Title: Hemodynamics and arterial properties underlying pressure responses to cognitive stress in borderline hypertensives
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Title: Hemodynamics and arterial properties underlying pressure responses to cognitive stress in borderline hypertensives
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Language: English
Creator: Tsai, Pei-Shan
Publisher: University of Florida
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Publication Date: 2001
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Subject: arterial compliance, augmentation index, borderline hypertension, hemodynamics, reactivity, stress
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Abstract: ABSTRACT: It has been postulated that the blood pressure (BP) elevation observed in borderline hypertension is caused by enhanced reactivity to stress. To further elucidate the nature of pressure hyperreactivity in borderline hypertension, hemodynamic and arterial responses to the Stroop Color Word Test (SCWT) were studied in 23 borderline hypertensives and 19 normotensives, aged 20 to 63 and 24 to 64 respectively. Twenty borderline hypertensives had a cardiac index less than the mean plus one standard deviation of the normotensive group and were classified as the normokinetic borderline hypertensive subgroup. Blood pressure reactivity to stress of the borderline hypertensives was compared to that of the normotensives. Impedance-derived hemodynamics and arterial properties underlying BP responses to stress were compared between the normokinetic borderline hypertensive and the normotensive group. Blood pressure was continuously recorded using a radial artery tonometer during the stress protocol. Heart rate and stroke volume were measured using the Minnesota impedance cardiograph. Augmentation index, an estimate of aortic wave reflection, was measured using a radial applanation tonometer and a pulse wave analysis system with a generalized transfer function. Arterial compliance was estimated using the stroke volume to aortic pulse pressure ratio. Ambulatory BP was also recorded at 30 to 60 minute intervals for a 24-hour period using an autonomic noninvasive cuff-oscillometric recorder. Total peripheral resistance was higher in borderline hypertensive than in normotensive subjects.
Abstract: While arterial compliance was lower in normokinetic borderline hypertensives than in normotensives, augmentation index was similar between groups. The SCWT induced significant increases in systolic BP, diastolic BP and mean arterial pressure, which were of similar magnitude for borderline hypertensives and age-matched normotensives. Overall, hemodynamic and arterial responses to the SCWT were similar in normokinetic borderline hypertensives and normotensives. The BP reactivity to cognitive stress likely resulted from tachycardia rather than a vasoconstriction response, and was not associated with a change in wave reflection or compliance. Evaluated with ambulatory BP monitoring, borderline hypertensive subjects had a generally higher BP variability than normotensive subjects. Augmentation index did not predict the degree of nocturnal BP reduction, nor did it differentiate borderline hypertensives from normotensives, or dippers from nondippers.
Thesis: Thesis (Ph. D.)--University of Florida, 2001.
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HEMODYNAMICS AND ARTERIAL PROPERTIES UNDERLYING PRESSURE
RESPONSES TO COGNITIVE STRESS IN BORDERLINE HYPERTENSIVES














By

PEI-SHAN TSAI


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


UNIVERSITY OF FLORIDA


2001














Copyright 2001

By

Pei-Shan Tsai














This dissertation is dedicated to my husband and my son,
Chun-Jen and Michael Huang who have given me all these years of
love and support.














ACKNOWLEDGEMENTS

I gratefully acknowledge the assistance of Kristine Stouffer Calderon,

Ph.D., in data collection and of Sean Burket, Breah Elliott, and Elizabeth

Stevens, in subject recruitment; their dedication and hard work made this project

possible.

I extend my appreciation to my dissertation committee members, Carolyn

Yucha, Ph.D., Hossein Yarandi, Ph.D., Joyce Stechmiller, Wilmer Nichols, Ph.D.,

and Randy Braith, Ph.D, for their contributions and support of this project.















TABLE OF CONTENTS

Page

ACKNOW LEDGEM ENTS ......... ...... ...... ..... ........................... iv

LIST OF TABLES .............. ................ ........... ... ... ....... vii

LIST OF FIGURES ................ ............ ........... ............. viii

ABSTRACT ................. ...... ............ ........ .. ......... x

CHAPTERS

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

Background and Problem Statement ................. ........... ...... 1
Purposes of the Study ............ ............ ................... 3
Hypotheses ............. ........... ............ ........ ....... 4
Definitions of Terms ......... .......... ............ ....... 5
Assumptions .................................... ......... ......... 7
Lim stations .................. ..... ................................ ... .... 7
Significance of the Study ................................... 8

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

Mental Stress and Cardiovascular Reactivity in Hypertension ........... 10
Large-Artery Compliance .................................. ........ ............... 19
Noninvasive Measurements of Aortic Wave Reflection Amplitude by
Pulse W ave A analysis ............................................... ............... 23
Indirect Measurement of Total Arterial Compliance ......................... 26
Decreased Large-Artery Compliance and Arterial Structural
Adaptation in Hypertension ............. ... ......... ................ 27
Assessing Cardiovascular Reactivity ......... ...... .. ............ .......... 32
Im pedance Cardiography ............ ........................................... 34
Ambulatory Blood Pressure Monitoring ............... ...... ............ 36
Blood Pressure Hyperreactivity to Stress in Borderline
Hypertensives ......... .................... .......................... ......... 40
Summary ............. .......... .. .. ................. ..... ..... 48









3 PROCEDURES AND METHODS ...... ....... ........................... 50

D esign ............. ...................................... .. ...... 50
Population and Sam ple .............. ............. .. .......... ............... 50
S getting ........... .. ............. ...... .... ............... ... . . .... 52
Research Variables and Instruments .............. ............ ........... 53
Study Protocol .............................. .................... .......... 60
Methods of Statistical Analyses .............. .......... ................ 65

4 R ESU LTS ............. ......... ............................ ........ 66

Descriptive Results .......... ............. .............................. 66
Analytic Results for Hypotheses ............ .......... ... .......... 69

5 DISCUSSION AND CONCLUSIONS ............................ 97

Discussion of Results ........................... .... ......... . ........ 97
C conclusions .................................................................... 107
Implications for Clinical Practice ......................... ... ........... 109
Recommendations for Future Research ................................... 110
S u m m a ry .................................................................. ............ 1 12

APPENDICES

A PATIENT CONSENT ...... ....... ........ ... ...... ............ 113

B DEMOGRAPHIC AND CLINICAL DATA COLLECTION SHEET... 119

REFERENCES ........ .... ......... ............................... ............ 120

BIOGRAPHICAL SKETCH ....... .................... ............... 131















LIST OF TABLES

Table page

3. Major variables measured or calculated during the laboratory
session ......... ... ......... ... .............. .. ................ ............. 64

4.1. Demographic data for the borderline hypertensive and
norm otensive subjects studied ...... ..... .................... .............. 68

4.2. Clinical characteristics of the borderline hypertensive and
normotensive subjects studied ............ ..... .............. ............ 69

4.3. Resting hemodynamics of the borderline hypertensive and
norm otensive subjects studied ...... ..... .................... .............. 70

4.4. Summary of beat-to-beat radial blood pressure during the stress
protoco l ............................................ .................... ... ... . ... 73

4.5. Group comparison of ambulatory blood pressure and variability
m measures ................................................... .... .......... ........... 81

4.6. Group comparison of nocturnal blood pressure and heart rate
reduction .. ........................................ .. 81

4.7. Group comparison of blood pressure reactivity and recovery ............. 93

4.8. Group comparison of ambulatory heart rate and variability
measures ......... .. ... ...... ................................... ........... 96















LIST OF FIGURES


Figure page

2.1. Hypothesized link between stress and hypertension ........................... 14

2.2. The configuration of the ascending aortic pressure wave ................... 23

2.3. Hypothesized changes in hemodynamics underlying enhanced pressure
responses to cognitive stress of normokinetic borderline hypertensives
versus normotensives ............ ......... .................... ............ 49

3. Calculation of the augmentation index ....... .............. ... .. ............56

4.1. Systolic blood pressure changes across the three experimental periods
................................................................................................. 74

4.2. Diastolic blood pressure changes across the three experimental periods
.............. .................... ............ ............ .......... . ....... 75

4.3. Pulse pressure changes across the three experimental periods ............. 76

4.4. Heart rate changes across the three experimental periods .................. 77

4.5. A comparison of arterial compliance between the normotensive control
group and the normokinetic borderline hypertensive group ............... 80

4.6 Relationship between augmentation index (Al) and age (bivariate
correlation) ............................................. .......... 86

4.7. Relationship between augmentation index (Al) and height (bivariate
correlation) .............. .. ....................... ................... .... ......... 87

4.8 .Relationship between augmentation index (Al) and stroke volume
(bivariate correlation) ............ ............................. 88

4.9. Gender comparison of augmentation index (Al) ............. ............. 89

4.10. Augmentation index across the three experimental periods in the
normal control versus normokinetic borderline hypertensive groups ..... 90









4.11. Relationship between augmentation index (Al) and arterial compliance
(SV/PP) ........ ..................................................... .... ......... 91

4.12. Arterial compliance across the three experimental periods in the
normotensive control versus normokinetic borderline hypertensive
g ro u p s ........................................ ........................ ...... .... 9 2

4.13. A comparison of ambulatory, clinic and laboratory systolic blood
pressure ................................. .......... ... .......... 94

4.14. A comparison of ambulatory, clinic and laboratory diastolic blood
pressure ................................. .......... ... .......... 95














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

HEMODYNAMICS AND ARTERIAL PROPERTIES UNDERLYING PRESSURE
RESPONSES TO COGNITIVE STRESS IN BORDERLINE HYPERTENSION

By

Pei-Shan Tsai

August 2001

Chairperson: Carolyn B. Yucha
Major Department: College of Nursing

It has been postulated that the blood pressure (BP) elevation observed in

borderline hypertension is caused by enhanced reactivity to stress. To further

elucidate the nature of pressure hyperreactivity in borderline hypertension,

hemodynamic and arterial responses to the Stroop Color Word Test (SCWT)

were studied in 23 borderline hypertensives and 19 normotensives, aged 20 to

63 and 24 to 64 respectively. Twenty borderline hypertensives had a cardiac

index less than the mean plus one standard deviation of the normotensive group

and were classified as the normokinetic borderline hypertensive subgroup. Blood

pressure reactivity to stress of the borderline hypertensives was compared to that

of the normotensives. Impedance-derived hemodynamics and arterial properties

underlying BP responses to stress were compared between the normokinetic

borderline hypertensive and the normotensive group.









Blood pressure was continuously recorded using a radial artery tonometer

during the stress protocol. Heart rate and stroke volume were measured using

the Minnesota impedance cardiograph. Augmentation index, an estimate of aortic

wave reflection, was measured using a radial applanation tonometer and a pulse

wave analysis system with a generalized transfer function. Arterial compliance

was estimated using the stroke volume to aortic pulse pressure ratio. Ambulatory

BP was also recorded at 30 to 60 minute intervals for a 24-hour period using an

autonomic noninvasive cuff-oscillometric recorder.

