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Quantification of Left Ventricular Regional Filling Patterns with Correlation to Systolic Events

Permanent Link: http://ufdc.ufl.edu/UFE0041507/00001

Material Information

Title: Quantification of Left Ventricular Regional Filling Patterns with Correlation to Systolic Events
Physical Description: 1 online resource (28 p.)
Language: english
Creator: Petersen, John
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: QUANTIFICATION OF LEFT VENTRICULAR REGIONAL FILLING PATTERNS WITH CORRELATION TO SYSTOLIC EVENTS By John William Petersen May 2010 Chair: Marian Limacher Major: Medical Sciences Clinical and Translational Science Growing knowledge suggests that normal filling of the left ventricle (LV) is dependent on events that occur during systole. During systole potential energy is stored which during diastole allows for deformation of the LV. This deformation allows for a decrease in pressure in the LV. The greatest decrease in pressure in the LV during diastole is likely at the apex. Therefore, we hypothesized that in patients with normal systolic events the apical region of the LV will fill with blood the earliest. We performed a retrospective evaluation of cardiac MRI images obtained as a part of routine clinical care between January 1, 2007 and July 31, 2008. We analyzed MRI images off-line and generated volume-time curves for both the basal and apical regions. These curves were transformed to display the percent of filling achieved over the percent of the cardiac cycle for both the basal and apical regions. These graphs allowed determination of the point in the cardiac cycle at which 10% and 20% of filling was achieved in the apical and basal regions. Additionally, apical and basal ejection fractions (EF) were determined to assist in the classification of a patient s systolic pattern. Among the 21 patients with a normal pattern of systolic events, i.e. the apical EF was greater than the basal EF, filling occurred earlier in the apical region as compared to the basal region. On average the apical region reached 10% of filling 57msec earlier than the basal region. This difference represented 7% of the cardiac cycle (P value < 0.001). Also, on average the apical region reached 20% of filling 28msec earlier than the basal region. This difference represented 3.5% of the cardiac cycle (P=0.011). In the 4 patients with an abnormal pattern of systolic events, i.e. the basal EF was greater than the apical EF, parameters of LV filling occurred earlier in the basal region as compared to the apical region. On average the basal region reached 20% of filling 57msec earlier than the apical region. This difference represented 6.9% of the cardiac cycle (P value 0.043). The mean difference between the points in the cardiac cycle at which the apical and basal regions reached 10% of filling was different between the patients with a normal pattern of systolic events and those patients with an abnormal pattern of systolic events (P value=0.001). Also, the mean difference between the points in the cardiac cycle at which the apical and basal regions reached 20% of filling was different between the patients with a normal pattern of systolic events and those patients with an abnormal pattern of systolic events (P value=0.006). The pattern of LV systolic events predicts the pattern of LV diastolic events. Those patients whose apical EF was greater than their basal EF had earlier filling in the apical region relative to the basal region. This finding supports the relationship between systolic and diastolic events. Further, this supports the concept that systolic events can contribute to the generation of diastolic suction.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by John Petersen.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Limacher, Marian C.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2012-04-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041507:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041507/00001

