69

14. Participants at 3.0 T for Cardiac P-31 Spectroscopy .......... 126

15. In Magnet Hydraulic Exercise Handgrip Participants ............ 127

16. Oblique DRESS Acquisition P-31 Metabolite area Values
Obtained with Different TR gating Intervals for the
Purpose of Relaxation Measurements ........................... 158

17. Summary of Resulting T, values for PCr and ATP.c ................ 159






x



18. WISE 1.5 T Cardiac Spectroscopy Acquisition Success Rate ....... 161

19. 3.0 T Cardiac P-31 Spectroscopy at Rest Only, 3xRR Gating ...... 162

20. 3.0 T Cardiac P-31 Results Categorized by P-31 Surface Coil .... 165

21. Heart rate (HR) and Systolic Blood Pressure (SBP) Response
from 30% of Maximum Effort Isometric Hydraulic Handgrip ....... 166

22. Handgrip exercise compared to dobutamine and treadmill
responses for known WISE studies .............................. 167

23. Handgrip 30% Maximum Effort Isometric Exercise Results of
K.S. Subject Tested Repeatedly................................. 168

24. Results from 1.5 T Cardiac P-31 Exercise Study on Reference
Normal Volunteer .............................................. 170

25. Ischemic and WISE Studies at 3.0 T Show Drop in [PCrl/[ATP]
with Handgrip Exercise ......................................... 171

26. Myocardial pH as Measured on Human Volunteers Using Oblique
DRESS Cardiac P-31 MRS on the GE 3.0 T SIGNA'" for those
Studies where the Pi Peak was Discernible due to Adequate
SNR...................... ................................ ...... 172

27. Comparison of Cardiac P-31 Post-Processing Software. ........... 252

















LIST OF FIGURES


Figure page

1. STEAM Pulse Sequence ............................................ 58

2. PRESS Pulse Sequence ........... ........................ ....... 58

3. ISIS Volumes for 8 Acquisition Voxel Localization. .............. 59

4. Gate-able-Phantom (a) photograph and (b) position in magnet,
without the liquids and with movement direction demonstrated... 87

5. Gate-able-Phantom images, (a) axial, (b) coronal and
(c) sagittal views, as imaged with 25cm square proton coil..... 87

6. The Depth-Changing-Phantom (a) photograph with top open and
(b) position in magnet, with movement direction demonstrated... 88

7. Depth-Changing-Phantom images, (a) axial, (b) coronal and
(c) sagittal views, as imaged with 25cm square proton coil..... 88

8. Axial slice image of Slice Profile Phantom and details on
how oblique DRESS slices were placed within phantom to
estimate the amount of potential contamination from outside
the localized slice ................... ............. ............ 89

9. Photographs of GE's 14.7 M P-31 Phantom from (a) front,
(b) back and relative position in magnet ...................... 89

10. Photographs of quadrature phosphorus and square proton
coil as (a) a paired set and (b) separated onto individual
platforms for 3.0 Tesla ......................................... 90

11. Schematic diagrams of (a) the 25 x 25 cm2 square proton
coil set (tuned to 127.75 MHz) used with (b) the 10 cm
phosphorus quadrature coil at 3.0 T (tuned to 51.71 MHz) ....... 90

12. Photograph of the single turn, 9.5 cm diameter, phosphorus
transceive coil tuned to 51.71 MHz (3.0 Tesla) ................ 91

13. Schematic diagram of the single-turn phosphorus transceive
9.5 cm diameter coil at 3.0 T tuned to 51.71 MHz............... 91

14. Comparisons of single-turn versus quadrature P-31 RF coils
in terms of relative signal based on 25 mm thick DRESS
acquisitions of 14.7 M phantom at 0.5 cm intervals with
TG optimized at each position. ................................. 92










15. Photograph of the single turn, 9.5 cm diameter, phosphorus
transceive coil tuned to 25.87 MHz (1.5 Tesla) with three
small vials that are used to locate the coil in the
proton images........................................ ............ 93

16. Schematic diagram of the single-turn phosphorus transceive
10 cm diameter coil at 1.5 T tuned to 25.87 MHz ................ 93

17. Photograph of 1.5 T quadrature P-31 coil. ....................... 94

18. Schematic diagram of the quadrature phosphorus transceive
10 cm diameter coil at 1.5 T tuned to 25.87 MHz ................ 94

19. Axial images of gate-able phantom comparing images obtained
on 3.0 T using a 25 cm square proton surface coil with the
image pulse-sequences of (a) spin echo, (b) fast spin echo,
(c) gradient echo and (d) fast gradient echo imaging ........... 95

20. The STEAMCSI pulse sequence, GE's version of STEAM for
spectroscopy voxel localization. ................................ .96

21. The PRESSCSI pulse sequence, GE's version of PRESS for
spectroscopy voxel localization ................................... 96

22. Frequency domain of (a) PRESSCSI voxel localized phosphorus
spectroscopy with (b) diagram demonstrating localization ....... 97

23. Frequency domain of (a) STEAMCSI voxel localized phosphorus
spectroscopy with (b) diagram demonstrating localization....... 97

24. The ECHOCSI pulse sequence, one of GE's versions of
Spin Echo for spectroscopy acquisition ....................... 98

25. Frequency domain of (a) ECHOCSI voxel localized phosphorus
spectroscopy with (b) diagram demonstrating localization....... 98

26. Chemical shift imaging (CSI) voxel sizes versus time of
slice plus 2D CSI acquisition on GE Signa Advantage" ............ 99

27. The SPINECHO pulse sequence, one of GE's versions of
Spin Echo for spectroscopy acquisition. ...................... 100

28. Frequency domain of SPINECHO CSI multivoxel localized
phosphorus spectroscopy .................. ....................... 100

29. The ISISCSI pulse sequence (as shown for one gradient),
GE's versions of ISIS for volume, slice, column or voxel
localization ...................................................... 101

30. Frequency domain of (a) ISISCSI slice localized phosphorus
spectroscopy with (b) diagram demonstrating localization ...... 101

31. Frequency domain of (a) ISISCSI column localized phosphorus
spectroscopy with (b) diagram demonstrating localization...... 102

32. Frequency domain of (a) ISISCSI voxel localized phosphorus
spectroscopy with (b) diagram demonstrating localization...... 102






xiii


33. Visual display example of the acquisition where the total
number of acquisitions is 32 performed by (a) the current
GE ISISCSI technique, and (b) the modified ISIS technique..... 103

34. Frequency domain of (a) modified ISISCSI localized voxel
sequence for phosphorus (created from eight separate
acquisitions, added and subtracted appropriately during
post-processing) with (b) diagram demonstrating localization.. 104

35. The FIDCSI pulse sequence without phase encoding gradients
turned on, GE's versions of the simple single RF pulse
necessary to produce an FID for a spectroscopy acquisition ... 104

36. Charts comparing (a) relative signal obtained by varying
transmitter gain (TG) values at various depths for slice
localized FIDCSI at 1.5 Tesla, using the quadrature coil
and (b) relative optimized TG value versus depth for the
single turn coil ............................................. 105

37. Charts comparing relative signal obtained by varying
transmitter gain (TG) values at various depths for slice
localized FIDCSI at 3.0 Tesla, using (a) the quadrature
coil, or (b) the single turn coil .... ......................... 106

38. Frequency domain of FIDCSI slice localized phosphorus
spectroscopy of (a) gate-able phantom and (b) depth phantom... 107

39. Multivoxel phosphorus FIDCSI plus CSI of the (a) gate-able
phantom (b) depth phantom................. ................... 108

40. Comparison of 1.5 to 3.0 Tesla results of phosphorus FIDCSI
plus CSI localized voxel scaled by noise level ............... 109

41. Comparison of 1.5 to 3.0 Tesla results of phosphorus,
modified ISISCSI localized voxel (created from eight
separate acquisitions, added and subtracted appropriately
during post-processing) ..................... .................. 109

42. 1.5 T, P-31 single turn RF coil signal from a set of
25 mm thick, oblique DRESS slices (FIDCSI oblique slice)
moved across the internal phosphoric acid vial in the
Slice Profile Phantom.......................................... 110

43. 3.0 T, P-31 single turn RF coil signal from a set of
25 mm thick, oblique DRESS slices (FIDCSI oblique slice)
moved across the internal phosphoric acid vial in the
Slice Profile Phantom .......................................... 110

44. 3.0 T, P-31 quadrature RF coil signal from a set of
25 mm thick, oblique DRESS slices (FIDCSI oblique slice)
moved across the internal phosphoric acid vial in the
Slice Profile Phantom ........................................... 111

45. Human cardiac imaging with the spin-echo pulse sequence
at (a) 1.5 T with the body coil and at (b) 3.0 T with
a surface coil ................. ....... ...... .............. 141






xiv


46. Human cardiac imaging with the fast gradient echo pulse
sequence at (a) 1.5 T with the body coil and at (b) 3.0 T
with a surface coil .............................................. 142

47. Prone positioner for in-magnet cardiac spectroscopy ............ 143

48. A comparison of the heart's position in the (a) prone and
(b) supine positions, as shown from a 3.0 T axial slice ....... 144

49. Waveforms of (a) peripheral gating and (b) ECG gating on
the 3.0 T from a normal human volunteer (TEB) on
Sept 20, 1998, displayed at a rate of 21 mm/sec............... 144

50. A comparison of peripheral gating (pg) versus ECG gating,
and breathing during the image versus breath-hold images ...... 145

51. Human proton voxel localized spectroscopy of the heart
and chest wall obtained during one volunteer's shim using
the techniques of GE's (a) STEAMCSI and (b) PRESSCSI .......... 146

52. P-31 FIDCSI with CSI of a human subject at 3.0 T ............... 147

53. DRESS localization via oblique slice select combined
with sensitivity region of coil ............................... 148

54. Examples of 1.5 T cardiac phosphorus spectra localization
problems resulting in (a) liver contamination, or
(b) skeletal muscle contamination, in comparison with
(c) a non-contaminated cardiac spectrum ...................... 149

55. P-31 FIDCSI oblique slice localized human cardiac
spectroscopy (oblique DRESS) of the same subject,
at 1.5 and 3.0 T, on different days showing examples
of resting and exercise spectra, raw and fitted ............... 150

56. Series of cardiac region oblique DRESS spectra
representing decreased skeletal muscle contamination
with increase in depth of spectroscopy slice localization ..... 151

57. Relative size of oblique DRESS slice with (a) a 10-cm
diameter single-turn P-31 surface coil and (b) a 16 x 10
cm2 quadrature P-31 surface coil. ............ ................ 152

58. Water, hydraulic, hand-squeeze ergometer/static-exerciser,
modified from original design by North Coast Medical .......... 153

59. The linear response of the hydraulic handgrip to added
weight on the rubber bulb is illustrated ...................... 154

60. Dinamap" blood pressure and pulse monitoring equipment. ......... 154

61. Myocardial pH is proportional to the frequency
difference of the Pi and PCr peaks in the human, in-vivo
phosphorus NMR spectrum ..................... ........... ....... 155






XV


62. Relaxation correction factors at 3.0 T for cardiac
[PCr]/[ATP] values based on repetition time (TR) values....... 173

63. ECG lead placement for 3.0 T gating. ........................... 230

64. Example 3.0 T data set analyzed by FITMASTER.. ................. 238

65. Example 3.0 T data set analyzed by Sage_IDL". ................... 241

66. Example 3.0 T data set analyzed by Sage_IDL' with baseline
correction points selected. .................. ............... 241

67. Example 3.0 T data set analyzed by Sage_IDL' with baseline
correction.......................................................... 242

68. Example 3.0 T data set processed by MRUIT. ..................... 244

69. Example 3.0 T data set analyzed by MRUI". ...................... 245

70. Example 3.0 T data set processed by FELIX.. ..................... 248

71. Example 3.0 T data set processed by FELIX' with peaks picked. .. 249

72. Example 3.0 T data set processed by FELIX' with baseline
correction.................... ........................... .....250

73. Example 3.0 T data set analyzed by FELIX". ..................... 250

74. Example 1.5 T data set with low SNR analyzed by SAGE_IDL". ..... 252

75. Example 1.5 T data set with low SNR analyzed by FITMASTERT. .... 254

76. 1.5 T Ti relaxation curve for MDPA (Ti = 5.53 sec) ............ 259

77. 3.0 T Ti relaxation curve for MDPA (TI = 6.04 sec) .............. 259

















Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy


HUMAN IN-VIVO CARDIAC PHOSPHORUS NMR SPECTROSCOPY AT 3.0 TESLA

By

Angela Properzio Bruner

August 1999

Chairman: Katherine N. Scott
Major Department: Nuclear and Radiological Engineering


One of the newest methods with great potential for use in clinical

diagnosis of heart disease is human, cardiac, phosphorus NMR

spectroscopy (cardiac P-31 MRS). Cardiac P-31 MRS is able to provide

quantitative, non-invasive, functional information about the myocardial

energy metabolites such as phosphocreatine (PCr), adenosinetriphosphate

(ATP) and pH. In addition to the use of cardiac P-31 MRS for other types

of cardiac problems, studies have shown that the ratio of [PCr]/[ATP]

and pH are sensitive and specific markers of ischemia at the myocardial

level. In human studies, typically performed at 1.5 Tesla, [PCr]/[ATP]

has been relatively easy to measure but often requires long scan times

to provide adequate signal-to-noise (SNR). In addition, pH which relies

on identification of inorganic phosphate (Pi), has rarely been obtained.

Significant improvement in the quality of cardiac P-31 MRS was

achieved through the use of the General Electric SIGNA" 3.0 Tesla whole

body magnet, improved coil designs and optimized pulse sequences.

Phantom and human studies performed with many types of imaging and






xvii


spectroscopy sequences identified breathhold gradient-echo imaging and

oblique DRESS P-31 spectroscopy as the best compromises among SNR,

flexibility and quality of localization. Both single-turn and quadrature

10-cm diameter, P-31 radio frequency coils were tested. The quadrature

coil provided greater SNR, but had to be used at a greater depth to

avoid skeletal muscle contamination. Gated cardiac P-31 MRS obtained in

just 6 to 8 minutes, showed both improved SNR and discernment of Pi

allowing for pH measurement.

A handgrip, in-magnet exerciser was designed, created and tested

at 1.5 and 3.0 Tesla on volunteers and patients. In ischemic patients,

this exercise was adequate to cause a repeated drop in [PCr]/[ATP] and

pH with approximately eight minutes of isometric exercise at 30% maximum

effort. As expected from the literature, this exercise did not cause a

drop in [PCr]/[ATP] for reference volunteers.

















CHAPTER 1
INTRODUCTION




The statistics placing heart disease as a leading killer are

remarkable. Considering all age groups and genders, heart disease is

the number one killer, above other common killers such as cancer,

accidents, and diabetes.' Cardiovascular disease kills about 2,500

people each day or more than one million each year in the United

States.2 Some form of heart disease affects one in four persons, with

the combination of costs from treatment and loss of productivity

approaching 50 billion dollars annually.2

One of the most common types of heart disease is myocardial

ischemia. In myocardial ischemia, individual cells in affected areas

of the myocardium can no longer function due to significant decreases

in blood flow to the region, which results in chest pain (angina

pectoris). The blood flow reduction is typically due to a gradual

blockage in the large and/or small vessels, which substantially

increases the risk for acute and total blockage infarctionn). Ischemia

limited to the small vessels is termed microvascular ischemia or

microvascular dysfunction (MVSF). MVSF seldom results in death but is

very disabling due to fatigue and anxiety resulting from the chest

pain.' Although patients with chest pain are usually checked for heart

disease, asymptomatic patients are also tested based on risk factors

such as age, weight, life-style (high fat diet, smoking) and family

history. Ischemia is often clinically silent or associated with











atypical symptoms. Unfortunately its presence is a significant risk

factor for a fatal heart attack. The American Heart Association

estimates that as many at 3 to 4 million Americans have silent or

asymptomatic ischemic episodes that are eventually diagnosed by testing

for reasons unrelated to the symptoms.2



Statement of Problem


None of the current clinical methods for diagnosing cardiac

ischemia is 100% accurate. This is especially true of the most common

cardiac test, measurement of the heart's electrical function via

electrocardiogram (ECG). Most especially for women, but also for men,

the ECG often does not assist in the diagnosis of cardiac dysfunction.4

In addition, although large vessel ischemia is commonly quantified by

the degree of stenosis in the coronary arteries via a coronary

angiography (CA) catheterization study, microvascular ischemia cannot

be diagnosed with CA because the vessels are too small to resolve.

Of all the tests clinically available to diagnose myocardial

ischemia, most do not provide a direct quantitative measure of ischemia

in the affected myocardial tissue. Most of the tests that look

directly at the myocardial tissue are qualitative imaging studies, such

as clinical nuclear medicine, ultrasound, computed tomography, and

magnetic resonance imaging methods, where information such as wall

motion and perfusion defects can be qualitatively determined. However,

these evaluations do not provide quantitative information about levels

of ischemia, although the technique of MR tagging (now at a research

stage only) may be used in the near future to quantify wall motion.











Those tests that do provide quantitative information do so indirectly,

rather than as a direct measure of the myocardial tissue, such as the

electrical signal measured via ECG or the percent stenosis of the

coronary arteries as measured in a CA study. Individually, none of

these tests can provide a direct diagnosis of ischemia. In this

context, it is common practice to perform multiple tests for added

accuracy in diagnosing myocardial ischemia.



Spectroscopy's Contribution to Diagnosing Myocardial Ischemia


Human, cardiac phosphorus NMR spectroscopy (cardiac P-31 MRS) is

a non-invasive technique that directly measures pH and the levels of

intracellular myocardial phosphocreatine (PCr), adenosine triphosphate

(ATP), phosphodiester (PDE), and inorganic phosphate (Pi) in a non-

destructive manner. Both the reduction in the ratio of [PCr]/[ATP] and

pH have been shown to be sensitive and specific markers of ischemia at

the tissue level in animal models'6 and in humans.'8 Cardiac P-31 MRS

is an additional tool that can add to the degree of sensitivity and

specificity in diagnosis of ischemic heart disease by providing

quantitative information as a measure of the myocardial tissue

directly, regardless of whether it is caused by macro- or micro-

vascular ischemia.

Cardiac P-31 MRS is currently in limited use clinically. The

reasons for this pertain partially to the degree of difficulty in

obtaining cardiac P-31 MRS in a reasonable amount of time and

uncontaminated by non-cardiac signal. Useful cardiac P-31 MRS requires

obtaining a phosphorus spectrum with good signal-to-noise ratio (SNR),











with the Pi peak discernible in order to measure pH, and without

contamination from skeletal muscle or liver. The spectrum must be

obtained from the heart, which is moving in a rhythmic motion with the

cardiac cycle. In addition, spectral acquisitions are sensitive to BO

homogeneity and generally require more swimming than do images to

enhance the SNR. Shimming of a moving, heterogeneous object is more

difficult than a stationary one. To compound the difficulties, the

anterior region of the heart is only 10 to 18 mm thick and at a depth

of 4 to 8 cm from the P-31 surface coil. The distance between the

heart and the surface P-31 radio frequency (RF) coil limits the

acquisition volume to the anterior wall of the heart because of

attenuation of B, and low SNR. Between the heart and the P-31 surface

coil is the chest wall skeletal muscle, below the heart is the liver,

and in the cardiac chambers is blood. Care must be taken so that

neither the skeletal muscle nor liver will contaminate the spectra

obtained from the cardiac muscle. Blood contamination can be corrected

for after the acquisition. The result of a cardiac P-31 acquisition is

typically a low SNR spectrum with an acquisition time of around 10 to

40 minutes. Because in-magnet exercise and/or drug-induced stress are

required for P-31 MRS studies of ischemic heart disease, a scan time of

more than 10 minutes is undesirable.


Research Hypotheses


The following hypotheses will be tested in this dissertation.

1. Human, phosphorus NMR spectroscopy of the heart can be implemented

at 3.0 Tesla (T) by overcoming technical problems to produce spectra

of higher quality than obtained at 1.5 T.











2. Mild exercise from an isometric, hydraulic handgrip, designed and

produced for this study, provides adequate stress on the heart to

cause a significant drop in [PCr]/[ATP] in the ischemic myocardium

and thus differentiates ischemic from non-ischemic myocardium.



Specific Obiectives


Localized phosphorus spectra will be obtained from both phantoms

and the anterior myocardium of human participants. All human

participants will be screened for MR incompatibility and will sign an

approved Institutional Review Board Informed Consent Form (Appendix A).

The optimal pulse sequence for obtaining human, cardiac

phosphorus spectroscopy will be determined from phantom and human

studies. All spectroscopy pulse sequences available on the General

Electric (GE) 3.0 T whole-body magnet will be compared using phantom

studies. Measurement of SNR and degree of localization will be made

for each pulse sequence. Select pulse sequences will then be tested

and compared using human subjects. Human study comparisons will be

based on SNR and the degree of contamination of cardiac muscle signal

from other sources (skeletal muscle and liver).

A 10-cm diameter, single-turn P-31 RF coil will be compared with

a 16 x 10-cm, quadrature P-31 RF coil (two, 10-cm diameter RF coils

overlapping). Comparisons will be based on quality factors, isolation,

SNR at different depths, and degree of signal contamination.

Select tests will be performed on both 1.5 and 3.0 T GE Signa

AdvantageM systems to compare the resulting SNR and spectral dispersion

obtained using the same pulse sequence, coil, and sample studied











(phantom or human). The human cardiac phosphorus spectra obtained at

3.0 T should show greater SNR and spectral dispersion allowing for the

discernment of the Pi peak and thus the measurement of pH.

A hydraulic handgrip exerciser, designed and produced for this

study, will be tested for adequacy as a cardiac stressor that should

cause a drop in [PCr]/[ATP] in ischemic myocardium but not in non-

ischemic myocardium. The adequacy will be demonstrated by obtaining

data on heart rate and blood pressure changes with isometric handgrip

exercise of 30% maximum effort. These data will be compared with

literature values where similar devices were used during cardiac

phosphorus spectroscopy acquisitions as well as compared with the

responses to clinical cardiac tests (treadmill and dobutamine) obtained

locally.



Assumptions


This work will build on past knowledge and technology for

assessing cardiac metabolites and thus heart function. It will be

assumed, in most cases, that data from previous publications are

correct, especially at 1.5 T, and this data will be used to help

validate the work developed in this dissertation by comparing it with

past publications and work on similar patients and procedures performed

locally.

In order to assess the procedure used to stress the participants

in the magnet, both suspected ischemic and non-ischemic subjects will

be tested. It will be assumed that these participants will be properly











categorized by risk factor assessment, current symptoms, and when

available ECG treadmill and cardiac catheterization results.



Scope of the Proiect


This work will be limited to creating a procedure for obtaining

human, in-vivo cardiac P-31 NMR spectroscopy optimized for the GE Signa

Advantage'" 3.0 T whole body magnet located in the tunnel between Shands

at UF and the Veterans Affairs hospitals in Gainesville, FL. The

ability to improve the results of acquisitions on the 3.0 T scanner is

limited by the capabilities of the system, such as gradient strength (1

Gauss/cm) and specific absorption rate (SAR) limitations.

This work also will not use extensive pulse programming to

improve the system performance. Instead, the available sequences on

the 3.0 T system will be optimized, most often via the choice of

parameters and protocols. When necessary, small pulse programming

changes may be performed by Dr. Hee-Won Kim.

The numbers of subjects in the studies will be limited but should

still be adequate to demonstrate the feasibility and reproducibility of

the technique. A true set of controls free of ischemic heart disease

would first have to be evaluated by a cardiologist, at a cost that is

not available for this project. Taking any willing volunteer would

potentially introduce bias into the results as some might have silent

ischemia. In addition, a cardiologist will refer all participants

identified with ischemic heart disease. This work is intended as a

feasibility study where the results could then be used to justify

further research.










Significance


Human cardiac spectroscopy has been commonly performed at 1.5 T91'

and occasionally at 4.0 T,16." but never before at 3.0 T. With all

other factors the same, an increase in magnet field strength will

theoretically result in a linear increase in the spectral dispersion

and at least a linear increase in the SNR. In addition, the use of a

quadrature surface coil is expected to further increase the SNR

compared to the simpler single loop surface coil currently used in

previously reported human cardiac spectroscopy studies..-24

Finally, the use of in-magnet exercise while non-invasively

measuring human cardiac phosphorus metabolites has been accomplished by

just a few research groups. 13'2'25-28 In-magnet exercise with our

technique and device is easy to incorporate and looks very promising

for helping to distinguish normal from diseased cardiac muscle,

especially in cases of myocardial ischemia.

In terms of potential research and clinical use of human cardiac

phosphorus spectroscopy, there are many potential future benefits.

First, this test may provide increased accuracy of diagnosis of

ischemia and microvascular ischemia, for which new treatment modalities

may exist. Because cardiac P-31 MRS is a quantitative measure of

ischemia at the tissue level, it could be used to monitor or follow-up

treatment regimes or to help develop new treatments for ischemic heart

disease. In addition, a noninvasive MR diagnostic test of ischemia may

eliminate unnecessary invasive cardiac catheterization procedures,

reducing both risk of medical complications and cost. Based on data

from the Health Care Finance Administration, National Physician Fee






9




Schedule Relative Value File," a cardiac catheterization study costs

four times as much as a cardiac MR exam.

















CHAPTER 2
REVIEW OF LITERATURE




Magnetic resonance (MR) is a technique for using the interactions

of atoms and molecules with external magnetic fields to extract image

and chemical data from a sample. Using the classical description, the

proton possesses a spin angular momentum, S and a gyromagnetic ratio,

y, where the product is the magnetic dipole moment, .



S= yS Equation 1


Hydrogen and nuclei with either an odd number of protons (such as

phosphorus-31 with 15 protons and 16 neutrons) or an odd number of

neutrons possess magnetic moments whereas even-even nuclei have zero

magnetic moment. NMR takes advantage of the spin magnetic moment to

obtain a signal from these nuclei, especially if they are already

somewhat plentiful in the human body like proton (H-l) and phosphorus

(P-31) .

Placing a bulk of material, having nuclei with spin magnetic

moments, into a strong and uniform external magnetic field (Bo) causes

the nuclei's magnetic moment to attempt to align with the applied

magnetic field. This results in the spin processing around the

magnetic field analogous to a spinning top.30 The precession of the

nuclei in response to an applied magnetic field proceeds at a known

frequency described by the Larmor equation:










o = yB0 Equation 2


where c0 is the rate of precession in radians per second, and B0 is

the main magnetic field. The application of radio frequency energy at

the Larmor frequency for a nucleus constitutes a condition of

resonance, hence explaining the terms of Nuclear Magnetic Resonance or

NMR.

In practice, the distribution of electrons about any given

nucleus provides some shielding of the nucleus from the Bo field.

Since the distribution of electrons is a function of the molecular

structure in which the atoms (and their nuclei) are located, the actual

field experienced by the nucleus differs from the Bo field by some

small amount.30 Equation 2 can be modified to include the shielding

constant for chemical shift, G for a nucleus in a specific molecular

environment3":



io = yB0(1-) Equation 3


A basic NMR experiment consists of placing a sample in a constant

external magnetic field (Bo) where the nuclei's magnetic moment

attempts to align with Bo, also called the equilibrium condition.

After applying an oscillating radio-frequency (BI) identical to the

precession frequency of the nucleus of interest (the Larmor frequency),

the nuclei absorb energy and tip away from their alignment with the

external magnetic field. This displacement with the Bi field causes the

individual spins to coalesce, creating a combined magnetic moment in

the transverse plane. Once the BI field is removed, the magnetic moment

rotates at the Larmor frequency, slowly losing phase coherence due to











magnetic field variations affecting the individual spins." A signal is

induced in a receiver RF coil (either the same or different from the RF

transmitting coil) by the rotating magnetic moment in the transverse

plane. This produces a damped sinusoidally varying signal of positive

and negative polarity at the Larmor frequency, known as the free

induction decay (FID). Only when the net magnetic moment in the

transverse plane is nonzero, and the spins are in phase coherence will

a signal be generated."

The MR technique is both non-invasive and sensitive to the

molecular environments of the atoms. These factors have led to the use

of MR in several areas, primarily for imaging and spectroscopy. In MR

imaging (MRI) the signals from fat and water hydrogen atoms are mapped

according to their location and their characteristics. The second area

of use, MR spectroscopy (MRS), is a technique that was first used in

chemistry and physics laboratories in the analysis and identification

of chemical compounds.32 Biologically, MRS has also been used in the

identification and analysis of protein and macromolecular structures

and conformation using high resolution NMR." Another biological use of

MRS has been the examination of cell samples or organs, ex vivo." The

most clinically relevant use of MRS, however, is in vivo where the

patient's tissue metabolites can be examined directly and non-

invasively using techniques to localize to the region of interest

within the body.

The two main isotopes that are most studied in human, in-vivo

spectroscopy are proton (H-l) and phosphorus (P-31) because of their

natural abundance, relative sensitivity and chemical significance

within the body. H-1 MRS is the most commonly performed clinical MRS











patient examination because it can be done using standard MRI equipment

and software available on most clinical systems. It has been shown to

be useful in measuring markers of a variety of brain abnormalities such

as stroke,3' tumors6 and epilepsy,3 through the relative increase or

decrease of the metabolites (such as NAA, choline, and creatine). P-31

has a larger chemical shift range (-30 ppm) than H-1 (-10 ppm) and a

much lower sensitivity, as shown in Table 1. Water suppression is not

necessary in P-31 MRS, but lower spatial resolution and/or increased

scan times are required to obtain the same signal to noise (SNR) as

with H-1 MRS. P-31 MRS can detect a number of metabolites involved in

cellular energy metabolism, such as phosphocreatine (PCr),

adenosinetriphosphate (ATP) and inorganic phosphate (Pi). The chemical

shift of the Pi peak is pH dependent. In addition, relative peak areas

of PCr, Pi and ATP peaks have been used to evaluate fatigue and/or

ischemia in muscle, as will later be discussed in this chapter.


Table 1. Nuclear Spin Parameters".

Gyromagnetic Resonance Resonance
% Natural Ratio Frequency Frequency Relative
Isotope Abundance (MHz/T) at 1.5 T at 3.0 T Sensitivity

H-1 99.985 42.58 63.86 127.74 100

P-31 100 17.25 25.88 51.75 6.6518



P-31 Spectroscopy Pulse Sequence Options for the Heart


A variety of pulse sequences have been employed to localize to

the myocardium when performing in-vivo cardiac spectroscopy. The most

basic pulse sequence, a square excitation pulse, uses no gradients and

thus performs no localization, but instead takes in all signal within











the sensitive volume of the coil. This sensitive volume is generally

defined, for a surface coil, as the volume of a sphere of one coil

diameter." Such unlocalized acquisition methods have been used with

animal studies where open chest experiments allow for small surface

coils to be placed directly on the heart.40'.1 This uses the surface

coil as a localizer. For human studies, where we prefer to work non-

invasively, a combination of coil and pulse sequence localization

techniques have been used. This presents a technical challenge to

optimize a localization technique for obtaining spectra from a moving

heart, at a depth into the body, without adding signal from the chest

skeletal muscle that lies between the coil and the heart.



Slice Localization Techniques


Slice selection is accomplished in MR by simultaneously turning

on a slice-selective RF pulse and a gradient along the direction of the

slice. The gradient is on for just a few milliseconds. The RF pulse

designed for slice selection has a time-varying shape in the form of a

sin t/t or since function,424 which is used for both spectroscopy and

imaging. The RF pulse is generated at the resonance frequency of the

nuclei of interest. With the gradient on, this allows the since RF

pulse to excite just those frequencies in a narrow bandwidth to either

side of the center resonance frequency. A since pulse can produce a

sharp cutoff of frequencies thus exciting just within a slice region.

The thickness of the excitation slice is related to the bandwidth of

the RF pulse and the gradient strength. For example, the steeper the

gradient or the narrower the RF pulse bandwidth (the longer the RF











pulse) the thinner the selected slice. In terms of spectroscopy

acquisitions, the shorter the RF transmit pulse the larger the range of

frequencies acquired.

Slice localized pulse sequences, such as DRESS (Depth Resolved

Surface Coil Spectroscopy) ,4 SLIT-DRESS (SLice INterleaved DRESS) ,56"4

Rotating Frame MR,48 FROGS (Fast Rotating Gradient Spectroscopy)," and

1D-CSI (chemical shift imaging)," allow for acquisition of signal from

a slice at a depth parallel to the coil. DRESS for cardiac studies

involves acquiring from a coronal or oblique slice through the cardiac

muscle at a depth from the chest, thus avoiding contamination from the

skeletal muscle directly under the surface coil. Sometimes it requires

outer volume suppression to avoid contamination of the signal from the

adjacent skeletal muscle at the sides of the body. Most studies have

not used outer volume suppression, but relied on reduced regions of

coil sensitivity to prevent contamination from the sides of the body.

Because it is simple and not extremely motion sensitive, DRESS has

been widely used for obtaining spectroscopy slice profiles of human

cardiac muscle -12 1 '.24s51 56


Multi-Voxel Localization Techniques


The spectrum of the cardiac muscle is easily contaminated by the

surrounding skeletal muscle and blood, therefore localization and

suppression of unwanted signal outside the volume of interest is

important and accomplished with single- or multi-voxel localization

techniques. Multiple voxel acquisition via chemical shift imaging

(CSI) involves the use of the gradients to split up the selected slice

or slices into a number of smaller voxel areas. Spatial localization











is done by phase encoding gradients in one (1D-CSI), two (2D-CSI) or

three dimensions (3D-CSI)." There are no gradients on, however, during

signal acquisition. The advantage of CSI is that multiple voxels are

sampled as part of the same acquisition protocol. However, this is

accomplished at the cost of increased scan time for the phase encoding

for each axis. CSI is generally utilized to further partition a volume

already selected by another pulse sequence.

There are a number of technical problems associated with

acquiring spectra with CSI. One problem is achieving a good shim over

a large region of interest and possible changes in magnetic

susceptibility encompassing the multivoxel acquisition volume. In

addition, the point-spread function from the spatial Fourier transform

reconstruction implies that any given voxel in the multivoxel

acquisition contains contributions from neighboring voxels.3 This

leads to lesser ability to prevent contamination outside the voxel of

interest, such as the skeletal muscle contaminating the cardiac muscle.

In addition, depending on the size of the voxel of interest and

size of the field of view, the time of the acquisition can be

dramatically increased beyond the reasonable limit for performing in-

magnet exercise during the study. This is primarily due to the

increased time necessary for the CSI phase encoding steps. For

example, the total measurement time for a 3D CSI acquisition is given

by


Time (seconds) = TR Nacq Nx Ny N


Equation 4











where TR is the repetition time, Nacq is the number of acquisitions,

and Nx, Ny and N1 are the number of phase encoding steps in the x, y

and z directions."

Despite these faults with CSI, a number of studies of cardiac

phosphorus spectroscopy have utilized 1D, 11',227,'-64 2D,10'65s-7 and 3D

CSI,64'70-7 and techniques similar to CSI such as 3D fourier series

window.7 Among these studies, some were performed on animals

alone,62 69~'7374 but the majority were performed on humans.


Single Voxel Localization Techniques


Single voxel localization techniques rely on the pulse sequence

to obtain a localized voxel of data, selected from within a larger

volume. This protocol of obtaining a single voxel of data per

acquisition typically takes less time than the CSI multivoxel approach

because of the added phase encoding steps needed for CSI. Single voxel

acquisition pulse sequences that have been reported include PRESS

(Point Resolved Spectroscopy Sequence) ,7 PROGRESS (a version of

PRESS),7 STEAM (Stimulated Echo Acquisition Mode)," ISIS (Image

Selective In-Vivo Spectroscopy),s, 1'0-83 and modified ISIS pulse

sequences such as CRISIS (combination of ISIS and DRESS with x- and z-

selective 1800 pulses followed by a 900 y-slice selection pulse; which

eliminates y-direction motion artifacts and benefits from reduced cycle

time),84 FLAX-ISIS,41 and 2D ISIS plus Outer Volume Suppression (OVS).8"

With PRESS and STEAM, three slice selective RF pulses are used to

select three intersecting orthogonal planes. Only spins in the voxel

defined by the intersection of the three planes experience the three RF

pulses and contribute to the final signal. Both STEAM and PRESS











acquire a voxel with each acquisition (also called single-shot

localization),"8 thus being less motion sensitive than techniques

requiring multiple acquisitions to localize. STEAM uses a 900 RF pulse

for all three excitations thus creating a stimulated echo, as shown in

Figure 1. PRESS creates a double echo by using a 900 and two 1800 RF

pulses, as shown in Figure 2.38.86 Echo time (TE) for STEAM is

designated as twice the time between the first and second RF pulse.

PRESS has two echo times, TEl and TE2, where TE1 is equal to twice the

time between the first (900) and second (1800) pulses and the total time

to produce the first signal echo.3 TE2 is twice the time from the

first echo to the second 1800 RF pulse and the full time between the

first and second signal echo. In general, each TE for both STEAM and

PRESS must be relatively short to successfully acquire phosphorus

spectra, so that the signal losses due to transverse relaxation (T2) are

small. PRESS offers the advantage of having twice the SNR of STEAM,

but cannot be run with short TE's,"6 while STEAM can handle some shorter

TE's down to the system limit.

PRESS and STEAM differ primarily in the nature of the echo signal

created. PRESS forms the echo from 180 RF refocusing of the net

magnetization, whereas in STEAM, only part of the available signal is

used to form the stimulated echo via the use of 90 RF pulses. This

theoretically results in a factor of 2 increase in SNR for PRESS over

STEAM. Experimentally, the factor of 2 increase in SNR has also been

documented.86.87

Both PRESS and STEAM have occasionally been accomplished

successfully at the phosphorus frequency, but never on the heart.

STEAM has been shown to work on a phantom (400 mmolar solution of











NasP3O0 in H20) at 1.5 T using a TE of 3.1 msec"8 and on human brain at

2.0 T using a TE of 3.0 msec." PRESS has also been used to obtain

phosphorus spectroscopy of a newborn human brain at 2.4 T using a TE of

10 msec.90 Note that in each of these cases, the TE was set at a

minimum value. Neither PRESS nor STEAM are well suited for phosphorus

MR spectroscopy due to reasons related to the characteristically short

T, times of phosphorus metabolites, but STEAM does work marginally

better than PRESS." The echo times achievable with PRESS are too

long for the acquisition of signals from nuclei with short T, relaxation

times." In contrast, STEAM's shorter TE values reduce signal loss from

T, relaxation and allow some observation of short T2 metabolites, such

as P-31 metabolites."

ISIS allows for volume, slice, column or voxel selection based on

one, two, four or eight acquisitions.92 Zero to three selective-

inversion pulses in the presence of gradients precedes each acquisition

exciting different areas within the volume. A combination of areas,

added and subtracted, results in the localization achieved with ISIS as

shown in Figure 3.7"9 ISIS has proved to be one of the best voxel

localization techniques for P-31 spectroscopy. Unlike PRESS and STEAM,

ISIS is not sensitive to the T2 values of the acquired resonances but is

sensitive to the Ti values, as part of the time delay between the

selective excitation and signal acquisition." Most P-31 biological T,

values are on the order of a few seconds, therefore obtaining in vivo

ISIS spectra from living tissue should not be a problem in terms of

relaxation times.9 Also, for any localized spectroscopy pulse

sequence, when long repetition times are used to allow for Ti

relaxation, there is no T, error in terms of signal cancellation. ISIS











may require eight separate acquisitions in order to localize to a

voxel, but the final SNR is still equivalent to an acquisition taken

with eight acquisitions (i.e. no signal is lost due to localization).

This is also true for CSI acquisitions. ISIS is also flexible in that

fewer than eight acquisitions can be used to obtain a volume (1

acquisition), a slice (2 acquisitions), a column (4 acquisitions), or a

voxel (8 acquisitions).

ISIS uses an adiabatic RF pulse that allows for uniform

excitation of signals over a larger volume of the sample.9u"96 The

adiabatic pulse, a modification of the since pulse, was specially

designed for use with surface coils where uniform excitation is

difficult to obtain.94

The adiabatic pulse is frequency selective and B, insensitive, and

can achieve uniform excitation in an area of B, field inhomogeneities.

The adiabatic pulse is designed using frequency modulation to satisfy

two constraints. First, the RF pulse is designed to cause negligible

decay of the transverse magnetization during the pulse. Second, the

rate of change of the net magnetization orientation is considerably

slower than its rate of precession."

In addition, adiabatic pulses are different from since or square

RF pulses in that they are designed to excite maximally at a high gain

and remain maximal even when the gain is further increased."'"96 Sine or

square RF waves excite an area based on the gain of the signal with an

optimal signal peaking at some point between low and high levels of

gain. Unfortunately, the ISIS adiabatic pulse require a greater power

than since or square pulses, therefore it is important to have a quality

amplifier designed for the higher requirements. Since power











requirements increase with field strength, special consideration needs

to be made to provide enough power for ISIS while still remaining

within the safety guidelines. Specifically, the Food and Drug

Administration (FDA) has limited the specific absorption rate (SAR) of

the RF power to a maximum of 8 Watts/kg in the head or torso for any

period of 5 minutes." This applies to all pulse sequences and all

field strengths used on human subjects.

ISIS is prone to many possible causes of signal contamination."

As ISIS selects outside the volume of interest and attempts to subtract

this signal, only partial cancellation of the unwanted signal is

achieved." This effect is greater when the volume of interest (VOI) is

much smaller than the complete volume detected by the coil. Since

signal is detected from a large volume after each acquisition, the

receiver gain cannot be optimized for the smaller VOI.98 In addition,

the adiabatic pulse does not acquire equally all the chemically shifted

resonance's at the acquired frequency." Finally, T, smearing" caused

by residual magnetization left from the observation pulse from the

previous acquisition, also results in less than total subtraction of

unwanted signal outside the ISIS selected volume of interest." ISIS is

also motion sensitive due to its volume subtraction method of

localization involving eight separate acquisitions to obtain the

spectrum from one voxel." In addition, ISIS is affected by spatial

displacement of chemically shifted species in the slice selection at

high field at the P-31 frequency."

The issues of contamination with ISIS have been tested in a

computer simulation and published." Despite its faults, only ISIS and

ISIS derived pulse sequences are useful as single-voxel localization











pulse sequence techniques for P-31 MRS. A number of cardiac

spectroscopy studies have been done using ISIS or ISIS derived pulse

sequences. "4",117',23.2s,80-82,1-117 All except one11 of this list of studies

was performed on humans.


Cardiac P-31 Spectroscopy Results in the Literature




Animal studies


Animal studies have been essential for predicting potential areas

for human use. A majority of cardiac spectroscopy animal studies have

been done with the animal's chest open, thus allowing the surface coil

to be placed directly on the heart,40,41 via a catheter coil inside the

heart,11 or by excising the heart and maintaining it artificially in an

isolated heart perfusion studys~51 122. There have also been closed-

chested animal experiments 67123'124 that more closely match what would

happen if the same test were performed on humans. The promise of the

open-chested experiments is that a great deal of information from the

heart via spectroscopy can be obtained when SNR is maximized.

Unfortunately, outstanding SNR is generally only achieved when the RF

receive coil is placed directly on the heart, allowing for unlocalized

acquisitions. The open-chested in situ mode can also take advantage of

the increased SNR and use localization acquisition methods, such as 2D

ISIS, 1D spectroscopic imaging (SI), or FLAX-ISIS, to obtain

spectroscopic information about discrete layers of the myocardium, sub-

endocardium and sub-epicardium individually. 4112s 26

Animal hearts can be stressed to a much greater degree while

under anesthesia 27 than we would ethically stress a human volunteer.











Although most human studies of normal myocardium have shown no change

in the phosphorus metabolites with the stress levels that do produce

changes in ischemic hearts, normal animal hearts have often been

stressed beyond what can be done in humans to the point where a change

in the phosphorus metabolites can be induced. Care must be taken,

therefore, when making extrapolation to humans based on these animal

studies, because often the heart is damaged by the level of stress or

by the deliberate infarction..24'128

Animal studies allow for tighter control of the disease state and

measurement than can be ethically accomplished in humans and therefore

reveal the potential for P-31 MRS to provide feedback of specific

cardiac disease states. Studies of permanent coronary occlusion in

dogs with open chest, measured up to 6 hours after occlusion.2 and up to

5 days after occlusion.24 show that residual Pi remains in the region of

the infarction for a period of days although tissue pH returns to

normal within a day.' Human cerebral infarction measured by phosphorus

MRS has shown similar behavior.7'2 A study on open-chested dogs showed

that phosphorus spectroscopy could differentiate between viable and

non-viable myocardium from 6 to 54 hours after an ischemic insult based

on measurements of PCr and [Pi]/ [PCr]." Another animal study of

assayed myocardium after coronary occlusion or low-flow ischemia showed

a depletion of PCr and ATP with irreversible injury.31 Animal studies

have shown reduced phosphorus metabolites in cases of hereditary

cardiomyopathy,132'.1 cardiomyopathy from chronic chemical exposure,134-'15

dietary deficiencies, 13 and diabetes3'. In another animal study, PCr

was shown to be preserved until the blood flow was reduced to about 50%

of that in an originally healthy heart."18 This is another example of











the type of understanding that can be achieved with animal studies but

would be unethical for human studies.

Specifically, both a decrease in the [PCr]/[ATP] ratio and a

downfield shift of the inorganic phosphate resonance due to acidosis

have been measured occurring with the onset of ischemia.56 In cases

with mild reductions in blood flow (approximately 17%), only the Pi and

pH changed significantly when compared to a control group. When the

blood flow reduction was more substantial (on the order of 50% or

more), the [PCr]/[ATP] ratio was also shown to decrease while ECG

monitoring was also abnormal (reduction in segment shortening).139'14


Human Studies


Nuclear medicine thallium scans clinically show a reversible

thallium defect where the area fills with thallium during rest but does

not during stress indicating an area of ischemia. If the defect is not

reversible, meaning the area doesn't fill with thallium during rest or

stress, then the area is infarcted. P-31 exercise tests on subjects

with severe CAD and/or reversible thallium defects showed a significant

decrease in the [PCr]/[ATP] ratio.12,49 Although a change in the

[PCr]/[ATP] ratio is seen in the ischemic heart with stress, tests on

normal controls and patients with non-coronary cardiomyopathy show no

significant change with exercise. In patients with stenosis of the

macrovessels, a drop in the [PCr]/[ATP] ratio is no longer present

after revascularization." These findings prove that in the absence of

blood flow reduction or scar to an area of the myocardium, the

metabolite energy values will remain constant. These studies showed a











direct correlation between ischemia and a decrease in [PCr]/[ATP] and

pH with stress as measured via phosphorus NMR spectroscopy.

A number of research groups from a variety of locations around

the world have been utilizing human, in-vivo cardiac NMR P-31

spectroscopy. Assorted magnet systems, coils and techniques have been

employed. In addition, a wide number of patient types have been

studied. Even through there is a wide variation in heart problems

studied, some trends in the type of techniques and RF coils used have

started to appear that may prove diagnostically and clinically

feasible. In the least, P-31 MRS should provide information that

scientists and physicians can utilize to better understand the workings

of the human heart under all types of disease conditions.

A condensed summary of all the research locations that have

conducted in-vivo cardiac phosphorus NMR spectroscopy acquisitions of

the human heart are listed in Table 2. This table is given in an

effort to simultaneously demonstrate how much and how little work has

been done since the late 1980s. Since each type of cardiac problem

will have its own trends and results in terms of cardiac P-31 MRS,

research on each of the main types of heart disease has also been

detailed in the remainder of this chapter.










Table 2. Research Published on Human, In-Vivo


Spectroscopy of Studies on
Work.


Normal-Controls or


Cardiac P-31 NMR
Patients and Related


Major Magnet P-31 P-31
Location Players Tesla Method Coils References


Neubauer
Loeffler
Sieverding
Siemens


Erlangen,
Werzberg,
Tubingen,
Germany




Otsu, Mie,
Toyko,
Tsukuba,
Japan

Baltimore,
Maryland,
Schenectady,
New York

Oxford,
England



San
Francisco,
California

Leiden,
Netherlands


1.5 T ISIS
Philips CSI
1.5 T CSI/SLOOP
Siemens


10-15cm
diam R/T


1.5 T DRESS 5-15cm
GE CSI diam R/T,
20cm T +
12cm R

1.5 T DRESS 40cm T +
GE CSI 7cm R,
7cm diam
R/T

2.0 T PMRFI 5-6.5 cm
Bruker CSI diam R/T,
DANTE 15cm T +
7cm R

1.5 T ISIS 9-14cm
2.0 T CSI diam R/T
Philips


1.5 T CSI
Philips ISIS


Birmingham, Evanochko 1.5 T ISIS
Alabama Hetherington Philips
den Hollander 4.1 T
Buchthal
Pohost


117 141 142
82 14 71 105
68 100 143
111 109 65
104 10 144
113 145 18
146

56 55 147 148
52 54 13 51
12 27 60 53
19

9 149 70 63
67 49 11 150
151 152 153
154 20

48 155 25 156
157 57 58 158
159 59 21 160


83 15 161 64
162 163


Mitsunami
Okada
Yabe
Sakuma

Bottomley
Weiss
Hardy
GE

Rajogopalan
Conway
Radda
Blackledge

Matson
Schaefer
Aufferman

Lamb
de Roos
den Hollander
Philips


Minneapolis Menon Uc
Minnesota

Philadelphia Whitman
Pennsylvania

Durham, Herfkens
North
Carolina

Paulo, Kalik-Fi
Brazil


Gainesville, Bruner
Florida Scott, Kim


purbil 4.0 T CSI
Siemens ISIS

1.9 T Coil
Oxford localized

S 1.5 T CSI


lbo 1.5 T ISIS
Philips


1.5T GE Oblique
3.0T GE DRESS


10-14cm 116 164 108
diam R/T 165 28 22 166
167 112 114
168

10-14cm 103 106 169
diam R/T 81 102 170
171 80 28 16
23


llcm diam
R/T

5cm diam
R/T

6cm diam
R/T


Not
Listed


10cm diam,
Quadrature


17 76


172


24



173



174 175











P-31 Spectroscopy Acquisition Techniques. In terms of techniques

for acquiring human, in vivo, cardiac P-31 MRS, there is a trend that

emerges. For those locations with clinical Philips systems, the most

common technique used is ISIS followed by CSI. For clinical GE sites,

the most common technique is DRESS followed by CSI. The two Siemens

sites conducting human, in-vivo P-31 MRS primarily utilize CSI.'144'17

This chapter summarizes the results from studies of various types

of cardiac diseases. When available, the acquisition times are listed

in Table 3 through Table 7. Notice that DRESSn'149 and ID-CSI"49"' are

the shortest duration sequences, generally being under 10 minutes,

although running them for longer further increases SNR. ISIS typically

is run for slightly longer periods of time at around 20

minutes,B2.'10.16s,17 although it can be run the same amount of time as

DRESS at around 10 minutes1'. Two dimensional and 3D-CSI are the

longest duration,1" with some scans lasting an hour for just a single P-

31 acquisition'".

A few truly unique techniques for obtaining human cardiac P-31

MRS, SLOOP and PMRFI, are utilized only at their originating locations.

Spectral localization with optimal pointspread function or SLOOP was

created and used by a group in Germany, utilizing a Siemens 1.5 T

system. a'6B1'411314 The SLOOP technique is a combination of a 3D-CSI

acquisition with sophisticated post-processing that uses anatomical

information from the proton image to group the spectra by tissue type.

Anatomical compartments, such as for cardiac muscle, skeletal muscle,

and liver are defined with the proton image. The overlaying P-31

spectral data is then separated into each of these compartments. The

papers that have been published from this group using SLOOP seem











outstanding as they achieve cardiac spectra with greater SNR, due to

the larger volume they can utilize to obtain the signal. In addition,

they seem to have solved the problems with contamination.

Unfortunately, until the technique is tried and evaluated at other

locations, judgment on the true accuracy of the method cannot be fully

established.

Phase modulated rotating frame-depth imaging selection technique

or PMRFI is a technique used for cardiac P-31 MRS solely at Oxford,

England.4's .1s5' PMRFI allows for a 2D-spectroscopy signal to be

collected from the sample within the sensitivity of the coil via a set

of free induction decays. The data is collected from a volume formed

by a stack of disc shaped slices at various depths into the chest with

the entire data set taking approximately 35 minutes to acquire."4 The

PMRFI technique claims to produce high-resolution, high SNR spectral

images with limited spatial distortion."

In addition, at Oxford, they have also utilized DANTE for cardiac

P-31 MRS of human volunteers."' DANTE allows for the selective

excitation/suppression of individual peaks in the frequency domain in

this case used to distinguish the intracellular and extracellular Pi.

This group also utilized an initial saturation pulse to eliminate any

contamination from skeletal muscle."' Many of these types of unique

pulse sequences were originally developed on research magnets for

animal studies and then recently extended to human use on a Bruker

research magnet system. This may be the reason why these techniques

have not been published for use on clinical 1.5 T systems, such as from

GE, Philips or Siemens. Users often have the ability to pulse program











clinical systems, but with less flexibility and ease in programming

options.

P-31 Radio Frequency Coils. Surface coils have been used for all

human cardiac spectroscopy studies to date. The reasons are simple.

Compared to a volume coil that would need to encompass the chest,

surface coils provide a much greater signal-to-noise ratio (SNR) than

the volume coil. The simplest surface coil, a single loop of wire,

provides a means of obtaining spectra from a volume of tissue adjacent

to the coil.4 The sensitivity of the surface coil is greatest for the

tissue closest to the coil, with sensitivity decreasing rapidly with

depth.4 This sensitivity range extends approximately one radius away

from the center of the surface coil," with the majority of the signal

obtained from a disc-shaped region at the plane of the coil and

decreasing in size with depth.4 Typically, the result is relatively

good SNR from the anterior wall of the heart, but not enough depth

penetration to cover the entire heart. Surface coils can be adapted to

a variety of specific tasks by changing the size and shape of the coil.

Surface coils are commonly used in both MRI and MRS as receivers

because of their high sensitivity, providing good SNR. In

spectroscopy, especially with nuclei other than H-l, surface coils are

frequently used both as RF transmitters and receivers." Their

applications evolved from small animal P-31 spectroscopy studies17 to

spectroscopy investigations of muscle and superficial organs in

humans.'" Unfortunately, surface coils suffer from non-uniform RF

excitation and inadequate spatial localization when used without a

localized pulse sequence. The sensitivity of the surface coil to a

point in the sample is proportional to the B, field achieved by the coil











at that point, with the most signal received from sample points closest

to the coil.41"'17 Fortunately, pulse sequences designed for

localization, utilizing selective RF pulses or gradients such as

ISIS179 '.8 and CSI,B1-1'B or multiple RF pulses"'8 can localize spectra to

regions where the B, field is relatively constant such as in a localized

voxel volume."'7 For example, the ISIS pulse sequence uses an adiabatic

excitation pulse that with enough power is specifically designed to

excite spins in a manner that is independent of the B, field for more

uniform excitation.41 Such a pulse has been shown to improve the

localization abilities when used with a surface coil."4 In addition,

there is the option of using a larger transmit coil to provide better

homogeneity of the B, field, with a smaller receive coil for optimal

SNR.

The B, inhomogeneity inherent with using a surface coil can

degrade the performance of the RF pulses resulting in an incorrect

tipping angle, decreasing signal from the volume of interest (VOI), and

potentially increasing signal contamination from regions outside the

VOI.15, 'I9,8 Contamination is most probable from the tissue closest to

the coil since such tissue will have the highest degree of sensitivity

by the coil." In the case of cardiac spectroscopy, the skeletal muscle

has a large potential to contaminate the cardiac muscle signal in this

manner. Larger coils provide higher homogeneity at the expense of

reduced sensitivity to small, shallow VOI's.93'185 This compromise

between increased-size resulting in increased homogeneity versus

decreased-size resulting in increasing sensitivity has led to many

different sizes of transceive and a few combinations of transmit and

receive coils being built.











A trend that appears when looking at Table 2 involves the design

of the P-31 coils. The greater majority (over 95%) of human, in-vivo,

cardiac P-31 MRS patient studies are conducted using a simple single

turn P-31 coil of 5 to 15 cm diameter to act as a transceive radio

frequency (RF) coil. Beyond this, the next largest minority uses a

larger transmit (15 to 40 cm) to excite and a smaller 6.5 or 7 cm

diameter coil to receive.

The purpose of a larger RF transmit coil used with a smaller

receive coil is to improve the homogeneity and still have a small

spatial sensitivity.7 The two coils can be arranged coplanar'86 or

slightly displaced.4 The sensitive volume is determined by the overlap

region of the two coils.' Unfortunately, there are more drawbacks to

using separate transmit and receive coil for localized phosphorus

spectroscopy. The complexity of the setup creates difficulties when

trying to control accurately the position and thickness of a plane or

volume of a voxel. Multiple acquisitions are required in order to

localize the signal.' This is due to the fact that the placement of the

RF coil is critical within a few centimeters over a prime spot anterior

to the heart. Often, the placement is not correct the first time

and/or the pulse sequence localization position and/or transmitter gain

must be modified for better localization to the cardiac muscle.

There are also designs in the literature for quadrature coils and

array designs for human P-31 cardiac spectroscopy with a theoretical

improvement in SNR, but there is no known literature on such coils

being used with patient studies to date. Phased array and quadrature

coils offer the advantage of a larger sensitive coil region without

increased acquisition time or a decrease in SNR.152'18' Quadrature and











phased array coils have been used more extensively in imaging than

spectroscopy modes of human in-vivo data acquisitions. Several

experimental designs have been considered for cardiac imaging and

spectroscopy including (1) a 4-coil, diamond shaped design by Hardy et

al.,"2 (2) two pairs of surface coils placed on the chest and back,

surrounding the heart by Constantinides et al.,"' (3) a single pair of

coils designed for placement on the chest, ~."' and (4) a double-tuned

quadrature surface coil by Menon et al.76 There has also been a

theoretical study performed to determine the optimum configuration of 2

to 10 circular coils combined in a phased array system designed for

cardiac imaging."' This paper argued that theoretically the best

results would be obtained from a 4 coil array, producing 560% signal

improvement relative to a whole body coil and up to 360% improvement

over some commercial cardiac imaging coils.19o

Cardiac RF surface coils are placed on the front of the chest,

over the heart. Coil placement is critical for optimum signal from the

intended volume of interest. Incorrect coil placement can result in

decreased signal from the desired VOI.' This is especially true of

small (5 to 10 cm diameter), transceive, single-turn surface coils.

Incorrect coil placement can also increase contamination from areas

outside the VOI.' The problem with positioning can be theoretically

minimized by using a phased array or quadrature coil that will cover a

larger area with the improved SNR up to square root of two.7,'12,191

Patient Studies. In a normal, disease-free heart, a phosphorus

spectrum will show a consistent level of each of the phosphorus

metabolites"'" ~'1"'63 of phosphomonoester (PME) inorganic phosphate

(Pi), phosphodiester (PDE), phosphocreatine (PCr), and the three











adenosine triphosphate peaks (y a -ATP). Conversely, in patients

and animals with myocardial infarction or myocardial ischemia, in vivo

phosphorus cardiac spectroscopy will demonstrate either a reduction in

the overall amounts of each metabolite192"'1 or a change from the normal

ratios of one metabolite to another12'4'60"124'194 Such a measurement has

the potential to differentiate a healthy heart from one with myocardial

infarction or ischemia. In addition, some cardiac diseases, such as

cardiomyopathy or hypertrophy, both involving thickness changes of the

heart wall, are easier to diagnose with cardiac images. Even these

types of heart problems can potentially benefit diagnostically from the

added feedback of the chemical information provided by P-31 MRS.

Patient studies have proven over and over again that P-31

spectroscopy is a sensitive marker for clinical cardiac disease

states.82'1 A quick overview will be presented here to prove how solid

the P-31 spectroscopy measurement has been shown to be. As part of a

study on patients with severe stenosis of the left anterior descending

coronary artery (greater than 70% blockage), the [PCr]/[ATP] ratio

decreased significantly with exercise." A group of normal controls and

patients with non-ischemic heart disease showed no significant change

in the [PCr]/[ATP] ratio when they underwent the same stress as part of

the same study. A repeat P-31 NMR spectroscopy measurement was made of

five of the patients with severe stenosis of the left anterior

descending coronary artery after revascularization. In all five cases,

a significant improvement in the [PCr]/[ATP] measurement was seen in

terms of a smaller decrease in [PCr]/[ATP] during in-magnet stress. In

a similar study by Yabe et al.,12 P-31 NMR spectroscopy with in-magnet

exercise was performed on patients with ischemia, patients with











blockages infarctionn), and normal controls. The patients were first

categorized based on results from radionuclide testing with thallium-

201. Those patients with reversible thallium defects (ischemia),

showed a reduction in [PCr]/[ATP] during in-magnet handgrip exercise,

that normalized during rest. Those patients with irreversible thallium

defects infarctionn or dead myocardial tissue) and normal controls

showed no change in the [PCr]/[ATP] ratios with exercise. It is

believed that the [PCr]/[ATP] ratio does not change in cases of pure

infarction because the affected tissue is completely dead while the

remaining tissue is essentially sound. Therefore, the resulting signal

is less overall due to a lesser amount of viable tissue, but the ratio

remains the same. It is theorized that more complex techniques that

would measure the absolute quantity of the metabolite levels would be

able to differentiate even myocardial infarction as the overall amounts

would be lower, assuming measurement of a known volume of cardiac

muscle.

Healthy Volunteers. Multiple studies have confirmed that for

healthy volunteers free of substantial coronary artery disease, in-

magnet exercise stress tests with non-drug stimuli have not produced a

significant change in the anterior myocardial [PCr]/[ATP]

ratio. 12'25s'49.s~, 16 Such results are shown in Table 3 where both leg

and handgrip exercises show no drop in [PCr]/[ATP] with normal control

groups. These results have been repeated in animal studies, without

handgrip exercise. No significant change in the [PCr]/[ATP] ratio was

found in the normal intact dog heart over a five-fold range of rate-

pressure products.127 In this case the stress was in the form of a











pacemaker which increased the rate of the heartbeats by threefold and

increased the rate-pressure product by 1.5.

There is however, the potential to use drug stimulus to stress

the healthy human heart to the point that a drop in [PCr]/[ATP] can be

seen. The first attempt at doing this was by Schaefer et al.16 where 2

to 16 pg/kg/min of dobutamine was used. Dobutamine has the effect of

increasing the heart rate, contractility and blood pressure. In this

case, this amount of dobutamine alone was enough to increase the rate-

pressure product (heart rate times systolic blood pressure) in normal

controls from 7,000 to 15,000. Despite this increase of stress on the

heart with dobutamine, the [PCr]/[ATP] at stress was not significantly

different from [PCr]/[ATP] at rest for the normal control group, as

shown in Table 3. In the same study a group of dilated cardiomyopathy

patients under the same stress also did not produce a significant

change in [PCr]/[ATP] with dobutamine stress ([PCr]/[ATP] at rest =

1.630.24, with drug = 1.570.24, p=0.38). Two other published

studies repeated these experiments with a slightly different protocol

and succeeded in dropping the [PCr]/[ATP] ratio even in normal

controls. Lamb et al.112'16 and Pluim et al.,16e both of Oxford, England,

first utilized 10 pg/kg and 0.03 mg/kg, respectively, of atropine

sulfate to block the cholinergic nervous system which will allow for

increased heart rates. They then both used 10 to 40 pg/kg/min of

dobutamine to achieve a steady heart rate, based on subject age. This

protocol produced a significant drop in the [PCr]/[ATP] ratio of the

normal controls being studied.










Table 3. Cardiac [PCr]/[ATP] Ratio of Healthy Volunteers (Normal
Controls) at Rest and During Stress.

[PCr]/[ATP] [PCr]/[ATP] Magnet P-31
at Rest at Stress Stress Form Tesla Method Reference
1.5+0.2 1.58+0.14 leg exercise 1.9 T Not 25, 157
(n=6) listed

1.51+0.03 1.51+0.03 Bicycle 1.5 T DRESS 13
(M=6) ergometer
1.72 0.15 1.74+0.17 handgrip 1.5 T 1D-CSI 49
(n=ll) exercise 5-14 min

1.77+0.16* 1.74+0.19* handgrip 1.5 T 1D-CSI 63
(n=8) exercise 8-16 min

1.80+0.28* 1.84+0.26* handgrip 1.5 T DRESS 54
(n=ll) exercise

1.85+0.28* 1.900.23* handgrip 1.5 T DRESS 12
(n=11) exercise 7-8 min
1.86+0.17 1.900.22 dobutamine 2.0 T 1D-CSI 163
(M=14) (drug) 7 min

1.420.18* 1.220.20* Atropine/ 1.5 T 3D-ISIS 112,167
(F=2, M=18) dobutamine 10 min
(drugs)

1.41+0.18* 1.16+0.13* Atropine/ 1.5 T 3D-ISIS 168
(M=12) dobutamine
(drugs)
* blood corrected; M = Male; F = Female


There has been one interesting study by Lamb et al.28.'66 where

reproducibility of each method and comparisons of the results from

different methods were determined for the Philips 1.5 T system. Using

16 normal controls, the same area of the anterior left ventricle

produced a [PCr]/[ATP] ratio of 1.3110.19 for ISIS alone, 0.98+0.20

for CSI alone and 1.41+0.20 for ISIS plus CSI. Lamb et al. concluded

that the CSI contained liver contamination resulting in a low

[PCr]/[ATP] ratio. In addition, the intra-examination difference of

repeated studies of each volunteer produced a smaller difference than

the inter-examination, volunteer-to-volunteer [PCr]/[ATP] difference.











Myocardial Infarction. In some of the studies in patients with

myocardial infarction, the phosphorus spectrum shows a normal ratio of

[PCr]/ [ATP] 82.9.'93 but the overall concentrations of the phosphorus

metabolites are lower than normal .2'3 as described by Bottomley et al.7

and Luney et al.8' These characteristics are theorized to occur since

the dead myocyctes can not contribute a metabolic signal to the

observed spectrum.7 The observed PCr and ATP signals are derived from

surviving myocytes surrounding or interspersed with the infarcted

myocytes.2~049 More recent publications are providing evidence that the

[PCr]/[ATP] ratio can be lower for infarction than in normal

controls,12jss o0. and reduce [PCr]/[ATP] slightly during stress'~"4. It

has been suggested that the reduction in the [PCr]/[ATP] ratio for the

patients with myocardial infarction represents an ongoing metabolic

stress in the myocytes remaining within the scarred region of the

myocardium." It is still not clear how the expected ratio of the

myocardium with infarction should present, but it is known that the

amounts of the metabolites will differ significantly from normal.

Therefore, measurements of the absolute concentrations of the

phosphorus metabolites, rather than the ratios, should provide

appropriate characterization of myocardial infarction.

The published results for [PCr]/[ATP] of myocardial infarction

are summarized in Table 4. Notice that there is not a significant

change in [PCr]/[ATP] with handgrip exercise. Table 5 compares the

amounts of [PCr] and [ATP] in normal controls to patients with

myocardial infarction. Observe that in more than one case the overall

amount of each metabolite (pmol/g) is significantly reduced for cases

of myocardial infarction60 'i'1" compared to normal controls."D0"' There











is even a slight reduction in the amount of [PCr] and [ATP) for the

case of myocardial ischemia."o This data shows that P-31 cardiac

spectroscopy has the potential to evaluate myocardial viability.


Table 4. Cardiac [PCr]/[ATP] Ratio of Patients with Myocardial
Infarction at Rest and During Stress.

Degree of [PCr/ [ATP] [PCr]/[ATP] Magnet P-31
Disease at Rest at Stress Tesla Method Reference
Infarction 1.6 0.2 1.5 T DRESS 149
After (ENDO) 2.5-9 min
angioplasty (M=2, F=2)
and drug
therapy

Infarction 1.8+0.2 1.5 T DRESS 149
After (EPI) 2.5-9 min
angioplasty (M=2, F=2)
and drug
therapy

Myocardial 0.48+0.21 1.5 T 2D-ISIS + 81 **
"Scar" (M=5) 1D-CSI

Chronic Normal 1.5 T ISIS 82
anterior wall (M=6) 32 min
infarction

Chronic Normal 1.5 T ISIS 82
posterior (M=4) 32 min
wall
infarction

Fixed T1-201 0.940.41* 1.5 T DRESS 60
defects (M=8, F=4) 12-15min

Fixed T1-201 1.18 0.28 1.12 0.24 1.5 T DRESS 54
defects (n=12) handgripp)

Fixed T1-201 1.240.28 1.19+0.28 1.5 T DRESS 12
defects (M=9, F=3) handgripp) 7-8 min
* = blood corrected; M = Male; F = Female
ENDO = localized to endocardium; EPI = localized to epicardium;
** = 3 out of 5 patients had a prior history of heart failure










Table 5. Cardiac [PCr]
Myocardial Infarction,


and [ATP] Amounts at Rest in Patients with
Ischemia and in Normal Controls.


Patient [PCr] [ATP] Magnet Quantify P-31
Type pmol/g pmol/g Tesla to: Method Reference
Infarction < normal < normal 1.5 T External DRESS 193
Standard

Infarction < normal < normal 1.5 T External DRESS 192
Standard

Infarction 3.94+2.21 4.351.52 1.5 T External DRESS 60
(M=8, F=4) Standard 12-15 min

Ischemia 7.64 3.00 6.35 3.17 1.5 T External DRESS 60
(M=22, F=7) Standard 12-15 min

Normal 11.7 2.5 7.2 1.2 1.5 T External 1D-CSI + 67
Standard 2D-Phase
Encode

Normal 12.14 4.25 7.72 2.97 1.5 T External DRESS 60
(n=11) Standard 12-15 min

Normal 10+2 5.8+1.6 1.5 T Internal 1D-CSI 20
(n=21) Water
(M=21)
M= Male; F = Female


There is also potential value in observing the Pi and pH of

patients with myocardial infarction. One study at 1.5 T of six

patients with anterior myocardial infarction, with blood contamination

corrections performed on the spectra, showed a slight but non-

significant elevation of Pi in the patient set.49 This study was early

on in human, cardiac P-31 MRS, used only a simple 1D-CSI acquisition,

and may have mistaken blood contamination for Pi. There are not many

studies that follow this one in identifying changes with Pi at 1.5 T.