Total peripheral resistance was higher in borderline hypertensive than in

normotensive subjects. While arterial compliance was lower in normokinetic

borderline hypertensives than in normotensives, augmentation index was similar

between groups. The SCWT induced significant increases in systolic BP,

diastolic BP and mean arterial pressure, which were of similar magnitude for

borderline hypertensives and age-matched normotensives. Overall,

hemodynamic and arterial responses to the SCWT were similar in normokinetic

borderline hypertensives and normotensives. The BP reactivity to cognitive

stress likely resulted from tachycardia rather than a vasoconstriction response,

and was not associated with a change in wave reflection or compliance.

Evaluated with ambulatory BP monitoring, borderline hypertensive subjects had a

generally higher BP variability than normotensive subjects. Augmentation index

did not predict the degree of nocturnal BP reduction, nor did it differentiate

borderline hypertensives from normotensives, or dippers from nondippers.














CHAPTER 1
INTRODUCTION

This chapter will introduce the main variables under investigation including

cardiovascular reactivity, aortic wave reflection, arterial compliance, impedance-

derived hemodynamics, and ambulatory blood pressure. It will state 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 will also be described.


Background and Problem Statement

A widely held hypothesis is that cardiovascular hyperreactivity is a risk

factor for the development of essential hypertension. The reactivity hypothesis

draws on the response of the sympathetic nervous system (SNS) to stressful

environmental stimuli. Studies of the SNS response to stress involve several

limitations, including limited reproducibility of stressful stimuli-induced responses

(Mancia, 1997), limited external validity of laboratory stressors (Olga, Lucio,

Gueseppe, Stefano, & Paolo, 1995; Seibt, Boucsein, & Scheuch, 1998; Steptoe,

Roy, Evans, & Snashall, 1995), and the limited role the SNS is believed to play in

the long-term regulation of arterial pressure (Mark, 1996). Decreased arterial

compliance, which is associated with cardiovascular risk (Blacher, Asmar, Djane,

London, & Safar, 1999; Bortolotto, Blacher, Kondo, Takazawa, & Safar,









2000; Lehmann et al., 1998) and resetting of baroreceptors (Shepherd, 1990),

may provide the link between cardiovascular hyperreactivity and the

development of hypertension. Ambulatory monitoring of blood pressure (BP) and

heart rate (HR) offers valuable information to describe cardiovascular reactivity to

naturally occurring stress. Therefore it is important to incorporate measurements

of arterial compliance and ambulatory BP (ABP) monitoring in studies that

investigate the physiological mechanisms of cardiovascular reactivity in order to

further our knowledge of the link between cardiovascular reactivity and

hypertension.

Borderline hypertensives are individuals whose BP fluctuates around the

normal cut-off point defining hypertension. They are perfect human subjects for

studies of reactivity hypothesis because 1) cardiovascular changes during

psychological stressors resemble the pattern of cardiovascular activity observed

in borderline hypertension (Turner, 1994), and 2) the risk of developing

hypertension is increased in borderline hypertensives (Julius, 1986). However,

circulatory patterns are not uniformly identical among all subjects with borderline

hypertension. Borderline hypertensives with different circulatory states may

exhibit differences in the degree of nocturnal BP reductions and may respond to

stress via different physiological pathways (Jern, Bergbrant, Hedner, & Hansson,

1995). Arterial wall properties may explain the degree of nocturnal BP reduction

(Amar et al., 1997; Asar et al., 1996).

Hence, this study was proposed to undertake measurements of BP,

impedance-derived hemodynamics, and arterial properties noninvasively in









normotensives and age-matched borderline hypertensives (the latter subdivided

into normokinetic and hyperkinetic) before, during, and after a Stroop Color Word

Test. Ambulatory BP was also recorded at 30 to 60 minute intervals for a 24-hour

period. Measurements of the physiological basis and hemodynamic patterns

underlying blood pressure responses to laboratory stressors further our

understanding of possible mechanisms of hypertension development. Assessing

impedance-derived hemodynamic parameters and arterial properties during

stress helps to elucidate the mechanism of enhanced blood pressure responses

to cognitive stress in borderline hypertensives. Ambulatory BP recordings

document the circadian variations and clarify BP reactivity during everyday life.

Measuring arterial compliance as indexed by the SV/PP ratio contributes to a

better understanding of individual differences in circadian blood pressure

variation.


Purposes of the Study

1. To examine impedance-derived hemodyamic parameters underlying BP
responses to laboratory cognitive stress in borderline hypertensives and age-
matched normotensive subjects. Borderline hypertensives were further
divided into hyperkinetic and normokinetic subgroups on the basis of cardiac
index (CI). Blood pressure responses were measured using continuous
noninvasive arterial tonometry. Heart rate, stroke volume (SV) and total
peripheral vascular resistance (TPR) were measured using impedance
cardiography.

2. To characterize the difference in aortic wave reflection between
normotensives and normokinetic borderline hypertensives. Al measured by
applanation tonometry and a generalized transfer function indexed aortic
wave reflection amplitude.

3. To characterize the difference in arterial compliance between normotensives
and normokinetic borderline hypertensives. Arterial compliance was
estimated by the ratio of stroke volume and aortic pulse pressure: SV/PP.











4. To explore the pattern of changes in arterial compliance underlying BP
responses to cognitive stress in normotensives and borderline hypertensives.

5. To investigate the difference in 24-hour ABP profiles between borderline
hypertensives and normotensives.

6. To determine the association between augmentation index and the day-night
BP difference.

7. To determine the association between arterial compliance and the day-night
BP difference.

8. To determine the predictive power of pressure reactivity to cognitive stress on
ABP parameters.


Hypotheses

1. Borderline hypertensives have a greater increase in BP in response to
cognitive stress as compared to age-matched normotensive subjects.

2. Normotensives and normokinetic borderline hypertensives differ significantly
in their responses in HR, SV, and TPR to cognitive stress.

3. Normotensives and normokinetic borderline hypertensive subjects differ
significantly in aortic wave reflection as indexed by Al.

4. Normotensives and normokinetic borderline hypertensive subjects differ
significantly in arterial compliance as indexed by SV/PP.

5. Borderline hypertensives exhibit a greater ABP variability as determined by a
greater standard deviation of the average 24-hour BP, as compared to the
age-matched normotensives.

6. Normotensives exhibit a significantly greater day-night BP difference as
compared to normokinetic borderline hypertensives.

7. Aortic wave reflection as indexed by Al is predictive of the day-night BP
difference.

8. Arterial compliance as indexed by SV/PP is predictive of the day-night BP
difference.

9. Pressure reactivity is predictive of the average 24-hour and daytime BP.











Definitions of Terms

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. Al

was calculated as an index of aortic wave reflection amplitude (Kelly, Hayward,

Avolio, & O'Rourke, 1989). As arterial compliance decreases, Al increases.

Arterial Compliance

Compliance (inverse of stiffness) is defined as the change in volume per

unit change in pressure. In this study, arterial compliance is estimated as the

ratio of SV to aortic PP (Chemla et al., 1998; Ferguson, Julius, & Randall, 1984).

Impedance Cardiography

Impedance cardiography refers to the measurement of thoracic blood

volume changes in relating to myocardial performance derived from changes in

the electrical impedance (Sherwood et al., 1990).

Impedance-derived Hemodynamics

Impedance-derived hemodynamics refer to cardiac output (CO), SV, HR,

and TPR derived by measuring impedance changes occurring with each

heartbeat. In this study, these hemodynamic measures were obtained via the

Minnesota Impedance Cardiogram and SV was derived by the formula

developed by Kubicek et al. (1974):









SV = p x (L/Zo)2 x Tx (dZ/dt)min

where Rho (p) is the resistivity of blood, L is the mean distance between the two

inner electrodes in cm, Zo is the mean thoracic impedance between electrodes 2

and 3, T is the ventricular ejection time in seconds, and (dZ/dt)min is the minimum

value of dZ/dt occurring during the cardiac cycle in ohms per second. CO was

calculated from the formula: SV x HR. TPR was derived from the formula: MAP -

CO, where MAP is the mean arterial blood pressure derived from simultaneous

measurement of BP.

Pressure Reactivity

Pressure reactivity was defined as the absolute change of BP from the

baseline to the stress level. The absolute reactivity score was calculated by

subtracting the baseline BP from the stress level.

Pressure Recovery

Pressure recovery was defined as the absolute change of BP from the

stress to the recovery level. The absolute recovery score was calculated by

subtracting the recovery BP from the stress level.

Borderline Hypertension

There is no universally accepted operational definition for borderline

hypertension, which is usually referred to pressures fluctuating around the border

of the cutoffs defining hypertension (Sherwood, Hinderliter, & Light, 1995). In this

study, borderline hypertension is referred to as a transition from normotension to

hypertension. The definition of the "high-normal" and "hypertension-stage 1"

defined by the Sixth Report of the Joint National Committee (JNC-VI) on









Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-

VI, 1997) was selected as the definition of borderline hypertension.

Borderline Hypertensives

Subjects were categorized as borderline hypertensive if both of the two

screening systolic BP (SBP) measurements obtained on two separate occasions

fell in the range of 130 to 159 mm Hg and/or diastolic BP (DBP) measurements

fell in the range of 85 to 99 mm Hg.

Normotensives

Subjects were categorized as normotensive if both of the two screening

SBP measurements obtained on two separate occasions fell below 130 mm Hg

and DBP fell below 85 mm Hg.


Assumptions

1. Blood pressure response is obligatory and stereotypical.

2. A decrease in cardiac responsiveness must be accompanied by an
increase in vascular responsiveness.


Limitations

Categorization of hyperkinetic versus normokinetic borderline

hypertension was based on impedance-derived CI measurements. Borderline

hypertensive subjects who had a CI greater than the mean plus one standard

deviation of the normotensive control group were categorized as the hyperkinetic

borderline hypertensive subgroup. Those who had a CI below that level were

referred to as the normokinetic borderline hypertensive subgroup. As will be

discussed in Chapter 2, impedance cardiography is highly reliable in measuring









changes in CO but may not reflect individual absolute values. One might argue

that the accuracy of hemodynamic subgrouping within borderline hypertensives

was questionable. It has been suggested that the sources of measurement error

with impedance-derived measures are assumed to be systematic (Sherwood et

al., 1990). Based on this assumption, hemodynamic subgrouping remained

unchanged whether there was a systematic underestimation or overestimation of

CO.

Only 3 out of 23 borderline hypertensive subjects studied were

hyperkinetic by the subgrouping strategy. This uneven distribution made the

original intent to compare the two subgroups of borderline hypertensives

impossible. Nevertheless, a comparison between the normokinetic borderline

hypertensives and normotensives still offered valuable information.


Significance of the Study

Hypertension is one of the major causes of death in the United States

(Murphy, 2000). Borderline hypertensives have an increased risk of developing

essential hypertension (Julius, 1986). Enhanced BP responses to laboratory

stress have been found in borderline hypertensive subjects. The underlying

physiologic changes of enhanced pressure response to stress in borderline

hypertensives are still poorly understood. Whether increased BP responses in

borderline hypertensives are caused by an autonomic hyperreactivity or caused

by structural changes in peripheral vasculature remains controversial. This study

characterized differences in impedance-derived hemodyamic parameters and

arterial properties underlying BP responses to laboratory cognitive stress









between normokinetic borderline hypertensives and normotensives. A better

understanding of the physiologic mechanisms of BP variability in borderline

hypertensives may help in the selection of treatments for hypertension.