Material Information

Title: Quantification of Left Ventricular Regional Filling Patterns with Correlation to Systolic Events
Physical Description: 1 online resource (28 p.)
Language: english
Creator: Petersen, John
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: QUANTIFICATION OF LEFT VENTRICULAR REGIONAL FILLING PATTERNS WITH CORRELATION TO SYSTOLIC EVENTS By John William Petersen May 2010 Chair: Marian Limacher Major: Medical Sciences Clinical and Translational Science Growing knowledge suggests that normal filling of the left ventricle (LV) is dependent on events that occur during systole. During systole potential energy is stored which during diastole allows for deformation of the LV. This deformation allows for a decrease in pressure in the LV. The greatest decrease in pressure in the LV during diastole is likely at the apex. Therefore, we hypothesized that in patients with normal systolic events the apical region of the LV will fill with blood the earliest. We performed a retrospective evaluation of cardiac MRI images obtained as a part of routine clinical care between January 1, 2007 and July 31, 2008. We analyzed MRI images off-line and generated volume-time curves for both the basal and apical regions. These curves were transformed to display the percent of filling achieved over the percent of the cardiac cycle for both the basal and apical regions. These graphs allowed determination of the point in the cardiac cycle at which 10% and 20% of filling was achieved in the apical and basal regions. Additionally, apical and basal ejection fractions (EF) were determined to assist in the classification of a patient s systolic pattern. Among the 21 patients with a normal pattern of systolic events, i.e. the apical EF was greater than the basal EF, filling occurred earlier in the apical region as compared to the basal region. On average the apical region reached 10% of filling 57msec earlier than the basal region. This difference represented 7% of the cardiac cycle (P value < 0.001). Also, on average the apical region reached 20% of filling 28msec earlier than the basal region. This difference represented 3.5% of the cardiac cycle (P=0.011). In the 4 patients with an abnormal pattern of systolic events, i.e. the basal EF was greater than the apical EF, parameters of LV filling occurred earlier in the basal region as compared to the apical region. On average the basal region reached 20% of filling 57msec earlier than the apical region. This difference represented 6.9% of the cardiac cycle (P value 0.043). The mean difference between the points in the cardiac cycle at which the apical and basal regions reached 10% of filling was different between the patients with a normal pattern of systolic events and those patients with an abnormal pattern of systolic events (P value=0.001). Also, the mean difference between the points in the cardiac cycle at which the apical and basal regions reached 20% of filling was different between the patients with a normal pattern of systolic events and those patients with an abnormal pattern of systolic events (P value=0.006). The pattern of LV systolic events predicts the pattern of LV diastolic events. Those patients whose apical EF was greater than their basal EF had earlier filling in the apical region relative to the basal region. This finding supports the relationship between systolic and diastolic events. Further, this supports the concept that systolic events can contribute to the generation of diastolic suction.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by John Petersen.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Limacher, Marian C.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2012-04-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041507:00001


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1 QUANTIFICATION OF LEFT VENTRICULAR REGIONAL FI LLING PATTERNS WITH CORRELATION TO SYSTOLIC EVENTS By JOHN WILLIAM PETERSEN A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF TH E REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2010

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2 2010 John William Petersen

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3 To those who persevere in the setting of left ventricular dysfunction

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4 ACKNOWLEDGMENTS I thank the members of m y advisory committee for their mentoring, guidance and motivation throughout this project. I thank my parents for their support of my academic pursuits. I thank my wife for sacrificing while understanding why pursuits of knowledge are important to me I thank my daughters for inspiring me to make them proud.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 6 LIST OF FIGURES .......................................................................................................... 7 ABSTRACT ..................................................................................................................... 8 CHAPTER 1 INTRODUCTION .................................................................................................... 10 Mechani sms of Left Ventricular (LV) Filling ............................................................. 10 Diastolic Suction ............................................................................................... 10 Intra Ventricular Pressure Gradient .................................................................. 10 Quantification of the Effects of Diastolic Suction ..................................................... 11 2 METHODS .............................................................................................................. 12 Patient Selection ..................................................................................................... 12 MRI Analysis ........................................................................................................... 12 Classification of LV Systolic State ........................................................................... 13 Statistical A nalysis .................................................................................................. 14 3 RESULTS ............................................................................................................... 16 Patients ................................................................................................................... 16 Differences in Time to Achieve Filling in the Apical and Basal Regions ................. 16 Differences in All Patients ................................................................................. 16 Differences in LV Systolic Groups .................................................................... 16 4 DISCUSSION ......................................................................................................... 21 Limitations and Future Directions ........................................................................... 22 Conclusions ............................................................................................................ 24 LIST OF REFERENCES ............................................................................................... 26 BIOGRAPHICAL SKETCH ............................................................................................ 28

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6 LIST OF TABLES Table page 3 1 Patients baseline characteristics ........................................................................ 17 3 2 Analyzed variables for all patients ...................................................................... 18

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7 LIST OF FIGURES Figure page 2 1 Cardiac MRI image demonstrating the typical position of the apical and basal slices used for this analysis ................................................................................ 15 3 1 Mea n difference between points in the cardiac cycle (in %) at which the apical and basal regions reached 10% and 20% of filling. .................................. 20 4 1 Two patients with normal echocardiographic parameters of gl obal LV systolic and diastolic function but different regional filling patterns. ................................ 25