Despite this fact, there is interest in identifying the Pi peak as a

means of identifying a decrease in the pH of the myocardium that would

also be a sign of ischemia.











Difficulty with blood contamination has made the measurement of

Pi more complicated in human cardiac spectroscopy studies. This is due

to the fact that at 1.5 T or below, the Pi is most often overlapped by

the 2,3-DPG (2,3-diphosphoglycerate) peaks from the blood

contamination. The Pi has been repeatedly seen at 1.5 T with the use

of specialized pulse sequences such as DANTE selective excitation,"9

nuclear Overhauser effect (NOE) for signal enhancement, magnetization

transfer," and proton decoupling for enhanced spectral resolution."

These options are not currently available on the GE 3.0 T system.

Also, long acquisition times can increase the probability of

visualizing the Pi peak by increasing the SNR. These problems are

overcome at 3.0 T. Work at 3.0 T allows for the Pi peak to be

distinguished even over relatively short scan times (i.e. 6 to 8

minutes) due to the enhanced SNR and wider spectral dispersion achieved

at the higher field strength.

Myocardial Ischemia. One of the most common types of heart

disease is cardiac ischemia. In the diseased heart affected by

myocardial ischemia, individual cells in affected areas of the

myocardium can no longer function due to significant decreases in blood

flow to the region. The blood flow reduction is typically due to a

gradual blockage forming in the coronary arteries. These patients have

symptoms of angina which are usually temporary and brought on by stress

when the required blood flow to the heart is inadequate. Although

typically these patients will suffer from angina and fatigue without

triggering a deadly heart attack, a diagnosis of ischemia does

substantially increase the risk of a heart attack. Since the blood

flow is already reduced, there is greater potential for acute and total











blockage infarctionn). The result is a disorder that is very disabling

partially due to the fatigue but also due to the anxiety related to the

chest pain.

The typical diagnosis of cardiac ischemia is based on signs,

symptoms and laboratory tests that can be performed by a family-

practice or emergency room physician. Cardiologists and radiologists

at the local hospital can also perform further diagnostic exams. In

addition to patients with angina being tested for ischemia,

asymptomatic patients at risk for heart problems based on risk factors

such as age, weight, life-style (high fat diet, smoking) and family

history are also tested. This is due to the fact ischemia is often

clinically silent or associated with atypical symptoms. The AHA

estimates that as many at 3 to 4 million Americans have silent or

asymptomatic ischemic episodes that are eventually diagnosed by testing

for reasons unrelated to the symptoms, such as a routine physical

examination.2

Ischemia is primarily quantified by the identification of

stenosis in the larger vessels of the coronary arteries, but ischemia

can also be confined to the microvessels. Microvascular ischemia can

involve angina-like chest pain that is coincidental with exertion and

thus may resemble typical angina pectoris but without stenosis of the

main coronary arteries. More often, however, the chest pain associated

with microvascular ischemia has characteristics that differentiate it

from typical angina. For example, the pain is generally prolonged,

repetitive, occurring at night, and poorly responsive to rest and

medications. Dr. Carl Pepine, a cardiologist at the University of

Florida, was one of the first to observe that patients' with symptoms











of microvascular disease are most often not predictive of a life

threatening disorder. Whereas in age-matched patients with coronary

artery disease such symptoms are indications of a life-threatening

event.' Despite microvascular disease not being life threatening, it

still has a great impact on the quality of life. In addition,

undiagnosed conditions, lethal or not, traditionally place added costs

on the medical system as the patient will continue to seek diagnosis,

go to new physicians and have more and more tests performed. Often the

quality of life is diminished to an extent that many remain unemployed

or retire from work and limit their activities, with obvious

socioeconomic implications. From a clinical and financial point of

view, these patients need to be diagnosed and treated.

In cases of myocardial ischemia, the localized phosphorus

spectrum will show a small level of depletion in the [PCr]/[ATP] ratio

at rest, compared with reference normal controls (i.e.: Ischemic

Anterior Myocardium [PCr]/[ATP]: 1.450.31, n=16; Disease-Free Controls

[PCr]/[ATP]: 1.720.15, n=11)." A more significant difference occurs

when comparing the [PCr]/[ATP] ratio during minor stress test (leg or

handgrip exercise) to that with the resting value, as shown in Table 6.

Similar results have been shown in both animal124t'1 and human

experiments1",5'6.










Table 6. Cardiac [PCr]/[ATP] at Rest and Stress in Patients with
Myocardial Ischemia.

Degree of [PCr]/[ATP] [PCr]/[ATP] Magnet P-31
Ischemia at Rest at Stress Tesla Method Reference
>= 70% 1.45 0.31 0.910.24 1.5 T 1D-CSI 49
stenosis (n=16) handgripp 5-14 min
exercise)

>=70% 1.46+0.39* 0.94 0.28* 1.5 T 1D-CSI 150
stenosis (M=14) handgripp 8-16 min
exercise)

>=75% 1.560.19 0.94+0.27 1.5 T DRESS 54
stenosis (n=15) handgripp
exercise)

>75% 1.600.19* 0.960.28* 1.5 T DRESS 12
stenosis (M=1, F=4) handgripp 7-8 min
exercise)

*= blood corrected; M = Male; F = Female


Table 7 demonstrates the descriptive value of cardiac P-31 MRS

for ischemia that has been treated. The first two rows show a study

where five ischemic patients were tested with and without in magnet

exercise handgripp) after revascularization surgery. In the case of

the patients with revascularization, the [PCr]/[ATP] ratio does not

drop when exercised, although the same patients did drop their

[PCr]/[ATP] ratio prior to surgery.49 This provides a quantitative

means for evaluating the success of revascularization surgery. Another

method for treating a heart attack that is thought to be primarily

ischemic is to provide drug therapy intravenously, such as thrombolytic

agents. The third row shows such a study where the region of the

heart, even after being treated, remained in a stunned state, where the

wall motion in the region is still impaired even after intervention.17

In this case, investigators were able to show that despite the

myocardium remaining stunned, the tissue [PCr]/[ATP] values were not











significantly depleted as they would normally be under an ischemic

situation under stress, showing the potential of cardiac P-31 MRS as a

feedback measure after treatment."' Unfortunately, no pre-treatment

data was obtained so it is difficult to conclude that the ratio of

[PCr]/[ATP] alone was a marker for ischemia. The last two rows show a

study done only at rest of ischemic patients before and after

angioplasty, which showed no change in [PCr]/[ATP]. This study would

have been more effective if in magnet exercise or drug stress was used

during the [PCr]/[ATP] acquisition.


Table 7. Cardiac [PCr]/[ATP] at Rest and Stress in Patients with
Myocardial Ischemia with Some Type of Intervention.

Disease Description [PCr] / ATP] [PCr] / ATP] Magnet P-31
at Rest at Stress Tesla Method Source
Ischemia before 1.510.19 1.020.26 1.5 T 1D-CSI 49
revascularization normal < normal 5-14 min
(n=5)

Postischemic after 1.600.20 1.620.18 1.5 T 1D-CSI 49
revascularization normal normal 5-14 min
(n=5)
Drug infused 1.51 0.17* 1.5 T ISIS 173
Postischemic, normal 22 min
Stunned Myocardium
(M=15, F=6)
Ischemia >= 75% 1.50.7* 1.5 T DRESS 51
stenosis before normal 15 min
angioplasty
(n=7)

Postischemic after 1.41.0* 1.5 T DRESS 51
angioplasty normal 15 min
(n=7)
* blood corrected; M = Male; F = Female


Microvascular Ischemia Study: WISE. An NIH sponsored study

concentrated on women's ischemic syndrome evaluation (WISE) is studying

microvascular ischemia in women with phosphorus NMR spectroscopy as

part of a multi-center study including the University of Florida. The











specific feasibility of phosphorus NMR spectroscopy to look at

microvascular ischemia was initially demonstrated during a pilot study

performed on a 1.5 T Philips system at the University of Alabama at

Birmingham (UAB).1"' In this study, women were identified who had

angina-like chest pain characteristic of ischemia and CA tested to

measure the degree of stenosis in their macrovessels. The patients

with insignificant stenosis (less than 30% stenosis) were also

evaluated for all other possible causes for their chest pain, without

diagnosis. UAB's study identified micro-vascular dysfunction (MVDS) in

30% of the women with previously unidentified chest pain. This data

was also compared with 17 normal volunteers (ages 21 to 53 years;

average age 32 10; 10 males, 7 females), who underwent 8 minutes of

isometric handgrip exercise at 30% maximum force. There was no

significant change (-0.1%10.3%) in the [PCr]/[ATP] ratio as compared

to rest. These values are consistent with similar handgrip exercise

literature where Weiss et al.4 and Yabe et al.12 have similar estimated

percent change statistics in their normal population samples of

1.9%7.0% and 0.5%9.0%. The determination of significance was set at

two standard deviations (20.4%) of a percent drop in the [PCr]/[ATP]

ratio of the normal volunteers with handgrip exercise." In eight

patients (7 male, 1 female) with CA proven stenosis greater than 70%

blockage, the same amount of exercise resulted in a -24%2% drop in

[PCr]/[ATP] This comparison of normal volunteers versus patients with

proven stenosis proves that the phosphorus NMR spectroscopy test is

viable for differentiating non-ischemic versus highly ischemic hearts.

The Birmingham study also evaluated 17 women with less than 30%

stenosis (very little blockage) and undiagnosed chest pain (suspected











microvascular ischemia). The same amount of exercise produced little

[PCRI/[ATP] change (-2%7%) in 12 of these women, but 5 women had a PCr

change of -27%. This change is attributed to MVDF, because of what is

expected by the ischemic angina-like symptoms and the lack of

macrovascular disease.'1 Accordingly, cardiac P-31 MRS shows

significant potential as a quantitative test for myocardial ischemia

that does not depend on the presence of macrovascular disease. No

other current diagnostic modality is able to quantitatively assess the

degree of ischemia of the heart in this way.



In-Magnet Exercise. For patients with myocardial ischemia, there

is a significant difference between phosphorus cardiac spectra obtained

at rest and during stress (in-magnet exercise).4" It is clearly

valuable to use some type of in-magnet exercise during one period of

the cardiac spectroscopy acquisition protocol. Studies using in-magnet

exercise have been done by exercising the legs, 1',5's7.197 arms with a

hand-grip,49'5,'i098 ~ 9s and drug-induced (dobutamine infusion) cardiac

stress13. The leg exercises can allow for prone position exercises

(prone position is best for cardiac imaging and spectroscopy to reduce

respiratory motion artifacts). One design by Conway et al.1s7 has the

subject lie in a prone position, lifting 5-kg weights with the legs by

bending at the knee. This stress test tends to produce an increase in

the heart rate pressure product of around 70%.25'157 Isometric, hand-grip

exercise, where the subject squeezes continuously at a constant 30% of

the subject's maximal force,"4 can also be performed simply in any

position. In-magnet exercise tests have been also done with devices as

simple as a bottle of water. Widmaier et al."' successfully implemented











a dynamic hand-grip finger flexion exercise consisting of squeezing a

50-mm diameter, water-filled, plastic bottle at a Maximum Voluntary

Contraction (MVC) approximately once every second for a 130 seconds

acquisition. Such an exercise increases the heart rate pressure

product by approximately 30 to 35%, which is still enough to increase

coronary vasoconstriction in the presence of critical levels of

coronary stenosis.19' The two types of handgrip exercise used are either

dynamic, where the grip is released and regrabbed up to the 30% maximum

level repeatedly during the test, or isometric, where the handgrip is

held constant at the 30% of maximum effort level. As can be seen from

Table 8, both dynamic and isometric handgrip raise the heart rate and

blood pressure, but the isometric method is a harder level of work and

therefore responds with a greater heart rate and blood pressure

response. Finally, dobutamine infusion (drug infusion) has the ability

to increase the rate-pressure product by 60 to 130%.7'16










Table 8. Literature Review of In-Magnet Handgrip Exercise Response.

Avg Rest Avg Rest Rate
30% Max & & Pressure Avg Rest &
Handgrip Exercise Exercise Product Exercise Patient
Exercise HR SBP (HRxSBP) [PCr] / [ATP] Type Reference
dynamic 67+8 117 12 7839 1.850.28 control 12
77+11 13113 10087 1.900.23


dynamic 6812 11813 8024 1.600.19 ischemia 12
7513 134+16 10050 0.960.28 >= 75%
stenosis

dynamic 63+11 11514 7245 1.24+0.30 infarction 12
74+13 128+13 9472 1.190.28 >= 75%
stenosis

isometric 6712 143 9600 1.720.15 control 49
81+10 156 12600 1.740.17


isometric 77+ 13 132 10200 1.45+0.31 CAD and 49
8916 151 13400 0.910.24 ischemia
>= 70%
stenosis

isometric 75+13 132 9900 1.59+0.31 Non- 49
85+14 159 13500 1.55+0.24 ischemic


F = Female; M = Male


Post-Processing Calculations and Corrections


Simply obtaining a phosphorus spectrum from a voxel in the

myocardium is not enough to ensure useful spectral data. The cardiac

spectrum is generally contaminated from unwanted signal from

surrounding blood and skeletal muscle. Also, T, relaxation corrections

must be made when TR < 5 x T1 and T2 relaxation corrections when

acquiring an echo instead of an FID. Finally, calculation of absolute

concentrations of metabolites may show changes undetected by metabolite

ratios.

Starting with the first human study of cardiac phosphorus

spectroscopy, the techniques for gathering phosphorus cardiac spectra











have gradually changed and improved. The first cardiac spectrum was

obtained by Bottomley et al. in 1984,45 corrections for relaxation by

1987 by Bottomley et al.,14 and blood contamination corrections as early

as 1991 by Sakuma et al.55 The pulse sequences and post-processing

methods have been gradually refined and duplicated by different

research groups and yielded very comparable results. In each case the

ratio of myocardial [PCr]/[ATP] was comparable for reference controls

during rest: 1.800.21 (n=12)," 1.930.21 (n=17),150 1.95+0.45

(n=19),82 1.650.26 (n=9).'65 Uncorrected cardiac spectra produce

unreliable results,7 therefore studies of human cardiac spectroscopy are

no longer publishable without corrections for blood contamination and

relaxation effects. In addition, since there is no method for

correcting for skeletal muscle contamination, such contamination

invalidates the study results.


Skeletal Muscle Contamination


Skeletal muscle contains the same phosphorus peaks as cardiac

muscle, but in different quantities. The primary method for ensuring

that there is no skeletal muscle contamination in the cardiac spectrum

is to use good methods of localization with an appropriate pulse

sequence.5" This dissertation project will evaluate ISIS and CSI

derived pulse sequences for elimination of skeletal muscle

contamination.


Blood Contamination


Blood contains ATP and PDE as does myocardium, but no PCr."

Blood also contains 2,3-DPG (2,3-diphosphoglycerate), which produces a











doublet in the phosphorus spectrum at chemical shift positions of 5.4

and 6.3 ppm, near Pi and phosphomonoester resonances. Blood

contamination causes the [PCr]/[ATP] ratio to appear reduced." Also,

the myocardial Pi peak in normal heart is small and difficult to

resolve from the blood DPG signal.7.148

The correction method for blood contamination is to determine the

relative signal contributions of 2,3-DPG and ATP from blood and use

this knowledge to correct for blood's contribution to ATP. This is

accomplished with the use of a correction factor, which is the ratio of

blood [ATP]/[2,3-DPG]. Such a correction factor for the cardiac muscle

[PCr]/[ATP] ratio typically increases its value by 13% 6% at 1.5

T.,..2.14,is5oI The blood correction is considered small enough that a

substantial error in [ATP]/[DPG] bid ratio will not severely compromise

the final [PCr] / [ATP] crd.ac. pec.um ratio, although the final value of

myocardial [PCr] /[ ATP] caac spectrum will still be better than the

uncorrected value.' The ratio of blood ATP to DPG obtained from basic

spectrometer methods is 0.30.200-202

Spectra from pure blood are usually obtained in vitro using

heparinized (anti-coagulant) blood samples. Unfortunately, one study

using proton decoupling of blood samples resulted in spectra with the

contribution from 2,3-DPG overestimated and ATP underestimated.202 In

addition, most of these types of blood studies were conducted days and

weeks after the sample was obtained, since most studies were performed

to test the survival of stored blood. These studies showed increased

Pi which indicate the breakdown of 2,3-DPG. However, ATP was shown to

remain constant when the cells were maintained under appropriate

conditions of 37 C temperature and the appropriate gas mixture..o..20











The excess Pi signal appears as soon as two hours after obtaining the

blood sample.2"' As the 2,3-DPG breaks down over time the ATP/2,3-DPG

ratio increases.202 Consequently, the published ratio of 0.30 may be

elevated due to the delay before acquisition. There are thus several

reasons to distrust the results of these experiments when determining

the proper ratios to correct for blood contamination in the in vivo

cardiac muscle spectrum.

At least two human cardiac NMR research groups have dealt with

the problems of obtaining adequate blood spectra by determining their

own correction factors for blood ratios. They extracted venous blood

(-50 milliliters) from their volunteers and obtained phosphorus spectra

of the blood in the same magnet used for the cardiac study,2.'14s in one

case using the same NMR acquisition techniques as well.148 In both cases

studies were conducted at 1.5 T and the blood [ATP]/[2,3-DPG]

concentration was much lower than the reported values from the standard

spectrometer experiments: 0.110.0282 and 0.14 0.02.18 These research

groups were also able to correct for the blood 2,3-DPG contamination of

the muscle PDE peak with correction ratios of [PDE]/[DPG] of 0.19+/-

0.0382 and 0.21+/-0.02.'" Theoretically, the blood could be measured

in-vivo directly from inside the heart, but has not been documented in

the literature to date.

Ischemia causes a reduction in systolic wall thickness. It has

been debated that because of the reduced volume of myocardium, the

phosphorus spectrum will be more contaminated with blood for ischemic

patients. As blood contains ATP, blood contamination can alter the

[PCr]/[ATP] ratio. Fortunately, the amount of blood contamination can

be corrected for, and it has been shown that the [PCr]/[ATP] ratio is











still reduced with exercise for ischemic patients even after blood

correction.1


Relaxation Corrections


Two components of the macroscopic magnetization in NMR are

subject to time dependent exponential relaxation effect. The

longitudinal magnetization or spin-lattice relaxation along the z-axis

is an increasing exponential function (Ti dependent) with a maximum of

magnetization of Mo. The transverse magnetization or spin-spin

relaxation in the x,y plane is a decreasing exponential function (T,

dependent) with a minimum magnetization of near zero.208

The relaxation time T0, is the time required for the net

magnetization (M) to return to 63% of its original value following an

excitation pulse.38 Ti relaxation rates depend on the presence of

molecular interactions in the vicinity of the excited spin that

modulates with an intrinsic frequency (wJ) ." When w, is near in

frequency to the resonance frequency (w) the interaction will more

readily absorb the resonant energy and this energy transfer will occur

more frequently. This allows the collection of spins to return to the

equilibrium configuration sooner, resulting in a shorter T, value.38 In-

vivo metabolites as studied with P-31 spectroscopy are usually small

molecules where the rate of molecular motion is rapid. This results in

a poor match between w, and w0 and thus relatively long Tl relaxation

times.as In addition, because of the relationship with resonant

frequency, Ti is also dependent on the main magnetic field strength.

In a typical P-31 MR spectroscopy experiment, the time between

successive radio frequency pulses (TR) is usually insufficient for











complete Ti relaxation. Successive acquisitions applied at a short TR

result in a steady state of M where the spins are partially saturated

and the resulting MR signals are reduced from their completely relaxed

values." This situation makes quantitation difficult since the correct

MR signal from each P-31 metabolite is directly proportional to the

number of spins only when the collection of spins is at equilibrium.

Different metabolites relax at different rates. For example, the

[PCr]/[ATP] ratio will typically be too small due to the faster

relaxation of ATP. Fortunately, there is a way to correct this

situation.

T, relaxation corrections are necessary for cardiac spectroscopy

studies since the pulse repetition time, TR, is generally much shorter

(minimum 1 sec when gated) than the total time for complete relaxation,

five times T,"1 (Ti = -4 sec for PCr and ~2 sec for P-ATP at 1.5 T).s5

The method for determining the relaxation factor for cardiac

spectroscopy is to obtain two sets of phosphorus spectra, one at short

TR (TR < T,) and one at a fully relaxed TR (TR >> Ti) Then a simple

division of the ratio of [PCr]/[ATP] measured at the fully relaxed TR,

over the [PCr]/[ATP] ratio measured at the shorter TR, provides the

relaxation factor, assuming the same TR for each relaxation corrected

experiment.209 This factor can in turn be multiplied by the [PCr]/[ATP]

ratio of the localized spectra obtained with the shorter TR value to

obtain the relaxation corrected results.

The relaxation correction factor (RCF) ideally should be obtained

directly from the myocardium, with localized techniques. This requires

a set of volunteers be used to gather data to estimate the relaxation

correction factor for all studies at that field strength and frequency.











This is because it would take an extra 30 minutes to an hour to gather

data for RCF for each subject, an unreasonable request to be tacked on

after a current two-hour study. However, Bottomley et al.6,209.210

obtains the relaxation data from each subject by using unlocalized

acquisitions at long and short TR times, adding only six minutes of

scan time2' and allowing the calculation of RCF for each participant.

This method also assures that the flip angle, pulse power, RF coils,

and patient is the same for the localized spectrum and for the

measurement of the correction factor.20 In doing so, a large assumption

is made that the P-31 metabolites of skeletal and cardiac muscle have

the same relaxation rates and thus the same RCFs. This assumption is

based on animal studies in rat skeletal muscle211 and canine cardiac

muscle. -

Those research groups that have measured animal and human

localized cardiac P-31 metabolite Ti values directly have shown that it

is possible to obtain relatively consistent values although there are

still discrepancies between research sites. This is demonstrated in

Table 9 where the standard deviations of some published values of Ti are

relatively low with greater discrepancies between reports, such as

between Neubauer et al." and most of the other human studies164'193212 at

1.5 T. There is no need to rely on assumptions about cardiac and

skeletal muscle metabolites, when the Ti relaxation values of the P-31

metabolites can be measured from the cardiac muscle directly. A

correction factor of 1.28, has been measured at UAB'95 and is used in the

WISE study to correct for relaxation effects at 1.5 T. To use this

correction factor, simply multiply it by the blood corrected

[PCr]/[ATP] ratio.












Table 9. Published Spin-Lattice Relaxation Times of Myocardial PCr and
ATP.

Field TI (PCr) Ti (y-ATP) TI (P-ATP)
Subject (Tesla) (sec) (sec) (sec) Reference
Dog 1.9 4.40.1 1.8+0.2 1.60.1 118

Pig 4.7 4.80.9 3.0+1.7 2.61.7 213

Pig 2.0 6.30.4 2.2+0.8 2.2+0.7 213

Human 4.0 5.31.6 2.7.6 -17

Human 1.5 4.2 1.7 193

Human 1.5 4.0 1.80.2 212

Human 1.5 4.1 2.70.8 164

Human 1.5 6.1 5.4+0.5 5.81.0 14


The relaxation time T., is the time required for the transverse

component of M to decay 37% of its initial value. At equilibrium, Mo

is oriented only along the z (Bo = main magnetic field) axis and no

portion of Mo is in the x,y plane. The coherence or uniformity of the

spins is entirely longitudinal with no transverse component.38 A 90

radio frequency pulse causes Mo to rotate entirely into the xy plane,

so that the coherence is in the transverse plane at the end of the

pulse. After the pulse, the coherence gradually disappears, the spins

lose phase coherence, and reorient themselves along Bo. The

disappearing coherence produces the free induction decay (FID) with a

dephasing time of T2 or T2*, where T2 is always less than T, and T2* is

less than T2.3'

After the application of the 90 radio frequency pulse, when M is

oriented in the transverse plane, each spin processes at the same

frequency wo, and the spins are in phase. Each nearby spin of the same











type and the same molecular environment will have the same w,. The wo

will not remain the same, however, as intra- and inter-molecular

interactions will cause the local magnetic field to modulate around

each spin causing wo to vary. The variations will produce a gradual,

irreversible loss of phase coherence and a reduction in the transverse

magnetization." In addition, non-uniformity in the Bo field and

magnetic susceptibility differences can cause additional loss in

transverse phase coherence and T,* relaxation." Fortunately, neither T2

nor T2* are factors that need to be corrected for quantitation of a P-31

spectrum using ISIS or DRESS, but they can affect the quality of the

spectrum. The Ti component of relaxation determines the amplitude of

the metabolite signal while the T, or T2' has an effect on the decay of

signal with time and the linewidth. Shimming of the region of interest

can attempt to correct for some losses in phase coherence, but P-31

metabolites have inherently fast and unalterable T2 times.


Calculation of pH


Some values of cardiac pH as found in the literature are shown in

Table 10. The pH is proportional to the frequency difference of the Pi

and PCr P-31 metabolite peaks. In the literature it is well stated

that it is not always possible to see the Pi peak in every case due to

SNR differences between cases. None of the publications listed were

able to obtain pH values on every single subject. There are also no

known publications of human cardiac pH during in-magnet stress.






57



Table 10. Myocardial pH in the Literature as Measured by Human, In-vivo
Phosphorus NMR Spectroscopy.

Type of patient n pH at rest Reference
Normal Control 4 7.150.03 165

Normal Control ? 7.15 0.02 149

Normal Control 1 7.17 159

Infarction 4 7.15 0.06 149








RF
ox-- A A------

,.Q___ A r


Acquire


Echo


TE/2 TM
Figure 1. STEAM Pulse Sequence


TE/2
TE/2


RF 1800
RF -t A -
.~ rv


f-N
-I-

A~~


Acquire


Echo
TE1/2 TE1/2 TE2/2 >< TE2/2
Figure 2. PRESS Pulse Sequence


I C










Acquisitions:
1t 2nd 3rd 4th









5th 6tt 7"h 8th








Localization:
Volume: Slice: Column: Voxel:
(1") l) (1 2d ) ( 2nd+3' _-4th) (L'-2"d+3 Cd -4 t h
+5th-6th+7th-8 h)










Figure 3. ISIS Volumes for 8 Acquisition Voxel Localization.

















CHAPTER 3
PHANTOM P-31 SPECTROSCOPY ACQUISITION TECHNIQUES




This chapter covers the design and implementation of the phantom

techniques for evaluating the 3.0 Tesla GE Signa Advantage' magnet in

Gainesville, Florida for purposes of performing cardiac spectroscopy on

human subjects. The 3.0 Tesla magnet located in the tunnel between

Shands at the University of Florida (UF) and the Veterans Affairs

Medical Center (VAMC) is owned by the VAMC, Shands at UP, and the Brain

Institute at UF. Phantom and coil combinations were tested with a

variety of imaging and spectroscopy pulse sequences. The purpose of

utilizing a phantom is to take the opportunity to test all the possible

pulse sequences and options with a standard sample (the phantom) to

compare each method. In addition having a phantom prevents the need to

have an endless supply of human volunteers to test out each pulse

sequence and option. In addition, it is often difficult for humans to

lie perfectly still in the magnet for a long period of time, as they

are generally required to do for all MRI and MRS studies (with the

exception of exercise studies, where special procedures are

implemented). When new protocols are initially being tested, they tend

to take longer to run than after they are better defined, again

pointing to the advantage of using a constant, stationary phantom.

Although there is not enough room in each figure caption to capture the

full protocol under which each image and spectrum were obtained, this











information can be found in the appendix, identified with its reference

figure.


Phantom Design


Four phosphorus phantoms have been identified or built for the

purpose of initially testing the parameters for each pulse sequence and

protocol, before use on human subjects.


Gate-able and Depth Phantoms


Two phantoms, the gate-able and depth phantoms consist of two

compartments, each containing a different phosphorus compound, which

present as separate chemical peaks in the phosphorus spectrum.

Photographs and images of the gate-able and depth phantoms, in each of

the three planes can be found in Figure 4, Figure 5, Figure 6, and

Figure 7. The outer and inner compartments (OC and IC) are filled with

the phosphorus containing chemicals of sodium dihydrogen phosphate

(NaH2PO ) and methylenediphosphonic acid (MDPA), respectively, each

diluted in distilled water. The compartment sizes and concentrations

for each phantom are described in Table 11. Two sections are necessary

to test the ability of each pulse sequence to localize to the desired

voxel (represented by the IC) and exclude the outer voxel signal

(represented by the OC) .1 The OC represents the unwanted signal from

skeletal muscle and blood that surrounds the myocardium. The IC

represents the phosphorus signal from the myocardium. In addition, the

depth phantom's IC is surrounded by a layer of water (compartment 2 in

Table 11) which is just thick enough to eliminate most of the

contamination from just outside the selected volume. For this reason











the depth phantom is especially useful in demonstrating complete

elimination of the OC signal of NaH2PO, when the pulse sequence is able

to do so. Both phantoms were designed to load the H-1 and P-31 coils

similar to a human chest load. The estimation of loading equivalency

is demonstrated by the resulting quality factors (Q-factor) values of

the loaded H-1 and P-31 coils compared to a human chest load, as shown

in

Table 12. The Q-factor will be explained further in the section

of this chapter on coil designs. The center of the gate-able phantom's

IC is at a depth of 5 cm, to approximate the depth of the anterior wall

of the heart, while the depth phantom has variable depth IC.


Table 11. Gate-able and Depth Phantom Compartment Sizes and
Concentrations.

Inner Inner Outer Outer
Compartment Compartment Compartment Compartment
Phantoms Size Concentration Size Concentration
Gate- Container: Container:
able 4.7-cm length, 80 mM MDPA 11-cm max height, 80 mM NaHPO,
2.7-cm ID*; 28-cm ID*;
35 ml partially filled
with 4 liters

Depth Container 1: Container:
3-cm length, -80 mM MDPA 16-cm max height, 30 mM NaHPO,
2.3 cm ID* 30-cm ID*; plus 70 mM
partially filled NaCl
Container 2: with 7 liters
3-cm length, water
3.6 cm ID* barrier
Abbreviations: ID* = inside diameter


The gate-able phantom was initially designed to test the degree

of localization of each pulse sequence and to do this while the IC was

moved in and out of the volume of acquisition in a gated fashion. A

volunteer standing outside of the magnet would gate the magnet

acquisition with a peripheral-gating device reading the pulse rate in











the volunteer's finger. While viewing the pulse waveform, the

volunteer would use an extension rod attached to the IC of the gate-

able phantom to coincide the movement of the IC with the peripheral

pulse gating, pushing and pulling the IC in or out of the acquisition

volume (AV) with each beat. The system gated the sequence to the peak

of the peripheral pulse waveform. It was found that placement of the

IC in the AV at the peak of the pulse waveform resulted in a signal

that was equivalent to that achieved by placing the IC in the AV

without movement. In addition, when the cycle was reversed such that

the IC was outside of the AV at the peak of the peripheral pulse, and

moved inside between gated pulses, the result was equivalent to having

the IC outside of the AV for the entire sequence without movement.

Therefore, the gating was found to be predictable and accurate.

The depth-changing phantom (or simply "depth phantom") was

borrowed from Hee-won Kim's dissertation work. This phantom is

designed with an inner compartment that can be moved to different

depths away from the coil surface, thus simulating different cardiac

depths. Unlike the gate-able phantom, the IC position is fixed before

the start of acquisition and cannot be moved during acquisition,

although it can be moved to different depths between acquisitions. The

IC of the depth phantom consists of two separate containers, an inner

container of MDPA surrounded by a second container providing a layer of

water between the IC and OC. The water layer is thin (-0.7 mm) but

large enough to help eliminate a majority of signal just outside the

selected volume of interest. This phantom is therefore ideal to use

when demonstrating the ideal localization ability of a pulse sequence

and to show virtually no external contamination from the external











NaHPO4. The primary use of the depth phantom, however, is to estimate

the optimal transmitter gain (TG) which determines the optimal flip

angle at each depth. For the human studies, these phantom measurements

will provide initial guesses of TG values for human cardiac P-31 MRS

acquisitions.


Slice Profile Phantom


A third phantom, the slice profile phantom, as shown in Figure 8,

consists of a 2 ml vial of 14.7 M phosphoric acid (HPO4), placed at an

angle of 40 at depth of 5.5 cm with a plastic arch that is glued in

place. The vial is surrounded by an outer compartment (22 x 22 cm2 base

x 10 cm tall) of 4 to 5 liters of 70 mM sodium chloride to load the

coil. This phantom was used to more precisely detect the degree of

contamination in a slice from a source (the 2 ml vial of HPPO4) just

outside the slice.


GE Phosphoric Acid Phantom


A GE plastic bottle phantom consisting of a larger volume (-450

ml) of phosphoric acid (H3PO4) provided a strong P-31 signal for use in

comparing the different types of P-31 coils. This phantom provided

enough P-31 signal for adequate imaging at the P-31 frequency. It was

used for quick working checks of coils and equipment, as well as to

verify dimensionally the depth ranges of each phosphorus coil used in

this work. The bottle is 18 cm tall (including cap) and has a 7.3 cm

diameter at its widest. GE's 14.7 M Phosphorus Phantom is labeled as

"GE Medical Systems, 46-317299G2, Spectroscopy Service Phantom, 14.7 M

H3PO4 Phosphoric Acid" as shown in Figure 9.










Radio Frequency Coil Design


Sets of proton and phosphorus radio frequency coils were selected

in order to obtain the best performance from a study. The proton coil

is used for imaging, swimming and ensuring correct positioning of the

phosphorus coil. To prevent changes in shim values and localization

due to patient movement, it is essential to have the proton coil and

phosphorus coils in place during the entire study, independent of

whether the magnet is set at the proton or phosphorus frequency. In

terms of RF coils, this means having proton and phosphorus coil(s) that

are compatible and maximize the SNR for the phosphorus spectrum. The

coils were designed dimensionally by the author, with the author

sometimes providing the platform and placing the copper tape on the

coil former with proper dimensions. All of the capacitor, resistor and

cable placements for proper coil tuning and usage, in addition to some

initial platform creations, were performed by Dave Peterson and Bryan

Wolverton in Dr. Fitzsimmons' coil lab, at the Veterans Affairs Medical

Center, Gainesville, FL. In addition, Dave Peterson provided

assistance in measuring coil parameters as are shown in Table 12 and

Table 13.


3.0 Tesla Square Proton Coil Paired with Quadrature Phosphorus Coil


The GE 3.0 Tesla magnet does not have a body coil, therefore it

is necessary to build a proton surface coil in addition to the

phosphorus surface coil. A 10 x 16 cm2 quadrature transceive phosphorus

coil (two 10-cm diameter coils overlapping), coplanar with a 25-cm

square transceive proton coil was created and was shown to provide

adequate imaging and spectroscopy performance. The quadrature coil











provides an advantage over the basic single-turn coil. Theoretically,

a quadrature coil will provide up to 2 times the signal to noise of a

single turn coil."' In practice, the signal to noise improvement can be

better or worse depending on the quality of the coils that are

compared. A quadrature coil, acting as receive only, provided 1.4

times the signal-to-noise ratio of a single turn coil having the same

shape and total dimension, in a cardiac imaging acquisition.'18

Originally, the quadrature phosphorus coil and the square proton coil

were permanently positioned together on one holder as shown in Figure

10a. A schematic diagram of the proton square coil is shown in Figure

lla, whereas a schematic diagram of the phosphorus quadrature coil is

shown in Figure llb. It was found that this pairing, when positions

were permanently placed, offered limited flexibility in centering the

quadrature coil over the heart, where the coil holder was often

protruding into the chin of the volunteer. A modification was made to

mount the two RF coils on separate holders so each could be optimally

and comfortably positioned. This modification is shown in Figure 10b.


3.0 Tesla Phosphorus Single-Turn Coil


Most cardiac spectroscopy work is currently done with a simple,

single turn surface coil. It is for this reason that tests were

performed with a single-turn phosphorus coil for comparison with the

quadrature coil results. The single turn coil is a 10 cm diameter

transceive design tuned to 51.71 MHz for phosphorus at 3.0 Tesla. A

photograph of this coil is shown in Figure 12, and a schematic diagram

of this coil is found in Figure 13.










3.0 Tesla Coil Comparisons


Phantom tests with the GE 14.7 M phantom show that the quadrature

coil overall performs significantly better than the single turn

phosphorus coil, especially at greater depth.

Table 12 lists values of the basic coil parameters of quality (Q-

factor = quality factor) and isolation for each of the 3 Tesla tuned

coils. The quality factor is defined as the center frequency over

bandwidth, where the bandwidth is the frequency +3dB and -3dB from the

center frequency."' The parameters were measured with help from David

Peterson in Dr. Fitzsimmons' coil lab, using the HP 8752A Network

Analyzer.


Table 12. A Comparison of 3.0 Tesla Coil Parameters.

Square Quadrature Single-Turn
H-1 P-31 P-31
Q-factor Unloaded: 16 44 30
Q-factor Human* Chest Load: 2.2 24 19
Q-factor Depth Phantom Load: 2.8 12 13
Q-factor Gate-able Phantom Load: 2.5 16 16
Isolation of Quadrature: 15.4 dB
Isolation of P-31 coplanar with H-: 36 dB 42 dB
human chest load of 29 year old male with body mass index of 25.5.


In addition to measurements of the quality factor and isolation,

each phosphorus coil's performance was mapped. Comparative mapping of

the quadrature versus single-turn coil performance was achieved by a

series of P-31 spectroscopy slice acquisitions where the TG was

optimized at each slice. Using a larger proton slab phantom beneath

the coil for loading, and placing the 14.7 M phantom on top of the

coil, which provided excellent SNR, a DRESS slice (25 mm thick) was

obtained at 5 mm intervals from each coil, as shown in Figure 14. At











each slice, the TG was optimized. The maximum distance from each coil

measured was at 96 mm, just under 10 cm, where the 14.7 M P-31 phantom

bottle's neck formed. The bottle also had curved edges at the bottom

and top as well as a slight concave area at the bottom, which can

explain part of the reduction in signal in the first few slices from

the RF coils. Based on the results, the single-turn RF coil has

optimal SNR at a depth of 25 mm while the quadrature RF coil has an

optimal SNR at a depth of 42 mm. This data reinforces the fact that

the quadrature coil penetrates deeper with greater SNR and is therefore

more ideal for reaching the depths of hearts of thicker chested

individuals. This result is duplicated when the ratio of quadrature to

single-turn signal is plotted, showing the quadrature coil peaks with

the greater signal at both the coil surface and at a depth of 42 mm.

In addition, until the depth of 60 mm, the quadrature coil outperforms

the single-turn coil in terms of relative signal. Increase in signal

from the depth of zero to 3 cm in Figure 14 can also be explained.

Starting at the coil position (zero distance from the coil), only half

of the first slice contains the phantom material. As the depth

increases, the entire phantom is in the slice by a depth of 1.25 cm.

Acquisition of a spectroscopy slice is not 100% accurate at the edges,

where a Gaussian like function describes the contamination of signal

from outside the slice. At the first slice depth where the entire

phantom is in the selected slice, only one edge is contributing signal

contamination. As the depth increases, eventually both edges will

contribute a small bit of contamination. In addition, although the

14.7 M P-31 phantom is only 73 mm in diameter, this test is not 100%











accurate because the profile of each coil (single turn and quadrature)

may not have equally obtained signal from each slice.


1.5 Tesla Coils


One main argument for using the 3.0 Tesla magnet is its superior

performance when compared to 1.5 Tesla. All comparisons between the

1.5 Tesla and 3.0 T were done on GE scanners with identical software

(version 5.4) and with components as similar as possible. The 1.5

Tesla GE Signa Advantage" has a body coil, therefore no proton coils

were created. A single turn phosphorus coil of 10 cm diameter was

created. In addition, a quadrature coil of the same dimensions as the

3.0 Tesla P-31 quadrature coil was constructed. The same parameter

measurements taken from the 3.0 Tesla coils, were also performed on the

1.5 Tesla coils as shown in Table 13, with the exception of the 1.5

Tesla body coil, which cannot be moved for such testing in the coil

lab. In addition, a photograph of each of the coils can be found in

Figure 15 and Figure 17, and a schematic for each can be found in

Figure 16 and Figure 18.


Table 13. Comparison of 1.5 Tesla Coil Parameters.

Quadrature Single-Turn
P-31 P-31
Q-factor Unloaded: 77 48
Q-factor Human* Chest Load: 45 33
Isolation: -18.6 dB not applicable
Match: 68 pF per side not applicable
reflections: -18 dB / -29 dB not applicable
* human chest load of 29 year old male with body mass index of 25.5.












Coil Ideas for Future Cardiac Spectroscopy Studies


Future coil sets may consist of a smaller proton coil or a set of

phosphorus coils with a separate, larger transmit coil, thus reducing

spatially dependent spectral distortions from the excitation field.2n1

There is also the possibility of other coil designs, if one is found to

significantly improve the performance of the cardiac imaging and

spectroscopy acquisition.


Imaging


Both Spin Echo and Gradient Echo imaging pulse sequences are the

most common MRI techniques for proton imaging on the GE system. The

goal of the phantom imaging was to predict which pulse sequence would

provide the best image uniformity and depth of penetration, when used

with a simple surface coil. In this chapter, imaging is briefly

examined at 3.0 T and only in phantoms, but in the next chapter images

taken at 1.5 Tesla will be compared with 3.0 T and explained in greater

depth. Imaging with the spin echo pulse sequence on the 3.0 Tesla with

a surface coil has its limitations. Even with a maximum transmitter

gain (TG) the signal depth is not as good as the gradient echo images.

This is shown in Figure 19 where the top corners of the phantom are cut

off when spin echo imaging is used, but are still visible when gradient

echo imaging is used. In contrast, the spin echo pulse sequence works

better at producing images than the gradient echo sequence on the 1.5

T, where a body coil provides more uniform excitation of the axial

slice and requires less overall power. Human cardiac images shown in

the next chapter emphasize this point. Also note the slight asymmetry











in signal brightness in the gradient echo images, which is due to the

slightly off center placement of the 25 cm proton coil with the center

of the gate-able phantom. Gradient echo imaging, especially with a

flip angle of less than 90 (600 was used) was found to work best for

imaging an axial slice with a simple surface coil.

Phosphorus imaging can only been done with a phosphorus sample of

extremely high concentration, such as with the GE 14.7 M phosphorus

phantom. The phosphorus concentrations in the human body, or in the

depth or gate-able phantoms, are not high enough to produce an image

within the standard phase and frequency steps designed for proton

imaging. The result of imaging a phosphorus sample with normal tissue

amounts of phosphorus in the millimolar range was simply an image of

noise. The only phosphorus imaging that is presented in this write-up

is of the GE 14.7 M phosphorus phantom. The GE 14.7 M phantom images

were used to compare the depth penetration abilities of each of the

phosphorus coils.


Spectroscopy


GE offers a number of spectroscopy pulse sequences of different

characteristics and qualities. Due to characteristic differences of

metabolites at different frequency ranges, there are pulse sequences

that are more appropriate for either H-l or P-31. In addition, some

pulse sequences are designed to acquire spectra unlocalized, while

others can slice, column or voxel localize. There is no direct purpose

for using unlocalized H-1 or P-31 spectroscopy acquisitions, assuming T,

corrections will be based on spectra localized to the cardiac muscle.

The discussion will be limited to localized spectroscopy sequences that











would be of use in a cardiac MRS protocol. Using phantom studies the

GE pulse sequences will be described and evaluated for the later

purposes of H-1 localized acquisition for swimming and P-31 localized

acquisition for evaluation of cardiac disease. Quality of the

phosphorus spectra from the phantom studies will be determined based on

acquisition time, SNR, and degree of localization (i.e. increased

signal from the VOI and reduction of signal outside the VOI).

Note that most figures of complex P-31 spectral data in the

figures of this dissertation are graphed as real, phased data, as noted

by "REAL" as labeled by GE's SAGE_IDL"' spectral post-processing

software.


Localized Proton Spectroscopy


Although the magnet's homogeneity is optimized upon installation,

any individual person or object that goes in the magnet will distort

the main magnetic field to some degree. SNR and the resolution of

peaks with frequencies that are close together depend partially on good

field homogeneity. Homogeneity can be increased in a region of

interest with a technique called swimming. Shimming involves obtaining

an unsuppressed H-1 MRS signal from the region of interest and

adjusting the gradients to optimize the H-1 MRS signal. The H-1 MRS

signal is used because the water peak provides high SNR and optimizing

the magnetic field for the water protons will also improve the signal

for the P-31 metabolites. Since the linewidth of a resonance peak is

inversely proportional to T,*, the homogeneity can be optimized by

either minimizing the full width at half maximum (FWHM) of the water











peak or maximizing the extension of the T:* dependent free induction

decay (FID) of the H-1 MRS signal.

The two spectroscopy pulse sequences on the GE system most

appropriate for voxel localized H-1 spectroscopy are STEAMCSI and

PRESSCSI, based on the standard STEAM and PRESS techniques in the

literature. GE's STEAMCSI pulse sequence incorporates three slice-

selective 90 RF pulses and a set of crusher gradients, as shown in

Figure 20. GE's PRESSCSI voxel localized pulse sequence is obtained

through three slice-selective RF pulses and utilizes a spin-echo with

900, 1800 and 1800 pulses and two sets of crusher gradients, as shown in

Figure 21. The PRESSCSI pulse sequence was preferred because of its

general ability to provide twice the SNR of the STEAM sequence, as

explained previously in the literature review. The FWHM values of the

water peak from the phantom studies with PRESSCSI and STEAMCSI were

5.78 Hz (0.045 ppm) and 14.09 Hz (0.110 ppm), respectively.


Localized Phosphorus Spectroscopy


Using the best possible scenario for obtaining a phosphorus

spectrum, namely using a phantom, it is easy to definitively compare

the quality of the results of each of the available GE pulse sequences,

and some modified GE pulse sequences. The use of a phantom is ideal

because it allows for a standardized cross-comparison of pulse sequence

acquisition results with a non-moving, non-changing phantom. Each of

the available GE pulse sequences, PRESSCSI, STEAMCSI, ECHOCSI,

SPINECHO, ISISCSI, and FIDCSI are compared in increasing order of

quality of localized results within a reasonable amount of time

(usually less than ten minutes per acquisition). Such an increase in











quality of MDPA localization can be seen through the progression of

quality of all GE spectroscopy pulse sequences via progressively

smaller localization volumes, as seen in Figure 22 through Figure 32,

and Figure 34 through Figure 38. Also presented are some modifications

of the most viable phosphorus localized pulse sequences, ISISCSI and

FIDCSI, which produce even better results.


Phosphorus STEAMCSI and PRESSCSI


GE's STEAMCSI and PRESSCSI pulse sequences, as explained

previously, allow for the acquisition of a single voxel with each TR

acquisition. In addition, both of GE sequences can be used along with

CSI phase encoding gradients to further divide the field of view into

multivoxels. As expected from the literature on PRESS and STEAM,

PRESSCSI doesn't work as well as STEAMCSI, although neither was ideal

for obtaining localized phosphorus spectra, as shown in Figure 22 and

Figure 23, respectively. Note that the STEAM sequence was acquired in

a fourth of the time of the PRESS sequence, but is better able to

display the P-31 peaks.


Phosphorus ECHOCSI


ECHOCSI is GE's modification of the standard spin echo 90-1800

pulse sequence combined with 2-D CSI, as shown in Figure 24.9" GE's

version of ECHOCSI for localized spectroscopy employs a slice selection

and CSI option. The use of a surface coil with this pulse sequence

combines an inhomogeneous B, field with a pulse sequence requiring

somewhat accurate 90 and 180 pulses. In addition, the reliance on CSI

for voxel localization leads to intervoxel signal bleed. The result of











a P-31 ECHOCSI CSI voxel localized acquisition is shown in Figure 25

and demonstrates low SNR and inadequate localization to the MDPA inner

compartment of the phantom.

In addition, reliance on CSI is done at an additional cost of

increased scan time. A specific example of acquisition times, for

various field of views and voxel sizes is shown in Figure 26 for a

sample data set of 128 acquisitions and TR of 2 seconds with the

ECHOCSI pulse sequence. These parameters were chosen based on the same

parameters being used to obtain a localized P-31 spectrum successfully

with GE's FIDCSI pulse sequence, as described later in this chapter.

Notice when the voxel sizes are decreased to reasonable values for

localizing to the cardiac muscle (2 x 2 x 2 cm3 or less) the scan time

increases substantially from 18 to over 60 minutes, depending on the

field of view (FOV). The FOV is centered with the magnet bore so the

region of interest must be within the FOV to obtained spectral data.

Considering this protocol will be used for cardiac spectroscopy

acquisitions, the heart is not centered but to the left of the center 5

to 10 cm (depending on the person). In addition, this figure does not

take into account the increased number of acquisitions that would be

needed to keep the SNR constant as the voxel size decreases, thus

further increasing the scan time.


Phosphorus SPINECHO


GE has available a second spectroscopy pulse sequence based on

the spin echo idea. Like, ECHOCSI, GE's SPINECHO is based on the 90-

1800 spin-echo pulse sequence, except that the pulse and the parameters

associated with the sequence have been optimized with the RF pulse











reformed, as shown in Figure 27. The oddly shaped amplitude (Rhol) and

phase (Theta) modulated RF pulses are the result of a back calculation

of the RF pulse based on an input of the echo time and slice profile"'.

The pulse is a composite of the initial 900 pulse and the refocusing

1800 pulse. These pulses are combined together because if these two

pulses are optimized separately, the resulting echo time is limited by

the length of each individual pulse. The SPINECHO pulse available on

the GE system has been calculated for a specific set of parameters and

is not available for the user to change. The excitation pulse has an

effective flip angle of 60 and an echo time of 2.5 msec. The radio-

frequency pulse is optimized for the acquisition of phosphorus spectra

from 3.0 x 3.0 x 3.0 cm3 CSI volumes. The reported benefit of the

optimization was the elimination of the need for baseline correction

during post-processing. A test of this sequence on 3.0 T is shown for

a CSI experiment in Figure 28. The limitations of a 3 x 3 x 3 cm' voxel

areas positioned with CSI would make it difficult to localize to the

anterior myocardium, where a rectangle would be more appropriate. It

is also not clear that this pulse sequence was optimized for use at 3.0

T.


Phosphorus ISISCSI


The ISISCSI pulse sequence, GE's version of ISIS, is the most

appropriate voxel localization pulse sequence for phosphorus as

provided by GE for the 3.0 Tesla scanner, as shown in Figure 29. On

the GE system, ISISCSI uses an adiabatic RF pulse that allows for

uniform excitation of signals over a larger volume of the sample."











The ISISCSI sequence allows for various options in acquisition

areas such as volume, slice, column, and voxel acquisition. As the

acquisition volume size decreases, the ISISCSI sequence is successful

in eliminating more and more of the outer phantom volume (NaHPO,).

This causes the NaHPO, signal to decrease with increasingly smaller

localized volumes, such as the slice and column and shown in Figure 30

and Figure 31. One step smaller than the column is the voxel. The

voxel acquisition is the most desirable localization technique for

cardiac spectroscopy, because of the need to avoid contaminating the

cardiac muscle signal with signals from skeletal muscle and blood.

ISISCSI, however, is plagued by poor localization due to short TR

times between acquisitions of the next of eight separate volumes, not

allowing for complete relaxation to occur between volume acquisitions.

If the localization was ideal, the spectrum shown in Figure 32 would

show just the peak on the left, MDPA, with no added signal from the

outer volume signal of NaHPO4.

A modified ISISCI sequence can be developed to overcome the

relaxation error problems of the original GE pulse sequence. The

original GE pulse sequence gathers each of the eight volumes (for a

voxel acquisition) that will be added and subtracted from each other in

sequence, with the same TR between each. The acquisition proceeds in

the manner that all eight parts are acquired, and then the process is

repeated until the number of acquisitions (a number divisible by eight)

has been acquired. Without rewriting the ISISCSI pulse sequence, a

modification that improves the ISISCSI localization results has been

made. By acquiring an average of each of the eight volumes separately,

with a delay time of at least 15 seconds between acquisition of each











volume, a much improved voxel acquisition can be acquired with very

little compromise in overall acquisition time. This idea is explained

visually in Figure 33 for an acquisition example of 32 NEX. When all

eight volumes were acquired separately with a short TR time during each

acquisition, but a longer TR between acquisitions, the localization

results were significantly improved, as shown in Figure 34.


Phosphorus FIDCSI


GE's FIDCSI spectroscopy pulse sequence is the most basic of the

spectroscopy sequences involving a single RF pulse, as shown in Figure

35." In addition, CSI is an option to gather multivoxel acquisitions.

The FIDCSI pulse sequence provides a good signal and slice

localization. Slice localization without phase encoding can be done at

a minimum thickness of 25 mm (also called depth resolved surface coil

spectroscopy or DRESS). FIDCSI can do multi-voxel acquisition via

phase encoded CSI. Slice localized spectroscopy that is acquired in

the manner of FIDCSI is often referred to by the general term of DRESS

(depth resolved surface coil spectroscopy), regardless of the machine

or pulse sequence designer. This technique is often used for cardiac

spectroscopy because it is a simple sequence with one spectrum output

per acquisition. As long as the slice is sufficiently deep, the

surface coil sufficiently narrow, and the slice properly positioned,

there is only a small risk of skeletal muscle contamination. In

addition, the transmitter gain (TG) must be optimized to ensure maximum

signal from the slice. The proper TG values have been pre-measured

using the depth phantom, as shown in Figure 36 at 1.5 Tesla and Figure

37 at 3.0 T. These measurement can then be used as a first estimate in











optimizing the signal from human FIDCSI slice localized studies at the

same distance from the coil.

The DRESS slice localized spectrum of a phantom as obtained using

the standard GE FIDCSI pulse sequence is shown in Figure 38.

Unfortunately, the pulse sequence suffers from a significant delay time

before the free induction decay is recorded. Some delay, 1 to 4 msec,

is essential to prevent eddy current signals from contaminating the

signal of interest. Long delays, as 20 msec for human FIDCSI oblique

slice acquisitions at 3.0 T, are less desirable because they cut off

too much signal from the ATP part of the phosphorus spectrum, which has

the shortest T2 relaxation time. Fortunately, there are post-processing

programs, such as FITMASTER" (Philips) which can estimate the missing

part of the FID and provide excellent results.

All parameter options were evaluated for oblique and coronal

FIDCSI slice selections. The oblique slice uses more than one gradient

set to specify the slice and therefore can have more conservative

parameter limits. Available parameter options with the FIDCSI slice

selection protocol include changing a parameter called SQUEEZE, which

reduces or increases the overall time taken for the RF pulse. If the

time is reduced, as it is for SQUEEZE = 2, the delay time until the

start of the FID is also reduced. A delay in the FID creates a

increase in the frequency dependent phase shift (first order phase

correction). A 1800 phase shift will be created for each dwell

period."2 The delay time issue is even greater with the oblique slice

as the system must be "tricked" by changing the variable pwgph to 4

msec to even do an oblique slice localization. This is due to oblique

slice using multiple gradients and having the GE software at the most











conservative level for error messages. The pw_gph variable actually

increases the delay time to 20 msec when used at 3.0 Tesla with a

spectral width of 4000, and with the SQUEEZE parameter set to 1.

After careful evaluation of the FIDCSI pulse sequence and after

speaking with both Napapon Sailasuta and Ralph Hurd, both of GE, a

rewriting of the FIDCSI pulse sequence was necessary to fix this delay

problem. The FIDCSI pulse sequence program file was modified (by Dr.

Hee-Won Kim using GE's EPIC) to decrease the delay time for an oblique

slice and renamed FIDOBL on the GE console. This modification

basically allows for a larger gradient strength, still within the

system and safety limits, so that the RF and gradient pulses are as

tall as possible, with the area and thus power remaining the same. A

taller pulse takes less time, therefore, the delay time before

acquisition was reduced. In addition, the need to change the pwgph

control variable is eliminated.

The FIDCSI pulse sequence can be utilized in one other way. The

sequence can be set up to obtain a localized slice, which is segmented

into multiple voxels. The limitations of this procedure come from

inflexible placement of the multivoxels, timing necessary to acquire

CSI phase encoding steps, and unwanted spectral bleed due to point-

spread function inherent with CSI and the Fourier transform. As shown

in Figure 39, the multivoxel FIDCSI with CSI option allows for a set of

voxels to be placed within a set field of view. The field of view is

centered on the image and the voxel placement within the field of view

is dependent on how many times in the x and y direction the field of

view is broken up by phase encoding gradient steps. It should also be

noted that the standard GE FIDCSI pulse sequence on the 3.0 Tesla does











not allow for less than a 36 cm FOV if you let the console continue to

think it is operating at the proton frequency while the acquisition is

at a phosphorus frequency. This was the initial setup recommended by

GE. In this case it is also necessary to change control variables

"asfov" to 48 and "GAM" to 1723.5 to ensure the correct localization

dimensions. It was found that with a few tricks with the control

variables, a minimum FOV of 14 cm can be achieved. This is

accomplished by setting the console to run at the P-31 frequency and

then changing the following control variables to prevent system errors:

"pibbandfilt" equals 0 and "pixmtband" equals 1. These control

variables correct for the absence of a separate RF amplifier for P-31.

The 3.0 Tesla system uses one amplifier for all frequencies, unlike the

default of separate amplifiers expected by the software.

Finally, with some pulse programming corrections, as has been

done with the modified FIDCSI protocol locally called FIDFOVH, FOVs

below 14 cm can be achieved. Dr. Hee-Won Kim performed the

modification of the FIDCSI pulse sequence program with EPIC pulse

programming. The modification basically removed the protection limits

for the gradient amplifiers. The FIDFOVH, modified FIDCSI pulse

sequence, should only be used without the autoprescan, as parts of the

autoprescan (where transmitter gain and receiver amplifiers are

maximized) will exceed the limits of the gradients and do so without

warning. Autoprescan is generally useless for phosphorus spectroscopy,

therefore it would be a mistake to use autoprescan with phosphorus.

This allows the FIDFOVH modified sequence to be used safely.










1.5 Tesla to 3.0 Tesla Phosphorus Spectroscopy Comparisons


One of the main arguments for using 3.0 T over using a 1.5 T

magnet is the significant improvement in the amount of signal that is

obtained with an increase in field strength. To prove this point,

proton and phosphorus spectra of the depth phantom were taken at 1.5 T

and 3.0 T with similar parameters and compared. In addition, the same

parameter was again compared at 3.0 T to compare the single-turn and

quadrature RF coils.

The first comparison was of an FIDCSI acquisition with CSI voxel

localization of the depth phantom, as shown in Figure 40. In each case

the parameters were set as follows: 256 acquisitions, 25 mm thick

slice, 8 x 8 x 1 CSI, 16 cm field of view, 2 x 2 x 2.5 cm' voxels, scan

times = 4:26, and 10Hz line-broadening. In each case the phantom was

positioned so that one of the voxels would select just the inner

compartment of the depth phantom, at a depth of 5.5 cm.

Experimentally, the resulting SNR of the MDPA peak of the P-31 spectrum

for the single turn RF coil at 1.5 T was 7.4 while at 3.0 T it was

21.65, and the SNR of the quadrature RF coil at 3.0 T was 26.1. This

shows a significant improvement in signal from 1.5 T to 3.0 T, but only

a moderate improvement of the quadrature over the single turn coil.

The MDPA TI relaxation rate was also measured at 1.5 T and 3.0 T and

found to be 5.52 and 6.04 seconds, respectively (Appendix G). These

relaxation rates are negligibly different from each other and do not

significantly alter the MDPA SNR at each field strength.

The second comparison was of the modified ISISCSI acquisition of

a voxel positioned over the center compartment (5.5 cm depth) of the

depth phantom, as shown in Figure 41. The parameters used for the











ISISCSI acquisitions were as follows: 256 acquisitions, 16 cm field of

view, 2 x 2 x 2 cm3 voxel, scan times = 2:13 for each of 8 acquisition,

and 10Hz line-broadening. Experimentally, the resulting SNR of the

MDPA peak of the P-31 spectrum for the single turn RF coil at 1.5 T was

6.2 while at 3.0 it was 10.1, and the SNR of the quadrature RF coil at

3.0 T was 14.5. This shows a moderate improvement in signal from 1.5 T

to 3.0 T and another moderate improvement in the results of the

quadrature over the single turn coil.

To verify the extent to which the slice profile of the oblique,

FIDCSI modified slice selection is accurate, a series of tests on the

1.5 and 3.0 Tesla were conducted using the slice profile phantom.

Slices of 25 mm thick, tilted at an angle though the vial, were

obtained across the vial, as shown in Figure 8. The results of the

signal profile over the slice are shown in Figure 42 for the 1.5 Tesla

with the single turn P-31 coil and Figure 43 and Figure 44 for the 3.0

Tesla for the single turn and quadrature P-31 coils, respectively. The

slice profile tails (where none of the H2PO4 phantom was in the slice)

widened slightly more at 3.0 T, most likely due to the same gradient

pulse from the same pulse sequence on both systems despite different

magnet field strengths. This is shown via slightly larger area of

signal when no part of the phantom was in the slice (representing

potential contamination by skeletal muscle or blood) at 3.0 T, as shown

in Figure 43 and Figure 44, and compared to 1.5 Tesla as shown in

Figure 42.

The volume where the slice selection was below the phantom

represents the potential contamination from skeletal muscle. This is

due to the fact that the phantom, in that case being above the selected




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HUMAN INVIVO CARDIAC PHOSPHORUS NMR SPECTROSCOPY AT 3.0 TESLA By ANGELA PROPERZIO BRUNER A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 1999

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Copyright 1999 by Angela Properzio Bruner

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This work is dedicated to my loving husband, Thom Bruner, and my parents, Sharon and Bill Properzio, without whom I would not have had the loving support I needed to complete this work.

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ACKNOWLEDGMENTS I would like to thank the following individuals for their assistance and for making this work possible. The greatest thanks go to my advisor and mentor, Dr. Kate Scott, who encouraged and advised me through this project. Thanks also goes to Dr. Hee-Won Kim, who taught me the basics of the ISIS pulse sequence, shared experiences in working on the General Electric (GE) Signa, and offered valuable pulse programming support. Credit must be given to David Peterson and Bryan Wolverton, under the direction of Dr. Fitzsimmons, who built the coils that were used in this study. Thanks also go to the combined efforts of Dr. Scott, Dr. Fitzsimmons, Dr. Ballinger, Shands at UF, the VA Hospital, and the Brain Institute for their efforts in getting a 3 0 T whole body magnet to the University of Florida. Thanks are also well deserved for Jim Scott who taught me the chemistry for the phantom preparations. After starting this project, I was lucky to begin collaborative work with a number of individuals in cardiology both here at the University of Florida (UF) and at the University of Alabama at Birmingham (UAB). Great appreciation goes to Dr. Carl Pepine, currently the division chief of cardiology, Shands at UF, who fully supported my efforts and encouraged greater work. Also, countless thanks and appreciation are well deserved for Alice Boyette, the Women's Ischemic Syndrome Evaluation (WISE) research cardiology technologist. Alice not iv

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V only attended all the WISE meetings and scheduled the cardiac patient studies on the 1.5 and 3.0 T, but also provided patient handholding and technical support during the studies. In addition, WISE research nurse Eileen Handberg-Thurmond was very supportive and made sure that all financial issues were under control and the necessary equipment purchased. It was through the efforts of cardiology at UF that the Dinamap vital signs monitor was purchased and that all patient studies were financially compensated. I was also fortunate to have my protocol and my study results analyzed by a group at UAB who already had a published history in doing cardiac phosphorus spectroscopy as well as some experience with higher Tesla whole body systems (a 4.1 Tesla). The expertise, careful analysis, and approval of my data by Dr. Steven Buchthal, Dr. Jan den Hollander, and Dr. Gerald Pohost provided excellent feedback that I was on the right track and succeeding in my methodology. I would especially like to thank all of the members of my committee, Dr. Katherine Scott (Chair), Dr. Jeffrey Fitzsimmons, Dr. J Ray Ballinger, Dr. Richard Briggs, Dr. Christine Stopka and Dr. David Hintenlang. These individuals took time out of their busy scheduled to review my work and support my efforts. I would also like to sincerely thank those who believed in me and helped me achieve my doctorate through their continuous moral support. This includes a long list of family members (Thom Bruner, Sharon Properzio, Bill Properzio, Tom Bruner Sr, Jess Bruner, Dee Dee Haun, Carter Haun) and friends (Manuel Arreola, Libby Brateman, Lynn Rill, Michelle Werner, Cathy Carruthers, Mark Knudsen, Beth Knudsen, Sheila Marks).

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TABLE OF CONTENTS page ACKN'OWLEDG.MENT S . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 V LIST OF TABLES .................................. ......... ............. ix LIST OF FIGURES ....................................................... Xl ABSTRACT ........................................ .............. ...... xvi CHAPTERS 1 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Statement of Problem ................................................ 2 Spectroscopy's Contribution to Diagnosing Myocardial Ischernia . ..................................................... 3 Research Hypotheses ................................................. 4 Specific Objectives ............................ .................... 5 Assumptions ......................................................... 6 Scope of the Project ................................................ 7 Significance .................................. ...... ................ 8 2 REVIEW OF LITERATURE ............................................... 10 P-31 Spectroscopy Pulse Sequence Options for the Heart ............. 13 Slice Localization Techniques ................................... 14 Multi-Voxel Localization Techniques ............................. 15 Single Voxel Localization Techniques ........................ .... 17 Cardiac P-31 Spectroscopy Results in the Literature ............... 22 Animal studies .............................................. ... 22 Human Studies .................................................... 24 Post-Processing Calculations and Corrections ....................... 48 Skeletal Muscle Contamination ........... ........................ 49 Blood Contamination ............................................. 4 9 Relaxation Corrections .......................................... 52 Calculation of pH .......................... ..................... 56 3 PHANTOM P-31 SPECTROSCOPY ACQUISITION TECHNIQUES .................. 60 Phantom Design ...................................................... 61 Gate-able and Depth Phantoms ............... ..................... 61 Slice Profile Phantom ........................................... 64 GE Phosphoric Acid Phantom ..................................... 64 Radio Frequency Coil Design ........................................ 65 3.0 Tesla Square Proton Coil Paired with Quadrature Phosphorus Coil .............................................. 65 3.0 Tesla Phosphorus Single-Turn Coil ........................... 66 VJ.