It is important to examine blood pressure variability during everyday life

when evaluating the reactivity hypothesis, given the limited external validity of

laboratory stressors. Therefore, this study also investigated the differences in BP

variability between borderline hypertensives and normotensives using ABP

monitoring.

This study also utilized ABP monitoring to gather information on the day-

night BP difference. Determining the association between arterial compliance

and the day-night BP difference may help to increase our understanding of the

nature of individual differences in circadian BP variation.














CHAPTER 2
REVIEW OF LITERATURE

This chapter will present a literature review of the following areas of

research: mental stress and cardiovascular reactivity in hypertension, large-

artery compliance, noninvasive measurements of aortic wave reflection

amplitude by pulse wave analysis, indirect measurement of total arterial

compliance, decreased large-artery compliance and arterial structural adaptation

in hypertension, assessing cardiovascular reactivity, impedance cardiography,

ambulatory blood pressure monitoring, and pressure reactivity to mental stress in

borderline hypertensives. A summary linking these areas together to provide the

research rationale for this study will conclude this chapter.


Mental Stress and Cardiovascular Reactivity in Hypertension

Overview of Stress and Reactivity in Hypertension

The reactivity hypothesis holds that exaggerated cardiovascular

responses to stress may contribute to the long-term development of essential

hypertension, or more precisely to the initiation of its development (Turner,

1994). No definitive evidence supports the link between cardiovascular

hyperreactivity and hypertension in human subjects. However, several lines of

evidence suggest that high reactors respond to behavioral stressors with

inappropriate cardiovascular responses (Light, 1987). The inappropriate









cardiovascular responses to stressful stimuli set pathophysiologic alterations in

motion that may eventually lead to the development of hypertension.

The reactivity hypothesis is based on the observations that offspring of

hypertensive parents (Falkner, 1991; Fredrikson, Tuomisto, & Bergman-Losman,

1991; & Perini et al., 1990) and borderline hypertensive subjects (Falkner, 1991;

Perini et al., 1990; Spence et al., 1990) exhibit greater circulatory and/or

neurohormonal reactivity to mental stress than normotensives. The evidence that

cardiovascular changes during psychological stressors resemble the pattern of

cardiovascular activity observed in borderline hypertension further supports the

notion of a hypothesized link between reactivity and hypertension (Turner, 1994).

Fredrikson (1991) suggested that a neurogenically mediated hyperreactivity to

stress is a precursor not a consequence of hypertension. Yet, the mechanism of

cardiovascular reactivity to stress in the etiology of hypertension has not been

clearly elucidated.

A critical question underlying the role of the reactivity hypothesis in

hypertension is whether reactivity to laboratory stress can predict future

hypertension. Higher SBP and DBP responses to a combination of mental and

physical stressors were associated with subsequent higher resting DBP among

206 middle-aged adults 6.5 years later (Matthews, Woodall, & Allen, 1993). In an

attempt to further clarify the predictive value of stress reactivity on later BP, 103

men originally tested at age 18 to 22 were reevaluated 10 years later (Light et al.,

1999). High reactors (top 25% on the basis of BP and cardiac responses during

both reaction time and cold pressor test) with positive family history of









hypertension demonstrated significantly higher SBP and DBP at follow-up. In a

subgroup of subjects who provided ratings of daily stress, the interactions among

positive family history, high daily stress and high stress reactivity were significant

in predicting follow-up SBP and DBP, suggesting that stress reactivity as a long-

term predictor is modulated by both genetic and environmental factors.

The reactivity hypothesis emphasizes individual differences in response to

stress with little attention paid to the nature of stress. Evidence suggests that

enhanced reactivity among hypertensive individuals may be related to the nature

of stressors. More specifically, mild hypertensives display exaggerated BP

reactivity to stress requiring active coping but not passive coping (Fredrikson,

1992; Steptoe, Melville, & Ross, 1984). Tasks involving active coping such as the

Stroop Color Word Test (SCWT) elicit predominantly beta-adrenergically

mediated cardiac activation (Hjemdahl, Freyschuss, Juhlin-Dannfelt, & Linde,

1984). Moreover, some researchers suggested that certain conditions such as

the presence of an incentive condition (Waldstein, Bachen, & Manuck, 1997) or

the level of task difficulty (Callister Suwarno, & Seals, 1992) also modulate the

hemodynamic basis of reactivity. However, in a study assessing hemodynamics

of BP responses during active and passive coping in 90 young healthy adult male

subjects, hemodyamic patterns of reactivity were an individual characteristic only

partially modified by coping demands (Sherwood, Dolan, & Light, 1990).

Hypothesized Link between Stress Hyperreactivity and Hypertension

Manuck and Kranz (1984) proposed two models to explain the relationship

between stress and hypertension: the recurrent activation model and the









prevailing state model. In the recurrent activation model, repeated transient

episodes of sympathetic arousal caused by stress increase the susceptibility to

hypertension. In the prevailing state model, a relatively persistent sympathetic

arousal alters autonomic regulation of BP. In the recurrent activation model,

laboratory-induced BP or HR reactivity corresponds to the magnitude of BP peak

during the everyday life, whereas in the prevailing state model laboratory-induced

BP or HR reactivity is indicative of the magnitude of the constant elevation of BP

during the waking hours (Manuck & Krantz, 1984). These two models differed

from each other not only in the presumptions but also in the underlying

pathophysiologic mechanisms. The differences with reference to underlying

mechanisms will be discussed later. Hypothesized links between hyperreactivity

to stress and the development of hypertension have been proposed, including

autoregulation theory, structural adaptation, and baroreceptor resetting (see

Figure 2.1).

Autorequlation. Obrist (1976) suggested that transient episodes of SNS

arousal result in excessive CO that may lead to the development of hypertension.

Obrist's notion appears to be in line with the recurrent activation model. Obrist

(1981) further indicated that the presence of exaggerated CO increases during

psychological stress lead to overperfusion of the body that eventually increases

peripheral vascular resistance through compensatory autoregulatory

vasoconstriction. Obrist (1981) also maintained that autoregulation is a transition

mechanism between the early stage and the more advanced stage of

hypertension. As described by Guyton and Coleman (1969), the whole body








autoregulates vascular tone and vascular resistance increases under conditions
of volume expansion. As vascular resistance increases a new equilibrium of
normal CO will be reached accompanied by a high BP.


3. Resetting of
Baroreceptor


Heart

S\4
T HR T CO
\400


Hypertrophy


Increased Arterial Pressure


Figure 2.1. Hypothesized links between stress and hypertension.

Fredrikson (1991) described two interrelated theories on SNS overactivity
in the development of essential hypertension. The "hyperreactivity theory"









suggests that individual differences in the autonomic nervous system activity are

the pathophysiological mechanism in the development of essential hypertension

and the "symptom-specificity theory" suggests that stereotypical SNS responses

enhance the risk of hypertension. The hyperreactivity theory is consistent with

the recurrent activation model and the above mentioned hypothesis proposed by

Obrist that transient episodes of increased CO induce hypertension by increasing

peripheral vascular resistance (Fredrikson, 1991).

Structural adaptation. As cited by Manuck and Krantz (1984), Julius and

colleagues proposed a model resembling the prevailing state model, which

stated that certain behavioral characteristics induce a permanent state of

enhanced arousal accompanied by alterations in centrally integrated

cardiovascular autonomic tone that accounts for an increased SNS activity that

increases CO and consequently BP. Julius and Nesbitt (1996) further showed

evidence against autoregulation as the mechanism explaining the transition of

borderline hypertension to established hypertension. They found a lack of volume

expansion and no evidence of increased oxygen consumption in borderline

hypertension, suggesting that the increased CO is appropriate for the increased

metabolic needs of the body.

As previously discussed, once hypertension is established CO is usually

not increased, but rather peripheral vascular resistance is increased. The whole-

body autoregulation theory does not apply to the chain of hemodynamic

transitions including a decrease in CI and an increase in TPR over time (Lund-

Johansen, 1986; Julius & Nesbitt, 1996) as the whole-body oxygen consumption









is increased (Lund-Johansen, 1986) and plasma volume is relatively low (Julius

& Nesbitt, 1996) in borderline hypertensives.

Folkow (1993) suggested that in the early phase essential hypertension is

mainly manifested as enhanced central neurohormonal activity and CO is

increased more than TPR. As the interaction among genetic predisposition,

environmental effects, and aging effects progresses, structural upward resetting

of the heart and vessels becomes more evident and manifested as increased

systemic resistance.

Julius and Nesbitt (1996) indicated that increased sympathetic stimulation

and decreased parasympathetic tone mediate the early phase (hyperkinetic

state) of hypertension. The involvement of both enhanced alpha- and beta-

adrenergic tone combined with a blunted parasympathetic tone suggests a

centrally integrated abnormality. Continued sympathetic stimulation in

hypertension eventually leads to myocardial (i.e., decreased beta-receptor

responsiveness and cardiac compliance) and vascular (i.e., vascular

hypertrophy) structural changes, which then cause decreased cardiac

responsiveness and increased vascular responsiveness. Decreased beta-

adrenergic responsiveness and decreased end-diastolic distention of the heart in

combination with increased alpha-adrenergic responsiveness of the resistance

vessels lead to the hemodynamic transition (from high CO to high resistance)

over the course of hypertension (Julius, 1991). In parallel to the hemodynamic

transition, the SNS tone is down regulated since less sympathetic drive is

needed with exaggerated vascular responsiveness (Julius, 1991). Although









focusing on different aspects of pathogenesis, the pathophysiological

mechanisms underlying hemodynamic transition over the course of hypertension

proposed by Julius seem to be consistent with Folkow's structural upward

resetting hypothesis.

Resetting of arterial baroreceptors. Arterial baroreceptors are sensitive to

arterial pressure. In the short term, they detect a change in pressure and regulate

blood pressure through a sino-aortic baroreflex feedback loop (Guyton, 1991).

Arterial baroreceptors respond to an increase in blood pressure by increasing the

afferent traffic to the cardiac acceleration center in the medulla. As a result, the

efferent sympathetic traffic is decreased. In chronic hypertension, the

baroreceptors can become reset over time, so that the pressure is maintained at

a higher level.

