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HEMODYNAMIC PARAMETERS OF PATIENTS WITH TREATED
HYPERTENSION AND CORONARY ARTERY DISEASE
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
This dissertation is dedicated to my brother, Beau, who has been my best friend since as
long as I can remember and also to my lovely wife, Jen, without whom I would be much
more annoying and not have eaten nearly as well as I have this past year.
I gratefully acknowledge my doctoral committee, Carolyn Yucha, James Jessup,
Eileen Handberg, and Randy Braith. Without their support, instruction, and guidance,
this dissertation would never have existed. I also acknowledge Houssein Yarandi for his
advice on statistical analysis. A final acknowledgement goes to my family, my parents,
and my lovely wife, Jen.
TABLE OF CONTENTS
A C K N O W L E D G M E N T S ................................................................................................. iv
LIST OF TABLES ......... ... ............. .. ...... ... .............. ............ .. vii
LIST OF FIGURES ..................... .......... .................................. viii
ABSTRACT .............. ......................................... ix
1 IN TR O D U C TIO N ........................ .... ........................ ........ ..... ................
Background and Problem Statement................................................................. 1
Purposes of the Study .................................................. .... .. .......... 3
H y p o th e se s ....................................................................... 4
D definition of Term s ........................................................ .............. 4
L im itatio n s ....................................................................... 5
Significan ce of th e Stu dy ................................................................................. ..... 6
2 LITER A TU R E R EV IEW ............................................................. .....................8
D ilem m as in BP m easurem ent.......................................... .......................... 8
History of blood pressure measurement ..................................... .............. 11
C cardiovascular D disease ........................................................................... 23
Sphygm ocardiography ....................................................................... 29
S u m m a ry ..................................................................................................... 3 3
3 PROCEDURES AND METHODS.................................... ........................ 35
D e sig n ..................................................... 3 5
Population and Sam ple ................................................ ............................. 35
S ettin g .................. ........ .................................................................... 3 7
Research Variables and Instruments .......................................... ............. 38
S tu dy P roto co l .............................................................................. 4 3
M ethods of Statistical A nalyses..................................... ......................... ........ 48
4 R E SU L T S ........................................... ............................ 49
Descriptive Results ......................................... ............... 49
A nalytic R results ................................................ ........ .............. .. 50
5 DISCUSSION AND CONCLUSIONS ...................................... ............... 63
D iscu ssion of R esu lts ................................................... .............. ................ .. 6 3
Conclusions............................. ............ 69
Im plications for Clinical Practice ........................................ ..................... 70
Recom m endations for Further Research ............................................................ 73
S u m m a ry ..................................................................................................... 7 4
E m erging T rends......................... ...... ..... .. ........ ............. .. 75
Cost of Entry: A Final Word on Applanation Tonometry and ABP.................... 76
A CONSENT DOCUMENT .......................................................................79
B ABP D IAR Y ................................................... ........... ............85
REFERENCES ................... ......... .. ...... ... ..................87
B IO G R A PH IC A L SK E TCH ..................................................................... ..................94
LIST OF TABLES
2-1: JNC VI Recommendations for Blood Pressure Measurement.............. .....................14
4-1: Demographic Summary by INVEST Group and Total ...........................................51
4-2: M education Usage for INVEST ABP Substudy ............................... ............... .53
4-3: Summary Statistics for Clinical M easurements .............. ............ .....................54
4-4: Comparison of Means 2SE for Clinical, Central, and Ambulatory Measurements 56
4-5: Estimated Difference Between Daytime and Nighttime Measures............................58
4-6: Mean + 2SE for Central Hemodynamic Blood Pressures .......................................60
4-7: Mean Difference between NCAS and CAS Arms of INVEST..............................62
LIST OF FIGURES
3-1. Calculation of the augmentation index. ................................................................... 40
3-2. Calculation of SEVR from recorded radial pulse wave. .........................................41
3-3. ABP Spreadsheet with directly copied ABP data..................... ............................ 47
3-4. ABP Excel Spreadsheet after parsing .............................................. ............... 47
4.1 Scatter matrices for Systolic, Diastolic, Mean, and Pulse pressures. ........................55
4.2. Relationship of peripheral and central measures ................................ .. ...............61
4.3. Relationship of AI to AI normalized for HR ...........................................61
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
HEMODYNAMIC PARAMETERS OF PATIENTS WITH TREATED
HYPERTENSION AND CORONARY ARTERY DISEASE
Chair: Carolyn B. Yucha
Major Department: College of Nursing
Central elastic arteries are very different from the more peripheral muscular arteries.
It has long been argued that the research and management of hypertension should not be
based on blood pressures (BP) measured in the brachial artery (a muscular artery).
Moreover, BP is a dynamic physiologic function that changes with the demands placed
on the body and mind throughout the day. It has been argued that ambulatory BP
(average of multiple BP readings over the course of a given period-usually 24 hours) is
a better assessment of true BP than traditional clinic BPs. The purpose of this study is to
demonstrate the differences, if any, among BPs measured by conventional methods,
ambulatory BP, and aortic blood measured noninvasively by applanation tonometry and a
generalized transfer function. BP measurements using all three techniques were taken on
30 subjects from the INternational VErapamil/TRandolapril STudy (INVEST).
There is a highly linear relationship between central and clinic BPs in regards to
systolic BP, diastolic BP, mean arterial BP, and pulse pressure (PP). Systolic BP and PP
are significantly different using the two methodologies. It is not known whether central
BP changes linearly with changes in clinic pressure. There was no difference between
ABP and clinic BPs, which demonstrated a weak but significant linear relationship. A
significant drop in nocturnal BP was demonstrated, but the drop was not large enough to
classify the subjects as dippers. No conclusions could be made about differences
between the INVEST treatment groups due to the small sample size. Systolic
augmentation by wave reflection accounted for more than 30% of systolic pressure. The
increased pressure was not likely to cause subendocardial ischemia according to the
average subendocardial viability ratio.
This was the first study that assessed both ambulatory BP and noninvasively measured
central hemodynamic parameters. Areas of both technologies are identified that will help
future studies to avoid certain pitfalls. The largest area for improvement is in the
database systems that each device uses to store subjects' results. The largest barrier to
widespread use in either clinical or research settings remains price.
This chapter introduces the main variables under investigation including pulse wave
velocity, aortic wave reflection, arterial elastance, applanation tonometry, and ambulatory
blood pressure. It states the background and main research problem to be investigated as
well as the hypotheses to be tested. The definitions of the major terms, assumptions,
limitations, and significance of the study also are described.
Background and Problem Statement
Traditional hypertensive theory has been that increased peripheral resistance caused
elevated blood pressure (BP). Diastolic pressure was seen as the direct reflection of
peripheral resistance, while elevated systolic pressure was seen as the sign of a healthy
and vigorous heart (Nichols & Edwards, 2001; Nichols & O'Rourke, 1998). Thus, most
hypertension treatments and research studies targeted diastolic pressure. Ironically, the
treatments studied-diuretics and beta-blockers-lowered diastolic BP, not by targeting
peripheral resistance, but by decreasing preload and contractility. Their efficacy was
established in reducing mortality, even though the mechanism did not fit the theory. In
time, it became apparent that low diastolic pressures were not desirable (Benetos et al.,
2000; Cruikshank, 1992; Franklin, Khan, Wong, Larson & Levy, 1999) and that elevated
systolic pressure was not the benign sign of a vigorous heart as it was thought to be. Two
other classes of antihypertensive drugs that did not have the benefit of large clinical trial
evidence-angiotensin converting enzyme inhibitors (ACE Inhibitors) and calcium
channel antagonists-began to be seen as effective due to their theoretical models of
action (Nichols & O'Rourke, 1998).
Recent years have shown the first results of large clinical trials with ACE Inhibitors to
be overwhelmingly positive in their benefits not only for patients with hypertension but
with other cardiovascular risk factors such as diabetes, renal disease, and heart failure
(Song & White, 2002). Meanwhile, there had been no published data from large clinical
trials comparing calcium channel antagonists to beta blockers in patients with coronary
artery disease and hypertension; previous trials had studied either beta blockers or
calcium antagonists alone versus placebo. With this in mind, the INternational
VErapamil/Trandolapril STudy (INVEST) was designed to compare the effect of the two
strategies for BP control-calcium antagonist based versus noncalcium antagonist based
therapy-on mortality and morbidity in patients with both coronary artery disease and
hypertension (Pepine et al., 1998). (During the investigation period of INVEST, the
results of the ALLHAT study showed no difference in mortality between patients initially
treated with either an ACE inhibitor, diuretic, or dihydropyridine calcium channel
blocker [ALLHAT Collaborative Research Group, 2002; Kaplan, 2003].) Patients in
INVEST have been randomized to one of two treatment strategies. One is calcium-
antagonist based, while the other is noncalcium channel-antagonist based. Both
strategies provide three medications to be used in a stepped care approach to achieve
Joint National Committee for the Prevention, Detection, Evaluation, and Treatment of
Hypertension goals for hypertension treatment (JNC VI, 1997). The calcium channel
antagonist based strategy started with verapamil SR, followed by the ACE inhibitor
trandolapril, and if BP was not controlled with the two-drug combination, a thiazide
diuretic, HCTZ, could be added. The noncalcium antagonist strategy started with the
beta blocker, atenolol, followed by HCTZ. IfBP was not controlled, then trandolapril
Although patients are being treated and monitored according to JNC VI standards,
there is growing understanding in the scientific and medical community that traditional
BP measurements are not the best way to diagnose or treat hypertension. Ambulatory
blood pressure (ABP) measurements are 3 times more reproducible than traditional BP
measurements, more highly correlated with target organ damage, and allow for
measurement of BP and heart rate (HR) throughout the day and night (Mancia & Parati,
2000). Applanation tonometry allows for the estimation of aortic BP and measurements
of arterial elastance, which are highly correlated with mortality and myocardial damage
(Nichols & Edwards, 2001; Nichols & O'Rourke, 1998).
With these differences in mind, this study was undertaken with a subpopulation of
INVEST subjects to compare these BP methodologies. INVEST patients have two clinic
blood pressures taken with the traditional cuff measurements at every visit. The subjects
of this study wore an ambulatory BP monitor that takes measurements every 20 minutes
for a 24-hour period and arterial tonometry measurements were taken. For the BPs of the
three methodologies-traditional clinic BPs, ABP, and tonometry-derived measures-
various measures of arterial elastance are reported for the substudy population as a whole.
Purposes of the Study
The purposes of the study are as follows:
1. To determine the difference between the clinic measurements, ABPM
measurements, and calculated central BPs in patients participating in the
2. To determine the circadian systolic and diastolic BP parameters of INVEST
3. Characterize the central hemodynamic parameters for patients participating in
INVEST augmentation index and of patients participating in INVEST.
4. To compare the two treatment strategies in INVEST in terms of differences
between 24-hour, daytime, and nighttime BP values and BP variability.
The following hypotheses are investigated in this dissertation:
Hypothesis 1: There is no difference between clinic BP, ambulatory BP, and
calculated aortic BP.
Hypothesis 2: There is no difference between Daytime and Nighttime values for
systolic and daytime blood pressures.
Hypothesis 3: There are no differences between the two treatment strategies in
INVEST in terms of differences between daytime and nighttime BP
values and BP variability.
Definition of Terms
Ambulatory Blood Pressure (ABP)
Ambulatory blood pressure is defined as the average of a number of BP readings taken
throughout a given time period while the subject goes about his or her daily activities. A
small automatic oscillometric BP monitor is worn for a length of time (24 hours for this
study), and brachial measurements are taken at regular intervals (every 20 minutes)
(Yucha, 2001). These may be reported as awake, asleep, and 24 hour SBP and DBP.
Aortic Wave Reflection Amplitude
In this study, radial pulse waves were obtained via applanation tonometry and aortic
pressure waveforms were then derived using a transfer function. Augmentation Index
(AIx) was calculated as an index of aortic wave reflection amplitude (Kelly, Hayward,
Avolio, & O'Rourke, 1989). As arterial elastance increases, AIx increases.
Aortic Blood Pressure
BP in the ascending aorta can only be measured directly by using invasive methods.
For this study aortic BP is estimated using applanation tonometry and a validated
generalized transfer function (Pauca et al., 2001).
Augmentation Index (AIx)
The augmentation index is the proportion of systolic pressure due to wave reflection.
It is measured as the difference between the systolic peak and the pressure at the first
inflection point of the pulse wave contour divided by the pulse pressure and is expressed
as a percentage.
Subendocardial Viability Ratio (SEVR)
The subendocardial viability ratio is the ratio of mean diastolic pressure times diastolic
duration divided by mean systolic pressure times systolic duration (Buckberg, Fixler,
Archie, & Hoffman, 1972a). It is a measure of how well the subendocardium can be
perfused by hemodynamic parameters. In this study SEVR is estimated as the integral of
the aortic pressure wave under diastole divided by the integral of the same wave under
systole (Nichols & O'Rourke, 1998).
The primary limitation of the proposed study is its observational nature. While the
patients studied are participating in a randomized controlled clinical trial, all patients
have been randomized to their treatment group at least one and a half years prior to data
collection. This precludes the collection of baseline data for ambulatory BP and
tonometry-derived hemodynamic parameters. Thus, while comparisons can be made
between the two groups, conclusions as to the nature of the changes under treatment
cannot be verified.
The second limitation of the study is geographical in nature. INVEST is an
international, multi-site study, but to carry out ABP and tonometry measurements on all
22,576 patients would prove prohibitively expensive and is probably unnecessary. Thus,
this study was limited to the geographical area of Gainesville, FL, and surrounding areas.
Significance of the Study
Cardiovascular disease is the leading cause of morbidity and mortality in the Western
nations (American Heart Association [AHA], 2001). Additionally, it has been the
leading cause of mortality for Americans since 1900, except for 1918-when the leading
cause of death was World War I. In 1999, coronary artery disease claimed the lives of
almost a million Americans. More than 12 million Americans have coronary artery
disease, and more than 6 million have angina pectoris, that is, chest pain caused by
coronary ischemia. High BP is associated with or is a contributing factor to vascular
diseases such as coronary artery disease, stroke, heart failure, and kidney disease (Mancia
& Parati, 2000). Twenty-five percent of American adults and 20% of all Americans (50
million) have hypertension (AHA, 2001). In the year 1999, hypertension was the primary
cause of death of 42,000 Americans and listed as the primary or contributing cause of
death for 200,000 more Americans.
However, various methodologies used to measure BP often do not correlate with each
other or with organ damage (Mancia & Parati, 2000). The need to accurately assess BP
and its relationship to disease processes is vital to both the management of hypertension
and the research that assesses hypertension's relationship to the different diseases. This
study compared three different methods of BP assessment in patients with both coronary
artery disease and hypertension who are currently being treated according to JNC-VI
(1997) guidelines. Furthermore, this study also collected additional hemodynamic
parameters, which may be useful in interpreting the results of the larger clinical trial. The
HOPE study (Ramipril) showed that reductions in BP of only 2-3 mmHg dramatically
reduced mortality rate (Dagenais et al., 2001). Traditional theory cannot explain this
improvement, although elastance and wave reflection improvements might be able to.
However, the HOPE study used cuff-based clinic measurements and did not measure
augmentation index, ambulatory BP, or calculated aortic BP, so valuable data were lost.
This study represents the only collection of augmentation index and calculated aortic BP
in INVEST patients.
Furthermore, in their meta-analysis, Mancia and Parati (2000) found that BP
variability is a key indicator of cardiac damage and mortality. The medical field is
moving toward once-daily dosing medications because of convenience to the patient and
adherence issues (Claxton, Cramer, & Pierce, 2001; JNC VI, 1997). The collection of
ambulatory BP may allow an assessment of the efficacy of the once-daily dosing
medications used in INVEST.