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8 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for th e Degree of Master of Science QUANTIFICATION OF LEFT VENTRICULAR REGIONAL FILLING PATTERNS WITH CORRELATION TO SYSTOLIC EVENTS By John William Petersen M ay 2010 Chair: Marian Limacher Major: Medical Sciences Clinical and Translational Science Growing knowledge suggests that normal filling of the left ventricle (LV) is dependent on events that occur during systole. During systole potential energy is stored which during diastole allows for deformation of the LV This deformation allows for a decrease in pressure in the LV. T he greatest decrease in pressure in the LV during diastole is likely at the apex. Therefore, we hypothesized that in patients with normal systolic events the apical region of the LV will fill with blood the earliest. We performed a r etrospective evaluation of cardiac MRI images obtained as a part of routine clinical care between January 1, 2007 and July 31, 2008. We analyzed MRI images off line and generated volumetime curves for both the basal and apical regions. T h ese curves were transformed to display the percent of filling achieved over the percent of the cardiac cycle for both the basal and apical regions. These graphs allowed determination of the point in the cardiac cycle at which 10% and 2 0% of filling was ach ieved in the apical and basal regions. Additionally, apical and basal ejection fractions (EF) were determined to assist in the classification of a patients systolic pattern.

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9 Among the 21 patients with a normal pattern of systolic events, i.e. the api cal EF was greater than the basal EF, filling occurred earlier in the apical region as compared to the bas al region. On average the apical region reached 10% of filling 57msec earlier than the basal region This difference represented 7% of the cardiac cyc le (P value<0.001) Also, on average the apical region reached 20% of filling 28msec earlier than the basal region. This difference represented 3.5% of the cardiac cycle (P=0.011) In the 4 patients with an abnormal pattern of systolic events, i.e. the bas al EF was greater than the apical EF, parameters of LV filling occurred earlier in the basal region as compared to the apical region. On average the basal region reached 20% of filling 57msec earlier than the apical region. This difference represented 6.9% of the cardiac cycle (P value 0.043). The mean difference between the points in the cardiac cycle at which the apical and basa l regions reached 10% of filling was different between the patients with a normal pattern of systolic events and those patients w ith an abnormal pattern of systolic events ( P value=0.001 ). Also the mean difference between the points in the cardiac cycle at which the apical and basal regions reached 20% of filling was different between the patients with a normal pattern of systolic events and those patients with an abnormal pattern of systolic events (P value= 0.006). The pattern of LV systolic events predicts the pattern of LV diastolic events. Those patients whose apical EF was greater than their basal EF had earlier filling i n the apical region relative to the basal region. This finding supports the relationship between systolic and diastolic events. Further, this supports the concept that systolic events can contribute to the generation of diastolic suction.

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10 CHAPTER 1 INTRODUCTION Mechanisms of Left Ventricular (LV) Filling Diastolic Suction Diastolic dysfunction of the left ventricle (LV) can lead to significant morbidity and mortality (1) The primary function of diastole is LV filling. Therefore, understanding the m echanisms of normal and abnormal LV filling is important. LV filling has long been considered a passive process. However, growing knowledge suggest s that normal LV filling depends on active processes. These active processes occur during both diastole and s ystole. Specifically, during systole, shortening of the myocardium places strain on elastic elements in the LV, such as the protein titin, that allows for t he storage of potential energy ( 2 ) During isovolumic relaxation (IVR) this stored energy is release d allowing the LV to deform back to its preejection configuration. This deformation of the LV, in the setting of an isovolumic state, allows for a decrease in intraventricular pressure. The generation of a decreasing intraventricular pressure during IVR and the early part of LV filling is referred to as di astolic suction (3 ) Intra Ventricular Pressure Gradient Deformation of the LV during IVR and the early part of LV filling is felt to be dependent on, and correlate with, the potential energy that is stored during systole. The apical region of a normal LV has a more vigorous systolic contraction as compared to the basal region. For example, the apical region typically twists 15 degrees counterclockwise during systole, whereas the basal region twist s only 3 degrees clockwise ( 4 ) Therefore, the apical region, as compared to the basal region, will store more potential energy during systole allowing for a more vigorous change in LV