Several mechanisms for resetting the arterial baroreceptors have been

suggested, including viscoelastic relaxation of wall elements, genetic

abnormalities in membrane permeability, decreased arterial compliance,

alterations in endothelium-derived factors (Shepherd, 1990), and a defect in

central mediation of the baroreflex (Chapleau, Cunningham, Sullivan, Wachtel, &

Abboud, 1995). Of more relevance for present concerns, decreased arterial

compliance seems to provide the link among stress, sympathetic overactivity and

hypertension. Markedly increased carotid artery compliance has been shown

following sympathectomy in rats, suggesting a sympathetic modulation of arterial

compliance (Mangoni, Mircoli, Giannattasio, Mancia, & Ferrari, 1997). In chronic

hypertension, an increase in collagen as a result of structural changes in the









vessel wall secondary to increased sympathetic outflow might stiffen the large

arterial walls. Stiffening of vessel walls in the aortic arch and carotid sinus alters

the responsiveness of baroreceptors to stretch. Hence, decreased

mechanoreceptor activity and chronic resetting could occur.

On the other hand, however, baroreflex impairment has not been

demonstrated for the blood pressure component of the reflex in hypertension

(Mancia, 1997). Thus, the baroreflex does not appear to be the origin of

sympathetic activation.

Limitations of the Reactivity Hypothesis

Despite years of investigation, the role played by cardiovascular

hyperreactivity in the development of hypertension remains largely unknown.

Reactivity hypothesis draws on the response of the SNS to stressful

environmental stimuli. Studies of the response of the SNS to stress involve

several limitations. First, the effect of any given stressful stimuli has limited

reproducibility (Mancia, 1997). An individual can respond to one stressor with

profound cardiovascular responses and respond to other stressors without

cardiovascular arousal. Second, laboratory stressors have limited external

validity. Some suggest that the BP response (Olga et al., 1995) or reactivity

(Seibt et al., 1998; Steptoe et al., 1995) to laboratory stressors does not predict

ambulatory blood pressure during everyday life. Finally, it has been argued that

the SNS is not important in the long-term regulation of arterial pressure (Mark,

1996). This argument is based on the observation that several pathological









conditions with marked sympathetic activation, such as heart failure and

cirrhosis, are not accompanied by increased arterial pressure (Mark, 1996).

To date, no definitive evidence supports the link between stress

hyperreactivity and the development of hypertension in human subjects, although

several possible links between stress hyperreactivity and hypertension have

been proposed. The following section will review arterial compliance, an

important concept in the natural history of hypertension. Investigating the

contribution of arterial compliance to cardiovascular hyperreactivity may provide

new insights into the role of stress hyperreactivity in the development of

hypertension.


Large-Artery Compliance

Arterial Compliance and Pulse Wave Amplitude, Velocity, and Reflection

Compliance, distensibility and stiffness are often used interchangeably by

researchers. Mathematically and conceptually, they are different. Compliance of

an arterial segment represents the increase in its cross-sectional volume for a

given increase in pressure, which does not account for the diastolic dimension

before distension begins. Distensibility is compliance normalized by arterial

diameter. Stiffness is the reciprocal of dispensability.

Recently, the concept of hypertension as a condition characterized by

elevated peripheral vascular resistance has been challenged because it ignores

the pulsatile component, PP, of arterial pressure. Ventricular ejection interacting

with viscoelastic properties of the large arteries and wave reflection are two

major determinants of the pulsatile component of BP. An increased PP reflects









decreased arterial compliance (inverse of stiffness). Thus, elevated SBP and PP

are now considered to be more reliable indicators of cardiovascular risk than is

DBP (Alderman, 1999; Benetos, 1999; Safar, 1999).

In order to better understand this reevaluation of the indicators of

cardiovascular risk, it is important to reexamine the concept of large arteries as

simple passive conduits. Large arteries cushion pulsatile flow generated by

ventricular contraction during each cardiac cycle, transforming intermittent flow

into a steady flow of blood in the periphery and reducing the pressure oscillations

caused by the intermittent ventricular ejection (London & Guerin, 1999 & Safar,

1989). The viscoelastic properties of the arterial wall, termed arterial compliance

or distensibility, determine the artery's ability to perform this cushion function.

During systole, large arteries (e.g., the proximal aorta) expand to accommodate

SV and rebound during diastole to facilitate forward blood flow. When arterial

compliance is decreased, less cushioning of SV occurs in the arterial bed during

systole, so a greater proportion of SV is forwarded to the periphery.

Consequently, the amplitude of the arterial pulse wave during systole increases

and diastolic pressure falls (London & Guerin, 1999).

Arterial compliance also determines pressure wave travel and reflection in

the arterial system. The incident wave generated by the ventricular ejection

moves away from the heart at a finite speed. The speed of pulse wave

propagation (pulse wave velocity) increases as arterial compliance decreases.

The proximal aorta is relatively compliant to accepting the stroke volume. As the

aorta extends distally, it becomes less compliant.









The compliance of the arteries also decreases with distance from the

heart. Because the velocity of wave travel is faster in stiffer and smaller vessels,

this structure causes a progressive increase in pulse wave velocity along the

arterial tree (Nichols & O'Rourke, 1998). There is also a progressive increase in

pulse pressure from the central aorta to peripheral sites. This pulse pressure

amplification is less evident with aging (Nichols & O'Rourke, 1998), probably due

to the increased aortic pulse wave velocity, which is secondary to aortic stiffness.

In healthy adults, the pulse wave velocity is approximately 7.3 m/s from the heart

to the radial artery, and 8.0 m/s from the heart to the femoral artery (Nichols &

O'Rourke, 1998).

The incident (forward) wave is reflected backward along the arterial

system from peripheral reflection sites to the ascending aorta. A high level of

arterial stiffness (decreased compliance) causes an increase in pulse wave

velocity and earlier return of the reflected wave to the ascending aorta (Nichols &

O'Rourke, 1998; O'Rourke, 1990). Early return of reflected pressure waves adds

to the amplitude of the incident wave during the systolic phase. Thus, the

augmentation in the systolic part of the ascending aortic pressure further

increases systolic pressure and ventricular afterload.

In summary, as arterial compliance decreases, both the amplitude of the

pressure wave generated by ventricular ejection and pulse wave velocity

increase, causing an early return of the reflected pressure waves from the

periphery to the aorta. An increase in large-artery stiffness and a consequent

increase in the amplitude of wave reflection results in a disproportionate increase









in SBP and arterial pulsatility. This disproportionate increase in SBP increases

pulse pressure, producing the phenomenon known as isolated systolic

hypertension (Nichols, Nicolini, & Pepine, 1992).

Aortic Pressure Wave Contours

The aortic pulse pressure waveform generally contains an inflection point,

caused by the reflected wave, that divides the pressure wave into an early and a

late systolic peak (Type A and Type B contours, according to Murgo's

classification) (Nichols & O'Rourke, 1998). Middle-aged adults or individuals with

hypertension exhibit Murgo Type A and B aortic pressure wave contours with

peak systolic pressure (Ps) occurring in late systole after an inflection point (Pi).

(Ps Pi) / (Ps Pd) has been termed the augmentation index (Al), where Pi is

the first systolic shoulder or inflection point, Ps is the second systolic shoulder or

peak systolic pressure (SBP), and Pd is the minimum DBP (Kelly et al., 1989). A

Type A pressure wave contour has an Al of greater than 12%. Al is between 0

and 12% in a Type B pressure wave contour. Younger adults exhibit a Murgo

Type C contour with a smaller reflected wave beginning in late systole or

diastole. In such cases, Ps precedes Pi. Al is less than zero in a Type C pressure

wave contour. The Type A and Type C pressure wave contours are graphically

presented in Figure 2.2. A Type D beat classified by Nichols and colleagues, is

only seen in adults over 65 years of age (Nichols & O'Rourke, 1998). In Type D

beats, there is no inflection point because the reflected pressure wave begins in

early systole and merges with the incident wave. In summary, the aortic pressure









wave contour and Al change with age. Augmentation index is an index of aortic

wave reflection amplitude and will be discussed in the following section.



Ps P


Pi



Pi Pd
Pd




Figure 2.2. The configuration of the ascending aortic pressure wave. Pi: inflection
point, Ps: peak systolic pressure, Pd: minimum diastolic pressure. The diagram
on the left is a Type A contour. Notice that in a Type A contour the peak systolic
pressure (Ps) occurs in late systole after an inflection point (Pi). The right
diagram is a type C contour. Notice that in a Type C contour the peak systolic
pressure (Ps) precedes the inflection point (Pi).


Noninvasive Measurements of Aortic Wave Reflection Amplitude by Pulse
Wave Analysis

In studying arterial modifications in hypertension, the determination of

arterial compliance and wave reflection amplitude can be estimated by pulse

wave analysis (PWA) (O'Rourke & Gallagher, 1996; Nichols & O'Rourke, 1998).

PWA or sphygmocardiography is the analysis of aortic pulse waveforms to

identify systolic and diastolic periods and to generate indices of ventricular and

vascular interaction, including the aortic augmentation index (O'Rourke &

Gallagher, 1996). Modern PWA allows synthesis of the ascending aortic pressure

wave, central arterial BP and related indices from carotid or radial artery pressure









waves by use of noninvasive arterial applanation tonometry with a validated

generalized transfer function (Karamanoglu, O'Rourke, Avolio, & Kelly, 1993;

Nichols & O'Rourke, 1998; O'Rourke & Gallagher, 1996; Siebenhofer, Kemp,

Sutton, & Williams, 1999).

The application of applanation tonometry is based on the principle that

when the curved surface of a rounded pressure-containing chamber (artery) is

partially flattened, pressures are normalized and a sensor on the flattened

surface can record the pressure within the artery (O'Rourke & Gallagher, 1996).

Augmentation Index (Al)

The aortic Al is an indicator of the magnitude of wave reflection, which is

closely linked to aortic pulse wave velocity (Kelly et al., 1989). Aortic pulse wave

velocity is an well-established measurement of arterial compliance. Pulse wave

augmentation of the synthesized wave is determined by identification of the tidal

wavefoot and expressed as a percentage of pulse pressure (O'Rourke &

Gallagher, 1996). Al measures the relative contribution of the reflected wave to

the SBP in central arteries. Kelly et al. defined Al as the percentage of aortic

pulse pressure due to the late systolic peak, which is attributed to the reflected

wave. Al is calculated as the difference between early and late aortic systolic

peaks divided by aortic PP.

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) have









demonstrated that measurement of Al with applanation tonometry is highly

reproducible and precise, with a correlation coefficient of .98 between visits and a

coefficient of variation of 1.3%. Likewise, Siebenhofer et al. (1999) also reported

that Al by applanation tonometry and PWA has excellent interobserver

reproducibility, with interobserver measurement difference being only 2.7%.

The reproducibility of Al 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 Al. They observed a low standard deviation

for within-observer and between-observer measurement differences (5.37% and

3.80 %, respectively).

Possible correlates of Al include age (Cameron, McGrath, & Dart, 1998;

Kelly, Millasseau, Ritter, & Chowienczyk, 2001; Liang et al., 1998, Yasmin &

Brown, 1999), body height (Cameron et al., 1998; Rietzschel, Boeykens, De

Buyzere, Duprez, & Clement, 2001; Yasmin & Brown, 1999), and HR (Cameron

et al., 1998; Wilkinson et al., 2000). A positive correlation between age and Al

was found by previous reports with a correlation coefficient ranging from .40 to

.70. A negative correlation was found between height and Al with a correlation

coefficient ranging from -.43 to -.49. The correlation coefficient for HR and Al

varied among studies and ranged from -.28 to -.76.