This chapter presents a literature review of the following areas of research: BP
measurement-dilemmas and history-including ambulatory blood pressure and
ambulatory blood pressure monitoring as well as the noninvasive measurements of aortic
blood pressure; pulse wave velocity; wave reflection amplitude; and subendocardial
viability ratio by pulse wave analysis, cardiovascular disease, coronary perfusion, pulse
wave contour, large artery elastance, and vascular-ventricular interaction. A summary
linking these areas together to provide the research rationale for this study 1 concludes
Dilemmas in BP Measurement
There are four central dilemmas concerning blood pressure measurements. The first is
whether the measurement methodology is continuous or intermittent. The second is
whether the method is invasive or noninvasive. The third is whether the measurement
site is central or peripheral. The weaknesses and benefits inherent to the various
methodologies are discussed. The fourth is not a question of methodology but of
interpretation of the measurements. Each of these dilemmas is examined along with three
common noninvasive methods of blood pressure measurement.
Continuous vs. Intermittent
The first dilemma of blood pressure-continuous versus intermittent measurement-
concerns the quality and quantity of information obtained. Because the human body is
not a static entity, the dynamic nature of blood pressure cannot be captured in a single
reading. The heart generates pressure by pumping, which provides a pulsatile wave
through the arteries. Continuous methods can provide information about the contour of
the entire pulse wave, while intermittent measurements only provide information about
the peak and trough values (Drzewiecki, Melbin, & Noordergraaf, 1983). Peak and
trough values are systolic and diastolic pressures respectively; mean pressure and pulse
pressure can be interpolated. The quantity of information concerns the body's cyclical
nature. Blood pressure varies with circadian rhythm in response to varying amounts of
endogenous biochemicals. Therefore, a blood pressure measurement, whether taken
continuously or intermittently, does not provide a full picture of blood pressure load,
unless taken for a 24-hour period. Thus, 24-hour monitoring provides a more complete
and accurate representation of the body's circadian blood pressure load (Mancia & Parati,
Invasive vs. Noninvasive
The second issue concerns the invasiveness of the methodology. Invasive blood
pressure measurement is the gold standard by which all other methods are compared (Bos
et al., 1992; Drzewiecki, Melbin, & Noordergraaf, 1983). It involves placing a probe into
the lumen of the artery in question and directly measuring the hydrostatic forces present.
In addition to monitoring blood pressure directly, invasive blood pressure measurement
can be used to measure both peripheral and central pressures. Invasive methods also
have the advantage of being able to record the entire pulse wave. Thus, invasive blood
pressure measurement provides the most reliable and complete information possible to
clinicians and researchers. However, because of the increased risk for infection, embolic
events, hemorrhage, and pain associated with intra-arterial techniques, invasive
methodologies have substantial disadvantages as well. Furthermore, invasive techniques
require expensive equipment and highly trained personnel, resulting in significant cost.
Therefore, despite the enormous benefits of invasive measures, quick and accurate
noninvasive blood pressure measurements are highly desired (Noordergraaf, 1978).
Central vs. Peripheral
The third issue involves the location of the measurements. Peripheral measurements
are often used because they are more convenient. However, peripheral arteries are
inherently muscular, whereas the central arteries are more elastic, causing pressure
amplification in the peripheral arteries (Nichols & O'Rourke, 1998). Moreover, due to
their muscular nature, peripheral arteries do not have a large change in elastance with
age, while the elastance (stiffness) of central arteries tends to increase with age, changing
the peripheral/central pressure gradient. Because of the changing gradient and wave
reflections with age, central pressures are more closely related to aortic stiffness, a
predictor of mortality (Laurent, Boutouyrie, Asmar, Gautier, Laloux, Guize, Ducimetiere,
& Benetos, 2000). Accordingly, central pressures have greater relation to heart disease
than peripheral measurements (Waddell, Dart, Medley, Cameron, & Kingwell, 2001) and
are more useful in the assessment of cardiovascular risk.
Which Parameter Is the Most Useful?
The final dilemma is a question of interpretation. Blood pressure measurements yield
a variety of parameters such as systolic, diastolic, and pulse pressure. Additionally,
continuous methods record the contour of the pulse wave generating even more
parameters. With all the information that can be obtained from a given blood pressure
measurement, the following questions concerning the relationship of these parameters to
actual clinical outcomes should be considered:
1. Which parameter is most important in the prediction of mortality and
2. Which parameter should antihypertensive therapies target?
Historically, it has been thought and widely accepted that diastolic blood pressure
correlated most closely with end organ damage (Swales, 2000). This theory, however,
has recently been challenged by new findings suggesting that pulse pressure and systolic
blood pressure are more important indicators of disease in the elderly (Swales, 2000).
The elderly are also more likely to have hypertension than the young. Arterial wall
stiffening offers one explanation for such age-related differences. Unfortunately, arterial
stiffening is not uniform; while it does increase with age, it does not increase uniformly
throughout the body or with regard to gender. For example, aortic elastance increases
with age, while brachial artery elastance does not. In fact in women, brachial artery
elastance actually decreases with age (van der Heijden-Spek, Staessen, Fagard, Hoeks,
Struijker Boudier, & Van Bortel, 2000).
The differences between brachial and aortic artery compliance can seriously confound
the validity of brachial blood pressures as a predictor for organ damage. Moreover, they
emphasize the need for central pressure measurement methodologies. In the meantime,
care must be taken by the researcher to stratify patients according to their age and for the
clinician to treat them accordingly. The younger patient requires therapy targeting
diastolic pressure, while the elderly patient requires therapy targeting systolic and pulse
pressure (Mourad, Blacher, Blin, & Warzocha, 2000).
History of Blood Pressure Measurement
The interpretation of the arterial pulse has been of great importance to both Western
and Eastern medicine from ancient times (Lee & Porcello, 1993; O'Rourke & Gallagher,
1996;). The first graphic recordings of pulse waves date back to the late 1800s. Marey in
Paris and Mahomed in London separately developed sphygmographs capable of
recording a patient's pulse wave but not capable of recording actual pressure. Using his
device, Frederick Akbar Mahomed was able to diagnose asymptomatic hypertension,
describe essential hypertension's natural history, and distinguish between essential and
renal-induced secondary hypertension (O'Rourke, 1992). He noted that essential
hypertension could end in nephrosclerosis and renal failure. With the aid of his
sphygmograph, he described the pulse wave contours of various stages of hypertension
and was able to describe age related changes. One of these first descriptions was the
observation that in patients with hypertension "the tidal wave is prolonged and too much
sustained" (Nichols & O'Rourke, 1998, p. 426). This statement would not be
corroborated fully for almost a hundred years. Unfortunately, Mahomed would die an
early death from typhoid fever at the height of his career in 1885, prematurely ending this
line of scientific and medical inquiry.
Riva-Rocci-Korotkoff Cuff Based Measurement
The other contributor to the demise of the sphygmogram's popularity was the
development of the cuff-based sphygmomanometer. In 1896, Riva and Rocci developed
a cuff-based method of determining absolute systolic pressure. In itself, the Riva-Rocci
technique was not all that useful, but it set the stage for a young Russian named
Korotfoff. In 1905, Sergei Korotkoff used a Riva-Rocci device, consisting of an
inflatable cuff attached to a sphygmomanometer. The cuff encircles the upper arm and is
inflated until it occludes blood flow of the brachial artery. A stethoscope is applied to the
brachial artery just below the cuff. The pressure is released from the cuff. As the cuff
pressure lowers and blood flow returns to the artery, the researcher listens for a pulsing
sound caused by turbulent blood flow. These so-called Korotkoff sounds trail off, as the
cuff pressure reaches the resting pressure of the artery and blood flow becomes laminar.
The beginning of the Korotkoff sounds denotes the systolic blood pressure, and the end
of the sounds denotes diastolic blood pressure. This technique is often referred to as the
Riva-Rocci-Korotkoff (RRK) method (Shevchenko & Tsitlik, 1996).
The RRK method of blood pressure was useful because the equipment needed was not
very expensive and it allowed researchers and clinicians to measure absolute systolic and
diastolic blood pressures. For a while cuff-based measurement complemented
sphygmograms. Sir James MacKenzie warned in his first text (1917) against uncritical
acceptance of cuff-based measurements and short-cuts in scientific reasoning, but the
posthumous publication of the third edition (1926) of his text contained the same
uncritical acceptance of these shortcuts (Nichols & O'Rourke, 1998). Life insurance
companies played a role in popularizing cuff-based measurements by promoting them as
a screening tool. The sphygmogram began to be left behind.
As it became apparent that there were discrepancies in the measurement technique and
reproducibility of cuff-based measurement, several organizations including the AHA and
NIH's National High Blood Pressure Education Program (NHBPEP) released
recommendations to standardize the collection of blood pressure (Perloff et al., 1993);
these recommendations have changed several times since the inception of the NHBPEP
in 1972. The current JNC VI guidelines (1997) are based on the 1993 AHA guidelines
(Perloff, et al). Table 2-1 contains these recommendations.
Any deviation from these guidelines invites errors to blood pressure measurements.
Even if the guidelines are followed, RRK blood pressures are subject to a variety of
errors. Aural acuity and quality of stethoscope are immediately identifiable as potential
sources for error. Additionally, the clinician's mood and perception of the subject may
also influence the blood pressure reading. If the clinician measures an obese or elderly
patient, he may "hear" higher values of Korotkoff signs, while "hearing" lower values for
a small or younger person based on prejudices as to who should have high blood
pressure. Alternatively, if the clinician is in a hurry or has a heavy patient load, he may
interpret the Korotkoff sounds more loosely, allowing higher blood pressures to be
recorded as normal (Cranney, Warren, Barton, Gardner, & Walley 2001).
Table 2-1: JNC VI Recommendations for Blood Pressure Measurement
1. Patients should be seated in a chair with their backs supported and arms supported
at heart level.
2. Patients should not smoke or take caffeine for at least thirty minutes prior.
3. Patients should rest for at least five minutes.
4. The cuff should be of appropriate size. (The bladder should encircle at least 75%
of the circumference of the arm, and the width should be approximately 1/3 the
circumference of the arm.)
5. Two or more readings separated by two minutes should be averaged; if the
readings differ by more than 5 mm mercury, then additional readings should be
taken and averaged (JNC VI, 1997).
The RRK method of blood pressure can be automated, removing many of the above
errors. Automated blood pressure machines have sensors that record the blood pressure
and display it digitally. The clinician then only has to ensure proper cuff size (Alexander,
Cohen, & Steinfeld, 1979) and that the patient has rested and not smoked or ingested
caffeine (JNC VI, 1997). Automated blood pressure machines are currently used
throughout the United States in diverse settings such as hospitals, private practices,
pharmacies, grocery markets, and private homes.
Automated blood pressure machines use one of two different technologies. The first is
an auscultatory technology, in which a mechanical "ear" listens for Korotkoff sounds in
the same way that a human would. The second method is called oscillometric, in which a
sensor measures minute movements in the arm to determine when blood flow begins and
returns to normal. Both methods take most of the subjectivity out of reading blood
pressures. They do, however, introduce new sources of error. Machines must be
periodically calibrated. Auscultatory monitors can be influenced by outside noises, while
external vibrations and arm movements or tremor can influence oscillometric
measurements (Prisant, Bottini, & Carr, 1996).
Ambulatory Blood Pressure
The culmination of RRK blood pressure is ambulatory blood pressure. Instead of
averaging two readings over 2 to 5 minutes, it averages 20 to 50 measurements over the
course of an entire day. Ambulatory blood pressure monitoring (ABP) uses automated
cuff devices to measure blood pressure at a given interval for a specified period of time-
often 24 hours. Monitors are typically small, battery-powered, automatic blood pressure
machines that can be worn while the subject goes about his ordinary daily routine. The
monitor can be programmed to take blood pressure readings at various intervals and
record them in its memory. At the end of the recording session, the blood pressure
monitors are returned to the clinician or researcher who can then download the readings
for analysis (Yucha, 2001). This methodology limits threats to external validity and the
effects on observers of psychological and physiological response. Ambulatory blood
pressure monitoring provides various useful parameters, including the average 24-hour
BP (SBP, DBP, MAP, and PP) and HR, BP variability (the standard deviation of the
average 24-hour, daytime, and nighttime measures), diurnal BP and HR changes (day-
night BP and HR differences), and BP load (percentage of systolic and diastolic readings
greater than 140 and 90 mmHg, respectively, during the day or greater than 120 and 90
mmHg during the night).
In their meta analysis, Mancia and Parati (2000) concluded that the correlation
coefficient between office systolic and diastolic readings and their corresponding 24-hour
averages is rarely greater than 0.5. This discrepancy occurs in patients with normal blood
pressure (normotensives) as well as hypertensive patients. Cross-sectional studies have
shown that 24-hour averages are more closely associated with target organ damage than
office blood pressures. This is true of the heart (left ventricular hypertrophy), kidneys
(proteinuria), brain (cerebral lacunae or white matter lesions identified by magnetic
resonance imaging), and arteries.
In the Hypertension and Ambulatory Recording Venetia Study (HARVEST), the rate
of excretion of albumin was highly related to 24-hour BP (Palatini, 1999). In the
European Lacidipine Study on Atherosclerosis trial (ELSA), the intima-media thickness
of the common carotid artery correlated significantly with average 24-hour SBP (r = .22,
p < .0001), average 24-hour PP (r = .31, p < .0001), 24-hour SBP variability (r = .11, p <
.0001), and 24-hour PP variability (r = .23, p < .0001) (Mancia, Giannattasio, Failla,
Sega, & Parati, 1999). Verdecchia (2000) also indicated that ambulatory SBP, DBP, and
PP were independently and directly associated with cardiovascular risk. The European
Lacidipine Study on Atherosclerosis (Zanchetti et al., 1998) showed in 2,200 patients that
24-hour average systolic blood pressure and pulse pressure are more highly correlated
with carotid intimal wall thickening and number of carotid plaques. Twenty-four hour
average systolic pressure is second only to age in correlation to carotid intima thickness.
The Study on Ambulatory Monitoring of Pressure and Lisinopril Administration
(SAMPLE) (Mancia et al., 1997) showed that left-ventricular hypertrophy regression was
more closely associated with controlled 24-hour averages than with office blood
pressures. Before treatment, left ventricular mass index (LVMI) did not correlate with
clinic BP, but it showed a correlation with systolic and diastolic 24-hour average BP (r =
.34/.27, P < .01). The LVMI reduction was not related to the reduction in clinic BP, but it
was related to the reduction in 24-hour average BP (r= .42/.38, P < .01). Treatment-
induced changes in average daytime and nighttime BPs correlated with LVMI changes as
strongly as 24-hour BP changes. No substantial advantage over clinic supine BP was
shown by clinic orthostatic, random-zero, and home BP. Daytime and nighttime
pressures were also significantly correlated with hypertrophy regression, indicating that a
monitoring period of fewer than 24 hours may be adequate for diagnostic and
management purposes. Finally, the European Study on Isolated Systolic Hypertension in
the Elderly (Staessen, 1999) showed that 24-hour averages are more closely associated
with cardiovascular events than office blood pressures.
Ambulatory blood pressure monitoring can provide more than just 24-hour average
blood pressures. Additional measures that can be obtained include daytime average
pressure, nighttime average pressure, morning rise in blood pressure, and blood pressure
variability. Typically, a decrease in blood pressure is seen at night due to decreased
sympathetic activity and increased vagal tone (Mancia & Parati, 2000). Those subjects in
whom a nocturnal BP reduction (BP reduction from day to night) is 10% or greater are
classified as dippers, whereas nondippers are defined as those who show a reduction in
BP of less than 10% between the day and night (Mallion, Baguet, Siche, Tremel, & de
Gaudemaris, 1999). It has been postulated that the absence of nocturnal BP reduction is
related to more severe target organ damage, either left ventricular hypertrophy or disease
of major arteries, though the data remain inconclusive (Mallion et al., 1999). In the study
by Mallion et al., nondippers had a significantly higher frequency of stroke and higher
urinary excretion of albumin. The degree of nocturnal BP was inversely related to
cardiovascular morbidity (Verdecchia et al., 1997).