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11 configuration during IVR. Because of this vigorous change in apical LV c onfiguration during IVR, the greatest decrease in pressure during IVR exists in the apical region of the LV cavity (5 ). The discrepancy between the decrease in pressure at the apex and basal region of the LV creates an intraventricular pressure gradient that starts during IVR but reaches peak in the early part of diastolic filling (5 ). Blood should preferentially accelerate toward the area of the LV with the lowest pressure. Therefore, in patients with an intact intraventricular pressure gradient, we expect that after mitral valve opening blood would first accelerate toward the apical region. Quantification of the Effects of Diastolic Suction A number of studies have documented the temporal sequence of myocardial segment deformations that contribute to the generation o f diastolic suction (69 ). However, no previous study has evaluated the temporal sequence of regional changes in the intraventricular cavity during LV filling. Patterns of regional LV filling could allow for the diagnosis of abnormal LV function and serve as a therapeutic target. We developed a technique to evaluate and compare the filling patterns of the apical and basal intraventricular regions. Because we expect that after mitral valve opening blood will first accelerate toward th e api cal region in normal patients, this technique should reveal that the apical region will fill prior to the basal region.

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12 CHAPTER 2 METHODS Patient Selection After obtaining approval from the IRB, we performed a retrospective evaluation of cardi ac MRI images obtained between January 1, 2007 and July 31, 2008. All cardiac MRIs were ordered as a part of routine clinical care and performed at Shands Hospital at the University of Florida. Only the cardiac MRIs of patients who also had an echocardiogram within 6 months of the cardiac MRI and prior to July 31, 2008 were considered. Between January 1, 2007 and July 31, 2008, 236 adult patients had cardiac MRIs performed. Of these patients, 141 also had an echocardiogram within 6 months of the cardiac MRI and prior to July 31, 2008. Because we compared data between the MRIs and echocardiograms, only the 75 patients with the shortest time interval between their MRI and echocardiogram were enrolled into the study population. Of these 75 patients, 8 pat ients with normal ejection fraction (EF) and normal diastolic echocardiographic parameters, 6 patients with normal EF and abnormal diastolic echocardiographic parameters, and 11 patients with abnormal EF were included in the current analysis. The remaining 50 patients were not included in the current analysis because they had congenital abnormalities or had severe LV systolic dysfunction Specifically, those patients with an apical or basal EF <10% were not included in the current analysis because the filli ng volumes were too small to permit an accurate interpretation of the filling curves MRI Analysis We used a Pi e Medical work station (BV, Maastricht, The Netherlands) to analyze the cardiac MRIs First, we determined which short axis cine slices encompassed the

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13 entire LV Second, we determined which of these slices correl ated with either the basal or apical regions of the left ventricle. The two slices chosen to represent the apical region included the most apically positioned slice at endsystole that contained a circular portion of the LV cavity as well as the slice basal to it. The two slices chosen to represent the basal region included the slice closest to the mitral annulus that did not include a portion of the LV outflow tract and the slice apical to it. Next, within the slices included in the basal region, the endocardium was traced in the endsystolic frame and all diastolic frames included in the cine series. These tracings were then used to generate a graph of volume over time. This pr ocedure was then repeated for the apical region. Therefore, a separate graph of volume over time was produced for the basal and apical regions. This data was transformed in two ways. First, to account for differences i n heart rate between patients time in msec was transformed to represent the percent of a single cardiac cycle Systole began at 0% of the cardiac cycle and diastole was complete at 100% of the cardiac cycle. Second, to account for the difference between basal and apical regional volume s within subjects, volume in mL was transformed to represent the percent of filling volume achieved in a given region. Filling volume was defined as the difference between maximal volume and minimal volume in a given region. An example of the raw and trans formed data for the apical and basal regions is shown in Figure 21 These graphs allowed determination of the point in the cardiac cycle at which 10% and 2 0% of filling was achieved for the apical and basal regions Classification of LV Systolic State MRI images were analyzed with a Pi e Medical work station (BV, Maastricht, The Netherlands) to determine t he regional ejection fraction (EF) for the apical and basal

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14 regions. Previous work has demonstrated that in normal subjects the apical region of the LV has a more vigorous systolic contraction as compared to the basal region (4). Therefore, t hose patients whose EF was greater in the apical region as compared to the basal region were classified as having a normal pattern of LV systolic function. Those patients whose EF was greater in the basal region as compared to the apical region were classified as having an abnormal pattern of LV systolic function. Statistical Analysis A paired T test was used to determine if the point in the cardiac cycle at which 10% and 20% filling was achieved was different between the apical and basal regions of the LV in all 25 patients. Then a separate paired T test was performed in those with a normal pattern of LV systolic function and those with an abnormal pattern of LV systolic function to determine if the point in the cardiac cycle at which 10% and 20% filling was achieved was different between the apical and basal regions of the LV. Finally, an independent sample T test was then used to determine if the mean differ ence between the time to achieve 10% and 20% filling in the apical and basal regions was different between those with a normal pattern and an abnormal pattern of LV systolic function. Power calculations were not performed, as this is a pilot study.

