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Hemodynamic Parameters of Patients With Treated Hypertension and Coronary Artery Disease


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HEMODYNAMIC PARAMETERS OF PATIENTS WITH TREATED HYPERTENSION AND CORONARY ARTERY DISEASE By PATRICK HEYMAN A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2003

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Copyright 2003 by Patrick Heyman

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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.

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ACKNOWLEDGMENTS 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. iv

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TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES............................................................................................................vii LIST OF FIGURES.........................................................................................................viii ABSTRACT.......................................................................................................................ix CHAPTER 1 INTRODUCTION...................................................................................................1 Background and Problem Statement.......................................................................1 Purposes of the Study..............................................................................................3 Hypotheses..............................................................................................................4 Definition of Terms.................................................................................................4 Limitations..............................................................................................................5 Significance of the Study........................................................................................6 2 LITERATURE REVIEW........................................................................................8 Dilemmas in BP measurement................................................................................8 History of blood pressure measurement...............................................................11 Cardiovascular Disease.........................................................................................23 Sphygmocardiography..........................................................................................29 Summary...............................................................................................................33 3 PROCEDURES AND METHODS........................................................................35 Design...................................................................................................................35 Population and Sample.........................................................................................35 Setting...................................................................................................................37 Research Variables and Instruments.....................................................................38 Study Protocol.......................................................................................................43 Methods of Statistical Analyses............................................................................48 4 RESULTS..............................................................................................................49 Descriptive Results...............................................................................................49 v

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Analytic Results....................................................................................................50 5 DISCUSSION AND CONCLUSIONS.................................................................63 Discussion of Results............................................................................................63 Conclusions...........................................................................................................69 Implications for Clinical Practice.........................................................................70 Recommendations for Further Research...............................................................73 Summary...............................................................................................................74 Emerging Trends...................................................................................................75 Cost of Entry: A Final Word on Applanation Tonometry and ABP.....................76 APPENDIX A CONSENT DOCUMENT.....................................................................................79 B ABP DIARY..........................................................................................................85 REFERENCES..................................................................................................................87 BIOGRAPHICAL SKETCH.............................................................................................94 vi

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LIST OF TABLES Table page 2-1: JNC VI Recommendations for Blood Pressure Measurement...................................14 4-1: Demographic Summary by INVEST Group and Total..............................................51 4-2: Medication Usage for INVEST ABP Substudy.........................................................53 4-3: Summary Statistics for Clinical Measurements.........................................................54 4-4: Comparison of Means 2SE for Clinical, Central, and Ambulatory Measurements56 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 vii

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LIST OF FIGURES Figure page 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 viii

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Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy HEMODYNAMIC PARAMETERS OF PATIENTS WITH TREATED HYPERTENSION AND CORONARY ARTERY DISEASE By Patrick Heyman May 2003 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 periodusually 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 ix

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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. x

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CHAPTER 1 INTRODUCTION 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 & ORourke, 1998). Thus, most hypertension treatments and research studies targeted diastolic pressure. Ironically, the treatments studieddiuretics and beta-blockerslowered 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 evidenceangiotensin converting enzyme inhibitors (ACE Inhibitors) and calcium 1

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2 channel antagonistsbegan to be seen as effective due to their theoretical models of action (Nichols & ORourke, 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 controlcalcium antagonist based versus noncalcium antagonist based therapyon 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

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3 diuretic, HCTZ, could be added. The noncalcium antagonist strategy started with the beta blocker, atenolol, followed by HCTZ. If BP was not controlled, then trandolapril was recommended. 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 & ORourke, 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 methodologiestraditional clinic BPs, ABP, and tonometry-derived measuresvarious 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 INVEST.

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4 2. To determine the circadian systolic and diastolic BP parameters of INVEST patients. 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. Hypotheses 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, & ORourke, 1989). As arterial elastance increases, AIx increases.

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5 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 & ORourke, 1998). Limitations 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.

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6 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 1918when 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 hypertensions 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

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7 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.

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CHAPTER 2 LITERATURE REVIEW This chapter presents a literature review of the following areas of research: BP measurementdilemmas and historyincluding 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 l concludes this chapter. 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 pressurecontinuous versus intermittent measurementconcerns 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 8

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9 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 bodys 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 bodys circadian blood pressure load (Mancia & Parati, 2000). 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

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10 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 & ORourke, 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:

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11 1. Which parameter is most important in the prediction of mortality and morbidity? 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 Sphygmogram The interpretation of the arterial pulse has been of great importance to both Western and Eastern medicine from ancient times (Lee & Porcello, 1993; ORourke & Gallagher,

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12 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 patients pulse wave but not capable of recording actual pressure. Using his device, Frederick Akbar Mahomed was able to diagnose asymptomatic hypertension, describe essential hypertensions natural history, and distinguish between essential and renal-induced secondary hypertension (ORourke, 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 & ORourke, 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 sphygmograms 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

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13 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 & ORourke, 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 NIHs 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

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14 errors. Aural acuity and quality of stethoscope are immediately identifiable as potential sources for error. Additionally, the clinicians 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

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15 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 timeoften 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

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16 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

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17 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

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18 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 ORourke (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

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19 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

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20 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. Applanation Tonometry 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

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21 brachial and carotid sites (Nichols & ORourke, 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 & ORourke, 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 analysis (PWA). 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

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22 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, ORourke, & 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).