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VJ.J. 3. O Tesla Coil Comparisons ...................................... 67 1. 5 Tesla Coils ................................................. 69 Coil Ideas for Future Cardiac Spectroscopy Studies .............. 70 Imaging ............................................................ 7 0 Spectroscopy ........................................................... 71 Localized Proton Spectroscopy ................................... 72 Localized Phosphorus Spectroscopy ............................... 73 Phosphorus STEAMCSI and PRESSCSI ............................... 74 Phosphorus ECHOCSI .............................................. 7 4 Phosphorus SPINECHO .................. ........................... 7 5 Phosphorus ISISCSI .............................................. 76 Phosphorus FIDCS I .. .. ............................... ........... 7 8 1.5 Tesla to 3.0 Tesla Phosphorus Spectroscopy Comparisons ...... 82 Phantom Results ....................................... .... ........... 84 4 HUMAN CARDIAC P-31 SPECTROSCOPY ACQUISITION TECHNIQUES ............ 112 Imaging ............................................................. 113 Spin-Echo Imaging ........ ................... ............ ...... 113 Gradient-Echo Imaging ....................... .................. 114 Human Positioning .............................................. 114 Gating ................................. ................ ........ 116 Shimming with Localized Proton Spectroscopy ....................... 119 Cardiac Phosphorus Spectroscopy In-Vivo Acquisition ............... 120 Localized P-31 Multi voxel CSI .................................. 12 O Localized P-31 ISISCSI ............. ........................... 121 Slice Localized P-31 FIDCSI (DRESS) ........... ................ 122 Single Turn versus Quadrature Surface P-31 Coil at 3.0 T ....... 123 Human Test Participants .............. ... .......................... 123 In-Magnet Exercise ............ .. ..... ... .......................... 128 Spectroscopy Post-Processing ...................................... 12 9 Post-Processing Software ............. ................... ...... 130 Skeletal Muscle ..................... .......................... 13 6 Blood Contamination .......................... ................. 136 T 1 Relaxation Corrections ..................... ................ 13 7 Calculations of pH ................... ................... .... ... 139 Analysis . .... ................ ...................... . ........... 140 5 HUMAN DATA REPRODUCIBILITY ........................................ 156 T1 Relaxation Corrections .................................. .... ... 157 Overall Reproducibility of the Oblique DRESS Method ... ... . ...... 159 Adequacy of the Hydraulic, In-Magnet, Handgrip Exerciser .......... 165 Reproducibility of the Hydraulic Handgrip .......... .............. 167 No Drop in [PCr]/[ATP] During Exercise with Reference Volunteer ... 168 Drop in [PCr]/[ATP] Seen with the Handgrip Exerciser with Ischemia ......... .................... ......................... 170 Myocardial pH Measured at 3 0 T ..................... ............. l 71 6 SUMMARY AND CONCLUSIONS ........................................... 174 Implications for Future Research .................................. 176 APPENDICES A IRBS AND SCREENING FORMS .......................................... 180

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V1.1.1 B FIGURE ACQUISITION PARAMETERS ..................................... 193 C HYDRAULIC HANDGRI P ....................... ......................... 2 2 4 D 3.0 T CARDIAC ACQUISITION PROTOCOL ................................ 228 E SPECTROSCOPY POST-PROCESSING INSTRUCTIONS ...... ....... ........... 236 F HUMAN T1 RELAXATION DATA .......................................... 256 G T1 RELAXATION RATES OF DEPTH PHANTOM ............... .............. 259 REFERENCES ........................................................... 260 BIOGRAPHICAL SKETCH .................................................. 281

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LIST OF TABLES Table page 1. Nuclear Spin Parameters ......................................... 13 2. Research Published on Human, In-Vivo Cardiac P-31 NMR Spectroscopy of Studies on Normal-Controls or Patients and Related Work ...................................... 26 3 Cardiac [PCr]/[ATP] Ratio of Healthy Volunteers (Normal Controls) at Rest and During Stress .................... 36 4 Cardiac [PCr]/[ATP] Ratio of Patients with Myocardial Infarction at Rest and During Stress ......... .... ............. 38 5 Cardiac [PCr] and [ATP] Amounts at Rest in Patients with Myocardial Infarction, Ischemia and in Normal Controls ......... 39 6 Cardiac [PCr]/[ATP] at Rest and Stress in Patients with Myocardial Ischemia ............................... ............. 43 7. Cardiac [PCr]/[ATP] at Rest and Stress in Patients with Myocardial Ischemia with Some Type of Intervention ............ 44 8 Literature Review of In-Magnet Handgrip Exercise Response 48 9. Published Spin-Lattice Relaxation Times of Myocardial PCr and ATP . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 5 5 10. Myocardial pH in the Literature as Measured by Human, In-vivo Phosphorus NMR Spectroscopy ............................ 57 11. Gate-able and Depth Phantom Compartment Sizes and Concentrations ................. ..................................... 62 12. A Comparison of 3.0 Tesla Coil Parameters ...................... 67 13. Comparison of 1.5 Tesla Coil Parameters ......................... 69 14. Participants at 3.0 T for Cardiac P-31 Spectroscopy ............ 126 15. In Magnet Hydraulic Exercise Handgrip Participants ............. 127 16. Oblique DRESS Acquisition P-31 Metabolite area Values Obtained with Different TR gating Intervals for the Purpose of Relaxation Measurements ............................ 158 17. Summary of Resulting T1 values for PCr and ATP8c ........... 159 lX

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X 18. WISE 1.5 T Cardiac Spectroscopy Acquisition Success Rate ....... 161 19. 3.0 T Cardiac P-31 Spectroscopy at Rest Only, 3xRR Gating ...... 162 20. 3.0 T Cardiac P-31 Results Categorized by P-31 Surface Coil 165 21. Heart rate (HR) and Systolic Blood Pressure (SBP) Response from 30% of Maximum Effort Isometric Hydraulic Handgrip ....... 166 22. Handgrip exercise compared to dobutamine and treadmill responses for known WISE studies ...... ........................ 167 23. Handgrip 30% Maximum Effort Isometric Exercise Results of K.S. Subject Tested Repeatedly . .................. ....... ... 168 24. Results from 1.5 T Cardiac P-31 Exercise Study on Reference Norma 1 Vo 1 un teer . . . . . . . . . . . . . . . . . . . . . . . 1 7 0 25. Ischemic and WISE Studies at 3.0 T Show Drop in [PCr]/[ATP] with Handgrip Exercise ........................................ 171 26. Myocardial pH as Measured on Human Volunteers Using Oblique DRESS Cardiac P-31 MRS on the GE 3.0 T SIGNA for those Studies where the Pi Peak was Discernible due to Adequate SNR . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . 172 27. Comparison of Cardiac P-31 Post-Processing Software .... ....... 252

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LIST OF FIGURES Figure page 1. STEAM Pulse Sequence ............................................ 58 2 PRESS Pulse Sequence . . . . . . . . . . . . . . . . . . . . . . 5 8 3. ISIS Volumes for 8 Acquisition Voxel Localization ....... ........ 59 4. Gate-able-Phantom (a) photograph and (b) position in magnet, without the liquids and with movement direction demonstrated . 87 5. Gate-able-Phantom images, (a) axial, (b) coronal and (c) sagittal views, as imaged with 25cm square proton coil ..... 87 6. The Depth-Changing-Phantom (a) photograph with top open and 7. (b) position in magnet, with movement direction demonstrated ... 88 Depth-Changing-Phantom images, (c) sagittal views, as imaged (a) axial, with 25cm (b) coronal and square proton coi 1 . . 8 8 8. Axial slice image of Slice Profile Phantom and details on how oblique DRESS slices were placed within phantom to estimate the amount of potential contamination from outside the localized slice .......................... ... ............... 89 9. Photographs of GE's 14.7 M P-31 Phantom from (a) front, (b) back and relative position in magnet ....................... 89 10. Photographs of quadrature phosphorus and square proton coil as (a) a paired set and (b) separated onto individual platforms for 3.0 Tesla ....................................... 90 11. Schematic diagrams of (a) the 25 x 25 cm2 square proton coil set (tuned to 127.75 MHz) used with (b) the 10 cm phosphorus quadrature coil at 3.0 T (tuned to 51.71 MHz) ....... 90 12. Photograph of the single turn, 9.5 cm diameter, phosphorus transceive coil tuned to 51.71 MHz (3.0 Tesla) ................. 91 13. Schematic diagram of the single-turn phosphorus transceive 9.5 cm diameter coil at 3.0 T tuned to 51.71 MHz . ............. 91 14. Comparisons of single-turn versus quadrature P-31 RF coils in terms of relative signal based on 25 mm thick DRESS acquisitions of 14.7 M phantom at 0.5 cm intervals with TG optimized at each position .......... ........................ 92 Xl

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Xll 15. Photograph of the single turn, 9.5 cm diameter, phosphorus transceive coil tuned to 25.87 MHz {1.5 Tesla) with three small vials that are used to locate the coil in the proton images .................................................. 93 16. Schematic diagram of the single-turn phosphorus transceive 10 cm diameter coil at 1.5 T tuned to 25 87 MHz ................ 93 17. Photograph of 1.5 T quadrature P-31 coil ........................ 94 18. Schematic diagram of the quadrature phosphorus transceive 10 cm diameter coil at 1.5 T tuned to 25.87 MHz ................ 94 19. Axial images of gate-able phantom comparing images obtained on 3.0 Tusing a 25 cm square proton surface coil with the image pulse-sequences of (a) spin echo, {b) fast spin echo, (c) gradient echo and (d) fast gradient echo imaging .......... 95 20. The STEAMCSI pulse sequence, GE's version of STEAM for spectroscopy voxel localization ................................ 96 21. The PRESSCSI pulse sequence, GE's version of PRESS for spectroscopy voxel localization ................................ 96 22. Frequency domain of (a) PRESSCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization ....... 97 23. Frequency domain of (a) STEAMCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization ....... 97 24. The ECHOCSI pulse sequence, one of GE's versions of Spin Echo for spectroscopy acquisition ........................ 98 25. Frequency domain of (a) ECHOCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization ....... 98 26. Chemical shift imaging {CSI) voxel sizes versus time of slice plus 2D CSI acquisition on GE Signa Advantage ........... 99 27. The SPINECHO pulse sequence, Spin Echo for spectroscopy one of GE's versions of acquisition. 100 28. Frequency domain of SPINECHO CSI multivoxel localized phosphorus spectroscopy ...................................... 10 O 29. The ISISCSI pulse sequence (as shown for one gradient), GE's versions of ISIS for volume, slice, column or voxel localization .................................................... 101 30. Frequency domain of (a) ISISCSI slice localized phosphorus 31. spectroscopy with (b) diagram demonstrating localization ...... 101 Frequency domain of spectroscopy with ( a) (b) ISISCSI column localized phosphorus diagram demonstrating localization. . . 102 32. Frequency domain of {a) ISISCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization ...... 102

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. Xl.l.l. 33. Visual display example of the acquisition where the total number of acquisitions is 32 performed by (a) the current GE ISISCSI technique, and (b) the modified ISIS technique ..... 103 34. Frequency domain of (a) modified ISISCSI localized voxel sequence for phosphorus (created from eight separate acquisitions, added and subtracted appropriately during post-processing) with (b) diagram demonstrating localization .. 104 35. The FIDCSI pulse sequence without phase encoding gradients turned on, GE's versions of the simple single RF pulse 36. necessary to produce an FID for a spectroscopy acquisition .... 104 Charts comparing transmitter gain localized FIDCSI and (b) relative (a) relative signal obtained by varying (TG) values at various depths for slice at 1.5 Tesla, using the quadrature coil optimized TG value versus depth for the single turn coil .............................................. 105 37. Charts comparing relative signal obtained by varying transmitter gain (TG) values at various depths for slice localized FIDCSI at 3.0 Tesla, using (a) the quadrature coil, or (b) the single turn coil ............................. 106 38. Frequency domain of FIDCSI slice localized phosphorus spectroscopy of (a) gate-able phantom and (b) depth phantom ... 107 39. Multivoxel phosphorus FIDCSI plus CSI of the (a) gate-able phantom (b) depth phantom ..................................... 108 40. Comparison of 1.5 to 3.0 Tesla results of phosphorus FIDCSI plus CSI localized voxel scaled by noise level ................ 109 41. Comparison of 1.5 to 3.0 Tesla results of phosphorus, modified ISISCSI localized voxel (created from eight separate acquisitions, added and subtracted appropriately during post-processing) ....................................... 109 42. 1.5 T, P-31 single turn RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice) moved across the internal phosphoric acid vial in the Slice Profile Phantom ......................................... 110 43. 3.0 T, P-31 single turn RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice) moved across the internal phosphoric acid vial in the Slice Profile Phantom ......................................... 110 44. 3.0 T, P-31 quadrature RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice) moved across the internal phosphoric acid vial in the Slice Profile Phantom ......................................... 111 45. Human cardiac imaging with the spin-echo pulse sequence at (a) 1.5 T with the body coil and at (b) 3.0 T with a surface coil ................................................. 141

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XJ.V 46. Human cardiac imaging with the fast gradient echo pulse sequence at (a) 1.5 T with the body coil and at (b) 3.0 T with a surface coil ............. . ........................... 142 47. Prone positioner for in-magnet cardiac spectroscopy ............ 143 48. A comparison of the heart's position in the (a) prone and (b) supine positions, as shown from a 3.0 T axial slice ....... 144 49. Waveforms of (a) peripheral gating and {b) ECG gating on the 3 0 T from a normal human volunteer (TEB) on Sept 20, 1998, displayed at a rate of 21 mm/sec ............... 144 50. A comparison of peripheral gating (pg) versus ECG gating, and breathing during the image versus breath-hold images ...... 145 51. Human proton voxel localized spectroscopy of the heart and chest wall obtained during one volunteer's shim using the techniques of GE's (a) STEAMCSI and (b) PRESSCSI .......... 146 52. P-31 FIDCSI with CSI of a human subject at 3.0 T ............... 147 53. 54. 55. 56. 57. 58. 59. 60. DRESS localization via oblique slice select combined h . . f wit sensitivity region o coi ............... .............. Examples of 1.5 T cardiac phosphorus spectra localization problems resulting in (a) liver contamination, or (b) skeletal muscle contamination, in comparison with (c) a non-contaminated cardiac spectrum ...................... P-31 FIDCSI oblique slice localized human cardiac spectroscopy (oblique DRESS) of the same subject, at 1.5 and 3.0 T, on different days showning examples of resting and exercise spectra, raw and fitted .............. Series of cardiac region oblique DRESS spectra representing decreased skeletal muscle contamination with increase in depth of spectroscopy slice localization ..... Relative size of oblique DRESS slice with (a) a 10-cm diameter single-turn P-31 surface coil and {b) a 16 x 10 cm2 quadrature P-31 surface coil ............................. Water, hydraulic, hand-squeeze ergometer/static-exerciser, modified from original design by North Coast Medical ......... The linear response of the hydraulic handgrip to added weight on the rubber bulb is illustrated ..................... Dinamap blood pressure and pulse monitoring equipment. 148 149 150 151 152 153 154 154 61. Myocardial pH is proportional to the frequency difference of the Pi and PCr peaks in the human, in-vivo phosphorus NMR spectrum ....................................... 155

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62. xv Relaxation correction factors at 3.0 T for cardiac [PCr)/ [ATP] values based on repetition time (TR) values. 173 63. ECG lead placement for 3.0 T gating ............................ 230 64. Example 3.0 T data set analyzed by FITMASTER. 238 65. Example 3.0 T data set analyzed by Sage_IDL ................... 241 66. Example 3. 0 T data set analyzed by Sage_IDLrr.1 with baseline correction points selected .................................... 241 67. Example 3.0 T data set analyzed by Sage_IDL with baseline correction ....................................................... 242 6 8 Example 3. O T data set processed by MRUI. .................... 244 69. Example 3. 0 T data set analyzed by MRUir M ....................... 245 70. Example 3.0 T data set processed by FELIX ..................... 248 71. Example 3. 0 T data set processed by FELIX with peaks picked ... 249 72 Example 3.0 T data set processed by FELIX with baseline correction .......................... ........................... 250 73. Example 3.0 T data set analyzed by FELIX ...... ........ ....... 250 74. Example 1.5 T data set with low SNR analyzed by SAGE IDL ...... 252 75. Example 1. 5 T data set with low SNR analyzed by FITMASTER ..... 254 76. 77. 1.5 T T i relaxation curve for MDPA (Ti = 3.0 T T1 relaxation curve for MDPA (T1 = 5.53 sec) 6.04 sec) . . . .. . . . 259 259

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Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy HUMAN IN-VIVO CARDIAC PHOSPHORUS NMR SPECTROSCOPY AT 3.0 TESLA By Angela Properzio Bruner August 1999 Chairman: Katherine N. Scott Major Department: Nuclear and Radiological Engineering One of the newest methods with great potential for use in clinical diagnosis of heart disease is human, cardiac, phosphorus NMR spectroscopy (cardiac P-31 MRS). Cardiac P-31 MRS is able to provide quantitative, non-invasive, functional information about the myocardial energy metabolites such as phosphocreatine (PCr), adenosinetriphosphate (ATP) and pH. In addition to the use of cardiac P-31 MRS for other types of cardiac problems, studies have shown that the ratio of (PCr]/(ATP] and pH are sensitive and specific markers of ischemia at the myocardial level. In human studies, typically performed at 1.5 Tesla, (PCr]/[ATP] has been relatively easy to measure but often requires long scan times to provide adequate signal-to-noise (SNR). In addition, pH which relies on identification of inorganic phosphate (Pi), has rarely been obtained. Significant improvement in the quality of cardiac P-31 MRS was achieved through the use of the General Electric SIGNA 3.0 Tesla whole body magnet, improved coil designs and optimized pulse sequences. Phantom and human studies performed with many types of imaging and XV.l.

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XVll spectroscopy sequences identified breathhold gradient-echo imaging and oblique DRESS P-31 spectroscopy as the best compromises among SNR, flexibility and quality of localization. Both single-turn and quadrature 10-cm diameter, P-31 radio frequency coils were tested. The quadrature coil provided greater SNR, but had to be used at a greater depth to avoid skeletal muscle contamination. Gated cardiac P-31 MRS obtained in just 6 to 8 minutes, showed both improved SNR and discernment of Pi allowing for pH measurement. A handgrip, in-magnet exerciser was designed, created and tested at 1.5 and 3.0 Tesla on volunteers and patients. In ischemic patients, this exercise was adequate to cause a repeated drop in [PCr]/[ATP] and pH with approximately eight minutes of isometric exercise at 30% maximum effort. As expected from the literature, this exercise did not cause a drop in [PCr]/[ATP] for reference volunteers.

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CHAPTER 1 INTRODUCTION The statistics placing heart disease as a leading killer are remarkable. Considering all age groups and genders, heart disease is the number one killer, above other common killers such as cancer, accidents, and diabetes.1 Cardiovascular disease kills about 2,500 people each day or more than one million each year in the United States.2 Some form of heart disease affects one in four persons, with the combination of costs from treatment and loss of productivity approaching 50 billion dollars annually.2 One of the most common types of heart disease is myocardial ischemia. In myocardial ischemia, individual cells in affected areas of the myocardium can no longer function due to significant decreases in blood flow to the region, which results in chest pain (angina pectoris). The blood flow reduction is typically due to a gradual blockage in the large and/or small vessels, which substantially increases the risk for acute and total blockage (infarction). Ischemia limited to the small vessels is termed microvascular ischemia or microvascular dysfunction (MVSF). MVSF seldom results in death but is very disabling due to fatigue and anxiety resulting from the chest pain.3 Although patients with chest pain are usually checked for heart disease, asymptomatic patients are also tested based on risk factors such as age, weight, life-style (high fat diet, smoking) and family history. Ischemia is often clinically silent or associated with 1

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2 atypical symptoms. Unfortunately its presence is a significant risk factor for a fatal heart attack. The American Heart Association estimates that as many at 3 to 4 million Americans have silent or asymptomatic ischemic episodes that are eventually diagnosed by testing for reasons unrelated to the symptoms.2 Statement of Problem None of the current clinical methods for diagnosing cardiac ischemia is 100% accurate. This is especially true of the most common cardiac test, measurement of the heart's electrical function via electrocardiogram (ECG). Most especially for women, but also for men, the ECG often does not assist in the diagnosis of cardiac dysfunction.4 In addition, although large vessel ischemia is commonly quantified by the degree of stenosis in the coronary arteries via a coronary angiography (CA) catheterization study, microvascular ischemia cannot be diagnosed with CA because the vessels are too small to resolve. Of all the tests clinically available to diagnose myocardial ischemia, most do not provide a direct quantitative measure of ischemia in the affected myocardial tissue. Most of the tests that look directly at the myocardial tissue are qualitative imaging studies, such as clinical nuclear medicine, ultrasound, computed tomography, and magnetic resonance imaging methods, where information such as wall motion and perfusion defects can be qualitatively determined. However, these evaluations do not provide quantitative information about levels of ischemia, although the technique of MR tagging (now at a research stage only) may be used in the near future to quantify wall motion.

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3 Those tests that do provide quantitative information do so indirectly, rather than as a direct measure of the myocardial tissue, such as the electrical signal measured via ECG or the percent stenosis of the coronary arteries as measured in a CA study. Individually, none of these tests can provide a direct diagnosis of ischemia. In this context, it is common practice to perform multiple tests for added accuracy in diagnosing myocardial ischemia. Spectroscopy's Contribution to Diagnosing Myocardial Ischemia Human, cardiac phosphorus NMR spectroscopy (cardiac P-31 MRS) l.S a non-invasive technique that directly measures pH and the levels of intracellular myocardial phosphocreatine (PCr), adenosine triphosphate (ATP), phosphodiester (PDE), and inorganic phosphate (Pi) 1.n a non-destructive manner. Both the reduction in the ratio of [PCr]/[ATP] and pH have been shown to be sensitive and specific markers of ischemia at the tissue level in animal models5 6 and in humans. 7 8 Cardiac P-31 MRS is an additional tool that can add to the degree of sensitivity and specificity in diagnosis of ischemic heart disease by providing quantitative information as a measure of the myocardial tissue directly, regardless of whether it is caused by macro-or micro-vascular ischemia. Cardiac P-31 MRS is currently in limited use clinically. The reasons for this pertain partially to the degree of difficulty in obtaining cardiac P-31 MRS in a reasonable amount of time and uncontaminated by non-cardiac signal. Useful cardiac P-31 MRS requires obtaining a phosphorus spectrum with good signal-to-noise ratio (SNR),

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4 with the Pi peak discernible in order to measure pH, and without contamination from skeletal muscle or liver. The spectrum must be obtained from the heart, which is moving in a rhythmic motion with the cardiac cycle. In addition, spectral acquisitions are sensitive to B0 homogeneity and generally require more shimming than do images to enhance the SNR. Shimming of a moving, heterogeneous object is more difficult than a stationary one. To compound the difficulties, the anterior region of the heart is only 10 to 18 mm thick and at a depth of 4 to 8 cm from the P-31 surface coil. The distance between the heart and the surface P-31 radio frequency (RF) coil limits the acquisition volume to the anterior wall of the heart because of attenuation of B1 and low SNR. Between the heart and the P-31 surface coil is the chest wall skeletal muscle, below the heart is the liver, and in the cardiac chambers is blood. Care must be taken so that neither the skeletal muscle nor liver will contaminate the spectra obtained from the cardiac muscle. Blood contamination can be corrected for after the acquisition. The result of a cardiac P-31 acquisition is typically a low SNR spectrum with an acquisition time of around 10 to 40 minutes. Because in-magnet exercise and/or drug-induced stress are required for P-31 MRS studies of ischemic heart disease, a scan time of more than 10 minutes is undesirable. Research Hypotheses The following hypotheses will be tested in this dissertation. 1. Human, phosphorus NMR spectroscopy of the heart can be implemented at 3.0 Tesla (T) by overcoming technical problems to produce spectra of higher quality than obtained at 1.5 T.

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5 2. Mild exercise from an isometric, hydraulic handgrip, designed and produced for this study, provides adequate stress on the heart to cause a significant drop in [PCr]/[ATP] in the ischemic myocardium and thus differentiates ischemic from non-ischemic myocardium. Specific Objectives Localized phosphorus spectra will be obtained from both phantoms and the anterior myocardium of human participants. All human participants will be screened for MR incompatibility and will sign an approved Institutional Review Board Informed Consent Form (Appendix A). The optimal pulse sequence for obtaining human, cardiac phosphorus spectroscopy will be determined from phantom and human studies. All spectroscopy pulse sequences available on the General Electric (GE) 3.0 T whole-body magnet will be compared using phantom studies. Measurement of SNR and degree of localization will be made for each pulse sequence. Select pulse sequences will then be tested and compared using human subjects. Human study comparisons will be based on SNR and the degree of contamination of cardiac muscle signal from other sources (skeletal muscle and liver). A 10-cm diameter, single-turn P-31 RF coil will be compared with a 16 x 10-cm, quadrature P-31 RF coil (two, 10-cm diameter RF coils overlapping). Comparisons will be based on quality factors, isolation, SNR at different depths, and degree of signal contamination. Select tests will be performed on both 1.5 and 3.0 T GE Signa Advantage systems to compare the resulting SNR and spectral dispersion obtained using the same pulse sequence, coil, and sample studied

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6 (phantom or human). The human cardiac phosphorus spectra obtained at 3.0 T should show greater SNR and spectral dispersion allowing for the discernment of the Pi peak and thus the measurement of pH. A hydraulic handgrip exerciser, designed and produced for this study, will be tested for adequacy as a cardiac stressor that should cause a drop in [PCr]/[ATP] in ischemic myocardium but not in nonischemic myocardium. The adequacy will be demonstrated by obtaining data on heart rate and blood pressure changes with isometric handgrip exercise of 30% maximum effort. These data will be compared with literature values where similar devices were used during cardiac phosphorus spectroscopy acquisitions as well as compared with the responses to clinical cardiac tests (treadmill and dobutamine) obtained locally. Assumptions This work will build on past knowledge and technology for assessing cardiac metabolites and thus heart function. It will be assumed, in most cases, that data from previous publications are correct, especially at 1.5 T, and this data will be used to help validate the work developed in this dissertation by comparing it with past publications and work on similar patients and procedures performed locally. In order to assess the procedure used to stress the participants in the magnet, both suspected ischemic and non-ischemic subjects will be tested. It will be assumed that these participants will be properly

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7 categorized by risk factor assessment, current symptoms, and when available ECG treadmill and cardiac catheterization results. Scope of the Project This work will be limited to creating a procedure for obtaining human, in-vivo cardiac P-31 NMR spectroscopy optimized for the GE Signa Advantage 3.0 T whole body magnet located in the tunnel between Shands at UF and the Veterans Affairs hospitals in Gainesville, FL. The ability to improve the results of acquisitions on the 3.0 T scanner is limited by the capabilities of the system, such as gradient strength (1 Gauss/cm) and specific absorption rate (SAR) limitations. This work also will not use extensive pulse programming to improve the system performance. Instead, the available sequences on the 3.0 T system will be optimized, most often via the choice of parameters and protocols. When necessary, small pulse programming changes may be performed by Dr. Hee-Won Kim. The numbers of subjects in the studies will be limited but should still be adequate to demonstrate the feasibility and reproducibility of the technique. A true set of controls free of ischemic heart disease would first have to be evaluated by a cardiologist, at a cost that is not available for this project. Taking any willing volunteer would potentially introduce bias into the results as some might have silent ischemia. In addition, a cardiologist will refer all participants identified with ischemic heart disease. This work is intended as a feasibility study where the results could then be used to justify further research.

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8 Significance Human cardiac spectroscopy has been commonly performed at 1. 5 T9 -15 and occasionally at 4 0 T, 16 17 but never before at 3 0 T. With all other factors the same, an increase in magnet field strength will theoretically result in a linear increase in the spectral dispersion and at least a linear increase in the SNR. In addition, the use of a quadrature surface coil is expected to further increase the SNR compared to the simpler single loop surface coil currently used in previously reported human cardiac spectroscopy studies. 18-24 Finally, the use of in-magnet exercise while non-invasively measuring human cardiac phosphorus metabolites has been accomplished by just a few research groups. 132125-28 In-magnet exercise with our technique and device is easy to incorporate and looks very promising for helping to distinguish normal from diseased cardiac muscle, especially in cases of myocardial ischemia. In terms of potential research and clinical use of human cardiac phosphorus spectroscopy, there are many potential future benefits. First, this test may provide increased accuracy of diagnosis of ischemia and microvascular ischemia, for which new treatment modalities may exist. Because cardiac P-31 MRS is a quantitative measure of ischemia at the tissue level, it could be used to monitor or follow-up treatment regimes or to help develop new treatments for ischemic heart disease. In addition, a noninvasive MR diagnostic test of ischemia may eliminate unnecessary invasive cardiac catheterization procedures, reducing both risk of medical complications and cost. Based on data from the Health Care Finance Administration, National Physician Fee

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9 Schedule Relative Value File,29 a cardiac catheterization study costs four times as much as a cardiac MR exam.

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CHAPTER 2 REVIEW OF LITERATURE Magnetic resonance (MR) is a technique for using the interactions of atoms and molecules with external magnetic fields to extract image and chemical data from a sample. Using the classical description, the proton possesses a spin angular momentum, S and a gyromagnetic ratio, I y, where the product is the magnetic dipole moment, -ys Equation 1 Hydrogen and nuclei with either an odd number of protons (such as phosphorus-31 with 15 protons and 16 neutrons) or an odd number of neutrons possess magnetic moments whereas even-even nuclei have zero magnetic moment. NMR takes advantage of the spin magnetic moment to obtain a signal from these nuclei, especially if they are already somewhat plentiful in the human body like proton (H-1) and phosphorus (P-31) Placing a bulk of material, having nuclei with spin magnetic moments, into a strong and uniform external magnetic field (Bo) causes the nuclei's magnetic moment to attempt to align with the applied magnetic field. This results in the spin precessing around the magnetic field analogous to a spinning top.30 The precession of the nuclei in response to an applied magnetic field proceeds at a known frequency described by the Larmor equation: 10

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11 Equation 2 where @0 is the rate of precession in radians per second, and B0 is the main magnetic field. The application of radio frequency energy at the Larmor frequency for a nucleus constitutes a condition of resonance, hence explaining the terms of Nuclear Magnetic Resonance or NMR. In practice, the distribution of electrons about any given nucleus provides some shielding of the nucleus from the Bo field. Since the distribution of electrons is a function of the molecular structure in which the atoms (and their nuclei) are located, the actual field experienced by the nucleus differs from the Bo field by some small amount.30 Equation 2 can be modified to include the shielding constant for chemical shift, cr, for a nucleus i n a specific molecular environment 30 : Equation 3 A basic NMR experiment consists of placing a sample in a constant external magnetic field (Bo) where the nuclei's magnetic moment attempts to align with Bo, also called the equilibrium condition. After applying an oscillating radio-frequency (B1 ) identical to the precession frequency of the nucleus of interest (the Larmor frequency), the nuclei absorb energy and tip away from their alignment with the external magnetic field. This displacement with the B1 field causes the individual spins to coalesce, creating a combined magnetic moment in the transverse plane. Once the B1 field is removed, the magnetic moment rotates at the Larmor frequency, slowly losing phase coherence due to

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12 magnetic field variations affecting the individual spins.31 A signal is induced in a receiver RF coil (either the same or different from the RF transmitting coil) by the rotating magnetic moment in the transverse plane. This produces a damped sinusoidally varying signal of positive and negative polarity at the Larmer frequency, known as the free induction decay (FID). Only when the net magnetic moment in the transverse plane is nonzero, and the spins are in phase coherence will a signal be generated.31 The MR technique is both non-invasive and sensitive to the molecular environments of the atoms. These factors have led to the use of M R in several areas, primarily for imaging and spectroscopy. In MR imaging (MRI) the signals from fat and water hydrogen atoms are mapped according to their location and their characteristics. The second area of use, MR spectroscopy (MRS), is a technique that was first used in chemistry and physics laboratories in the analysis and identification of chemical compounds.32 Biologically, MRS has also been used in the identification and analysis of protein and macromolecular structures and conformation using high resolution NMR.33 Another biological use of MRS has been the examination of cell samples or organs, ex vivo.34 The most clinically relevant use of MRS, however, is in vivo where the patient's tissue metabolites can be examined directly and noninvasively using techniques to localize to the region of interest within the body. The two main isotopes that are most studied in human, in-vivo spectroscopy are proton (H-1) and phosphorus (P-31) because of their natural abundance, relative sensitivity and chemical significance within the body. H-1 MRS is the most commonly performed clinical MRS

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13 patient examination because it can be done using standard MRI equipment and software available on most clinical systems. It has been shown to be useful in measuring markers of a variety of brain abnormalities such as stroke,35 tumors36 and epilepsy,37 through the relative increase or decrease of the metabolites (such as NAA, choline, and creatine). P-31 has a larger chemical shift range (-30 ppm) than H-1 (-10 ppm) and a much lower sensitivity, as shown in Table 1 Water suppression is not necessary in P-31 MRS, but lower spatial resolution and/or increased scan times are required to obtain the same signal to noise (SNR) as with H-1 MRS. P-31 MRS can detect a number of metabolites involved in cellular energy metabolism, such as phosphocreatine (PCr), adenosinetriphosphate (ATP) and inorganic phosphate (Pi). The chemical shift of the Pi peak is pH dependent. In addition, relative peak areas of PCr, Pi and ATP peaks have been used to evaluate fatigue and/or ischemia in muscle, as will later be discussed in this chapter. Table 1. Nuclear Spin Parameters38 % Natural Isotope Abundance H-1 99.985 P-31 100 Gyromagnetic Ratio (MHz/ T) 42.58 17.25 Resonance Frequency at 1.5 T 63.86 25.88 Resonance Frequency at 3.0 T 127.74 51.75 Relative Sensitivity 100 6.6518 P-31 Spectroscopy Pulse Sequence Options for the Heart A variety of pulse sequences have been employed to localize to the myocardium when performing in-vivo cardiac spectroscopy. The most basic pulse sequence, a square excitation pulse, uses no gradients and thus performs no localization, but instead takes in all signal within

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14 the sensitive volume of the coil. This sensitive volume is generally defined, for a surface coil, as the volume of a sphere of one coil diameter.39 Such unlocalized acquisition methods have been used with animal studies where open chest experiments allow for small surface coils to be placed directly on the heart. 4 0 '41 This uses the surface coil as a localizer. For human studies, where we prefer to work noninvasively, a combination of coil and pulse sequence localization techniques have been used. This presents a technical challenge to optimize a localization technique for obtaining spectra from a moving heart, at a depth into the body, without adding signal from the chest skeletal muscle that lies between the coil and the heart. Slice Localization Techniques Slice selection is accomplished in MR by simultaneously turning on a slice-selective RF pulse and a gradient along the direction of the slice. The gradient is on for just a few milliseconds. The RF pulse designed for slice selection has a time-varying shape in the form of a sin t/t or "sine" function, 4 2 -44 which is used for both spectroscopy and imaging. The RF pulse is generated at the resonance frequency of the nuclei of interest. With the gradient on, this allows the sine RF pulse to excite just those frequencies in a narrow bandwidth to either side of the center resonance frequency. A sine pulse can produce a sharp cutoff of frequencies thus exciting just within a slice region. The thickness of the excitation slice is related to the bandwidth of the RF pulse and the gradient strength. For example, the steeper the gradient or the narrower the RF pulse bandwidth (the longer the RF

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15 pulse) the thinner the selected slice. In terms of spectroscopy acquisitions, the shorter the RF transmit pulse the larger the range of frequencies acquired. Slice localized pulse sequences, such as DRESS (Depth Resolved Surface Coil Spectroscopy) 1 45 SLIT-DRESS (SLice INterleaved DRESS) 1 4647 Rotating Frame MR, 48 FROGS (Fast Rotating Gradient Spectroscopy), 41 and lD-CSI (chemical shift imaging) ,49 allow for acquisition of signal from a slice at a depth parallel to the coil. DRESS for cardiac studies involves acquiring from a coronal or oblique slice through the cardiac muscle at a depth from the chest, thus avoiding contamination from the skeletal muscle directly under the surface coil. Sometimes it requires outer volume suppression to avoid contamination of the signal from the adjacent skeletal muscle at the sides of the body. Most studies have not used outer volume suppression, but relied on reduced regions of coil sensitivity to prevent contamination from the sides of the body. Because it is simple and not extremely motion sensitive,50 DRESS has been widely used for obtaining spectroscopy slice profiles of human cardiac muscle. 12,13,19,27,45,51 -s6 Multi-Voxel Localization Techniques The spectrum of the cardiac muscle is easily contaminated by the surrounding skeletal muscle and blood, therefore localization and suppression of unwanted signal outside the volume of interest is important and accomplished with single-or multi-voxel localization techniques. Multiple voxel acquisition via chemical shift imaging (CSI) involves the use of the gradients to split up the selected slice or slices into a number of smaller voxel areas. Spatial localization

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16 is done by phase encoding gradients in one (lD-CSI), two (2D-CSI) or three dimensions (3D-CSI) .38 There are no gradients on, however, during signal acquisition. The advantage of CSI is that multiple voxels are sampled as part of the same acquisition protocol. However, this is accomplished at the cost of increased scan time for the phase encoding for each axis. CSI is generally utilized to further partition a volume already selected by another pulse sequence. There are a number of technical problems associated with acquiring spectra with CSI. One problem is achieving a good shim over a large region of interest and possible changes in magnetic susceptibility encompassing the multivoxel acquisition volume. In addition, the point-spread function from the spatial Fourier transform reconstruction implies that any given voxel in the multivoxel acquisition contains contributions from neighboring voxels.38 This leads to lesser ability to prevent contamination outside the voxel of interest, such as the skeletal muscle contaminating the cardiac muscle. In addition, depending on the size of the voxel of interest and size of the field of view, the time of the acquisition can be dramatically increased beyond the reasonable limit for performing inmagnet exercise during the study. This is primarily due to the increased time necessary for the CSI phase encoding steps. For example, the total measurement time for a 3D CSI acquisition is given by Time (seconds) TR Nacq Nx Ny Nz Equation 4

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17 where TR is the repetition time, Nacq is the number of acquisitions, and Nx Ny and Nz are the number of phase encoding steps in the x, y and z directions. 38 Despite these faults with CSI, a number of studies of cardiac phosphorus spectroscopy have utilized lD, 112327576 4 2D, 1065-70 and 3D CSI, 64 7o-75 and techniques similar to CSI such as 3D fourier series window.76 Among these studies, some were performed on animals alone,62697374 but the majority were performed on humans. Single Voxel Localization Techniques Single voxel localization techniques rely on the pulse sequence to obtain a localized voxel of data, selected from within a larger volume. This protocol of obtaining a single voxel of data per acquisition typically takes less time than the CSI multivoxel approach because of the added phase encoding steps needed for CSI. Single voxel acquisition pulse sequences that have been reported include PRESS (Point Resolved Spectroscopy Sequence) ,77 PROGRESS (a version of PRESS) 78 STEAM (Stimulated Echo Acquisition Mode) 79 ISIS (Image Selective In-Vivo Spectroscopy), 1 5 1780-83 and modified ISIS pulse sequences such as CRISIS (combination of ISIS and DRESS with x-and zselective 180 pulses followed by a 90 y-slice selection pulse; which eliminates y-direction motion artifacts and benefits from reduced cycle time) 84 FLAX-ISIS, 41 and 2D ISIS plus Outer Volume Suppression (OVS) 85 With PRESS and STEAM, three slice selective RF pulses are used to select three intersecting orthogonal planes. Only spins in the voxel defined by the intersection of the three planes experience the three RF pulses and contribute to the final signal. Both STEAM and PRESS

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18 acquire a voxel with each acquisition (also called single-shot localization) ,86 thus being less motion sensitive than techniques requiring multiple acquisitions to localize. STEAM uses a 90 RF pulse for all three excitations thus creating a stimulated echo, as shown in Figure 1. PRESS creates a double echo by using a 90 and two 180 RF pulses, as shown in Figure 2. 3886 Echo time (TE) for STEAM is designated as twice the time between the first and second RF pulse. PRESS has two echo times, TEl and TE2, where TEl is equal to twice the time between the first (90 ) and second (180 ) pulses and the total time to produce the first signal echo.38 TE2 is twice the time from the first echo to the second 180 RF pulse and the full time between the first and second signal echo. In general, each TE for both STEAM and PRESS must be relatively short to successfully acquire phosphorus spectra, so that the signal losses due to transverse relaxation (T2 ) are small. PRESS offers the advantage of having twice the SNR of STEAM, but cannot be run with short TE's,86 while STEAM can handle some shorter TE's down to the system limit. PRESS and STEAM differ primarily in the nature of the echo signal created. PRESS forms the echo from 180 RF refocusing of the net magnetization, whereas in STEAM, only part of the available signal is used to form the stimulated echo via the use of 90 RF pulses. This theoretically results in a factor of 2 increase in SNR for PRESS over STEAM. Experimentally, the factor of 2 increase in SNR has also been documented. 8687 Both PRESS and STEAM have occasionally been accomplished successfully at the phosphorus frequency, but never on the heart. STEAM has been shown to work on a phantom (400 mmolar solution of

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19 Na5Pj 010 in H20) at 1. 5 T using a TE of 3. 1 msec88 and on human brain at 2.0 Tusing a TE of 3.0 msec.89 PRESS has also been used to obtain phosphorus spectroscopy of a newborn human brain at 2.4 Tusing a TE of 10 msec.90 Note that in each of these cases, the TE was set at a minimum value. Neither PRESS nor STEAM are well suited for phosphorus MR spectroscopy due to reasons related to the characteristically short T2 times of phosphorus metabolites, but STEAM does work marginally better than PRESS. 4 1 '77 The echo times achievable with PRESS are too long for the acquisition of signals from nuclei with short T2 relaxation times.91 In contrast, STEAM'S shorter TE values reduce signal loss from T2 relaxation and allow some observation of short T2 metabolites, such as P-31 metabolites. 3 8 ISIS allows for volume, slice, column or voxel selection based on one, two, four or eight acquisitions.92 Zero to three selectiveinversion pulses in the presence of gradients precedes each acquisition exciting different areas within the volume. A combination of areas, added and subtracted, results in the localization achieved with ISIS as shown in Figure 3. 7 93 ISIS has proved to be one of the best voxel localization techniques for P-31 spectroscopy. Unlike PRESS and STEAM, ISIS is not sensitive to the T2 values of the acquired resonances but is sensitive to the T1 values, as part of the time delay between the selective excitation and signal acquisition.92 Most P-31 biological T1 values are on the order of a few seconds, therefore obtaining in vivo ISIS spectra from living tissue should not be a problem in terms of relaxation times. 92 Also, for any localized spectroscopy pulse sequence, when long repetition times are used to allow for T1 relaxation, there is no T1 error in terms of signal cancellation. ISIS

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20 may require eight separate acquisitions in order to localize to a voxel, but the final SNR is still equivalent to an acquisition taken with eight acquisitions (i.e. no signal is lost due to localization). This is also true for CSI acquisitions. ISIS is also flexible in that fewer than eight acquisitions can be used to obtain a volume (1 acquisition), a slice (2 acquisitions), a column (4 acquisitions), or a voxel (8 acquisitions) ISIS uses an adiabatic RF pulse that allows for uniform excitation of signals over a larger volume of the sample. 94-96 The adiabatic pulse, a modification of the sine pulse, was specially designed for use with surface coils where uniform excitation is difficult to obtain. 94 The adiabatic pulse is frequency selective and B1 insensitive, and can achieve uniform excitation in an area of B1 field inhomogeneities. The adiabatic pulse is designed using frequency modulation to satisfy two constraints. First, the RF pulse is designed to cause negligible decay of the transverse magnetization during the pulse. Second, the rate of change of the net magnetization orientation is considerably slower than its rate of precession.38 In addition, adiabatic pulses are different from sine or square RF pulses in that they are designed to excite maximally at a high gain and remain maximal even when the gain is further increased. 951 96 Sine or square RF waves excite an area based on the gain of the signal with an optimal signal peaking at some point between low and high levels of gain. Unfortunately, the ISIS adiabatic pulse require a greater power than sine or square pulses, therefore it is important to have a quality amplifier designed for the higher requirements. Since power

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21 requirements increase with field strength, special consideration needs to be made to provide enough power for ISIS while still remaining within the safety guidelines. Specifically, the Food and Drug Administration (FDA) has limited the specific absorption rate (SAR) of the RF power to a maximum of 8 Watts/kg in the head or torso for any period of 5 minutes.97 This applies to all pulse sequences and all field strengths used on human subjects. ISIS is prone to many possible causes of signal contamination.93 As ISIS selects outside the volume of interest and attempts to subtract this signal, only partial cancellation of the unwanted signal is achieved. 93 This effect is greater when the volume of interest (VOI) much smaller than the complete volume detected by the coil. Since signal is detected from a large volume after each acquisition, the receiver gain cannot be optimized for the smaller VOI.98 In addition, 1.S the adiabatic pulse does not acquire equally all the chemically shifted resonance's at the acquired frequency. 93 Finally, T1 smearing93 caused by residual magnetization left from the observation pulse from the previous acquisition, also results in less than total subtraction of unwanted signal outside the ISIS selected volume of interest.93 ISIS is also motion sensitive due to its volume subtraction method of localization involving eight separate acquisitions to obtain the spectrum from one voxel. 93 In addition, ISIS is affected by spatial displacement of chemically shifted species in the slice selection at high field at the P-31 frequency. 99 The issues of contamination with ISIS have been tested in a computer simulation and published.93 Despite its faults, only ISIS and ISIS derived pulse sequences are useful as single-voxel localization

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22 pulse sequence techniques for P-31 MRS. A number of cardiac spectroscopy studies have been done using ISIS or ISIS derived pulse sequences .14115117232880-s2 ,100-117 All except one115 of this list of studies was performed on humans. Cardiac P -31 Spectroscopy Results in the Literature Animal studies Animal studies have been essential for predicting potential areas for human use. A majority of cardiac spectroscopy animal studies have been done with the animal's chest open, thus allowing the surface coil to be placed directly on the heart, 40'41 via a catheter coil inside the heart,118 or by excising the heart and maintaining it artificially in an isolated heart perfusion study5 119-122 There have also been closedchested animal experiments67'123'124 that more closely match what would happen if the same test were performed on humans. The promise of the open-chested experiments is that a great deal of information from the heart via spectroscopy can be obtained when SNR is maximized. Unfortunately, outstanding SNR is generally only achieved when the RF receive coil is placed directly on the heart, allowing for unlocalized acquisitions. The open-chested in situ mode can also take advantage of the increased SNR and use localization acquisition methods, such as 2D ISIS, lD spectroscopic imaging (SI), or FLAX-ISIS, to obtain spectroscopic information about discrete layers of the myocardium, subendocardium and sub-epicardium individually. 41 125,126 Animal hearts can be stressed to a much greater degree while under anesthesia127 than we would ethically stress a human volunteer.

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23 Although most human studies of normal myocardium have shown no change in the phosphorus metabolites with the stress levels that do produce changes in ischemic hearts, normal animal hearts have often been stressed beyond what can be done in humans to the point where a change in the phosphorus metabolites can be induced. Care must be taken, therefore, when making extrapolation to humans based on these animal studies, because often the heart is damaged by the level of stress or by the deliberate infarction. 124128 Animal studies allow for tighter control of the disease state and measurement than can be ethically accomplished in humans and therefore reveal the potential for P-31 MRS to provide feedback of specific cardiac disease states. Studies of permanent coronary occlusion in dogs with open chest, measured up to 6 hours after occlusion128 and up to 5 days after occlusion124 show that residual Pi remains in the region of the infarction for a period of days although tissue pH returns to normal within a day.7 Human cerebral infarction measured by phosphorus MRS has shown similar behavior. 7 '129 A study on open-chested dogs showed that phosphorus spectroscopy could differentiate between viable and non-viable myocardium from 6 to 54 hours after an ischemic insult based on measurements of PCr and [Pi]/ [PCr] 130 Another animal study of assayed myocardium after coronary occlusion or low-flow ischemia showed a depletion of PCr and ATP with irreversible injury.131 Animal studies have shown reduced phosphorus metabolites in cases of hereditary cardiomyopathy, 132 133 cardiomyopathy from chronic chemical exposure, 134135 dietary deficiencies, 136 and diabetes137. In another animal study, PCr was shown to be preserved until the blood flow was reduced to about 50% of that in an originally healthy heart.138 This is another example of

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24 the type of understanding that can be achieved with animal studies but would be unethical for human studies. Specifically, both a decrease in the [PCr]/[ATP] ratio and a downfield shift of the inorganic phosphate resonance due to acidosis have been measured occurring with the onset of ischemia.5 6 In cases with mild reductions in blood flow (approximately 17%), only the Pi and pH changed significantly when compared to a control group. When the blood flow reduction was more substantial (on the order of 50% or more), the [PCr]/[ATP] ratio was also shown to decrease while ECG monitoring was also abnormal (reduction in segment shortening) .139 1 4 0 Human Studies Nuclear medicine thallium scans clinically show a reversible thallium defect where the area fills with thallium during rest but does not during stress indicating an area of ischemia. If the defect is not reversible, meaning the area doesn't fill with thallium during rest or stress, then the area is infarcted. P-31 exercise tests on subjects with severe CAD and/or reversible thallium defects showed a significant decrease in the [PCr] / [ATP] ratio. 12'49 Although a change in the [PCr]/[ATP] ratio is seen in the ischemic heart with stress, tests on normal controls and patients with non-coronary cardiomyopathy show no significant change with exercise. In patients with stenosis of the macrovessels, a drop in the [PCrJ/[ATP] ratio is no longer present after revascularization.49 These findings prove that in the absence of blood flow reduction or scar to an area of the myocardium, the metabolite energy values will remain constant. These studies showed a

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25 direct correlation between ischemia and a decrease in [PCr]/[ATP] and pH with stress as measured via phosphorus NMR spectroscopy. A number of research groups from a variety of locations around the world have been utilizing human, in-vivo cardiac NMR P-31 spectroscopy. Assorted magnet systems, coils and techniques have been employed. In addition, a wide number of patient types have been studied. Even through there is a wide variation in heart problems studied, some trends in the type of techniques and RF coils used have started to appear that may prove diagnostically and clinically feasible. In the least, P-31 MRS should provide information that scientists and physicians can utilize to better u .nderstand the workings of the human heart under all types of disease conditions. A condensed summary of all the research locations that have conducted in-vivo cardiac phosphorus NMR spectroscopy acquisitions of the human heart are listed in Table 2 This table is given in an effort to simultaneously demonstrate how much and how little work has been done since the late 1980s. Since each type of cardiac problem will have its own trends and results in terms of cardiac P-31 MRS, research on each of the main types of heart disease has also been detailed in the remainder of this chapter.

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26 Table 2. Research Published on Human, In-Vivo Cardiac P-31 NMR Spectroscopy of Studies on Normal-Controls or Patients and Related Work. Location Erlangen, Werzberg, Tubingen, Germany Otsu, Mie, Toyko, Tsukuba, Japan Baltimore, Maryland, Schenectady, New York Oxford, England San Francisco, California Leiden, Netherlands Birmingham, Alabama Major Players Neubauer Loeffler Sieverding Siemens Mi tsunami Okada Yabe Sakuma Bottomley Weiss Hardy GE Rajogopalan Conway Radda Blackledge Matson Schaefer Aufferman Lamb de Roos den Hollander Philips Evanochko Hetherington den Hollander Buchthal Pohost Magnet Tesla 1.5 T Philips 1.5 T Siemens 1. 5 T GE P -31 Method ISIS CSI CSI/SLOOP DRESS CSI 1. 5 T DRESS GE CSI 2. 0 T PMRFI Bruker CSI DANTE 1. 5 T ISIS 2. 0 T CSI Philips 1.5 T CSI Philips ISIS 1 5 T Philips 4.1 T ISIS P-31 Coils 10-lScm diam R/T 5-15cm diam R/T, 20cm T + 12cm R 40cm T + 7cm R, 7cm diam R/T 5-6.5 cm diam R/T, 15cm T + 7cm R 9-14cm diam R/T 10-14cm diam R/T 10-14cm diam R/T Minneapolis Minnesota Menon Ugurbil 4.0 T CSI Siemens ISIS 11cm diam R/T Philadelphia Whitman Pennsylvania Durham, Herfkens North Carolina Paulo, Brazil Gainesville, Florida Kalik-Filbo Bruner Scott, Kim 1.9 T Coil 5cm diam Oxford localized R/T 1.5 T CSI 6cm diam 1. 5 T ISIS Philips 1. ST GE Oblique 3 OT GE DRESS R/T Not Listed 10cm diam, Quadrature References 117 141 142 82 14 71 105 68 100 143 111 109 65 104 10 144 113 145 18 146 56 55 147 148 52 54 13 51 12 27 60 53 19 9 149 70 63 67 49 11 150 151 152 153 154 20 48 155 25 156 157 57 58 158 159 59 21 160 83 15 161 64 162 163 116 164 108 165 28 22 166 167 112 114 168 103 106 169 81 102 170 171 80 28 16 23 17 76 172 24 173 174 175

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27 P-31 Spectroscopy Acquisition Techniques. In terms of techniques for acquiring human, in vivo, cardiac P-31 MRS, there is a trend that emerges. For those locations with clinical Philips systems, the most common technique used is ISIS followed by CSI. For clinical GE sites, the most common technique is DRESS followed by CSI. The two Siemens sites conducting human, in-vivo P-31 MRS primarily utilize CSI .144176 This chapter summarizes the results from studies of various types of cardiac diseases. When available, the acquisition times are listed in Table 3 through Table 7. Notice that DRESS12149 and 1D-CSI4 9 163 are the shortest duration sequences, generally being under 10 minutes, although running them for longer further increases SNR. ISIS typically is run for slightly longer periods of time at around 20 minutes, 82103165173 although it can be run the same amount of time as DRESS at around 10 minutes167. Two dimensional and 3D-CSI are the longest duration,144 with some scans lasting an hour for just a single P-31 acquisi tion101. A few truly unique techniques for obtaining human cardiac P-31 MRS, SLOOP and PMRFI, are utilized only at their originating locations. Spectral localization with optimal pointspread function or SLOOP was created and used by a group in Germany, utilizing a Siemens 1.5 T system. 1868 141 143 146 The SLOOP technique is a combination of a 3D-CSI acquisition with sophisticated post-processing that uses anatomical information from the proton image to group the spectra by tissue type. Anatomical compartments, such as for cardiac muscle, skeletal muscle, and liver are defined with the proton image. The overlaying P -31 spectral data is then separated into each of these compartments. The papers that have been published from this group using SLOOP seem

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28 outstanding as they achieve cardiac spectra with greater SNR, due to the larger volume they can utilize to obtain the signal. In addition, they seem to have solved the problems with contamination. Unfortunately, until the technique is tried and evaluated at other locations, judgment on the true accuracy of the method cannot be fully established. Phase modulated rotating frame-depth imaging selection technique or PMRFI is a technique used for cardiac P-31 MRS solely at Oxford, England. 4857 sa,iss PMRFI allows for a 2D-spectroscopy signal to be collected from the sample within the sensitivity of the coil via a set of free induction decays. The data is collected from a volume formed by a stack of disc shaped slices at various depths into the chest with the entire data set taking approximately 35 minutes to acquire.4 8 The PMRFI technique claims to produce high-resolution, high SNR spectral images with limited spatial distortion.48 In addition, at Oxford, they have also utilized DANTE for cardiac P-31 MRS of human volunteers.159 DANTE allows for the selective excitation/suppression of individual peaks in the frequency domain in this case used to distinguish the intracellular and extracellular Pi. This group also utilized an initial saturation pulse to eliminate any contamination from skeletal muscle.159 Many of these types of unique pulse sequences were originally developed on research magnets for animal studies and then recently extended to human use on a Bruker research magnet system. This may be the reason why these techniques have not been published for use on clinical l.S T systems, such as from GE, Philips or Siemens. Users often have the ability to pulse program

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29 clinical systems, but with less flexibility and ease in programming options. P-31 Radio Frequency Coils. Surface coils have been used for all human cardiac spectroscopy studies to date. The reasons are simple. Compared to a volume coil that would need to encompass the chest, surface coils provide a much greater signal-to-noise ratio (SNR) than the volume coil. The simplest surface coil, a single loop of wire, provides a means of obtaining spectra from a volume of tissue adjacent to the coil.41 The sensitivity of the surface coil is greatest for the tissue closest to the coil, with sensitivity decreasing rapidly with depth.41 This sensitivity range extends approximately one radius away from the center of the surface coil,98 with the majority of the signal obtained from a disc-shaped region at the plane of the coil and decreasing in size with depth.41 Typically, the result is relatively good SNR from the anterior wall of the heart, but not enough depth penetration to cover the entire heart. Surface coils can be adapted to a variety of specific tasks by changing the size and shape of the coil. Surface coils are commonly used in both MRI and MRS as receivers because of their high sensitivity, providing good SNR. In spectroscopy, especially with nuclei other than H-1, surface coils are frequently used both as RF transmitters and receivers.38 Their applications evolved from small animal P-31 spectroscopy studies177 to spectroscopy investigations of muscle and superficial organs in humans.38 Unfortunately, surface coils suffer from non-uniform RF excitation and inadequate spatial localization when used without a localized pulse sequence. The sensitivity of the surface coil to a point in the sample is proportional to the B1 field achieved by the c oil

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30 at that point, with the most signal received from sample points closest to the coil. 41' 178 Fortunately, pulse sequences designed for localization, utilizing selective RF pulses or gradients such as ISIS179 180 and CSI, 181-183 or multiple RF pulses1 8 4 can localize spectra to regions where the B1 field is relatively constant such as in a localized voxel volume.178 For example, the ISIS pulse sequence uses an adiabatic excitation pulse that with enough power is specifically designed to excite spins in a manner that is independent of the B1 field for more uniform excitation.41 Such a pulse has been shown to improve the localization abilities when used with a surface coil.94 In addition, there is the option of using a larger transmit coil to provide better homogeneity of the B1 field, with a smaller receive coil for optimal SNR. The B1 inhomogeneity inherent with using a surface coil can degrade the performance of the RF pulses resulting in an incorrect tipping angle, decreasing signal from the volume of interest (VOI), and potentially increasing signal contamination from regions outside the VOI. 15,93, 18 Contamination is most probable from the tissue closest to the coil since such tissue will have the highest degree of sensitivity by the coil.93 In the case of cardiac spectroscopy, the skeletal muscle has a large potential to contaminate the cardiac muscle signal in this manner. Larger coils provide higher homogeneity at the expense of reduced sensitivity to small, shallow VOI' s. 931185 This compromise between increased-size resulting in increased homogeneity versus decreased-size resulting in increasing sensitivity has led to many different sizes of transceive and a few combinations of transmit and receive coils being built.

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31 A trend that appears when looking at Table 2 involves the design of the P-31 coils. The greater majority (over 95%) of human, in-vivo, cardiac P-31 MRS patient studies are conducted using a simple single turn P-31 coil of 5 to 15 cm diameter to act as a transceive radio frequency (RF) coil. Beyond this, the next largest minority uses a larger transmit (15 to 40 cm) to excite and a smaller 6.5 or 7 cm diameter coil to receive. The purpose of a larger RF transmit coil used with a smaller receive coil is to improve the homogeneity and still have a small spatial sensi ti vi ty. 7 The two coils can be arranged coplanar186 or slightly displaced.4 5 The sensitive volume is determined by the overlap region of the two coils.7 Unfortunately, there are more drawbacks to using separate transmit and receive coil for localized phosphorus spectroscopy. The complexity of the setup creates difficulties when trying to control accurately the position and thickness of a plane or volume of a voxel. Multiple acquisitions are required in order to localize the signal.7 This is due to the fact that the placement of the RF coil is critical within a few centimeters over a prime spot anterior to the heart. Often, the placement is not correct the first time and/or the pulse sequence localization position and/or transmitter gain must be modified for better localization to the cardiac muscle. There are also designs in the literature for quadrature coils and array designs for human P-31 cardiac spectroscopy with a theoretical Ji. improvement in SNR, but there is no known literature on such coils being used with patient studies to date. Phased array and quadrature coils offer the advantage of a larger sensitive coil region without increased acquisition time or a decrease in SNR.152187 Quadrature and

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32 phased array coils have been used more extensively in imaging than spectroscopy modes of human in-vivo data acquisitions. Several experimental designs have been considered for cardiac imaging and spectroscopy including (1} a 4-coil, diamond shaped design by Hardy et al.,152 (2} two pairs of surface coils placed on the chest and back, surrounding the heart by Constantinides et al.,188 (3) a single pair of coils designed for p lacement on the chest, 189 190 and ( 4} a double-tuned quadrature surface coil by Menon et al.76 There has also been a theoretical study performed to determine the optimum configuration of 2 to 10 circular coils combined in a phased array system designed for cardiac imaging.190 This paper argued that theoretically the best results would be obtained from a 4 coil array, producing 560% signal improvement relative to a whole body coil and up to 360% improvement over some commercial cardiac imaging coils. 190 Cardiac RF surface coils are placed on the front of the chest, over the heart. Coil placement is critical for optimum signal from the intended volume of interest. Incorrect coil placement can result in decreased signal from the desired VOI.7 This is especially true of small (5 to 10 cm diameter), transce1.ve, single-turn surface coils. Incorrect coil placement can also increase contamination from areas outside the VOI.7 The problem with positioning can be theoretically minimized by using a phased array or quadrature coil that will cover a larger area with the improved SNR up to square root of two. 71 152 191 Patient Studies. In a normal, disease-free heart, a phosphorus spectrum will show a consistent level of each of the phosphorus metabolites25'49' 157' 163 of phosphomonoester (PME}, inorganic phosphate (Pi), phosphodiester (PDE), phosphocreatine (PCr), and the three

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33 adenosine triphosphate peaks (y, a, P-ATP). Conversely, in patients and animals with myocardial infarction or myocardial ischemia, in vivo phosphorus cardiac spectroscopy will demonstrate either a reduction in the overall amounts of each metabolite1921193 or a change from the normal ratios of one metabolite to another12149601124'194 Such a measurement has the potential to differentiate a healthy heart from one with myocardial infarction or ischemia. In addition, some cardiac diseases, such as cardiomyopathy or hypertrophy, both involving thickness changes of the heart wall, are easier to diagnose with cardiac images. Even these types of heart problems can potentially benefit diagnostically from the added feedback of the chemical information provided by P-31 MRS. Patient studies have proven over and over again that P-31 spectroscopy is a sensitive marker for clinical cardiac disease states. 82'149 A quick overview will be presented here to prove how solid the P-31 spectroscopy measurement has been shown to be. As part of a study on patients with severe stenosis of the left anterior descending coronary artery (greater than 70% blockage), the [PCr]/[ATP] ratio decreased significantly with exercise.4 9 A group of normal controls and patients with non-ischemic heart disease showed no significant change in the [PCr]/[ATP] ratio when they underwent the same stress as part of the same study. A repeat P-31 NMR spectroscopy measurement was made of five of the patients with severe stenosis of the left anterior descending coronary artery after revascularization. In all five cases, a significant improvement in the [PCr]/[ATP] measurement was seen in terms of a smaller decrease in [PCr]/[ATP] during in-magnet stress. In a similar study by Yabe et al.,12 P-31 NMR spectroscopy with in-magnet exercise was performed on patients with ischemia, patients with

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34 blockages (infarction), and normal controls. The patients were first categorized based on results from radionuclide testing with thallium-201. Those patients with reversible thallium defects (ischemia), showed a reduction in [PCr]/[ATP] during in-magnet handgrip exercise, that normalized during rest. Those patients with irreversible thallium defects (infarction or dead myocardial tissue) and normal controls showed no change in the [PCr]/[ATP] ratios with exercise. It is believed that the [PCr]/[ATP] ratio does not change in cases of pure infarction because the affected tissue is completely dead while the remaining tissue is essentially sound. Therefore, the resulting signal is less overall due to a lesser amount of viable tissue, but the ratio remains the same. It is theorized that more complex techniques that would measure the absolute quantity of the metabolite levels would be able to differentiate even myocardial infarction as the overall amounts would be lower, assuming measurement of a known volume of cardiac muscle. Healthy Volunteers. Multiple studies have confirmed that for healthy volunteers free of substantial coronary artery disease, inmagnet exercise stress tests with non-drug stimuli have not produced a significant change in the anterior myocardial [PCr]/[ATP] ratio.12254954157163 Such results are shown in Table 3 where both leg and handgrip exercises show no drop in [PCr]/(ATP] with normal control groups. These results have been repeated in animal studies, without handgrip exercise. No significant change in the [PCr]/[ATP] ratio was found in the normal intact dog heart over a five-fold range of ratepressure products.127 In this case the stress was in the form of a

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35 pacemaker which increased the rate of the heartbeats by threefold and increased the rate-pressure product by 1.5. There is however, the potential to use drug stimulus to stress the healthy human heart to the point that a drop in [PCr]/[ATP] can be seen. The first attempt at doing this was by Schaefer et al.163 where 2 to 16 g/kg/min of dobutamine was used. Dobutamine has the effect of increasing the heart rate, contractility and blood pressure. In this case, this amount of dobutamine alone was enough to increase the ratepressure product (heart rate times systolic blood pressure) in normal controls from 7,000 to 15,000. Despite this increase of stress on the heart with dobutamine, the [PCr]/[ATP] at stress was not significantly different from [PCr]/[ATP] at rest for the normal control group, as shown in Table 3. In the same study a group of dilated cardiomyopathy patients under the same stress also did not produce a significant change in [PCr]/(ATP] with dobutamine stress ([PCr]/[ATP] at rest= 1 63 0. 24, with drug = 1. 57 0. 24, p=O. 38) Two other published studies repeated these experiments with a slightly different protocol and succeeded in dropping the [PCr]/[ATP] ratio even in normal controls. Lamb et al. 112' 167 and Pluim et al., 168 both of Oxford, England, first utilized 10 g/kg and 0.03 mg/kg, respectively, of atropine sulfate to block the cholinergic nervous system which will allow for increased heart rates. They then both used 10 to 40 g/kg/min of dobutamine to achieve a steady heart rate, based on subject age. This protocol produced a significant drop in the [PCr]/[ATP] ratio of the normal controls being studied.

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36 Table 3. Cardiac [PCr]/[ATP] Ratio of Healthy Volunteers (Normal Controls) at Rest and During Stress. [PCr] / [ATP] [PCr] / [ATP] at Rest at Stress 1 .5.2 1 .58+0.14 (n=6) 1 .51.03 1. 51 + 0 03 (M=6) 1 72 + 0 .15 1.74.17 (n=ll) 1 .77.16* 1 .74+0.19* (n=8) 1 .80.28* 1.84.26* (n=ll) 1.85+0.28* 1 .90.23* (n=ll) 1 .86+0.17 1.90.22 (M=l4) 1 .42.18* 1.22.20* (F=2, M=l8) 1 .41.18* 1.16+0.13* (M=12) Stress Form leg exercise Bicycle ergometer handgrip exercise handgrip exercise handgrip exercise handgrip exercise dobutamine (drug) Atropine/ dobutamine (drugs) Atropine/ dobutamine (drugs) blood corrected; M Male; F Female Magnet P-31 Tesla Method 1 9 T Not listed 1.5 T DRESS 1.5 T lD-CSI 5-14 min 1.5 T lD-CSI 8-16 min 1 5 T DRESS 1 5 T DRESS 7-8 min 2.0 T lD-CSI 7 min 1.5 T 3D-ISIS 10 min 1.5 T 3D-ISIS Reference 25, 157 13 49 63 54 12 163 112,167 168 There has been one interesting study by Lamb et al. 28 166 where reproducibility of each method and comparisons of the results from different methods were determined for the Philips 1.5 T system. Using 16 normal controls, the same area of the anterior left ventricl e produced a [PCr] / [ATP] ratio of 1. 31 + O .19 for ISIS alone, O. 98 + O. 20 for CSI alone and 1 .41+0.20 for ISIS plus CSI. Lamb et al. concluded that the CSI contained liver contamination resulting in a low [PCr]/[ATP] ratio. In addition, the intra-examination difference of repeated studies of each volunteer produced a smaller difference than the inter-examination, volunteer-to-volunteer [PCr]/(ATP] difference.

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37 Myocardial Infarction. In some of the studies in patients with myocardial infarction, the phosphorus spectrum shows a normal ratio of [PCr] / [ATP] 1 82 1 4 9 193 but the overall concentrations of the phosphorus metabolites are lower than normal 1 9 2 193 as described by Bottomley et al. 7 and Luney et al.B1 These characteristics are theorized to occur since the dead myocyctes can not contribute a metabolic signal to the observed spectrum.7 The observed PCr and ATP signals are derived from surviving myocytes surrounding or interspersed with the infarcted myocytes. 20149 More recent publications are providing evidence that the [PCr]/[ATP] ratio can be lower for infarction than in normal controls, 1 2 5 4 6081 and reduce [PCr] / [ATP] slightly during stress1 2 5 4 It has been suggested that the reduction in the [PCr]/[ATP] ratio for the patients with myocardial infarction represents an ongoing metabolic stress in the myocytes remaining within the scarred region of the myocardium.B1 It is still not clear how the expected ratio of the myocardium with infarction should present, but it is known that the amounts of the metabolites will differ significantly from normal. Therefore, measurements of the absolute concentrations of the phosphorus metabolites, rather than the ratios, should provide appropriate characterization of myocardial infarction. The published results for [PCr]/[ATP] of myocardial infarction are summarized in Table 4. Notice that there is not a significant change in [PCr]/[ATP] with handgrip exercise. Table 5 compares the amounts of [PCr] and [ATP] in normal controls to patients with myocardial infarction. Observe that in more than one case the overall amount of each metabolite (mol/g) is significantly reduced for cases of myocardial infarction60192'193 compared to normal controls. 206067 There

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38 is even a slight reduction in the amount of [PCr] and [ATP] for the case of myocardial ischemia.60 This data shows that P-31 cardiac spectroscopy has the potential to evaluate myocardial viability. Table 4. Cardiac [PCr]/ [ATP] Ratio of Patients with Myocardial Infarction at Rest and During Stress. Degree of Disease [PCr] / [ATP] at Rest [PCr] / [ATP] at Stress Magnet Tesla P-31 Method Reference Infarction After angioplasty and drug therapy Infarction After angioplasty and drug therapy Myocardial "Scar" Chronic anterior wall infarction Chronic posterior wall infarction 1.6.2 (ENDO) (M=2, F=2) 1.8.2 (EPI) (M=2, F=2) 0.48+0.21 (M=5) Normal (M=6) Normal (M=4) Fixed Tl-201 0 .94+0.41* defects (M=8, F=4) Fixed Tl-201 1.18 O. 28 defects (n=l2) Fixed Tl-201 1.24 0 .28 defects (M=9, F=J) 1.5 T 1.5 T 1 5 T 1.5 T 1.5 T 1.5 T 1. 12 + 0. 24 1. 5 T (handgrip) 1 .19.28 1.5 T (handgrip) *=blood corrected; M = Male; F = Female DRESS 2.5-9 min DRESS 2.5-9 min 2D-ISIS + lD-CSI ISIS 32 min ISIS 32 min DRESS 12-15min DRESS DRESS 7-8 min ENDO= localized to endocardium; EPI = localized to epicardium; * = 3 out of 5 patients had a prior history of heart failure 149 149 81 ** 82 82 60 54 12

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39 Table 5. Cardiac [PCr] and [ATP] Amounts at Rest in Patients with Myocardial Infarction, Ischemia and in Normal Controls. Patient [PCr] [ATP] Magnet Quantify P-31 Type mol/g ~ lmol/g Tesla to: Method Reference Infarction < normal < normal 1 5 T External DRESS Standard Infarction < normal < normal 1.5 T External DRESS Standard Infarction 3 .94.21 4 .35+1.52 1 5 T External DRESS (M=8, F=4) Standard 12-15 min Ischemia 7.64+3.00 6 .35+3.17 1.5 T External DRESS F=7) Standard 12-15 (M=22, min Normal 11. 7 + 2 5 7.2 1 2 1.5 T External 1D-CSI + Standard 2D-Phase Encode Normal 12.14+4.25 7 72 + 2 97 1.5 T External DRESS (n=ll) Standard 12-15 min Normal 10+ 2 5 8 1.6 1.5 T Internal lD-CSI (n= 21) Water (M=21) M= Male; F Female There is also potential value in observing the Pi and pH of patients with myocardial infarction. One study at 1.5 T of six 193 192 60 60 67 60 20 patients with anterior myocardial infarction, with blood contamination corrections performed on the spectra, showed a slight but nonsignificant elevation of Pi in the patient set. 49 This study was early on in human, cardiac P-31 MRS, used only a simple lD-CSI acquisition, and may have mistaken blood contamination for Pi. There are not many studies that follow this one in identifying changes with Pi at 1.5 T. Despite this fact, there is interest in identifying the Pi peak as a means of identifying a decrease in the pH of the myocardium that would also be a sign of ischemia.