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15 Figu re 2 1. Cardiac MRI image demonstrating the typical position of the apical and basal slices used for this analysis. An example of the raw data of volume vs. time for the apical and basal regions is shown in the center. This raw data was transformed to dem onstrate the % f illing a chieved over the % c ardiac cycle (right). The green arrows show the points in the cardiac cycle when the apical and basal regions achieve 10% of filling.

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16 CHAPTER 3 RESULTS Patients Twenty five patients were enrolled in the cu rrent analysis For all 25 patients, the average age was 58 years, the average EF was 57%, and 60% were male. Twenty one had a normal pattern and 4 had an abnormal pattern of LV systolic funct ion. The average age, EF, QRS duration, and proportion male for the 21 patients with a normal pattern of LV systolic function and the 4 patients with an abnormal pattern of LV systolic function are shown in Table 31. Differenc es in Time to Achieve Filling in the Apical and Basal Regions Differences in All Patients The variables used in this analysis are shown in Table 32. In the 25 patients included in this analysis, parameters of LV filling occurred earlier in the apical region as compared to the basal region. The mean difference between the points in the cardi ac cycle at which the apical and basal regions reached 10% of filling represented 5.2% of the cardiac cycle (P value= 0.001). Similarly, on average the apical region of the LV achieved 20% of filling prior to the basal region. The mean difference between th e points in the cardiac cycle at which the apical and basal regions achieved 20% of filling represented 1.8% of the cardiac cycle. This difference in time to 20% filling between the apical and basal region was not statistically significant (P value=0.186). Differences in LV Systolic Groups In the 21 patients with a normal pattern of systolic events, parameters of LV filling occurred earlier in the apical region as compared to the basal region. On average the apical region reached 10% of filling 57msec earlier than the basal region. This

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17 difference represented 7% of the cardiac cycle (P value<0.001). Also, on average the apical region reached 20% of filling 28msec earlier than the basal region. This difference represented 3.5% of the cardiac cycle (P=0. 011). In the 4 patients with an abnormal pattern of systolic events parameters of LV filling occurred earlier in the basal region as compared to the apical region. On average the basal region reached 20% of filling 57msec earlier than the apical re gion This difference represented 6.9% of the cardiac cycle (P value= 0.043). Similarly, on average, in these 4 patients, the basal region achieved 10% of filling 40 msec earlier than the apical region. This difference represented 4.4% of the cardiac cycle, but was not statistically significant (P value=0.317). The mean difference between the points in the cardiac cycle at which the apical and basal regions reached 10% of filling was different between the patients with a normal pattern of systolic events and those patients with an abnormal pattern of systolic events (P value=0.001). Also, the mean difference between the points in the cardiac cycle at which the apical and basal regions reached 20% of filling was different between the patients with a norm al pattern of systolic events and those patients with an abnormal pattern of systolic events (P value=0.006). Figure 31 summarizes the mean difference between the points in the cardiac cycle at which the apical and basal regions reached 10% and 20% of fil ling. Table 31. Patients baseline characteristics Normal systolic pattern Abnormal systolic pattern P value n 21 4 Average age (years) 57.75 62.13 0.61 Average EF (%) 59.33 45.38 0.051 Average QRS duration (msec) 96.5 111 0.12 Proportion m ale 62 % 50%