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23 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 & ORourke, 1998). Cardiovascular Disease 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 & ORourke, 1998). Despite the hearts intimate relationship with blood, the myocardium does not receive any oxygen from the blood that is pumped through its chambers. Rather, the myocardiums demand for oxygen is met by an elaborate and extensive network of arteries that enshrine and penetrate the hearts 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.

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24 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 & ORourke, 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 Lumen diameter 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 & ORourke,

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25 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 hearts contractile nature, it can only be perfused during diastole. Blood is compressed out of the myocardial arteries during systole (Nichols & ORourke, 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).

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26 Benetos et al. (2000) reported the results of two French longitudinal studies of untreated subjectsInvestigations Prventives 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. Subendocardium The deeper layers of the hearts 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 & ORourke, 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

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27 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 subendocardiums 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 pacing. 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

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28 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) Diastolic Perfusion Time Index Systolic Pressure Time Index SEVR = 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 hearts 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 subendocardiums 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 & ORourke, 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

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29 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. Sphygmocardiography 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 Mackenzies first text on blood pressure and hypertension warned against the blind use of cuff-based methods (Nichols & ORourke, 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

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30 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 Mahomeds 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 Mahomeds 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 (P s P i ) divided by the pulse pressure (P s P d ). When this relationship is expressed as a percentage, it is known as Augmentation index (AIx). (P s P i ) x 100 (P s P d ) AIx = 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 & ORourke, 1998). The older the individual, the greater the shift toward Type B and Type A curves. In addition to the three pulse wave contours

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31 described by Murgo et al. (1980), Nichols and ORourke (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. Figure 2-1. Calculation of the augmentation index. The augmentation index is calculated as the difference between Ps and Pi (P), 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. Arterial Elastance 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 & ORourke, 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.

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32 The slope of the relationship of the change in pressure for a given change in diameter (P/D) 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 & ORourke, 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 & ORourke, 1998). The increase in aortic elastance causes disruptions in ventricular-vascular coupling directly and by increasing wave reflection and pulse wave velocity. Vascular-Ventricular Coupling When the third edition of Sir James Mackenzies 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 & ORourke, 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).

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33 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 hearts 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. Summary 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

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34 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.

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CHAPTER 3 PROCEDURES AND METHODS Design 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. Sample 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 35

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36 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. INVEST Participants 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.

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37 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. Parkinsons) because these may interfere with automated oscillometric measurement of BP. Setting This study was conducted at a human research laboratory in the University of Florida College of Nursing, the 11 th floor of Shands Teaching Hospital, University of Florida Cardiology Research Lab, a satellite Shands cardiology clinic, and a private doctors office who was an INVEST investigator. Institutional Review Board (IRB) for human subjects approval was obtained prior to data collection.

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38 Research Variables and Instruments Body Mass 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. Body Height 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/m 2 ). 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 viability ratio. 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)

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39 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 ORourke (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

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40 correlation coefficient of .98, standard deviation of intraobserver measurement difference of 2.70% to 5.37%, and standard deviation of interobserver measurement differences of 3.80%. Figure 3-1. Calculation of the augmentation index. The augmentation index is calculated as the difference between Ps and Pi (P), 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, SpaceLabs Inc., Redmond, WA) measured ambulatory blood pressure. This monitor measures BP by detection of oscillations transmitted from the brachial artery to the cuff. The SpaceLabs monitor was equipped with four different size adult cuffs. A SpaceLabs Model 9029 Data Interface Unit was used for report generation.

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41 End Systole Tension Time Index Diastolic Pressure time Index 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, respectively. 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 authors 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

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42 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 (OBrien, Atkins, & Staessen, 1995). 24-hour average Systolic BP (ASBP) 24-hour average Diastolic BP (ADBP) 24-hour average Pulse Pressure (APP): [(SBP DBP)]/N readings 24-hour average Mean Arterial Blood Pressure (AMAP): [(2*DBP + SBP)/3]/N readings 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)

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43 Study Protocol 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 patients 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 patients doctor. Tonometry Protocol 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 were used. 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 24hour 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 subjects 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

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44 the cuff and the arm to ensure the cuffs fit was not too tight. The monitor was then strapped to the patients hip or held in a sling on the patients 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 subjects diary entries. The individually defined periods of sleep and wake time indicated on the diary was used to compute the subjects 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.

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45 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 database. Tonometry 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 23 rd ) were imported correctly; however, dates that contained a day value of 12 or less had the month and day transposed, thus June 12 th would become December 6 th Every effort to stop this transposition or

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46 automatically reparse the dates was unsuccessful, and eventually the dates were simply corrected manually. ABP Data 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

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47 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. Figure 3-3. ABP Spreadsheet with directly copied ABP data. Highlighted cells are to be copied for all readings in the session. 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, PatientID, and Date. Averages and standard deviations were calculated for each variable as well as the number of valid readings for each patient.