May, Arildsen, and Damsgaard (1998) demonstrated that the nocturnal BP reduction
calculated from individually defined day and night times was larger than the fall
calculated from every possible fixed day/night definitions and concluded that the
assessment of the nocturnal BP dipping should be based on individually defined periods
of day and night. Blunting of the nocturnal drop is not necessarily correlated with organ
damage, although severe organ damage may obliterate nighttime decreases. Studies have
shown that nocturnal variation is highly individual, even within diseased populations, and
the results are also mixed with regard to correlating nighttime BP fall with organ damage
(compare Verdechia et al., 1990 & 1993, with Mancia et al., 1995; Omboni, 1998). This
makes the 10% drop classification somewhat arbitrary and supports the view of Nichols
and O'Rourke (1998) and Thomas Pickering (1982) that hypertension is not an absolute
disease but one of magnitude.
Arterial physical properties have also been studied to determine their association with
nocturnal BP reduction. Arterial compliance as indexed by aortic pulse wave velocity
predicts nocturnal SBP reduction in normotensives (Asar et al., 1996). Arterial
compliance, as estimated by pulse wave velocity measurement and its relationship to
nocturnal BP reduction, has been studied in a group of treated hypertensive patients on
hemodialysis (Amar et al., 1997). Results from this study indicated that pulse wave
velocity was significantly higher in nondippers. A stepwise regression analysis further
revealed that pulse wave velocity was one of the independent variables related to the lack
of inverse nocturnal BP reduction.
Despite these data, nighttime blood pressure cannot be considered a reliable indicator
of disease because blood pressure may vary as much as 10 mmHg when the patient is
sleeping with the monitored arm above the level of the heart as compared to when lying
on the other side (Schwan & Pavek, 1989). There is no way to guarantee position of the
monitored arm while sleeping unless a researcher monitors patients while they sleep;
thus, night time average pressure is inherently unreliable. Additionally, the SAMPLE
study found the repetition of ABP measurement in patients on stable therapy or with no
therapy showed a 40% change in dipping status, indicating that the measure is either
nonreproducible or highly influenced by individual sleeping patterns and physiology
(Omboni et al., 1998).
Blood pressure tends to rise in the early morning and corresponds with an increased
incidence of cardiovascular events. However, it is not possible to tell whether morning
rise is causal or coincidental. Theory suggests that attempts to blunt the morning rise in
blood pressure may make successive morning rises in blood pressure even more abrupt
(Mancia & Parati, 2000). Therefore, morning blood pressure is not a useful parameter for
diagnostic or management purposes. Blood pressure variability, on the other hand, has
been highly correlated with organ damage. Of patients with identical 24-hour blood
pressure averages, those with greater variability have consistently suffered greater organ
damage (Mancia & Parati, 2000). However, continuous monitoring must be used to
demonstrate this relationship most accurately.
According Mancia and Parati (2000), ambulatory blood pressure monitoring has
several advantages in addition to its higher correlation to organ damage. First,
measurements are not significantly affected by the white coat effect hypertension
phenomenon. Over weeks or months, ambulatory values are not substantially altered by
placebo. Twenty-four hour average blood pressure values are three times more
reproducible than office blood pressure values. Finally, 24-hour blood pressure
monitoring enables researchers to determine whether a once-daily dosing drug lowers
blood pressure consistently throughout the day and night. Inconsistent lowering may
inhibit organ perfusion and adversely affect organ damage by increasing variability.
Despite the advances in cuff-based measurement, RRK can never reveal more
information about blood pressure than gross systolic and diastolic pressure. Moreover, it
is limited to a peripheral measurement site. Arterial tonometry is a method of recording
arterial pulse waves noninvasively. Tonometry measures the pressure of an artery as it is
deformed between the tonometer and a bony structure. It can measure the pressure and
pulse wave contour of any superficial artery supported by a bony structure, such as radial,
brachial, femoral, and carotid arteries (Drzewiecki, Melbin, & Noordergraaf, 1983). In
theory, tonometry does not need to be calibrated, but in practice "hold down" pressure
needed to deform the artery is not constant from one person to another. Calibration can
take place by the RRK method. It is assumed that diastolic pressure is identical between
brachial and radial measurement sites and that mean arterial pressure is identical between
brachial and carotid sites (Nichols & O'Rourke, 1998). Sato, Nishinaga, Kawamoto,
Ozawa and Takatsuji (1993) found that the JENTOW continuous blood pressure monitor
based on applanation tonometry was highly correlated to intra-arterial pressures, with a
flat response ratio. Beat-to-beat variability was recorded almost perfectly. Slight
limitations were found in recording higher frequency intra-arterial waveforms and during
Valsalva maneuver, but not during tilt-table testing.
While the ability to measure peripheral arterial pressure noninvasively is impressive, it
is of limited usefulness in and of itself. A truly useful application is the generation of a
calculated ascending aortic pulse waveform, but even this would be of limited use if the
transfer function were required to be individualized, because that would require
catheterization in order to approximate aortic pressure noninvasively. So the quest began
to derive a generalized transfer function that would be applicable across a diverse array of
people. At first glance, the idea seems ludicrous. However, in practice, generalized
transfer functions have been remarkably accurate, largely because the errors involved in
biological measurement are relatively large, and the smallest meaningful frequency range
in human pulse waves is also quite large (Nichols & O'Rourke, 1998). Two different
generalized transfer functions have been developed independently (Chen et al., 1996;
Kelly et al., 1989). The process of recording pulse waveforms peripherally and
transforming them to derive an aortic pulse waveform has been christened pulse wave
While there has been some debate as to the validity of calculated aortic blood pressure
using a generalized transfer function (Lehmann, 2001), a recently published study has
shown that for patients with coronary artery disease in need of revascularization, the
comparison of radial to derived aortic blood pressure meets the Association for the
Advancement of Medical Instruments SP10 criteria for validity with regard to mean,
diastolic, systolic, and pulse pressures (Pauca, O'Rourke, & Kon, 2001). Furthermore,
the validity of the derived pressure values was established both under baseline conditions
and under nitroglycerine infusion but was only established while patients were lying
supine. In a separate validation study of 25 healthy subjects, the SEVR measurements
ranged from 119% to 254%; the inter-operator measurement difference was only 2.7%
(s.d. 15.4); and the augmentation index (AIx) by applanation tonometry and PWA has
excellent interobserver reproducibility, with the interobserver measurement difference
being only 2.7% (Seibenhofer, Kemp, Sutton, & Williams, 1999).
Results of a study by Karamanoglu et al. (1993) using a generalized transfer function
in adult humans indicate acceptable accuracy (> 90 %) in generating an aortic waveform
from the pressure wave in the radial or brachial artery. In healthy adult subjects with a
wide age range, Liang et al. (1998) demonstrated that measurement of AIx with
applanation tonometry is highly reproducible and precise, with a correlation coefficient of
.98 between visits and a coefficient of variation of 1.3%.
The reproducibility of AIx measurements via applanation tonometry has also been
tested on subjects with cardiovascular risk factors. Wilkinson et al. (1998) demonstrated
in a group of 33 subjects (12 diabetes, 16 hypertensives, and 5 controls) that PWA using
a radial applanation tonometry is a highly reproducible method for determining AIx.
They observed a low standard deviation for within-observer and between-observer
measurement differences (5.37% and 3.80 %, respectively).
The first experiments with PWA used the carotid artery because there is a closer
agreement between carotid and aortic blood pressures and than between radial and aortic
pressures. However, in practice, carotid measurements proved to be more difficult. The
carotid artery is not well supported by bony structure and measurement can be very
uncomfortable for the patients who described feeling choked; measurements sometimes
also caused coughing reflex. Moreover, external calibration is more difficult with carotid
measurement, because neither brachial systolic nor diastolic can be assumed to be equal
to their carotid counterparts. Thus, radial measurements are more useful because the
radial artery is better supported by bony structure and are more comfortable for the
patient. The assumption that diastolic pressure is equal between brachial and radial sites
is accurate (Nichols & O'Rourke, 1998).
Cardiovascular disease is the leading cause of morbidity and mortality in the Western
nations (American Heart Association, 2001). More than 12 million Americans have
coronary artery disease, and more than 6 million have angina pectoris, that is, chest pain
caused by coronary ischemia. Given its notoriety, coronary circulation is the most
studied system of arteries in the human body (Nichols & O'Rourke, 1998).
Despite the heart's intimate relationship with blood, the myocardium does not receive
any oxygen from the blood that is pumped through its chambers. Rather, the
myocardium's demand for oxygen is met by an elaborate and extensive network of
arteries that enshrine and penetrate the heart's muscle. Many diseases of the heart have
their root cause in myocardial ischemia, that is, an imbalance between myocardial oxygen
demand and coronary blood flow.
Myocardial Oxygen Demand
Myocardial oxygen demand has been divided into three parts: basal energy necessary
for myocyte life in the absence of activity, energy needed for the electrical activation of
muscle, and the energy needed for contraction. Of these components, contraction has
been estimated to take up 60% of total demand. In hypertrophy or exercise the
contractile demand also increases (Nichols & O'Rourke, 1998). Two models of demand
have been developed to help determine the oxygen demand of the working heart. One
model, developed by Suga (1990), focuses on tension development and ventricular
dimensions. The other model, developed by Sarnoff (1958), shows oxygen demand to be
related to pressure generation (tension) and the time under pressure, known as the time-
pressure index or tension-time index (TTI). Buckberg et al. (1972a) showed that the
aortic time-pressure index is an appropriate approximation of ventricular time-pressure
index in most situations but prefer the term systolic pressure time index (SPTI) because
tension is not actually being measured. The SPTI from a peripheral artery, however, is
not an adequate approximation due to differences in pressure augmentation.
Factors Contributing to Coronary Blood Flow
Coronary blood flow is dependant on several factors, including time, pressure
gradient, and artery caliber. The major factor in coronary blood flow is vessel caliber,
especially of the epicardial vessels. The larger coronary arteries have very little to no
resistance in comparison to total coronary resistance. The most common cause of lumen
stenosis is atherosclerosis. Coronary spasm may also completely occlude an artery but is
relatively rare compared to atherosclerosis. Many clinicians dealing with coronary
disease focus on lumen occluding lesions almost exclusively (Nichols & O'Rourke,
1998). A major focus of interventional cardiology is maintaining and restoring coronary
artery lumen diameter. According to the American Heart Association (2001) there were
more than a million angioplasties and more than half a million coronary artery bypass
grafts performed in the United States in 1999. Unfortunately, the focus on artery caliber
often causes clinicians to ignore the other factors of coronary blood flow. Coronary
stenosis and plaques are outside the scope of this study.
Diastolic pressure-time index
The other major determinant of coronary blood flow is time-pressure index under
diastole. Because of the heart's contractile nature, it can only be perfused during
diastole. Blood is compressed out of the myocardial arteries during systole (Nichols &
O'Rourke, 1998). Thus, increasing heart rate reduces the amount of the time the heart
has to perfuse between beats. Increasing the time under systole, as often happens during
heart failure and hypertension, can also result in decreased coronary blood flow. Blood
flow is determined by the pressure gradient between aorta and ventricles during diastole.
If diastolic pressure in the aorta falls or if systolic pressure in the ventricle remains high
longer than usual, coronary artery perfusion is compromised.
This problem is further exacerbated by blood viscosity. At low flow rates, the
viscosity of blood is higher than at high flow rates. Thus, even when the pressure
gradient may be adequate for perfusion, there may not be adequate perfusion because
there is not enough time for the gradient to overcome the higher viscosity of blood. As
with the tension-time index, the diastolic pressure-time index can be measured directly or
approximated from aortic values (Buckberg et al. 1972a; Buckberg, Towers, Paglia,
Mulder, & Maloney, 1972b).
Benetos et al. (2000) reported the results of two French longitudinal studies of
untreated subjects-Investigations Preventives et Cliniques (IPC), studying 15,000 men
for an average of 13 years, and the Paris Prospective Study, following 6,000 men for an
average of 17 years. After adjusting for other major risk factors, those whose diastolic
pressure lowered during the study and whose systolic pressures rose (increased pulse
pressure) had a risk ratio greater than two when compared to those whose blood pressure
remained constant. This suggests that pulse pressure is more important than either
systolic BP or diastolic BP.
The deeper layers of the heart's muscle, the subendocardium, are particularly
susceptible to ischemia for two reasons. The first reason is anatomic in nature. The
major coronary arteries are epicardial and run along the surface of the heart. As arteries
branch from these major vessels to penetrate the myocardium and perfuse the deeper
layers of muscle, they become narrower and offer more resistance. As they penetrate the
subendocardium, the caliber is not only reduced, but also the arteries become fewer in
number with little collateral circulation. There is little collateral circulation in the
subendocardium. The second factor contributing to subendocardial ischemic risk is its
contractile nature. Force generation is greatest in the subendocardium, causing the
compression of blood out of the arteries to be greatest in the subendocardium. This
combination of anatomic and functional factors makes the subendocardium extremely
sensitive to deficits in blood flow (Nichols & O'Rourke, 1998).
The ischemic susceptibility of the endocardium is exaggerated by arterial rarefaction
in hypertension and/or aging. A further complication of hypertension is left ventricular
hypertrophy without concomitant hyperplasia. The end result is that myocytes are larger
and have more oxidative demand; the muscle wall is thicker; and there is no
corresponding enlargement of the coronary system to make up for the increased demand.
The theoretical model of the subendocardium's propensity for ischemia has been
confirmed in experimental models with dogs (Buckberg et al., 1972a) and demonstrated
in humans (Buckberg et al., 1972b). Further, the ratio of diastolic pressure time index to
tension time index has been show to be an accurate indicator of subendocardial risk. As
long as the ratio is close to 1 or above 1, blood flow is not impeded, but when the ratio
falls below 0.7, coronary blood flow is compromised even in the absence of normal
vessels (Buckberg et al., 1972a). This finding was further corroborated by Ganz and
Marcus (1972) who found that nitroglycerine did not relieve angina induced by atrial
More recently, it has been shown that in patients with coronary stenosis diastolic
perfusion time consistently correlates with coronary artery stenosis at the ischemic
threshold throughout five different stress tests (Ferro et al., 1995). Ferro et al. concluded
that at a given degree of stenosis, once compensatory mechanisms are spent, the diastolic
perfusion time becomes the limiting factor in determining the ischemic threshold.
Moreover, patients seemed to be stratified into two groups. Those with greater stenosis
(lumen < 1 mm) required only a slight decrease in diastolic perfusion time to induce
angina, whereas those with less stenosis (lumen > 1 mm) required a significantly higher
reduction in diastolic perfusion time before reaching angina.
While diastolic perfusion time significantly correlated to coronary stenosis and
ischemic threshold, raw heart rate did not correlate with either diastolic perfusion time or
stenosis at ischemic threshold. The underlying reason for this anomaly is that diastolic
perfusion time is determined by heart rate and systolic duration together. At rest, heart
rate strongly correlates with diastolic perfusion time, but at higher heart rates, systolic
duration and heart rate are not necessarily related. This prevents heart rate alone from
being used as a predictor of ischemic threshold (Ferro et al., 1995).
Buckberg subendocardial viability ratio (SEVR)
SEVR = Diastolic Perfusion Time Index
Systolic Pressure Time Index
From the above discussion, it has been established that the Systolic Pressure Time
Index (systolic duration time index) is a reliable and accurate method of approximating
the heart's oxygen demand. The Diastolic Perfusion Time Index is a reliable measure of
the heart ability to perfuse the subendocardium in the absence of coronary stenosis
(Baller et al., 1978). Buckberg et al. (1972a) have shown that the ratio of these two
parameters is indicative of the subendocardium's risk of ischemia, with subendocardial
ischemia apparent at ratios below 0.7 even with normal coronary arteries. It is important
to note that this finding only holds in the case of maximal coronary dilation. If the
coronary arteries are not maximally dilated, then subendocardial flow may be improved
by coronary dilation. There is some confusion in the literature as this relationship has
been called various names. The following names all refer to this index: (a) DPTI/TTI
ratio, (b) Subendocardial Viability Ratio (SEVR), (c) Endocardial Viability Ratio (EVR),
(d) Subendocardial Flow Index, (e) Buckberg SEVR, and simply (f) Buckberg ratio
(Dubiel, Dubiel, Frendo, Zmudka, & Horzela, 1986; Geitan, Martucci, & Levine, 1986;
Goran, 1996; Nichols & O'Rourke, 1998; Sphygmocor px, 2001).