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18 Table 32. Analyzed v ariables for all p atients Patient ID % cycle at which a pex r eaches 10% filling % cycle at which base reaches 10% filling Time (msec) at which apex reaches 10% filling time at which base reaches 10% filling % cycle at whic h apex reaches 20% filling % cycle at which base reaches 20% filling Time (msec) at which a pex reaches 20% filling time at which base reaches 20% filling Overall EF Apical EF Basal EF Gender Age (years) RR interval (msec) Diastolic time (msec) QRS (mse c) 49 0.063 46.99296 0.052 38.78784 80 79.2703 54.849 f 20.40 745.92 497.28 90.00 76 0.015 9.3744 0.02 12.4992 63 91.3635 51.6023 m 39.60 624.96 390.60 90.00 63 0.067 61.68288 0.005 4.6032 70 84.2759 45.4644 m 44.90 920.64 690.48 76.00 14 0.085 74.3376 0.015 13.1184 68 88.5694 67.4838 f 75.70 874.56 546.60 90.00 26 0.01 6.4128 0.01 6.4128 67 87.7005 62.3254 f 57.50 641.28 427.52 86.00 18 0.075 67.968 0.02 18.1248 62.5 78.658 41.3923 m 47.90 906.24 641.92 96.00 44 0.083 73.46496 0.023 20.35776 63 75.2865 53.3275 m 69.60 885.12 590.08 80.00 66 0.105 78.3216 0.123 91.74816 67 85.3534 52.5597 m 64.40 745.92 466.20 84.00 71 0.148 88.23168 0.018 10.73088 68 89.7014 53.7321 m 59.30 596.16 397.44 84.00 48 0.093 98.58 0.083 87.98 62 75.2484 37.3792 f 71.50 1060.00 706.40 84.00 94 0.002 1.80288 0 0 62.5 83.4856 67.1661 f 52.00 901.44 600.96 96.00 75 0.02 15.7248 0.003 2.35872 62.5 94.2314 57.8928 m 63.60 786.24 589.68 135.00 23 0.005 4.1472 0.038 31.51872 62 90.092 53.4953 m 64.90 829.44 518.40 82.00 80 0.0155 13.42176 0.03 25.9776 57.5 40.207 31.7582 f 66.20 865.92 577.28 114.00 65 0.02 15.5904 0.007 5.45664 46 73.3309 48.3133 f 43.70 779.52 519.68 118.00 95 0.078 73.15776 0.09 84.4128 49 63.22 65.3563 f 64.80 937 .92 664.36 96.00 99 0.132 99.85536 0.132 99.85536 54 84.9345 18.1537 m 54.60 756.48 535.84 106.00 20 0.105 87.7968 0.072 60.20352 44 62.9898 29.3853 m 83.10 836.16 487.76 118.00 42 0.125 131.04 0.117 122.65344 43 73.9832 43.0926 f 70.20 1048 .32 653.88 90.00 29 0.1075 94.944 0.0075 6.624 52 74.6158 43.1624 m 68.30 883.20 552.00 100.00 60 0.05 27.552 0.028 15.42912 66 73.9581 34.8153 m 26.10 551.04 183.68 88.00

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19 Table 32. Continued. Patient ID % cycle at which apex reaches 10% fillin g % cycle at which base reaches 10% filling Time (msec) at which apex reaches 10% filling time at which base reaches 10% filling % cycle at which apex reaches 20% filling % cycle at which base reaches 20% filling Time (msec) at which apex reaches 20% filling time at which base reaches 20% filling Overall EF Apical EF Basal EF Gender Age (years) RR interval (msec) Diastolic time (msec) QRS (msec) 74 0.127 103.0224 0.11 89.232 57.5 46.7753 51.9428 m 54.80 811.20 574.60 110.00 58 0.187 123.15072 0.155 102.0768 26 22.8115 13.2367 m 69.30 658.56 439.04 120.00 9 0.037 23.72736 0.06 38.4768 22 16.34 29.7243 m 77.10 641.28 320.64 138.00 1 0.007 7.17696 0.016 16.40448 53 35.7876 36.9613 f 51.80 1025.28 512.64 100.00

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20 Figure 31. Mean differenc e between points in the cardiac cycle (in %) at which the apical and basal regions reached 10% and 20% of filling.

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21 CHAPTER 4 DISCUSSION Our results suggest that in patients with a normal pattern of LV systolic function, in which the apical systolic c ontraction is more vigorous then the basal systolic contraction, the apical LV region achieves parameters of early LV filling prior to the basal LV region. Further, our results suggest that in patient s with an abnormal pattern of LV systolic function, in w hich the basal region has a more vigorous systolic contraction, the basal LV region achieves parameters of early LV filling prior to the apical LV region. T ogether these findings support the concept that events in systole contribute to changes in the patte rn of filling during early LV filling Specifically, these findings suggest that the region of the LV with the most vigorous systoli c contraction will fill earliest. This process is likely explained by the fact that during systole potential energy is stored This stored energy allows for the deformation of the LV during diastole and creates a decrease in intra ventricular pressure. In patients with a normal pattern of LV systolic function, the most vigorous region of the LV is the apex. Therefore, the apex has the greatest decrease in intra ventricular pressure during isovolumic relaxation and early diastole. After mitral valve opening there is a suction of blood toward the apex This theory of diastolic suction is support ed by research which demonstrates a declining pressure within the apical region of the LV and documents the movement of blood toward the apex during is ovolumic relaxation and early LV filling ( 5, 1011). By demonstrating that the apical region achieves parameters of filling earlier then the basal region, our described method of quantifying LV regional filling may allow for a universal means of measuring the effects of intact diastolic suction.