In summary, Al is an index of the magnitude of aortic wave reflection. Al

measurements via applanation tonometry and PWA demonstrated acceptable









accuracy and reproducibility in previous studies. Yet, this measure is slightly to

moderately correlated with HR, height, and age.


Indirect Measurement of Total Arterial Compliance

Arterial compliance provides information about the viscoelastic properties

of the arteries. The SV/PP ratio has been proposed as an estimate of total

arterial compliance (Chemla et al., 1998; Ferguson et al., 1984; Randall,

Westerhof, van den Bos, & Alexander, 1986). Randall et al. demonstrated a

close relation between compliance estimated by the SV/PP ratio and by the ratio

of the diastolic-decay time constant using a Windkessel model (r = .58). Chemla

et al. demonstrated that the difference between the SV/PP ratio and compliance

estimated by the area method was not significant and there was a linear

correlation between the two measurements (r = .98). Resnick et al. (2000)

demonstrated that the ratio of SV to PP was correlated with both capacitive (C1)

and oscillatory (C2) compliance of the arterial tree using a modified Windkessel

model (r = .92 and .68, respectively). Such studies have validated the accuracy

of the SV/PP ratio as an estimate of arterial compliance.

SV/PP may also be a possible predictor of cardiovascular morbid events.

de Simone et al. (1999) demonstrated that the SV/PP ratio was an independent

predictor of total cardiovascular events in Cox proportional hazards analysis

independent of age and left ventricular mass.

Possible correlates of the SV/PP ratio include age, body size, and HR

(Gudbrandsson et al., 1992). The distribution of the SV/PP ratio was skewed

toward larger values in normal young adults with larger body size. Those









subjects with the lowest SV/PP ratio had higher SBP, lower DBP, higher HR,

and higher left ventricular wall thickness ratio compared to subjects with higher

arterial compliance.


Decreased Large-Artery Compliance and Arterial Structural Adaptation in
Hypertension

Although decreased large-artery compliance has been identified as a

major risk factor for cardiovascular events (Blacher et al., 1999; Bortolotto et al.,

2000; Lehmann et al., 1998), its role in the pathogenesis of arterial hypertension

remains largely unknown. Decreased arterial compliance is most markedly seen

in central elastic arteries such as the aorta (O'Rourke, 1990; O'Rourke, 1999;

Smulyan & Safar, 1997). The compliance or distensibility of the aorta, which is

determined by its wall structure, its smooth muscle tone, and the BP level,

decreases with aging and arterial hypertension (O'Rourke, 1990; O'Rourke,

1999).

Since Folkow (1987) demonstrated that structural adaptation occurs in

response to altered functional demands in hypertension, increased arterial wall

thickness, termed intima-media thickness, is widely regarded as a hallmark of

hypertension. Increasing strong evidence suggests that the increased intima-

media thickness is caused by rearrangement of existing materials around a

vascular lumen and a consequent reduction in lumen diameter, a process called

vascular remodeling (Kaplan, 1998).

Decreased arterial compliance may play a role in the pathogenesis of

hypertension. It may occur irreversibly as a result of arterial changes (mainly an

increased intima-media thickness). Alternatively, decreased arterial compliance









may be a consequence of elevated arterial pressure, which occurs without any

structural change in the artery.

Gribbin, Pickering and Sleight (1997) found that an acute rise in arterial

distending pressure induced a rise in pulse wave velocity. Pulse wave velocity is

a well-accepted index of arterial compliance (Nichols & O'Rourke, 1998; Smulyan

& Safar, 1997). However, no difference in pulse wave velocity was found

between hypertensives (n = 17) and normotensives (n = 21) after mechanically

inducing identical arterial distending pressures of 120 mm Hg. The findings from

this study suggest that decreased compliance of large arteries in hypertension is

a consequence of high arterial pressure and is not due to irreversible arterial

changes. Laurent et al. (1993) also found no difference in isobaric compliance

and distensibility of the radial artery between hypertensive and normotensive

subjects.

Reduced compliance of large arteries in patients with mild essential

hypertension might occur in the absence of structural vessel wall alterations

(Barentbrock et al., 1999). In this study 10 mild untreated hypertensive subjects

with normal intima-media thickness, 10 with increased intima-media thickness

(above 95% CI of normal controls) and 13 age-matched normotensives were

studied. Both groups of hypertensives did not differ in systolic and diastolic blood

pressure or heart rates. Brachial and carotid distensibility coefficients were

significantly lower in both groups of hypertensives when compared with

normotensives. Analysis of covariance further revealed that brachial artery

distensibility coefficients were significantly lower in both groups of hypertensives









when compared with normotensives, independent of age and brachial artery end-

diastolic diameter. There was no correlation between carotid artery intima-media

thickness and carotid or brachial artery distensibility coefficients.

In the Atherosclerosis Risk in Communities study, the relationship

between hypertension and arterial compliance assessed in 10,712 men and

women of 45 to 64 years of age (Arnett et al., 2000). Carotid artery compliance

was assessed using ultrasound technique with concurrent measurement of

brachial artery blood pressure. Hypertension was classified using the blood

pressure classification from the Fifth Joint National Committee. Using statistical

models to control for DBP and PP, arterial diameter change was calculated in

normotensive, medicated and nonmedicated hypertensives. Hypertension was

associated with a smaller adjusted carotid diameter change (greater stiffness)

when compared to normotensives, or medicated hypertensives with optimal

blood pressure. The pressure-adjusted diameter change was inversely related to

DBP in all gender-medication groups. Moreover, the relationship between PP

and carotid arterial diameter change (the slope of the PP and diameter change)

did not differ between hypertensives and normotensives, suggesting that

hypertension-related carotid arterial stiffness is the effect of distending pressure

rather than structural changes in the carotid artery.

Animal studies, however, have shown that hypertension decreases arterial

distensibility or compliance by inducing arterial structural changes, including

hypertrophy and increasing collagen in the extracellular matrix (Albaladejo at al.,

1994; Bunkenburg, van Amelsvoort, Rogg, Wood, 1992). In a newly published









report, van Gorp et al. (2000) assessed thoracic aortic wall properties using an

ultrasound technique combined with invasive BP measurements in 1.5, 3, and 6

month-old spontaneously hypertensive rats (SHR) and normotensive rats. In 1.5

month-old SHR, both compliance and the distensibility coefficient were

significantly lower and media thickness and cross-sectional areas were

significantly larger than normotensive rats, but blood pressure was not

significantly different. Compliance was significantly lower and blood pressure was

significantly higher in 3- and 6-month-old SHR than normotensive rats at the

corresponding age. Yet, the total collagen density and content of the thoracic

aortic wall were not significantly different between strains, van Gorp et al.

suggested that 1) in SHR in which hypertension develops over weeks, altered

thoracic aortic properties precede the development of hypertension; and 2) the

alterations in aortic properties are most likely caused by media hypertrophy

rather than a change in the composition of the wall.

The association of large arterial wall hypertrophy and decreased

compliance has been confirmed in human subjects. In 1996 Tice et al. examined

carotid artery intima-media thickness using B-mode ultrasound imaging and

carotid arterial waveforms using applanation tonometry in a group of 20 patients

with newly diagnosed essential hypertension, 18 patients with chronic

hypertension, and 32 subjects with normal BP. These investigators found that

carotid intima-media thickness was significantly greater in patients with early

hypertension and chronic hypertension as compared with that in control subjects.

In patients with chronic hypertension, an increased incidence of early waveform









refection on carotid arterial waveform was evident. Using multiple regression

analysis, age, SBP and Murgo class of arterial waveform (type A, B and C aortic

pressure wave contours) are independent predictors of increased intima-media

thickness. Tice et al. concluded that conduit artery thickness is significantly

related to the degree of pressure elevation and the arterial waveform contour.

Again, in a study investigating arterial structure and function in 50 healthy

volunteers (aged 20 70), all indices of arterial compliance measured by

ultrasonography technique (DC), Doppler technique (systemic arterial

compliance) or applanation tonometry (pulse wave velocity and Al) were

significantly correlated with carotid intima-media thickness (Liang et al., 1998).

Similarly, Boutouyrie et al. (1999) demonstrated a prominent influence of

pulsatile mechanical load, as determined by carotid PP, on arterial remodeling. In

this study, carotid PP, a surrogate measure of arterial compliance was

associated with carotid internal diameter (r = .33) and intima media thickness (r =

.42) in healthy (n = 43) and untreated hypertensive subjects (n = 124). Kohara,

Jiang, Igase and Hiwada (1999) also demonstrated a significant positive

correlation between carotid Al assessed with a strain gauge transducer and

carotid intima-media thickness (r = .28, p = .018) in patients with essential

hypertension.

Despite the evidence of pressure-independent changes on arterial wall

properties, the exact nature of the alterations in the aortic structural properties

that lead to a decrease in aortic compliance with hypertension is still poorly

understood. Nevertheless, animal and human studies have confirmed the









association between decreased compliance and hypertrophic structural changes

in large arteries, suggesting an important role played by decreased large-artery

compliance in the pathogenesis of hypertension.

The role of arterial compliance in cardiovascular reactivity has not yet

been elucidated. As discussed earlier, decreased arterial compliance is one of

the mechanisms leading to resetting of baroreceptors. Resetting of baroreceptors

is a hypothesized link between stress hyperreactivity and hypertension.

Therefore, decreased arterial compliance may provide the link between

hyperreactivity and the development of hypertension.


Assessing Cardiovascular Reactivity

Measuring Blood Pressure Reactivity

Reactivity is defined as a change in physiological activity from a resting

baseline period to a task period (Turner, 1994). Blood pressure reactivity is

calculated by subtracting the baseline blood pressure value from the blood

pressure value in the task period. Both mean raw changes and percent change

from baseline have been reported in the literature (Turner, 1994). Since

anticipatory psychological arousal may affect pretask baseline values and

consequently the estimation of reactivity, a period of stabilization and relaxation

of 15 30 minutes is commonly adopted.

Blood pressure responses to stress were often measured by noninvasive

methods, which were employed either manually or automatically to sample blood

pressure at intervals (de Champlan, Petrovich, Gonzalez, Lebeau, & Nadeau,

1991; Sherwood et al., 1995; Nawarycz, Ostrowska-Nawarycz, & Kaczmarek,









1999). Sampling blood pressures at intervals may not be able to detect the

reactivity. It is suggested that cardiovascular responses to stressors have such a

dynamic time course that they can only be assessed by continuous intraarterial

blood pressure monitoring (Parati et al., 1991). Such an invasive measure

excludes a large number of participants and renders the issue of self-selection.

Also the subject's discomfort and distraction may confound the results of testing.

In this regard, Parati et al. suggested that a noninvasive apparatus that provides

continuous beat-to-beat blood pressure values is preferable.