Buckberg et al (1972a) also established that aortic pressure is an accurate substitute
ventricular pressure in the determination of subendocardial risk. Nevertheless, whether
measured via ventricle or aorta, assessment of the Buckberg ratio required arterial
catheterization with all the inherent risks that it involves, making it relatively difficult to
use in clinical diagnosis. Indeed, his original critical value of 0.7 has been called into
question. As clinical experience grew, the critical value was lowered by up to 50%.
Most of the clinical data were obtained by indwelling radial artery catheters (Reitan,
Martucci, & Levine, 1986). As was previously noted, peripheral arteries do not offer an
accurate assessment of diastolic pressure time index or tension time index because of
inconsistent pressure amplification. Reitan et al. (1986) demonstrated this phenomenon
clearly in their experiments with dogs. They measured the Buckberg ratio from aortic
readings and peripheral readings. Discrepancies of up to 25% were found. The authors
concluded that much of the controversy surrounding the critical value of the
subendocardial viability ratio is due to a lack of rigor in its calculations.
Pulse Wave Contour
Despite the pervasiveness of cuff-based methods, cuff measurements were never
meant to be a holy grail of diagnosis and management. In fact, Sir James Mackenzie's
first text on blood pressure and hypertension warned against the blind use of cuff-based
methods (Nichols & O'Rourke, 2001). Thus, it is ironic that the third edition of his work
(published posthumously by his editor) contained part of the foundation for the eventual
dominance of cuff-based measurements and an incorrect understanding of blood pressure.
Indeed, hypertension theory has always trailed the techniques used to measure blood
pressure, and in the early 1900s pulsatile pressure could be measured invasively, but flow
could not. From early experiments in animals by Earnest Starling, it was assumed that
flow followed a pulse curve similar to pressure, but arterial flow was rarely measured
directly in humans. Why bother when absolute systolic and diastolic pressures could be
measured noninvasively by RRK method? And so, the older form of blood pressure
measurement used by Mahomed faded into the background. Almost a hundred years
later, Murgo et al. (1980) would corroborate Mahomed's descriptions of pulse wave
contour in their seminal paper.
Murgo et al. (1980) described three types of aortic pulse wave contours, which they
termed Types A, B, and C. The curves were classified by the location of their inflection
point and the relative magnitude of the pulse wave above the inflection point. The
inflection represents the return of the reflected wave (see Figure 2-1). In Type C waves,
the inflection point occurs after systole, indicating a slow return of the reflected wave. In
Type A and Type B waves, the reflected wave returned early during systole, causing an
augmentation in systolic pressure and a prolongation of systole (similar to Mahomed's
finding). In addition to the location of the inflection point, Murgo et al. calculated the
relative intensity of the reflected wave. This calculation is the pressure difference above
the inflection point (Ps Pi) divided by the pulse pressure (Ps Pd). When this
relationship is expressed as a percentage, it is known as Augmentation index (AIx).
AIx = T_- Pi) x 100
Patients with Type A curves had augmentation indices greater that 12%, while Type B
curves had augmentation indexes of 0%-12%. Because the inflection point of Type C
curves occurs after systole, there is a negative augmentation index, meaning that the
reflected wave is augmenting diastolic pressure, which helps to maintain coronary
perfusion pressures (Nichols & O'Rourke, 1998). The older the individual, the greater
the shift toward Type B and Type A curves. In addition to the three pulse wave contours
described by Murgo et al. (1980), Nichols and O'Rourke (1998) described a fourth
contour they called Type D which only occurs in patients age 65 and older. In a Type D
beat, there is no inflection point because the reflected wave occurs early in systole.
Almost all human pulse wave contours show a sharp inflection point, Murgo et al. (1980)
reported, in contrast with animal models where there is almost never an inflection point.
Pi \ / AP
i ____P PP
Figure 2-1. Calculation of the augmentation index. The augmentation index is calculated
as the difference between Ps and Pi (AP), expressed as a percentage of the difference
between Ps and Pd (pulse pressure, PP). T is the time between the foot of the wave and
the infection point, which provides a measure of the travel time of the pressure wave to
and from the major reflection site.
The conduit arteries and arterioles are characterized by a thick muscular media, while
the central arteries, especially the proximal aorta, are characterized by elastic fibers and
less muscular media (Nichols & O'Rourke, 1998). The elastic nature of the central
arteries is mainly due to elastin protein fibers in the vessel wall. If pressures dilate the
artery, the elastic artery is backed by stronger, stiffer collagen fibers. As the collagen
fibers are engaged at higher pressures, the slope of the elastance curve increases
drastically (i.e., the resulting pressure change is very large for a very small change in
vessel diameter). Several terms are used to describe the stiffness of arteries and are often
used interchangeably although they represent very different concepts.
The slope of the relationship of the change in pressure for a given change in diameter
(AP/AD) is called elastance and is a measure of the stiffness of an artery. The term
compliance is the inverse of elastance and represents the change in volume of an artery
for a given change in pressure. Compliance represents the relative ease of change in
diameter for a given pressure, while distensibility is how easily an artery distends. For
the purpose of this dissertation, elastance is used because it is directly related to elastic
modulus, pulse wave velocity, and augmentation index (Nichols & Edwards, 2001).
As humans age, elastin fibers tend to be stretched to their limit and central artery
elastance increases, causing the aorta to be stiffer and less accepting of pulsatile elements
of blood flow (Nichols & O'Rourke, 1998). Muscular arteries, on the other hand, are
protected by their thick media and do not experience this age related increase in
elastance. The same age-related changes of central arterial elastance also are seen in
hypertension at younger ages; thus, hypertension can be viewed as an early form of aging
(Nichols & O'Rourke, 1998). The increase in aortic elastance causes disruptions in
ventricular-vascular coupling directly and by increasing wave reflection and pulse wave
When the third edition of Sir James Mackenzie's text was published, his editor, James
Orr, apparently inserted the following advice: "As regards the relative importance of
systolic and diastolic pressures, it may be said that the systolic pressure represents the
maximum force of the heart, while the diastolic pressure measures the resistance the heart
has to overcome" (Nichols & O'Rourke, 1998, p. 381). Thus, the concept that high
diastolic pressure is harmful while high systolic pressure is the sign of a vigorous and fit
heart gained widespread popularity and is still taught today (Nichols & Edwards, 2001).
This early hypertensive theory could not possibly have been more wrong. In a normal
human being, the proximal aorta is elastic and expands to receive systolic pressure from
the heart, storing it in elastic fibers as potential energy. This transfer of energy allows
systole to occur in a relatively short amount of time and for maximum ejection to occur
with the least amount of myocardial force. After systole, the elastic fibers in the aorta
rebound, releasing their energy as kinetic energy and aiding blood flow. With age the
aortic elastance increases (Nichols et al., 1995), and the force required for contraction
increases and systolic pressure concomitantly increases (Nichols & Edwards, 2001).
Because the aorta cannot absorb as much of the heart's energy as potential energy, the
pulse wave velocity increases while the diastolic pressure decreases. This has been
shown to be true in experiments where the aorta is replaced with a stiff tube and in
humans with increased arterial elastance. Because pulse wave velocity increases, the
reflected wave returns earlier during systole as described above, further increasing
systolic pressure and increasing the systolic duration. This mismatch in vascular-
ventricular coupling has far-ranging implications that not only impact blood pressure but
also coronary perfusion as it increases the systolic duration and pressure (SPTI), thereby
increasing myocardial demand and concomitantly decreasing diastolic pressure and
duration (DPTI), decreasing coronary artery perfusion.
Cardiovascular disease is the largest cause of mortality worldwide, and hypertension is
a primary risk factor for both mortality and morbidity (myocardial infarction or
cerebrovascular accident). Hypertension is a problem of degree, and traditional office or
clinic blood pressure is not a good predictor of target organ damage. Ambulatory blood
pressure is an improvement on clinic blood pressures by reflecting changes throughout
the day and by being more reproducible and more highly associated with both mortality
and morbidity. Sphygmocardiography improves on traditional blood pressure
measurement, and even surpasses ambulatory blood pressure measurement, by allowing
the detection and assessment of a variety of hypertension pathologies such as increased
arterial elastance, pressure amplification by wave reflection, ventricular-vascular
coupling mismatch, and hemodynamic risk for subendocardial ischemia. The current
research seeks to study the interaction of all three blood pressure measurement techniques
in patients with coronary artery disease and hypertension.
PROCEDURES AND METHODS
This study utilized an observational design within the framework of an ongoing
international mulit-center clinical trial. The same data were collected on all subjects,
regardless of INVEST treatment group between April 2002 and January 2003.
Population and Sample
International Verapamil/Trandolapril Study (INVEST)
INVEST was a large multi-site randomized clinical trial. It had 22,576 with a
minimum treatment periods of 2 years at study closeout. The current study was an
ancillary study to INVEST. All INVEST subjects were above the age of 50, had essential
hypertension, and documented coronary artery disease. Each subject was randomized to
one of two treatment strategies: a calcium channel antagonist based strategy comprised of
the heart rate slowing calcium antagonist Verapamil, and a noncalcium channel
antagonist strategy comprised of the beta blocker atenolol. Each group was also allowed
to receive additional medications including an ACE inhibitor or diuretic to attain JNC VI
guidelines (Pepine et al., 1998). At the beginning of this research study, every INVEST
subject had been on treatment for at least a year.
Subjects were recruited from three sites of INVEST (Pepine et al., 1998).
Approximately 200 INVEST participants were being followed in the Gainesville, FL,
area. Many participants lived as far away as West Palm Beach and traveled to
Gainesville for their cardiology care at Shands Teaching Hospital. Additionally, other
subjects refer to themselves as "Snow birds" and live in the northern states, returning to
Florida for the winter season. Thus, although patients were only recruited from the
Gainesville area, the actual sample population is more diverse than might be expected of
a localized recruitment effort. INVEST participants in the Gainesville area were asked to
participate in this study by their physician or INVEST investigator. This researcher then
presented the study to patients who were asked to sign the consent document. More then
64 subjects were recruited, and 41 signed the consent document. Eleven withdrew their
consent after trying to wear the ambulatory blood pressure monitor but before obtaining
any useful ABP data.
The INVEST subjects are (a) either male or female, (b) above the age of 50, (c) have
documented hypertension according to JNC VI (1997) criteria and the need for drug
therapy, and (d) have documented coronary artery disease (e.g., classic angina pectoris,
myocardial infarction 3 months or more ago, abnormal angiography or concordant
abnormalities on two different types of stress tests).
INVEST Exclusion Criteria
The following were exclusion criteria for INVEST, but since patients had been under
the protocol for more than a year, some criteria were no longer applicable (e.g., some
patients were taking atenolol, a beta blocker, under the INVEST protocol).
1. Unstable angina, angioplasty, CABG, or stroke within 1 month. Patients taking
beta blockers after myocardial infarction are excluded if study enrollment is
planned within 12 months of myocardial infarction. No time limitation if not
taking beta blocker.
2. Use of beta blocker within past 2 weeks.
3. Patients without a pacemaker and any of the following: Sinus bradycardia (<50
beats/min), Sick sinus syndrome, AV-block of more than 1st degree.
4. Documented contraindication to verapamil, atenolol, and hydrochlorothiazide.
5. Severe heart failure (NYHA IV).
6. Concomitant severe illnesses that may affect outcome variables where life
expectancy is 2 years or less or which are likely to require frequent
hospitalizations and/or treatment adjustments.
7. Patients with psychiatric, cognitive, or social conditions that would interfere with
giving consent, cooperating or remaining available for up to 2 years.
Specific inclusion criterion (for this study):
1. Patients with documented hypertension, and coronary artery disease who are
participating in the INVEST trial.
Specific exclusion criteria (for this study):
1. Unwilling to provide written informed consent.
2. Atrial Fibrillation; traditionally, patients with fibrillation have been excluded from
ABP studies because of irregular systole and diastole times.
3. Physically unable to wear blood pressure monitoring device because of previous
axillary lymph node resection or upper extremity neuropathy.
4. Severe muscle tremors (e.g. Parkinson's) because these may interfere with
automated oscillometric measurement of BP.
This study was conducted at a human research laboratory in the University of Florida
College of Nursing, the 11th floor of Shands Teaching Hospital, University of Florida
Cardiology Research Lab, a satellite Shands cardiology clinic, and a private doctor's
office who was an INVEST investigator. Institutional Review Board (IRB) for human
subjects approval was obtained prior to data collection.
Research Variables and Instruments
Mass was measured either by the clinic nurses or this author using either a calibrated
beam balance scale or digital electronic scale and recorded in kilograms.
Height was self-reported and recorded in centimeters.
Body Mass Index (BMI)
BMI is a composite measurement incorporating both mass and height. It is calculated
by dividing the mass in kilograms by the square of height in meters (kg/m2).
Ascending Aortic Pulse Wave
Previous published results (Chen et al., 1997; Pauca et al., 2001; Siebenhofer et al.,
1999) suggest that accurate contours of the ascending aortic pressure waveform can be
obtained from the radial artery pressure waveform using a generalized mathematical
transfer function. In the present study, radial artery pressure waveforms were recorded by
applanation tonometry and central aortic pressure waveforms calculated using the
SphygmoCor (Atcor Medical, Sydney Australia) system. This system averages 10
pressure pulse waves and generates ascending aortic pressures and indices of
ventricular/vascular coupling, including ascending aortic pressure wave augmentation
index, wave reflection travel time, systolic pressure time index and subendocardial
Using the transfer function to synthesize the central aortic wave from the peripheral
wave, agreement between the central aortic and peripheral pressure wave is good;
differences between recorded aortic and calculated aortic systolic pressure were 2.4 +/-
1.0 mmHg, whereas recorded systolic pressure differed by 20.4 +/- 2.6 (mean +/- SEM)
mmHg (Karamanoglu et al., 1993). Linear relationships also have been demonstrated
between brachial blood pressures and corresponding central pressures derived by the
transfer function method (Karamanolglu et al., 1993). The transfer function has recently
been validated by AAMI SP10 standards in patients with coronary artery disease under
both baseline and nitroglycerine infusion (Pauca et al., 2001).
The following variables are obtained from the aortic pulse wave:
* Central Systolic BP (CSBP)
* Central Diastolic BP (CDBP)
* Central Pulse Pressure (CPP): (CSBP) (CDBP)
* Central Mean Arterial Blood Pressure (CMAP): [2(CDBP) + CSBP)]/3
* Heart Rate (HR)
Augmentation Index (AIx)
Kelly, Daley, Avolio, and O'Rourke (1989) defined AIx as the ratio of augmentation
pressure and PP expressed as a percentage. Augmentation pressure is defined as the
difference in pressure between the early and late systolic shoulders of central aortic
pressure waveforms. In this study the central aortic wave was synthesized from a
recorded peripheral wave recorded using a radial applanation tonometer (Millar Pressure
Tonometer, Millar Instruments) and a pulse wave analysis system with a generalized
transfer function (SCOR-Px/P, SphygmoCorTM pulse wave analysis system, PWV
Medical, Sydney, Australia). This device automates the assessment of AIx, expressed as a
percentage, using the following formula: AIx = 100 x (Ps Pi) / (Ps Pd), where Pi is the
first systolic shoulder (inflection point), Ps is the peak systolic pressure (SBP), and Pd is
the minimum DBP (see Figure 3-1).
Several studies (Liang et al., 1998; Seibenhofer, 1999; Wilkinson et al., 1998)
previously reported excellent reproducibility for AIx measurements with a between-visit
correlation coefficient of .98, standard deviation of intraobserver measurement difference
of 2.70% to 5.37%, and standard deviation of interobserver measurement differences of
Pi \ / AP
i ___ r PP
Figure 3-1. Calculation of the augmentation index. The augmentation index is calculated
as the difference between Ps and Pi (AP), expressed as a percentage of the difference
between Ps and Pd (pulse pressure, PP). T is the time between the foot of the wave and
the infection point, which provides a measure of the travel time of the pressure wave to
and from the major reflection site.