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48 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.

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CHAPTER 4 RESULTS 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. Descriptive Results Subject Demographics 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. 49

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50 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. Clinical Measurements 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. Analytic Results Purpose 1: To Determine the Difference Between the Clinic Measurements, ABPM Measurements, and Calculated Central BPs in Patients Participating in the NVEST. For each blood pressure parametersystolic, diastolic, etc.General linear Model with repeated measures analysis was used. An example follows below: PROC GLM; MODEL CLDBP CDBP ADBP = / NOUNI; REPEATED TIME 3 / PRINTE; REPEATED TIME 3 CONTRAST(1)/ SUMMARY NOU NOM; REPEATED TIME 3 PROFILE / SUMMARY NOU NOM;

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51 Table 4-1: Demographic Summary by INVEST Group and Total Invest Group Total NCAS* CAS* N % N % N % Total 19 63.3 11 36.7 30 100 Gender Male 13 68.4 6 54.5 19 63.3 Female 6 31.6 5 45.5 11 36.7 Race 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 Age 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 Angina Pectoris No 13 68.4.5 6 37.5 19 63.3 Yes 6 54.5 5 35.7 11 36.7 Abnormal Angiogram No 10 62.5 6 37.5 16 53.3 Yes 9 64.3 5 35.7 13 46.7 Myocardial Infarction No 15 60.0 10 40.0 19 63.3 Yes 4 80.0 1 20.0 11 36.7 Stroke 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 PTCA (angioplasty) No 17 63.0 10 37.0 19 63.3 Yes 2 66.7 1 33.3 11 36.7 Renal Insufficiency No 18 62.1 11 37.9 19 63.3 Yes 1 100.0 11 36.7

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52 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 Cancer No 19 67.9 9 32.1 19 63.3 Yes 0 0 2 100.0 11 36.7 Carotid Bruit No 18 62.1 11 37.9 19 63.3 Yes 1 100.0 11 36.7 Peripheral Edema No 18 64.3 10 35.7 19 63.3 Yes 1 50.0 1 50.0 11 36.7 Diabetes Mellitus No 18 64.3 10 35.7 19 63.3 Yes 1 50.0 1 50.0 11 36.7 Lipid disorder 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, Alzheimers, Gastrointestinal bleed, TIA, jugular venous distension, rales, cardiomegaly, or S3 gallop.

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53 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% Statin 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%

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54 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

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55 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 ( 2 = 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.

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56 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 ( 2 = 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 Measurements 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

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57 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 mmHg. Purpose 2: To Determine the Circadian Systolic and Diastolic BP Parameters of INVEST Patients 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.

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58 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 nocturnal dipper. Table 4-5: Estimated Difference Between Daytime and Nighttime Measures (Mean 2SE) Mean of (Day Night) Percentage Drop C v (%) (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 2.0 3% 50% Heart Rate (bpm) 2.3 2.0 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. Denotes 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 INVEST

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59 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 Variability 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 Bonferronis (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 (C v ). 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.

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60 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 AIx (%) 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 Pressure (mmHg) 15 2 6 28 6 30 Central AIx (%) 31 4 11 54 10 30 Central AIx normalize for HR75 (%) 24 2 14 43 8 30 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 (mmHg) 109 4 80 142 14 30 Central DBP (mmHg) 74 4 59 102 11 30 Central Diastolic Mean BP (mmHg) 86 4 66 118 12 30 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 AI (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

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61 Central T11301201101009080Peripheral T1 (ms)18016014012010080 Central T2280260240220200180Peripheral T2 (ms)260240220200180160 Central AIx (%)605040302010Peripher AIx (%)1401201008060 Central end Systolic pressure150140130120110100908070Peripheral End-systolic presssure140130120110100908070 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 point. Central AIx normalize for HR75 (%)5040302010Central AIx (%)605040302010 Figure 4-3. Relationship of AI to AI normalized for HR.

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62 Table 4-7: Mean Difference between NCAS and CAS Arms of INVEST Mean Diff 2SE* t df Sig. (2-tailed) C v 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 readings -.8 8.6 -.173 16 .865 578% Number of Nighttime ABP readings 1.6 4.8 .652 15 .525 153% *Means are NCAS-CAS. Positive readings indicate that the NCAS has a higher mean than CAS group.

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CHAPTER 5 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 Demographics 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 nitroglycerine. Clinical Characteristics 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 63

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64 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 SDstandard deviationwhile all figures used for estimation are given mean 2SEstandard 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

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65 (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 ORourke (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 (ORourke, 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 a priori minimum clinically significant difference, although the 95% confidence interval is from 1 to 7 mmHg.

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66 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 Paratis 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. Circadian Characteristics 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% during daytime versus 33% during nighttimeone 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 readingsseveral subjects simply turned off the

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67 monitor sometime during the night. This underscores the importance of Schwan and Paveks 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 authors 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.

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68 Central Hemodynamics 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 % to %. 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 scheme.

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69 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 & ORourke, 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. Conclusions 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

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70 correlation of ambulatory to clinic pressure is similar to that of previously reported studies. 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 sample size. 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.