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40 Difficulty with blood contamination has made the measurement of Pi more complicated in human cardiac spectroscopy studies. This is due to the fact that at 1.5 Tor below, the Pi is most often overlapped by the 2,3-DPG (2,3-diphosphoglycerate) peaks from the blood contamination. The Pi has been repeatedly seen at 1.5 T with the use of specialized pulse sequences such as DANTE selective excitation,159 nuclear Overhauser effect (NOE) for signal enhancement, magnetization transfer,99 and proton decoupling for enhanced spectral resolution.7 1 These options are not currently available on the GE 3.0 T system. Also, long acquisition times can increase the probability of visualizing the Pi peak by increasing the SNR. These problems are overcome at 3.0 T. Work at 3.0 Tallows for the Pi peak to be distinguished even over relatively short scan times (i.e. 6 to 8 minutes) due to the enhanced SNR and wider spectral dispersion achieved at the higher field strength. Myocardial Ischemia. One of the most common types of heart disease is cardiac ischemia. In the diseased heart affected by myocardial ischemia, individual cells in affected areas of the myocardium can no longer function due to significant decreases in blood flow to the region. The blood flow reduction is typically due to a gradual blockage forming in the coronary arteries. These patients have symptoms of angina which are usually temporary and brought on by stress when the required blood flow to the heart is inadequate. Although typically these patients will suffer from angina and fatigue without triggering a deadly heart attack, a diagnosis of ischemia does substantially increase the risk of a heart attack. Since the blood flow is already reduced, there is greater potential for acute and total

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41 blockage (infarction). The result is a disorder that is very disabling partially due to the fatigue but also due to the anxiety related to the chest pain. The typical diagnosis of cardiac ischemia is based on signs, symptoms and laboratory tests that can be performed by a familypractice or emergency room physician. Cardiologists and radiologists at the local hospital can also perform further diagnostic exams. In addition to patients with angina being tested for ischemia, asymptomatic patients at risk for heart problems based on risk factors such as age, weight, life-style (high fat diet, smoking) and family history are also tested. This is due to the fact ischemia is often clinically silent or associated with atypical symptoms. The AHA estimates that as many at 3 to 4 million Americans have silent or asymptomatic ischemic episodes that are eventually diagnosed by testing for reasons unrelated to the symptoms, such as a routine physical examination.2 Ischemia is primarily quantified by the identification of stenosis in the larger vessels of the coronary arteries, but ischemia can also be confined to the microvessels. Microvascular ischemia can involve angina-like chest pain that is coincidental with exertion and thus may resemble typical angina pectoris but without stenosis of the main coronary arteries. More often, however, the chest pain associated with microvascular ischemia has characteristics that differentiate it from typical angina. For example, the pain is generally prolonged, repetitive, occurring at night, and poorly responsive to rest and medications. Dr. Carl Pepine, a cardiologist at the University of Florida, was one of the first to observe that patients' with symptoms

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42 of microvascular disease are most often not predictive of a life threatening disorder. Whereas in age-matched patients with coronary artery disease such symptoms are indications of a life-threatening event.3 Despite microvascular disease not being life threatening, it still has a great impact on the quality of life. In addition, undiagnosed conditions, lethal or not, traditionally place added costs on the medical system as the patient will continue to seek diagnosis, go to new physicians and have more and more tests performed. Often the quality of life is diminished to an extent that many remain unemployed or retire from work and limit their activities, with obvious socioeconomic implications. From a clinical and financial point of view, these patients need to be diagnosed and treated. In cases of myocardial ischemia, the localized phosphorus spectrum will show a small level of depletion in the (PCr]/[ATP] ratio at rest, compared with reference normal controls (i.e.: Ischemic Anterior Myocardium [PCr] /(ATP]: 1.450.31, n=l6; Disease-Free Controls [PCr] / [ATP] : 1. 72 O .15, n=ll) 49 A more significant difference occurs when comparing the [PCr] /[ATP] ratio during minor stress test (leg or handgrip exercise) to that with the resting value, as shown in Table 6. Similar results have been shown in both animal124'194 and human experiments12'54' 60

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43 Table 6. Cardiac [PCr] / [ATP] at Rest and Stress in Patients with Myocardial Ischemia. Degree of Ischemia >= 70% stenosis >=70% stenosis >=75% stenosis >75% stenosis [PCr] / [ATP] at Rest 1 .45+ 0 .31 (n=l6) l .46+ 0 39 (M=l4) 1 .56.19 (n=l5) 1.60+ 0 .19* (M=ll, F=4) [PCr] / [ATP] at Stress 0. 91 + 0. 24 (handgrip exercise) 0. 94 + 0. 2 8 (handgrip exercise) 0. 94 0. 2 7 (handgrip exercise) 0.96+0.28* (handgrip exercise) Magnet Tesla 1 5 T 1.5 T 1.5 T 1.5 T blood corrected; M -Male; F = Female P-31 Method lD-CSI 5-14 min lD-CSI 8-16 min DRESS DRESS 7-8 min Reference 49 150 54 12 Table 7 demonstrates the descriptive value of cardiac P-31 MRS for ischemia that has been treated. The first two rows show a study where five ischemic patients were tested with and without in magnet exercise (handgrip} after revascularization surgery. In the case of the patients with revascularization, the [PCr]/[ATP] ratio does not drop when exercised, although the same patients did drop their [PCr]/[ATP] ratio prior to surgery.49 This provides a quantitative means for evaluating the success of revascularization surgery. Another method for treating a heart attack that is thought to be primarily ischemic is to provide drug therapy intravenously, such as thrombolytic agents. The third row shows such a study where the region of the heart, even after being treated, remained in a stunned state, where the wall motion in the region is still impaired even after intervention.173 In this case, investigators were able to show that despite the myocardium remaining stunned, the tissue [PCr]/ [ATP] values were not

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44 significantly depleted as they would normally be under an ischemic situation under stress, showing the potential of cardiac P-31 MRS as a feedback measure after treatment.173 Unfortunately, no pre-treatment data was obtained so it is difficult to conclude that the ratio of [PCr]/[ATP] alone was a marker for ischemia. The last two rows show a study done only at rest of ischemic patients before and after angioplasty, which showed no change in [PCr)/[ATP]. This study would have been more effective if in magnet exercise or drug stress was used during the [PCr]/[ATP] acquisition. Table 7. Cardiac [PCr]/[ATP] at Rest and Stress in Patients with Myocardial Ischemia with Some Type of Intervention. Disease Description [PCr] / [ATP] [PCr] / [ATP] Magnet P-31 at Rest at Stress Tesla Method Source Ischemia before 1. 51 + 0. 19 1.02+0.26 1.5 T lD-CSI 49 revascularization normal normal 5-14 < min (n=S) Postischemic after 1.60+0.20 1.62.18 1 5 T lD-CSI 49 revascularization normal normal 5-14 min (n=5) Drug infused 1.51.17* 1.5 T ISIS 173 Postischemic, normal 22 min Stunned Myocardium (M=l5, F=6) Ischemia >= 75% 1 .5.7* -1 5 T DRESS 51 stenosis before normal 15 min angioplasty (n=7) Postischemic after 1.4+1.0* -1.5 T DRESS 51 angioplasty normal 15 min (n=7) blood corrected; M Male; F Female Microvascular Ischemia Study: WISE. An NIH sponsored study concentrated on women's ischemic syndrome evaluation (WISE) is studying microvascular ischemia in women with phosphorus NMR spectroscopy as part of a multi-center study including the University of Florida. The

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45 specific feasibility of phosphorus NMR spectroscopy to look at microvascular ischemia was initially demonstrated during a pilot study performed on a 1.5 T Philips system at the University of Alabama at Birmingham (UAB) .195 In this study, women were identified who had angina-like chest pain characteristic of ischemia and CA tested to measure the degree of stenosis in their macrovessels. The patients with insignificant stenosis {less than 30% stenosis) were also evaluated for all other possible causes for their chest pain, without diagnosis. UAB's study identified micro-vascular dysfunction (MVDS) 30% of the women with previously unidentified chest pain. This data was also compared with 17 normal volunteers (ages 21 to 53 years; average age 32 ; 10 males, 7 females), who underwent 8 minutes of isometric handgrip exercise at 30% maximum force. There was no in significant change (-0.1%+10.3%) in the [PCr]/[ATP] ratio as compared to rest. These values are consistent with similar handgrip exercise literature where Weiss et al.49 and Yabe et al.12 have similar estimated percent change statistics in their normal population samples of 1.9%.0% and 0.5%.0%. The determination of significance was set at two standard deviations (20.4%) of a percent drop in the [PCr]/[ATP] ratio of the normal volunteers with handgrip exercise.195 In eight patients (7 male, 1 female) with CA proven stenosis greater than 70% blockage, the same amount of exercise resulted in a -24%% drop in [PCr]/[ATP]. This comparison of normal volunteers versus patients with proven stenosis proves that the phosphorus NMR spectroscopy test is viable for differentiating non-ischemic versus highly ischemic hearts. The Birmingham study also evaluated 17 women with less than 30% stenosis (very little blockage) and undiagnosed chest pain (suspected

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46 microvascular ischemia). The same amount of exercise produced little [PCR]/[ATP] change (-2%%) in 12 of these women, but 5 women had a PCr change of -27%. This change is attributed to MVDF, because of what is expected by the ischemic angina-like symptoms and the lack of macrovascular disease.196 Accordingly, cardiac P-31 MRS shows significant potential as a quantitative test for myocardial ischemia that does not depend on the presence of macrovascular disease. No other current diagnostic modality is able to quantitatively assess the degree of ischemia of the heart in this way. In-Magnet Exercise. For patients with myocardial ischemia, there is a significant difference between phosphorus cardiac spectra obtained at rest and during stress (in-magnet exercise) .49 It is clearly valuable to use some type of in-magnet exercise during one period of the cardiac spectroscopy acquisition protocol. Studies using in-magnet exercise have been done by exercising the legs,1325157197 arms with a hand-grip, 495460198'199 and drug-induced (dobutamine infusion) cardiac stress163 The leg exercises can allow for prone position exercises (prone position is best for cardiac imaging and spectroscopy to reduce respiratory motion artifacts). One design by Conway et al.157 has the subject lie in a prone position, lifting 5-kg weights with the legs by bending at the knee. This stress test tends to produce an increase in the heart rate pressure product of around 70%. 25157 Isometric, hand-grip exercise, where the subject squeezes continuously at a constant 30% of the subject's maximal force,49 can also be performed simply in any position. In-magnet exercise tests have been also done with devices as simple as a bottle of water. Widmaier et al.199 successfully implemented

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47 a dynamic hand-grip finger flexion exercise consisting of squeezing a 50-mm diameter, water-filled, plastic bottle at a Maximum Voluntary Contraction (MVC) approximately once every second for a 130 seconds acquisition. Such an exercise increases the heart rate pressure product by approximately 30 to 35%, which is still enough to increase coronary vasoconstriction in the presence of critical levels of coronary stenosis.198 The two types of handgrip exercise used are either dynamic, where the grip is released and regrabbed up to the 30% maximum level repeatedly during the test, or isometric, where the handgrip is held constant at the 30% of maximum effort level. As can be seen from Table 8, both dynamic and isometric handgrip raise the heart rate and blood pressure, but the isometric method is a harder level of work and therefore responds with a greater heart rate and blood pressure response. Finally, dobutamine infusion (drug infusion) has the ability to increase the rate-pressure product by 60 to 130i. 7 163

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48 Table 8. Literature Review of In-Magnet Handgrip Exercise Response. Avg Rest Avg Rest Rate 30% Max & & Pressure Avg Rest & Handgrip Exercise Exercise Product Exercise Patient Exercise HR SBP ( HRxSBP) [PCr] / [ATP] Type Reference dynamic 67 8 117 12 7839 1 85.28 control 12 77 11 131 13 10087 1.90.23 dynamic 68 12 118 + 13 8024 1.60.19 ischemia 12 75+ 13 134 16 10050 0.96+0.28 >= 75% stenosis dynamic 63 11 115 + 14 7245 1. 24 0. 3 0 infarction 12 74+ 13 128 + 13 9472 1.19.28 >= 75% stenosis isometric 67+ 12 143 9600 1.72+0.15 control 49 81 10 156 12600 1.74.17 isometric 77+ 13 132 10200 1.45.31 CAD and 49 89 16 151 13400 0.91.24 ischemia >= 70% stenosis isometric 75 13 132 9900 1 .59+0.31 Non-49 85+ 14 159 13500 1.55.24 ischemic F -Female; M -Male Post-Processing Calculations and Corrections Simply obtaining a phosphorus spectrum from a voxel in the myocardium is not enough to ensure useful spectral data. The cardiac spectrum is generally contaminated from unwanted signal from surrounding blood and skeletal muscle. Also, T1 relaxation corrections must be made when TR< 5 x Tl and T2 relaxation corrections when acquiring an echo instead of an FID. Finally, calculation of absolute concentrations of metabolites may show changes undetected by metabolite ratios. Starting with the first human study of cardiac phosphorus spectroscopy, the techniques for gathering phosphorus cardiac spectra

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49 have gradually changed and improved. The first cardiac spectrum was obtained by Bottomley et al. in 1984,45 corrections for relaxation by 1987 by Bottomley et al.,149 and blood contamination corrections as early as 1991 by Sakuma et al.55 The pulse sequences and post-processing methods have been gradually refined and duplicated by different research groups and yielded very comparable results. In each case the ratio of myocardial [PCr] /[ATP] was comparable for reference controls during rest: 1.80.21 (n=l2) ,11 1.93.21 (n=17) ,150 1.95.45 (n=l9), 82 1. 65 O. 26 (n=9) 165 Uncorrected cardiac spectra produce unreliable results,7 therefore studies of human cardiac spectroscopy are no longer publishable without corrections for blood contamination and relaxation effects. In addition, since there is no method for correcting for skeletal muscle contamination, such contamination invalidates the study results. Skeletal Muscle Contamination Skeletal muscle contains the same phosphorus peaks as cardiac muscle, but in different quantities. The primary method for ensuring that there is no skeletal muscle contamination in the cardiac spectrum is to use good methods of localization with an appropriate pulse sequence.50 This dissertation project will evaluate ISIS and CSI derived pulse sequences for elimination of skeletal muscle contamination. Blood Contamination Blood contains ATP and PDE as does myocardium, but no PCr.50 Blood also contains 2,3-DPG (2,3-diphosphoglycerate), which produces a

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50 doublet in the phosphorus spectrum at chemical shift positions of 5.4 and 6 3 ppm, near Pi and phosphomonoester resonances. Blood contamination causes the [PCr]/[ATP] ratio to appear reduced.11 Also, the myocardial Pi peak in normal heart is small and difficult to resolve from the blood DPG signal. 7 148 The correction method for blood contamination is to determine the relative signal contributions of 2,3-DPG and ATP from blood and use this knowledge to correct for blood's contribution to ATP. This is accomplished with the use of a correction factor, which is the ratio of blood [ATP]/[2,3-DPG]. Such a correction factor for the cardiac muscle [PCr]/(ATP] ratio typically increases its value by 13%+6% at 1.5 T .7 1182 1 4 8 150165 The blood correction is considered small enough that a substantial error in [ATP] / [DPG] blood ratio wil l not severely compromise the final [PCr] / [ATP] cardiac spectrum ratio, al though the final value of myocardial [PCr] / [ ATP] cardiac s pectrum will still be better than the uncorrected value.7 The ratio of blood ATP to DPG obtained from basic spectrometer methods is O. 3 o. 200-202 Spectra from pure blood are usually obtained in vitro using heparinized (anti-coagulant) blood samples. Unfortunately, one study using proton decoupling of blood samples resulted in spectra with the contribution from 2,3-DPG overestimated and ATP underestimated.202 In addition, most of these types of blood studies were conducted days and weeks after the sample was obtained, since most studies were performed to test the survival of stored blood. These studies showed increased Pi which indicate the breakdown of 2,3-DPG. However, ATP was shown to remain constant when the cells were maintained under appropriate conditions of 3 7 C temperature and the appropriate gas mixture. 202-206

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51 The excess Pi signal appears as soon as two hours after obtaining the blood sample.207 As the 2,3-DPG breaks down over time the ATP/2,3-DPG ratio increases.202 Consequently, the published ratio of 0.30 may be elevated due to the delay before acquisition. There are thus several reasons to distrust the results of these experiments when determining the proper ratios to correct for blood contamination in the in vivo cardiac muscle spectrum. At least two human cardiac NMR research groups have dealt with the problems of obtaining adequate blood spectra by determining their own correction factors for blood ratios. They extracted venous blood (-50 milliliters) from their volunteers and obtained phosphorus spectra of the blood in the same magnet used for the cardiac study, 82 148 in one case using the same NMR acquisition techniques as well.148 In both cases studies were conducted at 1 5 T and the blood [ATP]/[2,3-DPG] concentration was much lower than the reported values from the standard spectrometer experiments: 0 .11 + O. 0282 and O .14 + 0. 02. 1 4 8 These research groups were also able to correct for the blood 2,3-DPG contamination of the muscle PDE peak with correction ratios of [PDE]/[DPG] of 0.19+/-0.0382 and 0.21+/-0.02.148 Theoretically, the blood could be measured in-vivo directly from inside the heart, but has not been documented in the literature to date. Ischemia causes a reduction in systolic wall thickness. It has been debated that because of the reduced volume of myocardium, the phosphorus spectrum will be more contaminated with blood for ischemic patients. As blood contains ATP, blood contamination can alter the [PCr]/[ATP] ratio. Fortunately, the amount of blood contamination can be corrected for, and it has been shown that the [PCr]/[ATP] ratio is

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52 still reduced with exercise for ischemic patients even after blood correction. 12 Relaxation Corrections Two components of the macroscopic magnetization in NMR are subject to time dependent exponential relaxation effect. The longitudinal magnetization or spin-lattice relaxation along the z-axis is an increasing exponential function (T1 dependent) with a maximum of magnetization of Mo. The transverse magnetization or spin-spin relaxation in the x,y plane is a decreasing exponential function (T2 dependent) with a minimum magnetization of near zero.208 The relaxation time T1 is the time required for the net magnetization (M) to return to 63% of its original value following an excitation pulse.38 T1 relaxation rates depend on the presence of molecular interactions in the vicinity of the excited spin that modulates with an intrinsic frequency (w L ) .38 When w L is near in frequency to the resonance frequency (w0), the interaction will more readily absorb the resonant energy and this energy transfer will occur more frequently. This allows the collection of spins to return to the equilibrium configuration sooner, resulting in a shorter T1 value.38 Invivo metabolites as studied with P-31 spectroscopy are usually small molecules where the rate of molecular motion is rapid. This results in a poor match between wL and w0 and thus relatively long Tl relaxation times. 38 In addition, because of the relationship with resonant frequency, T1 is also dependent on the main magnetic field strength. In a typical P-31 MR spectroscopy experiment, the time between successive radio frequency pulses (TR) is usually insufficient for

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53 complete T1 relaxation. Successive acquisitions applied at a short TR result in a steady state of M where the spins are partially saturated and the resulting MR signals are reduced from their completely relaxed values.38 This situation makes quantitation difficult since the correct MR signal from each P-31 metabolite is directly proportional to the number of spins only when the collection of spins is at equilibrium. Different metabolites relax at different rates. For example, the [PCr]/[ATP] ratio will typically be too small due to the faster relaxation of ATP. Fortunately, there is a way to correct this situation. T1 relaxation corrections are necessary for cardiac spectroscopy studies since the pulse repetition time, TR, is generally much shorter (minimum l sec when gated) than the total time for complete relaxation, five times T1118 (T1 = -4 sec for PCr and -2 sec for P-ATP at 1.5 T) .50 The method for determining the relaxation factor for cardiac spectroscopy is to obtain two sets of phosphorus spectra, one at short TR (TR< T1 ) and one at a fully relaxed TR (TR > > T1 ) Then a simple division of the ratio of [PCr]/[ATP] measured at the fully relaxed T R over the [PCr]/ [ATP] ratio measured at the shorter TR, provides the relaxation factor, assuming the same TR for each relaxation corrected experiment.209 This factor can in turn be multiplied by the [PCr]/ [ATP] ratio of the localized spectra obtained with the shorter TR value to obtain the relaxation corrected results. The relaxation correction factor (RCF) ideally should be obtained directly from the myocardium, with localized techniques. This requires a set of volunteers be used to gather data to estimate the relaxation correction factor for all studies at that field strength and frequency.

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54 This is because it would take an extra 30 minutes to an hour to gather data for RCF for each subject, an unreasonable request to be tacked on after a current two-hour study. However, Bottomley et al. 67209210 obtains the relaxation data from each subject by using unlocalized acquisitions at long and short TR times, adding only six minutes of scan time209 and allowing the calculation of RCF for each participant. This method also assures that the flip angle, pulse power, RF coils, and patient is the same for the localized spectrum and for the measurement of the correction factor.209 In doing so, a large assumption is made that the P-31 metabolites of skeletal and cardiac muscle have the same relaxation rates and thus the same RCFs. This assumption is based on animal studies in rat skeletal muscle211 and canine cardiac muscle. 1 1 8 Those research groups that have measured animal and human localized cardiac P-31 metabolite T1 values directly have shown that it is possible to obtain relatively consistent values although there are still discrepancies between research sites. This is demonstrated in Table 9 where the standard deviations of some published values of T1 are relatively low with greater discrepancies between reports, such as between Neu .bauer et al. 14 and most of the other human studiesi6 4 1 193 2i2 at 1.5 T. There is no need to rely on assumptions about cardiac and skeletal muscle metabolites, when the T1 relaxation values of the P-31 metabolites can be measured from the cardiac muscle directly. A correction factor of 1.28, has been measured at UAB195 and is used in the WISE study to correct for relaxation effects at 1.5 T. To use this correction factor, simply multiply it by the blood corrected [PCr]/[ATP] ratio.

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55 Table 9 Published Spin-Lattice Relaxation Times of Myocardial PCr and ATP. Subject Dog Pig Pig Human Human Human Human Human Field (Tesla) 1.9 4.7 2.0 4 0 1.5 1.5 1.5 1.5 T1 (PCr) {sec) 4.4.1 4.8 0 9 6.3.4 5 .3+1.6 4.2 4.0 4.1 6.1 T1 {y-ATP) (sec) 1.8. 2 3.0.7 2.2. 8 2.7+ .6 5.4. 5 T1 {J3-ATP) {sec) 1.6+0.l 2.6+1. 7 2.2+0.7 1.7 1.8+ 0.2 2.7.8 5.8+1.0 Reference 118 213 213 17 193 212 164 14 The relaxation time T2 is the time required for the transverse component of M to decay 37% of its initial value. At equilibrium, Mo is oriented only along the z {Bo= main magnetic field) axis and no portion of Mo is in the x,y plane. The coherence or uniformity of the spins is entirely longitudinal with no transverse component.38 A 90 radio frequency pulse causes Mo to rotate entirely into the xy plane, so that the coherence is in the transverse plane at the end of the pulse. After the pulse, the coherence gradually disappears, the spins lose phase coherence, and reorient themselves along Bo. The disappearing coherence produces the free induction decay (FID) with a dephasing time of T2 or T2*, where T2 is always less than T1 and T2* is less than T2 38 After the application of the 90 radio frequency pulse, when Mis oriented in the transverse plane, each spin precesses at the same frequency w0 and the spins are in phase. Each nearby spin of the same

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56 type and the same molecular environment will have the same w0 The w0 will not remain the same, however, as intra-and inter-molecular interactions will cause the local magnetic field to modulate around each spin causing w0 to vary. The variations will produce a gradual, irreversible loss of phase coherence and a reduction in the transverse magnetization.38 In addition, non-uniformity in the Bo field and magnetic susceptibility differences can cause additional loss in transverse phase coherence and T 2 relaxation.38 Fortunately, neither T2 nor T 2 are factors that need to be corrected for quantitation of a P-31 spectrum using ISIS or DRESS, but they can affect the quality of the spectrum. The T1 component of relaxation determines the amplitude of the metabolite signal while the T 2 or T / has an effect on the decay of signal with time and the linewidth. Shimming of the region of interest can attempt to correct for some losses in phase coherence, but P-31 metabolites have inherently fast and unalterable T2 times. Calculation of pH Some values of cardiac pH as found in the literature are shown in Table 10. The pH is proportional to the frequency difference of the Pi and PCr P-31 metabolite peaks. In the literature it is well stated that it is not always possible to see the Pi peak in every case due to SNR differences between cases. None of the publications listed were able to obtain pH values on every single subject. There are also no known publications of human cardiac pH during in-magnet stress.

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57 Table 10. Myocardial pH in the Literature as Measured by Human, In-vivo Phosphorus NMR Spectroscopy. Type of patient Normal Control Normal Control Normal Control Infarction n 4 ? 1 4 pH at rest 7.15+0.03 7.15+0.02 7.17 7 15 + 0. 06 Reference 165 149 159 149

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58 90 RF Acquire Echo < TE/2 >< >< TM TE/2 > Figure l STEAM Pulse Sequence 90 180 RF Acquire Echo < TEl/2 >< TEl/2 >< TE2/2 >< TE2/2 > Figure 2. PRESS Pulse Sequence

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Acquisitions: l st Localization: Volume: ( l st) Slice: ( 1st_ 2nd} 59 Column: ( l st _2nd+3 rd_4 th) 4th 9th Voxel: (lst_2nd+3ro _4th +5th_6th+ 7th_ 9th) Figure 3. ISIS Volumes for 8 Acquisition Voxel Localization.

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CHAPTER 3 PHANTOM P-31 SPECTROSCOPY ACQUISITION TECHNIQUES This chapter covers the design and implementation of the phantom techniques for evaluating the 3.0 Tesla GE Signa Advantage magnet in Gainesville, Florida for purposes of performing cardiac spectroscopy on human subjects. The 3.0 Tesla magnet located in the tunnel between Shands at the University of Florida (UF) and the Veterans Affairs Medical Center (VAMC) is owned by the VAMC, Shands at UF, and the Brain Institute at UF. Phantom and coil combinations were tested with a variety of imaging and spectroscopy pulse sequences. The purpose of utilizing a phantom is to take the opportunity to test all the possible pulse sequences and options with a standard sample (the phantom) to compare each method. In addition having a phantom prevents the need to have an endless supply of human volunteers to test out each pulse sequence and option. In addition, it is often difficult for humans to lie perfectly still in the magnet for a long period of time, as they are generally required to do for all MRI and MRS studies (with the exception of exercise studies, where special procedures are implemented). When new protocols are initially being tested, they tend to take longer to run than after they are better defined, again pointing to the advantage of using a constant, stationary phantom. Although there is not enough room in each figure caption to capture the full protocol under which each image and spectrum were obtained, this 60

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61 information can be found in the appendix, identified with its reference figure. Phantom Design Four phosphorus phantoms have been identified or built for the purpose of initially testing the parameters for each pulse sequence and protocol, before use on human subjects. Gate-able and Depth Phantoms Two phantoms, the gate-able and depth phantoms consist of two compartments, each containing a different phosphorus compound, which present as separate chemical peaks in the phosphorus spectrum. Photographs and images of the gate-able and depth phantoms, in each of the three planes can be found in Figure 4, Figure 5, Figure 6, and Figure 7. The outer and inner compartments (OC and IC) are filled with the phosphorus containing chemicals of sodium dihydrogen phosphate (NaH2P04 ) and methylenediphosphonic acid (MDPA), respectively, each diluted in distilled water. The compartment sizes and concentrations for each phantom are described in Table 11. Two sections are necessary to test the ability of each pulse sequence to localize to the desired voxel (represented by the IC) and exclude the outer voxel signal (represented by the OC) .214 The OC represents the unwanted signal from skeletal muscle and blood that surrounds the myocardium. The IC represents the phosphorus signal from the myocardium. In addition, the depth phantom's IC is surrounded by a layer of water (compartment 2 in Table 11) which is just thick enough to eliminate most of the contamination from just outside the selected volume. For this reason

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62 the depth phantom is especially useful in demonstrating complete elimination of the OC signal of NaH2P04 when the pulse sequence is able to do so. Both phantoms were designed to load the H-1 and P-31 coils similar to a human chest load. The estimation of loading equivalency is demonstrated by the resulting quality factors (Q-factor) values of the loaded H-1 and P-31 coils compared to a human chest load, as shown in Table 12. The Q-factor will be explained further in the section of this chapter on coil designs. The center of the gate-able phantom's IC is at a depth of S cm, to approximate the depth of the anterior wall of the heart, while the depth phantom has variable depth IC. Table ll. Gate-able and Depth Phantom Compartment Sizes and Concentrations. Phantoms Gateable Depth Inner Compartment Size Container: 4.7-cm length, 2.7-cm ID*; 35 ml Container 1: 3-cm length, 2.3 cm ID* Container 2: Inner Compartment Concentration 80 mM MDPA -80 mM MDPA 3-cm length, water 3.6 cm ID* barrier Abbreviations: ID*= inside diameter Outer Compartment Size Container: 11-cm max height, 28-cm ID*; partially filled with 4 liters Container: 16-cm max height, 30-cm ID*; partially filled with 7 liters Outer Compartment Concentration 3 0 mM NaH2 P04 plus 70 mM NaCl The gate-able phantom was initially designed to test the degree of localization of each pulse sequence and to do this while the IC was moved in and out of the volume of acquisition in a gated fashion. A volunteer standing outside of the magnet would gate the magnet acquisition with a peripheral-gating device reading the pulse rate in

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63 the volunteer's finger. While viewing the pulse waveform, the volunteer would use an extension rod attached to the IC of the gate-able phantom to coincide the movement of the IC with the peripheral pulse gating, pushing and pulling the IC in or out of the acquisition volume (AV) with each beat. The system gated the sequence to the peak of the peripheral pulse waveform. It was found that placement of the IC in the AV at the peak of the pulse waveform resulted in a signal that was equivalent to that achieved by placing the IC in the AV without movement. In addition, when the cycle was reversed such that the IC was outside of the AV at the peak of the peripheral pulse, and moved inside between gated pulses, the result was equivalent to having the IC outside of the AV for the entire sequence without movement. Therefore, the gating was found to be predictable and accurate. The depth-changing phantom (or simply "depth phantom") was borrowed from Hee-won Kim's dissertation work. This phantom is designed with an inner compartment that can be moved to different depths away from the coil surface, thus simulating different cardiac depths. Unlike the gate-able phantom, the IC position is fixed before the start of acquisition and cannot be moved during acquisition, a lthough it can be moved to different depths between acquisitions. The IC of the depth phantom consists of two separate containers, an 1.nner container of MDPA surrounded by a second container providing a layer of water between the IC and OC. The water layer is thin (-0.7 mm) but large enough to help eliminate a majority of signal just outside the selected volume of interest. This phantom is therefore ideal to use when demonstrating the ideal localization ability of a pulse sequence and to show virtually no external contamination from the external

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64 NaH2P04 The primary use of the depth phantom, however, is to estimate the optimal transmitter gain (TG) which determines the optimal flip angle at each depth. For the human studies, these phantom measurements will provide initial guesses of TG values for human cardiac P-31 MRS acquisitions. Slice Profile Phantom A third phantom, the slice profile phantom, as shown in Figure 8, consists of a 2 ml vial of 14.7 M phosphoric acid (H3P04), placed at an angle of 4 at depth of 5.5 cm with a plastic arch that is glued in place. The vial is surrounded by an outer compartment (22 x 22 cm2 base x 10 cm tall) of 4 to 5 liters of 70 mM sodium chloride to load the coil. This phantom was used to more precisely detect the degree of contamination in a slice from a source (the 2 ml vial of H3P04 ) just outside the slice. GE Phosphoric Acid Phantom A GE plastic bottle phantom consisting of a larger volume (-450 ml) of phosphoric acid (H3P04 ) provided a strong P-31 signal for use in comparing the different types of P-31 coils. This phantom provided enough P-31 signal for adequate imaging at the P-31 frequency. It was used for quick working checks of coils and equipment, as well as to verify dimensionally the depth ranges of each phosphorus coil used in this work. The bottle is 18 cm tall (including cap) and has a 7.3 cm diameter at its widest. GE's 14.7 M Phosphorus Phantom is labeled as \\GE Medical Systems, 46-317299G2 Spectroscopy Service Phantom, 14.7 M H3P04 Phosphoric Acid" as shown in Figure 9.

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65 Radio Frequency Coil Design Sets of proton and phosphorus radio frequency coils were selected in order to obtain the best performance from a study. The proton coil is used for imaging, shimming and ensuring correct positioning of the phosphorus coil. To prevent changes in shim values and localization due to patient movement, it is essential to have the proton coil and phosphorus coils in place during the entire study, independent of whether the magnet is set at the proton or phosphorus frequency. In terms of RF coils, this means having proton and phosphorus coil(s) that are compatible and maximize the SNR for the phosphorus spectrum. The coils were designed dimensionally by the author, with the author sometimes providin g the platform and placing the copper tape on the coil former with proper dimensions. All of the capacitor, resistor and cable placements for proper coil tuning and usage, in addition to some initial platform creations, were performed by Dave Peterson and Bryan Wolverton in Dr. Fitzsimmons' coil lab, at the Veterans Affairs Medical Center, Gainesville, FL. In addition, Dave Peterson provided assistance in measuring coil parameters as are shown in Table 12 and Table 13. 3 0 Tesla Square Proton Coil Paired with Quadrature Phosphorus Coil The GE 3.0 Tesla magnet does not have a body coil, therefore it is necessary to build a proton surface coil in addition to the phosphorus surface coil. A 10 x 16 cm2 quadrature transceive phosphorus coil (two 10-cm diameter coils overlapping), coplanar with a 25-cm square transceive proton coil was created and was shown to provide adequate imaging and spectroscopy performance. The quadrature coil

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66 provides an advantage over the basic single-turn coil. Theoretically, a quadrature coil will provide up to Ji. times the signal to noise of a single turn coil.189 In practice, the signal to noise improvement can be better or worse depending on the quality of the coils that are compared. A quadrature coil, acting as receive only, provided 1.4 times the signal-to-noise ratio of a single turn coil having the same shape and total dimension, in a cardiac imaging acquisition.189 Originally, the quadrature phosphorus coil and the square proton coil were permanently positioned together on one holder as shown in Figure 10a. A schematic diagram of the proton square coil is shown in Figure lla, whereas a schematic diagram of the phosphorus quadrature coil is shown in Figure llb. It was found that this pairing, when positions were permanently placed, offered limited flexibility in centering the quadrature coil over the heart, where the coil holder was often protruding into the chin of the volunteer. A modification was made to mount the two RF coils on separate holders so each could be optimally and comfortably positioned. This modification is shown in Figure 10b. 3.0 Tesla Phosphorus Single-Turn Coil Most cardiac spectroscopy work is currently done with a simple, single turn surface coil. It is for this reason that tests were performed with a single-turn phosphorus coil for comparison with the quadrature coil results. The single turn coil is a 10 cm diameter transceive design tuned to 51.71 MHz for phosphorus at 3.0 Tesla. A photograph of this coil is shown in Figure 12, and a schematic diagram of this coil is found in Figure 13.

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67 3.0 Tesla Coil Comparisons Phantom tests with the GE 14.7 M phantom show that the quadrature coil overall performs significantly better than the single turn phosphorus coil, especially at greater depth. Table 12 lists values of the basic coil parameters of quality (Qfactor = quality factor) and isolation for each of the 3 Tesla tuned coils. The quality factor is defined as the center frequency over bandwidth, where the bandwidth is the frequency +3dB and -3dB from the center frequency.215 The parameters were measured with help from David Peterson in Dr. Fitzsimmons' coil lab, using the HP 8752A Network Analyzer. Table 12. A Comparison of 3.0 Tesla Coil Parameters. Q-factor Unloaded: Q-factor Human* Chest Load: Q-factor Depth Phantom Load: Q-factor Gate-able Phantom Load: Isolation of Quadrature: Isolation of P-31 coplanar with H-1: human chest load of 29 year old male Square H 1 16 2.2 2.8 2.5 Quadrature P -31 44 24 12 16 15.4 dB 36 dB Single-Turn P -31 30 19 13 16 42 dB with body mass index of 25.5. In addition to measurements of the quality factor and isolation, each phosphorus coil's performance was mapped. Comparative mapping of the quadrature versus single-turn coil performance was achieved by a series of P-31 spectroscopy slice acquisitions where the TG was optimized at each slice. Using a larger proton slab phantom beneath the coil for loading, and placing the 14.7 M phantom on top of the coil, which provided excellent SNR, a DRESS slice (25 mm thick) was obtained at 5 mm intervals from each coil, as shown in Figure 14. At

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68 each slice, the TG was optimized. The maximum distance from each coil measured was at 96 mm, just under 10 cm, where the 14.7 M P-31 phantom bottle's neck formed. The bottle also had curved edges at the bottom and top as well as a slight concave area at the bottom, which can explain part of the reduction in signal in the first few slices from the RF coils. Based on the results, the single-turn RF coil has optimal SNR at a depth of 25 mm while the quadrature RF coil has an optimal SNR at a depth of 42 mm. This data reinforces the fact that the quadrature coil penetrates deeper with greater SNR and is therefore more ideal for reaching the depths of hearts of thicker chested individuals. This result is duplicated when the ratio of quadrature to single-turn signal is plotted, showing the quadrature coil peaks with the greater signal at both the coil surface and at a depth of 42 mm. In addition, until the depth of 60 mm, the quadrature coil outperforms the single-turn coil in terms of relative signal. Increase in signal from the depth of zero to 3 cm in Figure 14 can also be explained. Starting at the coil position (zero distance from the coil), only half of the first slice contains the phantom material. As the depth increases, the entire phantom is in the slice by a depth of 1.25 cm. Acquisition of a spectroscopy slice is not 100% accurate at the edges, where a Gaussian like function describes the contamination of signal from outside the slice. At the first slice depth where the entire phantom is in the selected slice, only one edge is contributing signal contamination. As the depth increases, eventually both edges will contribute a small bit of contamination. In addition, although the 14.7 M P-31 phantom is only 73 mm in diameter, this test is not 100%

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69 accurate because the profile of each coil (single turn and quadrature) may not have equally obtained signal from each slice. 1.5 Tesla Coils One main argument for using the 3.0 Tesla magnet is its superior performance when compared to 1.5 Tesla. All comparisons between the 1.5 Tesla and 3.0 T were done on GE scanners with identical software (version 5.4) and with components as similar as possible. The 1.5 Tesla GE Signa Advantage has a body coil, therefore no proton coils were created. A single turn phosphorus coil of 10 cm diameter was created. In addition, a quadrature coil of the same dimensions as the 3.0 Tesla P-31 quadrature coil was constructed. The same parameter measurement s taken from the 3.0 Tesla coils, were also performed on the 1.5 Tesla coils as shown in Table 13, with the exception of the 1 5 Tesla body coil, which cannot be moved for such testing in the coil lab. In addition, a photograph of each of the coils can be found in Figure 15 and Figure 17, and a schematic for each can be found in Figure 16 and Figure 18. Table 13. Comparison of 1.5 Tesla Coil Parameters. Q-factor Unloaded: Q-factor Human* Chest Load: Quadrature P-31 77 45 Single-Turn P-31 48 33 Isolation: -18.6 dB not applicable Match: 68 pF per side not applicable reflections: -18 dB/ -29 dB not applicable human chest load of 29 year old male with body mass index of 25.5.

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70 Coil Ideas for Future Cardiac Spectroscopy Studies Future coil sets may consist of a smaller proton coil or a set of phosphorus coils with a separate, larger transmit coil, thus reducing spatially dependent spectral distortions from the excitation field.216 7 There is also the possibility of other coil designs, if one is found to significantly improve the performance of the cardiac imaging and spectroscopy acquisition. Imaging Both Spin Echo and Gradient Echo imaging pulse sequences are the most common MRI techniques for proton imaging on the GE system. The goal of the phantom imaging was to predict which pulse sequence would provide the best image uniformity and depth of penetration, when used with a simple surface coil. In this chapter, imaging is briefly examined at 3.0 T and only in phantoms, but in the next chapter images taken at 1.5 Tesla will be compared with 3.0 T and explained in greater depth. Imaging with the spin echo pulse sequence on the 3.0 Tesla with a surface coil has its limitations. Even with a maximum transmitter gain (TG) the signal depth is not as good as the gradient echo images. This is shown in Figure 19 where the top corners of the phantom are cut off when spin echo imaging is used, but are still visible when gradient echo imaging is used. In contrast, the spin echo pulse sequence works better at producing images than the gradient echo sequence on the 1.5 T, where a body coil provides more uniform excitation of the axial slice and requires less overall power. Human cardiac images shown in the next chapter emphasize this point. Also note the slight asymmetry

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71 in signal brightness in the gradient echo images, which is due to the slightly off center placement of the 25 cm proton coil with the center of the gate-able phantom. Gradient echo imaging, especially with a flip angle of less than 90 (60 was used) was found to work best for imaging an axial slice with a simple surface coil. Phosphorus imaging can only been done with a phosphorus sample of extremely high concentration, such as with the GE 14.7 M phosphorus phantom. The phosphorus concentrations in the human body, or in the depth or gate-able phantoms, are not high enough to produce an image within the standard phase and frequency steps designed for proton imaging. The result of imaging a phosphorus sample with normal tissue amounts of phosphorus in the millimolar range was simply an image of noise. The only phosphorus imaging that is presented in this write-up is of the GE 14.7 M phosphorus phantom. The GE 14.7 M phantom images were used to compare the depth penetration abilities of each of the phosphorus coils. Spectroscopy GE offers a number of spectroscopy pulse sequences of different characteristics and qualities. Due to characteristic differences of metabolites at different frequency ranges, there are pulse sequences that are more appropriate for either H-1 or P-31. In addition, some pulse sequences are designed to acquire spectra unlocalized, while others can slice, column or voxel localize. There is no direct purpose for using unlocalized H-1 or P-31 spectroscopy acquisitions, assuming T1 corrections will be based on spectra localized to the cardiac muscle. The discussion will be limited to localized spectroscopy sequences that

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72 would be of use in a cardiac MRS protocol. Using phantom studies the GE pulse sequences will be described and evaluated for the later purposes of H-1 localized acquisition for shimming and P-31 localized acquisition for evaluation of cardiac disease. Quality of the phosphorus spectra from the phantom studies will be determined based on acquisition time, SNR, and degree of localization (i.e. increased signal from the VOI and reduction of signal outside the VOI). Note that most figures of complex P-31 spectral data in the figures of this dissertation are graphed as real, phased data, as noted by "REAL" as labeled by GE's SAGE IDL spectral post-processing software. Localized Proton Spectroscopy Although the magnet's homogeneity is optimized upon installation, any individual person or object that goes in the magnet will distort the main magnetic field to some degree. SNR and the resolution of peaks with frequencies that are close together depend partially on good field homogeneity. Homogeneity can be increased in a region of interest with a technique called shimming. Shimming involves obtaining an unsuppressed H-1 MRS signal from the region of interest and adjusting the gradients to optimize the H-1 MRS signal. The H-1 MRS signal is used because the water peak provides high SNR and optimizing the magnetic field for the water protons will also improve the signal for the P-31 metabolites. Since the linewidth of a resonance peak is inversely proportional to T2*, the homogeneity can be optimized by either minimizing the full width at half maximum (FWHM) of the water

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73 peak or maximizing the extension of the T2* dependent free induction decay (FID) of the H-1 MRS signal. The two spectroscopy pulse sequences on the GE system most appropriate for voxel localized H-1 spectroscopy are STEAMCSI and PRESSCSI, based on the standard STEAM and PRESS techniques in the literature. GE's STEAMCSI pulse sequence incorporates three sliceselective 90 RF pulses and a set of crusher gradients, as shown in Figure 20. GE's PRESSCSI voxel localized pulse sequence is obtained through three slice-selective RF pulses and utilizes a spin-echo with 90 180 and 180 pulses and two sets of crusher gradients, as shown in Figure 21. The PRESSCSI pulse sequence was preferred because of its general ability to provide twice the SNR of the STEAM sequence, as explained previously in the literature review. The FWHM values of the water peak from the phantom studies with PRESSCSI and STEAMCSI were 5.78 Hz (0.045 ppm) and 14.09 Hz (0.110 ppm), respectively. Localized Phosphorus Spectroscopy Using the best possible scenario for obtaining a phosphorus spectrum, namely using a phantom, it is easy to definitively compare the quality of the results of each of the available GE pulse sequences, and some modified GE pulse sequences. The use of a phantom is ideal because it allows for a standardized cross-comparison of pulse sequence acquisition results with a non-moving, non-changing phantom. Each of the available GE pulse sequences, PRESSCSI, STEAMCSI, ECHOCSI, SPINECHO, ISISCSI, and FIDCSI are compared in increasing order of quality of localized results within a reasonable amount of time (usually less than ten minutes per acquisition). Such an increase in

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74 quality of MDPA localization can be seen through the progression of quality of all GE spectroscopy pulse sequences via progressively smaller localization volumes, as seen in Figure 22 through Figure 32, and Figure 34 through Figure 38. Also presented are some modifications of the most viable phosphorus localized pulse sequences, ISISCSI and FIDCSI, which produce even better results. Phosphorus STEAMCSI and PRESSCSI GE's STEAMCSI and PRESSCSI pulse sequences, as explained previously, allow for the acquisition of a single voxel with each TR acquisition. In addition, both of GE sequences can be used along with CSI phase encoding gradients to further divide the field of view into multivoxels. As expected from the literature on PRESS and STEAM, PRESSCSI doesn't work as well as STEAMCSI, although neither was ideal for obtaining localized phosphorus spectra, as shown in Figure 22 and Figure 23, respectively. Note that the STEAM sequence was acquired in a fourth of the time of the PRESS sequence, but is better able to display the P-31 peaks. Phosphorus ECHOCSI ECHOCSI is GE's modification of the standard spin echo 90-180 pulse sequence combined with 2-D CSI, as shown in Figure 24.91 GE's version of ECHOCSI for localized spectroscopy employs a slice selection and CSI option. The use of a surface coil with this pulse sequence combines an inhomogeneous B1 field with a pulse sequence requiring somewhat accurate 90 and 180 pulses. In addition, the reliance on CSI for voxel localization leads to intervoxel signal bleed. The result of

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75 a P-31 ECHOCSI CSI voxel localized acquisition is shown in Figure 25 and demonstrates low SNR and inadequate localization to the MDPA inner compartment of the phantom. In addition, reliance on CSI is done at an additional cost of increased scan time. A specific example of acquisition times, for various field of views and voxel sizes is shown in Figure 26 for a sample data set of 128 acquisitions and TR of 2 seconds with the ECHOCSI pulse sequence. These parameters were chosen based on the same parameters being used to obtain a localized P-31 spectrum successfully with GE's FIDCSI pulse sequence, as described later in this chapter. Notice when the voxel sizes are decreased to reasonable values for localizing to the cardiac muscle (2 x 2 x 2 cm3 or less) the scan time increases substantially from 18 to over 60 minutes, depending on the field of view (FOV). The FOV is centered with the magnet bore so the region of interest must be within the FOV to obtained spectral data. Considering this protocol will be used for cardiac spectroscopy acquisitions, the heart is not centered but to the left of the center 5 to 10 cm (depending on the person). In addition, this figure does not take into account the increased number of acquisitions that would be needed to keep the SNR constant as the voxel size decreases, thus further increasing the scan time. Phosphorus SPINECHO GE has available a second spectroscopy pulse sequence based on the spin echo idea. Like, ECHOCSI, GE's SPINECHO is based on the 90-1800 spin-echo pulse sequence, except that the pulse and the parameters associated with the sequence have been optimized with the RF pulse

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76 reformed, as shown in Figure 27. The oddly shaped amplitude (Rhol) and phase (Theta) modulated RF pulses are the result of a back calculation of the RF pulse based on an input of the echo time and slice profile'17. The pulse is a composite of the initial 90 pulse and the refocusing 180 pulse. These pulses are combined together because if these two pulses are optimized separately, the resulting echo time is limited by the length of each individual pulse. The SPINECHO pulse available on the GE system has been calculated for a specific set of parameters and is not available for the user to change. The excitation pulse has an effective flip angle of 60 and an echo time of 2.5 msec. The radiofrequency pulse is optimized for the acquisition of phosphorus spectra from 3.0 x 3.0 x 3.0 cm3 CSI volumes. The reported benefit of the optimization was the elimination of the need for baseline correction during post-processing. A test of this sequence on 3.0 Tis shown for a CSI experiment in Figure 28. The limitations of a 3 x 3 x 3 cm3 voxel areas positioned with CSI would make it difficult to localize to the anterior myocardium, where a rectangle would be more appropriate. It is also not clear that this pulse sequence was optimized for use at 3.0 T. Phosphorus ISISCSI The ISISCSI pulse sequence, GE's version of ISIS, is the most appropriate voxel localization pulse sequence for phosphorus as provided by GE for the 3.0 Tesla scanner, as shown in Figure 29. On the GE system, ISISCSI uses an adiabatic RF pulse that allows for uniform excitation of signals over a larger volume of the sample.94

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77 The ISISCSI sequence allows for various options in acquisition areas such as volume, slice, column, and voxel acquisition. As the acquisition volume size decreases, the ISISCSI sequence is successful in eliminating more and more of the outer phantom volume (NaH2P04} This causes the NaH2P04 signal to decrease with increasingly smaller localized volumes, such as the slice and column and shown in Figure 30 and Figure 31. One step smaller than the column is the voxel. The voxel acquisition is the most desirable localization technique for cardiac spectroscopy, because of the need to avoid contaminating the cardiac muscle signal with signals from skeletal muscle and blood. ISISCSI, however, is plagued by poor localization due to short TR times between acquisitions of the next of eight separate volumes, not allowing for complete relaxation to occur between volume acquisitions. If the localization was ideal, the spectrum shown in Figure 32 would show just the peak on the left, MDPA, with no added signal from the outer volume signal of NaH2P04 A modified ISISCI sequence can be developed to overcome the relaxation error problems of the original GE pulse sequence. The original GE pulse sequence gathers each of the eight volumes (for a voxel acquisition) that will be added and subtracted from each other in sequence, with the same TR between each. The acquisition proceeds in the manner that all eight parts are acquired, and then the process is repeated until the number of acquisitions (a number divisible by eight) has been acquired. Without rewriting the ISISCSI pulse sequence, a modification that improves the ISISCSI localization results has been made. By acquiring an average of each of the eight volumes separately, with a delay time of at least 15 seconds between acquisition of each

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78 volume, a much improved voxel acquisition can be acquired with very little compromise in overall acquisition time. This idea is explained visually in Figure 33 for an acquisition example of 32 NEX. When all eight volumes were acquired separately with a short TR time during each acquisition, but a longer TR between acquisitions, the localization results were significantly improved, as shown in Figure 34. Phosphorus FIDCSI GE's FIDCSI spectroscopy pulse sequence is the most basic of the spectroscopy sequences involving a single RF pulse, as shown in Figure 35.91 In addition, CSI is an option to gather multivoxel acquisitions. The FIDCSI pulse sequence provides a good signal and slice localization. Slice localization without phase encoding can be done at a minimum thickness of 25 mm {also called depth resolved surface coil spectroscopy or DRESS). FIDCSI can do multi-voxel acquisition via phase encoded CSI. Slice localized spectroscopy that is acquired in the manner of FIDCSI is often referred to by the general term of DRESS (depth resolved surface coil spectroscopy), regardless of the machine or pulse sequence designer. This technique is often used for cardiac spectroscopy because it is a simple sequence with one spectrum output per acquisition. As long as the slice is sufficiently deep, the surface coil sufficiently narrow, and the slice properly positioned, there is only a small risk of skeletal muscle contamination. In addition, the transmitter gain (TG) must be optimized to ensure maximum signal from the slice. The proper TG values have been pre-measured using the depth phantom, as shown in Figure 36 at l.5 Tesla and Figure 37 at 3.0 T. These measurement can then be used as a first estimate in

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79 optimizing the signal from human FIDCSI slice localized studies at the same distance from the coil. The DRESS slice localized spectrum of a phantom as obtained using the standard GE FIDCSI pulse sequence is shown in Figure 38. Unfortunately, the pulse sequence suffers from a significant delay time before the free induction decay is recorded. Some delay, 1 to 4 msec, is essential to prevent eddy current signals from contaminating the signal of interest. Long delays, as 20 msec for human FIDCSI oblique slice acquisitions at 3.0 T, are less desirable because they cut off too much signal from the ATP part of the phosphorus spectrum, which has the shortest T2 relaxation time. Fortunately, there are post-processing programs, such as FITMASTER (Philips) which can estimate the missing part of the FID and provide excellent results. All parameter options were evaluated for oblique and coronal FIDCSI slice selections. The oblique slice uses more than one gradient set to specify the slice and therefore can have more conservative parameter limits. Available parameter options with the FIDCSI slice selection protocol include changing a parameter called SQUEEZE, which reduces or increases the overall time taken for the RF pulse. If the time is reduced, as it is for SQUEEZE= 2, the delay time until the start of the FID is also reduced. A delay in the FID creates a increase in the frequency dependent phase shift (first order phase correction). A 180 phase shift will be created for each dwell period.218 The delay time issue is even greater with the oblique slice as the system must be "tricked" by changing the variable pw_gph to 4 msec to even do an oblique slice localization. This is due to oblique slice using multiple gradients and having the GE software at the most

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80 conservative level for error messages. The pw_gph variable actually increases the delay time to 20 msec when used at 3.0 Tesla with a spectral width of 4000, and with the SQUEEZE parameter set to 1. After careful evaluation of the FIDCSI pulse sequence and after speaking with both Napapon Sailasuta and Ralph Hurd, both of GE, a rewriting of the FIDCSI pulse sequence was necessary to fix this delay problem. The FIDCSI pulse sequence program file was modified (by Dr. Hee-Won Kim using GE's EPIC) to decrease the delay time for an oblique slice and renamed FIDOBL on the GE console. This modification basically allows for a larger gradient strength, still within the system and safety limits, so that the RF and gradient pulses are as tall as possible, with the area and thus power remaining the same. A taller pulse takes less time, therefore, the delay time before acquisition was reduced. In addition, the need to change the pw gph control variable is eliminated. The FIDCSI pulse sequence can be utilized in one other way. The sequence can be set up to obtain a localized slice, which is segmented into multiple voxels. The limitations of this procedure come from inflexible placement of the multivoxels, timing necessary to acquire CSI phase encoding steps, and unwanted spectral bleed due to pointspread function inherent with CSI and the Fourier transform. As shown in Figure 39, the multivoxel FIDCSI with CSI option allows for a set of voxels to be placed within a set field of view. The field of view is centered on the image and the voxel placement within the field of view is dependent on how many times in the x and y direction the field of view is broken up by phase encoding gradient steps. It should also be noted that the standard GE FIDCSI pulse sequence on the 3.0 Tesla does

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81 not allow for less than a 36 cm FOV if you let the console continue to think it is operating at the proton frequency while the acquisition is at a phosphorus frequency. This was the initial setup recommended by GE. In this case it is also necessary to change control variables "asfov" to 48 and ''GAM" to 1723. 5 to ensure the correct localization dimensions. It was found that with a few tricks with the control variables, a minimum FOV of 14 cm can be achieved. This is accomplished by setting the console to run at the P-31 frequency and then changing the following control variables to prevent system errors: "pibbandfilt" equals O and "pixmtband" equals 1. These control variables correct for the absence of a separate RF amplifier for P-31. The 3 0 Tesla system uses one amplifier for all frequencies, unlike the default of separate amplifiers expected by the software. Finally, with some pulse programming corrections, as has been done with the modified FIDCSI protocol locally called FIDFOVH, FOVs below 14 cm can be achieved. Dr. Hee-Won Kim performed the modification of the FIDCSI pulse sequence program with EPIC pulse programming. The modification basically removed the protection limits for the gradient amplifiers. The FIDFOVH, modified FIDCSI pulse sequence, should only be used without the autoprescan, as parts of the autoprescan (where transmitter gain and receiver amplifiers are maximized) will exceed the limits of the gradients and do so without warning. Autoprescan is generally useless for phosphorus spectroscopy, therefore it would be a mistake to use autoprescan with phosphorus. This allows the FIDFOVH modified sequence to be used safely.

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82 1.5 Tesla to 3.0 Tesla Phosphorus Spectroscopy Comparisons One of the main arguments for using 3.0 T over using a 1.5 T magnet is the significant improvement in the amount of signal that is obtained with an increase in field strength. To prove this point, proton and phosphorus spectra of the depth phantom were taken at 1.5 T and 3.0 T with similar parameters and compared. In addition, the same parameter was again compared at 3.0 T to compare the single-turn and quadrature RF coils. The first comparison was of an FIDCSI acquisition with CSI voxel localization of the depth phantom, as shown in Figure 40. In each case the parameters were set as follows: 256 acquisitions, 25 mm thick slice, 8 x 8 x 1 CSI, 16 cm field of view, 2 x 2 x 2.5 cm3 voxels, scan times= 4:26, and lOHz line-broadening. In each case the phantom was positioned so that one of the voxels would select just the inner compartment of the depth phantom, at a depth of 5.5 cm. Experimentally, the resulting SNR of the MDPA peak of the P-31 spectrum for the single turn RF coil at 1.5 Twas 7.4 while at 3.0 Tit was 21.65, and the SNR of the quadrature RF coil at 3 0 Twas 26.1. This shows a significant improvement in signal from 1.5 T to 3.0 T, but only a moderate improvement of the quadrature over the single turn coil. The MDPA T1 relaxation rate was also measured at 1.5 T and 3.0 T and found to be 5 .52 and 6 .04 seconds, respectively (Appendix G). These relaxation rates are negligibly different from each other and do not significantly alter the MDPA SNR at each field strength. The second comparison was of the modified ISISCSI acquisition of a voxel positioned over the center compartment (5 5 cm depth) of the depth phantom, as shown in Figure 41. The parameters used for the

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83 ISISCSI acquisitions were as follows: 256 acquisitions, 16 cm field of view, 2 x 2 x 2 cm3 voxel, scan times= 2:13 for each of 8 acquisition, and lOHz line-broadening. Experimentally, the resulting SNR of the MDPA peak of the P-31 spectrum for the single turn RF coil at 1.5 Twas 6.2 while at 3 0 it was 10.1, and the SNR of the quadrature RF coil at 3.0 Twas 14.5. This shows a moderate improvement in signal from 1.5 T to 3.0 T and another moderate improvement in the results of the quadrature over the single turn coil. To verify the extent to which the slice profile of the oblique, FIDCSI modified slice selection is accurate, a series of tests on the 1 5 and 3.0 Tesla were conducted using the slice profile phantom. Slices of 25 mm thick, tilted at an angle though the vial, were obtained across the vial, as shown in Figure 8. The results of the signal profile over the slice are shown in Figure 42 for the 1 5 Tesla with the single turn P-31 coil and Figure 43 and Figure 44 for the 3.0 Tesla for the single turn and quadrature P-31 coils, respectively. The slice profile tails (where none of the H2P04 phantom was in the slice) widened slightly more at 3.0 T, most likely due to the same gradient pulse from the same pulse sequence on both systems despite different magnet field strengths. This is shown via slightly larger area of signal when no part of the phantom was in the slice (representing potential contamination by skeletal muscle or blood) at 3.0 T, as shown in Figure 43 and Figure 44, and compared to 1.5 Tesla as shown in Figure 42. The volume where the slice selection was below the phantom represents the potential contamination from skeletal muscle. This lS due to the fact that the phantom, in that case being above the selected

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84 slice represents the skeletal muscle which would be above the selected cardiac slice. In the same way, the volume where the slice selection was above the phantom represents potential contamination from blood, typically concentrated below the cardiac muscle slice selection. At 1.5 T, at the first point where the prescribed acquisition slice does not contain the phantom, there is -9% potential contamination by skeletal muscle and blood. This increases slightly at 3.0 T, where for the single turn coil, the contamination at the first point where the prescribed acquisition slice does not contain the phantom is 19% and 12%, for skeletal muscle and blood. For the quadrature coil at 3.0 T, the numbers are similar with 17% and 12% potential skeletal muscle and blood contamination, at the point just beyond the slice prescription. The 1.5 and 3.0 T percent contamination numbers for the quadrature and single turn coils are not significantly different. Considering the distance away from the prescribed slice, the amount of potential contamination drops off quickly with near 0% contamination within approximately 8 mm at 1.5 Tesla and 10 mm at 3.0 T. In summary, the oblique DRESS pulse sequence slice profile has some signal contamination at both 1.5 T and 3.0 T but it is not significantly different on each system. Phantom Results In summary of the phantom results, proton imaging was performed at 3.0 T, whereas both proton and phosphorus spectroscopy techniques were tried at 1.5 and 3 0 T. Proton phantom images were obtained with spinecho, fast spinecho, gradient echo and fast gradient echo pulse sequence techniques, with fast gradient echo being the best option for

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85 3.0 T imaging with a surface coil. In the next chapter, further evaluation of imaging will be done based on the clinical image quality of the human heart. In terms of voxel localized proton spectroscopy, PRESSCSI without water suppression offers the best water signal for evaluation of the shim quality. The evaluation of phosphorus spectroscopy included all available spectroscopy pulse sequences and some modifications of these sequences to improve their quality. For voxel localized phosphorus spectroscopy a number of pulse sequences were evaluated. The worst voxel localized phosphorus spectra resulted from the PRESSCSI and STEAMCSI pulse sequences. The ECHOCSI provided only slight improvement in signal to noise ratio (SNR), over the STEAM and PRESS sequences. The SPINECHO sequence, similar to the FIDCSI but promising no phase post-processing, was an optimized sequence for 1.5 Tesla but did not provide the expected phase attributes at 3.0 T. The ISISCSI voxel localization, run as a single sequence with a reasonable repetition time (under 15 seconds), suffered from volume localization inaccuracies due to relaxation effects. This problem could, in part, be fixed by acquiring eight separate acquisitions, with a 15-second or more delay time between acquisitions, and post-processed to create a significantly improved voxel localization result. Unfortunately, for patients, this would be difficult to acquire, therefore a modified ISIS sequence should be implemented. The modified ISIS sequence could automate what the eight separate acquisitions plus delay time between acquisition accomplished but without the need to do many multiple button presses. Finally, FIDCSI plus CSI for multivoxel acquisition, allows for

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86 localization that is even better than the best ISIS voxel localization in terms of quality of localization and overall signal to noise. Unfortunately, for the current GE software some flexibility limits exist in terms of scan areas, voxel position and scan timing, in addition to extended post-processing. This may make CSI more difficult to use clinically. In comparing 1 5 and 3.0 T performance it was clear from CSI localized FIDCSI and modified ISISCSI that the 3 0 T provided substantially more signal than the 1.5 T, and the quadrature coil improved the signal of the localized voxels slightly more. Unfortunately, the human body is multi-compartmental, so evaluations done on phantoms must be extended to humans for a true test of the optimal pulse sequence and coil combination for human cardiac use. The two most viable GE pulse sequences for phosphorus spectroscopy use on the GE 3 0 T magnet are ISISCI and FIDCSI.

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87 (a) photograph Outer Compartment (OC) (NaH2P04 ) Inner Compartment (IC) (MDPA) y z 0 X (b) position in the magnet Figure 4. Gate-able-Phantom (a) photograph and (b) position in magnet, without the liquids and with movement direction demonstrated (Lid not shown) (a) axial (b) coronal Figure 5. Gate-able-Phantom images, sagittal views, as imaged with 25cm P-31 Coil Position (c) sagittal (a) axial, (b) coronal and (c) square proton coil.

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88 photograph Outer Compartment (OC) (NaH2P04 ) Inner Compartment (IC) (MDPA & Water) y z 0 X (b) position in magnet Figure 6 The Depth-Changing-Phantom (a) photograph with top open and (b) position in magnet, with movement direction demonstrated (Note: The phantom was created by Dr. Heewon Kim). (a) axial a (b) coronal IC Container 1 (MDPA) ~---IC Container 2 (Water) P -31 Coil Position (c) sagittal Figure 7. Depth-Changing-Phantom images, (a) axial, (b) coronal and (c) sagittal views, as imaged with 25cm square proton coil.

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89 Figure 8. Axial slice image of Slice Profile Phantom and details on how oblique DRESS slices were placed within phantom to estimate the amount of potential contamination from outside the localized slice. y X (a) front back (c) position in magnet Figure 9. Photographs of GE's 14.7 M P-31 Phantom from (a) front, (b) back and relative position in magnet. 0

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(a) paired set 90 (b) separated Figure 10. Photographs of quadrature phosphorus and square proton coil as (a) a paired set and (b) separated onto individual platforms for 3 0 Tesla. TX/RX 127.7 MHz 48. 6 nH 31. 8 28.6 17.2 21. 8 pF 21.8 pF pF pF pF 21.8 pF Phosp4orus 21.8 pF 54.8 pF Quadrc}ture 54 8 pF 21.8 44.7 21. 8 21.8 pF 21. 8 pF pF pF pF (a) 3 T, H-1 Square Coil 141 pF TX/RXl 51. 7 MHz 120 pF 10 cm 188 pF 141 pF 144.3 pF 120 pF .4 10 141 pF 144. 3 pF TX/RX2 51. 7 MHz 120 pF cm 141 pF (b) 3 T, Quadrature P-31 Coil Figure 11. Schematic diagrams of (a) the 25 x 25 cm2 square proton coil set (tuned to 127.75 MHz) used with (b) the 10 cm phosphorus quadrature coil at 3.0 T (tuned to 51.71 MHz) (numerical parameters obtained from David Peterson and Bryan Wolverton, Coil Lab).

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91 Figure 12. Photograph of the single turn, 9.5 cm diameter, phosphorus transceive coil tuned to 51.71 MHz (3.0 Tesla). 137. 3 pF TX/RX 51. 7 r-~ MHz 240 pF 188 pF Figure 13. Schematic diagram of the single-turn phosphorus transceive 9.5 cm diameter coil at 3.0 T tuned to 51.71 MHz (numerical parameters obtained from David Peterson and Bryan Wolverton, Coil Lab).

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92 20.00 .--l 18.00 I \ fO i:: __ ..., tn 16.00 -rl (f) , 4-l 14.00 I 0 I Q) 12.00 --'O single-turn ;:::l 10.00 I .w rl I .quadrature .--l -p. 8.00 6.00 Q) > 4.00 rl .w fO 2.00 .--l (]) 0.00 0 20 40 60 80 100 Distance from RF Coil (mm) ( a) I 2 (]) .--l (]) tn > 1.8 I::: rl .--l rl .w fO ' (f) fO i:: -......... .--l tn 1.6 ,_ Q) Q) rl H (f) _, ;:::l .w 4-l 1.4 ' fO ,-, (/) 0 H .--l 'O rl Q) 1.2 ..,_, fO 0 'O ;:::l () ;:::l \ 0 .w .__. .., 1 \ rl -0:: .--l _, 4-l p. .., --' 0 i:: E 0.8 ..,~ -~ H r:t: 0 ;:::l rl E-t .w 0.6 fO 0:: 0 20 40 60 80 100 Distance from RF Coil (mm) (b) Figure 14. Comparisons of single-tum versus quadrature P-31 RF coils in terms of relative signal based on 25 mm thick DRESS acquisitions of 14.7 M phantom at 0.5 cm intervals with TG optimized at each position. (a) Relative amplitude of signal from single-tum and quadrature coils, with noise level at 0.02. (b) Ratio of signal from quadrature over single-turn coils showing optimal SNR from the quadrature coil.

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93 Figure 15. Photograph of the single turn, 9.5 cm diameter, phosphorus transceive coil tuned to 25.87 MHz (1.5 Tesla) with three small vials that are used to locate the coil in the proton images. 206 pF 349 pF TX/RX 25.87 MHz 50.3 pF Figure 16. Schematic diagram of the single-turn phosphorus transceive 10 cm diameter coil at 1 5 T tuned to 25.87 MHz (numerical parameters obtained from David Peterson and Bryan Wolverton, Coil Lab)

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94 Figure 17. Photograph of 1 5 T quadrature P-31 coil. TX/RXl 25.87 MHz 10 cm 300 pF 313. 8 pF 368 pF 10 c m 1 4 cm T X /RX2 25.87 MHz 296. 4 pF Figure 18. Schematic diagram of the quadrature phosphorus transceive 10 cm diameter coil at 1 5 T tuned to 25.87 MHz (numerical parameters obtained from David Peterson and Bryan Wolverton, Coil Lab).

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95 (a) spin echo spin (c) gradient echo (d) fast gradient echo Figure 19. Axial images of gate-able phantom comparing images obtained on 3 0 Tusing a 25 cm square proton surface coil with the image pulsesequences of (a) spin echo, (b) fast spin echo, (c) gradient echo and (d) fast gradient echo imaging. Asymmetry of image due to non-centered placement of phantom on 25 cm square proton surface coil.

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RF Pulse Gradient X Gradient Y Gradient Z 90 sine 90 sine 96 90 sine Crusher f---1-~1-~---1-___;1---Gradients .-Figure 20. The STEAMCSI pulse sequence, GE's version of STEAM for spectroscopy voxel localization. RF Pulse Gradient X Gradient Y Gradient Z Crusher Gradients 90 sine 180 sine 180 sine Figure 21. The PRESSCSI pulse sequence, GE's version of PRESS for spectroscopy voxel localization.

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1000 500 0 -500 -1000 Real MDPA 10 0 -10 Frequency (ppm) (a) 97 X r y NaH2P04 ,,. .~ z MDPA -.... J I "> --.. "> ,_. -.., (b) Figure 22. Frequency domain of (a) PRESSCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization. (Parameters: 128 acquisitions, 2000 Hz spectral width, 2 sec TR, 2 x 2 x 2 cm3 voxel, scan time of 4 :24, 3 T, quadrature RF coil and lOHz line-broadening; see Appendix B for more detail). 600 400 200 0 -200 400 Real MDPA 10 0 -10 Frequency (ppm ) ( a) .,.,. ..._ y NaH2P04 ...-' .... X MDPA -.... _/ I _.., "> "> ' z (b) Figure 23. Frequency domain of (a) STEAMCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization. (Parameters: 32 acquisitions, 2000 Hz spectral width, 2 sec TR, 2 x 2 x 2 cm3 voxel, scan time of 1:14, 3 T, quadrature RF coil and lOHz line-broadening; see Appendix B for more detail).

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RF Pulse Slice 90 sine 98 180 sine Selective _..._ __ _,i.,__...,. __ .._ ___ ._ _____________ Gradient Signal Figure 24. The ECHOCSI pulse sequence, one of GE's versions of Spin Echo for spectroscopy acquisition. 1000 800 600 400 200 0 -200 Real MDPA 10 0 -10 Frequency (ppm) (a) MDPA y X z (b) Figure 25. Frequency domain of (a) ECHOCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization. (Parameters: 256 acquisitions, 2000 Hz spectral width, 2 sec TR, 4.5 x 4.5 x 2 cm3 voxel, scan time of 8:44, 3 T, quadrature RF coil and 30Hz linebroadening; see Appendix B for more detail).

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99 0 1 .... + + -# -.... -. . ... . + ... -.. --. ---- -~ . .+ 2 -- E ---,( - CJ ..-+-. -_--tr a ,,. l=l ,,. -)( r-1 ,,. Field of ,,. D - r-1 3 -.,, 0 View L 7 Q) D X / I-~/ 0 :> 0 -0 .42 cm .: f X / p _, Q) 4 o-38 cm H I m I 0 & 6 _34 cm I + U) I 30 I ,, # I -)( cm 4-1 5 : / 0 )I( 26 cm I 0 Q) 22 'O cm rl : I U) 6 ,'' 18 cm ---, ... +. -I Q) I ,P. 14 cm N r-1 U) ., 7 r-1 ; I Q) I X 0 I :> 8 H ... U) ,' I u .' I I ' 9 I I t +I I I I I 10 I 0 20 40 60 Time of Acquisition (minutes) Figure 26. Chemical shift imaging (CSI) voxel sizes versus time of slice plus 2D CSI acquisition on GE Signa Advantage ( *TR= 2 seconds, 128 acquisitions, and 8 NEX). The figure demonstrates the long times necessary to obtain smaller voxel sizes with CSI.