Subendocardial Viability Ratio (SEVR)
Buckberg et al. (1972a) first described the subendocardial viability ratio as the ratio of
diastolic pressure time index to the systolic pressure time index. The integral of systolic
portion of the ascending aortic pulse wave is calculated as the systolic pressure time
index (SPTI), and a similar calculation is made for the diastolic portion of the wave
corresponding to diastolic pressure time index (DPTI). Figure 3-2 depicts the process.
Ambulatory Blood Pressure (ABP) Parameters
An autonomic noninvasive cuff-oscillometric recorder (Model 90207, SpaceLabsTM
Inc., Redmond, WA) measured ambulatory blood pressure. This monitor measures BP by
detection of oscillations transmitted from the brachial artery to the cuff. The SpaceLabsTM
monitor was equipped with four different size adult cuffs. A SpaceLabsTM Model 9029
Data Interface Unit was used for report generation.
Recorded Radial Pulse Wave Derived Aortic Pulse Wave
Figure 3-2. Calculation of SEVR from recorded radial pulse wave. The radial pulse wave
is transformed via a transfer function to an ascending aortic pulse wave. The aortic wave
is divided into systolic (darker shaded) and diastolic (lighter shaded) periods. The
integral of the area under the curve for each portion represents the SPTI and DPTI,
Average pressures and standard deviations were calculated. Two methods may be used
to calculate average pressures. One may average all the readings for a given hour and
then average the hour averages. Alternatively, one may simply average all the readings
in the specified time period. The former method may give undue weight to measures
taken during hours that have fewer readings. Furthermore, it makes analysis of variation
and error more difficult. The second method was used in this study as it also reflects the
author's belief that the true value of ambulatory blood pressure is in averaging 40 to 50
readings of a continuous biological variable rather than taking a single reading. Using
this method 24-hour, daytime, and nighttime averages were calculated. Ambulatory BP
variability was defined as the standard deviation of the 24-hour APB average. The day-
night BP difference, or nocturnal BP reduction, was defined as the difference between the
nighttime pressure average (NP) and the daytime pressure average (DP), using
individually defined periods of sleep and wake time parameters. Percentages of nocturnal
BP reduction were computed by the following formula: 100 % x (DP-NP)/(DP).
The validity of the SpaceLabs 90207 ABP monitor has been established. According to
the validation protocols of British Hypertension Society and the Advancement of Medical
Instrumentation, the SpaceLabs 90207 satisfies the criteria for accuracy (O'Brien, Atkins,
& Staessen, 1995).
* 24-hour average Systolic BP (ASBP)
* 24-hour average Diastolic BP (ADBP)
* 24-hour average Pulse Pressure (APP): [I(SBP DBP)]/Nreadings
* 24-hour average Mean Arterial Blood Pressure (AMAP): [1(2*DBP +
* 24-hour average Heart Rate (AHR)
* Blood Pressure Variability ASBPST: Standard Deviation of ASBP
* Daytime average Systolic BP (DSBP)
* Daytime average Diastolic BP (DDBP)
* Daytime average Pulse Pressure (DPP): DSBP DDBP
* Daytime average Mean Arterial Blood Pressure (DMAP): (2*DDBP + DSBP)/3
* Daytime average Heart Rate (DHR)
* Nighttime average Systolic BP (NSBP)
* Nighttime average Diastolic BP (NDBP)
* Nighttime average Pulse Pressure (NPP): (NSBP) (NDBP)
* Nighttime average Mean Arterial Blood Pressure (NMAP): (2*NDBP + NSBP)/3
* Nighttime average Heart Rate (N-HR)
Clinic Blood Pressure
Clinic brachial BP was measured by the INVEST investigators using a traditional cuff
and stethoscope. Two readings were obtained at every visit.
* Clinic Systolic BP (CLSBP)
* Clinic Diastolic BP (CLDBP)
* Clinic Pulse Pressure (CLPP): CLSBP CLDBP
* Clinic Mean Arterial Blood Pressure (CLMAP): (2*CLDBP + CLSBP)/3
* Clinic Heart Rate (CLHR)
History and Clinic Assessment
All subjects signed a consent document before any measurements were made. Health
history and demographic data (other than gender and birth date) were obtained from the
patient's chart. The nurses running the clinics took blood pressure in accordance with
JNC VI guidelines. A second reading was obtained by either an INVEST investigator or
the patient's doctor.
All tonometry measurements were taken at the right radial artery with the patient
sitting upright. The internal software calculates a quality index. Measurements were
repeated until two readings with quality indices greater than 80 were obtained. If after 10
readings a quality index of 80 was not attainable, then the two highest quality readings
Ambulatory Blood Pressure Monitoring Protocol
The subjects were instructed to keep a regular sleep and wake pattern and to avoid
abnormal physical exertion and psychological stress during the ABP recording day.
Ambulatory BP was recorded on an ordinary weekday.
Subjects were fitted with an ABP monitor and were familiarized with its operation.
The monitor was programmed to measure blood pressure over a 24- hour period at the
frequency of every 20 minutes throughout the duration. A cuff of the proper size,
determined by upper arm circumference, was placed on the subject's preferred arm and
attached by flexible tubing to the monitor. The center of the inflatable bladder of the cuff
was placed directly over the brachial artery. The investigator inserted a finger between
the cuff and the arm to ensure the cuff s fit was not too tight. The monitor was then
strapped to the patient's hip or held in a sling on the patient's shoulder.
The monitor emitted a series of alarm sounds 5 seconds prior to cuff inflation between
the hours of 0900 and 2100. It was silent during the nighttime hours. The investigator
instructed the subjects to keep the limb quiet and allow their arm to hang freely at their
side during cuff inflation and deflation. To avoid reading errors due to hydrostatic
pressure differences, the subjects were instructed to keep the level of the cuff near the
heart level. Subjects were given a diary and asked to record their hour of recline and
awakening as well as the times they took their medications. On the back of the diary
were troubleshooting and frequently asked questions regarding the ABP monitor.
Subjects were asked to return the monitor and the diary to the investigator after a
minimum elapsed time of 24 hours. (Subjects who lived more than 30 minutes from
Gainesville were given a stamped self-addressed mailer to return the monitor.) The 24-
hour data for each subject was then downloaded and compared with the subject's diary
entries. The individually defined periods of sleep and wake time indicated on the diary
was used to compute the subject's nocturnal blood pressure reduction. However, less
than half of the subjects returned their diaries, so fixed wake and sleep periods were
defined. Daytime was defined from 0900 to 2100. Nighttime was defined from 0000 to
0600. An observer would immediately notice that several hours of the day were missing
in these definitions. The reason for these conservative definitions of daytime/nighttime is
to ensure that patients are actually awake or asleep during the defined times. More liberal
definitions would probably have included measurements on patients who were sleeping
during daytime and awake during nighttime.
Data Collection Methods and Data Reduction
Every attempt was made to ensure data integrity during the data collection and
reduction process. Wherever possible, data were handled by the computer rather than
being entered manually from forms or printouts. All data were collected or entered on a
Compaq Presario 2715 Notebook computer. Tonometry data were collected directly onto
the computer in real time via a serial connection. ABP monitors were downloaded to the
computer upon their receipt via serial cable. Subjects' height, mass, date of birth, gender,
medications, and clinic blood pressures were entered into the appropriate fields within the
Tonometry data were exported to an ASCII text file. The file was then imported to an
Access (MicroSoft, Redmond, WA) database. All the central blood pressures were
calculated by the tonometry software and were exported directly.
Height, Mass, Date of Birth, Gender, Medications and Clinic Blood Pressures
These data were already in the Access database, having been a part of the tonometry
database. The BMI was automatically calculated from the mass and height by the
tonometry program, as was clinic MAP and PP (CLMAP, CLPP). These data were
exported directly to the database. However, the date of birth and date of tonometry
reading were recorded in dd/mm/yyyy format (Sphygmocor is an Australian based
company), and the US software assumes that dates are formatted mm/dd/yyyy. So dates
that contained day values greater than 12 (e.g., June 23rd) were imported correctly;
however, dates that contained a day value of 12 or less had the month and day transposed,
thus June 12th would become December 6t. Every effort to stop this transposition or
automatically reparse the dates was unsuccessful, and eventually the dates were simply
Management of the ABP data is extremely important, as 72 readings are anticipated
per patient (3 readings an hour for 24 hours). For only 30 patients, more than 2,000
readings are anticipated. Thus, manually copying the readings into a database is an
effective way to ensure data errors. Ideally, the data simply would be exported in a
usable and analyzable format to a database or spreadsheet. There is no way to export
either the entire database or any subsets of the database. Individual readings can be
exported, but to some unknown proprietary format that is not readable by Excel
(spreadsheet software), Access, or a text editor. The raw data tables can, however, be
copied to an Excel spreadsheet as shown in Figure 3-3.
Unfortunately, the raw data as copied are not very usable. A series of parsing steps
are necessary in order to make the spreadsheet useful for interpretation. Column E
contains the reading number; however, it is mixed with two letter codes M and R,
respectively, for manual and repeated readings. In cases where a code is used, a space is
inserted before the reading number. To separate these two codes, extra columns are
inserted after column E in the above figure. In the new blank column F is inserted the
following formula =Trim(E). Thus, column F consists of column E without the extra
spaces. In column G the formula =Right(F,1) which fills column G with the right most
character from column F. Next, the data are sorted by column G, so that readings with a
letter code appear at the top of the list; the readings with only numbers are deleted, so that
column G consists only of reading codes. The formula =Left(F, (Len(F)-2)) is applied to
column H. This makes column H consist of only the number part of Column F. At this
point, columns G and H are selected, copied, and then pasted over themselves using the
Paste > Special > Values command. This converts the cells from formulas to actual
numbers. At this point, columns E and F can be deleted and columns G and H take their
place as seen in Figure 3-4.
[ F le Edit View Insert Format Tools Data Window Help -J x
j Li e; H 9 | a a Y i6 b ^ i X L Ia 19 16 a k 0 1 3 C
A I B i C B D E F G H I J K L I M I N
1 Day &&TIIn Systolic Diastolic MAP Heart Rate Event Cod Edit Statu Diary Activity
I I I I I
4 3R 1-1301 184 79 120 53
Sa 1-1qn 1 n n n n 11 FE
Figure 3-3. ABP Spreadsheet with directly copied ABP data. Highlighted cells are to be
jl F] ile Edit View Insert Forrat Tools Data Window Help -i x
al 10. U %, -
A B C I D E F I G H I I J K L M N 0
F-i F I- i. i- ,, T, F F- Hi-F 4 F -I i=- il. F-i i -i -
Using a Totals query, the data were then summarized by grouping on SiteD,
j ,1 i ii
I rI I 1 I1
Figure 3-4. ABP Excel Spreadsheet after parsing.
At this point, the ABP data were imported to the same Access database as the
tonometry data. MAP and PP were calculated by using a query with the appropriate
formulas. Filtering out readings with a systolic pressure of zero eliminated error
readings. Using a Totals query, the data were then summarized by grouping on SiteID,
PatientlD, and Date. Averages and standard deviations were calculated for each variable
as well as the number of valid readings for each patient.
Daytime and nighttime averages were also created at this time by filtering on the field
DayTime (e.g., 1-18:46). The middle number, 18, is the number of interest, as it denotes
the hour in which the reading took place. By filtering based on this number using the
function =Mid(DayTime, 3,2), daytime was defined as the hours between 09 and 21.
Nighttime was defined as the hours between 00 and 06.
Merging the Data
At this point, the data from the Tonometry and ABP source tables were ready to be
merged. A query was created that linked the data together by the SiteID, PatientID, and
Date of reading. The data were then exported to an Excel spreadsheet where it could be
imported into either SAS or SPSS.
Methods of Statistical Analyses
Data were analyzed using SAS (SAS Institute Inc., Cary, North Carolina) and SPSS.
Descriptive statistics and graphs were calculated in SPSS as well as T-tests, and SAS was
used to analyze the data with the general linear model for repeated measures, where each
subject served as his own control. A difference of 5 mm of mercury was set as the
minimum clinically significant difference. Estimates were calculated with a 95%
confidence coefficient. An alpha of 0.05 was set for statistical tests.
The primary purpose of this study was to determine the differences in blood pressure
readings between clinic blood pressure, ambulatory blood pressure, and tonometry-
derived central blood pressure in patients of INVEST. Secondary purposes of the study
were to characterize the hemodynamic profiles of INVEST patients using various
parameters of ambulatory blood pressure (circadian rhythm) and applanation tonometry
(SEVR and Augmentation index). A third purpose of the study was to compare the two
treatment groups in INVEST with regard to the above parameters.
This chapter first presents descriptive results, including means, standard deviations,
and frequency data for each variable. The three hypotheses posed in Chapter 1 are
addressed using repeated measure ANOVA and paired t-tests.
Over 70 INVEST subjects were contacted regarding this substudy in person or by
phone. The study was presented in person to 64 subjects. Of those three were not asked
to participate due to impaired cognitive function, as the investigators deemed they would
be unable to wear the ambulatory blood pressure monitor. Forty-one subjects signed the
consent document. Six withdrew after wearing the ambulatory blood pressure monitor
but without having any usable readings; another five never wore the monitor, citing
schedule or lifestyle conflicts.
Subject demographics expressed in numbers and percentages were gender, race, and
age. Table 4-1 shows the subject demographics. The statistics are given for both
treatment strategies as well as the total for this study. Table 4-2 shows the medication
usage for subjects in the study.
Table 4-3 lists the mean clinical measurements for the entire study. The mean age was
67 9 years. The mean BMI was 28.62 5.82. The mean clinical SBP and DBP were
134 16 mmHg and 72 10 mmHg, respectively.
Figure 4-1 shows scatter plot matrices of the relationships of the clinical, central, and
24-hour average measurements for systolic, diastolic, mean, and pulse pressure. Note
that in every case the central and clinical pressures seem to have very strong linear
relationships, with the relationship being strongest for diastolic pressure, and weakest for
pulse pressure. It is important to note that a strong linear relationship does not mean that
they are the same, but that they seem to change at a similar rate.
Purpose 1: To Determine the Difference Between the Clinic Measurements, ABPM
Measurements, and Calculated Central BPs in Patients Participating in the
For each blood pressure parameter-systolic, diastolic, etc.-General linear Model
with repeated measures analysis was used. An example follows below:
MODEL CLDBP CDBP ADBP = /NOUNI;
REPEATED TIME 3 / PRINTED;
REPEATED TIME 3 CONTRAST(1)/ SUMMARY NOU NOM;
REPEATED TIME 3 PROFILE / SUMMARY NOU NOM;
Table 4-1: Demographic Summary by INVEST Group and Total
Invest Group Total
N % N % N %
Total 19 63.3 11 36.7 30 100
Male 13 68.4 6 54.5 19 63.3
Female 6 31.6 5 45.5 11 36.7
White 15 78.9 8 72.7 23 76.7
Black 2 10.5 1 9.1 3 10.0
Asian 1 5.3 0 0 1 3.3
Hispanic 1 5.3 2 18.2 3 10.0
50-59 4 21.1 3 27.3 7 23.3
60-69 7 36.8 3 27.3 10 33.3
70-79 7 36.8 4 36.4 11 36.7
80-89 1 5.3 1 9.1 2 6.7
Positive Stress Test
No 18 64.3 10 35.7 19 63.3
Yes 1 50.0 1 50.0 11 36.7
No 13 68.4.5 6 37.5 19 63.3
Yes 6 54.5 5 35.7 11 36.7
No 10 62.5 6 37.5 16 53.3
Yes 9 64.3 5 35.7 13 46.7
No 15 60.0 10 40.0 19 63.3
Yes 4 80.0 1 20.0 11 36.7
No 18 64.3 10 35.7 19 63.3
Yes 1 50.0 1 50.0 11 36.7
CABG (bypass surgery)
No 16 61.5 10 38.5 19 63.3
Yes 3 75.0 1 25.0 11 36.7
No 17 63.0 10 37.0 19 63.3
Yes 2 66.7 1 33.3 11 36.7
Table 4-1 (continued).