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71 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.

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72 Subjects were instructed in the use of the monitor and given an information sheet with frequently asked questions and troubleshooting information, and this researchers 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

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73 and trough of a periodic wave. Nurses must be trained to understand the inherent nature of blood pressures 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 ORourke (2001) contend that perhaps the benefit was from lowered central blood pressure. The linear relationship found in this study lends weight to the HOPE trials 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

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74 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. Summary 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

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75 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. Emerging Trends 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

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76 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 eventsdecreases 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 authors 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

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77 $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 doctors offices to be read. In fact, the software is able to download the monitors 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

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78 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 and management.

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APPENDIX A CONSENT DOCUMENT IRB# _______ 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 Abbott Inc. 79

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80 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 consent form. 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.

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81 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? No 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.

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82 12. What other options or treatments are available if you do not want to be in this study? 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 anaysis. 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 pressure monitor.

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83 14. How will your privacy and the confidentiality of your research records be protected? 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 researcher(s) 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.

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84 16. Signatures 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 studys 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 Date

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APPENDIX B ABP DIARY INVEST SUBSTUDY 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 again. Please wear the machine until ____________ on ___________. Then press the START/STOP button until it beeps and return the machine to the cardiology clinic. If you have any problems or questions you can reach Pat Heyman at 352-281-3634. 85

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86 INVEST SUBSTUDY Subject: _________________________________________ Please list the time you go to bed tonight and the time you get up in the morning. 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. Medication: Time _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________ _______________________

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REFERENCES Albaladejo, P., Asmar, R., Safar, M., & Benetos, A. (2000) Association between 24-hour ambulatory heart rate and arterial stiffness. Journal of Human Hypertension, 14 (2), 137-41. Alderman, M.H., & Madhavan, S. (1981). Management of the hypertensive patient: A continuing dilemma. Hypertension, 3 192-197. Alexander, H., Cohen, M. L., and Steinfeld, L. (1977). Criteria in the choice of an occluding cuff for the indirect measurement blood pressure. Medical & Biological Engineering & Computing, 15 (1), 2-10. ALLHAT Collaborative Research Group. (2002). Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker versus diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA, 288, 2981-2997. American Heart Association (2001). 2002 Heart and stroke statistical update. Dallas, TX: The American Heart Association. Antikainen, R., Jousilahti, P., & Tuomilehto, J. (1998). Systolic blood pressure, isolated systolic hypertension and risk of coronary heart disease, strokes, cardiovascular disease and all-cause mortality in the middle-aged population. Journal of Hypertension, 15 (5), 577-583. Benetos, A. (1999). Pulse pressure and cardiovascular risk. Journal of Hypertension, 5 S21-S24. Benetos, A., Zureik, M., Morcet, J., Thomas, F., Bean, K., Safar, M., Ducimetiere, P., & Guize, L. (2000). A decrease in diastolic blood pressure combined with an increase in systolic blood pressure is associated with a higher cardiovascular mortality in men. Journal of American College of Cardiology, 35 (3), 673-680. Black, H. R. (1999). The paradigm has shifted, to systolic blood pressure. Hypertension 34 386-387. 87

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88 Buckberg, G.D., Fixler, D.E., Archie, J.P., & Hoffman, J.I. (1972a). Experimental subendocardial ischemia in dogs with normal coronary arteries. Circulation Research, 30 (1), 67-81. Buckberg, G.D., Towers, B., Paglia, D.E., Mulder, D.G., & Maloney, J.V. (1972b). Subendocardial ischemia after cardiopulmonary bypass. Journal of Thoracic Cardiovascular Surgery, 64 (5), 669-684. Bos, W.J., van Goudoever, J., Wesseling, K. H., Rongen, G. A., Hoedemaker, G., Lenders, J.W., and van Montfrans, G.A. (1992). Pseudohypertension and the measurement of blood pressure. Hypertension, 20 26-31. Chen, C. H., Nevo, E., Fetics, B., Pak, P. H., Yin, F. C .P., Maughan, W. L., & Kass, D.A. (1997). Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure: Validation of generalized transfer function. Circulation, 95 1827-1836. Claxton, A. J., Cramer, J., & Pierce, C. (2001). A systematic review of the associations between dose regimens and medication compliance. Clinincal Therapeutics, 23 (8), 1296-1310. Cranney, M., Warren, E., Barton, S., Gardner, K., & Walley, T. (2001). Why do GPs not implement evidence-based guidelines? A descriptive study. Family Practice, 18 359-363. Cruikshank, J.M., (1992). Clinical importance of coronary perfusion pressure in the hypertensives patient with left ventricular hypertrophy. Cardiology, 81 (4), 283-290. Dagenais, G. R., Yusuf, S., Bourassa, M. G., Yi, Q., Bosch, J., Lonn, E. M., Kouz, S., & Grover, J. (2001). Effects of ramipril on coronary events in high-risk persons: Results of the Heart Outcomes Prevention Evaluation Study. Circulation, 104 (5), 522-526. Drzewiecki, G.M., Melbin, J., & Noordergraaf, A. (1983). Arterial tonometry: Review and analysis. Journal of Biomechanics, 16 141-152. Fang, J., Madhavan, S. Cohen, H., & Alderman, M.H. (1995). Isolated diastolic hypertension a favorable finding among young and middle-aged hypertensive subjects. Hypertension, 26 377-382. Franklin, S.S., Khan, S.A., Wong, N.D., Larson, M.G., & Levy, D. (1999). Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham heart study. Circulation, 27( 100), 354-360.