Hemodynamic Measurements of Reactivity

Noninvasive hemodynamic measures, such as SV, CO, and TPR are

facilitated by impedance cardiography in studies on hemodynamic effects of

physiological and psychological interventions. Measuring thoracic impedance

changes during each cardiac cycle derives SV. CO is calculated from the

formula: SV x HR. TPR is derived from the formula: MAP CO, where MAP is

the mean arterial blood pressure derived from simultaneous measurement of BP.

Recording impedance-derived hemodynamic parameters during stress

can help to assess cardiac and vascular components of responses underlying BP

changes. The application of impedance cardiography is useful in differentiating

underlying cardiovascular changes in blood pressure responses between two

stress tasks and between two study groups performing an identical task (Parati et

al., 1991).









Impedance Cardiography

Impedance cardiography involves the creation of an electrical field in the

chest by passing a small current between four electrodes placed around the neck

and lower thorax (Kubicek et al., 1974). Resistance associated with alternating

current is known as impedance. The change in impedance seen during each

cardiac cycle is indicative of the amount of blood flowing in the aorta and

therefore being ejected by the heart into the arterial tree. Greater decreases in

impedance are associated with greater amounts of blood.

The impedance cardiograph generates the following through the electrical

signals: 1) the mean thoracic impedance between electrodes 2 and 3 (Zo); 2) the

impedance change during the cardiac cycle, delta Z (AZ); 3) the first derivative of

AZ with respect to time; and 4) the electrocardiogram (EKG). When blood is

ejected from the left ventricle, changes in electrical impedance can be monitored

electronically to obtain a measurement of SV using the following formula derived

by Kubicek et al. in 1974:

SV = p x (L/Zo)2 x T x (dZ/dt)min

where Rho (p) is the resistivity of blood, L is the mean distance between the two

inner electrodes in cm, Zo is the mean thoracic impedance between electrodes 2

and 3, T is the ventricular ejection time in seconds, and (dZ/dt)min is the

minimum value of dZ/dt occurring during the cardiac cycle in ohms per second.

The validity of the impedance-derived measurements has been

established by comparison with reference measures. White et al. (1990)

demonstrated a linear correlation between SV derived from impedance









cardiography using the Kubicek equation and SV derived from an

electromagnetic flowmeter in dogs at any level of hematocrit over a wide range of

SV. These findings were also supported by studies in humans and rabbits where

impedance-derived SV were compared simultaneously with Fick and

thermodilution-derived SV (White et al., 1990). A close agreement between

impedance derived-CO and CO measured by the thermodilution method in

humans has been reported in the absolute values (r = .85) and in the percent

change (r = .87) (Goldstein, Cannon, Zimilichman, & Keiser, 1986). A high

correlation (r = .82) has also been shown between impedance-derived SV and

SV measured by nuclear ventriculography in humans (Wilson, Sung, Pincomb, &

Lovallo, 1989). However, researchers have shown that impedance cardiography

tends to overestimate the absolute values of CO (Mehlsen et al., 1991).

Investigators have provided evidence that supports outstanding

reproducibility for impedance-derived measurements. SV measured by

impedance cardiography showed good reliability across and within days in the

same subjects (r = .92 ~ .96) (Wilson et al., 1989). In 1991 Mehlsen et al. studied

37 healthy subjects and 25 unmedicated patients with ischemic heart disease

and obtained highly reproducible measures within the same day (standard

deviation of the differences in CO = 0.12 L/min) and on different days (standard

deviation of the differences in CO = 0.45 L/min) based on a total of 270

measurements. Mehlsen et al. also reported low intraobserver variability

(standard deviation of differences in CO = 0.12 L/min).









Although impedance-derived measures do not reflect individual absolute

values, the sources of measurement error with impedance-derived measures are

assumed to be systematic (Sherwood et al., 1990). Hence, the applicability of

relative changes in these measures within subjects is generally accepted.

In conclusion, impedance cardiography is reliable in measuring changes in

CO and suitable for repeated measurements in studies on the hemodynamic

effects of physiological and psychological interventions.


Ambulatory Blood Pressure Monitoring

Overview of Ambulatory Blood Pressure Monitoring

Ambulatory BP monitoring has now become an established research tool

in clinical trials. This methodology limits threats to external validity and the effects

of observers on psychological and physiological response. In addition, ABP

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 difference), and BP load (percentage of systolic and

diastolic readings greater than 140 and 90 mm Hg during the day or greater than

120 and 90 mm Hg during the night).

Several of these variables correlate with the extent of target organ

damage or risk of cardiovascular events. In the HARVEST study, the rate of

excretion of albumin was highly related to 24-hour BP (Palatini, 1999). In the

ELSA trial, 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.

Circadian Blood Pressure Variations

One of the most important parameters of ABP is the day-night BP

difference, or nocturnal BP reduction. 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). May, Arildsen, & Damsgaard (1998) indicated 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.

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).









The mechanisms responsible for differences between individuals who

show a nocturnal reduction in BP and those who demonstrate no such reduction

in BP are still unclear. Schillaci et al. (1996) studied a large population of

subjects with essential hypertension to determine the independent predictors of

diurnal BP changes. Schillaci et al. demonstrated that predictors of day-night BP

difference included age, clinical BP, diabetes, the reported duration of sleep,

smoking habit and working activity during ABP monitoring. The nocturnal BP

reduction decreased with age and the prevalence of nondippers was greater in

elderly than in younger subjects (Di Lorio, Marini, Lupinetti, Zito, & Abate, 1999).

Both the absolute value and the ratio of nocturnal BP reduction showed a

curvilinear correlation with age with the smallest reduction and the largest ratio

observed in the elderly (> 70 years) (Staessen et al., 1997).

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 have 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 or inverse

nocturnal BP reduction.









Ambulatory Blood Pressure and Blood Pressure Reactivity

An important question with regard to reactivity observed in laboratory

settings is: Do those people who show exaggerated responses to laboratory

stressors also show large responses to stress in the natural environment during

normal daily activities? Combining laboratory stress research with 24-hour

ambulatory monitoring of blood pressure and heart rate has become a common

approach in reactivity research (Krantz & Wing, 1984). Ambulatory monitoring of

blood pressure and heart rate offers valuable information to describe

cardiovascular reactivity to naturally occurring stress. Ambulatory blood pressure

monitors can be programmed to measure blood pressure and heart rate every 30

to 60 minutes during a 24-hour period. Blood pressure variability (e.g., the

standard deviation of the 24-hour BP) can then be calculated. Greater variability

corresponds to heightened cardiovascular reactivity during naturalistic conditions

(Parati et al., 1991).

Two models of laboratory-field generalization have been adopted: (1) to

obtain ambulatory measures when a selected real-life stress occurs, or (2) to

obtain ambulatory measures when subjects go about their normal daily activity

(Turner, 1994). Given the complexity of the context in which stressors occur, and

the factors operating on subjects to produce the BP responses, subjects should

keep a brief diary, which describes circumstances each time a recording occurs

(Krantz & Wing, 1984). Behavioral information such as posture, physical activity,

consumption of caffeine, alcohol, and nicotine, and the subject's affective state

are of particular interest (Krantz & Wing, 1984; Turner, 1994). This behavioral









information is also useful in disentangling the influences resulting from factors

other than psychological stressors on cardiovascular responses (Turner, 1994).

Contradictory findings have been reported in studies using correlational

analyses to examine the relationship between psychologically induced laboratory

reactivity and reactivity obtained by ambulatory measurements (Fredrikson,

Blumenthal, Evans, Sherwood, & Light, 1989; Georgiades, Lemne, de Faire,

Lindvall, Fredrikson, 1996; Jern et al., 1995; & Seibt et al., 1998). Confounding

influences on ambulatory measures of cardiovascular activity may obscure this

relationship.


Blood Pressure Hyperactivity to Stress in Borderline Hypertensives
Characteristics of Borderline Hypertensives

Borderline hypertension represents a transitional phase from

normotension to hypertension. The risk of developing hypertension is increased

in borderline hypertensives (Julius, 1986). Lindvall, Kahan, de Faire, Ostergren,

and Hjemdahl (1991) indicated that mild hypertension is associated with

enhanced arousal and cardiac activation during rest. Increased CO and HR have

been found in young borderline hypertensives. Young (age 40 and less)

borderline hypertensives have a higher resting Cl and HR than normotensive

age-matched controls (Lund-Johansen, 1986). Circulatory patterns in the history

of borderline hypertension exhibit a hyperkinetic state characterized by high Cl

and HR preceding a normokinetic state characterized by normal/low Cl and high

TPR index (Lund-Johansen, 1989). In a sample of 458 subjects who developed

hypertension four years after the initial screening in the Framingham heart study,









subsequent onset of hypertension was associated with initially increased HR

(men) and CI (both sexes) (Post, Larson, & Levy, 1994). However, none of the

hemodynamic variables of a hyperkinetic state was a significant predictor of the

development of hypertension after adjusting for age and baseline BP.

Petrin, Egan and Julius (1989) indicated that baseline arterial compliance

as indexed by the SV:PP ratio was significantly higher in a hyperkinetic

borderline hypertensive group in comparison to a normokinetic group. After the

administration of beta-adrenergic blockade, the intergroup difference in arterial

compliance was no longer significant, suggesting that the group difference in

arterial compliance is attributed to observed disparities in vascular beta-

adrenergic tone between hyperkinetic and normokinetic borderline hypertensives.

In 1993 Bergbrant, Hansson, and Jern further demonstrated that minimal

forearm vascular resistance was significantly higher in the normokinetic

borderline hypertensive group than that observed in the hyperkinetic borderline

hypertensive group, suggesting the presence of structure vascular changes (i.e.,

vascular hypertrophy) in the former.

Hemodynamic and Physiological Basis of Enhanced Pressure Reactivity

Pressure hyperreactivity to stress is characteristic of borderline

hypertensives. However, the hemodynamic determinants and physiological

mechanisms of reactivity to stress have not been fully elucidated. Elliason (1985)

demonstrated that borderline hypertensives showed a tendency towards

enhanced alpha-adrenergic vasoconstriction during isometric handgrip test when

compared with both established hypertensives and normotensives. An









enhancement of the hypothalamic defense reaction (increased BP and plasma

adrenaline levels) during mental stress was evident in borderline hypertensives

as compared to established hypertensives and normotensives, whereas physical

stress produced more similar responses among groups.

de Champlain et al. (1991) examined cardiovascular reactivity to isometric

exercise with M-mode echocardiography, phonocardiography, carotidography

and circulating catecholamines in 15 borderline and 42 mild hypertensives and

25 normotensives of either sex. These investigators found that sympathoadrenal

reactivity, pressor and chronotropic responses were similarly increased during

exercise in the two groups of hypertensives and normotensives. In

normotensives, an increase in cardiac contractility and performance accounts for

the increase in BP, whereas in both groups of hypertensives the increase in BP

is mainly associated with an increase in TPR.

In contrast, a recent study using the impedance cardiography to assess

cardiovascular reactions to a passive orthostatic test, a cold pressor test, and a

hyperventilation test of 30 borderline hypertensive young men and 29 age-

matched normotensive men found that CI, SV, MAP and left ventricle work index

were increased in borderline hypertensives accompanying normal TPR

(Nawarycz et al., 1999).