Past Smoking History
No 17 68.0 8 32.0 19 63.3
Yes 2 40.0 3 60.0 11 36.7
Recent Smoking History
No 18 64.3 10 35.7 19 63.3
Yes 1 50.0 1 50.0 11 36.7
No 19 67.9 9 32.1 19 63.3
Yes 0 0 2 100.0 11 36.7
No 18 62.1 11 37.9 19 63.3
Yes 1 100.0 11 36.7
No 18 64.3 10 35.7 19 63.3
Yes 1 50.0 1 50.0 11 36.7
No 18 64.3 10 35.7 19 63.3
Yes 1 50.0 1 50.0 11 36.7
No 15 68.2 7 31.8 19 63.3
Yes 4 50.0 4 50.0 11 36.7
*NCAS represents those randomized to the arm initially assigned to atenolol. CAS
represents subjects who had been randomized to the verapamil arm of INVEST No
subjects had a history of the following illnesses: Unstable angina, Sick sinus syndrome,
Class VI Heart Failure, Sinus Bradycardia, A-V Block < 1, Left ventricular hypertrophy,
arrhythmia, Alzheimer's, Gastrointestinal bleed, TIA, jugular venous distension, rales,
cardiomegaly, or S3 gallop.
Table 4-2: Medication Usage for INVEST ABP Substudy
Yes Yes (%) No No (%)
Beta Blocker 14 47% 16 53%
Calcium Channel Blocker 11 37% 19 63%
Diuretic 13 43% 17 57%
ACE Inhibitor 18 60% 12 40%
Angiotensin Receptor Blocker 23 77% 7 23%
Nitrate 3 10% 27 90%
Station 8 27% 22 73%
Aspirin 18 60% 12 40%
Anti-Platelet (other than aspirin) 15 50% 15 50%
Coumadin 2 7% 28 93%
Psychotropic (including SSRI) 1 3% 29 97%
Antihistamine 4 13% 26 87%
Synthroid 2 7% 28 93%
Narcotics 3 10% 27 90%
Hypoglycemics (including insulin) 1 3% 29 97%
Digoxin 6 20% 24 80%
Other Medications 16 53% 14 47%
Table 4-3: Summary Statistics for Clinical Measurements
N Mean Std. Deviation Minimum Maximum
Age 30 66.9 9.1 51.0 83.0
Height (cm) 30 170.8 9.0 149.0 188.0
Mass (kg) 30 83.3 17.1 45.0 120.0
BMI (kg/m2) 30 28.6 5.8 15.9 41.4
Clinical SBP (mmHg) 30 134.0 16.3 96.0 170.0
Central SBP (mmHg) 30 124.1 15.8 87.5 156.5
24 hour SBP (mmHg) 30 130.3 13.4 108.2 160.2
Daytime SBP (mmHg) 30 132.4 13.8 107.7 162.9
Nighttime SBP (mmHg) 30 124.3 16.0 96.6 158.3
Clinical DBP (mmHg) 30 72.8 10.9 58.0 100.0
Central DBP (mmHg) 30 73.4 11.1 58.5 102.0
24 hour DBP (mmHg) 30 68.7 8.5 52.0 88.3
Daytime DBP (mmHg) 30 70.3 9.0 51.8 91.7
Nighttime DBP (mmHg) 30 64.2 10.0 48.1 85.3
Clinical MAP (mmHg) 30 93.2 11.7 72.0 123.3
Central MAP (mmHg) 30 92.9 13.1 70.5 127.5
24 hour MAP (mmHg) 30 91.5 9.5 77.0 112.2
Daytime MAP (mmHg) 30 93.2 10.1 77.0 114.0
Nighttime MAP (mmHg) 30 86.7 11.5 69.9 113.0
Clinical PP (mmHg) 30 61.3 12.0 33.0 88.0
Central PP (mmHg) 30 50.7 9.0 27.5 72.0
24 hour PP (mmHg) 30 61.6 9.9 42.5 85.2
Daytime PP (mmHg) 30 62.1 10.5 43.6 86.6
Nighttime PP (mmHg) 30 60.1 9.7 38.8 81.4
Heart Rate (bpm) 30 59.6 11.1 37.5 79.0
24 hour HR (bpm) 30 62.2 8.9 47.2 78.3
Daytime HR (bpm) 30 63.0 9.4 47.5 80.2
Nighttime HR (bpm) 30 60.7 9.1 46.4 84.5
24 hour HR SD 30 6.8 2.9 3.0 17.4
Daytime HR SD 30 7.0 3.2 3.0 20.2
Nighttime HR SD 30 3.8 2.0 0.7 10.0
24 hour SBP SD 30 14.3 3.1 9.0 21.2
24 hour DBP SD 30 9.9 2.0 6.6 15.5
24 hour MAP SD 30 11.6 2.3 8.5 16.6
Daytime SBP SD 30 13.8 3.3 9.0 21.2
Daytime DBP SD 30 9.3 2.4 6.7 17.3
Daytime MAP SD 30 11.0 2.8 7.1 18.1
Nighttime SBP SD 30 10.6 4.1 0.7 20.2
Nighttime DBP SD 30 8.1 2.5 4.0 15.1
Nighttime MAP SD 30 8.9 2.8 3.7 16.6
Number of ABP readings 30 63.7 10.7 28.0 77.0
Number of Daytime ABP readings 30 48.4 10.2 25.0 68.0
Number of Nighttime ABP readings 30 15.3 5.6 2.0 22.0
0 o 00co 0
Clinical SBP % o 0
o  Central SBP D c6
0 2 24hour SEP
Central MAP a
DO 0 013[
0 o-B a 24hour MAP
dfe n rf
Figure 4-1. Scatter matrices for Systolic, Diastolic, Mean, and Pulse pressures.
If the sphericity Chi-squared test was significant, indicating significant correlation
between one or more response variables, then univariate analysis was not appropriate,
and the multivariate analysis was used to assess significance. Contrast was used to
compare both central and ambulatory measurements to clinical measurements.
Systolic pressure showed a significant correlation (x = 56.29, p < 0.0001) among one
or more response variables. MANOVA tests for equality among systolic measurements
showed a significant difference (F = 58.09, p < 0.0001). Diastolic pressure showed a
significant correlation ( 2 = 56.29, p < 0.0001) among one or more response variables.
Clinical DBP /,0 o 0
0 f o
/iB' Central DBP 0 00D 0o
00 00 00 24 hourDBP
oOo 0 0o0; 30 [o
S 0o o
[ o a
a 0 0
0n 0.0 2 u
CliniCal PP enr
0 0 0 C 24 hour PP
0 0 0
oa a] a
^ u 4o]
f  
n % ] [D
 o  CnrlP ]g6p[
____________ ___ D _______ __________
MANOVA tests for equality among diastolic measurements showed a significant
difference (F = 58.09, p < 0.0001). Mean pressure showed a significant correlation (2 =
56.29, p < 0.0001) among one or more response variables. MANOVA tests for equality
among mean measurements showed a significant difference (F = 58.09, p < 0.0001).
Pulse pressure showed a significant correlation (x2 = 56.29, p < 0.0001) among one or
more response variables. MANOVA tests for equality among pulse measurements
showed a significant difference (F = 58.09, p < 0.0001). Table 4-4 summarizes the mean
differences for each blood pressure parameter:
Table 4-4: Comparison of Means 2SE for Clinical, Central, and Ambulatory
Clinical Central ABP
Systolic Pressure (mmHg) 134 6.0 124 5.8** 130 2.8
Diastolic Pressure (mmHg) 73 4.0 73 4.0 69 3*
Mean Arterial Pressure (mmHg) 93 4.2 93 4.8 91 3.4
Pulse Pressure (mmHg) 61 4.4 51 3.6** 62 2.6
** denotes statistical difference with Clinical BP at p < .0001. denotes statistical
significance with Clinical BP at p < 0.05
The difference between clinical and central SBP was 10 2 mmHg. The difference
between clinical PP was 11 2 mmHg. The difference between clinical and ambulatory
DBP was 4 3 mmHg. Clinic and central BPs were very highly correlated for both SBP
(r = .952, p < 0.0001) and DBP (r = .999, p < 0.0001). Clinic and ambulatory blood
pressures were also correlated, but to a much lesser degree; SBP correlation was r = .606
(p < 0.0001), and DBP correlation was r = .484 (p < 0.007).
The null hypothesis for Purpose 1 was that there is no difference between clinic,
ambulatory, and central measurements of blood pressure. We must reject the null
hypothesis and conclude that there is a significant difference between the three
measurements. Central systolic and pulse pressure were significantly different from
clinical pressures (p < 0.0001), while central diastolic and mean arterial pressure were not
significantly different. Diastolic ABP was the only ambulatory parameter that was
significantly different from the clinic BP (p < 0.05), however, the point estimate of the
difference was 4 3 mmHg is less than the a priori clinically significant value of 5
Purpose 2: To Determine the Circadian Systolic and Diastolic BP Parameters of
Independent sample paired t-tests were used to assess the null hypothesis that there is
no difference between the daytime and nighttime measurements for each BP parameter.
Systolic (t = 4.285, df = 29, p < 0.0001), diastolic (t = 4.414, df = 29, p < 0.0001), and
mean arterial pressure (t = 3.984, df = 29, p < 0.0001) all showed a significant difference
greater than 5 mmHg. Table 4-6 summarizes the findings for circadian characteristics.
Pulse pressure (t = 2.015, df = 29, p < 0.053) was not significantly different between
daytime and nighttime. Although approaching statistical significance, the mean PP
difference of 2 1 mmHg was not clinically significant. Heart rate (t = 2.212, df = 29, p
< 0.035) was significantly different with a drop of 2.3 2 bpm. It is not known whether
this amount of drop is clinically significant. BP variation as defined by average systolic
BP standard deviation was significantly different (t = 3.576, df = 29, p < 0.001) from day
to night with an average difference of 3.2 1.8 mmHg. Diastolic variation was not
statistically significant (t = 1.919, df = 29, p < 0.065). Heart Rate variation was
significantly different (t = 4.645, df= 29, p < 0.0001) with a mean difference of 3.2 1.4
bpm. Finally, there are approximately three times as many readings during daytime as
there are during nighttime.
Out of 4309 ABP readings, 1620, fully 38% of all ABP readings were errors. There
were 2310 daytime readings, of which 923 (40%) were errors. There were 995 nighttime
readings, with 331 errors, an error rate of 33%.
With regard to the null hypothesis for purpose 2, that there is no difference between
Daytime and Nighttime values for systolic and daytime blood pressures, we must reject
the null hypothesis and conclude that there is a statistically significant drop from daytime
to nighttime pressures. The study showed that, on average, subjects had a nocturnal drop
in MAP and DBP of approximately 6 3 mmHg. Nocturnal systolic drop was 8 4
mmHg. Table 4-5 shows that although all of these are statistically and clinically
significantly, no blood pressure parameter meets the 10% drop criteria to be considered a
Table 4-5: Estimated Difference Between Daytime and Nighttime Measures
Mean of Cv (%)
Mean of Percentage Drop ()
(Day Night) (SE/Mean)
Systolic (mmHg) 8.2 3.8** 6% 23%
Diastolic (mmHg) 6.2 2.8** 9% 23%
Mean (mmHg) 6.6 3.2** 7% 25%
Pulse (mmHg) 2.0 2.0t 3% 50%
Heart Rate (bpm) 2.3 2.0t 4% 45%
Systolic Variation (mmHg) 3.2 1.8* 23% 28%
Diastolic Variation 1.2 1.2 13% 52%
Heart Rate Variation (bpm) 3.2 1.4** 46% 22%
Number of readings 33.2 4.6** 68% 7%
Positive differences indicate a drop in the measurement from day to night. **Denotes
significant difference at p < 0.0001. *Denotes significant difference at p < 0.05.
tDenotes statistical significance that is not considered clinically significant (i.e. < 5
mmHg). It is important to note that this criterion is not applied to the differences in BP
variation, as the clinically significant variation is not known.
Purpose 3: Characterize the Central Hemodynamic Parameters for Patients
Participating in INVEST Augmentation Index and of Patients Participating in
Central hemodynamic blood pressures are listed in Table 4-6. The mean heart rate
was 61 4 bpm. Mean SEVR was 172 14%. Mean ejection duration was 32 2% of
the cardiac period. End systolic pressure was 111 3 mmHg. Central SBP was 124 6
mmHg, while systolic mean pressure (average pressure through systole) was 109 4, a
difference of 15 1.2 mmHg (t = 25.455, df= 31, p < 0.0001). However, the two
measurements were highly correlated (r = 0.986, p < 0.0001). Central DBP was 74 4
mmHg, while diastolic mean pressure (average pressure through diastole) was 86 4, a
difference of -12 + 1.2 mmHg (t = -18.589, df= 31, p < 0.0001). Again, the two
measurements were highly correlated (r = 0.958, p < 0.0001). The mean Augmentation
Index was 31 4%. When normalized for a constant heart rate of 75 bpm, the mean fell
to 24 2%, a difference of 6 2% (t = 6.633, df= 30, p < 0.0001). The two
measurements of augmentation were highly correlated (r = 0.827, p < 0.0001).
Purpose 4: To Compare the two Treatment Strategies in INVEST in Terms of
Differences Between 24-Hour, Daytime, and Nighttime BP Values and BP
Paired t-tests were used to analyze the differences between treatment strategies. The
only differences that were significant at the .05 level were daytime MAP, nighttime HR,
and nighttime SBP SD. However, with Bonferroni's (0.05/42 = 0.001) adjustments for
the number of tests performed in this segment, there were no statistically significant
differences. It is important to note that the small sample size limits the usefulness of
these tests as shown by the very large coefficient of variation (Cv). Thus regarding the
null hypothesis for purpose 4, that there is no difference between the INVEST groups, we
cannot reject the null hypothesis and conclude that there is not enough evidence to
suggest that the groups are different.
Table 4-6: Mean + 2SE for Central Hemodynamic Blood Pressures
Mean 2SE Minimum Maximum SD N
Peripheral SBP (mmHg) 135 6 96 170 17 30
Peripheral DBP (mmHg) 73 4 58 100 11 30
Peripheral MAP (mmHg) 93 4 71 128 13 30
Peripheral T1 (ms) 121 6 85 178 19 30
Peripheral T2 (ms) 212 8 170 255 23 30
Peripheral Alx (%) 90 6 66 138 14 30
Peripheral ESP (mmHg) 99 4 72 132 14 30
Peripheral P1 (mmHg) 134 6 96 170 17 30
Peripheral P2 (mmHg) 127 6 90 157 18 30
PT1 duration (%) 38 2 24 51 6 30
PT2 duration (%) 66 2 53 74 5 30
SEVR (%) 172 14 102 263 38 30
HR(BPM) 61 4 38 84 12 30
Cardiac Period (ms) 1025 76 711 1610 216 30
Ejection Duration (ms) 319 12 248 384 32 30
Diastolic Duration (ms) 706 70 426 1253 196 30
Ejection Duration (%) 32 2 23 44 5 30
Diastolic Duration (%) 68 2 57 78 5 30
Central Pulse PP (mmHg) 50 4 28 72 10 30
Central Augmentation 15 2 28 30
Central Alx (%) 31 4 11 54 10 30
Central Alx normalize for 30
24 2 14 43 8
Central P1 Height (mmHg) 35 2 14 52 8 30
Central TR (ms) 135 4 108 161 12 30
Central SBP (mmHg) 124 6 88 157 16 30
Central Systolic Mean BP 109 4 80 142 14 30
Central DBP (mmHg) 74 4 59 102 11 30
Central Diastolic Mean BP 30
86 +4 66 118 12
Central MAP (mmHg) 93 4 71 128 13 30
Central T1 (ms) 107 4 85 127 10 30
Central T2 (ms) 226 8 183 272 25 30
Central Al (P2/P1) 148 8 112 223 23 30
Central ESP 111 6 80 144 15 30
Central P1 (mmHg) 109 4 81 141 14 30
Central P2 (mmHg) 124 6 88 157 16 30
CT1 duration (%) 34 2 25 44 4 30
CT2 duration (%) 71 2 64 78 3 30
80 90 100 110 120 131
10 20 30 40 50 6C
Central Alx (%)
180 200 220 240 260 28
100 %a o
90 o o
Central end Systolic pressure
Figures 4-2. Relationship of peripheral and central measures. T1 is the time to the first
inflection point or shoulder of the pulse wave. T2 is the time to the second inflection
Central Alx normalize for HR75 (%)
Figure 4-3. Relationship of AI to AI normalized for HR.