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89 Glynn, R. J., L'Italien, G. J., Sesso, H. D., Jackson, E. A., Buring, J. E. (2002). Development of predictive models for long-term cardiovascular risk associated with systolic and diastolic blood pressure. Hypertension, 39 (1), 105-110. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. (2000). Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. New England Journal of Medicine, 342 145. JNC VI. (1997). Sixth report of the joint national committee on the prevention, detection, evaluation and treatment of high blood pressure (JNC VI). Washington, DC: Government Printing Office, NIH Publication No. 98-4080. Retrieved, March 5, 2002, from http://www.nhlbi.nih.gov/guidelines/hypertension/jncintro.htm Kannel, W.B., Gordon, T., Schwartz, M.J. (1971). Systolic versus diastolic blood pressure and risk of coronary heart disease: The Framingham study. American Journal of Cardiolology, 27 335-346. Kaplan, N. (2003). The meaning of ALLHAT. Journal of Hypertension, 21, 233-234. Karamanoglu, M., ORourke, M. F., Avolio, A. P., & Kelly, R. P. (1993). An analysis of the relationship between central aortic and peripheral upper limb blood pressure waves in men. European Heart Journal, 14 (2), 160-167. Kelly, R. P., Millasseau, S. C., Ritter, J. M., & Chowienczyk, P. J. (2001). Vasoactive drugs influence aortic augmentation index independently of pulse wave velocity in healthy men. Hypertension, 37 1429-1433. Kelly, R., Daley, J., Avolio, A., & O'Rourke, M. (1989). Arterial dilation and reduced wave reflection. Benefit of dilevalol in hypertension. Hypertension, 14 (1), 14-21. Kelly, R., Hayward, C., Avolio, A., & O'Rourke, M. (1989). Noninvasive determination of age-related changes in the human arterial pulse. Circulation, 80 (6), 1652-1659. Kelly, R.P., Gibbs, H.H., O'Rourke, M.F., Daley, J.E., Mang, K., Morgan, J.J., & Avolio, A.P. (1990). Nitroglycerin has more favourable effects on left ventricular afterload than apparent from measurement of pressure in a peripheral artery. European Heart Journal, 11 (2), 138-44. Laurent, S., Boutouyrie, P., Asmar, R., Gautier, I., Laloux, B., Guize, L., Ducimetiere, P., Benetos, A. (2000) Aortic stiffness is an independent predictor of all-cause mortality in hypertensive patients. Journal of Hypertension, 18 S20.

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90 Lee, Y.W., & Porcello, J.A. 1993. Introduction to acupuncture. Washington Acupuncture Center: West Palm Beach, FL. Liang, Y.L., Teede, H., Kotsopoulos, D., Shiel, L., Cameron, J. D., Dart, A. M., & McGrath, B. P. (1998). Non-invasive measurements of arterial structure and function: Repeatability, interrelationship and trial sample size. Clinical Science, 95 669-679. Madhavan, S., Ooi ,W.L., Cohen, H., & Alderman, M.H. (1994). Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension, 23 ,395-401. Mancia, G., & Parati, G. (2000). Ambulatory blood pressure monitoring and organ damage. Hypertension, 36 (5), 894-900. Mancia, G., Zanchetti, A., Agabiti-Rosei, E., Benemio, G., De Cesaris, R., Fogari, R., Pessina, A., Porcellati, C., Rappelli, A., Salvetti, A., & Trimarco, B. (1997). Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. Circulation, 95 1464-1470. McVeigh, G. E., Bratteli, C. W., Morgan, D. J., Alinder, C. M., Glasser, S. P., Finkelstein, S. M., Cohn, J. N. (1999). Age-related abnormalities in arterial compliance identified by pressure pulse contour analysis: Aging and arterial compliance. Hypertension, 33 1392-1398. Mitchell, G.F., Moye, L.A., & Braunwald, E. for the SAVE Investigators. (1997). Sphygmomanometric determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. Circulation, 96 4254. Mourad, J. J., Blacher, J., Blin, P., Warzocha, U. (2000). Conventional antihypertensive drug therapy does not prevent the increase of pulse pressure with age. Hypertension, 38 958-961. Nichols, W. W., & Edwards, D. G. (2001). Arterial elastance and wave reflection augmentation of systolic blood pressure: Deleterious effects and implications for therapy. Journal of Cardiovascular Pharmacolgical Therapeutics, 6 (1), 5-21. Nichols, W. W., & ORourke, M. F. (1998). McDonalds blood flow in arteries: Theoretical, experimental and clinical principles (4th ed.). New York: Oxford University Press.