Schulte and Neus (1983) demonstrated increased BP, HR and CO and

slightly decreased TPR during a mental arithmetic test in 20 hypertensive men

(10 borderline and 10 mild) as well as 10 age-matched normotensive men. The

rise in BP was greater in these two hypertensive groups than in the normotensive









group. The increase in BP also correlated with the CO elevation. Schulte and

Neus (1983) suggested that cardiovascular hyperreactivity in early hypertension

is attributed to increased beta-adrenergic stimulation of the heart.

Schulte, Ruddel, Jacobs, and von Eiff (1986) assessed cardiovascular

reactivity to mental stress in 41 borderline hypertensive men and 37 age-

matched normotensive men and found that the former group had higher absolute

or percentage of increased SBP and DBP during stress. In this study, the

increases in HR and CO and the decreases in TPR were higher in the borderline

hypertensive group as compared with the normotensive group, suggesting a

dominant cardiac reaction underlying the pressor response to mental stress in

borderline hypertensives.

Sherwood et al. (1995) examined cardiovascular reactivity to mental

stress (adverse reaction time test) that requires active coping and physical stress

(forehead cold pressor test) that elicits passive tolerance in borderline

hypertensive and age-matched normotensive men. These authors demonstrated

that the SBP increases were greater in borderline hypertensives when compared

with age-matched normotensives during the active task but not during the

passive task. During the active coping stress (mental stress), BP increases were

caused by marked augmentation of CO in borderline hypertensives despite

evidence of reduced cardiac beta-adrenergic receptor responsiveness.

Sherwood et al. indicated that the pressor hyperreactivity to a mental test in

borderline hypertensives was caused by an excessive rise in plasma epinephrine

and a consequently greater rise in CO. Similarly, Lindvall et al. (1991)









demonstrated a mental stress-induced CO-dependent increase in BP in both

normotensives and mild hypertensives. However, in the study by Lindvall et al.

smaller relative increases in DBP and MAP to mental stress were found in mild

hypertensives than in normotensives, suggesting that reduced SV

responsiveness caused by structural changes (i.e., left ventricular hypertrophy)

might account for this attenuated BP reactivity.

Sherwood et al. (1995) demonstrated that borderline hypertensives

reacted to passive coping (cold pressor test) with greater increases in TPR

possibly caused by vascular hypertrophy (as evidenced by significantly higher

minimal forearm vascular resistance) and an attenuation of CO in the presence

of normal baroreceptor reflex sensitivity. These changes lead to no greater net

increase of BP than that in normotensives. Other groups have also shown no

difference in the BP response to the cold pressor test between borderline

hypertensives and normotensives (Lafleche, Pannier, Laloux, & Safar, 1998;

Lindvall et al., 1991; & Ostergren et al., 1992).

Jern et al. (1995) studied hemodynamic responses to both mental and

physical stressors as well as daily-life ambulatory blood pressure in borderline

hypertensive men and normotensive control subjects from an unbiased

population of healthy young males. The group of borderline hypertensives were

further subdivided into hyperkinetic (CI greater than the mean + 1 standard

deviation of the normotensive control group) and normokinetic (CI below the

mean + 1 standard deviation of the normotensive control group) subgroups.

Resting MAP and HR were significantly higher in two borderline hypertensive









subgroups than those observed in the normotensive control group. Resting TPR,

forearm vascular resistance and calf vascular resistance were significantly lower

in the hyperkinetic borderline hypertensives than in the normotensive control

group. In contrast, TPR was higher in the normokinetic borderline hypertensive

group than in the normotensive control. These resting hemodynamics suggest

that in the hyperkinetic borderline hypertensive subgroup BP was elevated

through an increase in stroke volume, whereas in the normokinetic borderline

hypertensives BP was increased through an increase in TPR. SBP, DBP, and

MAP increased significantly during mental stress in all three groups. In

hyperkinetic borderline hypertensives, SBP, DBP, and MAP level during mental

stress were significantly greater than those observed in the normotensive control

group. Absolute and relative DBP reactivity were significantly greater in the

hyperkinetic borderline hypertensives than both the normokinetic borderline

hypertensives and normotensives. The stress-induced increase in CI was

significantly greater in the hyperkinetic borderline subgroup than in the

normotensive control group and tended to be higher than that in the normokinetic

borderline subgroup. Interestingly, TPR decreased in all groups during the

mental stress. While both hyperkinetic and normokinetic hypertensives exhibited

enhanced pressure reactivity to mental stress, the hyperkinetic hypertensive

subgroup demonstrated a greater nocturnal BP reduction than the latter

subgroup. Jern et al. concluded that enhanced stress reactivity in hyperkinetic

borderline reactivity is also reflected by greater day-night BP gradients and is not









explained by structural changes in the peripheral vasculature as determined by

forearm and calf minimal vascular resistance.

The choice of different stress tests by previous studies may explain the

disparity in results among studies that investigated hemodynamic determinants

of reactivity to stress. In addition, circulatory patterns are not uniformly identical

among all subjects with borderline hypertension. Therefore, different

hemodynamic patterns should have been taken into consideration when studying

stress reactivity of borderline hypertensives.

Physical Mechanisms of Enhanced Pressure Reactivity

As previously discussed, borderline hypertensives reacted to the cold

pressor test with greater increases in TPR (Sherwood et al., 1995) but no greater

increase in BP than that observed in normotensives (Lafleche et al., 1998;

Ostergren et al., 1992; & Sherwood et al., 1995). Sherwood et al. suggested that

the observed enhanced vascular reactivity to cold pressor stimulation might be

attributed to vascular hypertrophy evidenced in borderline hypertension.

In the study by Lafleche et al. (1998), arterial distensibility, compliance,

pulse wave velocity, and Al were assessed in 10 borderline hypertensives and 10

age- and sex- matched normotensive controls during the cold pressor test.

Arterial distensibility was determined by the relative change in diastolic diameter

during the systolic and diastolic period using the formula: 2 (Ds Dd) /PP, where

Ds is the systolic diameter, Dd is the diastolic diameter, and PP is pulse

pressure. Compliance was the absolute change in diastolic diameter during the

systolic-diastolic period and was calculated using the formula: (Ds-Dd) /2PP.









Pulse wave velocity was the delay from the foot of the pressure wave to the

inflection point representing the travel time for the incident wave to reach the

peripheral reflection sites and return.

In both groups, the cold pressor test induced a significant increase in BP

without a significant difference between groups. Both groups experienced an

increase in PP, a decrease in arterial distensibility and compliance and an

increase in pulse wave velocity and Al. The increase in Al was explained by the

increase in pulse wave velocity and the decrease in the distance from the

peripheral reflection site to the heart secondary to the cold pressor test-induced

vasoconstriction. The Al increased more in normal subjects than borderline

hypertensives, suggesting a different hemodynamic pattern between groups at

the central artery.

The decreases in carotid and brachial compliance were more pronounced

in normotensives than in borderline hypertensives. In normotensives, the cold

pressor test induced both an increase in PP and a decrease in pulsatile diameter

leading to a decrease in compliance in the brachial artery. In subjects with

borderline hypertension, only the increase in PP contributed to the decrease in

distensibility, thereby a smaller change in arterial compliance occurred. Lafleche

et al. (1998) maintained that in normotensives both a mechanical (increase in

PP) and a nonmechanical (decrease in pulsatile diameter) mechanism contribute

to the decrease in arterial distensibility during the cold presssor test, whereas in

borderline hypertensives only the mechanical mechanism (increase in PP)









account for the decrease in distensibility, presumably a consequence of a higher

basal sympathetic tone in the latter group.


Summary

Circulatory patterns in the history of borderline hypertension exhibit a high

cardiac output (hyperkinetic) state preceding a normal cardiac output

(normokinetic) state. Hyperkinetic borderline hypertensives have a higher resting

cardiac index than normotensive age-matched controls. Normokinetic borderline

hypertensives have significantly higher peripheral vascular resistance, whereas

hyperkinetic borderline hypertensives have significantly higher arterial

compliance, possibly due to enhanced beta-adrenergic tone in the latter

subgroup or the presence of vascular changes in the former. While both

hyperkinetic and normokinetic hypertensives exhibit enhanced pressure reactivity

to mental stress, the hyperkinetic hypertensive subgroup demonstrate a greater

nocturnal BP reduction than the latter subgroup.

The investigator speculated that increased pressure reactivity to stress in

hyperkinetic borderline hypertensives is caused by autonomic hyperreactivity

presumably due to enhanced beta-adrenergic tone. In contrast, increased

pressure reactivity to stress in normokinetic borderline hypertensives is caused

by increased peripheral vascular resistance, presumably due to structural

changes in the vasculature and/or partially explained by underlying decreased

arterial compliance. Hypothesized changes in hemodynamics underlying BP

reactivity to cognitive stress in normokinetic borderline hypertensives as

compared with normotensives are graphically displayed in Figure 2.3.















Normokinetic Borderline
Hypertensives


ITBP


Figure 2.3. Hypothesized changes in hemodynamics underlying enhanced
pressure responses to cognitive stress of normokinetic borderline hypertensives
versus normotensives. A: change; T: increase; 1: decrease; HR: heart rate; SV:
stroke volume; TPR: total peripheral resistance; BP: blood pressure.














CHAPTER THREE
PROCEDURES AND METHODS


Design

This study utilized a comparative design. Both the borderline hypertensive

group and the age-matched normotensive control group performed the Stroop

Color Word Test (SCWT). The dependent variables, blood pressure (BP),

augmentation index (Al), and the impedance-derived hemodynamic parameters

were measured before, during and after the SCWT. The design for the laboratory

experiment is graphically displayed as follows:

Group Baseline Stress Recovery

Borderline Hypertensives 01 02 03

Normotensive Controls 01 02 03

where O1 represents measurements of the dependent variables during the 6-

minute baseline period; 02 represents measurements of the dependent variables

during the SCWT; and 03 represents measurements of the dependent variables

during the 6-minute recovery period.


Population and Sample

The population under investigation was adult borderline hypertensives,

aged 18 to 65, in one North Central Florida County. Subject recruitment was









done through both flier advertising and BP screening. The investigator offered BP

screening several times a month for over 7 months at various locations.

Before BP was measured, potential subjects were told that they would be offered

a chance to take part in a research study if they qualified.

Blood pressure inclusion criteria was based on the classification of blood

pressure for adults, age 18 and older from the sixth report of the Joint National

Committee on Prevention, Detection, Evaluation, and Treatment of High Blood

Pressure (JNC- VI, 1997). Subjects were categorized as normotensive if SBP fell

below 130 mm Hg and DBP fell below 85 mm Hg measured on at least two

separate occasions. The "high-normal" and "hypertension-stage 1" groups

defined by the JNC-VI were selected as the BP criteria for inclusion to the

borderline hypertensive group. Borderline hypertension was therefore defined as

a resting DBP of 85 mm Hg to 99 mm Hg and/or a SBP of 130 mm Hg to 159 mm

Hg measured on at least two separate occasions.