10 20 30 40 50
10 2b 30 40 50
0 8 90 100 110 120
Table 4-7: Mean Difference between NCAS and CAS Arms of INVEST
Mean Diff 2SE* t df Sig. (2-tailed) Cv
Age .4 7.2 .100 19 .921 1000%
Height (cm) .7 7.2 .203 18 .841 492%
Mass (kg) 4.0 12.4 .636 24 .531 157%
BMI (kg/m2) .9 4.6 .404 20 .691 248%
Clinical SBP (mmHg) -9.4 11.4 -1.650 24 .112 61%
Central SBP (mmHg) -6.7 11.4 -1.172 24 .253 85%
24 hour SBP (mmHg) -6.2 9.4 -1.321 25 .198 76%
Daytime SBP (mmHg) -7.0 9.6 -1.445 25 .161 69%
Nighttime SBP (mmHg) -2.7 11.4 -.470 25 .643 213%
Clinical DBP (mmHg) -5.2 8.6 -1.210 17 .242 83%
Central DBP (mmHg) -5.3 9 -1.179 17 .255 85%
24 hour DBP (mmHg) -6.2 6.0 -2.042 21 .054 49%
Daytime DBP (mmHg) -6.5 6.6 -1.973 20 .062 51%
Nighttime DBP (mmHg) -4.1 7.4 -1.125 23 .272 89%
Clinical MAP (mmHg) -6.6 8.8 -1.497 19 .151 67%
Central MAP (mmHg) -6.0 10.4 -1.149 18 .266 87%
24 hour MAP (mmHg) -6.7 6.8 -1.981 22 .060 50%
Daytime MAP (mmHg) -7.5 6.2* -2.096 22 .048 48%
Nighttime MAP (mmHg) -3.6 8.4 -.846 23 .406 118%
Clinical PP (mmHg) -4.2 8.2 -1.023 27 .315 98%
Central PP (mmHg) -1.5 6.6 -.446 28 .659 224%
24 hour PP (mmHg) .0 7.6 -.003 20 .998 34347%
Daytime PP (mmHg) -.5 8.2 -.125 20 .902 798%
Nighttime PP (mmHg) 1.4 7.4 .382 21 .706 262%
Heart Rate (bpm) -6.8 8.0 -1.677 21 .108 60%
24 hour HR (bpm) -6.2 6.6 -1.889 20 .073 53%
Daytime HR (bpm) -6.1 7.8 -1.781 21 .089 56%
Nighttime HR (bpm) -7.6 7* -2.189 16 .043 46%
24 hour HR SD (bpm) .6 1.8 .675 27 .505 148%
Daytime HR SD (bpm) .6 2.0 .566 26 .576 177%
Nighttime HR SD (bpm) .7 1.4 .940 22 .357 106%
24 hour SBP SD (mmHg) 1.1 2.0 1.047 28 .304 96%
24 hour DBP SD (mmHg) 1.1 1.4 1.626 28 .115 61%
24 hour MAP SD (mmHg) 1.0 1.6 1.323 28 .197 76%
Daytime SBP SD (mmHg) .8 2.2 .749 28 .460 134%
Daytime DBP SD (mmHg) 1.2 1.6 1.627 28 .115 61%
Daytime MAP SD (mmHg) 1.2 1.8 1.257 27 .219 80%
Nighttime SBP SD (mmHg) 3.2 2.8* 2.300 23 .031 43%
Nighttime DBP SD (mmHg) 1.1 2.0 1.165 18 .259 86%
Nighttime MAP SD (mmHg) 1.1 2.0 1.073 23 .294 93%
Number of ABP readings .8 8.0 .207 23 .838 484%
Number of Daytime ABP.6 -.1 .
-.8 + 8.6 -.173 16 .865
Number of Nighttime ABP 4. .
1.6 readings 4.8 652 15 525
*Means are NCAS-CAS.
than CAS group.
Positive readings indicate that the NCAS has a higher mean
DISCUSSION AND CONCLUSIONS
All descriptive and analytic results that addressed each research hypothesis are
discussed in this chapter. Conclusions and implications for clinical practice as well as
recommendations for future research also are provided.
Discussion of Results
Sixty-four percent of the subjects in the study were men, compared with
approximately 48% in the overall INVEST population (Pepine et al., 1998). Seventy-six
percent were white, 10% black, 3% Asian, and 10% Hispanic, compared to 48.3% white,
13.4% black, 35.7% Hispanic, 0.7% Asian, and 1.9% other in the overall INVEST
population. Seventy percent were above the age of 65, compared with 50.7% for
INVEST. Only 7% were diabetic compared with 22.6% reported for INVEST (Pepine, in
press). Sixty-four percent were on a lipid-lowering agent, while only 27% had
documented dyslipidemia. Thirty percent were on a nitrate other than sublingual
Of the 30 subjects who completed the study protocol and were included in the
analysis, 37% were taking a calcium channel blocker at the study visit. Meanwhile, 47%
of subjects taking a beta blocker. These numbers do not add up to 100% because
INVEST protocol allowed the subjects' physicians to customize hypertensive therapy
based on individual patient needs, first using the three drugs provided in each strategy
and then additional hypertensive therapy could be added so long as the strategy was
maintained. Thus, if a patient were intolerant to atenolol, trandolapril and/or HCTZ
could be used in its stead to maintain the noncalcium antagonist strategy. This explains
the missing 16%. The treatment groups for INVEST are based on intention to treat.
The mean BMI was 28.6 5.8. (Note: All summary statistics are given as mean
SD-standard deviation-while all figures used for estimation are given mean 2SE-
standard error.) This indicates that the average subject was overweight but not obese by
National Institutes of Health obesity guidelines (Obesity Education Initiative, 1998).
Purpose 1: To Determine the Difference Between the Clinic Measurements, ABPM
Measurements, and Calculated Central BPs in Patients Participating in the Invest
The null hypothesis for Purpose 1 was that there is no difference between clinic,
ambulatory, and central measurements of blood pressure. We must reject the null
hypothesis and conclude that there is a significant difference between the three
measurements. Central systolic and pulse pressure were significantly different from
clinical pressures (p < 0.0001), while central diastolic and mean arterial pressures were
not significantly different. Diastolic ABP was the only ambulatory parameter that was
significantly different from the clinic BP (p < 0.05); however, the point estimate of the
difference was 4 3 mmHg, so its clinical significance is somewhat dubious.
Central and clinic differences
Despite the large difference between central and clinic SBP (10 2 mmHg), the
highly linear relationship between them casts some doubt into the significance of this
finding. If this relationship can be generalized to the larger INVEST population, central
systolic pressure could simply be estimated by subtracting 10 mmHg from the clinic
blood pressure. This finding agrees with the conclusions of Cameron, McGrath, and Dart
(1998), who concluded that the use of a generalized transfer function (GTF) was
unnecessary, and simple linear relationships would suffice for the calculation of central
blood pressure parameters. It is important to note that in both the current study and the
study by Cameron, et al. (1998), the population studied was an average of 60 years or
older (66 years for the current study). Nichols and O'Rourke (1998) acknowledged that
in patients over the age of 60, brachial clinic BP is a good estimate of central BP.
Figure 4-1 shows that central diastolic pressure was essentially in unity with clinic
DBP. Central mean arterial pressure was strongly related to clinic MAP. Of all the
parameters, pulse pressure showed the weakest relationship between central and clinic
measures, but was still very strong at r = .908 (p < .0001). Using MAP and PP in
analysis instead of SBP and DBP may be useful in helping to tease out the clinically
significant relationships, as it is more representative of steady and pulsatile pressure
(O'Rourke, 1983, 1999), as opposed to merely recording the minimum and maximum
values of the pressure wave. The limited scope of this study does not permit any
conclusions about such speculations.
Ambulatory and clinic differences
Figure 4-1 shows that the relationship of clinic to ambulatory blood pressures is far
less linear. The correlations for SBP and DPB are .6 (p < .0001) and .5 (p < .007),
respectively. This agrees with Mancia and Parati (2000) who concluded that the
correlation of clinic and ambulatory pressures are rarely greater than .5 for either SBP or
DBP. Despite the lack of linear relationship, there was no significant difference seen
between the clinic and ambulatory pressures, except DBP, where the mean difference was
4 + 3 mmHg. The point estimate is less than 5, the apriori minimum clinically
significant difference, although the 95% confidence interval is from 1 to 7 mmHg.
Certainly this cannot be cited as evidence of a large difference in ambulatory and clinic
blood pressures. Because this study was cross sectional in design, it cannot evaluate
Mancia and Parati's claim that ABP is three times as reproducible as clinic blood
pressure. However, the standard error was consistently smaller than that of the other two
methodologies, sometimes by as much as half.
The study showed that on average, subjects had a nocturnal drop in MAP and DBP of
approximately 6 3 mmHg. Nocturnal systolic drop was 8 4 mmHg. Table 4-5 shows
that although all of these are statistically and clinically significantly, no blood pressure
parameter meets the 10% drop criteria to be considered a nocturnal dipper. It is
important to note that fixed day/night definitions were used (daytime: 0900-2100;
nighttime: 0000-0600), and that individually determined definitions show larger dipping
differences (May, Arildsen, & Damsgaard, 1998). This limitation was due to a large
number of subjects who did not return their activity diaries with the blood pressure
monitor. A further limitation was that the fixed definition of day was twice as long as the
night. Moreover, the definition of daytime and nighttime excludes the hours of 0600 to
0900, the time of early morning blood pressure rise and coincident increase in
cardiovascular events. However, as Mancia and Parati (2000) noted, the early morning
rise in blood pressure is not useful either as a diagnostic tool or as a treatment goal.
There were three times as many daytime readings as nighttime readings, instead of the
anticipated twice as many. However, looking at the rate of failed readings-40% during
daytime versus 33% during nighttime-one would assume that there should be a higher
than anticipated ratio of nighttime to daytime readings. The answer to this lies in the
total number of daytime and nighttime readings-several subjects simply turned off the
monitor sometime during the night. This underscores the importance of Schwan and
Pavek's findings (1989) that nocturnal blood pressure is not a reliable measure.
Moreover, Omboni et al. (1998) showed that repeated ABP measurements showed as
much as a 40% change in dipping status from night to night. Because of the difficulty in
getting subjects in this study to wear the monitor once, much less twice, it is impossible
to verify the assertion of Omboni, et al. However, systolic blood pressure variability and
heart rate variability dropped by 23% and 46%, respectively. The significance of this
reduction has not been established.
The high number of failed readings during both day and night reflects the inherent
oxymoron of ambulatory monitoring. In order to take the blood pressure, the patient
must remain still. Any movements, whether walking, arm motion, or even talking can
cause a failed reading. This reinforces this author's belief that the true value of ABP is in
the increased number of measurements rather than any actual diurnal pattern. Thus,
ambulatory monitoring is not truly ambulatory. The number of failed readings
compromised the data only in one patient at nighttime, and this is primarily because the
patient took the monitor off. The monitor reattempts failed readings after a 2-minute
delay, so the number of failed readings is not indicative of the total number of readings.
Despite the limitations of this study, it is quite apparent that there was a clinically
significant drop in blood pressure for SBP, DBP, and MAP, but that none of these was
considered great enough to classify the subjects as dippers. Because this study was
conducted after the randomization procedure for INVEST, it is impossible to know how
nocturnal reduction changed after beginning treatment.
This study represents the first use of applanation tonometry and noninvasive
measurements of central hemodynamic parameters in a subset of a large randomized
hypertension trial. As such, there are no published data with which to compare the data
at this time. It is important to note that 35 tonometry-derived parameters are reported, of
which 11 are peripheral readings, with the remainder being calculated central measures.
Figure 4-2 shows the relationship of various peripheral and derived central
measurements. The only measurements showing a strong linear relationship, similar to
that of central and clinic SBP (as previously discussed above), was end-systolic pressure
(r =.98, p < 0.0001).
A small but significant inverse correlation between HR and AI has been reported by
previous observational studies (Cameron et al, 1998; Yasmin & Brown, 1999). A
moderate and inverse linear relationship between HR and AI with incremental pacing has
also been reported (Wilkinson et al., 2000). In this study, the level of HR and AI did
display a significant, but weak, inverse linear relationship (r = -.6, p < .0001). Tsai
(2001) found that AI seemed to be more closely related to gender and age than to SBP or
BMI, indicating that perhaps AI is more a function of age than hypertension. The
influence of gender was not evaluated for this study. The Sphygomocor software
automatically calculates the AI normalized to an HR of 75 bpm. There was no
correlation between HR and AIHR75; furthermore, adjusting AI for HR reduced the 95%
confidence interval length by half, from 4% to 2%. The average AI when adjusted for
HR was 24 2%, and the minimum was 14%. Thus, the average INVEST subject would
be considered to have a Type A pulse wave contour according the Murgo classification
The average SEVR was 172 14%, indicating that the subjects are not likely to suffer
from coronary ischemia due to a lack of diastolic driving perfusion pressure combined
with an elevated tension-time index. The relatively low average heart rate of 60 4 bpm
most likely helps to contribute to the high SEVR in this study. The ejection duration took
up a mean of 32 2% of the cardiac cycle, giving an ejection/diastole ratio of 1:2. This
has been described as an ideal ratio, with ejection taking up approximately a third of the
cardiac cycle (Nichols & O'Rourke, 1998).
The other central hemodynamic parameters such as time to the first and second
inflection points (T1, T2) and pressure at those inflections (P1, P2) are also reported.
These parameters are used to calculate SEVR, and augmentation index, but are probably
not clinically significant in and of themselves.
Comparisons of INVEST Treatment Strategies
This purpose proved impossible to assess in the given study simply due to the small
sample size, resulting in very large coefficients of variation for the differences between
the groups, as Table 4-7 shows. To determine the differences in these parameters, the
sample size would need to be at least four times larger to detect any differences.
In this population of patients with coronary artery disease and hypertension, central
and clinic blood pressures had very strong linear relationships across the board, with SBP
and PP being significantly different. However, due to the very strong linear relationship,
it was unclear as to whether the generalized transfer function was truly necessary or
whether a simple linear correction can be used in subjects over the age of 55. With
regard to ambulatory pressure, the only parameter that was significantly different from
clinic pressure was DBP, but even then the difference was not clinically significant. The
correlation of ambulatory to clinic pressure is similar to that of previously reported
There was a drop in nocturnal BP, but not enough for the subjects to be considered
dippers. This might reflect the wearing off of blood pressure lowering medications
throughout the night, or because of the lack of baseline data, may simply indicate that
these patients are, in fact, nondippers. The reduction in blood pressure variability
certainly indicates that the study population is most likely highly reactive to stressors
throughout the day.
The AI adjusted for HR was 26%, indicating that the INVEST subjects had Type A
pulse wave contours and a quarter of their central pulse pressures were due to wave
reflection. The SEVR was relatively high at 174% indicating that the augmented systolic
pressure was not affecting coronary perfusion. Ejection duration was appropriate at one
third of the cardiac cycle.
No conclusion could be made about the differences between groups due to the small
Implications for Clinical Practice
The main implication for clinical practice is that in patients over the age of 60, central
blood pressure can be estimated by simple linear relationship to clinic blood pressures,
obviating the need for expensive tonometry equipment. The significance in younger
patients cannot be determined from this study. The simple linear relationships found in
the current study and by Cameron et al. (1998) may or may not be found in younger
populations. With the current trend to treat high blood pressure in younger patients,
knowing the impact of central blood pressure on mortality and long-term vascular
complications remains an important area of research.
Until more research is done, it will not be known whether the other tonometry derived
measures such as SEVR, AIx, and ejection duration will prove to be significant in
reducing organ damage associated with high blood pressure. Implementing tonometry
into practice should be very simple, although it does take more time to execute than a
simple clinic blood pressure. The main obstacle in its widespread adoption is the price
and the dubious clinical value of the derived central measures.