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RF Pulse Rhol RF Pulse Theta Slice Encoding Grad:Lent Phase Encoding Gradient 1 Phase Encoding Gradient 2 Signal 100 _____ ,,.--------'\"-----------------i .... Figure 27. The SPINECHO pulse sequence, one of GE's versions of Spin Echo for spectroscopy acquisition. MDPA . . . \ . . . . . . . Figure 28. Frequency domain of SPINECHO CSI multivoxel localized phosphorus spectroscopy. (Parameters: 512 acquisitions, 2000 Hz spectral width, 2 sec TR, 3 x 3 x 3 cm3 voxel, scan time of 32:40, 3 T, quadrature RF coil and 30Hz line-broadening; see Appendix B for more detail)

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RF Pulse _, Gradient~ Signal 101 180 adiabatic inversion pulse 90 adiabatic half pulse ,...... Rephase Pulse Figure 29. The ISISCSI pulse sequence (as shown for one gradient), GE's versions of ISIS for volume, slice, column or voxel localization. Real MDPA . I I . . I .. 6 4 NaH2P04 .. --y ,,,.. ..... NaH2P04 C. I -, .. -.. t ....., 2 4 MDPA . --' z J \.. 0 ,..., ' . I . 10 0 10 Frequency (ppm) ( a) (b) Figure 30. Frequency domain of (a) ISISCSI slice localized phosphorus spectroscopy with (b) diagram demonstrating localization. (Parameters: 256 acquisitions, 2000 Hz spectral width, 2 sec TR, 2 cm thick slice, scan time of 8:44, 3 T, quadrature RF coil and lOHz line-broadening; see Appendix B for more detail).

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2 .0-1 o4 1 .s-1 o4 0 Real MDPA 10 0 -10 Frequency (ppm) (a) 102 MDPA y z X (b) Figure 31. Frequency domain of (a) ISISCSI column localized phosphorus spectroscopy with (b) diagram demonstrating localization. (Parameters: 256 acquisitions, 2000 Hz spectral width, 2 sec TR, 2 x 2 cm2 column, scan time of 8:44, 3 T, quadrature RF coil and lOHz line-broadening; see Appendix B for more detail). Real 6000 MDPA MDPA 4000 y 2000 z 0 X 10 0 -10 Frequency (ppm) (a) (b) Figure 32. Frequency domain of (a) ISISCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization. (Parameters: 256 acquisitions, 2000 Hz spectral width, 2 sec TR, 2 x 2 x 2 cm3 voxel, scan time of 8:52, 3 T, quadrature RF coil and lOHz line-broadening; see Appendix B for more detail).

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103 I 2 3 4 5 6 7 8 I 2 3 4 5 6 7 8 I 2 J 4 5 6 7 8 I 2 3 4 5 6 7 8 (a) Total Acquisition Time= 32 x Short TR (or 32 x Long TR) 1 3 5 7 Result: Poorly Localized Voxel Acquisition with Short TR (Good Localization but Long Acquisition Time with Long TR) I 1 ] 2 2 2 2 3 3 3 4 4 4 4 5 5 5 6 6 6 6 7 7 7 8 8 8 8 (b) Total Acquisition Time= (32 x Short TR) + (7 x Long TR) Result: Well Localized Voxel Acquisition # .__,_ ISIS volume acquisition 1 to 8 = short TR = long TR Figure 33. Visual display example of the acquisition where the total number of acquisitions is 32 performed by (a) the current GE ISISCSI technique, and (b) the modified ISIS technique.

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104 Real MDPA MDPA y 4 5 2 5 z X 0 10 0 -10 Frequenc y (ppm) (a) (b) Figure 34. Frequency domain of (a) modified ISISCSI localized voxel sequence for phosphorus (created from eight separate acquisitions, added and subtracted appropriately during post-processing) with (b) diagram demonstrating localization. (Parameters: 64 acquisitions, 2000 Hz spectral width, 2 sec TR, 2 x 2 x 2 cm3 voxel, scan time of 2:13 for each of 8 acquisitions, and lOHz line-broadening; see Appendix B for more detail) RF Pu.lse s.11.ce Signa.l 90 pu.lse FID time Figure 35. The FIDCSI pulse sequence without phase encoding gradients turned on, GE's versions of the simple single RF pulse necessary to produce an FID for a spectroscopy acquisition.

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105 6000 5000 .-1 n:s 4000 -, tn 53 mm deep rt .. CJ} deep .. 63 mm 3000 ... .......... QJ -:> - 73 mm deep rt .. -.w lt1 2000 -.-1 - Q) ... .. Note: Optimum 0:: -.. - signal not -, 1000 -.. ,ill reached for 63 & 73 mm depth -0 (need TG >= 200) 0 50 100 150 200 Transmitter Gain (TG) (a) quadrature coil a t 1.5 T 10 9 8 7 6 5 4 150 160 170 180 190 200 Transmitter Gain (TG) (b) single turn coil at 1.5 T Figure 36. Charts comparing (a) relative signal obtained by varying transmitter gain (TG) values at various depths for slice localized FIDCSI at 1.5 Tesla, using the quadrature coil and (b) relative optimized TG value versus depth for the single turn coil (measurements done by Dr. Hee-Won Kim). These phantom values can be used to estimate proper TG values at depth in human studies.

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,--I m 80000 70000 60000 fii 50000 -rl Cf} 40000 ., 106 30000 -- -----, -.. -....... 20000 10000 ff 0 0 --"' so 100 TG (a) Quadrature Coil at 3.0 T ,--I m tn 35000 30000 25000 rl 2 0 0 0 0 Cf} 15000 . . -. -, r ... .. ' -# 10000 '-------~--5000 0 0 50 100 TG (b) Single turn coil at 3.0 T 150 -150 ' 200 ' ' 200 ___ 46 mm deep ___ . 5 7 mm deep 66 mm deep ___ 43 mm deep _ __ 52 mm deep 63 mm deep Figure 37. Charts comparing relative signal obtained by varying transmitter gain (TG) values at various depths for slice localized FIDCSI at 3.0 Tesla, using (a) the quadrature coil, or (b) the single turn coil. These phantom values can be used to estimate proper TG values at depth in human studies.

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3.0 5 2.5 5 2.0.1 o5 1 5 o5 1 .0-1 o5 5 0 4 MDPA Real Q-L----~--' 10 0 10 Frequency (ppm) Real MDPA 24 0 10 0 10 Frequency (ppm) 107 MDPA y z X ( a) MDPA y z X (b) Figure 38. Frequency domain of FIDCSI slice localized phosphorus spectroscopy of (a) gate-able phantom and (b) depth phantom. (Parameters: 128 acquisitions, 2000 Hz spectral width, 2 sec TR, 2.5 cm thick slice, scan time of 4:26, 3 T, single-turn RF coil and lOHz linebroadening; see Appendix B for more detail).

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.. ,~',(, }'f .. ,, '' 1:: I l I l i~ ,, '. -~ 11 .. II .. ., ' JI ~ II ., II -I Fl II n 11 11 n ~ ., ., ,.. n ,::(:t?: ll ... ;;-' .. ... .. ..... ,. I ;:,:f:'1 .. ,/' '' ,, .. '" .... ,, ... ,, t .+. ~:1,.,.1, 1-)j.'~~\';d!,, .:,1,,11.. ,,,. .. .;t , i, 1 .. ,: ,,,.,,. ,;:~. ,,,,:1:n:i. ';, . .' ""'" '')ti-1,11 " I , I ,~, lfl'I .. ,,:,, ''\\''''} -: '''."' ,_,J "1-,...,,,.,,, .,. '<,\f, -~" 1'-'-'-'( ,,,_,h ,1t, -,~'N".I' J !' '1.1,:':!:t:11:.+t!' ';,, ''<'/~:-:~ tt .. ~: ., -~''*11 ,,., ...,1: ,,~~NX, 108 (a) Gate-able Phanto m l 1 V ....... I 1 I I ' l I I'-.. .::,. . .. J . I ... . . ... .. I j . l . V \. / . \ ... .. .. V ... / . .. .. . ... ..' ...... . .. ... .. .. .. ... . .. . MDPA ( b ) Depth Phantom J . . I/ ........ l l I I 1 l .,,, ..1 _,,,; v~.. . l ./ / . . .. i I j I .. . .. I I l I .. I I . .. . . Figure 39. Multivoxel phosphorus FIDCSI plus CSI o f the ( a ) gate-a b l e phanto m ( b ) d e p t h phantom. (Parame t e r s : 256 a cquisitions, 2000 Hz spectral width, 2 sec TR, 2 x 2 x 2.5 c m3 v oxels scan time o f 4:59 and lOHz line-broadening; see Appendix B for more d etail)

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109 MDPA 10 0 -10 10 0 10 10 0 -10 Frequency (ppm) Frequency (ppm) Frequency (ppm) {a) 1.5 T Single Turn (b) 3 T Single Turn {c) 3 T Quadrature Figure 40. Comparison of 1.5 to 3.0 Tesla results of phosphorus FIDCSI plus CSI localized voxel scaled by noise level. (Parameters: 256 acquisitions, 1000 & 2000 Hz spectral width at 1 5 & 3 T, 2 sec TR, 2 x 2 x 2.5 cm3 voxels, scan time of 4:59, and lOHz line-broadening; see Appendix B for more detail). MDPA 1 0 0 -10 10 0 -10 10 0 -10 Frequency (ppm) Frequency (ppm) Frequency (ppm) (a) 1.5 T Single Turn (b) 3 T Single Turn {c) 3 T Quadrature Figure 41. Comparison of 1.5 to 3.0 Tesla results of phosphorus, modified ISISCSI localized voxel {created from eight separate acquisitions, added and subtracted appropriately during postprocessing). (Parameters: 256 acquisitions, 1000 & 2000 Hz spectral width at 1.5 & 3 T, 2 sec TR, 2 x 2 x 2 cm3 voxels, scan time of 2:13 each of 8, and lOHz line-broadening; see Appendix B for more detail).

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5 100.00% .-f .w Ill u 0 ..:i (1) u .-f ,-I C/) .c 0 Ill w Ill ,-I Ill 6i rl C/) Q) > .-f .w Ill .-I 90.00% 80.00% 70. 00% 60.00% 50. 00% 40.00% 30.00% 20.00% 10.00% 0.00% phanto m n o t part of phantom in slic e -rep:resents--i potential contamination _by skeletal --muscle 110 entire phantom in slice part of phantom in slice phantom not represents potential contami_nat1on by J:llood -40 -35 -30 -25 -2 -15 -10 0 1 0 15 20 25 30 35 40 Center Position of 25 mm Thicks ice Moved Across Slice Profile Phantom mm Below ( ) and Above(+) Ce nter of Internal P hantom (center=O) Figure 42. 1.5 T, P-31 single turn RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice) moved across the internal phosphoric acid vial in the Slice Profile Phantom. The data obtained when the entire slice was outside the H3P04 phantom represents the amount of potential contamination from above or below the slice. 100. 00% .-f .w Ill 0 0 ...::i Q) 0 .-l ,-I Cl) ..c: u ro w 111 ,-I .-f Cl) .-f .w Ill ,-I Q) 90. 00% 80.00% 70.00% 60.00% 50.00% 40.00% 30. 00\-20.00% 1 0 .00% 0.00% phantom not ._ represent s potential contamination ..b)L.Skeletal muscle part of phantom in slice entire phantom in slice part of phantom in slice phantom not rep :re s ent.. s potential contamination by blood l-----::!::~~ J --,----L J _H~3P~O~~\..-L---l~~~~~t!.:t:ti::::*=:J -40 -35 -30 -25 2 -15 -10 0 10 15 20 25 30 35 40 Center Position of 25 mm Thick S ice Moved Across Slice Profile Phantom mm Below() and Above(+) Center of Phantom (center=O) Figure 43. 3.0 T, P-31 single turn RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice) moved across the internal phosphoric acid vial in the Slice Profile Phantom. The data obtained when the entire slice was outside the H3P04 phantom represents the amount of p otential contamination from above or below the slice.

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100.00% ..... J.) 0 ..::i Ql u ..... rl C/l ..c: u "' lil .u "' rl Ill i:: Ol .-! Cf) QJ :> rl J.) ct! rl Cl) 0: 90.00% 80.00% 70.00% 60.00% 50.00% 40 .00% 30.00% 20.00% 10.00% 0.00% phantom not :represent..s potential contamination by skeletal muscle part of phantom in slice 111 entire phantom in slice part of phantom in slice phantom not repr.esent.s potential conta-mination b-})lood -40 -35 -30 -25 -2 -15 -10 0 10 15 20 25 30 35 40 Center Position of 25 mm Thick S ce Moved Across Slice Profile Phantom mm Below(-) and Above(+) Center of Phantom (center=O) Figure 44. 3.0 T, P-31 quadrature RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice) moved across the internal phosphoric acid vial in the Slice Profile Phantom. The data obtained when the entire slice was outside the H3P04 phantom represents the amount of potential contamination from above or below the slice.

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CHAPTER 4 HUMAN CARDIAC P-31 SPECTROSCOPY ACQUISITION TECHNIQUES Even after conducting phantom measurements to optimize the techniques for the human studies, further work must be done to maximize the quality of the human acquisitions and results. This chapter summarizes the tests and qualifications of the methods for looking noninvasively at the human heart with MR imaging and spectroscopy. First, the imaging is optimized for viewing the heart, via patient position, pulse sequences, and RF coils. Second, the spectroscopy acquisition techniques are optimized for the more complex human proton and phosphorus spectra, again based on patient position, pulse-sequences and coils. The optimization for each also includes looking at the best methods for gating the images and spectroscopy acquisitions from the heart. Next, the comfortable positioning of the participants was enhanced through ergonomic placement during the long study. A magnetsafe handgrip was designed for inducing stress on the heart via a steady grip. First, volunteers were tested to evaluate the quality of the protocol. The results of the studies were post-processed to eliminate blood contamination, evaluated for skeletal muscle contamination, and corrected for relaxation due to short repetition times during data acquisition. The results of the studies were evaluated in terms of peak amplitude ratios and peak area ratios. 112

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113 Imaging Images in this study are not used for diagnostic accuracy but instead to find landmark anatomical positions for purposes of localized phosphorus spectroscopy acquisitions. A simple, fast image is all that is needed to determine the proper location of the heart so that the phosphorus phantom can be positioned properly over the anterior of the heart, near the left ventricle. Gating is also important to keep the acquisitions timed with the cardiac cycle. Images are cardiac gated but not respiratory gated. Both spin echo and gradient echo images were obtained and compared at 1 5 T (GE Signa Advantage at Shands at UF) and 3 0 T (GE Signa Advantage in VAMC tunnel). Chest imaging was performed with the transceive body coil on the 1.5 T and with the 25 cm square proton surface coil at 3.0 T. Spin-Echo Imaging In the GE spin-echo imaging pulse sequence, a 90 RF pulse is followed by a 180 phase reversal pulse every TE/2, with the 90 pulse repeated every TR milliseconds. The 90 pulse creates transverse magnetization which is read in the form of a spin echo TE milliseconds after the initial 90 pulse.219 At 1.5 T the combination of the transceive body coil and spin echo imaging technique provided very homogeneous images over an axial slice of the heart, as shown in Figure 45(a). This image was achieved with a transmitter gain (TG) of 120. At 3.0 T, the combination of the 25-cm proton surface coil and the spin echo imaging technique, required a TG value above 200, although 200 is the system limit, to penetrate to the depth of the heart. There was not

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114 enough power, therefore, to penetrate to the depth of the heart, as shown in Figure 45(b). Breathhold imaging was not required. Gradient-Echo Imaging The gradient echo uses a single partial flip-selective RF pulse, which is then rephased by an inverted slice-selection gradient. As such, the 180 pulse in the spin echo sequence is replaced by actions of the gradients. The gradient echo can produce an image quicker by allowing shorter TR and TE times, but with less SNR than the spin echo sequence, due to the smaller tip angle. As shown in Figure 46 the image quality of the gradient echo with a 60 tip angle is reasonable at both 1.5 T and 3.0 T, although the breathhold is necessary to reduce motion artifacts. Human Positioning The total time a volunteer must remain in the GE Signa Advantage magnet to obtain cardiac localized phosphorus spectra, with in-magnet exercise, runs from about 1.5 to 2 hours total time. As this is much longer than the typical MRI clinical study, which runs from 20 minutes to 1 hour, it is critical that the person be positioned in the magnet as comfortably as possible, especially to ensure minimal motion during the study (due to restlessness). Both prone and supine positions were tried in the magnet at optimal comfort levels for each. The supine position was easily accomplished with a few added amenities. The magnet table was padded with an additional layer of egg-crate foam and a pillow was added for head and neck support. A second pillow was placed under the knees to

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115 relieve pressure from the lower back. This position has proved very comfortable based on the number of volunteers who had fallen asleep. Some even snored during the study. The prone position was maintained via the use of a foam, portable massage-bed (the M.A.T. by A2Z Possibilities, Inc. ) which elevated the shoulders and chest, positioning the head in a cradle and putting the neck at an ergonomic angle, as shown in Figure 47. This mat was designed to keep the spinal column in the proper muscular-skeletal position when face down. It includes a face cradle with a large breathing passage, a pelvic tilt in the main body support to alleviate lower back compression, and a foam roll for the ankles to lessen stress to the calves or shins. This setup was magnet safe, and the width was cut to fit into the magnet with a person. Unfortunately, this bed was not equally comfortable for all subjects: two subjects were able to stay in the magnet for the entire time, but another two subjects could not stay in the magnet for more than 20 minutes. This orientation also made it difficult to adjust the position of the surface coils (both proton and phosphorus) once the session had started, as it required that the volunteers lift themselves up while the coil was repositioned beneath them. This could also potentially be a major problem with women with large breasts, where other modifications in the massage bed would probably have to be made. Because of the heart's position, there are advantages and disadvantages for both prone and supine positioning of the person within the magnet, as shown in Figure 48. In the prone position, face down, there is a shorter distance from the heart to the chest wall. Rotating a person to a 30 angle can move the heart even closer to the

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116 chest wall, thereby minimizing the lung/air gap created between the heart and chest wall.1 4 9 Prone positioning thus allows for placement of the heart closer to the phosphorus surface coil, thereby increasing SNR. In addition, the shim is better over a consistent region of tissue (chest skeletal muscle and cardiac muscle layered), without the air gap. The respiratory motion artifacts will also be at a minimum in the prone position. Unfortunately, the positioning of the heart so close to the skeletal muscle in the chest wall puts more stringent requirements on the localization of the P-31 spectroscopy pulse sequence to eliminate skeletal muscle from the cardiac muscle acquisition. The supine position does allow the heart to fall back away from the chest wall, creating an air gap. This air gap, in addition to the motion of the heart, makes shimming more difficult, but localization to the cardiac muscle is more easily achieved. Therefore the supine position was used for most of the cardiac trial acquisitions in this chapter and for all of the repeated tests in the results chapter. Gating Gating is a method of monitoring the heart's cyclic behavior and using that signal to trigger the scanner acquisition in synchrony with the heartbeat, thus allowing multiple measurements to occur at the same time point in the cardiac cycle. Two options for gating can be used on the GE Signa Advantage 1 5 and 3.0 T systems, peripheral gating (via finger clip) or electrocardiogram (ECG) cables. Each option has its advantages and disadvantages. Both the ECG and peripheral gating (PG) provide a periodic up and down signal that represents the cycles of the

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117 heart's beats, as shown in Figure 49. PG is a measure of the pulse, or the mechanical action of the blood pulsing through the body. PG is obtained via a finger clip using a photopulse sensor to monitor the pulse within a person's finger. Conversely, the ECG directly measures the heart's electrical activity during the heart cycle. The signal measured by PG tends to produce a broad peak, while the ECG signal produces a narrow peak as part of the QRS complex of the signal. In addition, PG can be slightly delayed by the time it takes the pulse to travel from the heart to the finger. This delay time was shown to be negligible by comparing images gated with ECG and PG, where the same part of the cardiac cycle was frozen in time, as shown in the sagittal images of Figure 50. In ideal circumstances where the quality of both the ECG and PG signals are perfect, the ECG pulse is optimal. The PG uses a fiber optic cable and thus its signal is not compromised by the fluctuating magnetic fields in the bore. Conversely, the ECG cables are copper cables that can induce a signal, just like a radio frequency coil, especially when any curvature exists in the ECG cable line. It is very difficult to place the cables perfectly straight, in addition to getting the optimal signal from the electrodes that are placed on the body. In reality, the resulting signal from the PG is often of higher quality than that of the ECG due to the interactions with the magnetic field. In addition, the peripheral gating takes less time to set-up. At 1.5 T, the ECG signal is lost mostly during the use of the gradients, but at 3.0 T, just the act of sliding the patient into the main magnetic field is enough to reduce the quality and SNR of the ECG signal. The system uses the cyclic signal to predict when the next

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118 heart beat will occur, therefore the signal providing better SNR will allow for more accurate gating. Images can be further improved by performing a quick breathhold of 10 to 20 seconds, depending on heart rate, and using fast gradient echo imaging. This explains why the sagittal and axial peripheral gated images are sharp, during breathhold imaging, as shown in Figure 50. The option of respiratory gating was not considered optimal for this study. Respiratory gating relies on adequate use of a baffle that is stretched over the chest or abdomen and produces an oscillatory signal, corresponding to the breathing cycle. Combining gating of the heart and breathing produces a very long acquisition time, in addition to problems due to typically non-regular breathing rates if both the cardiac and respiratory gating cycles are to coincide to trigger acquisition. Since imaging can be done with fast gradient echo in less than 20 seconds, breathhold imaging makes more sense. Spectroscopy acquisitions, however, are too long (6 minutes or more) to allow for breathhold. If the sequence acquisition were triggered based on the heart rate and respiratory rate coinciding, an irregular and longer TR time would result, substantially increasing the total scan time. A possible future option is to record the heart rate and respiratory motion along with the spectrum acquisition and use post-processing techniques to compensate for the signal changes caused by the cardiac gating and respiratory motion. Advanced signal processing is being developed, such as independent component analysis (ICA), which can deconvolve the components of a complex signal into separate signals that are independent of each external contribution.220

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119 An alternative would be to eliminate gating and attempt to correct for the blood/skeletal muscle contamination that occurs even in the ungated data. This would be similar to the approach used in some nuclear medicine cardiac exams where gating is not used since the overall signal is small and would require long acquisition times.7 Such an approach could only be done in conjunction with multi-voxel CSI, as single voxel localization techniques such as ISIS are motion sensitive, depending on the subtraction of identical areas to suppress signal outside the voxel of interest. Even with multi-voxel CSI, the lack of gating would blur the signal into less precise volumes of interest. Shimming with Localized Proton Spectroscopy As explained in the last chapter, localized proton spectroscopy is necessary to perform shimming of the volume of interest before acquisition of the P-31 spectrum. From theory, it is expected that PRESS will provide twice the SNR of STEAM. On a single subject (Female, age 46), both the GE PRESSCSI and STEAMCSI were acquired from the same voxel. The PRESSCSI sequence was first used to acquire a voxel 41.0 x 59.1 x 30.0 mm3 voxel, with a majority over the anterior heart and a minority in the chest wall for added signal for shim. The PRESSCSI protocol was as follows: 1000 Hz spectral width, 1024 points, 16 acquisitions, 40 msec TE, TR peripheral gated to every other heart beat, TG 70, scan time 40 seconds and a depth of 66 mm. With no change in the shim settings or selected voxel, a second localized proton spectrum was then acquired with STEAMCSI, with all other parameter settings the same. The result of this human experiment comparing GE's PRESSCSI and STEAMCSI is shown in Figure 51. The resulting FWHM for

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120 the water peak for the PRESSCSI and STEAMCSI spectra are 40. 8 Hz (0.32 ppm) and 43. 4 Hz (0.34 ppm), respectively. In addition, the SNR for the water peak is 2330 for PRESSCSI and 1100 for STEAMCSI This data was obtained from a Gaussian fit of the peaks. Cardiac Phosphorus Spectroscopy In-Vivo Acquisition All 1.5 T and 3.0 T cardiac phosphorus spectroscopy results shown in this dissertation were obtained with either the P-31 single turn or quadrature RF coils. The P-31 RF coils were held in place on the anterior chest with an elastic and Velcro strap. Localized P-31 Multivoxel CSI Proceeding with introducing phosphorus spectra in order of increasing optimal acquisition results, the next sequence to consider is multivoxel chemical shift imaging (CSI). Multivoxel CSI is the acquisition of a slice of interest, which is then broken down into a set of voxels by additional phase encoding gradients. The finer the desired resolution, the greater the acquisition time, assuming a constant field of view (FOV). Smaller voxels within the CSI can be achieved in less time by reduction in the overall FOV. One of the main advantages of using multivoxel CSI is that spectra from several voxels can be obtained simultaneously although at the cost of increased scan time. In addition, compared to other phosphorus voxel localization techniques, CSI is able to obtain higher quality localization within each voxel although some signal bleed still does exist, especially along the same horizontal or vertical direction of voxels away from the voxel of interest. Additional problems with CSI include long

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121 acquisition times to achieve the desired small areas of localization and non-flexibility in moving voxel positions over the desired anatomy. (The CSI grid is centered in FOV). An example of how multivoxel CSI can be used to obtain cardiac spectra is shown in Figure 52, which shows a 6 x 6 CSI obtained in 12 minutes with a FOV of 20 cm, resulting in 35 x 35 x 30 mm3 voxels. Localized P-31 ISISCSI It has been shown via a phantom study that the ISISCSI protocol that comes standard on the 3.0 T system does not do an adequate job of localizing in a simple non-moving phantom. A protocol was created whereby the user could obtain 8 separate acquisitions and, via postprocessing, co-add and -subtract the acquisitions properly to obtain excellent localization of a cubic area predefined by the user within the FOV. Although this protocol works, it is not practical to use during human, in-vivo cardiac P-31 spectroscopy acquisitions for several reasons. First, the user must be able to see the spectra at the time of acquisition to be sure that the acquisition voxel is optimally placed to get maximal SNR from the cardiac muscle while minimizing the skeletal muscle contamination. Second, the acquisition of 8 separate spectra would be difficult to be coordinated enough to acquire while at the same time taking patient blood pressure and/or coaching the patient to exercise in the magnet. For these reasons, Dr. Hee-Won Kim has been attempting to create a more automated pulse program that would accurately acquire 8 or more separate spectra and, co-add and subtract the results in real time for display during the acquisition.

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122 Slice Localized P-31 FIDCSI {DRESS) The best possible working localization method on the 3.0 T system can be achieved with a slice select FIDCSI sequence that has been modified to allow oblique acquisitions close to the coronal plane. The pulse sequence modifications where performed by Dr. Hee-Won Kim using GE's EPIC pulse programming. This method of localized spectroscopy acquisition is based on the Depth Resolved Surface Coil Spectroscopy (DRESS) method. This method localizes via a combination of the oblique slice localization in combination with the sensitivity range of the phosphorus surface coil, as shown in Figure 53. This method of slice localized spectroscopy is a bit tricky to use for localization. As will be dealt with further in the next chapter, it is easy to obtain contaminated spectra, as shown in Figure 54. The results of slice localized spectroscopy at both 1.5 T and 3.0 T with rest and exercise are shown in Figure 55. At 3.0 T, due to the increased spectral dispersion, is it often easy to view the skeletal muscle contamination as a split in the PCr peak as shown in Figure 56. This figure shows slice localized phosphorus spectroscopy acquisitions, increasing with depth. It demonstrates how the skeletal muscle PCr peak dominates in the shallower slices. As the slices go deeper into the chest, the cardiac muscle PCr dominates, and the overall SNR decreases. This split of the PCr peak in cardiac phosphorus spectroscopy has been previously noted by Dr. Jan den Hol lander195 and Yabe et al 60.

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123 Single Turn versus Quadrature Surface P-31 Coil at 3.0 T The single turn coil is the most often used coil for obtaining in-vivo, human cardiac spectra as posted in the literature. Improved SNR can be achieved by using a quadrature coil in its place, as was demonstrated in the last chapter with phantom studies. The problem with using the quadrature coil for looking at the heart is that it has a large volume of sensitivity and thus greater potential for contamination. With localized pulse sequences such as multivoxel CSI and ISIS, the added SNR that the quad coil provides produces optimal results. Unfortunately, with DRESS, where the surface coil is used to help localize, there can be added skeletal muscle contamination unless the slice of interest is placed much deeper in the chest than would be done with a single turn coil on the same volunteer, as shown in Figure 57. A statistical comparison of the single and quadrature P-31 surface coils is available in the chapter on reproducibility. Human Test Participants Two main groups of participants were used. The first group was those used to obtaining cardiac P-31 MRS at 3.0 T. The second group was used to test the hydraulic handgrip exerciser at a 30% maximum exertion. To test the protocol of obtaining localized cardiac P-31 spectra at 3.0 T, three types of volunteers were used, as shown in Table 14. The first person listed is a referred cardiac patient from the WISE study with suspected microvascular ischemia. The second participant listed is a person who was asymptomatic, but had a recent treadmill ECG and was found to have a 1 mm ST segment depression indicating mild

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124 myocardial ischemia. Third, a group of participants (4 Male, 4 Female) who were not clinically tested for ischemia, but were non-symptomatic were also tested. These participants were also questioned about possible risk factors for heart disease (smoking, family history, exercise level, height/weight) and had their resting heart rate and blood pressure measured. Based on the results of height and weight, a body mass index (BMI) factor was calculated for each participant who had not been medically evaluated for ischemia. The BMI is a numerical factor that allows comparison, regardless of height, of the relative weight of individuals. 221 BMI = Weight(pound) 703 Heighttinches)2 Equation 5 Any BMI value far above 25 is considered overweight, a risk factor for heart disease. This group was used to obtain localize cardiac P-31 spectra at 2 to 3 different TR intervals for estimating T1 relaxation corrections at 3 T. The third group was not used to obtain any exercise cardiac P-31 MRS since although they were asymptomatic, their non-ischemic status was had not been verified by medical tests. The second group of participants, as shown in Table 15, was used to evaluate the adequacy of the hydraulic handgrip in producing sufficient changes in heart rate and blood pressure to adequately stress the heart. The hydraulic handgrip is used isometrically at 30% of maximum exertion. Four participants were non-symptomatic although one of the four had been tested clinically for myocardial ischemia and was found to have mild ischemia, based on an ECG treadmill test. The remaining 28 subjects were patients referred from cardiology based on

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125 chest pain, ''lowu percent stenosis (as measured in a coronary angiogram study), and suspected microvascular ischemia (the WISE study). Less than 50% stenosis is considered ''low''.4 Two participants had tests at both 1.5 and 3.0 T, as noted. Since most of these tests were performed at 1.5 T and not at 3.0 T, the data that is relevant to cardiac spectroscopy at 3.0 Tis limited to the use of the hydraulic handgrip cardiac response. Human participants signed an IRB consent form (examples found in Appendix A) and were screened individually for potential health risks associated with 3.0 T magnetic resonance proton imaging and phosphorus spectroscopy (metal in the body, peripheral vascular disease, heart disease etc.). Volunteers were positioned in the magnet and made as comfortable as possible. Although the phantom work is useful for determining the quality of the pulse sequence acquisitions, human volunteers are necessary at an early stage. Human volunteers were used to test techniques designed to obtain a phosphorus spectrum from a moving heart, and to apply post-processing techniques that correct for blood and skeletal muscle contamination and relaxation effects.

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126 Table 14. Participants at 3.0 T for Cardiac P-31 Spectroscopy. Initials E.O. K.S. T.B. C .M. W.P.* D.P. L.R. L.B. Age & Gender 54 y .o. Female 66 y.o. Female 29 y.o. Male 26 y .o. Female 59 y.o. Male 29 y.o. Male 28 y.o. Female 50 y.o. Female Heart disease? WISE referral: chest pain with suspected microvascular ischemia, low 39% stenosis non-symptomatic, mild myocardial ischemia, treadmill ECG showing 1 mm depression of ST segment indicating mild ischemia non-symptomatic, mildly physically active, not clinically evaluated for ischemia non-symptomatic, average physically activity, family history of heart disease, not clinically evaluated for ischemia non-symptomatic, highly physically activity, family history of heart disease, not clinically evaluated for ischemia non-symptomatic, average physically activity, family history of heart disease, not clinically evaluated, ischemia non-symptomatic, average physically activity, family history of heart disease, not clinically evaluated for ischemia mitral valve prolapsed, average physically activity, family history of heart disease, not clinically evaluated for ischemia BMI 25.9 23.9 25.7 19.2 25.1 25.5 20. 2 23.8 C.S.** 46 y.o. heart murmur, possible leak of mitral valve, highly physically active, family history of heart disease, not clinically evaluated for ischemia 27.41 Female R.B. 48 y.o. Male non-symptomatic, average physically activity, family history of heart disease, not clinically evaluated for ischemia 24.5 poor SNR with W.P. study resulted in data that Fitmaster'M was unable to process ** study not completed on C.S. due to claustrophobia while in the magnet

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127 Table 15. In Magnet Hydraulic Exercise Handgrip Participants. Cardiac Age & P -31 Initials Gender Heart disease? Site E.Q. 25 y.o. F non-symptomatic 1.5 T S.P. 56 y.o. F non-symptomatic 1.5 T 1.5 T A.B. 43 y.o. F non-symptomatic K.S. 66 y.o. F non-symptomatic, mild myocardial 1.5 & 3T ischemia E.O. 54 y.o. F WISE (39% stenosis) 1.5 & 3T G.N. 55 y.o. F WISE ( 0% stenosis) 1.5 T B.H. 51 y.o. F WISE (29% stenosis) 1.5 T S.E. 60 y.o. F WISE ( 0% stenosis) 1.5 T S.H. 58 y.o. F WISE (60% stenosis) 1.5 T E.K. 65 y.o. F WISE (36% stenosis) l.5 T E.B. 54 y.o. F WISE (no CA data available) 1.5 T H.P. 74 y.o. F WISE (24% stenosis) 1.5 T S.J. 53 y.o. F WISE ( 75% stenosis) 1.5 T S.A. 53 y.o. F WISE (0% stenosis) 1 5 T J.G. 65 y.o. F WISE (57% stenosis) 1.5 T L.C. 49 y.o. F WISE (0% stenosis) 1.5 T J .F. 67 y.o. F WISE (0% stenosis) 1.5 T H .T. 55 y.o. F WISE ( 0% stenosis) 1.5 T J.D. 72 y.o. F WISE (no CA data available) 1.5 T R.S. 40 y.o. F WISE ( 0% stenosis) 1.5 T M.P. 66 y.o. F WISE ( 0% stenosis) 1.5 T G.0. 56 y.o. F WISE (no CA data available) 1.5 T E.W. 50 y .o. F WISE (no CA data available) 1.5 T G.A. 60 y.o. F WISE ( 0% stenosis) 1.5 T A.S. 61 y.o. F WISE (36% stenosis) 1.5 T K.G. 39 y.o. F WISE (no CA data available) 1.5 T N.W. 62 y.o. F WISE (no CA data available) 1.5 T M.A. 52 y.o. F WISE (no CA data available) 1.5 T L.H. 51 y.o. F WISE (no CA data available) 1.5 T D.M. 69 y.o F WISE (no CA data available) 1.5 T Abbreviations: WISE= chest pain with suspected microvascular ischemia, F = female, -= measurement not made, *=blood pressure measured from ankle instead of forearm, CA= coronary angiogram where% stenosis is measured

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128 In-Magnet Exercise The design criterion of the in-magnet exerciser includes getting the most value for the least cost. In addition, the selected exercise device must not cause added motion to the chest region that would interfere with the signal acquisition, effectively decreasing the SNR. The exercise must be sustainable for the duration of the time necessary to obtain one set of data (i.e. averaged and gated). Studies have shown this time period can vary from three149 to 40 minutes,15 depending on the voxel size and selected pulse sequence, due to the small volume of the myocardium and the extended acquisition time necessary for gating. An isometric handgrip ergometer has been created that is simple and cost effective. A hydraulic system was designed with a rubber bulb at one end of 30 feet of plastic tubing, with a 30 psi, hydraulic, analog gauge at the other end, as shown in Figure 58. The rubber bulb is placed in the participant's hand while in the magnet. A maximum contraction of the bulb is recorded as a pressure difference on the analog gauge. The linear response of the handgrip was tested by placing a gradient of weights on the bulb and it was verified that the handgrip does respond linearly, as shown in Figure 59. Thirty percent of that maximum exertion is used as the level of work to keep the participant isometrically squeezing the handgrip to put a stress on the heart. The stress level is monitored both by the level of isometric grip and via vital signs measurements. Specifically, the blood pressure and heart rate are recorded every two minutes during rest, exercise and two recovery periods. The hand chosen to squeeze the bulb

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129 is the opposite to which the blood pressure is taken via a Dinamap monitor, as shown in Figure 60. The analog gauge on the exercise equipment could be replaced at some point with a digital gauge that would allow for recording of the pressure levels during rest and isometric exercise. Details on how to construct the hydraulic handgrip exerciser can be found in Appendix C. To test the adequacy of the hydraulic handgrip exerciser, all participants listed in Table 15 were monitored for heart rate and blood pressure during rest and during exercise. The exercise consisted of isometrically squeezing the hydraulic handgrip to a level at 30% of the subject's individual maximum squeeze effort. The results of these studies can be found in the next chapter. Spectroscopy Post-Processing Simply obtaining a phosphorus spectrum from a voxel in the myocardium is not enough to ensure useful spectral data. The spectra must be post-processed using specialized software such as Sage_ IDL, MRUI or FELIX. This software allows the spectrum to be measured to quantitatively produce ratios of different metabolites. The results of these ratios can then be examined for skeletal muscle contamination. Also, since the localization procedure obtains signal from cardiac muscle and blood, the spectrum must be corrected for blood contamination. Finally, relaxation corrections that account for acquisitions taken at times shorter than five times T1 (i.e. not fully relaxed) must be made. In addition, methods for calculating millimolar (mM) amounts will be evaluated.

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130 Post-Processing Software A number of spectroscopy post-processing programs are available for use; four different types were examined for this project: FITMASTER (Philips) 1 Sage_IDL (GE), MRUI (funded by European Community) and FELIX (Molecular Simulations, Inc.). Most human spectra obtained in the study for both 1.5 and 3.0 T were analyzed and evaluated by Dr. Steven Buchthal and Dr. Jan den Hollander at the University of Alabama at Birmingham (UAB). The UAB group has extensive publications with human, cardiac P -31 NMR spectroscopy beginning with Dr. den Hollander's work in Leiden, The Netherlands and continuing with work in Birmingham, Alabama. Their analysis was performed using FITMASTER. Post-processing techniques at UF were also evaluated using the available software of Sage_IDL1~, MRUI, EXCEL (Microsoft), FELIX and a header modification program created with help from Dr. Marian Buszko, UF Department of Microbiology and Cell Sciences. A detailed explanation of how each program was used to process data, in addition to comparative data analysis, can be found in Appendix E. Experience in post-processing human, in-vivo cardiac P-31 spectra was provided via a collaborative working arrangement with Dr. Jan den Hollander and Dr. Steven Buchthal at the University of Alabama at Birmingham (UAB). As part of an NIH contract on Women's Ischemic Syndrome Evaluation (WISE), 4 sites including UF and UAB took part in a study of women with chest pain, but not severe stenosis, in the major arteries of their heart as determined by cardiac catheterization. Both UAB and UF gathered MRS cardiac data on women in the WISE population, at rest and at exercise at 1.5 T and 3.0 T. All WISE data were sent to UAB for post-processing. UAB has a 1.5 T Philips system with

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131 exceptional capabilities for performing localized phosphorus spectroscopy. This system is in the Cardiology Division of the Department of Medicine at UAB and has been optimized for MR uses related to the heart. Dr. den Hollander originally came to UAB as an employee of Philips to work with UAB in optimizing their cardiac MRI and MRS capabilities. As part of his work with Philips, he helped create a post-processing program, called FITMASTER FITMASTER is optimized to do an excellent job of post-processing cardiac P-31 spectra, especially in terms of having the added ability to do linear prediction and fit the missing data at the start of the FID. Using FITMASTER, Dr. Buchthal has been able to do an excellent job at postprocessing the cardiac spectra for the WISE study, as was demonstrated by a very flat subtracted noise baseline of the FITMASTER fitted spectra for both 1.5 and 3.0 T. For all in-vivo cardiac P-31 spectroscopy figures the program that was used to post-process the data is noted in the appendix. Unfortunately, Philips only provides FITMASTER with the purchase of their magnet. The software cannot be purchased individually. Fortunately, we had the opportunity to work with UAB and get some results for this dissertation, which was analyzed by a group both experienced with cardiac P-31 spectroscopy and using the more sophisticated post-processing methods. This provides a standard to which the post-processing methods available at UF can be compared. As part of UAB's methodology for fitting the low SNR cardiac P-31 spectra, they first co-add all P-31 spectra obtained in the same study (rest, exercise, and recoveries). The summed data is then fit via back extrapolation to replace the initial, missing section of the FID.

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132 Fitting the beginning of the FID corrects for the baseline curve and creates a flat baselined spectrum. This higher SNR spectrum is then fit for each peak and the software is then primed with initial peak locations and widths. Next, spectra are individually fitted using the initial guesses for fit based on the summed spectra, but allowing just the peak heights to change, except for Pi which is allowed to change frequency position (as would be expected with a change in pH). This method takes advantage of optimizing SNR while obtaining the best results for even low SNR cardiac P-31 spectra. Other details of their post-processing include the use of Gaussian 15 Hz line broadening, and the fitting assumption that all three ATP peaks are of equal area. Unfortunately, we have found that the FITMASTER program's fitting routine is sensitive to SNR and does not work well with low SNR data. In one example, shown in Appendix E, a low SNR spectrum where each peak area was individually fit with SAGE IDL was found to not be contaminated by skeletal muscle based on a [PCr]/[ATP] ratio of -1.0. The same spectrum, processed and automatically peak area fit by FITMASTER, was found incorrectly to be a skeletal muscle contaminated spectrum based on a skewed [PCr]/[ATP] ratio of -2.00, when the true problem was low SNR. This is further proven visually by looking at the example spectra in the appendix, where the PCr peak is clearly altered from being shorter than ATP to being much larger. As shown in the next chapter, this may account for why the DRESS sequence appears to be so often more highly contaminated by skeletal muscle when compared to UAB's ISIS results. Despite this fault, this program has been designed to be extremely flexible and powerful in terms of post-processing cardiac P-31 MRS.

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133 Locally, the GE Signa Advantage system comes with a program designed to post-process spectroscopy data obtained on a GE system. This software, called Sage_IDL, is provided free to the user with the magnet. Like Microsoft Word runs on Windows 98, Sage_IDL runs on IDL (Interactive Data Language by Research Systems, Inc) a licensed program installed at the UNIX station. Sage_IDL requires the user first to convert the header of the GE data file using the "sdbm" command at the UNIX prompt. Once the new header has been created, the Sage_IDLr11 program can be run to do a variety of spectral post-processing tasks including apodization, zero-filling, fft, phase, basic baseline correction, peak picking, curve fitting, and spectral analysis. In addition, Sage_IDL can input and correlate images with multivoxel CSI data to overlay the voxels on the image for precise localization. Unfortunately, Sage_IDL does not have many options for baseline corrections. Missing is a method for performing time domain linear prediction and interpolation of missed data at the beginning of an FID, which is a necessary correction for localized cardiac spectroscopy acquisitions on the GE systems. Time domain extrapolation of the missing start of the FID has even been dealt with in a separate program by Schaefer et al.,161 due to the lack of its availability in most spectroscopy post-processing software. In addition, in Sage_IDLr11 the available baseline corrections in the frequency domain are based on a simple user input of points matching the spectral noise that represent the true baseline. For data with low SNR, such as cardiac P-31 MRS, points picked along the noisy baseline are jaggedly placed, creating unrepeatable and undesirable warpage rather than straightening of the baseline. This feature works well for spectra with high SNR and mostly

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134 flat baselines, but does very poorly for cardiac P-31 spectra which are inherently low SNR and have a non-flat baseline due to the loss of data at the start of the FID. The next viable software option for cardiac spectroscopy postprocessing is MRUI (Magnetic Resonance User Interface, the result of a collaborative project sponsored by the European Community). Since this software was developed as part of a research project, the licensure was free assuming a research agreement was signed. MRUI is designed to process data in the time domain, rather than the frequency domain. Like Sage_IDL, MRUI is able to do simple functions such as apodize, zero-fill, fft, phase, and fit spectra. As Sage_IDL ran from the IDL platform, MRUI runs from a Matlab (The Mathworks, Inc.) version 4X platform. Unfortunately, the most updated version of MRUI available (97.1 released September 1997) is not able to perform linear prediction and back fit the missing data at the start of the FID. Again, this fit when done using FITMASTER corrects for the distortion in the cardiac P-31 baseline caused by the cutoff of the start of the FID signal. In addition, because this software is designed for time domain fitting, frequency domain baseline correction methods are not available. FELIX (of Molecular Simulations, Inc) is the final postprocessing program available locally that has been evaluated in attempts to find the best software for post-processing cardiac P-31 spectra. FELIX runs on an SGI workstation, and standalone can be purchased at around $6,000 to $10,000 per site-license. At UF, FELIX is available for a single user at a rate of $160/quarter via the Brain Institute (David Parks, system administrator), as a shared expense site licensure. Along with the other standard spectroscopy post-processing

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135 techniques, such as apodization, zero-fill, fft, and phase, FELIX does have the ability to do linear prediction in a limited fashion. The linear prediction in the FELIX software is designed not to add missing points to the start of an FID, but to replace points at the start of an FID that have been corrupted by eddy currents. It appears that most spectroscopy acquisition systems acquire the entire FID and leave the choice of eliminating the beginning of the FID up to the operator during post-processing. The GE system, on the other hand, doesn't collect the start of the FID during acquisition that leads to problems, but their post-processing software does not provide a fix for these problems. To compound the problems with FELIX linear prediction, the utility for performing this task does its own peak selection based on the user inputting the number of peaks expected. The system can make mistakes, especially with split peaks or low SNR, and does not allow for user intervention to correct the computer's guesses for incorrect peak positions. The system then examines the peaks it has selected in the frequency domain and predicts the shape and number of co-added decaying sinusoids in the time domain resulting in an FID. It is clear that this program would work best with data with good SNR to ensure proper auto-selection of peak positions. This can be best achieved with the cardiac data by co-adding all the spectra from one study together (rest, exercise, recovery 1 and recovery 2) to get ideal fit parameters for all spectra with similar peak positions and widths. For the same sample and shim, you can assume that the peak positions and peak widths will remain constant, except for Pi. Each individual spectrum from the study can be refit, based on the parameters obtained by fitting the summed spectrum, but now allowing only the peak heights to change.

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136 This method is also used at UAB using FITMASTER to analyze cardiac spectroscopy data. Skeletal Muscle Skeletal muscle spectra contain the same phosphorus peaks as cardiac spectra, but in different quantities. The primary method for ensuring that there is no skeletal muscle contamination in the cardiac spectra is to use good methods of localization with an appropriate pulse sequence.50 Simply put, too much skeletal muscle contamination in the cardiac spectrum invalidates the study. This is determined by first post-processing the spectra and looking at the resulting ratio of [PCr]/[ATP] in each spectrum. A ratio of 1.5 to 2 or higher is indicative of skeletal muscle contamination. Blood Contamination UAB has also determined a blood correction factor. All of the WISE data and the data in this dissertation has been blood corrected by using an [ATP]/(2,3-DPG] correction factor of 0.18 based on data obtained at UAB using a vial sample of fresh heparinized blood with the same protocol used to acquire human cardiac P-31 spectra.195 This factor falls close in line with published values of 0.1982 and 0.21148 where the correction factor was obtained in a similar fashion. To correct for blood contamination for each cardiac P-31 spectra, first multiply the area of the 2,3-DPG peak in that spectrum with the [ATP]/[2,3-DPG] correction factor. Next, subtract the estimated blood contributions as shown in the following equations. The final equation

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137 given as [PCr/ATP] blood corrected is listed because it is the form of the output of the FITMASTER software. ATP AT%1ood 2,3DPGarea x 2,3DPG correction factor ATPcorrected PCr ATP blood corrected ATPconta min ated -AT%1ood PCr (ATPcorrected) T1 Relaxation Corrections Equation 6 Equation 7 Equation 8 Relaxation corrections adjust for the loss of area of a metabolite peak due to acquisition at short TR times, without complete relaxation between excitations. Assuming equal T1 relaxation times between subjects at the same magnetic field strength, an estimate for the correction factor can be obtained from one set of subjects and used to correct cardiac P-31 MRS obtained from future subjects. At a set TR time, the relaxation correction factor (RCF) is the ratio of the metabolite peak area value at long TR (fully relaxed condition) over short TR (the TR time used for the study). The peak area can also be substituted with a ratio of two peak areas, such as [PCr]/[ATP]. RCF Peak_ Arealong TR acquisition -Peak Areashort _TR_ acquisition Peak Arearelaxation corrected Peak Areashort TR x RCF acquisition Equation 9 Equation 10

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138 The RCF factor can also be determined based on the T1 relaxation factor at a specific field strength expected for a specific tissue metabolite (X). RCFx(TR) 1 l exp(-TR / 'Ii ) Equation 11 There are no literature values available for proper T1 relaxation corrections of human cardiac muscle at 3.0 T T1 can, however, be measured at 3 0 T (or other field strength) by acquiring localized cardiac P-31 spectra at two or more TR times. If values from just two TR times are acquired they must be acquired from a short TR that is typically used to acquire the data and a long TR where conditions are fully relaxed. A single correction factor can then be calculated for that exact short TR value. When the TR is not constant from subject to subject, as in the case of a TR value dependent on heart rate gating, a single correction factor is not correct. Despite this fact, some human cardiac P-31 data in the literature is still corrected based on a single relaxation correction factor.81 This practice is done even when exercise is involved which will change the TR between resting and exercise acquisitions in the same subject.195 With resting heart rates variable from 50 to 90 BPM, the TR value typically gated to every third or fourth heart beat will also vary between subjects, assuming a constant heart rate for each subject. Fortunately, acquisition of localized cardiac P -31 spectra for three or more different TR times (short, medium and long) provides enough data for an exponential fit and an estimation of the T1 relaxation rate for each metabolite peak area (X) for each subject.

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where 139 Equation 12 a and bare constants Areax is the area of a metabolite at time TR TR and T1 in seconds Repeating this for several subjects and averaging provides a more reliable T1 measure. The average T1 relaxation rate can then be used to determine the RCF for any TR time, as shown above. To estimate the value of T1 for both PCr and ATP at 3.0 T, eight non-symptomatic subjects, from Table 14, without suspected ischemia (4 Males, 4 Females) were tested for one study each to obtain cardiac P-31 spectra at two to three different TR times. Two studies failed due to poor SNR (W.P.) and clausterphobia (C.S.). An additional study (T.B.) was incomplete due to obtaining data at only two TR times (as recommended by the literature) but was not repeated to obtain data at three TR times. An RCF for a single TR based on this single subject is provided in Appendix F The total number of studies was limited based on advisement. Results of these studies can be found in the next chapter. Calculations of pH The measurement of pH on a phosphorus spectrum is proportional to the frequency difference, or chemical shift (cs) in ppm, between the Pi and PCr peaks.222 This relationship has been simply described by the Henderson-Hasselbalch equation. 223224 cs 3.27 pH = 6. 75 + log10 5. 69 cs Equation 13

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140 Locally, using oblique DRESS techniques at 1.5 T, the Pi peak is non-discernible from the blood 2,3-DPG peaks, as shown in Figure 61 (a). In the same subject, on the same day, the oblique DRESS sequence was repeated at 3.0 T, and the Pi peak was detectable separate from the 2,3-DPG peaks as shown in Figure 61 (b). This provides an example of the capabilities of the 3.0 T to show the Pi peak due to greater spectral dispersion and thus allow for pH calculations, with a simple DRESS protocol (6 to 8 minutes, 128 acquisitions gated to every fourth heart beat). Analysis Based on the results from this chapter, the DRESS oblique slice localized cardiac P-31 spectroscopy will be the best option to consider for repeatability and reliability. DRESS oblique slice localization provides the best compromise between SNR, flexibility and quality in localization. In addition, a quadrature P-31 radio frequency (RF) coil provided additional SNR improvements over the single-turn coil of similar single-loop dimensions.

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141 (a) 1.5 T, body coil, TG 120 (b) 3 T, 25 cm H-1 surface coil, TG = 200 P-31 Surface Coil Position P-31 Surface Coil Position Figure 45. Human cardiac imaging with the spin-echo pulse sequence at (a) 1.5 T with the body coil and at (b) 3.0 T with a surface coil. (Parameters: 1 echo, minimum full TE, TR each heart beat, 32kHz bandwidth, peripheral gated, 40 cm FOV, 7-8 mm thick, 3 mm space, scan time -2:20; see Appendix B for more detail).

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142 (a) 1.5 T, Gradient Echo, breathing (b) 3 T, Gradient Echo, breathhold Figure 46. Human cardiac imaging with the fast gradient echo pulse sequence at (a) 1.5 T with the body coil and at (b) 3 0 T with a surface coil. (Parameters: 60 flip angle, minimum full TE, TR each heart beat, 16k.Hz bandwidth, peripheral gated, 42 cm FOV, 7 mm thick, 1 mm space, scan time 0:20 per slice; see Appendix B for more detail).

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143 (a) (c) Figure 47. Prone positioner for in-magnet cardiac spectroscopy. (a) Prone massage M.A.T. by A2Z Possibilities, Inc. has a foam core with a removable and washable cover, along with a roll to place under the ankles. (b & c) The M .A.T. was trimmed a little in the side to side directions and then was perfect for prone positioning in the magnet.

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144 {a) prone (b) supine Figure 48. A comparison of the heart's position in the (a) prone and (b) supine positions, as shown from a 3.0 T axial slice. (Parameters: fast gradient echo, 60 flip angle, minimum full TE, TR each heart beat, BkHz bandwidth, peripheral gated, 30 cm FOV, 8 mm thick, 1 mm space, scan time 0:20 per slice; see Appendix B for more detail) (a) peripheral gating (b) ECG gating Figure 49. Waveforms of (a) peripheral gating and (b) ECG gating on the 3.0 T from a normal human volunteer (TEB) on Sept 20, 1998, displayed at a rate of 21 mm/sec.

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145 (a) (b) Figure 50. A comparison of peripheral gating (pg) versus ECG gating, and breathing during the image versus breath-hold images. All images are fast gradient echo: (a) sagittal, peripheral gating, breath-hold; (b)sagittal, peripheral gating, breathing; (c) sagittal, ECG gating, breath-hold; (d) sagittal, ECG gating, breathing, (e) axial, peripheral gating, breath-hold, (f) axial, peripheral gating, breathing.

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146 Real 3 5 water 0--4-----~----6 4 2 0 2 Frequenc y (ppm) (a) STEAMCSI Real water 3 5 0 ..]._ _____ 6 4 2 0 2 Frequency (ppm) (b) PRESSCSI fat 4 6 fat 4 6 Figure 51. Human proton voxel localized spectroscopy of the heart and chest wall obtained during one volunteer's shim using the techniques of GE's (a) STEAMCSI and (b) PRESSCSI. (Parameters for both: 16 acquisitions, 1000 Hz spectral width, 2 sec TR, 4 1 x 5 9 x 3.0 cm3 voxel, scan time of 0 :40, 3 T, single-turn R F coil and no linebroadeningi see Appendix B for more detail).

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' '"'-'--'-terior Heart Muscle & Skeletal Muscle & Blood Skeletal Muscle Heart Septum Muscle & Blood 147 Blood Figure 52. P-31 FIDCSI with CSI of a human subject at 3.0 T. (Parameters: 128 acquisitions, 4000 Hz spectral width, TR gated every other heart beat, 3 5 x 3.5 x 3 0 cm3 voxels, scan time of 12 minutes, lOHz line-broadening, & orient= transpose x-y, flip x; see Appendix B for more detail).

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148 Figure 53. DRESS localization via oblique slice select combined with sensitivity region of coil. (A) Position of surface coil and the 3 vials of external standard. (B) Dashed line indicates the reception volume of the surface coil. (C) Cardiac P-31 DRESS spectroscopy is acquired from an oblique slice region.

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Pi Pi PDE PME 2,3-DPG + Pi PDE 149 PDE y-ATP a-ATP P-ATP PCr (a) PCr y-ATP a-ATP P-ATP (b) PCr a-ATP y-ATP P-ATP ( C) Figure 54. Examples of 1.5 T cardiac phosphorus spectra localization problems resulting in (a) liver contamination, or (b) skeletal muscle contamination, in comparison with (c) a non-contaminated cardiac spectrum.

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2,3 -DPG + Pi\ 1. 5 Tesla PDE ATP STERTM FITMA Fit R est Raw Rest FITMASTER Fit Exercise Raw Exercise 150 2-DPG 3-DPG 3.0 Tesla -' ... ATP PCr I Pi PDE Figure 55. P-31 FIDCSI oblique slice localized human cardiac spectroscopy (oblique DRESS) of the same subject, at 1.5 and 3.0 T, on different days showning examples of resting and exercise spectra, raw and fitted. (Parameters: 128 acquisitions, 2000 & 4000 Hz spectral width for 1.5 and 3.0 T, TR gated every third heart beat, 25mm slice, scan time of 6 to 8 minutes, 15 Hz line-broadening; see Appendix B for more detail).

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151 Cardiac Skeletal -,--., ,--Muscle I Muscle PCr PCr 2,3-DPG + Pi + PME + PDE 2,3-DPG + Pi I I I I I I y-ATP a-ATP ~-ATP Figure 56. Series of cardiac region oblique DRESS spectra representing decreased skeletal muscle contamination with increase in depth of spectroscopy slice localization. Note the split in the PCr peak that designates the cardiac and skeletal muscle as separate peaks.

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sing1.e 1.52 11riiiif i JOI I I JI I J p-oi surface coil DRESS 3 s~ternal standards coi1. a ~II 1 11 I 11 J IPII 11a 1111rr11,'1ii: I p I p 11111111 llllPII @ p p 7 1. a 1.0-cm cm2 quadrature

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153 Figure 58. Water, hydraulic, hand-squeeze ergometer/static-exerciser, modified from original design by North Coast Medical (Bulb Dynamometer, Item# NC70154) by adding 30 ft hose between rubber squeeze ball and gauge, (a) coiled up for storage, (b) close up of rubber, hand-squeeze, and (c) close up of pressure gauge.

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154 25 Pi U) rl 20 'O l-1 C tn ;'.j 'O 0 C 15 Pi rtl ..c:: C r-1 C 0 10 ..c:: 'O tn Q) rl CJ 5 Q) rd .--i Pi 0 12 14 16 18 20 22 gauge reading Figure 59. The linear response of the hydraulic handgrip to added weight on the rubber bulb is illustrated. Due to initial water pressure, that changes depending on the position of the tubing (a constant in any individual MRS exercise case), the gauge will read a value above zero even when no weight has been applied. Figure 60. Dinamap blood pressure and pulse monitoring equipment.

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3-DPG 2-DPG Pi PDE I 155 PCr y-ATP 2,3-DPG + Pi PDE a-ATP P-ATP (a) PCr from myocardium PCr from skeletal muscle y-ATP a-ATP a-ATP from /skeletal muscle frequency difference (b) P-ATP ~-ATP from skeletal / muscle Figure 61. Myocardial pH is proportional to the frequency difference of the Pi and PCr peaks in the human, in-vivo phosphorus NMR spectrum. (a) At 1.5 T the Pi peak is hidden by blood 2,3-DPG. (b) At 3 0 T the Pi peak is discernible from the 2,3-DPG peak, allowing for the measurement of pH. Both spectra obtained on the same volunteer at rest using oblique DRESS. (Parameters: 128 Acquisitions, every third heart beat TR, Oblique DRESS, 25 mm thick slice, single-turn P-31 coil; see Appendix B for more detail).

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156 CHAPTER 5 HUMAN DATA REPRODUCIBILITY The previous chapter on human techniques allowed for an investigation of the best combination of pulse sequence and coils to be used at 3.0 T to achieve optimal acquisition of human, in-vivo, cardiac P-31 spectroscopy on the GE Signa Advantage 3.0 Tesla system at the University of Florida. Based on that chapter's investigations, the oblique DRESS sequence (via the FIDCSI GE sequence) provides the best compromise of the GE sequences between SNR, flexibility, accuracy in terms of localization over the desired region of the heart, and reasonable acquisition time. The oblique DRESS protocol will now be evaluated based on a number of human studies. The aim is to quantify reliability and repeatability specifically for the acquisition of human, in-vivo, cardiac P-31 spectroscopy. This chapter addresses the reproducibility of this technique for cardiac spectroscopy P-31 measurement. It is a chapter of multiple acquisitions and evaluation designed to show that the protocol selected for 3.0 T cardiac phosphorus spectroscopy acquisitions is optimal. These results are based on studies locally at 1.5 and 3.0 T, with the locally constructed hydraulic handgrip in-magnet exercise. In addition, these local studies will be compared with similar studies being conducted at University of Alabama at Birmingham for the WISE studies, and other publications on human, in-vivo cardiac spectroscopy.

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157 Ti Relaxation Corrections Six sets of resting P-31 cardiac spectra obtained with short {lRR), medium (3RR) and long (12RR or the closest time) TR times, were obtained on the 3.0 T. The protocol consisted of oblique DRESS, 128 acquisitions, and gated TR for each time interval. The data were sent to Birmingham for post-processing by Fitmaster. The three ATP signal areas (y-, a.and P-ATP) were "estimated" by the Fitmaster program to be approximately equal (whether truly correct or not), therefore only a single ATP area value is listed to represent all three peaks. The post-processed metabolite areas from each spectrum are shown in Table 16. Note that gating at every heart beat {lRR) and every third heart beat (3RR) was selected on the system, but the actual time that the system gated to was every other heart beat (2RR) and every fourth heart beat (4RR) based on recorded time between audible acquisition pulses. This also limits the minimum time that the system allows for a gated TR A shorter TR time would have otherwise been preferred, especially when determining the relaxation rate of ATP. In this table, ATP is corrected for blood contamination using the equations specified in Chapter 4, resulting in blood corrected (BC) ATP values.

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158 Table 16. Oblique DRESS Acquisition P-31 Metabolite Area Values Obtained with Different TR Gating Intervals for the Purpose of Relaxation Measurements (obtained by post-processing of spectra with Fitmaster). TR time 2,3-Subject RR* (sec) ATP/ 3 DPG/2 PCr/ATP PCr/ATPBc PCr ATPBc T.B. 4 4.2 3.04E+06 l.15E+06 1.511 1 .75 4 .589E+06 2.622E+06 T.B. 12* 14. 5 3.23E+06 l.08E+06 1.549 1.76 5.000E+06 2 .841E+06 C.M. 2 1.7 8.80E+05 l.11E+05 1.544 1.617 l.359E+06 8.406E+05 C.M. 4 3.8 l.04E+06 1.72E+05 1.589 1 .689 l .654E+06 9 .794E+05 C.M. 12* 10. 5 1 .06E+06 l.77E+05 1.855 1 .981 l .957E+06 9 .879E+05 D P 2 2.5 9.74E+05 2.60E+OS 1.146 1.268 1.117E+06 8.806E+OS D P 4 4.9 l.08E+06 2.47E+OS 1.175 1.281 l.269E+06 9.906E+05 D .P. 12* 12.1 l .06E+06 2.58E+OS 1. 31 1.435 l .393E+06 9.704E+05 L .R. 2 1.8 l.59E+06 4.48E+05 1.444 1.606 2 .300E+06 l.432E+06 L.R. 4 4 l.85E+06 4.85E+OS 1.517 1.676 2.799E+06 l.670E+06 L R 12* 11.2 l .80E+06 2.65E+OS 1 .604 1.694 2.884E+06 l.702E+06 L B 2 1.5 7.06E+05 6 .64E+04 0.551 5.703 3.891E+05 6 .823E+04 L.B. 4 3.3 7.04E+05 8.37E+04 0.674 0 .704 4 .741E+05 6.736E+05 L.B. 12* 9.3 6.85E+05 l.13E+05 0 .815 0.866 5.580E+05 6.444E+05 R.B. 2 2 6 6.10E+05 2.12E+OS 2.054 2.348 l.253E+06 5.336E+05 R.B. 4 4.1 8.44E+05 2 .60E+05 1.821 2.048 l.537E+06 7.505E+05 R.B. 12* 13.6 9.89E+OS 3 .48E+05 1 .977 2.264 l.955E+06 8.636E+05 *Gated to every RR heart beat (requested value of 12xRR may be less than 12 within constraints of a 15 second system maximum TR time) BC= blood corrected Five of the six studies (except T.B. ) were exponentially fit to estimate the T1 value for PCr and ATPec The resulting equations and figures of the fits can be found in Appendix F Based on these values, the cumulative result is shown in Table 17.

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159 Table 17. Summary of Resulting T1 values for PCr and ATPac Subject T1 (PCr} T1 (ATPBc) C.M. 3.47 0.74 D.P. 3 23 0.45 L R. 1.85 1.67 L.B. 2 83 0.23 R B 3 .16 1.59 Average 2.91 0.94 Std Dev 0.63 0.66 Abbreviations: BC -blood corrected Based on the average T1(PCr) and average T1(ATPBc), new equations for relaxation for each can be derived based on a relative signal scale of Oto 1, specific to 3 0 T. PCr(TR) -1 exp{ TR/ 2. 91) Equation 14 ATPBc(TR) 1 -exp(-TR / 0. 94) Equation 15 The T1 relaxation correction factor (RCF) for any TR can then be calculated for each peak or for the ratio of [PCr]/[ATP]. 1 1 -exp (-TR/ 2 91) 1 1 -exp (-TR/ 0. 94) RCF(Pc r / ATP)(TR) = 1 exp ( -TR / O 94) 1 -exp ( -TR/ 2. 91) Equation 16 Equation 17 Equation 18 The resulting RCF for [PCr]/ [ATP] has been graphed in Figure 62 Overall Reproducibility of the Oblique DRESS Method The overall reproducibility of the oblique DRESS protocol can be obtained by looking at both 1.5 and 3.0 T data acquired for the WISE

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160 study, and by looking at studies on the 3.0 T of group data at rest, and individuals repeated at 3.0 T. The opportunity of the WISE (Women's Ischemic Syndrome Evaluation) study to look at the same type of patients with 1 5 T cardiac P-31 spectroscopy at both UAB and UF has allowed for a unique comparison of techniques. The data from each site is evaluated at UAB using the same criteria and the Philips Fitmaster program for postprocessing of data. As shown in Table 18, the magnet systems and techniques are slightly different at each facility, which may account for the difference in degrees of success. At UF, use of the oblique DRESS protocol, which relies partially on the surface coil to perform some of the localization, has proved to be less than ideal in terms of perfect localization. Too often, it is difficult to place the slice to adequately reduce skeletal muscle contamination and get good SNR, thus being a difficult protocol for good reproducibility requirements. The ISIS sequence can work well when it can be placed obliquely for maximum flexibility in placement and localization, as can be accomplished on the Philips Gyroscan system at UAB. After local modifications of the ISIS sequence for the 3.0 T GE Signa Advantage at UF, non-oblique ISIS voxels should be a more reliable and flexible tool for future use. Use of the oblique ISIS voxel has given UAB an advantage in terms of successful studies, compared to a less reliable localization at UF, as shown in Table 18. The criteria for a successful study is the lack of skeletal muscle contamination, represented by [PCr]/[ATP] > 2.0 or an SNR low enough that the FITMASTER will not process the data due to confusion about which peak

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161 is relevant UF's success rate is lower, also due to the fact that this data includes the first patient cardiac P-31 acquisitions done at UF, and therefore the learning curve could account for some of the low numbers of successes. Unfortunately, large patients, typical for heart patients, and some difficulties in not having more flexible localization procedure than oblique DRESS capable of localizing to a smaller voxel volume, has meant that failures do occur. Of the last 15 studies done, the success rate was 67% or 10/15 studies successful, which is statistically the same as the overall success rate of 66%. Table 18. WISE 1.5 T Cardiac Spectroscopy Acquisition Success Rate. System Used P-31 Acquisition Method Total Studies (as of Jan/99) Number of Successful Studies % Success Average Resting [PCr]/[ATP] Standard Deviation of Average UF GE Signa Advantage Oblique DRESS Slice 32 21 66% 1 .27 0.48 UAB Philips Gyroscan Oblique ISIS Voxel 43 40 93% Data Not Available Data Not Available At 3.0 T, cardiac P-31 MRS was obtained at rest from nine studies as shown in Table 19. This excludes five studies where the spectra had poor SNR (W.P.) or were contaminated by excess skeletal muscle, demonstrated by a [PCr]/(ATP] value greater than 2.0 after relaxation and blood corrections (T.B., C.M, R.B. & L R .). It is also interesting to note that three of the four with skeletal muscle contamination (from Table 17) also had longer T1 relaxation times for ATP. Three of the non-excluded studies were obtained on the same individual, K.S., on different days. This data was obtained with cardiac gating option of "3xRR" on the GE software, which actually gated on every fourth heartbeat. Most data in the literature points to

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162 a normal resting [PCr]/[ATP] ratio for mild ischemia and infarction, therefore it is assumed that the resting values of different individuals will be equivalent. Table 19. 3.0 T Cardiac P-31 Spectroscopy at Rest Only, 3xRR Gating. Relax and Blood Blood Raw Resting Corrected Corrected Subject TR RCF [PCr] / [ATP] [PCr] / [ATP] [PCr] / [ATP] K.S. (Aug 1998) 3.7 1.36 0.867 1.02 1 .39 K S (Oct 1998) 3.8 1 .35 0.623 0.72 0.97 K S (Nov 1998) 3.7 1.36 0.925 1.025 1.40 D.P. 4 9 1.22 1.18 1.281 1.56 L.B. 3.3 1.43 0.67 0.704 1 .01 E.O. 4.1 1.31 0.926 0.993 1.30 Average: 1.27 Std Dev: 0 .24 As can been seen, the standard deviation of these six rest [PCr]/[ATP] ratios acquired at 3.0 T (0.24 from Table 19) is half the value of the standard deviation at 1.5 T (0.48 from Table 18). Part of the reason for this reduction in standard deviation of results may be due to having the same operator and shorter duration of the studies allowing for a more standard method of testing. Of 11 total tests at 3.0 T, five had problems with SNR or skeletal muscle contamination resulting in a success ratio of 55% which is similar to the 66% success rate at 1 .ST. Therefore, there was not an increase in successful acquisitions at 3.0 T with the oblique DRESS method. In terms of repeatability, one ischemic volunteer was tested three separate times at 3 0 T with an average [PCr]/[ATP] ratio of 1.25.24 (blood and relaxation corrected), which has the same standard

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163 deviation of the person to person variability of 1.28.23 (n=4). Regardless, this is highly variable data due to the conditions of obtaining data from a moving heart, with a small volume to acquire from while excluding external volumes that may present potential contamination. The last issue to consider for the protocol developed to obtain in-vivo, cardiac P-31 spectroscopy at 3.0 Tis the use of a single-turn or quadrature coil. The quadrature coil provides greater SNR, but can be a hindrance with oblique DRESS. The quadrature coil's broader profile leads to large volumes of acquisition and therefore more difficulty in localizing to cardiac muscle, as described in Chapter 4. In general, comparing single turn coils at 1.5 and 3.0 T, approximately the same volume could be acquired at each field strength, with some displacement error due to chemical shift. This displacement error between PCr and P-ATP is estimated at 2.8 mm at 1.5 T and 4.9 mm at 3.0 T, based on calculations from Ordidge et al.92 During the studies, use of a quadrature coil required a longer time for trying out proper placement of the oblique DRESS slice in order to avoid skeletal muscle contamination. The slice would continuously have to be repositioned at deeper and deeper depths to prevent the tall skeletal muscle PCr peak from appearing in the spectrum. From a study perspective, it seems that the quadrature coil is harder to use during the study with greater potential skeletal muscle contamination unless extra efforts are made to place the slice deeper, just posterior to the anterior wall of the heart, as explained in Chapter 4. In a few studies performed with the quadrature coil, however, the skeletal muscle contamination was eventually avoided. Comparing single to quadrature coils at 3.0 T,

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164 again the slice must be placed still deeper from the quadrature coil to obtain a spectrum without skeletal muscle contamination with DRESS. The quadrature coil, therefore may be more ideally suited for an ISIS protocol where the coil is not relied on to be part of the localization procedure. Some tests were performed at 3.0 T with both the quadrature and single turn coils and the results are shown in Table 20. Notice that the average [PCr]/[ATP] ratio (blood and relaxation corrected) for the quadrature coil group is slightly lower than for the single turn coil group although not significantly different (p=0.16 using attest). This shows that the quadrature coil is equally good at avoiding skeletal muscle contamination in practice, although the slice should be placed deeper to do so as was done in these examples. The tall skeletal muscle PCr peak that is seen more often with the quadrature coil may even be a good feedback mechanism, because more often the skeletal muscle contamination was avoided with the quadrature coil rather than the single turn coil. This peak is most likely obtained from the skeletal muscle to the left of the heart, where the larger periphery of the quadrature coil will reach. With the single turn coil, a slight amount of skeletal muscle contamination is hard to perceive at the time of acquisition, but does show up after postprocessing. This is demonstrated for subjects C.M., R.B., L.R., T.B., who had a blood and relaxation corrected [PCr]/[ATP] value greater than 2.0.