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22 Additionally, o ur method of quantifying LV regional filling may allow for improved classification of LV function. Figure 41 displays the filling patterns of two patients with normal echocardiographic parameters of global LV systolic and diastolic function. Patient As apical region achieves early filling parameters prior to the basal region, whereas Patient Bs basal region achieves early filling parameters prior to the apical region. Quantification of r egional filling patterns may improve classification of LV dysfunction. This improved classification may allow for personalized selection and follow up of pharmaceutical, mechanical and electrical interventions. Our findings that systolic events correlate with events in diastole are supported by recently published research. Systolic longitudinal and radial strain, at rest and after exercis e, w ere significantly lower in patients with diastolic heart failure as compared to healthy controls (12). Additionally, systolic apical rotation, at rest and after exercise, was significantly lower in patients with diastolic heart failure as compared to health y controls (12 ). Similarly, Wang et al. demonstrated a reduction in longitudinal and radial systolic strain in patients with diastolic heart failure as compared to healthy controls ( 13 ). Limitations and Future Directions Future efforts can over come the limitations of our study The sample size for our current analysis is small. Our results should be confirmed with a prospective analysis that would include normal volunteers as well as patients with defined systolic and diastolic LV abnormalities. The retr ospective design of our study prevented the determination of symptom classification at the time of cardiac imaging. We expect that patients with abnormal diastolic suction, as suggested by an abnormal regional filling pattern in which the basal region of the LV achieves filling prior to the apex, would be more likely to have elevated left atrial and pulmonary venous pressures. Therefore, we

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23 suspect that patients with abnormal regional filling patterns would be more likely to have a worse symptom cl assification. A prospective cohort study could help determine the correlation of regional filling patterns with symptom classification in addition to symptom progression and incidence of hospitalization. Our method of measuring volume has two lim itati ons. First, our measurements of volume are based on short axis images only and do not include long axis images. T hese short axis images are obtained at set positions in the thorax with no ability to account for through plane movement of a LV region. Theref ore, our technique has limit ed appreciation of long axis components of volume change. This limitation could ultimately be overcome by full volume acquisiti on, using technologies such as 320 slice computed tomography or newer echocardiographs. These non MR I based modalities would also allow analysis of the effects of right ventricular and left ventricular pacing on regional filling patterns. Second, our measurements depend on accurate determination of the endocardial border In certain patient s images this determination is challenging and subjective. This limitation could be overcome by improved automated endocardial border detection techniques Our study suggests that the pattern of apical and basal systolic function correlate with the pattern of reg ional LV filling. Identifying the pattern of apical and basal systolic function may therefore be an important aspect of a patient s evaluation. Our evaluation of the systolic pattern of the LV was limited to the determination of the apical and basal regional EF. M ore sophisticated techniques such as those with strain imaging might lead to a more detailed understanding of the pattern of systolic events that contribute to a normal pattern of regional LV filling. Specifically, determination of the relative

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24 strength and timing of apical and basal longitudinal, radial, and circumferential strain and twist could lead to a more advanced understanding of the appropriate pattern of systolic events. Our defined parameters of filling were limited to the point in the cardiac cycle at which a given region achieved 10% or 20% of filling. These discrete measures of filling were selected arbitrarily with the hopes of serving as an appropriate parameter of early LV filling The most clinically relevant parameter of filling is currently unknown. Longitudinal comparison of the entire apical and basal filling curves may be more relevant then assessment of the discrete parameters evaluated in this study. Conclusions Our study suggest s that events in systole contri bute to changes in the pattern of LV filling during early diastole. Further, in patients with a normal pattern of LV systolic function the apical LV region achieves parameters of early LV filling prior to the basal LV region. Our results support the evolv ing concept that normal LV filling includes suction of blood toward the apex after mitral valve opening. We suspect that this suction of blood toward the apex is dependent on the storage of potential energy at the apex during systole. Understanding the tim ing of an individuals regional LV filling provides improved classification of the mechanical deficits of that individual. Understanding the specific mechanical deficits of an individual may allow for personalized selection and follow up of pharmaceutical, mechanical and electrical interventions.