When first researching ambulatory blood pressure, it seems to be a panacea for all of
the faults of traditional blood pressure readings. It eliminates operator bias, is more
reproducible, is not significantly affected by placebo, and eliminates white coat
hypertension (Mancia & Parati, 2000). Yet, in the JNC VI guidelines (1997), it is only
indicated in a few circumstances and not for general follow-up. The reason for this
apparent dichotomy of usefulness and recommended usage becomes very clear when
using the ABP monitors. Only one unit can be used on any given day for one subject,
and if that subject was seen late in the day, then the unit may be out of commission for 2
days. Furthermore, subjects who live more than 20 minutes away may be unwilling to
come back to the office to return the monitor. This happened several times during this
study. Two subjects kept a monitor for more than 2 weeks. After 2 weeks one of the
monitors was returned with no usable data on it but just a long series of failed readings.
(These were not included in the number of failed readings reported in Chapter 4.) To get
around this logistic problem, subjects who lived more than 30 minutes away from the
clinic were given self-addressed stamped boxes to mail back the monitors. The problem
with this approach was that quite often monitor accessories such as the waist strap were
missing upon receipt of the mailed box.
Subjects were instructed in the use of the monitor and given an information sheet with
frequently asked questions and troubleshooting information, and this researcher's phone
number. Yet, there were numerous complaints of not being able to use the monitor
correctly. Some subjects complained that they had to wear their clothes the whole time
and that the inconvenience of not being able to take a shower was aggravating. Others
complained about not being able to roll over due to the monitor being strapped to their
waists at night. Such complaints that were clearly contrary to the operating instructions
were much more common in subjects above the age of 65, although young age was no
guarantee of a low percentage of failed readings. Five subjects felt strongly enough
about their experience that they included notes detailing their discontent with the ABP
monitors and refused to wear the monitor again. Several other subjects related that they
dreaded the thought of having to wear the monitor again.
Based on these experiences, this researcher cannot recommend that ABP be used on a
widespread basis and agrees with the JNC VI (1997) recommendations that ABP be used
only for selected purposes, such as evaluating white-coat hypertension.
As for the profession of nursing, neither ABP nor applanation tonometry will supplant
brachially measured clinic blood pressures for years to come. It is more critical than ever
that nurses use proper technique in measuring blood pressure. The seemingly simple
things, such as having the subject rest for 5 minutes, having back supported, having arm
supported at heart level, and using the right size cuff, can make quite a difference in the
measurement of blood pressure. However, nurses must always remember that blood
pressure is much more than two numbers recorded on a page, much more than the peak
and trough of a periodic wave. Nurses must be trained to understand the inherent nature
of blood pressure's relationship to central and muscular arteries.
Recommendations for Further Research
A limitation of this study is the lack of baseline ABP and tonometry data. INVEST
had been running for 4 years at the time data collection for this study began, making the
collection of baseline data an impossibility. This study was conducted to provide data
regarding the comparability of different blood pressure measurement methods. It is
recommended that ABP and tonometry would be a useful tool in future large clinical
trials to correlate changes from baseline BP parameters and to evaluate the effect of
treatment on BP parameters and how they ultimately effect end organ function.
The question raised by the HOPE trial (Dagenais et al., 2001) is whether some blood
pressure medications can have a beneficial effect on coronary artery disease that is
greater than can be attributed to the blood pressure alone. Nichols and O'Rourke (2001)
contend that perhaps the benefit was from lowered central blood pressure. The linear
relationship found in this study lends weight to the HOPE trial's theory. However, due to
the lack of baseline data, it cannot be determined whether the change in blood pressure
due to treatment also exhibits the same linear relationship. Future studies based on the
HOPE hypothesis such as the Ongoing Telmisartan Alone and in Combination with
Ramipril Global Endpoint Trial (ONTARGET) (Yusuf, 2002) should implement a
substudy comparison of clinic blood pressure to central blood pressure.
The accelerated timeline of this study, combined with a small number of ABP
monitors (as described above), accounted for the small sample size. The small study size
did not allow for any conclusions regarding comparisons of the two INVEST groups.
Another limitation was the geographic bias, reflected in the ethnic make up of the study
participants. Both of these limitations can be avoided in future studies by including ABP
and tonometry during the randomization process. The original study protocol called for
two ambulatory blood pressure readings, but it quickly became apparent that this would
not be possible, as more than half the enrolled subjects either refused outright to wear the
monitor again or cited schedule conflicts. The limited timeline combined with the limited
number of ambulatory blood pressure monitors did not allow enough repeated
measurements to be able to analyze two ABP measurements. Patients had no inducement
to continue the study; they were receiving free study medication for participating in
INVEST, but their participation in this study was uncompensated. The lack of incentive
plus the relatively short interval between ABP sessions are directly responsible for the
high dropout rate. It is recommended that future studies compensate patients for the ABP
use or make other study benefits contingent on wearing the ABP monitor, allow for a
longer time between ABP sessions, so that patients have had time to forget how much
they dislike wearing the monitor, and reduce the number of readings to every half hour
during the day and every hour at night.
In this population there is a highly linear relationship between central and clinic blood
pressures in regard to SBP, DBP, MAP, and PP. SBP and PP are significantly different
using the two methodologies. It is not known whether central blood pressure changes
linearly with changes in clinic pressure. There was no difference between ABP and
clinic blood pressures, which demonstrated weak but significant linear relationships. A
significant drop in nocturnal blood pressure was demonstrated, but the drop was not large
enough to classify the subjects as dippers. No conclusions could be made about
differences between the INVEST treatment groups due to the small sample size. Systolic
augmentation by wave reflection accounted for more than 30% of systolic pressure. The
increased pressure was not likely to cause subendocardial ischemia according to the
average SEVR. Recommendations for future studies are offered:
1. Replicate the study on a larger scale with enough time for baseline data.
2. Determine whether the simple linear relationships found here between central
and clinic BP are also found in younger hypertensive populations.
3. Include tonometry and ABP at the randomization phase of future studies to
allow these additional data to be correlated to changes in clinic BP.
4. Give incentive to participants to continue ABP use, and allow a longer
interval between repeated ABP sessions.
Blood Pressure by Any Means Necessary
There are two schools of thought among science and medical community concerning
blood pressure reduction. The first is that blood pressure reduction by any means is
effective in reducing mortality. This belief is supported by predictive models that show
no plateau or J-curve in the risk reduction with blood pressure reduction (Glynn,
L'Italien, Sesso, Jackson, & Buring, 2002). One pharmaceutical company even has
brochures advocating "going the extra millimeter." This theory has garnered recent
support by the results of the ALLHAT study that showed no difference between
treatment arms of an ACE inhibitor, calcium channel blocker, and a thiazide diuretic
(ALLHAT Collaborative Study Group, 2002). However, it should be noted that this
same study also undermines the theory, since a fourth treatment arm with an alpha-
receptor blocker was discontinued due to a high incidence of cardiovascular events.
The second school of thought states that not only is blood pressure reduction
important, but the method of blood pressure reduction is just as important because the
underlying physiological mechanism is what truly matters. This belief touts the HOPE
trial a shining example. Patients treated with a "tissue" ACE inhibitor exhibited huge
decreases in incidence of heart attack and other cardiovascular events-decreases much
larger than would be expected by the modest blood pressure reductions (Dagenais et al.,
2001). However, it must be remembered that the HOPE trial was not a blood pressure
trial. Patients enrolled in it were either normotensive or had hypertension already
controlled by other classes of drugs.
Unfortunately, no clinical trial to date has adequately resolved this dilemma. It is
hoped that the tools of ambulatory blood pressure and arterial tonometry will help us
reconcile these two schools of thought.
Vive le Difference
Over the years, a growing concern has been coronary artery disease in women. Large
advertising campaigns have been launched in the media to raise awareness in the United
States that coronary artery disease is the highest killer of women in the United States and
that heart attacks are more likely to be fatal in women. It has also become apparent that
science does not understand fully the differences in pathophysiology of heart disease
between the sexes. However, the WISE study has shown that men tend to suffer from
blockages of the large coronary arteries, while women tend to suffer from ischemia in the
smaller coronary vessels (Reis et al., 2001). The implications of this are not fully
understood, but it is this author's opinion that it may indicate that the Subendocardial
Viability Ratio may be more important in women than in men.
Cost of Entry: A Final Word on Applanation Tonometry and ABP
The cost of these two technologies is prohibitive at this juncture and is truly the largest
obstacle to their widespread adoption. A tonometry unit costs between $12,000 and
$16,000, while an ambulatory blood pressure monitor costs about $2,000. However, one
tonometry unit can be used on as many subjects or patients who come into the clinic in a
given day, thus making its cost per patient less than ABP. In order to collect data on five
patients in a day, five ABP monitors are necessary. It is easy to see that this can quite
quickly become expensive. It is also unclear as to why the ABP monitors cost so much
money. They are simply small automatic BP machines with a programmable memory
chip. If they were less expensive, say $100, it would be possible for patients to buy their
own monitors, which they could wear for a few hours or 24 hours and then bring it to
their doctor's offices to be read. In fact, the software is able to download the monitor's
data over the phone. Economies of scale would certainly make up the difference in lost
revenue due to the lower price.
The software of both Sphygmocor and ABP report manager needs to be updated. The
Sphygmocor software needs to allow users the option of exporting dates in an MDY
format to avoid the manual correction described in Chapter 3. Moreover, when the data
are exported, hemodynamic parameters are given cryptic 2-6 letter abbreviations that are
sometimes not at all obvious as to what they represent. Some parameters are repeated
multiple times. There is no documentation as to what these codes represent. In order to
analyze the results, this researcher had to compare the exported data with multiple
Sphygmocor reports looking for corresponding fields. The export function needs to use
more descriptive fields as well as documenting what each field represents. The ABP
Reports Manager software was similarly lacking. The software as it is currently designed
is only meant to print reports on an individual ABP session for one patient. Sessions are
stored as separate files in a proprietary format. The software needs to be redesigned so
that sessions are stored in a relational database. This will allow multiple sessions from
the same patient to be analyzed. It also needs to be able to export selected sessions to an
external database. Additionally, there were several combined fields that would have been
better if they were separated, such as the reading number and any modifier codes
indicating whether the reading was regular, manual, or a retry. These changes will enable
future research to go much more smoothly and will help to eliminate errors in data entry
Informed Consent to Participate in Research
The University of Florida
Health Science Center
Gainesville, Florida 32610
You are being asked to take part in a research study. This form provides you with
information about the study. The Principal Investigator (the person in charge of this
research) or a representative of the Principal Investigator will also describe this study to
you and answer all of your questions. Before you decide whether or not to take part, read
the information below and ask questions about anything you do not understand. Your
participation is entirely voluntary.
1. Name of Participant ("Study Subject")
2. Title of Research Study
Comparison of Non-Invasive Blood Pressure Methodologies: A Substudy of The
International Verapamil SR/Trandolapril Study (INVEST).
3. Principal Investigator and Telephone Number(s)
Eileen Handberg, PhD, ARNP (352-846-0612)
4. Source of Funding or Other Material Support
5. What is the purpose of this research study?
The purpose of this study is to collect additional blood pressure measurements that may
provide useful information in order to improve the way health care practitioners treat
patients with high blood pressure and heart disease.
6. What will be done if you take part in this research study?
You are being approached to participate in this research study because you have high
blood pressure and coronary artery disease and are participating in INVEST. Once the
study is explained to you, and if you wish to participate, you will be asked to sign this
Your participation will require you to take part in the following testing procedures: On
two occasions, you will be asked to wear a blood pressure monitor for 24 hours. When
you wear the blood pressure monitor, you will be asked to keep a simple journal that tells
what kind of activity you were doing when the cuff inflates. Additional measurements of
your blood pressure will be taken using a different method. Tonometry readings use a
device that looks like a blunt pencil. It will be pressed gently against the arteries in your
wrist, neck, and groin for a few seconds to measure the pressures there. These will be
taken in clinic on the days you have the blood pressure monitor placed. The procedures
takes about 15 minutes.
7. What are the possible discomforts and risks?
The 24 hour blood pressure machine will take readings every 20 minutes. This may
cause some discomfort as it inflates. There are no risks above your ordinary daily life
risks. There are no risks associated with the tonometry measurements.
Throughout the study, the researchers will notify you of new information that may become
available and might affect your decision to remain in the study.
If you wish to discuss the information above or any discomforts you may experience, you
may ask questions now or call the Principal Investigator or contact person listed on the
front page of this form.
8a. What are the possible benefits to you?
You will be given a copy of the blood pressure readings. These may assist your doctor in
treating your blood pressure and coronary artery disease.
8b. What are the possible benefits to others?
As we understand high blood pressure and its relationship to coronary artery disease
better, we may be able to treat patients with high blood pressure better, causing them to
live longer and with fewer complications like heart attacks and strokes.
9. If you choose to take part in this research study, will it cost you anything?
10. Will you receive compensation for taking part in this research study?
You will receive a copy of the blood pressure readings.
11. What if you are injured because of the study?
If you experience an injury that is directly caused by this study, only professional medical
care that you receive at the University of Florida Health Science Center will be provided
without charge. However, hospital expenses will have to be paid by you or your insurance
provider. No other compensation is offered.
12. What other options or treatments are available if you do not want to be in
You are free not to participate in this study. Alternative treatment would be to continue with
standard medical therapy currently available as decided by your doctor.
13a. Can you withdraw from this research study?
You are free to withdraw your consent and to stop participating in this research study at any
time. If you do withdraw your consent, there will be no penalty, and you will not lose any
benefits you are entitled to.
If you decide to withdraw your consent to participate in this research study for any reason,
you should contact Eileen Handberg, PhD, ARNP at (352) 846-0612.
If you have any questions regarding your rights as a research subject, you may phone the
Institutional Review Board (IRB) office at (352) 846-1494.
13b. If you withdraw, can information about you still be used and/or collected?
No further information will be collected on you, but information that has already been collected
will still be used in the analysis.
13c. Can the Principal Investigator withdraw you from this research study?
You may be withdrawn from the study without your consent for the following reasons:
If you are unable to tolerate, or there is a contraindication to wearing of the ambulatory blood
14. How will your privacy and the confidentiality of your research records be
Authorized persons from the University of 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 them to the extent permitted by law.
Otherwise, your research records will not be released without your consent unless required
by law or a court order.
If the results of this research are published or presented at scientific meetings, your identity
will not be disclosed.
15. How will the researchers) benefit from your being in this study?
In general, presenting research results helps the career of a scientist. Therefore, the
Principal Investigator may benefit if the results of this study are presented at scientific
meetings or in scientific journals.
As a representative of this study, I have explained to the participant the purpose, the
procedures, the possible benefits, and the risks of this research study; the alternatives to
being in the study; and how privacy will be protected:
Signature of Person Obtaining Consent Date
You have been informed about this study's purpose, procedures, possible benefits, and
risks; the alternatives to being in the study; and how your privacy will be protected. You
have received a copy of this Form. You have been given the opportunity to ask questions
before you sign, and you have been told that you can ask other questions at any time.
You voluntarily agree to participate in this study. By signing this form, you are not
waiving any of your legal rights.
Signature of Person Consenting
Ambulatory Blood Pressure Instructions
The blood pressure cuff will inflate every twenty minutes.
If the machine does not get a good blood pressure reading, it will inflate
again after two minutes. It will keep repeating until it gets a good reading.
The most common cause of bad readings are moving your arm while the
machine is inflated.
When the cuff inflates, hold your arm still and let it hang by your side.
If you cannot let your arm hang still for an extended period of time (if you
are driving for example), then the machine will try two more times and then
wait for the next scheduled reading.
If you want to exercise or take a shower, wait until it finishes taking reading
and then shower before the next reading. Do not forget to put the cuff
back on when you finish your shower or exercising.
If you take longer than twenty minutes, the cuff will inflate while not on your
arm. If this happens, press START/STOP, then unscrew the cuff from the
machine and deflate the cuff. Then reconnect it and press START/STOP
Please wear the machine until on Then
press the START/STOP button until it beeps and return the machine to the
If you have any problems or questions you can reach Pat Heyman at 352-
Please list the time you go to bed tonight and the time you get up in the
Time you went to bed:
Time you got up from bed:
Please list your medications and the time you took them while wearing the
blood pressure monitor.
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