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165 Table 20. 3.0 T Cardiac P-31 Results Categorized by P-31 Surface Coil. P -31 Coil Relax and Blood Subject Type Corrected [PCr]/ [ATP] K.S. (Aug 1998) Quadrature 1 .38 K.S. (Oct 1998) Quadrature 0.96 T.B. Quadrature 2.24* Average: 1.53 Std Dev: 0 .65 K.S. (Nov 1998) Single Turn 1.38 C.M Single Turn 2.50* D.P. Single Turn 1.55 L.R. Single Turn 2.20* L.B. Single Turn 1.00 R.B. Single Turn 2.64* E.O. Single Turn 1.29 Average: 1.79 Std Dev: 0.64 *Includes data with skeletal muscle contamination Adequacy of the Hydraulic, In-Magnet, Handgrip Exerciser Thirty separate individuals tested the hydraulic handgrip, most during scheduled studies for WISE at 1.5 T. The resulting resting and peak exercise, heart rate and systolic blood pressure for each participant is shown in Table 21. All participants are grouped, regardless of medical history, assuming that presence or absence of myocardial ischemia does not affect the response the heart will have to handgrip exercise. The resulting average values for rate pressure product (heart rate times systolic blood pressure) is comparable with the isometric handgrip responses in the literature.49 Statistically, the values from Weiss et al.49 of 9600 and 12600 for the rate pressure product for rest and exercise, is not statistically different (p=0.46 and p=0.32 using at-test assuming equal variance) from the average rate pressure product values shown in Table 21.

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166 Table 21. Heart Rate (HR) and Systolic Blood Pressure (SBP) Response from 30% of Maximum Effort Isometric Hydraulic Handgrip. Peak HR*SBP Resting Rest Rest Peak Peak Exer (Exer-Initials HR SBP HR*SBP Exer HR Exer SBP HR*SBP Rest) E.Q. 53 104 5512 100 161 16100 10588 S.P. 76 120 9120 88 150 13200 4080 A.B. 60 100 6000 72 130 9360 3360 K.S. 62 145 8990 84 219 18396 9406 E.O. 64 124 7936 72 160 11520 3584 G.N. 76 105 7980 92 145 13340 5360 B.H. 70 120 8400 78 160 12480 4080 S.E. 70 124 8680 100 175 17500 8820 S.H 84 135 11340 108 200 21600 10260 E .K. 84 140 11760 92 166 15272 3512 E .B. 96 160 15360 116 200 23200 7840 H .P. 60 176 10560 72 250 18000 7440 S.J. 96 170 16320 100 200 20000 3680 S .A. 84 120 10080 104 160 16640 6560 J.G. 75 120 9000 100 111 11100 2100 L.C. 80 143 11440 84 146 12264 824 J.F. 86 142 12212 90 179 16110 3898 H .T. 64 136 8704 63 1 4 3 9009 305 J .D. 72 156 11232 82 188 15416 4184 R .S. 57 110 6270 67 132 8844 2574 M P 65 141 9165 70 153 10710 1545 G .O. 81 122 9882 102 199 20298 10416 E W 76 200 15200 79 241 19039 3839 G.A. 77 112 8624 86 133 11438 2814 A.S. 82 114 9348 90 147 13230 3882 K.G. 83 128 10624 86 154 13244 2620 N .W. 70 127 8890 76 151 11476 2586 M.A. 54 117 6318 58 136 7888 1570 L.H. 72 113 8136 76 164 12464 4328 D.M 86 142 12212 96 158 15168 2956 Average: 74 132 9843 86 167 14477 4634 Std Dev: 11 23 2642 14 33 3998 2924 Another comparison for the adequacy of the stress level that the handgrip stress puts on the heart can be obtained by looking at data available through the WISE study. Each WISE participant who was tested with cardiac P-31 MR spectroscopy exercised in the magnet using the hydraulic handgri p in-magnet exerciser. On some WISE participants,

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167 there is also data on heart rate (HR) and systolic blood pressure (SBP) response from dobutamine (drug induced stressor) and aerobic exercise, treadmill tests. As shown in Table 22, the isometric handgrip exercise produced on average a smaller increase in heart rate but a greater increase in systolic blood pressure than both the dobutamine and treadmill tests were able to do on the same individuals. The blood pressure product (heart rate times systolic blood pressure) is lower for handgrip exercise due mostly to the lesser increase in heart rate. Table 22. Handgrip Exercise Compared to Dobutamine and Treadmill Responses for Known WISE Studies. Handgrip Dobutamine Treadmill Subject Max HR SBP HRxSBP Max HR SBP HRxSBP Max HR SBP HRxSBP B.H. 80 138 11040 136 131 17816 147 160 23520 S.E. 100 175 17500 138 150 20700 110 120 13200 G.N. 90 140 12600 147 130 19110 156 160 24960 C.F. 80 230 18400 97 161 15617 100 185 18500 S.H. 108 200 21600 139 200 27800 138 170 23460 L.C. 84 146 12264 153 156 23868 147 170 24990 J.F. 90 179 16110 134 178 23852 131 166 21746 Average 90 173 15645 135 158 21252 133 162 21482 Std Dev 10 34 3843 18 25 4182 21 20 4282 Reproducibility of the Hydraulic Handgrip The reproducibility of the level of stress provided by the hydraulic handgrip is also very steady, as shown in Table 23. The same volunteer was MR tested on three separate dates in the 3.0 T. Each time the maximum effort was measured for that day and a regimen of 30% of the maximum sustained by the volunteer during the isometric handgrip exercise. As can be seen from the results, the average exercise heart rate was close for all three days. The average diastolic blood

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168 pressure was different at the first date, but similar the last two dates. In contrast, the systolic blood pressure was similar for the first two dates but s lightly different for the third date. The resting blood pressure was also different for the first date. This may explain the slight difference in the blood pressure results from day to day. Table 23. Handgrip 30% Maximum Effort Isometric Exercise Results of K.S. Subject Tested Repeatedly. Date of Rest Exercise Rest Exercise Rest Exercise Study HR HR BP BP HR*SPB HR*SPB 8/10/98 65 77 162/76 178/97 10530 13706 10/12/98 63 77 145/75 191/95 9135 14707 11/11/98 65 79 149/68 195/103 9685 15405 Average 64 78 152/73 188/98 9783 14606 Std Dev 1 1 9/4 9/4 703 854 N o Drop in [PCr] / [ ATP ] During Exercise with Reference Volunteer As explained earlier in the literature review on ischemia, data is available from three sources on the percent change in [PCr]/[ATP] with handgrip exercise on groups of reference subjects without cardiac ischemia. From that data the threshold for significant drop in the percent change in [PCR]/[ATP] with handgrip exercise is -20.6% (UAB, n=l 7), 195 -14% (Weiss et al., n=ll), 49 or -18% (Yabe et al., n=ll) 12 based on two standard deviations. The study at UAB involved using non-ischemia symptomatic subjects, but none of the reference subjects were tested clinically for silent ischemia. The results at UAB may therefore include silent ischemic subjects, and this may explain the higher standard deviation compared to the other sites. Since threshold data was available, and because locally there was not funding to clinically test volunteers for possible silent ischemia prior to

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169 cardiac P-31 MRS, no non-clinically tested subjects were subjected to in-magnet exercise for the purpose of determining a standard deviation and threshold. Funding is being sought from NIH to perform adequate cardiac evaluations of reference group subjects prior to testing via cardiac P-31 MRS for the near future. The true threshold for studies at UF performed with oblique DRESS may be lesser or greater than the published values. The larger standard deviation threshold of -20.6% will be used to estimate statistical significance of [PCr]/[ATP] with handgrip exercise at this time. One subject who appeared quite healthy (E.Q.) but also was not clinically tested was, however, tested to demonstrate the ability of the handgrip exercise and P-31 measurement. This subject was tested at 1.5 T and substantially raised her heart rate and blood pressure during the exercise portion of the study, as detailed in Table 24. Despite the subject's significant response to the handgrip exercise, there is no significant difference in the rest versus exercise spectra with the small change of +2.84%. As duplicated in the literature, this study's result demonstrates that without cardiac ischemia one cannot lower the [PCr]/[ATP] ratio of the myocardium with in-magnet exercise of isometric handgrip at 30% maximum.

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170 Table 24. Results from 1.5 T Cardiac P-31 Exercise Study on Reference Normal Volunteer. Blood & HR Blood Relaxation Avg Avg Raw Corrected Corrected Acq HR BP SBP [PCr] / [ATP] [PCr] / [ATP] [PCr] / [ATP] Rest 53 104/64 5512 0.605 0 .762 0 .986 Exercise 83 136/86 11288 0.647 0.792 1.014 Recovery 1 55 105/62 5775 0.773 1 .005 1.286 Recovery 2 55 105/62 5775 0.682 0.828 0.828 % change +2.84% Drop in [PCr]/[ATP] Seen with the Handgrip Exerciser with Ischemia To prove that the hydraulic handgrip exerciser can produce a drop in [PCr]/[ATP] in the ischemic heart, subjects were tested that were thought to be ischemic. The first subject, K.S., had been shown by treadmill ECG to be mildly ischemic with high intensity exercise. The second subject, E.0., was a WISE study participant, meaning that microvascular ischemia was suspected based on symptoms and catheterization results. As shown in Table 25, K.S. was tested four times, once at 1.5 T In three of the five cases, a significant drop in [PCr]/[ATP] was measured, again based on the UAB data where a -20.6% drop was considered significant. The second study showed a large drop (-13.95%) but was not significant based on the data from UAB, although it could almost be considered significant based on the threshold determined from reference studies by Weiss et al.49 The fourth study did not show a drop, but this 3.0 T study was performed after and on the same day as the 1.5 T study. Perhaps some unknown factor prevents the cardiac study from being repeated on the same day reliably. There could be some degree of acidosis in the myocardium from stress earlier that day that changed the energy to a anaerobic state sooner, as will

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171 be further described in the section on pH measurements at 3.0 T. The second volunteer, a participant in the WISE study with chest pain and suspected of having microvascular ischemia, also showed a significant drop (-29.13% > -20%) in [PCr]/[ATP] with in-magnet, handgrip exercise. Table 25. Ischemic and WISE Studies at 3 0 T Show Drop in [PCr]/[ATP] with Handgrip Exercise. Field Resting Exercise Subject Study Date Strength [PCr] / [ATP] [PCr] / [ATP] % Change K.S. 11/11/98 1.5 T 1.61 1.24 -23.25 K.S. 8/10/98 3.0 T 1.15 0 .99 -13.95 K.S. 10/12/98 3.0 T 0 .81 0.57 -29.09 K.S. 11/11/98 3.0 T 1.16 1.14 -1.55 E.0. 2/25/99 3.0 T 1 .13 0.80 -29.13 Myocardial pH Measured at 3 0 T At 3.0 Tit is possible to differentiate the Pi peak from the blood 2,3-DPG peaks. Myocardial pH is proportional to the chemical shift difference in ppm between Pi and PCr. For seven (3 repeated with K.S. and 4 more on separate subjects) of the 3 0 T studies performed, the Pi peak was visible and the Pi to PCr ppm difference was recorded. Based on this, the pH was measured using the 3.0 T system, as described in the Human Techniques chapter, resulting in an average resting pH of 7.l0+0.14, as listed in Table 26. Referring back to the values for cardiac pH typically found in the literature, as listed in Table 10 the literature review chapter, the typical pH of the resting heart muscle has been shown to be around 7 .15. 165'149 This average resting in result measured at 3.0 Tis not statistically different from the literature values (p=0.41 based on at-test of two samples for means).

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172 An ischernic subject (K.S.) was tested three times at 3.0 T and all three times pH was recorded during rest and exercise. On two of the occasions, the pH did not drop significantly with exercise (p~0.45 and p=0.49 based on t-test for two samples for means), but on a third occasion a significant drop was seen (p=0.05), as shown in Table 26. The reason for this drop is hypothesized to be associated with receiving a cardiac stressor earlier that same day of the pH drop, causing the heart to use more anaerobic cycles during the second stressor which caused pH shift. Table 26. Myocardial pH as Measured on Human Volunteers using Oblique DRESS Cardiac P-31 MRS on the GE 3.0 T SIGNA for those Studies where the Pi Peak was Discernible due to Adequate SNR Pi-PCr ppm with pH with Pi-PCr ppm pH at handgrip Handgrip Subject (Date) at rest Rest exercise Exercise K.S. (Aug 1998) 4.945 7.10 4.873 7.04 K .S. (Oct 1998) 4.58 6.82 4.588 6.83 K .S. (Nov 1998) 4.949 7.11 3.839 6.24* C .M. 4.898 7.06 -D .P. 5.006 7.15 -L.B. 5.101 7.24 -R.B. 5.101 7.24 Average: 4.94 7.10 Std Dev: 0.18 0.14 Denotes significant dro ( p p =0.05) in p H corn ared p to restin g value with handgrip exercise

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173 3.5 -f--1 r::t: 3 '-l'-l (J 2.5 J..i 0 .w 0 m rx.. 2 s:::: 0 n .w 1.5 0 Q) J..i H 0 (J 1 s:::: 0 n .w m 0.5 X m rl Q) 0:: 0 0 5 10 15 TR (seconds) Figure 62. Relaxation correction factors at 3 0 T for cardiac [PCr]/[ATP] values based on repetition time (TR) values.

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CHAPTER 6 SUMMARY AND CONCLUSIONS Phosphorus, in-vivo, human, cardiac spectroscopy over the anterior region of the heart is not only possible at 3.0 Tesla, but eminently feasible. The 3.0 T GE Signa Advantage system at the University of Florida has been carefully evaluated in terms of imaging and spectroscopic capabilities, for gathering P-31 spectroscopy data of the heart. Advantages and disadvantages of such imaging and spectroscopy techniques such as spin echo imaging, multivoxel CSI and ISIS have been explored and a protocol for the 3 0 T GE Signa Advantage has been recommended. This protocol included using gradient echo imaging, PRESS proton spectroscopy for shimming, and oblique DRESS slice selection for cardiac P-31 acquisitions. A 25 x 25 cm2 square, single loop, proton surface coil was utilized for imaging and shimming. Two P-31 RF coils, a 9.5 cm diameter single-turn and a 10 x 16 cm2 quadrature design, were created and utilized. It was found that the quadrature coil has potential to provide greater SNR than the single turn RF coil, but at the price of needing to acquire a deeper slice when used with the oblique DRESS protocol. In addition, a hydraulic handgrip exerciser was designed and tested in the magnet. This in-magnet exercise was found to evoke a similar response, in terms of blood pressure and heart rate, when compared to similar literature studies and other types of cardiac stress such as drug induced dobutamine stress and treadmill exercise. 174

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175 In addition, three out of five cases of subjects with known or suspected ischemia showed a significant drop (-23.25%, -29.09% and -29.13%), of greater than 20% in their [PCr]/[ATP] ratios with the handgrip exercise. On two occasions where the drop was not greater than -20% there was still a large drop of -13.95% in [PCr]/[ATP], which falls between the first and second standard deviations (-10% and -20%) statistically based on studies of random volunteers not tested for ischemia. It is expected that future studies with more carefully controlled subjects who have been screened for the lack of cardiac ischemia, will provide tighter standard deviations. The final evaluation did not show a drop in [PCr]/[ATP], however, it did show a significant drop in pH (p=0.05). This may be the result of use of the anaerobic energy cycle due to stressing the heart earlier on the same day. As previously reported in the literature, volunteers not thought to have ischemia did not show a change in the [PCr]/[ ATP] ratio with exercise. No other volunteers were tested due to the lack of cardiac medical testing that would have ruled out ischemia. The handgrip exercise test was also shown to work on a linear scale and to be repeatable and equall y stress the heart each time it is used. In short, the protocol that has been designed here to obtain cardiac P-31 spectra at 3.0 T, on the GE Signa Advantage is adequate for continued use in testing more WISE patients and will be used with future cardiac patient studies.

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176 Implications for Future Research More extensive work should be done to improve the RF profiles for use at 3.0 T. All work done for this dissertation used the generic GE pulse sequences, with a few minor changes in EPIC by Dr. Kim. The consequence of this is that the RF pulse was the same as that designed for 1 5 T, resulting in more contamination from outside the slice at 3 0 T As of the date of this writing, an upgrade for the 3.0 T GE Signa Advantage at the University of Florida has been ordered. The upgrade will include increasing the gradient strength to 4 Gauss/cm up from the current 1 Gauss/cm. The increased gradient should provide for more accurate ISIS localization, especially with planned improvements to the ISIS pulse sequence. Improvements in the image quality were not focused on more sophisticated coil designs that provide a more homogeneous, volume excitation. The image quality in this work was good enough for spectroscopy localization purposes, but improving the image quality could help move toward more diagnostically acceptable images and techniques. It was the intention of this work to create a protocol that could be used to investigate cardiac function for the purpose of investigating ischemia, although this technique could easily be expanded to look at other types of cardiac disease states. Most of the WISE participants already studied at 1.5 T could be immediately restudied at 3 0 T, taking advantage of the visibility of the Pi peak, making pH measurement possible, in addition to increased SNR and spectral dispersion. In addition, the microvascular ischemia study can

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177 be extended to both male and female patients at the Veteran's Affairs Hospital to test the viability of P-31 spectroscopy as a screening test for microvascular ischemia. In a broader sense, the protocol can be used to study any type of cardiac problem where the cardiac metabolism is thought to be altered. In the literature, this has included disease states such as ischemia, infarction, cardiomyopathy, hypertrophy and heart transplants. This list could be expanded to looking at drug therapies and the cardiac muscle's response to intense exercise, studies that have been done on skeletal muscle. Further roles in research could also include investigating the heart with other nuclei such as H-1 and C-13, where there are opportunities to learn more about glycolytic and citric acid cycle energy metabolism as well as the tissue oxygenation status of the heart. Currently, research has also started on cardiac H-1 spectroscopy where creatine depletion is thought to be a measure of cardiac necrosis.225 Bottomley et al.225 studied 10 subjects with myocardial infarction and 10 controls. The study conjectures that not only does spatially localized H-1 MRS measure total creatine non-invasively in the heart, but that the detection of regional creatine depletion may provide a metabolic means to distinguish healthy from infarcted myocardium, as P-31 MRS offers with the drop in [PCr]/[ATP] and pH with exercise In order for cardiac P-31 spectroscopy to advance from the research to the clinical arena, much work must be done. First, there must be improvements in pulse sequence localization to the anterior myocardium without as much risk of skeletal muscle contamination. Second, there must be more studies to increase the statistical relevance of this testing procedure. Although reports of human, in-

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178 vivo, cardiac spectroscopy have been published for about 10 years, and data seems to clearly show a relationship between P-31 metabolite changes and ischemia, most studies are very small in number and have inherently large variability in resulting [PCr]/[ATP] values. In addition, diseases other than ischemia and infarction have shown wide variations in the literature in terms of being a marker for metabolic changes in cardiomyopathy or heart transplant cases. In addition, since in-vivo, cardiac spectroscopy is currently limited to the anterior portion of the heart due to SNR difficulties with depth, the abilities to look at the whole heart will also determine clinical viability. Such advancements may be obtained through improvements in coils (such as phased array designs), localized pulse sequence optimizations for cardiac spectroscopy, and increased gradient strength. Unfortunately, these advancements will be difficult to take advantage of due to obstacles such as increased sensitivity to motion, larger bandwidths of the required RF pulses, and limitations with specific absorption rate (SAR) guidelines.89 Another roadblock for clinical use of human, in-vivo, cardiac P-31 spectroscopy is the simple implementation of the technique. The moving heart is a challenge, especially in the motion sensitive MR environment. Advances in computing may also assist in the ability and increased accuracy of cardiac P-31 spectroscopy to move beyond peak metabolite ratios and provide metabolite concentrations. This can be closer to being accomplished when the true volume of myocardium that is contributing to the spectroscopy signal can be defined with little error using computer models based on empirical MR images. This will be useful for looking at infarction, where dead tissue contributes no

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179 signal, but also does not change [PCr]/ [ATP] ratio with exercise. In the case of infarction, a reduction in metabolite concentration in an area of interest will define the affected region. Advanced computer programs and graphics can also assist with the complicated post-processing needed to show an image of the heart in terms of a map of metabolite concentrations. This would show an image very comparable to SPECT nuclear medicine studies. At this point, some attempts at calculating metabolite concentrations in the heart and mapping the concentrations have been started, but are still crude, error prone and in need of improvements. Advancements in computer technology certainly wil l assist in this endeavor. While human, in-vivo, cardiac P-31 spectroscopy has yet to define a precise position in the diagnosis and treatment of heart disease, the technique has proved valuable in the measurement of cardiac function via the myocardial energy metabolites.

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180 APPENDIX A IRES AND SCREENING FORMS University of Florida Institutional Review Board (IRB) Informed Consent Forms and MRI Screening Forms for 1 5 and 3.0 Tesla Volunteers for Human, In-Vivo, MR Spectroscopy Cardiac Studies IRB Protocols This dissertation was covered under three separate IRB protocols. 1 IRB #459-97: Human In-Vivo Cardiac Phosphorus NMR Spectroscopy at 3.0 Tesla The first IRB covered all of the 3.0 T cardiac spectroscopy work on men and women volunteers for the period of time from the start of work up until January 9, 1999. This IRB was specifically designed for use with this dissertation with the principal investigator listed as Dr. Katherine N. Scott (IRB # 459-97). Most of the volunteer data in this work is covered by this IRB. The current IRB informed consent which as valid until 1/9/99 is included in this appendix. 2. IRB #376-96: Evaluation of Ischemic Heart Disease in Women -Clinical Centers (EIHDW) Women patient and volunteer studies at 1.5 T were originally covered under the IRB for the WISE study with the principal investigator listed as Dr. Carl Pepine (IRB # 376-96). This IRB was

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181 later expanded to include 3.0 T. The current IRB informed consent which is valid until 10/ 7 /99 is included in this appendix 3 IRB #452-98: P-31 Magnetic Resonance Evaluation of 3 0 T Ischemic Heart Disease in Men Men patients and volunteers for study at 3.0 Tare covered under this IRB with Dr. Katherine N. Scott listed as the principal investigator (IRB #452-98). This IRB was created in late 1998 to cover preliminary tests of men's ischemic heart disease in the 3.0 T whole body system. The current IRB informed consent which was valid until 1/9/99 is included in this appendix. Screening Forms In addition, an example of the screening forms used at the 1 5 and 3 0 T systems are shown. These screening forms are necessary to rule out a patient history that would indicate metal in the body, and thus make the MR system unsafe for that patient.

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IRB# VS9 -97 Informed Consent to Participate in Research The Un iversity of Flori da Health Science Center Gainesville, Florida 3261 O You are being Invited to participate in a research study. This form is designed to p rovide you with information about this st u dy. Toe Principal I nvestigator or representative will describe this study to you and answer any of your questions If you have any questions or complaints about the informed consent process or the research study, please contact the lnstttutlonal Review B oard (IRB), the committee that protects human subjects, at {352) 846-1494. 2. 3. Name of Subject Title o f Research Study Human In-Vivo Cardiac Phosph orus NMR Spectroscopy at 3.0 Tesla a Principal lnvestigato r(s) and Telephone Number(s) Katherine N. Scott, Ph.D. Professor of Radiology, University of Florida, Box 100374 & Career Research Scientist, Veterans Affairs Medical Center (352) 376-1611, X5066 b Sponsor o t the Study ( if any) None 4 The Purpose o f the Research Magnetic resonance Imaging ( MRI ) crea tes pictu res of the body with magnetic r ather than x ray energy. Magnetic r esonance spectroscopy (MRS) uses a technique similar to MRI to gather chemical infom,atlen i n the form of graphs about the tissue l o your body. We will be doing MRI and MRS of your heart while you rest o r do exercises in the magnet. The ultimate goal o f this work ls to provide diagnostic inform ation about the health of your heart You might also be asked to provide a sample o f blood for chemical analysis. APPROVED From Jy/9 ( To. t/Vf q lnet!tu~nal R evloW Sollrd C nj) I ~3-1.) 1 t:J 5. Procedures f o r This Research Chemical information about you r heart and pictures of your body will be obtained in the same fashion that an ordinary MRI scan w ould be done Toe 3 Tesla scanner ls similar lo an ordinary MRI scanner, except that It uses a higher strength of the magnetic field. P ictures and graphs will oe obtained and the effectiveness of the scanner and the procedure will be evaluated from this information. You may be asked to have repea ted scans with different settings on the scanner. You may be asked to pertorm some repetitive exercises while in the MRI scanner such as pushing or pulfi ng agains t a pedal, pulley or lever. You may be asked to have one to 10 visits or more, however, the number Is entirely u to you. We can obtain useful ntormat lon f rom even one visit The lime In the scanner will range from 30 m i nutes t o 2 hours at any one v i sit. This 3T MRI scanner Is curren t ly considered an lnvestigational device by the Food and Drug AdrninistraUon. You will be asked to prov ide up to a c u p ot blood for chemical analysis This volume is necessary to ensure accurate imaging when the b l ood sample i s placed ln the MRI scanner. A person qualified to withdraw blood (a ven i puncturisl) will perform this procedure. If you do not consent to blood testing, you will not have this procedure, but you still can participate in t he program You wish t o provide a sample of blood tor chemical analysis. YES ___ NO __ Signature o f Subject or Representative Dale w 0 t--3 CD (J) I-' S).) 1---1 H ::ti tp # u, I..O I I..O -..J 3 SlJ H I 1--'. < 0 () Ill Ii 1---1 Ill (X) () 1'J ltj 0 {/) "d p' 0 Ii (J) ::ti C/) "d CD () rt Ii 0 (/) () 0 "d '-< l.lJ rt

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6. Po t e nti a l Healt h Aisles o r Di sco mf orts The risk of this study to you will be minimal. MRI and MRS are procedures which allow doctors and researchers to l oo k at I nternal body parts using a scanner that sends out a stro ng magnetic f i eld and radio waves MRI and MRS are very safe for most people However, if you have any type of met al implanted in your body, you may not be able to have the MRVMR S Someone wm ask you questions bef ore you have your MRVMRS You will not be able to have the s tudy i f you have any pacing devices (such as a heart pacemaker) any metal in your eyes, any braln aneurysm clips or certain types of heart valves In addition, the MR scanner produces a "hammering noise which has been reported to have produced hearing loss in a very small number of patients You will be given earplugs to further reduce this ris k You will be mon i tored during the entire study. Because of t h e small space inside the MRI scanner, you may require sedation (medication to help you relax ) ii you are uncomfortable In close spaces. If you do require sedation, you will not be able to drive a car or perform other similar tasks for 4-6 hours afterwards because of drowsiness The minimal risks of the stronger scanner are similar to those of the current MRI scanner. The radio waves may or may not be highe r than that for a conventional MRI scanner. We keep the heating effects wit hin the guidelines of the FDA, but there is a small chance that the controls would tall and you may experience localized heating ot your skin All of the con trols used in this study have been speci f ically designed to prevent this f rom occurring. H owever, I f you feel any localized heatin g sensation, simply tell the operator and the scan will be stopped immediately The risks of taking a blood sample include discom fort at th e site o f the puncture; possibl e bruising and swelling: rarely an Infection; and, uncommonly faintness from the procedure If you w i sh to discuss these or any other discomforts you may experience, you may call the Principal Investigator listed In lt3 of this form. 7. Potential Hea lth Benefits to You o r to Others There will be no health benefits to you as a volunteer. In the fu ture we will be doin g pati en ts. We expect that bette r pictures and as much or more useful i nformation will be o btained from these studies than from a routine M RI. 8. Po t e ntial F i nan c i~I Ri s k s There is no charge to you as a volunteer for th i s study. R av.i"d l.2 l!J 7 9. Po t e n tia l Fin a n ci al Benefi ts t o You o r to Ot hers There 1s no financia l benefit t o you as a volunteer. 10. Co mpen s at i on f o r Researc h Related lnJury In the unlikely event o f you sustain ing a physical or psychological Injury whi ch is proximately caused by t his study: X professional medical ; or __ professional dental; or __ professional consultative care received at the University of F l orida Health Science Center will be provided witho u t charge However, hospital expenses w ill have to be paid by you or your insurance provider. You will not have to pay hospital expenses If you are being treated at the Veterans Administration M edical Center (VAMC) and sustain any phys ical injury during partic i pation i n VAMC-approved studies. 11. Conffic t of Interest There ls no conflict of interes t beyond the profess i onal benefit from academic publication or presentation of the results. 12 Alternativ es to Participating In thi s Re s earch Study You are free not to participate in this study. If you choose to participate, you are free to withdraw your consent and discontinue partici p ation In this research s tudy at any t ime without this decision affecting your medical care If you have any question regarding your righ t s as a subj ect, you m ay phone th e l nsfi t utional Review Boar d {IRB) office at (352) 846-149 4 Student Volunteers: You have b e en Invited t o part icipate I n this resea rch p r oject along with o ther volunteers The Inves tigators associated with tt,is project may o r may n o t teach In you r college or be associated with courses for wh ich you are enrolled or might be expected to register i n the fu ture. Your participation'rin this s tudy Is voluntary and any decision to take part or not to part i cipate will In no w ay affect your grade or class s t anding. If you believe that your p a rt icipation In thJs study o r your decision to withdraw from or to not participate in this study has Impro p erly attected you r grade(s), you s hould discuss th i s with the dean of your college or you may contact the IRB office. Revised 12/91 I-' CX) w

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13. Withdrawal From this Research Study II you wish to stop your participation in this research study for any reason, you should contact Katherine N. Scott at {352} 376-1611 ext 5066 -You may also contac t the lnst!tutlonal Review Board (IAB) O ffice at (352) 846-1494. 14. Confidentiality The University of Florida and the Veterans Administration Medical Center will protect the confidentiality of your records to the extent provided by Law. You understand !hat the Study Sponsor, Food and Drug Administration and the Institutional Review Board have the leg a l right to rev i ew your reco rd s 15. Assent Procedure (if applicable): Not Ap pl i cabl e 16. Signatures Sut>jec1's Name The Princlpal or Co-Principal lnvesligator or represantative has explained the nature and purpose of the above-described procedure and lhe benefits and risks that are involved l n thi s research p rotocol S i gnature of Princ i pal or Co-Princ ipal Investigator or representative obtaining consent Date You have been informed of the aboV&-described procedure 'Mth I t s possible benefits and risks and you have received a copy of this description. You have given pennlssion for your participation in this sludy. Signature of Subject or Representatlve Date If you are not the sUbj ect please print your name _________________ and I ndicate one of the f ollowing: Signatu r e of W i tness The s u bject's parent The subject s guardian A surroga t e A durable power of attorney A proxy Other, please explain: Date If a represen tative signs and it awopriate, the subject ol this research should i ndicate assen t by signi n g below. Subjec r s signature Date: Rflvi.d 12/ 9 7

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IRB# 376-96 /RB Condition Ltr. I 012196 Revision 5/6197 R evision 1 1 15198 IRB CondiJio n /tr 912/98 Informed Consent to Participat e i n Reseurc!I The University of F lorida Health S cience Center Gainesville, Florida 32610 You art! being asked to participate in a research study. This form p r ovides you with i nfonnation about the stu dy The Principal Investigato r ( the person in charge of this research) or his/her representative will also describe this study to you and answer all of your q uesti ons. Rend the infonn:i.rion b elow and ask q u estions abou t W'lything you don't unders tand before deciding ,vhether o r nor to truce part Your participation is entirely voluntary and you can refuse to participate \vithout penalty or loss of benefits to ,Yhich you are oth envise entitled. 'fnm e of the Subject Title of Research Stu d y Evaluation oflschemic Heart Disease in Women Clinical Centers (EIFIDW Principal Investigntor(s) and Telephone Number(s) Carl J. Pepine, M.D (352) 846-0620 S p o n so r o f the S tudy National Heart, Lung, and Blood I.ustirute What is the purpose of this study? The purpose of thi s study will be to better unders t and chest pain i n women, and ro develo p diagnostic studies Lbat i m prove a physicians ability lo acc ura tely de t ermine ,vhich women wilh chest pain have diseas e in t.he arteries that supply blood to your heart. APPROVED From to/'1/9t To 1o/zfft Institutional A.view 8oMd Q Q ,Q IRB-01 "Cl' Revis e d S/98 Page I of 8 What ivill be done if you take purt in this research study? If you agree to participat e in this study, you will be one o f approximately I 000 women asked to p articipate from four centers across the United States. There wilJ be app roximately 250 women enrolled from this site. You are currenUy being evaluated for ches t pain. o r have been told that you have disense in the artenes of your bean. As a result, you are being asked to participate in this s tudy which evaluates ,vomen with chest pain. If you meet 3.ll of the entry criteri a and sign an informed consent. you will be sche d uled t o undergo a battery of tests. The first sets of teslS involve filling out several baseline questionnaires to rec ord your sym ptom s of chest pain and quality of life assessments. In addition, you will undergo a complete history and pbysicnl examination, electrocardiogram (an electrical tracing of your heartbeat), exerc ise stress test, 48-hour ambulatory ECG moni t o r (a ponable monitor that is ,vom and that records your heart rhythm for 48 hours), and have blood dra'\\n. A total of 8 tablespoons wilJ be drown. This ,viii include a com p lete blood count, ren al profile, cholesterol profile including homocystine, and measure the fe male hormones FSH :ind Estradiol. A l thaL visi t yo u will be schedule d to have o dobutamine stress echocardiogram (a stress test that uses a medication to speed up your heart just as if you are exercising, while sol.lJldwave pictures of you r heart are taken). This allo,vs us to measure ch ange s in hean function with exe r cise. You will also have a forearm doppler study \Vbere the reactiv i ty of the anerie s in rour foreo.rm arc exami ned be f ore dunng and after the infla tion of a blood p r essure cuff. Measurements taken o f the blood flo\v in yo ur arm. This inv olves pla cing a blood p ressure cuff on yo ur left arm. With the cuff down. ultrasound pictures of your arteries will be taken, then the cuff wil l be inflated for 5 minures and u l trasound pictures w i l l be repea te d. The blood pressure cuff \Vil! then be d eflat e d :ind additional u l trasound picrures will be laken. A subse t of randomly c h osen (much like the toss of a coin) women will be asked to return in 2 weeks to 6 months to have the electrocardiogram, exercise stress test, quality of life assessment, 48 hour ambulatory monitor, and forearm study r epeated The purpose of this repeat lesting is to dete rm ine how reliable and reprod u ci ble over time these :ests are, w hen done i n women. The n you wil l undergo a c:u-diac catheteri zntion to determine the presence and exten t of the
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a~enosine will be infused as a ~!us i~ the coronary artery and the blood flow through the vessel will be measured. The adm1n1strauon of the adenosine and acetylcbo!ine ,ill prolong the procedure by approximately 15 minutes. After lhe cardiac catheterization, treatment recommendations \vill be given to you based o n tbe results of these tests. :nicse may include the recommendations for medical !henipy, procedures such as balloon angioplasty or bypuss surgery or referral to other specialists s uch as gastroenterologisls for further evaluation of the pain. After the cardiac cathet erization a subset of women \vill be asked to w,dergo imagi ng of the heart ~uscle in a special m~~er. 1hls test is cal led Magnetic Resonance Spectroscopy (MRS). This L~ a method of determLrung ~e energy level in the muscles of your heart using an imaging device sunilar to a CT scan but without the x-rays). During this test you will be asked to li e in the magnet for a resting period while baseline images are obtained. You will then be asked to s quee_ze a handgrip rep~titi~ely until you become fatigued. Images will be taken during the ex~rc1se ~d after ex~rc1se LS completed. The testing period will last approximately one hour This test \Vlll be done 1n one of two different strength magnets, the 1.5 Tor the 3.0 T Regard les s of the recommendations you receive.. you ,vil] be asked 10 return to the c linic annually for o. brief physical examination and assessment of your current medical status for the next four years and will be contacted by phone every six months co see how you are doing. If :ne~~ly indicuted. some o r all of the procedures may be repeated over the next 3-4 years. The lec1s1un to r epeat the tests \vill be made bet\vce n you and your physician. With your permission we \.\,111 obtain the information ob tained from these tests to provide a more co1nplete picture of your c ardiac status. Al the final visit o.t the end of year four, you will be asked to have a repeat physical examination ECG, exercise stress test, quality of life assessmenl, and foreann study. The C ardiac Cachet:nzatioo, exercise stress test, nnd cl inical evaluation are part of your siaOdnrd c.:are. The Dob1,11am1ne stress cest and Doppler flow reserve, in some patients, will be also be part uf standard c are. All ocher testing is for stu dy purposes only Yo~ p~cipa:tioo in this study can be terminated, w i thout your consent, by your physician. Part1cipu llon rnay be tenninated by your physiciWl in your best interests or if you fail to follow the directions of your physician. If you decide not to participate i n this study, your alternative is to continue your evaluation and treatment here \vith the doctors in the cardiovascular clinic, or \'lith your private doctor If you do not have a doctor, we can refer you to a doctor here or in yowcommunity. Wh11t arc the possib l e discomforts and risks? ECG (Electrocardi ogram ): No risks are involved. Dobucamine Stress Echocardiogrmn: This procedure involves the administration of dobutamine as a n infusion through n c atheter placed in your vein. This medication is increased gradually over a 20 m i nute period o.nd results i n a gradual increase your hen.rt rate, similar to what \VOuld occur if you were ro exercise. During the in.fusion a probe will be placed on your chest \vhich \'till provide ultrasound or sound \vaves Lo view the structure and function of the heart at baseline and in response to the rnedication. There are no risks involved with the dopp ler machine. Doburamine may be associated with nausea, vomiting, palpitatio ns, Wld flushing There have been rare reports (
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Quality of Life Questionnaires: Some of the questions in the quality of life questionnaires may ask you to consider areas of your life about which you may not commonly think about. There are ao physlcal risks from completing the survey, but the questions could caus e you concern or emotional distress. 48 Hout Holter Monitor: Involves no risks and only occasional skin i mtalion due to the adhesive for electrode placement. forearm Ultrasound: The ultrasound t est involves placing a probe on the artery to measure the b l ood flow in your rum. The test requires the inflation of a blood pressure cuff which may result in some temporary mild d i scomfon. There are no risks to the p r ocedure. Magnetic Resonance Spectroscopy (MRS): This is a procedure which allows your doctors to look a t internal body parts using a scanne r that sends o u t a strong magnetic field and rndio \Vaves. This is a routine med ical p rocedure and is very safe for most people. H owever, if you have any type of metal implan t ed in your body, you may not be able to have the MRS. Someone will ask you questions before you have the proced ur e. You will not be able to have the study if you have any pacing devices (such as a heart pacer), any metal in your eyes. or certain types of bean v alves and brain aneurysm c l ips. In addition, the MR scanner produces a hammering noise which has been repo ncd to have produced heoring loss in a very small number of patien t s You will be given earplugs to further reduce this risk. It is possible that you deve l op chest pain during the exercise portion ofrhe study. Some patients have experienced claustraphob1a (fear of confined spaces) which is relieved by getting out cf the magnet. You \Vil) be monito red during rhe entire Study. ff you wish to discuss these or any other discomforts you may c1
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H o w ,vill your privacy :ind the confidentiality of your resC3rcb records be protected ? Authorized persons from the Univer~ity o f Florida, the hospital or clinic (if any) involved in this research, and the Institutional Review Board have the legal right to review your research records and will protect the confidentiality of those record s to the exreot pennirted by la\v. If the resenrch projec t is sponso red or if it is being conducted W1der the authority of the United States Food and Drug Administration (FDA), then the spo nsor the sponsor's ag ent and lhe FDA also have the l egal right to review your research records. Othenvise, your research records ,viU not be released without your consent unless required by Jaw or a court o r der. I:fthe results of this research are published o r presented at scientific meetings, your identity will not be disclosed. WilJ the researchers benefit from your participation in this s tudy {beyo nd publi s hing o r presenting the results)? There is no conflict of interes t involved with this study beyond the professional benefit from :icademic publication or presentation of the results. Your name and personal infonnation will not appear in print or be presented in a manner which could identify you. PDf{t 7of 8 Signatures As a representative oftlus study, I have explained the purpose. lhe p r ocedures, the benefits, and the risks that are involved in this research s tudy : Signature of person ohraining consent Date You have been informed about this study's purp ose, procedures, possible benefits and risks, and you have received a copy of this Form You have been given the opportunity to ask questions before you sign. and yo u have been told that you can ask other questions at any time. You voluntarily agree to participate in this study. By sigrung this form, you are not waiving any of your legal rights Signature of S ubject Signa ture of Witness (if available) Date D a te Rewstd S/98 l'agt II of 8 ...... 00 00

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------ I nformed OJnsen c to Pflrfici.pa1e i n Research T he C niversity o f Fl o r i d a H ealth Scie nce Center Gainesville, Flo ri d a 32610 AP? POVS> ;::~ li{llt,/9f 7:-1 .,/J,} 9 9 11,r.'!t ..;~,r---~:-. :-;\> ::IOerC'. c.J..& You are being asked co pamcipa t e Ill a research study This form provides you with i ruonnanon about the study The Pnnctpal Invesugator (th e person 1n ch ar ge of this res ear ch) or his/her re oresentauve will also describe this study ro you and answ e r all of your questions Read the i nformation below and ask questions aboUl anything you don t understand b efore deciding whether or not to take part Your participation is entirely voluntary and you can refuse to parucipa te "Vlthout penalty or loss of benefits to which you are otherwise emitled Na m e o f the S u bject > Titl e o f Research S tud v P-31 Magneuc Resonance Evaluauon at 3T oflscbemic Hean Disease m Men Pnncip al l n vestigacor(s) a nd T ele phone Number\S) Katherine N Soon. Ph.D. Telephone : (353)376-1611, Extens i on 5066 S p o ns o r of the Study Veterans Affiurs Medic.al .Research Service W hat is th e purpos e o f t his s rud y? TI11s : est is pan of a research pro1ecr to learn more about rhe che nustrv of your bean Our ;,Lan 1s to get pictures of your heart without the use of X-rays. Tots part oi the test 1s called magneoc resonance imaging or \1Rl Then we will get tnfonnauon about the cbemisuy of your bean \Vltbout th e us e ofb1oosv and laboratory tests This part of the test 1s called magnenc resonance sp ecrroscopy or \!RS \.Vhat will be do u e i f you t a ke pan i n t his r esea r c h sru d y? You will he on a bed. which rolls in t o the operung of a large magnet. A flat coil ofwrre ( a radio frequency <:ii) will be placed on your chest, o ver your bean A computer looks at the radio waves passing through your bean and constructs pictures and chemical 1 nformanon of your bean. The tocal procedure will last approXJma-rely 90 trunures While you are 10 the magner. we will also ask you to squeeze a tlu1d-61led rubber bulb Thts will exercise your h ean. and will let us see how your heart responds to exercise Al a later date, { I month or years later) rhe procedure will be reoeated This will let us sec wheth e r th e chemistry o f your heart 1s c hanging The ch ~m1cal infonnauon part of the test is expenmerual, but has been done oa many vol umeers and paoents at o ther 1nst1rut1ons lt also has been done under Dr Scon s gwoance on maie and female volunteers and on female pauents at the Uruversity ofFlonda and the VA Medical Center We want co compare the results of tlus test with th e results of other tests that your doctor had orde r ed, such blood t eSts, resting eiectrocardiogram (ECG), treadmill ECG, nuclear medicme scans, an d cardiac catheteri.zation. We ask your permission to obtain this infonnation from your medical records, You give us permission to obwn t hls i nfonnauon from your medical r ecords YES __ ;-JO -Signa ture of Sub1ect Date ff you are a healthy volunteer I a reference sobJect), you did not have any othe r tescs done Therefore. we are not asJong you r permission ro obtam utiormauon from your medic.al r e cords You are a h e althy volunteer ( a reference subJect) YES _ Signature of Subject Date What a r e t he p ossible dis c o m f o m a n d ri s ks ? Your h an d will get tired from squeezmg the tiuid -filled rubber bulb b ut iliere 1s no other discomfort associated w i th the procedu r e The nsk cftlu.s srudy co y ou \vtl l b e m.Jnunal MRI and MRS are very sate for most p eople However, tfyou have anv type o f metal implanted into your body you may not be able to have rhe MRI/MRS Someone will ask you quesnons oefo r e you have the MRI/MRS You will not be w ::r: H (l) P.> to l'i rt =it: t:.l V, I-' (\.) CJ) I (l) '-0 P.> 00 CJ) .. (l) trj I-' I !:j w t-' 3 (l) 3 P.> LQ :::l (l) rt I-' n (l) CJ) 0 t-' P.> 00 :::1 '-0 0 (l) tZj
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able to have the study 1 .f you have any pacing devices ( such as a heart pacemake r), any m e tal in your eyes. any bnun aneurysm clips, or certain rypes of heart valves Likewise. me tal objectS such as coins, glasses. hatrpins ; ewelry and mascara should not be present when you go r n to the magncL In addition. the MR s cann er prod u ces a "hammenng" noise. wtuch nas b een r eport ed to h a ve produced beari n g ,oss 1n a v ery small num ber o f patients You \Viii be given earplugs to further red u ce tius risk You will b e monitored dunng the enti r e s tudy Because of the small space 1ns1de the MR scanner. you may require sedat1on (meciicauon lo h e l p vou relax) if you are uncomtortable 1 n small spaces If you do r equire s edation you will 101 o e ab1e to dnve a car or perform o ther similar tasks for 4-o hours anerwards because oi drowsiness The muumal nsks of this stro n ger scanner are similar to those of the conv e ntional MR scann e rs The r adio waves may or may not b e stronger chan thos e for a co nvenu onaJ MRI s canner We k ee p the heaung effec t s wit hin th e guideli nes of the FDA. But th ere is a small c hance tha t the co n trols would fatl. and y ou may exp e nen ce localiz ed heating 10 your skin . -\ll of the con tr ols us ed on the scanner and 1n rlus s t udy have been spe cifically des1gne d to orcven t tills from o ccumng However if You feel any loc alized heanng s ensauon, simply tell the operator, and the scan will be stopped 1 mmediaie ly If vou w ish 10 discuss t he informauon above o r any ot her oiscomiort s You may expenence, y ou may ask quesuons now or caU the Pnnc1pal lnvesugator listed o n the front pa ge of this form. \Vhat a r e the possible b enefilS t o you o r to others? There is a cha.nee that the mformauon we get from this r est may provide a better u n derstanding o f vour disease There 1s also a chance that you may not rec e ive a d i rect benefit. If the test ts useful 1t may provide tnforma u on about the chemistry of your h eart without the u se of bio p sy and l aboratory tests Fu tu re heart paoents may also b e n efit f r o m the added informati on that we obuun from this srudy If y o u c h o ose to ta k e pa_rt i n t h is study, w il l i t c os t y o u anythi n g ? This test \V1ll be perfonned at no co st t o you W ill y ou r e ce iv e compen s l\t i o n for y ou r part1CJpatioo in thi s s tu dy? You will not receive monetary compeosa u on for pamc 1 pan n g m this Study Wh111 i f y o u n r e injured because of t h e s tudy' 1 f vou ex perience an tnJurv t hat is directlv c aused by this study, only X_ profussionaJ medical or_ profess1onaJ d ental o r proressional consultarive c are that you receive at the Un1ver stty ofFlorida Heal t h Soc nce Center will be p r ovided without charge How e ver. hosp11al expenses \viii have 10 be paid by you or your insu ran ce provi der. No oth e r compensation 1s offered You w ill not have ro pa y hospttal e..'-1494 Bow will your privacy a n d t h e c onfidentiali ty of you r resCArch record s be protecred? Authorized perso ns from the Uruvcr sny of Florida, tbe Veterans Affairs Medical Cent e r and the l n snr u uonel Revi ew Bo ar d have th e l egal nght to revte w y our research records and will pro t ect th e confidenuality of those records to t h e exte n t penrutted by l a w rf t be research pro ject is s p onsored or uir 1s being cond u cted under the a u thonty of th e Unit e d States Food and Drug Admirustrauon (FDA ), th e n the sponsor, the sponso r's a gent, and the FDA also nav e the legal ngbt to revi e w your resear ch records. O t h erwise your r esear ch reco r ds wtll no t be released wnh out your co n s e nt u n l ess re qwred by l a w or a coun o rde r [f t h e res u11s o f this research are pubhsbed or presented at SC1ent1fic m ce nngs. vour i denurv will not o e 01sclosect. Will t h e res ea r c he rs be n efit f r o m y o u r pnrri ctpation i n t h i s stud y ( beyond p u bli s hing o r p r ese nrin g the res u lts) ? The researchers will e nefit from YOU parr1c1pauon in this sru.dy by l earning more about the c hemistry o f y our h e art ano. t n the finure, the hearts oi other pauents like you. Otherwise. th.e res e archers will no t o en ve anv o t her b enefit from your paroc i p a uoo 10 tlus study 1---' \D 0

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Sig na t u res As a representativ e of this StUdy, I have explained lhe purpose. the procedures, the benefits. and the nsks that are 1nvolved 1n tlus researcn studv Signan:re of person obcruntng consent Date You have been inf ormed about this swdy s purpose, proceoures, possible benefits and nsks. and you have received a .:opy of this Form. You have been given lhe opponun1cy to ask quesuons before you s ign and you have been told that you can ask other questions at any nme You voluntanl y agree to participate tn this srudy. By signing thls form, you are not waiving any of your l egal rights. Signature of SuoJect Signature o f \Vitness (if avallable I Date Date

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s 31th., Uru, coil) ut Hori lb Department of Radiology MRI Sc reen i ng Form D Inpatient D Outpatient Palleol Name: '-' Body WI.: Cllnlc D Yes D No Magnellc Resonance lmag1n_g (MRI) is a diagnostic procedure used Lo Image various organs and tissues inside the body It can be a useful tool to detect soft t issue abnormalities 1n any area of the body MRI operates with a radiofrequency pulse and a large magnet No x-rays or radioaot1v1ty are i nvolved. Because of the high magnetic rield, certain metallic im pla nts or dev ices are not permitted Some implants, whi le not hazardous to the patient, may deg r ade the M A images Others may be moved by the magne t or aHected by the radiotrequency pulse causing a poten tially Ille-th r eatening situation an internal inJury, or heating of the object w ithin the body. Please 1ndlcat e ii you have any of t he follo w ing items ; S i ckle cell d i sease HemolytJc anemia Kidney disease Liver disease Y e s D D D D Heart disease 0 Cardiac (heart) pacemaker D Artificial heart valve prosth e sis 0 A neurysm clip(s ) D Impl anted drug infusion device or pump D Any type of neurostimulator {spinal cord) D Any t ype of bone growth stimulator D Cochl ear implants or Inner ear prosthesis D N o D D D D 0 D D 0 D D D D Y e s Any ln tra vascular cons. niters or stint s D (for blood clots) Shrapnel or bullet{s) D Any other metallic Implants or devices? D Permanenlly tattooed eyeliner D Allergies_________ D Other D Are you pregnant, or do you suspect D you might be? A re you breas t reeding? D No D C C C C C C It yes, commen1; _____________________________ Have you ever worked I n a machine shop or similar environment where you may have been subjected to small metal snvers which may have gone In your eyes or elsewhere? D Yes :::J N o If you have had metal slivers In your eyes, or you are unsure, w e recommend x r ays of your head be performed pri or to the MRI since blindne ss may result. X-rays of the head required? O Yes ONo Results: ______________ Radiologist : _____________ I attest this information is correct to the best o r my know l edge. S i gned:----------,--(pa1ien1 or nea,cs1 re"1ll\lll or guardlan) Reviewer_ ________ __________ Date : ______ Time : __ Otstnbutlon Whitt Cl\ar1 00p)': Yellow Radiology .... l/112 PS188703925C 3 T VA MEDICAL CENTER MRI S CBE~ING F ORM PATIENT NAME: SSN: ____ __ WEIGHT; PLEAS! INDICATE 11 TSE PATIENT BAS ANY or THE F OLLOWING: Tattoo or pemeneut eyeliner? Aneuryam clip(a)? Cardiac Pacemker? Iaplanted drug infuaioo device or pump? Artificial beart valve proatbeaia? /Jly type of ueuroatimulator? A.y type of boo growth stimulator? Cochlear implant or ioo~r ear proathesia? Claustrophobic? July intravucular coil.a. filter or atenta? Sbrapnal or bullet injury? /Jly tal~ joint proatheau, roda, or plates If ao, how long ago vaa surgery? ______ Sickle call diaaue? liemolytic aoemia? 'lidney d1auset illergiaa? Priilgnant or br ... t feediD.& (fwl patianta)? If Y to uy above, c"!PIDeut: Yes No -----I --------------Haa patiallt ever metal in Y or vork&d in .achine ahop or ailllilar euviromuntf If yea, have x-raya or er of tbe orbits been d o lle? IAaulta; ladiologiat: Source o( 1Atorut1ou; ---------------the above 1Atorut1oo 1a true to the beat of Y mowladge. Maxt of 110 (circle ooe): -----Patient or Date: -----$ignature of reviewer: Date: -------------- Are there uy coapliot/aide effect froa ae&n? If yu, pleaae 11.at be1ov : Cl) () Ii (D (D ::, t--' ::, LQ 1-rj 0 co .. t--' I..O l\J

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APPENDIX B FIGURE ACQUISITION PARAMETERS List of MR Acquisition Parameters for Figures Figure 5. Gate-able-Phantom images, (a) axial, (b) coronal and (c) sagittal views, as imaged with 25cm square proton coil. Head 1st, prone, extremity coil, axial or coronal or sagittal 2D, gradient echo, extended dynamic range, fast (graphic Rx for coronal and sagittal) 60 flip angle, minimum full TE, 200 msec TR autoshim, water auto center frequency, 8 kHz bandwidth 36 cm FOV, 5 mm thick, 0 mm space, I40-S40 for axial with 17 slices, 256 x 128, R/L, 1 NEX, scan time= 0:58 Rl = 7, R2 = 30, TG = 200, power= 8.1 Date: 092397, axial: series 1 image 12, coronal: series 3 image 7, sagittal: series 2 image 12 Magnet: 3.0T; Coil: single-turn Hl; phantom: gate-able Figure 7. Depth-Changing-Phantom images, (a) axial, (b) coronal and (c) sagittal views, as imaged with 25cm square proton coil. Head 1st, prone, extremity coil, axial or coronal or sagittal 2D, gradient echo, extended dynamic range, fast (graphic Rx for coronal and sagittal) 60 flip angle, minimum full TE, 200 msec TR autoshim, water auto center frequency, 8 kHz bandwidth 193

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194 36 cm FOV, 5 mm thick, O mm space, I40-S40 for axial with 17 slices, 256 x 128, R /L, 1 NEX, scan time 0 :58 Rl = 7, R2 = 30, TG = 200, power= 8.7 Date: 070298, axial: series 1 image 7, coronal: series 4 image 6, sagittal: series 2 image 6 Magnet: 3.0T; Coil: single-turn Hl; phantom: depth Figure 19. Axial images of gate-able phantom comparing images obtained on 3.0 Tusing a 25 cm square proton surface coil with the image pulsesequences of (a) spin echo, (b) fast spin echo, (c) gradient echo and (d) fast gradient echo imaging. (a) spin echo: Head 1st, supine, nas1.on, extremity coil, axial 2D, Spinecho, no options, 1 echo, minimum full TE, 2000 msec TR autoshim, water auto center frequency, 16kHz receive bandwidth 36 cm FOV, 5 mm thick, 0 mm space, I20-S20 (9 slices) 256 x 128, A/P, 1 NEX, scan time 4:40 Rl = 7, R2 = 15, TG = 200, power 6.1 Date: 091098a, series 4, image 5 Magnet: 3.0T; Coil: single-turn Hl; phantom: gate-able (b) fast spin echo: Head 1s t supine, nasion, extremity coil, axial 2D, Spinecho, fast, fse optimization on 4 echo train length, 1 echo, 17 msec TE, 3000 msec TR autoshim, water auto center frequency, 32kHz receive bandwidth 36 cm FOV, 5 mm thick, O mm space, I20-S20 (9 slices) 256 x 128, R /L, 1 NEX, scan time= 1:48 Rl = 7, R 2 = 15, TG = 200, power 14.9 Date: 091098a, series 3, image 5

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195 Magnet: 3.0T; Coil: single-turn Hl; phantom: gate-able (c) gradient echo: Head 1st, supine, nasion, extremity coil, axial 2D, gradient echo, extended dynamic range 60 flip angle, 1 echo, minimum full TE, 250msec TR autoshim, water auto center frequency, 8kHz receive bandwidth 36 cm FOV, 5 mm thick, 0 mm space, 120-S20 (9 slices) 256 x 128, R/L, 1 NEX, scan time= 0:36 R1 = 7, R2 = 30, TG = 200, power= 5.6 Date: 091098a, series 2, image 32 Magnet: 3.0T; Coil: single-turn Hl; phantom: gate-able (d) fast gradient echo: Head 1st, supine, nasion, extremity coil, axial 2D, gradient echo, extended dynamic range, fast 60 flip angle, minimum full TE, 200msec TR autoshim, water auto center frequency, 8kHz receive bandwidth 36 cm FOV, 5 mm thick, 0 mm space, 120-S20 (9 slices) 256 x 128, R /L, 1 NEX, scan time 0:29 R1 = 7, R2 = 30, TG = 200, power -5.6 Date: 091098a, series 2, image 23 Magnet: 3.0T; Coil: single-turn H1; phantom: gate-able Figure 22. Frequency domain of {a) PRESSCSI voxel localized phosphorus spectroscopy Head 1st, prone, nasion, extremity coil, axial Spectra, spinecho, extended dynamic range, graphic roi, psd file = presscsi 2000 spectral width, 1024 points, console freq -P-31, spectra mode 1, 128 acquisitions, 1 x 1 x 1 CSI

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196 40 msec TE, 2000msec TR, water auto center frequency 24 cm FOV, 20 mm thick, 20 x 20 x 20 mm voxel 256 x 128, R /L, 2 NEX, scan time= 4:24 Rl = 7, R2 = 30, TG = 200 Change cv's: pibbandfilt = 0, pixmtband = 1 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase Date: 091098, series 7, file= G00325 Magnet: 3.0T; Coil: quadrature P-31; phantom: gate-able Figure 23. Frequency domain of (a) STEAMCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization. Head 1st I prone, nasion, extremity coil, axial Spectro, spinecho, extended dynamic range, graphic ro1., psd file = steamcsi 2000 spectral width, 2048 points, console freq= Hl (back room frequency P -31), spectro mode 1, 32 acquisitions, 1 x 1 x 1 CSI 10 msec TE, 2000msec TR, peak auto center frequency 36 cm FOV, 20 mm thick, 20 x 20 x 20 mm voxel 256 x 128, R /L, 2 NEX, scan time= 1:14 Rl = 7, R2 30, TG = 200 Change cv's: sup= O; suppress O; asfov 420; GAM 1723.5; sharp= 1 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order 180 first order 98 ) Date: 102897a, series 8, file= G00525 Magnet: 3.0T; Coil: quadrature P-31; phantom: gate-able

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197 Figure 25. Frequency domain of (a) ECHOCSI voxel localized phosphorus spectroscopy with (b) diagram demonstrating localization. Head 1st, prone, nasion, extremity coil, axial Spectre, spinecho, extended dynamic range, psd file= echocsi 2000 spectral width, 2048 points, console freq= Hl (back room frequency P -31), spectre mode 1, 256 acquisitions, 8 x 8 x 1 CSI, soft pulse (1) 35 msec TE, 2000msec TR, peak auto center frequency 36 cm FOV, 20 mm thick, 256 x 128, R/L, 4 NEX, scan time -8:44 Rl = 7, R2 = 30, TG = 200 Change cv's: sup= O; suppress -O; asfov -420; GAM = 1723.5; sharp= 1, opfov 33 Postprocessed with Sage_IDL: apodize exponential 30Hz line broadening, spectral zero-fill, fft, phase (zero order -59 first order -59 ) Date: 102897a, series 8, file= G00526 Magnet: 3 .0T; Coil: quadrature P-31; phantom: gate-able Figure 28. Frequency domain of SPINECHO CSI multivoxel localized phosphorus spectroscopy Head 1st, prone, nasion, extremity coil, axial Spectre, spinecho, extended dynamic range, psd file= spinecho 2000 spectral width, 2048 points, console freq= Hl (back room frequency P-31), spectre mode 1, 512 acquisitions (doesn't matter), 11 x 11 x 1 CSI, soft pulse (1) 2000msec TR, peak auto center frequency 33 cm FOV, 33 mm thick, O space, 1 slice 256 x 128, R /L, 8 NEX, scan time -32:40 Rl = 7, R 2 = 30, TG = 140

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198 Change cv's: sup= O; suppress -O; asfov 420; GAM = 1723.5; spec_chopletson = 0 Postprocessed with Sage_IDL: apodize exponential 30Hz line broadening, spectral zero-fill, fft Date: 102497a, series 3, file= P25600 Magnet: 3.0T; Coil: quadrature P-31; phantom: gate-able Figure 30. Frequency domain of (a) ISISCSI slice localized phosphorus spectroscopy Head 1st, prone, nasion, extremity coil, axial Spectra, spinecho, extended dynamic range, graphic roi, psd file ' = lSlSCSl 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 256 acquisitions, 1 x 1 x 1 CSI, soft pulse (1), plane (2) 2000msec TR, peak auto center frequency 24 cm FOV, 20 mm thick slice 256 x 128, R /L, 2 NEX, scan time -8:44 Rl = 7, R2 -30, TG = 200 Change cv's: pibbandfilt = O; pixmtband = 1 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= -106.51, first order= 170.84) Date: 091098a, series 7, file= G00327 Magnet: 3.0T; Coil: quadrature P-31; phantom: gate-able Figure 31. Frequency domain of (a) ISISCSI c olumn localized phosphorus spectroscopy Head 1st, prone, nasion, extremity c oil, axial

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199 Spectro, spinecho, extended dynamic range, graphic ro1., psd file = l.Sl.SCSl. 2000 spectral width, 1024 points, console freq= P-31, spectro mode 1, 256 acquisitions, 1 x 1 x 1 CSI, soft pulse (1), col (4) 2000msec TR, peak auto center frequency 24 cm FOV, 20 mm thick, 20 x 20 mm column 256 x 128, R/L, 4 NEX, scan time= 8 :44 Rl = 7, R2 = 30, TG = 200 Change cv's: pibbandfilt = O ; pixmtband = 1 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= -68.545, first order= 43.919) Date: 091098a, series 7, file= G00328 Magnet: 3 .0T; Coil: quadrature P-31; phantom: gate-able Figure 32. Frequency domain of (a) ISISCSI voxel localized phosphorus spectroscopy Head 1st, prone, nas1.on, extremity coil, axial Spectro, spinecho, extended dynamic range, graphic roi, psd file = lSlSCSJ. 2000 spectral width, 1024 points, console freq= P-31, spectro mode 1, 256 acquisitions, 1 x 1 x 1 CSI, soft pulse (1), vox (8) 2000msec TR, peak auto center frequency 24 cm FOV, 20 mm thick, 20 x 20 x 20 mm voxel 256 x 128, R /L, 8 NEX, scan time= 8:52 Rl = 7, R 2 = 30, TG = 200 Change cv's: pibbandfilt = O; pixmtband = 1

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200 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= -187.97, first order= 486.52) Date: 091098a, series 7, file= G00329 Magnet: 3.0T; Coil: quadrature P-31; phantom: gate-able Figure 34. Frequency domain of (a) modified ISISCSI localized voxel sequence for phosphorus Head 1st, prone, nasion, extremity coil, axial Spectre, spinecho, extended dynamic range, graphic roi, psd file . = isiscsi 2000 spectral width, 1024 points, console freq= P-31, spectre mode 1, 64 acquisitions, 1 x 1 x 1 CSI, soft pulse (1), sin (1) 2000msec TR, peak auto center frequency 24 cm FOV, 20 mm thick, 20 x 20 x 20 mm voxel 256 x 128, R/L, 1 NEX, scan time= 2:13 Rl = 7, R2 -30, TG = 200 Change cv's: pibbandfilt = O; pixmtband = 1, THISISIS -1 TO 8 (8 separate acquisitions Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase, combine acquisitions as such: Acq 1 Acq 2 + Acq 3 -Acq 4 + Acq 5 Acq 6 + Acq 7 -Acq 8 Date: 071298a, series 7, file= GOOOOS -G00006 + G00007 -G00008 + G00009 -GOOOlO + GOOOll -G00012 Magnet: 3.0T; Coil: quadrature P-31; phantom: gate-able Figure 38. Frequency domain of FIDCSI slice localized phosphorus spectroscopy of (a) gate-able phantom and (b) depth phantom

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201 (a) gate-able phantom Head 1st, prone, nasion, extremity coil, coronal Spectre, spinecho, extended dynamic range, graphic Rx, psd file -fidcsi 2000 spectral width, 2048 points, console freq= Hl (back room frequency P-31), spectre mode 1, 128 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) 2000msec TR, peak auto center frequency, 36 cm FOV, 25 mm thick, 256 x 128, R/L, 2 NEX, scan time= 4:26, Rl = 7, R2 = 30, TG = 20 Change cv's: sup= O; suppress= O; asfov = 420; GAM = 1723.5 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order -117 first order -210 ) Date: 012798, series 4, file G00005 (b) depth phantom Head 1st, supine, nasion, extremity coil, coronal Spectre, spinecho, extended dynamic range, graphic Rx, psd file - fidcsi 2000 spectral width, 1024 points, console freq= P-31, spectre mode 1, 128 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) 2000msec TR, peak auto center frequency 16 cm FOV, 25 mm thick, 256 x 128, R/L, 2 NEX, scan time= 4:26 Rl = 7, R2 = 30, TG = 50 Change cv's: pibbandfilt = 0, pixmtband = 1, pw_gph = 4msec Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase Date: 012798, series 5, file= G00034 Magnet: 3.0T; Coil: single-turn P-31 coil; phantom: gate-able and depth phantoms

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202 Figure 39. Multivoxel phosphorus FIDCSI plus CSI of the (a) gate-able phantom (b) depth phantom (a) gate-able phantom Head 1st, prone, nasion, extremity coil, axial Spectra, spinecho, extended dynamic range, graphic ROI, psd file = fidcsi 2000 spectral width, 1024 points, console freq= Hl (control room frequency P-31), spectra mode 1, 128 acquisitions, 6x6xl CSI, soft pulse (1) 2000msec TR, peak auto center frequency 34 cm FOV, 25 mm thick, 256 x 128, R/L, 4 NEX, scan time= 4:59 Rl = 7, R2 -30, TG = 30 Change cv's: suppress -O; sup= O; asfov = 480; GAM = 1723.5 Postprocessed with Sage_IDL: apodize exponential, spectral zero-fill, fft, phase Date: 022298a, series 3, file= P13824 Magnet: 3.0T; Coil: quadrature P-31; phantom: gate-able (b) depth phantom Head 1st, supine, nasion, extremity coil, axial Spectra, spinecho, extended dynamic range, graphic ROI, psd file = fidcsi 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 128 acquisitions, 8 x 8 x 1 CSI, soft pulse (1) 2000msec TR, peak auto center frequency 16 cm FOV, 30 mm thick, 256 x 128, R/L, 2 NEX, scan time= 4:26 Rl = 7, R2 -30, TG = 125 Change cv's: pibbandfilt = 0, pixmtband = 1, pw_gph 4msec