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25 Figure 41. Two patients with normal echocardiographic parameters of global LV systolic and diastolic function but different regional filling patterns.

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26 LIST OF REFERENCE S 1. Bhatia RS, Tu JV, Lee DS, et al. Outcom e of Heart Failure with Preserved Ejection Fraction in a PopulationBased Study. N Engl J Med 2006; 355: 260 9. 2. Helmes M, Trombitas K, Granzier H. Titin Develops Restorinng Force in Rat Cardiac Myocytes. Circ Res 1996; 79:61926. 3. Bell SP, Myland L, Tisch ler Md, McNabb M, et al. Alteration in the Determinates of Diastolic Suction During Pacing Tachycardia. Circ Res 2000; 87:235 240. 4. Goffinet C, Chenot F, Tobert A, et al. Assessment of Subendocardial vs. Subepicardial Left Ventricular Rotation and Twist U sing Two Dimensional Speckle Tracking Echocardiography: Comparison with Tagged Cardiac Magnetic Resonance. European Heart J ournal 2009; 30: 608 617. 5. Yotti R, Bermejo J, Antoranz C, et al A Noninvasive Method of Assessing Impaired Diastolic Suction in Pat ients With Dilated Cardiomyopathy. Circulation 2005; 112: 2921 29. 6. Rademakers FE, Buchalter MB, Rogers WJ, Zerhouni EA, Weisfeldt ML, et al. Dissociation between left ventricular untwisting and filling. Accenutation by catecholamines. Circ ulation 1992; 85: 1572 1581. 7. Sengupta PP, Khandheria BK, Korinek J, Wang J, et al. Apex to Base Dispersion in Regional Timing of Left Ventricular Shortening and Lengthening. J Am Coll Cardiol 2006; 47: 163 72. 8. Sengupta PP, Krishnamoorthy VK, Korinek J, Narula J, Vannan MA, Lester SJ, et al. Left Ventricular Form and Function Revisited: Applied Translational Science to Cardiovascular Ultrasound Imaging. J Am Soc Echocardiog 2007; 20: 539 551. 9. Notomi Y, Nartin Miklovic MG, Oryszak SJ, Shiota T, Deserranno D, et al. Enhanc ed ventricular untwisting during exercise: a mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Ci rc ulation 2006; 113: 25242533. 10. Greenberg NL, Vandervoort PM, Firstenberg MS, Garcia MJ, Thomas JD. Estimation of diastolic in traventricular pressure gradients by Doppler M mode echocardiography Am J Physiol 2001;280: H2507 H2515. 11. Sengupta P, Khandheria B, Korinek J et al. Left Ventricular Isovolumic Flow Sequence During Sinus and Paced Rhythms: New Insights From Use of HighRe solution Doppler and Ultrasonic Digital Particle Imaging Velocimetry. J Am Coll Cardiol 2007; 49: 899 908. 12. Tan YT, Wenzelburger F, Lee E, et al. The Pathophysiology of Heart Failure With Normal Ejection Fraction. J Am Coll Cardiol 2009; 54:36 46.

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27 13. Wang J Khoury DS, Yue Y, et al. Preserved Left Ventricular Twist and Circumferential Deformation, But Depressed Longitudinal and Radial Deformation in Patients With Diastolic Heart Failure. Eur Heart J 2008; 29: 1283 1289.

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28 BIOGRAPHICAL SKETCH John William Pet ersen, M D was born in 1979 in Chicago, Illinois. He graduated from Bishop Verot High School and then enrolled at the University of Florida. He was accepted into the Junior Honors Medical P rogram, a combined seven year B.S. and M .D. program. He was awarded his B.S. in i nterdisciplinary b asic m edical sciences in 2001 and his M.D. in 2004. He completed his internal medicine residency training at Duke University in 2007. He is scheduled to complete his cardiology fellowship training at the University of Flori da in June 2010. Johns current research focuses on the use of noninvasive imaging techniques to advance the understanding of normal and abnormal LV mechanics. John is married to Kimberly Register Petersen and has two daughters Kendall Joy and Kylee Grace.