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91 Noordergraaf A. (1979). The Herman C. Burger memorial lecture. Invasive versus noninvasive measurements. Bibliotheca Cardiologica, 37 1-9. OBrien, E., Atkins, N., & Staessen, J. (1995). A review of ambulatory blood pressure monitoring devices. Hypertension, 26 835-842. O'Rourke MF. (1999). Wave travel and reflection in the arterial system. Journal of Hypertension, 17 (5), S45-S47. O'Rourke, M.F. (1983). Hypertension is a myth. Australian New Zealand Journal of Medicine, 13 (1), 84-90. O'Rourke, M.F. (1992). Frederick Akbar Mahomed. Hypertension, 19 (2), 212-217. O'Rourke, M. (1994). Arterial stiffening and vascular/ventricular interaction. Journal of Human Hypertension 8 (1), S9-S15. O'Rourke, M.F., Kelly, R.P., Avolio, A.P., & Hayward, C. (1989). Effects of arterial dilator agents on central aortic systolic pressure and on left ventricular hydraulic load. American Journal of Cardiology, 63 (19), 38I-44I. O'Rourke, M.F., Gallagher, D.E. (1996). Pulse wave analysis. Journal of Hypertension, 14 (5), S147-S157. Palatini, P. (1999). Ambulatory blood pressure monitoring and borderline hypertension. Blood Press Monitoring, 4 (5), 233-240. Pauca, A.L., ORourke, M.F., & Kon, N.D. (2001). Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform Hypertension, 38 (4), 932-937. Pepine, C.J., Handberg-Thurmond, E., Marks, R.G., Conlon, M., Cooper-DeHoff, R., Volkers, P., & Zellig, P. (1998). Rationale and design of the INternational VErapamil SR/Trandolapril STudy (INVEST): An internet-based randomized trial in coronary artery disease patients with hypertension. Journal of American College of Cardiology, 32 ,1228-1237. Perloff, D., Grim, C., Flack, J., Frohlich, E.D.; Hill, M., McDonald, M., & Morgenstern, B.Z. (1993). Human blood pressure determination by sphygmomanometry. Circulation, 88 2460-2470.

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92 Pfeffer, M.A, Braunwald, E., Moye, L.A., Basta, L., Brown, E.J. Jr, Cuddy, T.E., Davis, B.R., Geltman, E.M., Goldman S., & Flaker, G.C. (1992). Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE investigators. New England Journal of Medicine, 327 669. Prisant, L.M., Bottini, P.B., Carr, A.A. (1996). Ambulatory blood pressure monitoring: Methodologic issues. American Journal of Nephrology, 16 (3), 190-201. Reis, S. E., Holubkov, R., Smith, A. J., Kelsey, S. F., Sharaf, B. L., Reichek, N., Rogers, W. J., Merz, C. N., Sopko, G., Pepine, C. J., & The WISE Investigators. (2001). Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: Results from the NHLBI WISE study. American Heart Journal, 141 (5), 735-741 Shevchenko, Y. L. and Tsitlik, J. E. (1996). 90th anniversary of the development by Nikolai S. Korotkoff of the auscultatory method of measuring blood pressure. Circulation, 94 116-118. Siebenhofer, A., Kemp, C., Sutton, A., & Williams, B. (1999). The reproducibility of central aortic blood pressure measurements in healthy subjects using applanation tonometry and sphygmocardiography. Journal Human Hypertension, 13 (9), 625-629. SOLVD Investigators. (1991). Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. England Journal of Medicine, 325 293-302. Song, J.C., & White, C.M. (2002). Clinical pharmacokinetics and selective pharmacodynamics of new Angiotensin converting enzyme inhibitors: An update. Clinical Pharmacokinetics, 41 (3), 207-224. Staessen, J.A., Thijs, L., Fagard, R., OBrien, E., Clement, D., de Leeuw, P.W., Mancia, G., Nachev, C., Palatini, P., Parati, G., Tuomiletho, J., & Webster, J. for the Hypertension in Europe Trial Investigators. (1999). Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with hypertension. JAMA, 282 539. Swales, J.D. (2000) Systolic versus diastolic pressure: Paradigm shift or cycle? Journal of Human Hypertension, 14 (8), 477-479.