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203 Postprocessed with Sage IDL: apodize exponential, spectral zero-fill, fft, phase Date: 073098b, series 3, file= Pl7920 b Magnet: 3.0T; Coil: quadrature P-31; phantom: depth Figure 40. Comparison of 1.5 to 3.0 Tesla results of phosphorus FIDCSI plus CSI localized voxel scaled by noise level. (a) 1.5 T single-turn coil Head 1st, supine, nasion, extremity coil, axial Spectra, spinecho, extended dynamic range, graphic ROI, psd file = fidcsi 1000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 256 acquisitions, 8 x 8 x 1 CSI, soft pulse (1) 2000msec TR, peak auto center frequency 16 cm FOV, 25 mm thick, 1 slice 256 x 128, R/L, 4 NEX, scan time= 4:26, Rl = 7, R2 = 30, TG SO Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= -79.393, first order 145.43), localized to voxel (4 to 4) x (4 to 4) Date: 071198, series 5, file= P17408 Magnet: 1.5 T; Coil: single-turn P-31; phantom: depth (b) 3.0 T single-turn P-31 coil Head 1st, supine, nasion, extremity coil, axial Spectra, spinecho, extended dynamic range, graphic ROI, psd file = fidcsi 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 256 acquisitions, 8 x 8 x 1 CSI, soft pulse (1) 2000msec TR, peak auto center frequency

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204 16 cm FOV, 20 mm thick, 1 slice 256 x 128, R /L, 2 NEX, scan time= 4:26 change cv's: pibbandfilt = 0, pixmtband 1, pw_gph = 4msec Rl = 7, R2 = 30, TG = 50 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= 128, first order O), localized to voxel (5 to 5) x (3 to 3) Date: 070998, series 8, file= P06144 Magnet: 3.0T; Coil: single-turn P-31; phantom: depth (c) 3.0 T quadrature P-31 coil Head 1st, supine, nasion, extremity coil, axial Spectre, spinecho, extended dynamic range, graphic ROI, psd file = fidcsi 2000 spectral width, 1024 points, console freq= P-31, spectre mode 1, 256 acquisitions, 8 x 8 x 1 CSI, soft pulse (1) 2000msec TR, peak auto center frequency 16 cm FOV, 20 mm thick, 1 slice 256 x 128, R /L, 2 NEX, scan time= 4:26 change cv's: pibbandfilt = 0, pixmtband 1, pw _gph 4msec Rl = 7, R 2 = 30, TG = 50 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= -11, first order 0), localized to voxel (5 to 5) x (4 to 4) Date: 071298, series 6, file= P04608 Magnet: 3.0T; Coil: quadrature P-31; phantom: depth Figure 41. Comparison of 1.5 to 3.0 Tesla results of phosphorus, modified ISISCSI localized voxel (created from eight separate

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205 acquisitions, added and subtracted appropriately during postprocessing). (a) 1.5 T single-turn P-31 coil Head 1s t supine, nasion, extremity coil, axial Spectra, spinecho, extended dynamic range, graphic ROI, psd file = lSlSCSl 1000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 256 acquisitions, 1 x 1 x 1 CSI, soft pulse (1), sin (1) 2000msec TR, peak auto center frequency 16 cm FOV, 20 mm thick, 20 x 20 x 20 mm voxel 256 x 128, R/L, 1 NEX, Rl = 7, R2 = 30, TG = 200 Change CV's: THISISIS = 1 to 8 for 8 separate acquisitions Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, ft, phase, sum of spectra Acq 1 -Acq 2 + Acq 3 Acq 4 + Acq 5 -Acq 6 + Acq 7 -Acq 8 Date: 071198, series 6, file= G00769 G00770 + G00771 -G00772 + G00773 -G00774 + G00775 -G00776 Magnet: 1.5 T; Coil: single-turn P-31; phantom: depth (b) 3.0T single-turn P-31 coil Head 1st, supine, nasion, extremity coil, axial Spectra, spinecho, extended dynamic range, graphic ROI, psd file = lSlSCSl 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 256 acquisitions, 1 x 1 x 1 CSI, soft pulse (1), sin (1) 2000msec TR, peak auto center frequency 16 cm FOV, 20 mm thick, 20 x 20 x 20 mm voxel 256 x 128, R/L, 1 NEX, Rl = 7, R2 = 30, TG = 200 Change CV's: pibbandfilt = O, pixmtband = 1, pw_gph = 4msec, THISISIS = 1 to 8 for 8 separate acquisitions

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206 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase, sum of spectra= Acq 1 -Acq 2 + Acq 3 -Acq 4 + Acq S -Acq 6 + Acq 7 -Acq 8 Date: 070998, series 9, file= G00234 -G00235 + G00236 -G00237 + G00238 G00239 + G00240 G00241 (c) 3 0T quadrature P-31 coil Head 1st, supine, nasion, extremity coil, axial Spectre, spinecho, extended dynamic range, graphic ROI, psd file = 1.Sl.SCSl. 2000 spectral width, 1024 points, console freq= P-31, spectre mode 1, 256 acquisitions, 1 x 1 x 1 CSI, soft pulse (1), sin (1) 2000msec TR, peak auto center frequency 16 cm FOV, 20 mm thick, 20 x 20 x 20 mm voxel 256 x 128, R/L, 1 NEX, Rl = 7, R2 = 30, TG = 200 Change CV's: pibbandfilt = 0, pixmtband = l, pw_gph 4msec, THISISIS = 1 to 8 for 8 separate acquisitions Postprocessed with Sage_IDL : apodize exponential lOHz line broadening, spectral zero-fill, fft phase, sum of spectra= Acq 1 -Acq 2 + Acq 3 -Acq 4 + Acq 5 -Acq 6 + Acq 7 -Acq 8 Date: 071298, series 7, file= G00005 G00006 + G00007 G00008 + G00009 GOOOlO + GOOOll G00012 Figure 42. 1.5 T, P-31 single turn RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice) moved across the internal phosphoric acid vial in the Slice Profile Phantom. Head 1st, supine, nasion, extremity coil, oblique Spectre, spinecho, extended dynamic range, graphic Rx, psd file -/usr/g/genesis/fidobl

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207 2000 spectral width, 1024 points, console freq= P-31, spectre mode 1, 32 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) lOOOmsec TR, peak auto center frequency 14 cm FOV, 25 mm thick, 256 x 128, S/I, 2 NEX, scan time 0:37 Rl = 7, R2 = 30, TG = 170; ax= 25868906 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= auto, first order -0) Date: 101298; Magnet: 1.5 T; Coil: single-turn P-31 coil; phantom: slice profile Figure 43. 3.0 T, P-31 single turn RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice} moved across the internal phosphoric acid vial in the Slice Profile Phantom. Head 1st, supine, nasion, extremity coil, oblique Spectre, spinecho, extended dynamic range, graphic Rx, psd file -/usr/g/genesis/fidobl 2000 spectral width, 1024 points, console freq= P-31, spectre mode 1, 32 acquisitions, l x 1 x 1 CSI, soft pulse (1) lOOOmsec TR, peak auto center frequency 14 cm FOV, 25 mm thick, 256 x 128, S/I, 2 NEX, scan time -0:37 control variables: pibbandfilt = 0, pixrntband = 1 Rl = 7, R2 = 30, TG = 100; ax= 21287799, back room freq -30427790 Postprocessed with Sage_ IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= auto, first order -O} Date: 101098; Magnet: 3 .0T; Coil: single-turn P-31 coil; phantom: slice profile

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208 Figure 44. 3.0 T, P-31 quadrature RF coil signal from a set of 25 mm thick, oblique DRESS slices (FIDCSI oblique slice) moved across the internal phosphoric acid vial in the Slice Profile Phantom. Head 1st, supine, nasion, extremity coil, oblique Spectra, spinecho, extended dynamic range, graphic Rx, psd file= /usr/g/genesis/fidobl 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 32 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) lOOOmsec TR, peak auto center frequency 14 cm FOV, 25 mm thick, 256 x 128, S/I, 2 NEX, scan time 0:37 control variables: pibbandfilt = 0, pixmtband = 1 Rl = 7, R2 = 30, TG = 100; ax= 21287799, back room freq 30427790 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order= auto, first order O) Date: 102398; Magnet: 3.0T; Coil: quadrature P-31 coil; phantom: slice profile Figure 45. Human cardiac imaging with the spin-echo pulse sequence at (a) 1.5 T with the body coil and at (b) 3.0 T with a surface coil. (a) 1 5 T with the body coil Head 1s t supine, body coil, axial 2D, spin echo, gating, no phase wrap, graphic Rx (based on previous sagittal scout) 1 echo, minimum full TE autoshim, water auto center frequency, default kHz bandwidth peak auto center frequency, 32kHz bandwidth

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209 gating menu, trigger type: ECG autolead, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger, intersequence delay= minimum, cardiac phases= single 40 cm FOV, 7 mm thick, 3 mm space, L70-R10 (I26.2) 256 x 128, A/P, 1 NEX, scan time -2:22 Rl = 7, R2 = 30, TG = autoset Date: 060698, series 2, image 17 Magnet: 1.5 T; Coil: body coil; volunteer: WISE#2 (b) 3 0T with a surface coil (update info) Head 1st, supine, extremity coil, axial 2D, spin echo, gating, no phase wrap, graphic Rx (based on previous sagittal scout) 1 echo, minimum full TE autoshim, water auto center frequency, 16 kHz bandwidth peak auto center frequency, 32kHz bandwidth gating menu, trigger type: ECG autolead, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger, intersequence delay= minimum, cardiac phases= single 36 cm FOV, 7 mm thick, 3 mm space, L70-Rl0 (I26.2) 256 x 128, A/P, 1 NEX, scan time= 2 :47 Rl = 6, R2 = 15, TG = 179 Date: 041898, series 4, image 5 Magnet: 3 .0T; Coil: 25cm square proton coil; volunteer: TB Figure 46. Human cardiac imaging with the fast gradient echo pulse sequence at (a) 1.5 T with the body coil and at (b) 3.0 T with a surface coil. (a) 1.5 T with the body coil head 1st, supine, sternal notch, body coil, axial

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210 2D, gradient echo, gating, no phase wrap, graphic Rx, fast arrythmia rejection= O, 60 flip angle, minimum full TE autoshim, water auto center frequency, 16kHz bandwidth gating menu, trigger type: peripheral gating, Trigger window= auto trigger window 42 cm FOV, 7 mm thick, 2.5 mm space 256 x 128, A/P, 2 NEX, scan time 6:18 Rl = 7, R2 = 30, TG = 200, power -10. 8 Date: 040599, series 3 Magnet: 1.5T; Coil: body coil; volunteer: TB (b) 3.0T with a surface coil feet 1st, supine, sternal notch, extremity coil, axial 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth arrythmia rejection= 0, 60 flip angle, minimum full TE autoshim, water auto center frequency, 32kHz bandwidth gating menu, trigger type: peripheral gating, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even 42 cm FOV, 7 mm thick, 1 mm space, I31.8 256 x 128, A/P, 1 NEX, scan time= 0 :20; breathold Rl = 7, R2 = 30, TG = 200, power 10.8 Date: 020599, series 6; image 4 Magnet: 3.0T; Coil: square Hl; volunteer: Relax#S LR Figure 48. A comparison of the heart's position in the (a) prone and (b) supine positions, as shown from a 3.0 T axial slice. (a) prone position: Head 1st, prone, extremity coil, axial

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211 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth 60 flip angle, minimum full TE, 200 msec TR autoshim, water auto center frequency, 8 kHz bandwidth peak auto center frequency gating menu, trigger type: peripheral gating, effective TR: lxRR, Trigger Delay= recommended, Trigger window -auto trigger window, intersequence delay= even, cardiac phases= single 30 cm FOV, 8 mm thick, 1 mm space, I20 to S20 256 x 128, R/L, 1 NEX, scan time -1:22 Rl = 7, R2 = 30, TG = 200, power= 11.2 Date: 101497B, series 2; breathhold Magnet: 3 .0T; Coil: square Hl; volunteer: HK (b) supine position; Head 1st, supine, extremity coil, axial 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth 60 flip angle, minimum full TE, 200 msec TR autoshim, water auto center frequency, 8 kHz bandwidth peak auto center frequency, 32kHz bandwidth gating menu, trigger type: peripheral gating, effective TR: lxRR, Trigger Delay= recommended, Trigger window auto trigger window, intersequence delay= even, cardiac phases= single 30 cm FOV, 8 mm thick, 1 mm space, I20 to S20 256 x 128, R/L, 1 NEX, scan time= 0 :20 Rl = 7, R2 = 30, TG = 200, power -9.3 Date: 101497B, series 2; breathhold Magnet: 3.0T; Coil: square Hl; volunteer: HK

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212 Figure 50. A comparison of peripheral gating (pg) versus ECG gating, and breathing during the image versus breath-hold images. All images are fast gradient echo: (a) sagittal, peripheral gating, breath-hold; (b)sagittal, peripheral gating, breathing; (c) sagittal, ECG gating, breath-hold; (d) sagittal, ECG gating, breathing, (e) axial, peripheral gating, breath-hold, (f) axial, peripheral gating, breathing. (a) sagittal, peripheral gating, breath-hold Head 1st, prone, extremity coil, sagittal 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth arrythmia rejection= 0, 60 flip angle, minimum full TE autoshim, water auto center frequency, 32kHz bandwidth gating menu, trigger type: peripheral gating, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even 24 cm FOV, 8 mm thick, RlO 256 x 128, S/I, 1 NEX, scan time 0:16; breathold Rl = 7, R2 = 30, TG = 200, power= 9.6 Date: 101497A, series 2; image 23 Magnet: 3.0T; Coil: square Hl; volunteer: DP (b) sagittal, peripheral gating, breathing Head 1st, prone, extremity coil, sagittal 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth arrythmia rejection= 0, 60 flip angle, minimum full TE autoshim, water auto center frequency, 32kHz bandwidth gating menu, trigger type: peripheral gating, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even

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213 24 cm FOV, 8 mm thick, RlO 256 x 128, S/I, 1 NEX, scan time 0 :16 Rl = 7, R2 = 30, TG = 200, power 9.6 Date: 101497A, series 2; image 28 Magnet: 3.0T; Coil: square Hl; volunteer: DP (c) sagittal, ECG gating, breath-hold Head 1st, prone, extremity coil, sagittal 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth arrythmia rejection= 0 60 flip angle, minimum full TE autoshim, water auto center frequency, 32kHz bandwidth gating menu, trigger type: ECG autolead, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even 24 cm FOV, 8 mm thick, RlO 256 x 128, S/I, 1 NEX, scan time 0:16; breathold Rl = 7, R2 = 30, TG = 200, power 9.6 Date: 101497A, series 2; image 18 Magnet: 3.0T; Coil: square Hl; volunteer: DP (d) sagittal, ECG gating, breathing Head 1st, prone, extremity coil, sagittal 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth arrythmia rejection= 0, 60 flip angle, minimum full TE autoshim, water auto center frequency, 32kHz bandwidth gating menu, trigger type: ECG autolead, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even

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214 24 cm FOV, 8 mm thick, RlO 256 x 128, S/I, 1 NEX, scan time 0:16 Rl = 7, R2 -30, TG = 200, power= 9.6 Date: 101497A, series 2; image 13 Magnet: 3.0T; Coil: square Hl; volunteer: DP (e) axial, peripheral gating, breath-hold feet 1st, supine, sternal notch, extremity coil, axial 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth arrythmia rejection= 0, 60 flip angle, minimum full TE autoshim, water auto center frequency, 32kHz bandwidth gating menu, trigger type: peripheral gating, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even 42 cm FOV, 7 mm thick, 1 mm space, 131.8 256 x 128, A/P, 1 NEX, scan time -0:20; breathold Rl = 7, R2 = 30, TG = 200, power= 10.8 Date: 020599, series 6; image 4 Magnet: 3.0T; Coil: square Hl; volunteer: Relax#5 LR (f) axial, peripheral gating, breathing feet 1s t supine, sternal notch, extremity coil, axial 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth arrythmia rejection= 0, 60 flip angle, minimum full TE autoshim, water auto center frequency, 32kHz bandwidth gating menu, trigger type: peripheral gating, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even 42 cm FOV, 7 mm thick, 1 mm space, I3l.8

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215 256 x 128, A/P, l NEX, scan time= 1:48 Rl = 7, R2 = 30, TG = 200, power 10.8 Date: 020599, series 5; image 52 Magnet: 3.0T; Coil: square Hl; volunteer: Relax#S LR Figure 51. Human proton voxel localized spectroscopy of the heart and chest wall obtained during one volunteer' s shim using the techniques of GE' s (a) STEAMCSI and (b) PRESSCSI. (a) STEAM Feet 1st, supine, sternal notch, extremity coil, axial Spectre, spinecho, gating, extended dynamic range, graphic ROI, psd file= steamcsi 1000 spectral width, 1024 points, console freq= Hl, spectre mode 1, 16 acquisitions, 1 x 1 x 1 CSI 2000msec TR, TE= 40msec, water auto center frequency gating menu, trigger type: peripheral gating, effective TR: 2xRR, Trigger Delay= recommended, Trigger window -auto trigger window, intersequence delay= even, cardiac phases -single 34 cm FOV, 30 mm thick, I6.5, 41.0 mm x 59.1 mm x 30 mm voxel 256 x 128, A/P, 4 NEX, scan time= 0:40 Rl = 7, R2 -30, TG = 70; depth= 66mm Change cv's: suppress= 0, sup= 0 Postprocessed with Sage_IDL: fft, phase (52.734, O) Date: 021299a, series 6, file= 3.0 T _RELAX#7_proton_shim_steam Magnet: 3 .0T; Coil: 25cm square proton, volunteer: relax#7 CS (b) PRESS Feet 1st, supine, sternal notch, extremity coil, axial Spectre, spinecho, gating, extended dynamic range, graphic ROI, psd file= presscsi

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216 1000 spectral width, 1024 points, console freq -Hl, spectre mode 1, 16 acquisitions, 1 x 1 x 1 CSI 2000msec TR, TE= 40msec, water auto center frequency gating menu, trigger type: peripheral gating, effective TR: 2xRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even, cardiac phases= single 34 cm FOV, 30 mm thick, I6.5, 41.0 mm x 59.1 mm x 30 mm voxel 256 x 128, A /P, 4 NEX, scan time= 0 :40 Rl = 7, R2 -30, TG = 70; depth= 66mm Change cv's: suppress o, sup= O Postprocessed with Sage_ IDL: fft, phase (52.734, 0) Date: 021299a, series 6, file -3 0 T_RELAX#7_proton_shim_press Magnet: 3.0T; Coil: 25cm square proton, volunteer: relax#7 CS Figure 52. P -31 FIDCSI with CSI of a human subject at 3.0 T. Head 1st, prone, sternal notch, extremity coil, axial Spectre, spinecho, gating, extended dynamic range, graphic ROI, psd file= /usr/g/genesis/fidfovH 4000 spectral width, 1024 points, console freq= P-31, spectre mode 1, 128 acquisitions, 6x6xl CSI, soft pulse (1) 2000msec TR, peak auto center frequency gating menu, trigger type: ECG autolead, effective TR: 2xRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even, cardiac phases= single 20 cm FOV, 30 mm thick, voxel 35 x 35 x 30 mm3 256 x 128, A /P, 8 NEX, scan time= 12 minutes Rl = 7, R2 -30, TG = 50 Change cv's: squeeze= 1, pibbandfilt = 0, pixmtband -1

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217 AX= 21287137, back room freq= 30427790, true frequence = 51.714927 MHz, resting heart rate= 50 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, orient= transpose x-y & flip x, magnitude plot (can not phase all parts of csi equally correctly) Date: 041898c, series 5, file= P05632 Magnet: 3.0T; Coil: quadrature P-31; volunteer: TB Figure 54. Examples of 1.5 T cardiac phosphorus spectra localization problems resulting in (a) liver contamination, or (b) skeletal muscle contamination, in comparison with (c) a non-contaminated cardiac spectrum. (a) liver contamination Head 1st, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd file= /usr/g/genesis/fidobl 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 128 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) 3000msec TR, peak auto center frequency gating menu, trigger type: ECG autolead, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even, cardiac phases= single 14 cm FOV, 25 mm thick 256 x 128, Not Swapped, 4 NEX, scan time 6 to 8 minutes Rl = 7, R2 = 30, TG = 185, Depth= 69mm resting heart rate= 83 Postprocessed with FITMASTER at UAB Date: 022299, file= G00994

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218 Magnet: 1.5 T; Coil: single-turn P-31; volunteer: WISE#33 (b) Skeletal muscle contamination Head 1st, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd file= fidcsi 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 128 acquisitions, 1 x 1 x 1 CSI, hard pulse (0) 7 later change to soft pulse 3000msec TR, peak auto center frequency gating menu, trigger type: ECG autolead, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even, cardiac phases= single 20 cm FOV, 30 mm thick, 0 space 256 x 128, S/I, 4 NEX, scan time -6 to 8 minutes Rl = 7, R2 = 30, TG = 185 Change cv's: squeeze= 0 Backup, review screen, users cv's to change to soft pulse, scanning range to change to 20 thick, erase slice, and reselect positioning and measure depth Depth= 45mm resting heart rate= 77 Postprocessed with FITMASTER at UAB Date: 031498, file G00540 Magnet: 1.5 T; Coil: single-turn P-31; volunteer: WISE#l (c) quality cardiac spectra Head 1st, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd file= /usr/ g /genesis/fidobl

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219 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 128 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) 3000msec TR, peak auto center frequency gating menu, trigger type: ECG autolead, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even, cardiac phases= single 14 cm FOV, 25 mm thick 256 x 128, Not Swapped, 4 NEX, scan time 6 to 8 minutes Rl = 7, R2 = 30, TG = 110, Depth= 55mm resting heart rate= 84 Postprocessed with FITMASTER at UAB Date: 052598, file G00693 Magnet: 1.5 T; Coil: single-turn P-31; volunteer: WISE#14 Figure 55. P-31 FIDCSI oblique slice localized human cardiac spectroscopy (oblique DRESS) of the same subject, at 1.5 and 3.0 T, on different days showning examples of resting and exercise spectra (a) 1 5 T Head 1st, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd file= /usr/g/genesis/fidobl 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 128 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) 3000msec TR, peak auto center frequency gating menu, trigger type: ECG autolead, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= auto, intersequence delay= even, cardiac phases= single 14 cm FOV, 25 mm thick, 256 x 128, not swapped, 4 NEX, scan time = 6:38

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220 control variables: pibbandfilt = O, pixmtband 1 Rl = 7, R2 = 30, TG = 165; ax= 25868826 Postprocessed with FITMASTER at UAB Date: 111198; Magnet: 1.5 T; Coil: single-turn P-31 coil; phantom: slice profile (b) 3. OT Head 1st, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd file= /usr/g/genesis/fidobl 4000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 128 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) 3000msec TR, peak auto center frequency gating menu, trigger type: ECG autolead, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= lOt intersequence delay= even, cardiac phases= single 20 cm FOV, 30 mm thick, 256 x 128, swapped, 4 NEX, scan time rest = 6:38 control variables: pibbandfilt = 0, pixmtband = 1 Rl = 7, R2 = 30, TG = 60; ax= 21287249, back room freq= 30427790 Postprocessed with FITMASTER at UAB Date: 081098; Magnet: 3 .0T; Coil: single-turn P-31 coil Figure 56. Series of cardiac region oblique DRESS spectra representing decreased skeletal muscle contamination with increase in depth of spectroscopy slice localization. Note the split in the PCr peak that designates the cardiac and skeletal muscle as separate peaks. (a) Images head 1st, supine, sternal notch, extremity coil, axial

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221 2D, gradient echo, gating, flow comp, extended dynamic range, fast, variable bandwidth, graphic Rx (based on sagittal image) arrythmia rejection= 0 60 flip angle, minimum full TE autoshim, water auto center frequency, 32kHz bandwidth gating menu, trigger type: peripheral gating, effective TR: lxRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even 42 cm FOV, 5 mm thick, 1 mm space, I31. 8 256 x 128, A/P, 1 NEX, scan time 4 :15 Rl = 7, R2 = 30, TG = 200, power 10.8 Date: 0110798, series 2 Magnet: 3.0T; Coil: square Hl; volunteer: Relax#S TB (b) Spectroscopy (update details) Head 1st, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd file= /usr/g/genesis/fidobl 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 256 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) 3000msec TR, peak auto center frequency gating menu, trigger type: peripheral gating, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= auto trigger, window, intersequence delay= even, cardiac phases= single 20 cm FOV, 30 mm thick: 4 separate acquisitions and slice positions, Tilt 274 256 x 128, R/L, 4 NEX, scan time= 4:26 change cv's: pibbandfilt = 0, pixmtband 11 pw_gph 4msec Rl = 7, R 2 = 30, TG = 115 ; depth varies

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222 Postprocessed with Sage_IDL: apodize exponential lOHz line broadening, spectral zero-fill, fft, phase (zero order first order O), localized to voxel (5 to 5) x (4 to 4) -11 I Date: 110798, series 5, files= G00634, G00628, G00633, G00635 Magnet: 3.0T; Coil: quadrature P-31; phantom: depth Figure 61. Myocardial pH is proportional to the frequency difference of the Pi and PCr peaks in the human, in-vivo phosphorus NMR spectrum. (a) At 1.5 T the Pi peak is hidden by blood 2,3-DPG. (b) At 3.0 T the Pi peak is discernible from the 2,3-DPG peak, allowing for the measurement of pH. Both spectra obtained on the same volunteer at rest using oblique DRESS. (Parameters: 128 Acquisitions, every third heart beat TR, Oblique DRESS, 25 mm thick slice, single-turn P-31 coil; see Appendix B (a) for more detail). 1.5 T Head 1st, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd file= /usr/g/genesis/fidobl 2000 spectral width, 1024 points, console freq= P-31, spectra mode 1, 128 acquisitions, l x 1 x 1 CSI, soft pulse (1) 3000msec TR, peak auto center frequency gating menu, trigger type: ECG autolead, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= auto, intersequence delay -even, cardiac phases= single 14 cm FOV, 25 mm thick, 256 x 128, not swapped, 4 NEX, scan time = 6:38 control variables: pibbandfilt = 0, pixmtband -1 Rl = 7, R2 = 30, TG = 165; ax= 25868826

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223 Postprocessed with FITMASTER at UAB Date: 111198; Magnet: 1 5 T; Coil: single-turn P-31 coil; phantom: slice profile (b) 3.0T Head 1st, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd file= /usr/g/genesis/fidobl 2500 spectral width, 1024 points, console freq= P-31, spectra mode 1, 128 acquisitions, 1 x l x l CSI, soft pulse (1) 3000msec TR, peak auto center frequency gating menu, trigger type: ECG autolead, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= 10%, intersequence delay even, cardiac phases= single 20 cm FOV, 30 mm thick, 256 x 128, swapped, 4 NEX, scan time rest = 6:38 control variables: pibbandfilt = 0, pixmtband = l Rl = 7, R2 = 30, TG = 60; ax= 21287249, back room freq 30427790 Postprocessed with FITMASTER at UAB Date: 111198; Magnet: 3.0T; Coil: single-turn P-31 coil

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APPENDIX C HYDRAULIC HANDGRIP Assembly Instructions for Hydraulic Handgrip Parts to purchase: 1. Bulb Dynamometer from North Coast Medical: Includes rubber bulb and gauge already assembled Part number NC70154 Phone: 1-800-821-9319 or 408-283-1900; fax: 408-283-1950 $80 + tax and shipping 2. 40 feet of stiff" inner diameter tubing 5/8'' outer diameter: 5/8'' OD x 11 ID poly purchased locally at Home Depot ..., $10 3. clear silicone (as used in bathrooms to water seal edges) 1 tube purchased at Home Depot $5 4. brass connector : I D. Barb Splicer" by" 1 piece purchased at Home Depot in plumbing department $1.50 5 tie wraps or other magnetically safe circular clamp (check with a refrigerator magnet if unsure) up to 10 224

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225 Directions for assembly: 1. The bulb dynamometer comes in the mail with the bulb attached directly to the gauge with a metal flashing at the neck. Remove the metal flashing and discard, as this piece is not magnet safe. Pour out the liquid contents. The liquid contents are believed to be just diluted soap, to prevent growth. 2. Dry off the rubber bulb and gauge. Dab silicone over one end of the brass connector. Be careful not to silicone the opening in the brass connector; just silicone the sides of the connector where it will have contact with the rubber neck of the bulb. Insert the siliconed brass connector into the neck of the rubber bulb. Use three tie wraps to secure in place. Move the tie wrap connection for each so that they are placed at thirds around the circumference of the neck of the rubber bulb. 3. Heat up one end of the stiff" ID tube. It is recommend to submerse it in boiling water for 30 seconds to a minute. If the tube is not heated enough to soften it sufficiently it will crack and leak later. Also, coat the other end of the brass connector (sticking out of the rubber bulb) with silicone. Once the tubing is hot and soft, quickly place it over the siliconed brass connector (don't silicone the opening, just the sides where the tubing and connector will contact). Use 2 to 3 (or what you have space for) tie wraps to secure the tube in place while soft. 4. Add more silicone to the cracks to make sure that there are no easy leak spots. 5. Leave this to set overnight to be sure of a good seal. 6. Find the liquid you want to fill the contraption with. The liquid can be just water or water with soap or other antigrowth additive. Just be sure that you aren't creating more bubbles, as soap can tend

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226 to do. Water can also be used but may need to be refilled if algae growth occurs. 7 Fill the tube with the liquid using two people and a set of stairs. One person stands at the top of the stairs and pours the liquid into the open end of the tube. The second person stands at the bottom of the stairs with the rubber bulb end of the tube and encourages the liquid to move down and the bubbles to move up (using gravity). 8. After the tubing is almost completely full of liquid, again put the remaining open end of the tube in boiling water to soften. Also put silicone over the threads of the gauge fitting, careful again not to silicone the opening. Quickly pour the liquid up to the top (heat this remaining bit of liquid first before topping off to reduce the heat loss from the softened tubing, but not so hot as to cause skin burns). Next, screw the gauge into the soft tubing, being careful not to strip the path the threads make (i.e. don't keep screwing once it is all the way in). Liquid will spill to the side, but that is ok. This will keep the bubbles to a minimum. 9. Tightly tie-wrap this end of the tubing in place and silicone around the base. 10. Again, let this sit overnight before putting any more stress on it. The next day it should be ready to work. TIPS: If liquid starts to leak out and/or air cavities are forming, the leak must be found and fixed. Experience has shown that it is usually at the gauge end where the leak occurs. Cut off just enough tubing to start fresh (a few inches) and reapply the connections with more heat (put the tube in near boiling water for 30 seconds) to make sure the

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227 tube was soft enough when the connections are made. Then reapply the silicone and tie wraps and leave the handgrip in a place where it can rest for 12 hours and set. Optional Data Recorder The analog gauge can be replaced with a digital gauge in which the signal can be outputted and electronically recorded.

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APPENDIX D 3.0 T CARDIAC ACQUISITION PROTOCOL Instructions for Obtaining Gated Cardiac P-31 Spectra on a GE 3.0 T SIGNA TM Version 5. 4 with In-Magnet Exercise via Handgrip I Setup: 1. Before the patient arrives: a. Reboot the 3.0 T system. Do this via utilities, shutdown, yes. When a prompt appears after shutdown, type "b" to reboot. b. Remove all coils from the magnet table and replace with padding that extends the length of the table. Over padding, place egg-foam crate material and cover with a sheet. Place a pillow in a pillowcase on the table. c. Place the narrow white elastic strap on the table in the position where the patient's heart will be. Later you will use this strap to hold the P-31 coil in place. Also, attach the GE gray strap (the thinner one) to the table. This will act to hold the proton coil in place and discourage motion or movement during the scanning. d. Setup the Dinamap monitor on a magnet-safe pole inside the magnet room such that the monitor is facing the scanning room window by the console. You will then be able to see the output of the monitor during scanning. Attach the 20 ft blue airhose and blood pressure cuff to the monitor. e. Uncoil the handgrip exerciser so that the handgrip end is by the magnet table and the gauge end is by the console. Using 1 to 3 228

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229 clamps, hold the gauge in place on the back of a chair or cart where it is easily visible to the person running the scanner. f. Get all paperwork together (IRB consent form, MRI screening form, WISE study forms, or other), check the protocol and place a set of earplugs out for the patient/volunteer. 2. First talk the patient/volunteer through the IRB informed consent form. Have the patient/volunteer sign the form, and then have study representative sign the form. Signing this form means that the patient/volunteer understands the study parameters and their role in the study. 3. Talk the patient/volunteer through the MRI screening form. Have the patient/volunteer sign the form, and then have the study representative sign the form. Signing this form means that the information given by the patient/volunteer is correct. If there are any adverse problems noted by this questionnaire, they should be addressed before letting the patient/volunteer into the scan room. 4. If necessary, have the patient/volunteer change from the waist up into a hospital gown. This is necessary if the patient/volunteer is wearing a button up shirt (removed for comfort purposes), a bra (metal must be removed and bra will add distance to heart from coil position on exterior of chest), or any nice clothing (laying in the magnet may wrinkle clothes). NOTE: when the patient/volunteer is changing, encourage them to use the bathroom, since they may be in the magnet for up to 2 hours without a break. 5. Two options for positioning are available: a. Peripheral gating on the big toe: Place the patient/volunteer head first, face up on the magnet table. Put the peripheral gating device over the big toe, being careful to have the foam side on the nail side of the big toe, to ensure pulse signal is

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230 reaching the sensor on the opposite side. (If not needing to do in-magnet exercise and/or measure blood pressure you also have the option of feet first, face up with the peripheral gating from a finger). b. ECG gating on back: You will be placing the patient/volunteer feet first, face up on the magnet table. This is the position recommended by GE for optimal ECG gating. Before the patient lies down, place the ECG electrodes on their back in the arrangement as pictured below. Also be sure to keep the ECG leads as straight as possible as they can add noise to the system, or pick up noise if they are not straight. Also, place a pad between the ECG wires and the patient/volunteer's skin to prevent possible burns. Keep ECG Wires As Straight as Possible! Left Arm Lead Left Leg Lead Right Arm Lead Right Leg Lead Figure 63. ECG lead placement for 3.0 T gating. 6 Place a pillow or blanket under the patient/volunteer's knees for lower back comfort. Also, check patient/volunteer temperature comfort levels. You may need to add a blanket and/or turn the

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231 magnet fan on or off. Make sure you also give the patient/volunteer a set of earplugs and they insert them. 7. Place the P-31 coil on the chest at an estimated position over the heart. This can be estimated by a position 2/3 down the sternum and about 5 to 7 cm to the patient/volunteer' s left. Use the white elastic band to keep this coil in place. Note that for the feet first positioning, you will need to use the extension for the cable to reach the end-of-bore RF coil connector. 8. Next place the 25 cm square proton coil on the chest over the P-31 coil. Be careful not to hit the patient/volunteer' s chin with this coil. Note that for the feet first positioning, you will need to use the extension for the cable to reach the end-of-bore RF coil connector. 9. Check with the patient/volunteer if they are ok with exercising with their right hand and getting blood pressure from their left arm. Sometimes, medical reasons will change this default. Place the blood pressure monitor on the left arm (typically) and have the patient hold the handgrip in the right hand (typically) in a comfortable position. While the patient holds the handgrip, carefully tape the hose to the end of the table for support during the study. Make sure there are no kinks in the handgrip hydraulic hose. 10. Landmark at the center position of the P-31 coil, or as close to it as possible. Send the patient/volunteer into the magnet. 11. Once the patient/volunteer is in the magnet. Check that the Dinamap blood pressure/heart rate monitor can function. This can be a problem, sometimes, with larger patients/volunteers where the arm and blood pressure cuff are squeezed against the inside of the

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232 magnet bore. In addition, if you get any error messages, check for leaks in the airhose connections. II. Scanning Protocol: (for head first protocol with peripheral gating: change as needed) 1 Sagittal Scout Parameters head 1s t supine, sternal notch, extremity coil, sagittal 2D, grad echo, flow comp, gating, extended dynamic range, fast, variable bandwidth arrythmia rejection 0, flip angle= 60 TE min full auto center frequency water, 32 kHz receive bandwidth, peripheral gating, auto trigger window 42 cm field of view, 8 mm thick, 1 mm space, L20-L60, 6 slices 256x128, A/P, 1 NEX (1:48) R=7 R=30 TG=200 power= 11.7 2. Axial Scout (a) Parameters: Head first, supine, sternal notch, extremity coil, axial 3D, gradient echo, flow comp, gating, extended dynamic range, fast, variable bandwidth, graphic Rx, arrhythmia rejection= O, flip angle= 60 TE= min full auto center frequency= water, 32 kHz receive bandwidth peripheral gating, autotrigger window, 42 cm field of view, 7 mm thick, 1 space, fallback 256x128, A/P, l NEX (1:48) Rl=7 R2=30 TG=200 power= 12.0 (b) After successful first acquisition of sagittal and axial images, move coil as necessary to position over heart (refer to figures in chapter on human techniques). After the coil is in the correct

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233 position, and the approximate correct slice has been located, repeat the axial fast gradient echo acquisition for just one slice with breathhold (10 to 20 seconds, depending on heart beat). 3. PRESS Shim (a) Parameters: Head first, supine, sternal notch, extremity coil, axial Spectra, spin echo, gating, extended dynamic range, graphic ROI, psd=presscsi 2000 spectral width, 1024 points, console freq -Hl, spectra mode 1, 16 acquisitions, 1 x 1 x 1 CSI TE=40 msec, TR= 1000 msec Auto center frequency= water, gating menu, trigger type: peripheral gating, effective TR: 2xRR, Trigger Delay= recommended, Trigger window auto trigger window, intersequence delay= even, cardiac phases= single 34 cm field of view, 30 mm thick, pick approximately 30 to 70 mm rectangle over anterior heart, directly in line with surface coil 256x128, A /P, 2 NEX (0:40) (b) change cv's: sup= O suppress O, (b) Spectra, start single use dx (if necessary) to center water peak (d) Gradient shim, autoshim, select region, 3D shim, write down numbers for x,y and z as well as set the window to 1 and move the level up and down to find the minimum and maximum points where the center column circles disappear. The difference between the two level values is a measure of the shim quality. (e) Manual shim to sharpen the auto-picked values. Start single and set up the window for manual vertical zooming (vz): vz Y vo -45 vm Se7 (or the vertical multiplier that works best). Then go into

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234 gradient shim and adjust the x, y and z gradients manually to maximize the height of the water peak. It is suggested to jump by steps of 10 or 20. (f) After optimal shimming, get an average saved: ent avg avg. 4. Oblique DRESS (a) Parameters: Head first, supine, sternal notch, extremity coil, oblique Spectra, spinecho, gating, extended dynamic range, graphic Rx, psd = /usr/g/genesis/fidobl 2500 spectral width, 2048 points, console freq= P-31, spectra mode 1, 128 acquisitions, 1 x 1 x 1 CSI, soft pulse (1) TR= 2000msec, autocenter frequency -peak gating menu, trigger type: peripheral gating, effective TR: 3xRR, Trigger Delay= recommended, Trigger window= auto trigger window, intersequence delay= even, cardiac phases= single 30 cm field of view, 25 mm thick, 0 mm space, place the slice as shown in figures from human techniques chapter 256xl28, swapped, 2 NEX(6 to 8 minutes) (b) Go to the magnet and disconnect the proton coil and connect the P-31 coil to the end of the magnet bore where the RF coils plug in. (c)Go to the computer room and switch 4 spots: 1. Change the frequency to read 20.427790, 2 change the switch box to P-31, 3 Change the connector from head to spectra, and 4 change a connection at the penetration panel to the P-31 receiver. (d) change cv's: pibbandfilt 0, pixmtband = 1 spectra, rl = 7, R2 = 30, TG ? (will depend on type of coil and depth from the coil ... see charts in chapter on phantom techniques)

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235 (e} "ent avg avg", will start average of 128 acquisitions. Use line broadening, phasing and other on the fly techniques to display the real data and try to examine for quality of spectra and reduced contamination from skeletal muscle and liver. (f) Take a resting spectrum, 128 average with at least 2 resting values of blood pressure and heart rate (with 2 minute break between) with Dinamap monitor. (g) Get the volunteer/patient to squeeze the handgrip as hard as they can. Record the gauge value at rest and during maximum squeeze. Take the difference of these two values, get 30 % of the difference and add to the resting value ... This is the value to use for 30% of maximum isometric exercise. (h) Get the patient/volunteer to start squeezing the handgrip at the 30% point, coaching via microphone if adjustments in squeezing need to be made. After 45 seconds to 1 minute of presqueezing, start the exercise 128 average acquisition. Take heart rate and blood pressure measurements every two minutes. (i) After the exercise acquisition has completed, allow the patient/volunteer to stop squeezing, wait another minute and then record a first 128 acquisition recovery session followed by a second recovery 128 acquisition session. 5. Fill in all necessary paperwork, save all data and let the patient go. If for WISE study, send data and copies of forms (always keep a copy of all forms) to UAB for processing.

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APPENDIX E SPECTROSCOPY POST-PROCESSING INSTRUCTIONS Instructions for Post-Processing Cardiac P-31 Spectra obtained Oblique FIDCSI (DRESS) on GE 3.0 T SIGNA Version 5.4 Introduction USJ.ng There are two types of files created by the GE 3 0 T SIGNA version 5.4 system: G-files and P-files. The G-files consist of a single spectrum that is the result of an average of one or more spectra. The P-files are more complex data files, which are formatted depending on their originating pulse-sequence. For example, a 6x6 CSI data set would consist of a P-file organized under a header that identifies the file is not just one spectrum, but 36 spectra organized into a 6x6 matrix of set dimension. All oblique DRESS files are Gfiles. Most of the data from this dissertation was analyzed with the "gold standard" for cardiac P-31 post-processing using FITMASTER (Philips) programmed and run by Dr. Jan den Hollander, with postdoctoral student Dr. Steven Buchthal. Dr. Jan den Hollander, a previous employee of Philips and current faculty at UAB, helped to develop this software and post-processing techniques partially for the purpose of optimized cardiac acquisitions. I was very fortunate to have his services in analyzing this data. Note, however, that FITMASTER requires a spectrum with good signal-to-noise ratio (SNR) to adequately operate. An example at the end of this description shows how poorly FITMASTER can perform when the SNR is poor. 236

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237 This section is a description of how to try and accomplish the same post-processing tasks accomplished with FITMASTER but using the software available in Gainesville, Florida. This includes the use of the following software packages: Sage IDL (GE), MRUI (project funded by the European Community), FELIX (Molecular Simulations Inc.) and a header modification program created by Dr. Marian Buzko, UF Department of Microbiology and Cell Sciences. Take for example the post-processing of a 3.0 T P-31 cardiac spectrum obtained on 11/11/98. The original G-file was renamed as FLA3T REST 111198. It is located on tesla at /angela/cardiac/3tcardiac/111198/. FITMASTER (Philips) The data file was FTPed to UAB. At UAB, Steve Buchthal processed the data using FITMASTER. To process the spectra, the rest, exercise, recovery 1 and recovery 2 data files from the same subject were first co-added. A Gaussian apodization with 15 Hz line-broadening, followed by Fourier transform, frequency flip and phasing. The fit of the summed spectra is then back extrapolated to fit the missing part of the start of the FID to achieve a flat baseline and remove the baseline roll. The sum of the spectra with the back extrapolation is then fit. The fit makes the assumption that the three ATP peaks are of equal area. The individual spectra are then individual fit based on the group fit, but now only allowing for the peak heights to change and fixing the peak positions and peak widths. The result for the resting spectrum is shown below. The bottom line shows the raw spectrum. Notice the flat baseline and the visibility of the Pi peak. The middle line is the fit of the data and the top line is the difference between the fit and the

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_,..._cc--=--.. w-:-....,__ . .. -.. ..-.-... -. . -------:--< .:;..... -~ .,_. ----=~~ ~--. ;,. --~ .. . -~----.... ---- .,... ~ ---. - -. raw part 238 data. The peak labels a r e added to this document only and are of the FITMASTER output. ---------------------------------------------------, -64 3-D P G '2DPG PCr Pi PME I y-ATP 'l' dc1.t a set --... -'-=---~ A.Tl? ---- -by not In addition, the FITMASTER program outputs the following useful ATP total/ 3 ATP-gamma ATP-alfa ATP-];)et~ ----~ C -. -=--==~_=:-:cV ;~~+:9-=9:= ., ~JnJ ( s n ~ o -g .~-=: ~ :l::::-= ~~t: . = ;::r::. ,--...... --------.. ---. -. ,.,.. ---. ---":.~-= < :: .... _.:-_:..:.:_-:_-.=:.::~-~-=-=~---=---.::=------:=---=--:~::-. ~-:--=~:-::-._.-...... -;--:.~::.;: ... -:.:::: --!-.---==-=----= ::-:-_ ... -.. ----._ ... _~.._'-'---~ --;;:----~ ---===----~,,,,, .... z-_ -. -...... ..--.,.. ------~ ..... ..,_;-:,___ .. __ .... -.: -----.. -.------..,-.-.. ----~?...-;;-:;,.~c;:;:-.-c_.=-,......;-:,.:"-.~:c kQSD ~-,,..::-#' -..-:~-:;+-~-xm~~. ~ -'I'=-~:4.~r':~ .x:_e~I~--t;t~ = -~~~~~ -~-;:~ ~-@ t.l.-~~_.: = ::~ ;;.,...:..:..: .,-;~--, -_ ..._...,--~..._-_, .. --,r-_-::--.._ ~ ----::,---'---..-.,._ ----> .. ,,.--_, -~-----'"' ----,--_ 41 -. -----. ,-..,,, ... -.. -:. --:........:---~: ------. ... ----__.,c;. -;--.., ,:,-_ :;:...,: .... ... .,._.~~-~ -..... ~::.-...... --,...;.. ----.. ~..: -:-:.:.,,. ---. _.,,,,.__ -======: -----, ?-....... _,.__ -:.., ,,,_ ~ _. ___ ----: --... . -. --. .... -.--~----~-:--~-,-----. ---'- ., --.:-.. ?~--------;..-:""7"'-___....::.-~...:....~-.------- ~ -~--.. .::.r-:<:-...:...:.;,-:; ;__..->_ -_,.-r. --,::;.-J ~.-..,..._ --. _,. .. -:-"' ---. -,. _,,,, ~ -m4~ ... _,, 4 ~ L -B _--.-...;:--,;_~ ~ .... .... ---; 7 o.~ ------> .... ~ = ;'\,,:::r .... -<;.:-: -:.:~~~ ... ~~-"' ... ~ -:>~~.;.. ~ ~ -=---~.--::!: ~""I' ~ ~ .:..-:~-=~ ...:.~..._ .::.: -z --~ -~-~ .,,.,.;;. __,__ ----.-,..._-..,__ ___ .. .. ...-,..:..,. ~ -~ .,--.~--=-,<:-~ -_-_.-:-... -:-.....--::.::--_ .... --..... __ ------... -. -.-._-_ ~ ..;.,o._~ -:-:.,., ..<;-::-'"".....-;.:~ ._ ---c. ... -... _...,..,,,..,. ~-------------... ....... --..._ ... ..... _ _ ._ . .,. ---_ ..._ ..,.._ ... -.,. .--c; --::-<""~ ----.,;_ -------..;;._.,-_;;.. -=---. -. ..,--.-. ::,,'I-~. -~ .. ...... --.;.. .:;......,. ... .-.::.-.-:;:----_..;--:_=--" ---=---._,_. ~ -..-...,..:-.--. .. ---... ~--r.--.-v.~ ... -:...-, --... --. ...._..._ _.. -..._ ? ..-.. .. ..._ ,,._,,.. t .., Z. "':. -3--::a-";:; ~-":.~"':-~ -:-. -:c -~-= o ~ ---'..9-~:-.-. ~ : ~ -... ~,,..-:..-~... -c~:..--:;~,-== ,-.: .,.-;;:_,..._ ...,_ .... --_...,_ -.-:..-. .t:!l~ ... ~ .; .,~ --~....: ... .--:-; c.,. -. -. --., .,_. ~ .... -__ ..... _-::: ~-----------. r--. ~----:.'I_.,.,,>.~ ... -.--. ,.,_ --~ ----"': = =-====~.... ..... ,..,.._. ( .-. -~ ,_ _.._ . .-:.. .. --=--<.,........ ..... -~"~ ---~-= --~ -~----:;-.. .. ..... .. .s ..... .:-:-.;-!,. .. -, ",-.. <~.-.;...-t::..,.-. ---.. .. --------.. ..: .. .-,, .... ----:x-; --=-_-c;--_, > -.--_..._--...:: ----=------ .......... ,.,. _ -. / --...... ---.... -. -----:::;..;,. ""~::-::-:...:::._ --~-..... ..... .-,.... .,. ---. ...-. ..... --:..---:--=---::..,,,c_ ---:c~ = -.::,;:----=. -==:: --~.-:-----,---.-,,._. ......... :, ,_ ----::..'- --~ . ,:;...- ., __ _,,...::.:.,..;:::;:;--;: -,- X .,. ~ _, .....,; ~..-~ -.. --:.---~ ... .,_. ~'3'.:::: -..... --~-.. ..... -~------.. ~-<"""~-::. ... --: --=::--5-:; :v ;f~-vi):-::.-_ : : c:-\ SJY = 7 -:-04 i e+1f4'",::::A, ~~'beit>J= :-::-:::-,:::: ...=-:..~ -9.549e+0 5 (SD 6.958e+04, 23-DPG total) 1 660e-0 1 (SD 6.349e-03, PCr/Ptot) -. ~-l.995e-01 (SD 6.410e-03, ATP-gamma/Ptot) ---_ .. __;;;,,;;:;~ --:: ~ -_,.,:----~8 816e-02 (SD 3.595e-02, Pi/ATP) [PCr] / [ATP] 8 3 23 e-01 (SD 2 831e-02, [PCr]/[ATP] ) [PCr]/ [ATP] gamma 8.323e-01 (SD 3.245e-02, [PCr]/ [ATP) gam m a ) [PCr] / [ATP] 9.39 4e-Ol (blood corrected )

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239 From this data, pH can also be calculated based on the ppm difference between Pi and PCr (line 1). pH 6. 75 + log10 cs 3.27 5. 69 -cs 4.832-3.27 6 7 5 + 1og1 0 5 69 4. 832 7.01 The following three programs are available locally and were used to process the 3T cardiac spectrum as a comparison. SAGE IDL (GE) 1 Data Conversion (a) To convert the GE G-file to a file that SAGE_IDL can read you first must convert the data file. At the unix prompt, type the following: (i) cd /cardiac/3tcardiac/ [enter] (ii) sdbm -c -q FLA3TREST_llll98 [enter] (iii) accept all prompts except: (iv)change site to Signa_ 3 0T VA SHANDS UF HOSP (v) change center_freq to 51.71 2. Data Processing (a) Follow these commands to process the data in Sage IDL, starting by loading the program at the unix prompt with "sage" and [enter]. (b) File load SAGEdata (i) Click on "Signa_3. 0T VA SHANDS UF HOSP" (ii) Click on ''111198b'' (iii) Click on ''2125" (iv) Click on "5" (v) Click on "FLA3TREST 111198.shf" (vi) "load data" (vii) "dismiss"

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240 (c) Processing -spectral apodize (i) Function -"exponential" (ii) LB -111511 Hz (iii) "Apodize" (iv) "dismiss" (d) Processing -zero-fill (i) "zero-fill" (ii) ''dismiss" (e) Processing -Fourier transform {FFT) (i) For a G-file type, simply hit "transform" because the spatial dimensions are not relevant for a single spectrum {ii) "dismiss" (f) Processing -Phasing (i) "phase zero/first" (ii) Use the "-90" and "+90" buttons and slide bar to phase (iii) In this case the phasing used was 158 for zero and -2215 for first order. (iv) ''apply phase'' (v) "dismiss" (vi) The results of the phased data are as the following figure. R al 2><10 .. 0 10 0 -10 -20 frequency (ppm)

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241 Figure 65 Example 3 0 T data set analyzed by Sage_IDL. (g) Processing baseline correct (i) ''pick BL pts'' (ii) The following baseline points were picked (look carefully at the baseline of the spectrum shown for grayed "x" signs) : R e al 0 '~ r 20 1 0 0 1 0 -20 Freq u e ncy ( ppm ) Figure 66 Example 3 0 T data set analyzed by Sage_ IDL with baseline correction points selected. (iii) Next button to push: ''correct BL" (iv) The result of a baseline correction with points manually picked to be the baseline are shown in the following figure. Note that the role of the baseline is not entirely fixed, as can be seen by the comparison of the baseline corrected spectrum with the FITMASTER backextrapolation corrected spectrum.

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242 Real 20 1 0 a 1 0 -20 F r e qu e ncy (p pm) Figure 67. Example 3 0 T data set analyzed by Sage_IDL with baseline correction. (h) Analysis -Create Peak Table (i) Threshold= 35%%, pick peaks (ii) 6 peaks (the 6 highest) are picked with the following ppm values: (10.06, 9.09, 3.73, 1 .25, -3.80, -12.44) (ii) Note that this method of analysis does not allow the Pi peak to become visible. (i) Analysis -Marquardt fitting (i) Function -Gaussian (ii) Fit (iii) The following parameters result (ppm from create peak table) : Peak 1 (2-DPG) 2 ( 3-DPG) 3 (PCr) 4 (y-ATP) ppm 10.06 9 .09 3 .73 1.2 5 Amplitude 8359. 4 7391.6 31197 17149 Area 1 .136le6 2.285e5 1.2486e6 l.979le6

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5 (a-ATP) 6 (P-ATP) -3.80 -12.44 243 24718 16926 l.8318e6 l.2354e6 MRUI (Magnetic Resonance User Interface, funded by European Community) 1. Conversion of data: All data conversion for MRUI is done within the program. To start the program, at the unix prompt type (a) "matlab" [enter] (b) If MatLab starts but does not start MRUITM, type MRUI at the MatLab prompt. (c) Once in MRUI use the following commands to convert the GE Gfile: (i) Conversion -GEdata -Sxfiles -Gfile (ii) /export/home/angela/cardiac/3tcardiac/111198 (iii) select file FLA3TREST 111198 (iv) save file as FLA3TREST 111198 mrui.dat 2 Data Processing (a) Follow these commands to process cardiac P-31 spectra in MRUI. Also remember to always use the dismiss button. Exiting out of any window in MRUI by closing the window itself will result in MRUI no longer working and requires restarting the program. (b) Database SETUP -experimental (i) File -load -file FLA3T REST 111198 mrui.dat (ii) SETUP (iii) Nucleus P-31 (iv) BO= 3.0 T (v) Tranmit freq -51.71 (c) Next Peak Pick (i) File -load file FLA3TREST 111198 mrui.dat

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244 (ii) When the data is opened, at the bottom of the window adjust the line-broadening to 15 Hz. (iii) At the top of the window adjust the phase, in this case phzero = 242.2 and tbegin = 2.651. (iv) This results in the following spectrum: r::.J. pui 0 .. p~tllwa fox FLMT_RI;ST _111198_ e,n,i.dai : __ _...__ ____ _._ _____ ...._ _____ ,.__ _____ ~,____ 40 20 0 -20 -40 ppm Figure 68. Example 3.0 T data set processed by MRUI. (d) Peakpick -start peakpick -peakpick u .ntil [done] (i) Pick 6 peaks. (e) Next -InputVARPRO (i) Input -done (f) Next -InputAMARES (i) Input -done (g) Next VARPRO/AMARES (i) Go (h) The result of a Varpro fit as shown as follows where the bottom line is the initial data, the middle line is the fit and the top line is the difference between the fit and the original data.

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245 n:&ult o.f TI.Ipro 60 40 :JO 0 -40 ppn, Figure 69. Example 3.0 T data set analyzed by MRUI. (i) In addition, the following data was outputted: Peak 1 (2-DPG) 2 ( 3-DPG) 3 (PCr) 4 (y-ATP) 5 (a-ATP) 6 (P-ATP) Freq 14.723 13.677 8 .434 6.013 0.999 -7.491 Line Width 10.759 33.104 12.923 31.226 35.046 43.927 Amplitude 57.39 215.99 289.02 326.30 435.12 416.29 Std Dev 16.57 59.52 17.57 50.00 58.70 83.48 (j) Unfortunately, the Pi peak was too small to be found with this software, as was also true for Sage/IDL. Provided that it had been found, the frequency difference between PCr and Pi can be converted to ppm and then the pH calculated.

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246 (h) Note that MRUI is a time domain post-processing and fit tool and therefore does not come with baseline corrections, which is a frequency domain fit tool. In addition, neither Sage_IDL nor MRUI come with back extrapolation or any method for fitting the missing start of the FID. FELIX (Molecular Simulations Inc.} FELIX is a program that does not run on "tesla" but on a SGI computer at the Brain Institute. An account can be setup by David Parks or Haiquan Dai. l. File Conversion (a) First, while still on "tesla" you must convert the data so that FELIX can read it. You will accomplish this through a combination of using MRUI, MatLab (which MRUir"' runs from), ws-ftp on your PC, and excel TM. (b) If you haven't already, convert the file to an MRUI compatible dat file as shown in the above MRUI1 "' conversion section. This process will also create a .mat file. (b) Quit MRUI, but keep MatLab running. At the MatLab prompt type "!a2b". Follow the instructions and convert the .mat file to a .gnu file. (c) Go to the PC and use ws-ftp to grab the .gnu file to the PC. (d) Open Microsoft Excel on the PC and open .gnu file. Select and delete the first column of data (the time). The next two columns represent real and imaginary data. Flip these two column positions. Save the file as a short file name .txt like FLAREST.txt. (e) Use the PC tool, ws-ftp, to put the 3Trest.txt file back on tesla.

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247 (f) In angela's account on tesla there is an executable file called ascii2felix or angela. To run these files type "ascii2felix" or "./angela" to get the prompt and instructions on format. (i) ascii2felix filename filesize basewidth{Hz) freq{MHz) (ii) As an example, to convert the 3TREST. txt to a FELixn1 type .dat file, type the following at the command prompt. (iii) Ascii2felix 3TREST.txt 1024 2500 51.71 (iv) FLAREST.dat is created. (g) Ftp this file to the computer that runs FELIX. 2. Data Processing {a) Connect to the computer with FELIX and ftp the .dat FELIX file to that computer as follows: (i) Xhost + (ii) telnet brain.ufbi.ufl.edu (iii) login and password (iv) setenv DISPLAY tesla.xray.ufl.edu:0.0 (v) cd data (vi) ftp 128.227.164.247 (vii) login and password (viii) bin {ix) cd /cardiac/3tcardiac/111198 (x) get FLAREST.dat (xi) by (b) at the promt, type "f elix" [enter] (c) at this point, don't open a database (i) file open (ii) felix new data {*.dat) (iii) FLAREST.dat

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248 (d) Process -Window Function (i) Exponential -ok (ii) Spectral width= 2500 (iii) Line broadening= 15, Ok (e) Process -transform -complex ft -ok (f) Process -Phase correction (i) Real time -OK (ii) Drag bars for phase O and phase 1 (iii) In this case, phase O = 207. 1 & phase 1 -2208.5 (iv) ''keep'' (v) Here is the result for this e xample: 100 200 300 400 500 600 700 800 900 potnt Figure 70. Example 3.0 T data set processed by FELIX. (g) Peakpick -PickAll (i) Cursor selection (ii) 1 s t put a line at the threshold of the peaks and it automatically peaks all peaks above the threshold

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249 --JOO 200 300 400 500 600 700 800 900 point Figure 71. Example 3.0 T data set processed by FELIX with peaks picked. (h) Process Baseline Correct (i) Baseline Point -Pick points via cursor, Ok (ii) [esc] when done (i) Process Baseline Correct (i) Baseline Correct Automatic w/abl (ii) Noise size (#pts) 4 (iii} Peak size (points) 40 (iv} The baseline correction was not optimal for the ATP peaks. It had a hard time with wide based peaks with uneven baselines to either side of the peak (due to missing start of FID causing rolling baseline).

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250 . I "'-a a ~ . . "' "" N V \,i ' I I I I I t 100 200 300 400 500 600 700 800 900 potnt Figure 72. Example 3.0 T data set processed by FELIX with baseline correction. (j) Peaks Optimize Optimize (to fit a spectrum) (i) Start wait to complete (ii) Use "previous" and "next" buttons to go through each peak. !00 200 aoo I 400 .. 500 pot~t I l i l / } r ' 600 Figure 73. Example 3.0 T data set analyzed by FELIX. 1 I I 700 \ \ 800 (iii) The output from FELIX is as follows (for baseline correction) : 900

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Peak 1 (2-DPG) 2 (3-DPG) 3 (PCr) 4 (g-ATP) 5 (a-ATP) 6 (b-ATP) Center (Freq) 298.0 318.0 432.0 481.0 590.0 773.0 251 Height 2613.5 2695.5 7915.5 5093.2 6655.3 3979. 8 Final Comparison of All Methods: Width 14.0 12.0 10.0 14. 0 18.0 18.0 Integral (Area) 56974.609 50429.828 1.236e5 1.llOeS l.861e5 l.113e5 Based on these results as shown in Table 27, it appears that in this case for a cardiac spectrum with good SNR, the locally applied methods were adequate at duplicating the FITMASTER result, with MRUir"' being the closest at getting the right value based on good fit algorithms. Note, that this FELIXr"' routine was performed with baseline correction but without the fit of the initial missing part of the FID. FELIX does have a routine, called linear prediction, for fitting of the beginning of the FID but it is designed to replace data but not add data to the start of the FID.

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252 Table 27. Comparison of Cardiac P-31 Post-Processing Software. Average 2,3-DPG [PCr] / [A Method ATP /2 PCr TP] Raw FITMASTER'm (areas) 3016000 954900 0.8323 Sage_IDL before 723507 287065 6. 71E+05 0. 9279 Baseline Correction (areas) Sage_IDL after 1682100 171055 l .2SE+06 0.7423 Baseline Correction (areas) MRUirM (no area/ 392. 57 136. 69 289. 02 0. 7362 amplitudes only) FELIX (integral 136133. 3 53702. 2 l .24E+05 0 .9079 areas) An Example Where Poor SNR caused FITMASTER to Fail: 1. Sage_IDL [PCr]/[ATP ] Blood Corrected 0.9394 1.0825 0.7705 0.8417 1 .0582 [PCr] / [ATP ] Blood and Relaxation Corrected 1 .0052 1 .1583 0 .8244 0 .9007 1 .1323 (a) Here is a 1 5 T WISE oblique DRESS P-31 Cardiac study where the SNR was low and there was no skeletal muscle contamination as shown in this figure from SAGE IDL. Real 1500 PCr 1000 500 0 -500 -1000 20 0 -20 Frequency (ppm) Figure 74. Example 1 5 T data set with low SNR analyzed by SAGE IDL.

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253 (b) Here is the data output from SAGE_IDL: Peak 1 (DPG) 2 (DPG) 3 (DPG) 4 (PCr) 5 (y-ATP) 6 (a-ATP) 7 (P-ATP) ppm 19.65 17.95 16.63 9.62 4.79 -3.25 -11.50 amplitude 327.01 364.12 376.60 984.90 1464.90 1336.70 1721.0 area 9188.5 16940 9443.8 36049 50305 60765 75723 (c) Based on this output, which seems to fit well with the spectrum, the PCr peak is below the average ATP peaks. (i) Avg_ ATP = 50305 + 60765 + 75723 3 -62264.3 (ii) Total DPG = 9188.5 + 16940 + 9443.8 = 35572. 3 (iii} [PCr]/[ATP] (raw) = 36049/62264.3 = 0.58 (iv) PCr -PCr / AT%iood corrected ATP -Total DPG blood correction (v) PCr / AT%iood corrected (vi) PCr / AT%iood and saturation corrected 36049 = 0.6453 62264.3 -35572.3 0.18 0.6453 X 1.1 0.71 factor (d) Therefore, with all of the correction factors included (which increase the [PCr]/[ATP] ratio) the maximum value of [PCr]/[ATP] is 0.71. And the baseline correction necessary does not look to be extreme enough to double the height of the PCr.

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254 ( 2) FITMASTERTM (a) Despite the results of Sage_IDL1"', FITMASTER1"' incorrectly corrected for and fitted in missing part of the FID to incorrectly enhance the PCr peak height, shown in the solution from the FITMASTER as below. PCr ATP / I~ Figure 75. Example 1. 5 T data set with low SNR analyzed by FITMASTERr"'. (b) The numerical output from the FITMASTERr"' program are listed below: (i) Pi-PCr = 4. 535 0 .15 ppm (ii) ATP total/3 = 3.817e5+2.lle4 (iii) 23-DPG total/ 2 = 1. 724e5 3. 4 7e4 (iv) [PCr]/[ATP] = 1.324+0.15 (v) [PCrJ / [ATP] (blood corrected) = 1. 58 (vi) [PCr]/[ATP] (blood and relaxation corrected (1.28)) = 2.024.31 (c) Their spectrum and numerical result puts the corrected [PCr]/[ATP] ratio at 2.024. This is due to the large amount of

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255 noise in the spectrum (low SNR) creating a situation that was difficult to correctly fit the missing part of the FID. Therefore, the resulting spectrum is incorrectly labeled as skeletal muscle contamination when the true cause of the problem is low SNR.