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93 van der Heijden-Spek, J. J., Staessen, J. A., Fagard, R. H., Hoeks, A. P., Struijker Boudier, H. A., Van Bortel, L. M. (2000). Effect of age on brachial artery wall properties differs from the aorta and is gender dependent a population study. Hypertension, 35 637-632. Verdecchia, P., Schillaci, G., Guerrieri, M., Gatteschi, C., Benemio, G., Boldrini, F., & Porcellati, C. (1990). Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation, 81 528. Verdecchia, P., Schillaci, G., Zampi, I., Gatteschi, C., Battistelli, M., Bartoccini, C., & Porcellati, C. (1993). Blunted nocturnal fall in blood pressure in hypertensive women with future cardiovascular morbid events. Circulation, 88 986. Wilkinson, I. B., Fuchs, S. A., Jansen, I. M., Spratt, J. C., Murray, G. D., Cockroft, J. R., & Webb, D. J. (1998). Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis. Journal of Hypertension, 16 (12 Pt. 2), 2079-2085. Yucha, C.B. (2001). Ambulatory blood pressure monitoring: Measurement implications for research. Journal of Nursing Measurement, 9 (1), 49-59. Yusuf, S., Pepine, C.J., Garces, C, Pouleur, H., Salem, D., Kostis, J., Benedict, C., Rousseau, M., Bourassa, M., & Pitt, B. (1992). Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet, 340 1173-1178. Waddell T. K., Dart A. M., Medley T. L., Cameron J. D., Kingwell B. A. Carotid pressure is a better predictor of coronary artery disease severity than brachial pressure. Hypertension, 38 (4), 927-931. Zanchetti, A., Bomd, M.G., Hennig, M., Neiss, A., Mancia, G., Dal Pal, C., Hansson, L., Magnani, B., Rahn, K.H., Reid, J., Rodicio, J., Safar, M., Eckes, L., & Ravinetto, R. (1998). Risk factors associated with alterations in carotid intima-media thickness in hypertension: Baseline data from the European Lacidipine Study on Atherosclerosis. Journal of Hypertension, 16 949-961.

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BIOGRAPHICAL SKETCH Patrick Heyman was born in Gainesville, Florida. His parents became missionaries when he was six, and he spent the rest of his formative years in Liberia, Costa Rica, and Uruguay. After two years at the United States Air Force Academy, he transferred to Palm Beach Atlantic College where he received a Bachelor of Science in biology. After two years of working in the travel industry, Patrick enrolled at the University of Florida in the College of Nursing. While in school he supported himself by working as a ballroom and Latin dance teacher, donating his talents to charities including Stop Childrens Cancer, Childrens Miracle Network, and the American Heart Association. Upon graduating with a Bachelor of Science in Nursing, Patrick was accepted to the newly formed, combined master/Ph.D program at the University of Florida. While in the masters portion, he worked as a research assistant in the College of Nursings Office for Research Support where he was responsible for poster presentations, website design, database design and management, and electronic form automation. He also served on the Research and Evaluation Committee as a student representative. He completed his Master of Science in Nursing in 2000 and took a leave of absence to hone his clinical skills at the cardiovascular nursing unit at Shands at AGH. Patrick also used this time to obtain his license as an Advanced Registered Nurse Practitioner (ARNP) in the state of Florida and national board certification from the American Nurses Credentialing Center (ANCC). After an eight-month absence, he resumed his doctoral studies. 94

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95 Upon returning to his studies, Patrick became involved in the International Verapamil/Trandolapril Study (INVEST) as co-investigator of the Ambulatory Blood Pressure Substudy. His involvement included drafting the protocol and Institutional Review Board (IRB) proposal, writing a grant, data collection, and write up of results. Patrick also began working at Gainesville Family Physicians during this time as an Adult Nurse Practitioner. He will graduate in May 2003 from the University of Florida with his Ph.D. in nursing and minor in exercise physiology. He will continue to practice as a nurse practitioner while teaching as a part time faculty at the College of Nursing.


Permanent Link: http://ufdc.ufl.edu/UFE0000701/00001

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Title: Hemodynamic Parameters of Patients With Treated Hypertension and Coronary Artery Disease
Physical Description: Mixed Material
Copyright Date: 2008

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Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
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Permanent Link: http://ufdc.ufl.edu/UFE0000701/00001

Material Information

Title: Hemodynamic Parameters of Patients With Treated Hypertension and Coronary Artery Disease
Physical Description: Mixed Material
Copyright Date: 2008

Record Information

Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
System ID: UFE0000701:00001


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HEMODYNAMIC PARAMETERS OF PATIENTS WITH TREATED
HYPERTENSION AND CORONARY ARTERY DISEASE












By

PATRICK HEYMAN


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


2003

























Copyright 2003

by

Patrick Heyman






























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.















ACKNOWLEDGMENTS

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
page

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

CHAPTER

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


v









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

APPENDIX

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


Table page

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


Figure p

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

By

Patrick Heyman

May 2003


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.














CHAPTER 1
INTRODUCTION

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

was recommended.

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
INVEST.









2. To determine the circadian systolic and diastolic BP parameters of INVEST
patients.

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.

Hypotheses

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).

Limitations

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.














CHAPTER 2
LITERATURE REVIEW

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

this chapter.

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,

2000).

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
morbidity?
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

Sphygmogram

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.

Applanation Tonometry

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

analysis (PWA).

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

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

Lumen diameter

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.

Subendocardium

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

pacing.

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.

Sphygmocardiography

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
(Ps- Pd)

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.


Ps
Inciaura

Pi \ / AP
,A L

i ____P PP

Pd


T


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.

Arterial Elastance

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

velocity.

Vascular-Ventricular Coupling

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.

Summary

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.














CHAPTER 3
PROCEDURES AND METHODS

Design

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.

Sample

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.

INVEST Participants

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.

Setting

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

Body Mass

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.

Body Height

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

viability ratio.

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

3.80%.


Ps
Inciaura

Pi \ / AP
,A L

i ___ r PP

Pd


T

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,
respectively.

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






42


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 +
SBP)/3]/Nreadings
* 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)









Study Protocol

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.

Tonometry Protocol

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

were used.

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 database.

Tonometry

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

corrected manually.

ABP Data

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







47



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.


1









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.














CHAPTER 4
RESULTS

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.

Descriptive Results

Subject Demographics

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.

Clinical Measurements

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.

Analytic Results

Purpose 1: To Determine the Difference Between the Clinic Measurements, ABPM
Measurements, and Calculated Central BPs in Patients Participating in the
NVEST.

For each blood pressure parameter-systolic, diastolic, etc.-General linear Model

with repeated measures analysis was used. An example follows below:

PROC GLM;
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
NCAS* CAS*
N % N % N %
Total 19 63.3 11 36.7 30 100

Gender

Male 13 68.4 6 54.5 19 63.3
Female 6 31.6 5 45.5 11 36.7
Race

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
Age

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
Angina Pectoris
No 13 68.4.5 6 37.5 19 63.3
Yes 6 54.5 5 35.7 11 36.7
Abnormal Angiogram
No 10 62.5 6 37.5 16 53.3
Yes 9 64.3 5 35.7 13 46.7
Myocardial Infarction
No 15 60.0 10 40.0 19 63.3
Yes 4 80.0 1 20.0 11 36.7
Stroke
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
PTCA (angioplasty)
No 17 63.0 10 37.0 19 63.3
Yes 2 66.7 1 33.3 11 36.7
Renal Insufficiency


62.1
100.0


37.9


63.3
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
Cancer
No 19 67.9 9 32.1 19 63.3
Yes 0 0 2 100.0 11 36.7
Carotid Bruit
No 18 62.1 11 37.9 19 63.3
Yes 1 100.0 11 36.7
Peripheral Edema
No 18 64.3 10 35.7 19 63.3
Yes 1 50.0 1 50.0 11 36.7
Diabetes Mellitus
No 18 64.3 10 35.7 19 63.3
Yes 1 50.0 1 50.0 11 36.7
Lipid disorder
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
DI0 0
Clinical SBP % o 0
000


o Do



o [] Central SBP D []c6







0 2 24hour SEP








Clinical MAP

0 0





Central MAP a
D D





















DO 0 013[




0 o-B a 24hour MAP
B o
















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.


0 0

Clinical DBP /,0 o 0


0 f o



Do 0
0 0
/iB' Central DBP 0 00D 0o







00 00 00 24 hourDBP
oOo 0 0o0; 30 [o




S 0o o
[ o a








D 0
a 0 0




0n 0.0 2 u
CliniCal PP enr










00 0
0 0


0 0 0 C 24 hour PP
0 0 0
D] D
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
Measurements
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

mmHg.

Purpose 2: To Determine the Circadian Systolic and Diastolic BP Parameters of
INVEST Patients

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

nocturnal dipper.



Table 4-5: Estimated Difference Between Daytime and Nighttime Measures
(Mean 2SE)
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
INVEST









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
Variability

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
Pressure (mmHg)
Central Alx (%) 31 4 11 54 10 30
Central Alx normalize for 30
24 2 14 43 8
HR75 (%)
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
(mmHg)
Central DBP (mmHg) 74 4 59 102 11 30
Central Diastolic Mean BP 30
86 +4 66 118 12
(mmHg)
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


















lbu




160




140.




120. a


Do
100



80
80 90 100 110 120 131


Central T1




140





120





100
aoo









60
10 20 30 40 50 6C


Central Alx (%)


260




240





a a
D o
220


o
200-

a60
o
180

o o

160
180 200 220 240 260 28


Central T2




140


130 o
o

120-
o


110


100 %a o
a a

90 o o
ao

80


70


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

point.


Central Alx normalize for HR75 (%)




Figure 4-3. Relationship of AI to AI normalized for HR.


60




50
oo



40 o

o o

30




20 B



10
10 20 30 40 50
10 2b 30 40 50


0 8 90 100 110 120


14U 150U


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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
readings 578%
Number of Nighttime ABP 4. .
1.6 readings 4.8 652 15 525
readings 153%


*Means are NCAS-CAS.
than CAS group.


Positive readings indicate that the NCAS has a higher mean














CHAPTER 5
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

Demographics

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

nitroglycerine.

Clinical Characteristics

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.

Circadian Characteristics

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.









Central Hemodynamics

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

scheme.









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.

Conclusions

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

studies.

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

sample size.

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.

Summary

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.

Emerging Trends

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






78


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

and management.














APPENDIX A
CONSENT DOCUMENT

IRB#

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

Abbott Inc.









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

consent form.



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?

No

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

this study?

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

pressure monitor.









14. How will your privacy and the confidentiality of your research records be

protected?

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.









16. Signatures

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


Date













APPENDIX B
ABP DIARY

INVEST SUBSTUDY

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
again.

Please wear the machine until on Then
press the START/STOP button until it beeps and return the machine to the
cardiology clinic.

If you have any problems or questions you can reach Pat Heyman at 352-
281-3634.









INVEST SUBSTUDY


Subject:

Please list the time you go to bed tonight and the time you get up in the
morning.

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.


Medication:


Time















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