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APPENDIX F HUMAN T1 RELAXATION DATA Results of fitting data to T i relaxation equation with Statistica sofware (StatSoft, Inc). Subject C.M. (a) PCr Fit T1 (PCr) (r=l.O) 3.47 seconds Model: V2-a(b-e11P(V 1/T1)) y=(1060051 t((1.69449)-ex p(-Xi(3 .46 5656))) 2e6r------------,--------.,----------.. 1 9e6 1 886 1 .7e6 1 .6e6 1.4e6 F;~:~:.:;.:;~--"----: ::.:::.:: :-..::.:.~ :.:.~ ~,t~~l ---'......... ._ .................. . .................. .......................... ~--. ---~--------~--.. . --------~-------------------~-------------------------t---. .................... ........................................................ ~--. .............................................................. ............................. 1.3e6 .___..._ ______ _._ ______ _,__ ______ _.__. 2 5 5 7 5 10 TR_TIME Subject D.P. (a) PCr Fit T1 ( PCr) (r=l.O) a: 0 a. 3.23 seconds M odel : V2~a0{b-ex.p(-v1 /T 1 )) y=(630427 2)"((2.2325 46 )exp(-Xl(3 232546))) 1 44e6 ~------------~-----------~ 1 38e6 -I j:[--~--~--~-~:.:.:.:~-:.:;..:.::.;.;,t-="' :-: .. -:-: . -:: . ::. ::.7 . 1 3286 -t--~-' .. . 1 .26e 6 1 ,2e6 114e6 . --~-----..... . ..................................... ...................... ~ . rr, 1 .08e6 ,._ _____ ....,,_ ______ _._ _____ ~~-----' 2.5 5 7 5 TR_TIME 10 I= <( (b) 1e6 980000 960000 940000 920000 900000 880000 860000 840000 ATPBc Fit T i (ATP) (r=l.O) 0 .74 seconds ' Model V3=a(b-exp{-v1/T1)) y=( 14 78 752) ((0.6680623)Xp (x/(0. 7371 397))) C 2 , ......... -----.......................... ... ... ................................... ---'~. . ........ ~-!~ . ...... ; .................... -}... ---....... -. : ........................... ; .. . . ........... - r ..... t r ,-~----r ' ... ............................. --................... .. .... ---.... . . ' ' .. .. -~-'------~ . . . 820000,.__..._ ______ ,.._ _____ ~~-----~~ (b) 2 5 ATP8c Fit T1 (ATP) 5 7 5 TR_TIME (r=0.98) 0.45 seconds Model : V3=a (ti-exp(.v1ff1 )) y=(2 441539e+00 7).((0,04016817)-exp(-x/(0 .454 7763))) 10 1e6~-------------------------~ c~ O ' 980000 .. -;.>---------i-------r----,1 -: 960000 940000 920000 900000 ............ - -# .. -....... ................................................ . ..................... ........................ ....................... .................. . ........................... 4 ............................ .......................................... . 880000 .......................... ................................ ........................ .................... 860000 '-------~------------------' 2 5 5 7.5 TR TIME 10 256

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Subject L.R. ( a) PCr Fit T1 (PCr) (r=l.O) a: (.) 11. 1.85 seconds Model : V2a (t>,el(p(-v1 /T 1 )) y=( 1321858 )(( 2. 184096) el(p( -x/( 1 846937) )) 2 9586 ,----,-------,-------,-------,----, 2 .85e6 2 75e6 2 65e6 2 55e6 2.45e6 2 3586 ~-~:;::;,---'0""f~-~----------:.: .:.:.:.:.:.:.:.:.:.:.:.:.: .. ;:t.:.:.:.~-~-~-~.~-~-1 r ,--r I ......... ..... ------~------~--. ' ' -------------' . . . -r ....... .. ...... ..... ............... ..., .. ....... ..... ....... .......... . I ......... .................................... .... ...... ._ ....... ............................. ........... l 2 2586 .__ __;_ _____ __,,.; ______ .;_, _____ _;_ ___J s 7 5 10 2 5 TR_TIME Subject L .B. (a) PCr T1 (PCr) Fit 2.8 ( r= 1. 0) seconds Model vica(t>-exp( ~1/T1)) y=(306647 9 ) '((1 857006)-exp( x/(2 825353))) 600000,---,-------,------.-------,------. 560000 520000 480000 440000 400000 ................ ................. ............. ~-~-~-~-~-~~-~-~-~-~-~-~;;~-~-~-~-~--~-~-~-~-~~-~-~~-~-~-~-~-~-~r~-~-~-~-~-~-~-~-~-~-~-~ . ...................... ............ ............... ....... ......................... --r . ....... .............. c.i ..... ;. ---.. ........ ,_ ....................... : ................ . ' ...................... ........................ J ..................... ..i.. .......... - ... . . ' ........................................ ._ .................. ..... ........................................ . 360000 L_..J... ____ .....,! _____ !__ _____ .:,__ __ -1 6 8 2 4 TR_TlME Subject R.B. 2 .1e6 (a) PCr T1(PCr) Fit 3.16 (r=l.O) seconds Model V2=a(t>-exp(-v1/T1)) y=(1635829 ) (( 1 208935) 8Xp(x/(3. 156525 ))) ' ....................... i ......................... ......................... -~ .......................... i 257 <( (b) ATPac Fit T1 (ATP) (r=l.O) 1 .67 seconds Model. V3=a(t>,exp(-v1/T1)) y:(665310 4)'((2 5601 ~) -eXp( x/( 1 689968))) 1 7686 ....--~-------------:-------,----, 1 .7e6 ........ ; ... -------------ii ~ -~-~-~~-~:~:::;::::;;;st-------"'"'.r--~ q2 : 164e6 ---. .. -....................... ...... ... ..... --....... ' 1 ,58e6 .. ' ................... ...... .... -... --................... ,.. ........ 1.52e6 ' ... ,: ............ ........... t .. ..................... t ...................... : ......... ....... ............................................................................................... ' . I : 1 4e6 L_ _;_ _____ _;. ______ .:...._ _____ _;_ __ .J 75 10 800000 700000 600000 500000 400000 3 00000 200000 100000 0 2 5 5 TR_TIME (b) ATPac Fit 0.30 T1 (ATP) (r=0.99) seconds Model: V3=a(t>-exp(-v1/T1 )) y=( 8 643198e + 007)" ( (0 007631666) 8Xp(-x/(0. 3009158 ) ) ) ; ' ..... :. --........... .c.;a. .... : ... ........................ : ........................... ; ............... : 0 : . .................... ... ........ ............................................................................... . ,. ....... -....... -........ ..... ............. .......................... .,, ........ ....... . 1 .. :,. ... ----...................... ; .... ....................... ......... .. .............. ; ...... ..-.......... . ..... } ...... ...................... t .............................. t .. ..... 't .. .. - ..... I. .... _ ...... .,. I ... .... .... f .... .... ~ .. ,.._..,.. ... . . . t '"' .. .. ........... ....................... ................ ...................... .. ' 2 4 TR_TIME (b) ATP8c Fit 1.47 T1 (ATP) : 6 8 (r=l.O) seconds Model: V3=a(b-exp(-v1/T1 )) y,,(1900191 )"((0 4545935)-exp( x/( 1 468548)) ) aooooo~----~----------~----~-2e6 1 .9e6 : .. l. ..... :.::.:=~==9 .......... .............. { ........................ _t::,:: .. .... ... ......................... ; ._ .......... 850000 .. .. .. ~::;;;a,,i0 0 0 0 0 0:.:.:.:.:.:.:.:.:.T.:.:.:.:.:.-..:.:.:.:.:.:.:.:.:. : . --::. :. f, .:.~.~-~.~.~.:--:. 800000 . .... ......................................... ..................................... .. ' 1 .8e6 a: 1 .7e6 (.) 1 .6e6 11. 1 5e6 1 4e6 1 .3e6 1 .2e6 .. ........................ -............................ ~. ................................................................................... . ............ ._ ..................................................................... ...... ..... ' . .......... J ......................... J ............................ .................. J . ' .............. ....................... i .. .. { .. ~.... ' ' ...................... ........................ .................. ......................... .......... . ' 5 75 TR_TIME 10 12. 5 750000 700000 650000 600000 550000 ; . ...... ~.. ~ ....................... ...................... ~ .. ---f .................... ....................... --~ ................ ....... ~ . ..... .. .. ~ ................ .. i .. .. .. ~ ..... .... ..... 1..... ........................ J ..................... 1. ....................... I ' ' ........................................................................................................... . ' 500000'------..L------'------'-----_J,'---' 10 12. 5 5 7. 5 TR_TIME

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258 At least three points are needed to fit a nonlinear function. Therefore, the two TR data acquisitions obtained on T.B. will not be used to estimate the T1 value of PCr and ATP. However, a ratio of the metabolite area values for short and long TR can be used as a correction factor provided the TR for the acquisition is the same as the short TR value for T.B., namely a TR of 4.2 seconds. The relaxation correction factor (RCF) is then given by the metabolite area value of the long TR time over that for the short TR time, for a given P-31 metabolite or ratio, using the blood corrected (BC) value for ATP. RCF(PCr) CF PCr ATPBc PCr1ongTR PC~hortTR 5. 000e6 4. 589e6 ATPBc,longTR 2. 841e6 ATPBc shortTR 2 622e6 [PCr / ATPBcl1ongTR [Per I ATPBc L hortTR 1.09 1.08 5. 000e6 / 2. 841e6 4 5 8 9e6 / 2 6 2 2e6 1.01 Therefore, 1.01 is a single measure approximation for the T1 relaxation correction factor for the TR time of 4.2 seconds.

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APPENDIX G RELAXATION RATES OF DEPTH PHANTOM Relaxation rates of MDPA in the depth measured on 1 5 and 3 0 T systems using phantom were an FIDCSI 35 cm slice <( a.. 0 320 280 2 4 0 200 160 120 80 4 0 M odel : v2=a*( b -exp(-v1 /T1 )) y=(288 .2954 )*((1 .014 155)-exp(-x/(5.527841 ))) ......................................................................................................................................................................... c .,. .................... 0 . . C : 7 . . C 6 ..................................................................................................... ~-------. ..... .................. ......... .......................... .............. C : 5 --------..................... ................................ ~-- ...................... ................................................ ; 4 C : 4 . -~~!-~t . -i --~ !~~ : ....................... > ......................... < .... .. ' ................... I ........................ ~.......................... > .. ....... .. . 2 4 6 8 10 12 14 T IM E SEC Figure 76 1.5 T T1 relaxation curve for MDPA (T1 5 53 sec) <( a.. 0 700000 600000 500000 4 00000 300000 200000 100000 Figure 77 M o d e l : v2=a*(b-exp(-v1/T1)) y=( 497698. 8)*((1 157 4 86)-exp(-x/(6.0 4 1721 ))) ........... ' ........ ....................... J ........................ ~ G'B .. -". . .. . : 0 < {~ ........... ~ .... 41 ........................ :- C : 5 : 6 0 0 .................................... .......................... ~. ................. ....................... .; ........................ .,:. ---.. -............ . C : 3 ............. .......... 9 .... ... ........................ .................... ....................... ........................ ........................ ............ 3 . . . . . , .. .. , .. - .. ,~ .. ~, .. v- 2 4 6 8 T IME SEC 0 T relaxation curve for 259 10 12 14 MDPA 6 04 sec) both the

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REFERENCES 1. AHA, The official web site of the American Heart Association. 1997, AHA: www.amhrt.org. 2 DeBakey, M.E. and A.M. Gotto, The New Living Heart. 1997, Holbrook, Massachusetts: Adams Media Corporation. 3. Bemiller, C.R. C.J. Pepine, and A.K. Rogers, Long-term observations in patients with angina and normal coronary arteriograms. Circulation, 1973. 47(1): p 36-43. 4 Pepine, C., personal communication. January 1998 -July 1999. 5 Nunnally, R and P Bottomley, Assessment of pharmacological treatment of myocardial infarction by phosphorus-JI NMR with surface coils. Science, 1981. 211(4478): p. 177-180. 6 Flaherty, J.R., M.L. Weisfeldt, B.H. Bulkley, T .J. Gardner, V.L. Gott, and W.E Jacobus, Mechanisms of ischemic myocardial cell damage assessed by phosphorus-JI nuclear magnetic resonance. Circulation, 1982. 65(3): p. 561-570. 7. Bottomley, P MR Spectroscopy of the human heart: the status and the challenges. Radiology, 1994. 191: p 593-612. 8 de Roos, A. and E.E. van der Wall, Evaluation of ischemic heart disease by magnetic resonance imaging and spectroscopy. Radial Clin North Am, 1994. 32(3): p. 581-92. 9 Bottomley, P.A., Noninvasive study of high-energy phosphate metabolism in human heart by depth-resolved 31P NMR spectroscopy. Science, 1985. 229(4715): p. 769-772. 10. Jung, W.-I., S. Widmaier, U. Seeger, M. Bunse, A Staubert, L. Sieverding, K. Straubinger, F van Erckelens, F. Schick, G. Dietze, and 0. Lutz, Phosphorus J coupling constants of ATP in human myocardium and calf muscle. J Magn Reson Series B, 1996. 110: p. 39-46. 11. Hardy, C.J., R.G. Weiss, P.A. Bottomley, and G. Gerstenblith, Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy. Am Heart J, 1991. 122(3 Pt 1): p. 795-801. 12. Yabe, T., K. Mitsunami, M. Okada, S Morikawa, T. Inubushi, and M. Kinoshita, Detection of myocardial ischemia by 31P magnetic resonance spectroscopy during handgrip exercise. Circulation, 1994. 89(4): p. 1709-1716. 260

PAGE 278

261 13. Kuno, s .-y., T. Ogawa, S Katsuta, and Y. Itai, In vivo human myocardial metabolism during aerobic exercise by phosphorus-31 nuclear magnetic resonance spectroscopy. Eur J Appl Physiol, 1994. 69: p 488-91. 14. Neubauer, S., T Krahe, R. Schindler, H. Hillenbrand, C. Entzeroth, M. Horn, W. Bauer, T Stephan, K. Lackner, A. Haase, and G. Ertl, Direct measurement of spin-lattice relaxation times of phosphorous metabolites in human myocardium. Magn Reson Med, 1992. 26(2): p. 300-307. 15. Matson, G.B., D.B. Twieg, G .S. Karczmar, T .J. Lawry, J .R. Gober, M. Valenza, M.D Boska, and M .W. Weiner, Application of imageguided surface coil P-31 spectroscopy to human liver, heart and kidney. Radiology, 1988. 169: p. 541-547. 16. Hetherington, H.P., D.J. Luney, J.T. Vaughan, J.W. Pan, S.L. Ponder, 0. Tschendel, D Twieg, and G.M Pohost, JD 31P spectroscopic imaging of the human heart at 4.1 T Magn Res Med, 1995. 33: p. 427-431. 17. Menon, R.S., K Hendrich, X. Hu, and K. Ugurbil, 31P NMR spectroscopy of the human heart at 4T: detection of substantially uncontaminated cardiac spectra and differentiation of subepicardium and subendocardium. Magn Res Med, 1992. 26: p. 268-276. 18. Loeffler, R., R. Sauter, H Kolem, A Haase, and M. von Kienlin, Localized spectroscopy from anatomically matched compartments: improved sensitivity and localization for cardiac 31P MRS in humans. J Magn Reson, 1998. 134(2): p. 287-299. 19. Mitsunami, K T. Yabe, S. Inoue, M. Kinoshita, S. Morikawa, and T. Inubushi, Left ventricular systolic and diastolic function and NMR-visible myocardial inorganic phosphate content determined by 31P NMR spectroscopy in hypertrophied human heart, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B. Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p. 1282. 20. Bottomley, P.A. E. Atalar, and R.G. Weiss, Human cardiac highenergy phosphate metabolite concentrations by lD-resolved NMR spectroscopy. Magn Reson Med, 1996. 35(5): p. 664-670. 21. Miall-Allen, V.M., G .J. Kemp, B. Rajagopalan, D.J. Taylor, G.K. Radda, and S.G. Haworth, Magnetic resonance spectroscopy in congenital heart disease. Heart, 1996. 75: p. 614-619. 22. Pluim, B.M., J.C. Chin, A. De Roos, J. Doornbos, H.M. Siebelink, A Van der Laarse, H.W. Vliegen, R.M Lamerichs, A. Bruschke, and E .E. Van der Wall, Cardiac anatomy, function and metabolism in elite cyclists assessed by magnetic resonance imaging and spectroscopy. Eur Heart J, 1996. 17(8): p. 1271-1278. 23. Buchthal, S., J. den Hollander, C Katholi, J. Caulfield, G. Pohost, and W. Evanochko, Clinical cardiac rejection assessed by

PAGE 279

262 P-31 MRS: the final phase I analysis, in Proceedings of the Society of Magnetic Resonance in Medicine: Fourth Scientific Meeting & Exhibition, N. New York, 1996, SMRM: Berkeley, CA, USA. p. 1011. 24. Herfkens, R., H. Charles, R. Negro-Vilar, and P. van Trigt, In vivo phosphorus-31 NMR spectroscopy of human heart transplants, in Book of Abstracts, Society of Magnetic Resonance in Medicine, 7th Annual Scientific Meeting & Exhibition, C. San Francisco, USA, 1988, SMRM: Berkeley, CA, USA. p. 827. 25. Conway, M., J. Bristow, M. Blackledge, B. Rajagopalan, and G. 26. Radda, Cardiac metabolism during exercise measured by magnetic resonance spectroscopy (letter). Lancet, 1988. ii: p. 692. Weiss, R., A clinical perspective of cardiac NMR spectroscopy, Book Of Abstracts, Society of Magnetic Resonance in Medicine, 10th Annual Scientific Meeting & Exhibition, C. San Francisco, USA, 1991, SMRM: Berkeley, CA, USA. p. 327. in 27. Yabe, T., K. Mitsunami, M. Okada, M. Kinoshita, S. Morikawa, and T. Inubushi, Quantitative measurements of phosphorus metabolites in coronary artery diseases by 31P slice-selected one-dimensional chemical shift imaging, in Proceedings of the Society for Magnetic Resonance in Medicine: 2nd Annual Scientific Meeting, C. San Francisco, USA, 1994, SMRM: Berkeley, CA, USA. p. 1220. 28. Lamb, H., J. Doornbos, J den Hollander, H. Beyerbacht, and A. de Roos, Strategies for cardiac 31P -MR spectroscopy at rest and during dobutamine stress: a study of reproducibility, in Proceedings of the Society of Magnetic Resonance: 3rd Scientific Meeting & Exhibition & The European Society for Magn Reson & Biol: 12th Annual Meeting & Exhibition, F Nice, 1995, SMRM: Berkeley, CA, USA. p. 96. 29. Health Care Finance Administration, National Physician Fee Schedule Relative Value File; http://www.hcfa.gov/stats/cpt/rvudown.htm. 1999, Department of Health and Human Services: Washington, DC. 30. Nunnally, R.L. ed. NMR spectroscopy for in vivo determination of metabolism: An overview. NMR in medicine: The instrumentation and clinical applications, ed. S .R. Thomas and R.L. Dixon. 1986, American Institute of Physics, Inc.: New York, New York. 249-268. 31. Bushberg, J.T., J.A. Seibert, E.M. Leidholdt, and J .M. Boone, The Essential Physics of Medical Imaging. 1994, Baltimore, Maryland: Williams & Wilkins. 32. Ernst, R., G. Bodenhausen, and A. Wokaun, Principles of Nuclear Magnetic Resonance Spectroscopy in One and Two Dimensions. 1987, Oxford, UK: Oxford University Press. 33. Brey, W., ed. Pulse Methods in lD and 2D Liquid Phase-NMR. 1988, Academic: San Diego, CA.

PAGE 280

263 34. Scott, A.I. and R.L. Baxter, Applications of C-13 to metabolic studies. Ann Rev Biophys Bioeng, 1981. 10: p 151-174. 35. Bruhn, H., J. Frahm, M.L. Gyngell, K.D. Merboldt, W. Hanicke, R. Sauter, and C Hamburger, Cerebral metabolism in man after acute stroke: new observations using localized proton NMR spectroscopy. Radiology, 1989. 9(1): p. 126-131. 36. Negengank, W Studies of human tumors by MRS : a review. NMR Biomed, 1992. 5(5): p 303-324. 37. Ng, T.c. Y .G. Comair, M. Xue, N. So, A Majors, H. Kolem, H. Luders, and M Modic, Temporal lobe epilepsy: presurgical localization with proton chemical shift imaging. Radiology, 1994. 193: p 465-472. 38. Salibi, N. and M.A. Brown, Clinical MR Spectroscopy: First Principles. 1998, New York, NY: Wiley-Liss. 39. Hayes, C.E., Radio frequency coils, in Medical Physics Monograph No. 14: NMR in Medicine: The Instrumentation and Clinical Applications, S .R. Thomas and R.L. Dixon, 19861 American Institute of Physics1 Inc.: New York, NY. 40. Robitaille, P .-M. H Merkle, E Sublett, K Hendrick1 B. Lew, G. Path, A .H.L. From, R.J. Bache, M. Garwood, and K. Ugurbil, Spectroscopic imaging and spatial localization using adiabatic pulses and applications to detect transmural metabolite distribution in the canine heart. Magn Reson Med, 1989. 10: p 14-37. 41. Hoffenberg, E.F., P. Kozlowski, T .A. Salerno, and R. Deslauriers, Evaluation of cardiac 31P magnetic resonance spectroscopy: reviewing NMR principles. J Surg Res, 1996. 62: p 135-43. 42. Moseley, M E ed. Imaging techniques: Pulse sequences from spinecho to diffusion. Magnetic Resonance Imaging of the Body, ed. C.E. Higgins, H Hricak, and C Helms. 1992, Raven Press: New York, New York. 157-174. 43. Hutchinson, J B Sutherland, and J. Mallard, Three dimensional NMR imaging using selective excitation. J Phys, 1978. 1 : p 217. 44. Crooks, L., Selective irradiation line-scan techniques of NMR imaging. IEEE Trans Nucl Sci, 1980. 27: p. 1239. 45. Bottomley, P.A., T.B. Foster, and R D Darrow, Depth-resolved surface-coil spectroscopy (DRESS) for in vivo lH, 31P, and lJC NMR. J Magn Reson, 1984. 59: p. 338-342. 46. Bottomley, P., L. Smith, W. Leue, and C. Charles, Sliceinterleaved depth resolved surface-coil spectroscopy (SLIT DRESS) for rapid 31P NMR in vivo. J Magn Reson, 1985. 64: p. 347-351. 47. Bottomley, P .A., B .P. Drayer, and L.S. Smith, Chronic Adult Cerebral Infarction Studied by Phosphorus NMR Spectroscopy. Radiology, 1986. 160: p. 763-766.

PAGE 281

264 48. Blackledge, M .J., B Rajagopalan, R.D. Oberhaensli, N.M. Bolas, P. Styles, and G.K. Radda, Quantitative studies of human cardiac metabolism by P-31 rotating frame NMR. Proc Natl Acad Sci, USA, 1987. 84: p. 4283-4287. 49. Weiss, R.G., P.A. Bottomley, C J Hardy, and G. Gerstenblith, Regional myocardial metabolism of high energy phosphates during isometric exercise in patients with coronary artery disease. N. Engl. J. Med., 1990. 323(23): p. 1593-1600. 50. Hartiala, J H. Sakuma, and C. Higgins, Magnetic resonance imaging and spectroscopy of the human heart. Scand J Clin Lab Invest, 1993. 53: p. 425-437. 51. Mitsunarni, K T. Yabe, M. Okada, S. Endoh, M Kinoshita, S. Morikawa, and T. Inubushi, Cardiac high-energy phosphate metabolism before and after percutaneous transluminal coronary angioplasty, in Proceedings of the Society for Magnetic Resonance in Medicine: 2nd Annual Scientific Meeting, C. San Francisco, USA, 1994, SMRM: Berkeley, CA, USA. p. 1229. 52. Okada, M., K. Mitsunarni, T Yabe, M. Kinoshita, S Morikawa, and T. Inubushi, Quantitative comparison of cardiac 31P NMR spectroscopy and 201TL SPECT imaging in patients with old myocardial infarction, in Proceedings of the Society of Magn Reson in Med : 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA p 1090. 53. Mitsunarni, K., T. Yabe, M. Okada, S Inoue, M. Kinoshita, S. Morikawa, and T. Inubushi, Quantitative analysis of myocardial phosphate metabolism in idiopathic cardiomyopathy by 31P NMR spectroscopy, in Proceedings of the Society of Magnetic Resonance: 3rd Scientific Meeting & Exhibition & The European Society for Magn Reson & Biol: 12th Annual Meeting & Exhibition, F. Nice, 1995, SMRM: Berkeley, CA, USA. p. 1441. 54. Yabe, T K. Mitsunami, M. Okada, S. Endoh, H Miura, T. Inubushi, and M. Kinoshita, Detection of myocardial ischemia by 31P -magnetic resonance spectroscopy during hand-grip exercise. J Arn Coll Cardiel, 1993. 21: p. 113A. 55. Sakuma, H K Takeda, T. Tagami, Y. Kinosada, T. Nakagawa, Okamoto, T. Konishi, and T. Nakano, P-31 MR spectroscopy in hypertrophic cardiomyopathy with correlation of blood contamination: Comparison with Tl-201 myocardial perfusion imaging, in Book Of Abstracts, Society of Magnetic Resonance in Medicine, 10th Annual Scientific Meeting & Exhibition, C. San Francisco, USA, 1991, SMRM: Berkeley, CA, USA. p. 75. 56. Sakuma, H., K. Takeda, K. Yamakado, Y. Kinosada, T. Nakagawa, S. Okamoto, T. Konishi, T. Nakano, Y. Okamoto, and K. Nagasawa, P -31 NMR spectroscopy in patients with hypertrophic cardiomyopathy, in Book Of Abstracts, Society of Magnetic Resonance in Medicine, 9th Annual Scientific Meeting & Exhibition, N. New York, 1990, SMRM: Berkeley, CA, USA. p. 248.

PAGE 282

265 57. Conway, M., R. Ouwerkerk, B Rajagopalan, G. Radda, and P. Bottomley, Low PCr/ATP ratio in eccentric hypertrophy in severe mitral regurgitation, in Proceedings of the Society for Magnetic Resonance in Medicine: 2nd Annual Scientific Meeting, C. San Francisco, USA, 1994, SMRM: Berkeley, CA, USA. p 1218. 58. Conway, M., R. Ouwerkerk, B. Rajagopalan, and G. Radda, 31P MRS of the human heart in 172 patients, in Proceedings of the Society of Magnetic Resonance: 3rd Scientific Meeting & Exhibition & The European Society for Magn Reson & Biol: 12th Annual Meeting & Exhibition, F. Nice, 1995, SMRM: Berkeley, CA, USA. p. 94. 59. Bastin, M., A. Blamire, and P. Styles, Numerical calculation of saturation factors in 31P human cardiac spectroscopy, in Proceedings of the Society of Magnetic Resonance in Medicine: Fourth Scientific Meeting & Exhibition, N. New York, 1996, SMRM: Berkeley, CA, USA. p. 1010. 60. Yabe, T K. Mitsunami, i.T. Inubush, and M. Kinoshita, Quantitative measurements of cardiac phosphorous metabolites in coronary artery disease by 31P magnetic resonance spectroscopy [see comments]. Circulation, 1995. 92: p. 15-23. 61. Sakuma, H S.J. Nelson, D .B. Vigneron, J. Hartiala, and C. Higgins, B, Measurement of Tl relaxation times of cardiac phosphate metabolites using BIR-4 adiabatic RF pulses and a variable mutation method. Magn Reson Med, 1993. 29: p. 688-691. 62. Bottomley, P .A. and R.G. Weiss, Reductions in creatine kinase metabolite concentrations in infarcted myocardium by noninvasive MRS, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B. Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p. 480. 63. Bottomley, P.A., R.G. Weiss, C.J. Hardy, and G. Gerstenblith, Assessment of myocardial ischemia in patients with coronary artery disease by 31P NMR stress-testing: Response to therapy, in Book Of Abstracts, Society of Magnetic Resonance in Medicine, 9th Annual Scientific Meeting & Exhibition, N. New York, 1990, SMRM: Berkeley, CA, USA. p. 244. 64. Schaefer, S., G .G. Schwartz, S. Steinman, D.J. Meyerhoff, B. Massie, and M.W. Weiner, Metabolic response of the heart to increased work: 31P NMR spectroscopy of normal and cardiomyopathic myocardium in man, in Book Of Abstracts, Society of Magnetic Resonance in Medicine, 9th Annual Scientific Meeting & Exhibition, N. New York, 1990, SMRM: Berkeley, CA, USA. p. 245. 65. Sieverding, L., J. Breuer, A Staubert, W. Jung, S. Widmaier, U. Seeger, G. Dietze, 0. Lutz, and J. Apitz. Proton decoupled myocardial 31P -NMR-spectroscopy reveals decreased PCr/Pi in patients with severe hypertrophic cardiomyopathy. in Proceedings of the Society of Magn Reson: 3rd Scientific Meeting & Exhibition & the European Society for Magn Reson & Biol: 12th Annual meeting and exhibition. 1995. Berkeley, Calif: Society of Magn Reson.

PAGE 283

266 66. Jung, W., M. Bunse, S. Widmaier, F. Schick, K. Kuper, G. Dietze, and O. Lutz, Localized 31P MRS of the human heart: decreasing errors in PCr signal intensities in 2D-CSI spectroscopy, in Proceedings of the Society of Magn Reson in Med: 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA. p 1097. 67. Bottomley, P.A., C.H. Hardy, and P.B. Roemer, Phosphate metabolite imaging and concentration measurements in human heart by nuclear magnetic resonance. Magn Reson Med, 1990. 14(3): p. 425-434. 68. Loeffler, R., M. von Kienlin, K. Wicklow, A. Haase, and R. Sauter, 31P spectra of the human heart in vivo with reduced spectral contamination using prior knowledge from MRI, in Proceedings of the Society for Magnetic Resonance in Medicine: 2nd Annual Scientific Meeting, C. San Francisco, USA, 1994, SMRM: Berkeley, CA, USA. p. 1171. 69. Campbell, C.M., R.T. Thompson, J. Sykes, and G. Wisenberg, Pharmaceutical moderation of myocardial metabolism during ischemia and reperfusion, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B. Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p. 1281. 70. Bottomley, P.A. and C.J. Hardy, 31P spectroscopic imaging of the human heart, in Book of Abstracts, Society of Magnetic Resonance in Medicine, 7th Annual Scientific Meeting & Exhibition, C. San Francisco, USA, 1988, SMRM: Berkeley, CA, USA. p. 832. 71. Kolem, H., R. Sauter, M. Friedrich, M. Schneider, K Wicklow, and K. Bachmann, A double-oblique JD CSI technique for 31P cardiac spectroscopy applied to patients with coronary artery disease, in Proceedings of the Society of Magn Reson in Med: 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA. p. 1096. 72. Tsekos, N.V., Comprehensive evaluation of cardiac physiology with magnetic resonance imaging and spectroscopy methods (myocardial perfusion, heart wall motion). 1995, University of Minnesota. 73. Rosch, C., M.v. Kienlin, M. Horn, S. Neubauer, and A Haase, Quantitative determination of phosphate distribution and infarct size in chronically infarcted rat heart using three-dimensional 31P spectroscopic imaging, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p 479. 74. Cho, Y.K., H. Merkle, N.V. Tsekos, J. Zhang, and K. Ugurbil, Noninvasive 31P 3D-CSI of the canine heart at 9 4 T, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B. Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p. 1288.

PAGE 284

267 75. Jaffer, F., H. Wen, R. Balaban, and S. Wolff, A method to improve the BO homogeneity of the heart in vivo. Magn Reson Med, 1996. 3 6 (3): p. 375-383. 76. Menon, R., X. Hu, K Hendrich, and K. Ugurbil. A 3-D fourier series window approach to 31P spectroscopy. in Proceedings of the Society of Magn Reson in Med: 12th Annual Scientific Meeting. 1993. Berkeley, Calif: Society of Magn Reson in Med. 77. Bottomley, P., Spatial Ann NY Acad Sci, 1987. localization in NMR 508: p. 333-348. spectroscopy in vivo. 78. Bottomley, P.A. and C.J. Hardy, PROGRESS in efficient threedimensional spatially localized in vivo 31P NMR spectroscopy using multidimensional spatially selective pulses. J Magn Reson, 1987. 74: p. 550-556. 79. Haase, A. and J. Frahm, Multiple chemical-shift-selective NMR imaging using stimulated echoes. J Magn Reson, 1985. 64: p. 94-102. 80. Hetherington, H D Luney, J. Vaughan, J. Pan, S. Ponder, O. Tschendel, D. Twieg, and G. Pohost, JD 31P spectroscopic imaging of the human heart at 4 .lT, in Proceedings of the Society for Magnetic Resonance in Medicine: 2nd Annual Scientific Meeting, C. San Francisco, USA, 1994, SMRM: Berkeley, CA, USA. p. 86. 81. Luney, D., J. den Hollander, W. Evanochko, L. Johnson, and G. Pohost, 31P nuclear magnetic resonance spectroscopy of human myocardial scar, in Proceedings of the Society of Magn Reson in Med : 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA. p. 1091. 82. Neubauer, S., T. Krahe, R. Schindler, M Horn, H. Hillenbrand, C Entzeroth, H. Mader, E.P. Kromer, G .A. Riegger, K. Lackner, and G. Ertl, 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease: altered cardiac highenergy phosphate metabolism in heart failure. Circulation, 1992. 86 (6): p. 1810-1818. 83. Schaefer, S., J. Gober, M. Valenza, G .S. Karczmar, G .B. Matson, S.A. Camacho, E H Botvinick, B. Massie, and M.W. Weiner, Nuclear magnetic resonance imaging-guided phosphorous-31 spectroscopy of the human heart. J Am Coll Cardiol, 1988. 12: p. 1449-1455. 84. Bottomley, P., CRISIS Pulse Sequence, 1988: US. 85. Kim, H., The development of phosphorus-31 in vivo human cardiac spectroscopy. 1996, University of Florida. 86. Moonen, C.T.W., M. von Kienlin, P.C.M. van Zijl, J. Cohen, J. Gillen, P. Daly, and G. Wolf, Comparison of single-shot localization methods (STEAM and PRESS) for in vivo proton NMR spectroscopy. NMR in Biomedicine, 1989. 2(5/6): p. 201-208. 87. Yongbi, N.M., G.S. Payne, D.J. Collins, and M.O. Leach, Quantification of signal selection efficiency, extra volume

PAGE 285

268 suppression and contamination for ISIS, STEAM, and PRESS localized H-1 NMR spectroscopy using an EEC localization test object. Phys Med Bio, 1995. 40: p. 1293-1303. 88. Jung, w .-I., K. Kuper, F. Schick, M. Bunse, M. Pfeffer, K Pfeffer, G. Dietze, and O. Lutz, Localized phosphorus NMR spectroscopy: a comparison of the FID, DRESS, CRISIS/CODEX, and STEAM methods in vitro and in vivo using a surface-coil. Magn Reson Imaging, 1992. 10(4): p. 655-662. 89. Frahm, J T. Michaelis, K.-D. Merboldt, W. Hanicke, M.L. Gyngell, D. Chien, and H. Bruhn, Localized NMR spectroscopy in vivo: Progress and problems. NMR Biomed, 1989. 2(5-6): p. 188-195. 90. Cady, E.B., M. Wylezinska, J. Penrice, A Lorek, and P. Amess, Quantitation of phosphorus metabolites in newborn human brain using internal water as reference standard. Magn Reson Imaging, 1996. 14(3): p. 293-304. 91. GE, Signa Advantage Spectroscopy Research Accessory Release 5 4 Operator's Manual. 1995, Milwaukee, Wisconsin: General Electric Medical Systems. 92. Ordidge, R., A. Connelly, and J. Lohman, Image-selected in vivo spectroscopy (ISIS): a new technique for spatially selective NMR spectroscopy. J Magn Reson, 1986. 66: p. 283-294. 93. Lawry, T., G. Karczmar, M. Weiner, and G. Matsno, Computer simulation of MRS techniques: an analysis of ISIS. Magn Reson Med, 1989. 9 : p. 299-314. 94. Bendall, M and D. Pegg, Uniform sample excitation with surface coils for in vivo spectroscopy by adiabatic rapid half passage. J Magn Reson, 1986. 67: p. 376. 95. de Graaf, R.A., Y Luo, M. Terpstra, H. Merkle, and M. Garwood, A new localization method using an adiabatic pulse, BIR-4. J Magn Reson B, 1995. 106(3): p. 245-252. 96. de Graaf, R.A. Y. Luo, M. Terpstra, and M Garwood, Spectral editing with adiabatic pulses. J Magn Reson B, 1995. 109(2): p. 184-193. 97. FDA, Magnetic Resonance Diagnostic Devices Criteria for Significant Risk Investigations (at www.fda.gov), 1997, Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH): Washington, DC. 98. Brown, J.J., S.A. Mirowitz, J .C. Sandstrom, and W.H. Perman, MR spectroscopy of the heart. AJR, 1990. 155: p. 1-11. 99. Briggs, R., personal communication. May, 1999. 100. Neubauer, S., M. Horn, H. Mader, D. Lubke, M. Godde, W. Kaiser, D. Hahn, and G. Ertl, Hemodynamic correlates of impaired cardiac high-energy phosphate metabolism in patients with dilated

PAGE 286

269 cardiomyopathy, in Proceedings of the Society for Magnetic Resonance in Medicine: 2nd Annual Scientific Meeting, C. San Francisco, USA, 1994, SMRM: Berkeley, CA, USA p. 90. 101. van Dobbenburgh, J., N de Jonge, C. Klopping, J. Lahpor, S 102. Woolley, and C. van Echteld, Altered myocardial energy metabolism in heart transplant patients: consequence of rejection or a postischemic phenomenon?, in Proceedings of the Society of Magn Reson in Med: 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA. p. 1093. Evanochko, W., J. den Hollander, D. Luney, G. Blackwell, and G. Pohost, 31P MRS in human heart transplants: a clinical update, Proceedings of the Society of Magn Reson in Med: 12th Annual Scientific Meeting & Exhibition, N New York, 1993, SMRM: Berkeley, CA, USA. p. 1092. in 103. Evanochko, W., A. Bouchard, J. Kirklin, R Bourge, D Luney, and G. Pohost Detection of cardiac transplant rejection in patients by 31P NMR spectroscopy, in Book Of Abstracts, Society of Magnetic Resonance in Medicine, 9th Annual Scientific Meeting & Exhibition, N. New York, 1990, SMRM: Berkeley, CA, USA. p. 246. 104. Horn, M M. Cramer, K Harre, T. Pabst, D. Hahn, and S. Neubauer, 6 years experience with 31P -MR spectroscopy of the human myocardium: 209 examinations in 163 patients, in Proceedings of the Society of Magnetic Resonance in Medicine: Fourth Scientific Meeting & Exhibition, N. New York, 1996, SMRM: Berkeley, CA, USA. p. 1009. 105. Neubauer, S., M. Horn, H. Mader, and et al., Clinical and hemodynamic correlates of impaired cardiac high-energy phosphate metabolism in patients with aortic valve disease, in Proceedings of the Society of Magn Reson in Med : 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA. p. 355. 106. Dell'Italia, L., W. Evanochko, G. Blackwell, J den Hollander, H. Singleton, and G. Pohost, Dissociation between mechanics and PCr/ATP in patients with volume overload hypertrophy, in Proceedings of the Society of Magn Reson in Med: 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA. p 356. 107. Keevil, S., M. Lewis, J. Garbutt, I. Huggoe, E. Baker, and P. Garlick, In vivo phosphorous-31 NMR spectroscopy of the myocardium in children with congenital heart abnormalities, in Proceedings of the Society of Magn Reson in Med: 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA. p. 1095. 108. Luyten, P.R., A. de Roos, L.J.M.J. Oosterwaal, J. Doornbos, and J.A. den Hollander, PCr/ATP ratio changes and pH values in dilated and hypertrophic cardiomyopathy patients determined by 31P NMR heart spectroscopy, in Book Of Abstracts, Society of Magnetic Resonance in Medicine, 10th Annual Scientific Meeting &

PAGE 287

270 Exhibition, C. San Francisco, USA, 1991, SMRM: Berkeley, CA, USA. p 74. 109. Neubauer, S., M. Horn, M. Goedde, K Harre, A. Laser, W Bauer, T. Pabst, D. Hahn, I. Reis, J. Ingwall, and G. Ertl, In patients with dilated cardiomyopathy abnormal cardiac energy metabolism can be detected invasively (endomyocardial biopsy) and noninvasively (31P -MR spectroscopy), in Proceedings of the Society of Magnetic Resonance: 3rd Scientific Meeting & Exhibition & The European Society for Magn Reson & Biol: 12th Annual Meeting & Exhibition, F. Nice, 1995, SMRM: Berkeley, CA, USA. p. 93. 110. Sharp, J.C. and M.O. Leach, Conformal NMR spectroscopy: Accurate localization to noncuboidal volumes with optimum SNR Magn Reson Med, 1989. 11: p. 376. 111. Neubauer, S., M. Horn, M Godde, D. Lubke, B. Jilling, D. Hahn, and G. Ertl, Contributions of 31P -magnetic resonance spectroscopy to the understanding of dilated heart muscle disease. Eur-Heart-J, 1995. 16(Supplement 0): p. 115-118. 112. Lamb, H., H.P. Beyerbacht, J. Doornbos, E.E. van der Wall, and A. de Roos, Evidence for altered myocardial HEP metabolism in hypertensive cardiac hypertrophy, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B. Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p. 361. 113. Neubauer, S., M. Horn, K. Harre, H. Stromer, T Pabst, J. Sandstede, D. Hahn, and K. Kochsiek, Impaired cardiac high-energy phosphate metabolism in patients with aortic stenosis but not in patients with aortic regurgitation, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B. Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p. 1283. 114. Lamb, H .J., R Ouwerkerk, J. Doorbos, v.d. Laarse, and A de Roos, Motion sensitivity of JD-ISIS: effects on human cardiac 31P-MRS during stress, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B. Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p 1290. 115. Ye, J., J.K. Sun, J. Shen, R. Summers, T.A. Salerno, and R. Deskauriers, Localized magnetic resonance spectroscopy is a useful tool for continuous assessment of metabolism in both ventricles during warm blood cardioplegia, in Proceedings of the International Society for Magnetic Resonance in Medicine: Fifth Scientific Meeting & Exhibition, B. Vancouver, Canada, 1997, SMRM: Berkeley, CA, USA. p. 1291. 116. Vermeulen, J.W. A .H., P R Lyuten, J.I. van der Heijden, and J A. den Hollander, Uncovering the Pi signal in the in vivo 31P NMR spectra of the human heart, in Book of Abstracts, Society of Magnetic Resonance in Medicine, 7th Annual Scientific Meeting & Exhibition, C. San Francisco, USA, 1988, SMRM: Berkeley, CA, USA. p. 833.

PAGE 288

271 117. Sauter, R., M. Friedrich, H. Requardt, J. Offermann, and A. Weikl, Localized phosphorus spectroscopy of the human myocardium, in Book of Abstracts, Society of Magnetic Resonance in Medicine, 7th Annual Scientific Meeting & Exhibition, C San Francisco, USA, 1988, SMRM: Berkeley, CA, USA. p. 828. 118. Kantor, H.L., R.W. Briggs, K.R. Metz, and R.S. Balaban, Gated in vivo examination of cardiac metabolites with 31P nuclear magnetic resonance. Am J Physiol, 1986. 251: p H171-Hl75. 119. Humphrey, S.M. and P.B. Garlick, NMR-visible ATP and Pi in normoxic and reperfused rat hearts: a quantitative study. Am J Physiol, 1991. 260: p. H6-Hl2. 120. Garlick, P. and R Townsend, NMR visibility of Pi in perfused rat hearts is affected by changes in substrate and contractility. Am J Physiol, 1992. 263: p. H497-H502. 121. Garlick, P., G. Radda, P. Seeley, and B. Chance, Phosphorous NMR studies on perfused hearts. Biochem Biophys Res Commun, 1977. 7 4 : p. 1256-1262. 122. Jacobus, W., G. Taylor, D. Hollis, and R. Nunnally, Phosphorus nuclear magnetic resonance of perfused working rat hearts. Nature (London), 1977. 265(5596): p 756-758. 123. Bottomley, P.A., R .J. Herfkens, L .S. Smith, S. Brazzamano, R. Blinder, L.W. Hedlund, J.L. Swain, and R.W. Redington, Noninvasive detection and monitoring of regional myocardial ischemia in situ using depth-resolved 31P NMR spectroscopy. Proc Natl Acad Sci USA, 1985. 82(24): p. 8747-8751. 124. Bottomley, P., L. Smith, S. Brazzamano, L. Hedlund, R. Redington, and R. Herfkens, The fate of inorganic phosphate and pH in regional myocardial ischemia and infarction: a noninvasive 31P NMR study. Magn Reson Med, 1987. 5(2): p. 129-142. 125. Jasinski, A., P. Kozlowski, A. Urbanshi, and J. Saunders, Hexagonal surface gradient coil for localized MRS of the heart. Magn Reson Med, 1991. 21: p. 296. 126. Robitaille, P.M., H. Merkle, B. Lew, G. Path, K. Hendrich, P. Lindstrom, A.H. From, M. Garwood, R.J. Bache, and K. Ugurbil, Transmural high energy phosphate distribution and response to alterations in workload in the normal canine myocardium as studied with spatially localized 31P NMR spectroscopy. Magn Reson Med, 1990. 16(1): p. 91-116. 127. Balaban, R.S., H.L. Kantor, L .A. Katz, and R.W. Briggs, Relation between work and phosphate metabolisms in the in vivo paced mammalian heart. Science, 1986. 2 3 2 : p. 1121-1123. 128. Rehr, R.B., J.L. Tatum, J.I. Hirsch, L. Wetstein, and G. Clarke, Effective separation of normal, acutely ischemic, and reperfused myocardium with P -31 MR spectroscopy. Radiology, 1988. 1 6 8 : p. 81-89.

PAGE 289

272 129. Levine, S.R., J.A. Helpern, K.M. Welch, A.M. Vande-Linde, K.L. Sawaya, E.E. Brown, N.M. Ramadan, R.K. Deveshware, and R.J. Ordidge, Human focal cerebral ischemia: evaluation of brain pH and energy metabolism with P-31 NMR spectroscopy. Radiology, 1992. 185(2): p 537-544. 130. Rehr, R .B., B.E. Fuhs, F Lee, J.L. Tatum, J.I. Hirsch, and R. Quint, Differentiation of reperfused-viable (stunned) from reperfused-infarcted myocardium at 1 to 3 days postreperfusion by in vivo phosphorus-31 nuclear magnetic spectroscopy. Am Heart J, 1991. 122: p. 1571-1582. 131. Jennings, R and K. Reimer, Lethal myocardial ischemic injury. Am J Pathol, 1981. 102: p. 241-255. 132. Markiewicz, W., S. Wu, W.W. Parmley, C.B. Higgins, R. Sievers, T.L. James, J Wikman-Coffelt, and G. Jasmin, Evaluation of the hereditary Syrian hamster cardiomyopathy by 31P nuclear magnetic resonance spectroscopy: improvement after acute verapamil therapy. Circ Res, 1986. 59(6): p 597-604. 133. Camacho, S.A., J. Wikman-Coffelt, S. Wu, T .A. Watters, E .H. Botvinick, R. Sievers, T.L. James, G. Jasmin, and W.W. Parmley, Improvement in myocardial performance without a decrease in highenergy phosphate metabolites after isoprotereno1 in Syrian cardiomyopathic hamsters. Circulation, 1988. 77: p. 712-719. 134. Wu, S., R. White, J. Wikman-Coffelt, R. Sievers, M. Wendland, J. Garrett, C .B. Higgins, T. James, and W .W. Parmley, The preventative effect of verapamil on ethanol-induced cardiac depression: phosphorus-31 nuclear magnetic resonance and highpressure liquid chromatographic studies of hamsters. Circulation, 1987. 75(5): p. 1058-1064. 135. Nicolay, K., W. Aue, J. Seelig, C. van Echteld, T Ruigrok, and B. de Kruijff, Effects of the anti-cancer drug adriamycin on the energy metabolism of the rat heart as measured by in vivo 31P NMR and implications for adriamycin-induced cardiotoxicity. Biochim Biophys Acta, 1987. 929: p. 5 13. 136. Kopp, S., L. Klevay, and J Feliksik, Physiological and metabolic characterization of a cardiomyopathy induced by chronic copper deficiency. Am J Physiol, 1983. 245: p. H855-H866. 137. Afzal, N P. Ganguly, K. Dhalla, G. Pierce, P. Signal, and N. Dhalla, Beneficial effects of verapamil in diabetic cardiomyopathy. Diabetes, 1988. 37: p 936-942. 138. Schaefer, S., G.G. Schwartz, J.R. Gober, B. Massie, and M.W. Weiner, Magnetic resonance spectroscopy. Evaluation of ischemic heart disease. Invest Radiol, 1989. 24: p. 969-972. 139. Schaefer, S., S. Camacho, J. Gober, R.G. Obregon, M.A. DeGroot, E.H. Botvinick, B. Massie, and M.W. Weiner, Response of myocardial metabolites to graded regional ischemia: 31P NMR

PAGE 290

273 spectroscopy of porcine myocardium in vivo. Circ Res, 1989. 64 (5): p 968-976. 140. Schaefer, S., G.G. Schwartz, J.R. Gober, A.K. Wong, S.A. Camacho, B. Massie, and M .W. Weiner, Relationship between myocardial metabolites and contractile abnormalities during graded regional ischemia. Phosphorus-31 nuclear magnetic resonance studies of porcine myocardium in vivo. J Clin Invest, 1990. 85(3): p 706-713. 141. Von Kienlin, M and R. Mejia, Spectral localization with optimal pointspread function. J Magn Reson, 1991. 9 4 : p. 268-287. 142. Neubauer, S., R. Schindler, T. Krahe, H. Hillenbrand, C. Entreroth, M. Horn, W. Bauer, T Stephan, K. Lackner, G. Ertl, and A. Haase, Direct measurement of spin-lattice relaxation times of phosphorus metabolites in human myocardium, in Works in Progress, Society of Magnetic Resonance in Medicine, 10th Annual Scientific Meeting & Exhibition, C. San Francisco, USA, 1991, SMRM: Berkeley, CA, USA. p. 987. 143. Loeffler, R., H. Kolem, K. Wicklow, A. Haase, and M. von Kienlin, Localized MR spectra in the human heart from anatomically matched compartments in three spatial dimensions, in Proceedings of the Society of Magnetic Resonance: 3rd Scientific Meeting & Exhibition & The European Society for Magn Reson & Biol: 12th Annual Meeting & Exhibition, F. Nice, 1995, SMRM: Berkeley, CA, USA. p 334. 144. Sieverding, L., W .I. Jung, J Breuer, S. Widmaier, A Staubert, F. van Erckelens, 0. Schmidt, M. Bunse, T Hoess, 0 Lutz, G.J. Dietze, and A. J, Proton-decoupled myocardial 31P NMR spectroscopy reveals decreased PCr/Pi in patients with severe hypertrophic cardiomyopathy. Am J Cardiel, 1997. 80(3A): p. 34A-40A. 145. Neubauer, S., M. Horn, M. Cramer, K Harre, J.B. Newell, W. Peters, T. Pabst, G. Ertl, D Hahn, J.S. Ingwall, and K. Kochsiek, Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation, 1997. 96(7}: p. 2190-2196. 146. Landschutz, W., M. Meininger, M. Beer, T. Seyfarth, M. Horn, T. Pabst, A. Haase, D. Hahn, S. Neubauer, and M. von Kienlin, Concentration of human cardiac 31P-metabolites determined by SLOOP 31P-MRS. MAGMA, 1998. 6(2-3): p. 155-156. 147. Masuda, Y., Y. Tateno, H. Ikehira, T. Hashimoto, F. Shishido, M. Sekiya, Y. Imazeki, H. Imai, S. Watanabe, and Y. Inagaki, Highenergy phosphate metabolism of the myocardium in normal subjects and patients with various cardiomyopathies: the study using ECG gated MR spectroscopy with a localization technique. Jpn Circ J, 1992. 56 (6): p. 620-626. 148. Sakuma, H K. Takeda, T. Tagami, T. Nakagawa, S. Okamoto, T. Konishi, and T. Nakano, 31P MR spectroscopy in hypertrophic

PAGE 291

274 cardiomyopathy: comparison with Tl-201 myocardial perfusion imaging. Arn Heart J, 1993. 125: p. 1323-1328. 149. Bottomley, P.A., R.J. Herfkens, L.S. Smith, and T.M. Bashore, Altered phosphate metabolism in myocardial infarction: P-31 MR spectroscopy. Radiology, 1987. 165(3): p. 703-707. 150. Bottomley, P.A., R.G. Weiss, C.J. Hardy, and W.A. Baumgartner, Myocardial high-energy phosphate metabolism and allograft rejection in patients with heart transplants. Radiology, 1991. 181(1): p. 67-75. 151. Bottomley, P., R. Weiss, C. Hardy, and G. Gerstenblith, 31P NMR stress testing in patients with coronary disease: evidence for myocardial PCr/Pi changes, in Book Of Abstracts, Society of Magnetic Resonance in Medicine, 10th Annual Scientific Meeting & Exhibition, C. San Francisco, USA, 1991, SMRM: Berkeley, CA, USA. p. 577. 152. Hardy, C.J., P.A. Bottomly, K.W. Rohling, and P.B. Roemer, An NMR phased array for human cardiac 31P spectroscopy. Magn Res Med, 1992. 28: p 54-64. 153. Bottomley, P.A. and C.J. Hardy, Proton Overhauser enhancements human cardiac phosphorous NMR spectroscopy at 1 .5T. Magn Reson Med, 1992. 24: p. 384-390. in 154. Bottomley, P.A. and C.J. Hardy, Mapping creatine kinase reaction rates in human brain and heart with 4 tesla saturation transfer 31P NMR. J Magn Reson, 1992. 99: p. 443-448. 155. Rajagopalan, B., M.J. Blackledge, W McKenna, N Bolas, and G.K. Radda, Measurement of phosphocreatine to ATP ratio in normal and diseased human heart by 31P magnetic resonance spectroscopy using the rotating frame-depth selection technique. Ann NY Acad Sci, 1987. 508: p. 321-332. 156. Conway, M .A., J. Allis, R. Ouwerkerk, T. Niioka, B. Rajagopalan, and G.K. Radda, Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet, 1991. 338(8773): p. 973-976. 157. Conway, M., J. Bristow, M. Blackledge, B. Rajagopalan, and G. Radda, Cardiac metabolism during exercise in healthy volunteers measured by 31P magnetic resonance spectroscopy. Br Heart J, 1991. 65: p. 25-30. 158. Blarnire, A.M., C. Liess, and B. Rajagopalan, Sine bell encoding and surface saturation techniques to obtain spectra from the whole human heart using a double surface coil, in Proceedings of the Society of Magnetic Resonance: 3rd Scientific Meeting & Exhibition & The European Society for Magn Reson & Biol: 12th Annual Meeting & Exhibition, F Nice, 1995, SMRM: Berkeley, CA, USA. p. 1942. 159. Blarnire, A.M., C. Liess, G.K. Radda, and B Rajagopalan, Measurement of myocardial pH by saturation transfer in man, in

PAGE 292

275 Proceedings of the Society of Magnetic Resonance: 3rd Scientific Meeting & Exhibition & The European Society for Magn Reson & Biol: 12th Annual Meeting & Exhibition, F. Nice, 1995, SMRM: Berkeley, CA, USA. p. 91. 160. Conway, M., P. Bottomley, R. Ouwerkerk, G. Radda, and B Rajagopalan, Mitral regurgitation: impaired systolic function, eccentric hypertrophy, and increased severity are linked to lower phosphocreatine/ATP ratios in humans. Circulation, 1998. 97(17): p. 1716-1723. 161. Schaefer, S., J.R. Gober, G.G. Schwartz, D.B. Twieg, M.W. Weiner, and B. Massie, In vivo phosphorous-31 spectroscopic imaging in patients with global myocardial disease. Am J Cardiol, 1990. 65(16): p 1154-1161. 162. Auffermann, W., W .M. Chew, C.L. Wolfe, N .J. Tavares, W.W. Parmley, R.C. Semelka, T. Donnelly, K. Chatterjee, and C.B. Higgins, Normal and diffusely abnormal myocardium in humans: functional and metabolic characterization with P-31 MR spectroscopy and cine MR imaging. Radiology, 1991. 179: p. 253-259. 163. Schaefer, S G. Schwartz, S. Steinman, D. Meyerhoff, B. Massie, and M. Weiner, Metabolic response of the human heart to inotropic stimulation: in vivo phosphorous-31 studies of normal and cardiomyopathic myocardium. Magn Reson Med, 1992. 25(2): p. 260-272. 164. van Dobbenburgh, J., C. Lekkerkerk, and C. van Echteld, Saturation effects in human heart and chest wall muscle measured by 31P lD spectroscopic imaging, in Book Of Abstracts, Society of Magnetic Resonance in Medicine, 10th Annual Scientific Meeting & Exhibition, C. San Francisco, USA, 1991, SMRM: Berkeley, CA, USA p. 988. 165. de Roos, A., J. Doornbos, P. Luyten, L. Oosterwaal, E. van der Wall, and J. den Hollander, Cardiac metabolism in patients with dilated and hypertrophic cardiomyopathy: assessment with protondecoupled P-31 MR spectroscopy. J Magn Reson Imaging, 1992. 2(6): p. 711-719. 166. Lamb, H.J., J. Doornbos, J .A. den Hollander, P .R. Luyten, H.P. Beyerbacht, E.E. van der Wall, and A. de Roos, Reproducibility of human cardiac 31P-NMR spectroscopy. NMR Biomed, 1996. 9(5): p 217-227. 167. Lamb, H.J., H.P. Beyerbacht, R. Ouwerkerk, J. Doornbos, B.M. Pluim, E.E. van der Wall, A. van der Laarse, and A de Roos, Metabolic response of normal human myocardium to high-dose atropine-dobutamine stress studied by JlP-MRS. Circulation, 1997. 96 (9): p. 2969-2977. 168. Pluim, B.M. H.J. Lamb, H.W. Kayser, F. Leujes, H.P. Beyerbacht, A.H. Zwinderman, A. van der Laarse, H.W. Vliegen, A. de Roos, and E.E. van der Wall, Functional and metabolic evaluation of the athlete's heart by magnetic resonance imaging and dobutamine

PAGE 293

276 stress magnetic resonance spectroscopy. Circulation, 1998. 97(7): p. 666-672. 169. den Hollander, J., W. Evanochko, L. Dell'Italia, and G. Pohost, 31P NMR Tl inversion recovery measurements of the human heart, in Proceedings of the Society of Magn Reson in Med: 12th Annual Scientific Meeting & Exhibition, N. New York, 1993, SMRM: Berkeley, CA, USA. p. 1098. 170. Doornbos, J., P Luyten, M. Janssen, r.M. Wasse, and A. de Roos, P-31 MR spectroscopy of skeletal and cardiac muscle metabolism in patients with systemic sclerosis: a multiple case study. J Magn Reson Imaging, 1994. 4 : p. 165-8. 171. Ponder, S.L. and D .B. Twieg, A novel sampling method for 31P spectroscopic imaging with improved sensitivity, resolution, and side lobe suppression. J Magn Reson, Series B, 1994. 104: p. 85-88. 172. Whitman, G.J. R B Chance, H Bode, J. Maris, J. Haselgrove, R Kelley, B.J. Clark, and A.H. Harken, Diagnosis and therapeutic evaluation of a pediatric case of cardiomyopathy using phosphorous-31 nuclear magnetic resonance spectroscopy. J Am Coll Cardiol, 1985. 5(3): p 745-749. 173. Kalil-Filho, R., C P de Albuquerque, R G Weiss, A. Mocelim, G Bellotti, G Cerri, and F. Pileggi, Normal high energy phosphate ratios in "stunned" human myocardium. J Am Coll Cardiel, 1997. 30(5): p. 1228-1232. 174. Bruner, A., H.-W. Kim, A. Boyette, C. Pepine, S. McGorray, S. Buchthal, J. den Hollander, and K. Scott, Human in vivo cardiac imaging and phosphorus DRESS spectroscopy of women with suspected microvascular dysfunction using the 1.5 T GE Signa, in International Society for Magnetic Resonance in Medicine Seventh Scientific Meeting and Exhibition, P. Philadelphia, 1999, MRM: Berkeley, CA. p. 281. 175. Bruner, A H.W. Kim, D. Peterson, J. Fitzsimmons, C. Pepine, S. Buchthal, J den Hollander, and K. Scott, Improvements in human in-vivo cardiac phosphorus spectroscopy at 3 0 Tesla in comparison with 1 5 Tesla for ischemic heart disease, in International Society for Magnetic Resonance in Medicine Seventh Scientific Meeting and Exhibition, P. Philadelphia, 1999, MRM: Berkeley, CA. p 1488. 176. Menon, R.S. K. Hendrich, X Hu, and K. Ugurbil, 31P NMR spectroscopy of the human heart at 4 T : detection of substantially uncontaminated cardiac spectra and differentiation of subepicardium and subendocardium. Magn Res Med, 1992. 26(2): p. 368-376. 177. Ackerman, J T. Grove, G. Wong, D Gadian, and G. Radda, Mapping of metabolites in whole animals by 31P NMR using surface coils. Nature, 1980. 283: p 167-170.

PAGE 294

277 178. Buchthal, S.D. W.J. Thoma, J .S. Taylor, S .J. Ne lson, and T.R. Brown, In vivo Tl values of phosphorus metabolites in human liver and muscle determined at 1 .5T by chemical shift imaging. NMR in Biomedicine, 1989. 2(5/6): p. 298-304. 179. Hubesch, B D .J. Meyerhoff, S Naruse, Gober, T.J. Lawry, M.D Bosck, G.B. Matson, and M .J. Weiner, Noninvasive quantitation of phosphorus metabolites in human tissue by NMR spectroscopy. J Magn Reson, 1989: p. 299-311. 180. Luyten, P., J Groen, J. Vermeulen, and J den Hollander, Experimental approaches to image localized human 31P NMR spectroscopy. Magn Reson Med, 1989. 11: p. 1-21. 181. Bailes, D., D Bryant, G. Bydder, H Case, A Collins, I Cox, P Evans, R Harman A. Hall, S Khenia, P. McArthur, A Oliver, M. Rose, B Ross, and I Young, Localized phosphorus-31 NMR spectroscopy of normal and pathological human organs in vivo using phase encoding techniques. J Magn Reson, 1987. 74: p 158-170. 182. Cox, I.J., D.J. Bryant, A.G. Collins, P George, R R Harman, A S Hall, H.J. F Hodgson, S Khenia, P McArthur, D .H. Spencer, and I.R. Young, Four-dimensional chemical shift MR imaging of phosphorus metabolites of normal and diseased human liver. J Comput Assist Tomogr, 1988. 12: p. 369-376. 183. Brown, T.R. S .D. Buchthal, J. Murphy-Boesch, S .J. Nelson, and J.S. Taylor, A multi-slice sequence for 31P in vivo spectroscopy. 1-D chemical shift imaging with an adiabatic half-passage pulse. J Magn Reson, 1989. 82: p. 629-633. 184. Blackledge, M.J., R.D. Oberhaensli, P. Styles, and G K Radda, Measurement of in vivo 31P relaxation rates and spectral editing in human organs using rotating-frame depth selection. J Magn Reson, 1987. 71: p 331-336. 185. Hayes, C.E. and L Axel, Noise performance of surface coils for magnetic resonance imaging at 1 5 T Med Phys, 1985. 12(5): p. 604-607. 186. Bendall, M J. McKendry, I. Cresshull, and R. Ordidge, Active detune switch for complete sensitive volume localization in in vivo spectroscopy using multiple rf coils and depth pulses. J Magn Reson, 1984. 60: p. 473-478. 187. Weiner, M.W. Magnetic Resonance Spectroscopy of Cardiac and Skeletal Muscle. in ISMRM 4th Scientific Meeting, Educational Course Syllabus. 1996, April 28th. 188. Constantinides, C.D., C.R. Westgate, O.D.W. G, E.A. Zerhouni, and E.R. Mcveigh, A phased array coil for human cardiac imaging. Magn Reson Med, 1995. 34(1): p 92-98. 189. Fayad, Z., T. Connick, and L Axel, An improved quadrature or phased-array coil for MR cardiac imaging. Magn Reson Med, 1995. 34(2): p. 186-193.

PAGE 295

278 190. Bottomley, P .A. and C.H. Olivieri, What is the optimum phasedarray coil design for cardiac magnetic resonance?, in Proceedings of the Society of Magnetic Resonance in Medicine: Fourth Scientific Meeting & Exhibition, N. New York, 1996, SMRM: Berkeley, CA, USA. p. 248. 191. Chen, C.N., D.I. Hoult, and V.J. Sank, Quadrature detection coils --A further sqrt(2) improvement in sensitivity. Journal of Magn Reson, 1983. 54: p. 324-327. 192. Mitsunami, K., M. Okada, T. Inoue, M. Hachisuka, M. Kinoshita, and T. Inubishi, In vivo 31P nuclear magnetic resonance spectroscopy in patients with old myocardial infarction. Jpn Circ J, 1992. 56: p. 614-619. 193. Okada, M K. Mitsunami, T Yabe, M. Kinoshita, S. Morikawa, and T. Inubushi, Quantitative measurements of phosphorus metabolites in normal and diseased human hearts by 31P NMR spectroscopy, in Proceedings of the Society of Magn Reson in Med : 11th Annual Scientific Meeting & Exhibition, 1992, SMRM: Berkeley, CA, USA. p. 2305. 194. Rozenman, Y. and H.L. Kantor, Heterotropic transplanted rat heart: a model for in vivo determination of phosphorus metabolites during iscbemia and reperfusion. J Magn Reson Med, 1990. 13 (3): p 450-457. 195. den Hollander, J. and S. Buchthal, personal communication. 1998. 196. Buchthal, S., J. den Hollander, E.T. Martin, W.J. Rogers, and G. Pohost, Ischemia by P-31 MR spectroscopy in women without CAD: Pilot phase data from WISE, in World Congress of Cardiology1998. 197. Yoshida, T H Watari, and K. Tagawa, Effects of active and passive recoveries on splitting of the inorganic phosphate peak determined by 31P -nuclear magnetic resonance spectroscopy. NMR in Biomedicine, 1996. 9 : p. 13-19. 198. Brown, B.G., A.B. Lee, E.L. Bolson, and H.T. Dodge, Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation, 1984. 70: p. 18-24. 199. Widmaier, S., W.-I. Jung, M. Bunse, F. van Erckelens, G. Dietze, and 0. Lutz, Change in chemical shift and splitting of 31P gamma-ATP signal and human skeletal muscle during exercise and recovery. NMR in Biomedicine, 1996. 9 : p. 1-7. 200. Minakami, S., C. Suzuki, T. Saito, and H. Yoshikawa, Studies on erythrocyte glycolysis. I Determination of the glycolytic intermediates in human erythrocytes. J Biochem, 1965. 58: p. 543-550. 201. Ting, T., S. Naccarato, A. Qualtieri, G. Chidichimo, and C. Brancati, In vivo metabolic studies of glucose, ATP and 2,3-DPG in thalassaemia intermedia, heterozygous beta-thalassaemic and

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279 normal erythrocytes: 13C and 31P MRS studies. J of Haematology, 1994. 88: p. 547-554. 202. Ambruso, D.R. B Hawkins, D.L. Johnson, A .R. Fritzberg, W .C. Klingensmith, and E.R. B McCabe, Measurement of adenosine triphosphate and 2,3-diphosphoglycerate in stored blood with 31P nuclear magnetic resonance spectroscopy. Biochemical Medicine and Metabolic Biology, 1986. 35: p. 376-383. 203. Moon, R B and J.H. Richards, Determination of intracellular pH by 31P magnetic resonance. The Journal of Biomedical Chemistry, 1973. 248(20): p. 7276-7278. 204. Henderson, T.O. A.J.R. Costello, and A. Omachi, Phosphate metabolism in intact human erytrocytes: determination by phosphorus-31 nuclear magnetic resonance spectroscopy. Proc Nat Acad Sci USA, 1974. 71(6): p 2487-2490. 205. Tehrani, A.Y., Y.-F. Lam, A.K.L.C. Lin, S.F. Dosch, and C. Ho, Phosphorus-31 nuclear magnetic resonance studies of human red blood cells. Blood Cells, 1982. 8: p. 245-261. 206. Lam, Y.-F. A.K.L.C. Lin, and C. Ho, A phosphorus-31 nuclear magnetic resonance investigation of intracellular environment in human normal and sickle cell blood. Blood, 1979. 54(1): p. 196-209. 207. Gupta, R.K., J.L. Benovic, and Z.B. Rose, The determination of the free magnesium level in the human red blood cell by 31P NMR. The Journal of Biological Chemistry, 1978. 253(17): p 6172-6176. 208. Gunther, H., NMR Spectroscopy. 1980, New York, NY: John Wiley & Sons. 209. Bottomley, P.A., C .J. Hardy, and R.G. Weiss, Correcting human heart 31P NMR spectra for partial saturation: evidence that saturation factors for PCr/ATP are homogeneous in normal and disease states. J Magn Reson, 1991. 95: p. 341-355. 210. Bottomley, P., The true Tl values of myocardial high-energy phosphates (letter)? Magn Reson Med, 1993. 29: p. 145-146. 211. Evelhoch, J.L., C.S. Ewy, B.A. Siegfried, J.J.H. Ackerman, D.W. Rice, and R.W. Briggs, 31P spin-lattice relaxation times and resonance linewidths of rat tissue in vivo: Dependence upon the static magnetic field strength. Magn Reson Med, 1985. 2 : p. 410-417. 212. Sakuma, H., S. Nelson, D. Vigneron, and C. Higgins, in Proceedings of the Society of Magn Reson in Med: 11th Annual Scientific Meeting & Exhibitionl992, SMRM: Berkeley, CA, USA. p 2306. 213. Martin, J.F., B.D. Guth, R.H. Griffey, and D.E. Hoekenga, Myocardial creatine kinase exchange rates and 31P NMR relaxation rates in intact pigs. Magn Reson Med, 1989. 11: p. 64-72.

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280 214. Howe, F .A. and J.R. Griffiths, A two-compartment phosphate-doped gel phantom for localized spectroscopy. Magn Reson Imag, 1992. 10: p. 119-126. 215. Boylestad, R L DC/AC: The Basics. 1989, Columbus, Ohio: Merrill Publishing Company. 771. 216. Bottomley, P.A. and C.J. Hardy, Strategies and protocols for clinical 31P research in the heart and brain. Phil Trans R Soc Lond A, 1990. 333: p 531-544. 217. Lim, K., J. Pauly, P Webb, R. Hurd, and Macovsky, Short TE phosphorus spectroscopy using a spin-echo pulse. Magn Reson Med, 1994. 32: p 98-103. 218. Cooper, J.W. An Introduction to Fourier Transform NMR and the Nicolet 1080 Data System. 1973, Madison, Wisconsin: Nicolet Instrument Corporation. 219. Field, S.A. and F.W. Wehrli, Signa Applications Guide: Volume I. 4th ed. Vol. 1. 1990, Milwaukie, Wisconsin: GE. 220. Fitzsimmons, J personal communication. June 1999. 221. Cohen, E. and A. McDermott Who's fat? New definition adopted, http://cnn.com/HEALTH/9806/17/weight.guidelines/index.html, 1998, CNN: Atlanta, GA. 222. Frohlich, 0. and M.A. Wallert, Methods of measuring intracellular pH in the heart. Cardiovasc Res, 1995. 29: p 194-202. 223. Arnold, D .L., P .M. Matthews, and G K Radda, Metabolic recovery after exercise and the assessment of mitochondrial function in vivo in human skeletal muscle by means of JlP NMR. Magnetic Resonance in Medicine, 1983. 1: p. 307-315. 224. Graham, R., A Taylor, and T Brown, A method for calculating the distribution of pH in tissues and a new source of pH error from the P-31 NMR spectrum. Am J Physiol, 1994. 266(2): p R638. 225. Bottomley, P. and R. Weiss, Non-invasive magnetic-resonance detection of creatine depletion in non-viable infarcted myocardium. Lancet, 1998. 351(9104): p 714-718.

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BIOGRAPHICAL SKETCH Angela Properzio Bruner attended the Georgia Institute of Technology (Georgia Tech) in Atlanta, Georgia, where she graduated with a bachelor's degree in mechanical engineering in 1993. During her time at Georgia Tech she participated in the cooperative work program and swapped each quarter with work at Critikon, a Johnson & Johnson company in Tampa, Florida. Her work at Critikon continued after graduation, in the Division of Research and Development including work on the Dinamap vital signs monitor (in use in hospitals from clinics to intensive care and operating rooms) for its design, development, manufacture and FDA approval. Her work also overlapped with the quality control and design of blood pressure cuffs and equipment. In pursuit of a Ph.D. in the summer of 1994 she enrolled in the medical physics program in the departments of nuclear engineering and radiology at the University of Florida. She started working with Dr. Katherine Scott in the area of MRI and MRS, with special interest in human patient studies. Including the research presented in this dissertation, she was also able to work with MRI and proton and phosphorus MRS in a variety of patient studies where MR provided both diagnostic and treatment feedback. This experience included patients with cardiac heart failure, peripheral vascular disease, tumor, stroke, Sturge Weber syndrome, schizophrenia and cardiac syndrome-X. In addition, Angela shared her time with the 281

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282 medical physicists at Shands at UF in annual physics tests, acceptance tests, and general quality control within the department of radiology. In June 1996, Angela Marie Properzio married Thom Bruner, an architect/graphic artist and computer programmer from Tuscaloosa, Alabama.

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I certify that I conforms to acceptable adequate, in scope and Doctor of Philosophy. have read this study and that in my opinion it standards of scholarly presentation and is fully quality, as a dissertation for the degree of Katherine N. Scott, Chair Professor of Nuclear and Radiological Engineering I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully adequate, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. R. Fit 1mmons r essor of Nuclear and Radiological Engineering I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully adequate, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. David E. Hinten g Associate Professor of Nuclear and Radiological Engineering I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully adequate, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. Christine B. Stopka Associate Professor of Exercise and Sport Sciences I certify that I have read this study and that in my opinion it conforms to acceptabl e standards of scholarly presentation and is fully adequate, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. 0ames R. Ballinger Assistant Professor of Radiology

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This dissertation was submitted to the Graduate Faculty of the College of Engineering and to the Graduate School and was accepted as partial fulfillment of the requirements forJ;;:.J~-tl1gree Doctor of Philosophy August 1999 ean, College of Engineering Dean, Graduate School

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