Blood pressure was measured twice 2 minutes apart after the subject sat

quietly for 3 to 5 minutes. If the BP readings differed from each other by more

than five mm Hg, more measurements were taken. The initial screening BP was

obtained by averaging the two readings that agreed within 5 mm Hg. Subjects

whose initial screening BP met the inclusion criteria were invited to visit the study

site for a second screening to confirm their eligibility for inclusion in the study.









Specific Inclusion Criteria

Subjects selected were healthy individuals, age 18 to 65, free from overt

cardiovascular diseases, or other chronic or acute medical or psychiatric

disorders.

Specific Exclusion Criteria

Subjects were excluded from the study if they were taking

antihypertensive or antidiuretic medicines, or if their history demonstrated

evidence of significant cardiovascular or renal diseases. There was no exclusion

of subjects from the study based on gender or race.

Hemodynamic Subgrouping of Borderline Hypertensive Subjects

The borderline hypertensive group was divided into two subgroups, the

hyperkinetic and normokinetic subgroups, on the basis of CI. Borderline

hypertensive subjects who had a Cl greater than the mean plus one standard

deviation of the normotensive control group were categorized as the hyperkinetic

borderline hypertensive subgroup (Jern et al., 1995). Those who had a Cl below

that level were referred to as the normokinetic borderline hypertensive subgroup.

Cardiac index was measured using the formula: CO/BSA, where BSA was the

individual's body surface area and CO was obtained from impedance

measurements.


Setting

This study was conducted at a human research laboratory in the

University of Florida College of Nursing.









Research Variables and Instruments

Body Weight

Weight was measured in bare feet using a calibrated balance-beam scale.

Body Height

Height was measured in bare feet using a wall-mounted height

standiometer.

Body Mass Index (BMI)

Body mass index (BMI) was calculated as weight (kg) divided by height

squared (m2).

Body Surface Area (BSA)

The Impedance Cardiogram Microcomputer automated the computation of

BSA from the formula: BSA = (H 0.725) x (W 0.425) x (0.007184), where H is height

in cm and W is weight in Kg.

The Stroop Color Word Test (SCWT)

The independent variable in this study was the SCWT. The SCWT is

composed of a color-name reading task, a color-naming task, and an

interference task. The SCWT is printed on three pages of white paper and each

page has 100 items, presented in five columns of 20 items each. Page one is the

color-naming reading task and consists of the words "RED", "BLUE", and

"GREEN" printed randomly in black ink. Subjects were presented with this page

and instructed to read the words, going from top to bottom. Page two is the color-

naming task and consists of "XXXX" printed in red, blue, or green ink and

arranged randomly. Subjects were presented with this page and instructed to









name the colors of "XXXX" from top to bottom. The interference task consists of

the words on Page 1, printed in the colors on Page 2 and with no word or color

match. Subjects were handed Page 3 and were asked to ignore the printed word

and name the color of the ink each word was printed in.

The SCWT is associated with significant increases in respiratory rate,

plasma and urinary adrenaline, electrodermal activity (Tulen, Moleman, van

Steenis, & Boomsma, 1989), cardiac output (Hjemdahl et al., 1984), heart rate

(Hjemdahl et al., 1984;Tulen at al., 1989), and blood pressure (Hjemdahl et al.,

1984; Seibt at al., 1998). Such studies have validated the efficacy of the SCWT

in inducing sympathetic responses.

Beat-to-Beat Radial Blood Pressure

Continuous noninvasive BP was measured using radial artery tonometry

(Model 7000, Colin, San Antonio, TX) coupled with a computerized data

acquisition system (WINDAQ, Dataq Instruments, Akron, Ohio). Continuously

noninvasive BP provided beat-to-beat blood pressure values and a high-fidelity

arterial pressure waveform. The tonometric sensor contained pressure

transducers in an array. When a pneumatic pump and bellows press the

transducer array against the skin and tissue above the artery, the sensor records

the pressure wave. The radial tonometry is also equipped with an oscillometric

cuff, a pressure transducer with electronic processing to determine brachial SBP,

DBP and mean MAP. These pressure values are used to calibrate radial sensor

output.









Continuously noninvasive BP measurements by radial artery tonometry

have been shown to offer a reliable trend indicator of pressure changes (Weiss,

Spahn, Rahmig, Rohling, & Pash, 1996).

Augmentation Index (Al)

Kelly et al. (1989) initially defined Al 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 Al, expressed as a percentage, using the formula: Al = 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).

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 (Karamanoglu et al., 1993). Linear relationships have also been

demonstrated between brachial blood pressures and corresponding central

pressures derived by the transfer function method (Karamanolglu et al., 1993).

Several studies (Liang et al., 1998; Seibenhofer, 1999; Wilkinson et al., 1998)

have previously reported excellent reproducibility for Al 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
Incisura


Pi / AP
PP


Pd



T

Figure 3. 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). Tis
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.


In terms of validity, slight but significant correlations were found between

Al and aortic pulse wave velocity obtained via applanation tonometry in healthy

adults (r = .386, p < .01) (Liang et al., 1998) and adults with a parental history of

hypertension (r = .29, p, < .005) (Yasmin, & Brown, 1999).

Hematocrit

Hematocrit was measured using the Micro-Capillary Reader (Damon / IEC

Division, Needham Hts, MA).

Impedance-derived Hemodynamic Parameters

Cardiac output was measured by the Minnesota impedance cardiograph

(MIC Model 304B, Surcom'nc, Minneapolis, MN). Three waveforms were









generated by the impedance cardiograph: (a) electrocardiogram (EKG); (b) basal

impedance (Zo); and (c) the first derivative of thoracic impedance (dZ / dt). The

impedance stroke volume in milliliters was calculated using the equation

developed by Kubicek et al. in 1974: SV = p x (L / Zo)2 x (VET) x (dZ / dt). Based

on the subject's hematocrit, the computer calculated the electrical resistivity of

blood Rho (p). VET is the left ventricular ejection time in seconds, as obtained

from the point where the impedance wave leaves the baseline to the sharp notch

or downward deflection in the wave. L is the front distance between the inner two

electrodes in cm. Zo is the mean thoracic impedance between the two inner

electrodes in ohms. dZ / dt is the maximum rate of change in impedance during

the ejection of blood from the left ventricle. dZ / dt was measured from baseline

to the maximum height of the waveform and recorded in ohms per second.

Stroke volume was calculated for each wave, and three to four waves were

averaged to obtain one value for each data collection point.

Heart rate in beats per minute was calculated from the R-R interval on the

EKG waveform. CO in liters per minute was calculated using the formula, CO =

(SV x HR) / 1000. TPR was estimated using the formula: TPR = MAP / CO x 80

(dynes-.cm-5), where MAP is the mean arterial blood pressure calculated using

the formula: (SBP + 2 DBP)/ 3.

Support for the validity of the impedance-derived measurements has been

well documented by comparison with reference measures. A close agreement

between impedance derived-CO and CO measured by the thermodilution method

in humans has been reported in the absolute values (r = .85) and in the percent









change (r = .87) (Goldstein et al., 1986). A high correlation (r = .82) has also

been shown between impedance-derived SV and SV measured by nuclear

ventriculography in humans (Wilson et al., 1989).

Mehlsen et al. (1991) have provided evidence that supports outstanding

reproducibility for impedance-derived measurements with low measurement

differences on the same day (standard deviation of the differences in CO = 0.12

L/min) and on different days (standard deviation of the differences in CO = 0.45

L/min), and low intraobserver variability (standard deviation of differences in CO

= 0.12 L/min).

Arterial Compliance

Arterial compliance was estimated by the SV/PP ratio. PP was calculated

by subtracting aortic DBP from aortic SBP. The aortic pressure wave was derived

from a radial pressure wave recorded using a radial applanation tonometer with a

generalized transfer function. SV was measured using the impedance

cardiography. The SV/PP ratio has been demonstrated to be a valid estimate of

total arterial compliance (Chemla et al., 1998; Randall et al., 1986; Resnick et al.,

2000).

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.

Average pressures and standard deviations were calculated. Ambulatory

BP variability was defined as the standard deviation of the 24-hour APB average.

The day-night BP difference, or nocturnal BP reduction was defined as the

difference between the nighttime pressure average (NP) and the daytime

pressure average (DP), using individually defined periods of sleep and wake time

parameters. Percentages of nocturnal BP reduction were computed by the

formula: 100 % x (DP-NP).

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).

Clinic Blood Pressure and Heart Rate

Clinic brachial BP and HR were measured manually with the ABP monitor

(SpaceLabs 90207, SpaceLabsTM Inc., Redmond, WA) that was used in the

recording of 24-hour ABP. The ABP monitor was programmed to show readings

of SBP, DBP, and HR. Multiple resting measurements 2 minutes apart were

taken 5 minutes after subjects were seated. The average of the two readings that

agreed within 5 mm Hg was defined as clinic BP. The average of the HR

recorded from the same set of BP readings selected was defined as clinic HR.









Study Protocol

Laboratory Session Protocol

The subject was instructed to keep a regular sleep and wake pattern and

to avoid abnormal physical exertion and psychological stress starting 3 days

before the laboratory session. Alcohol or caffeine containing beverages and

cigarette smoking was prohibited before or during the laboratory session. All

subjects signed a consent document before any measurements were made.

All subjects filled out a health history inventory consisting of information

about major medical history, life style, and family history of hypertension. Clinic

BP and HR were measured manually with the ABP monitor 5 minutes after

subjects were seated in a quiet room.

The subject was assessed individually in the laboratory session.

Consistency between subjects was assured by using a standardized test

administration protocol. The test administration was scripted. Persons

administering the test were trained by the investigator. All instruments were

calibrated prior to starting data collection.

Height and weight were measured in bare feet. One drop of capillary blood

was collected by the finger-stick method in a capillary tube, and centrifuged for 5

minutes for hematocrit determination. The investigator placed four pieces of

aluminum-coated Mylar tape around the subject's neck and chest, which were

attached to the electrodes of the MIC. Four pairs of impedance electrodes were

attached to the aluminum surface of the Mylar tape. The inner two electrodes

(Electrodes 2 and 3), or voltage electrodes, were used to record the EKG, basic









impedance of the thorax (Zo), and the small impedance change that occurred

during the cardiac cycle, and its first derivative (dZ/dt). The outer two electrodes

(Electrodes 1 and 4), or the current electrodes, were connected to a constant

current source (4mA, 100 kHz). Electrode 2 was placed at the base of the neck

as close as possible to the clavicles, and electrode 3 was placed at the

xiphisternal joint. Electrodes 1 and 4 were placed at least 3 to 5 cm above and

below the voltage electrodes

The sensor of the CNIBP radial tonometry was placed over the preferred

sensor site of the subject's left radial artery with proper hold down pressure and

optimal signal strength indicated on the tonometry screen. A pressure cuff was

applied to the ipsilateral arm over the brachial artery for initial and intermittent

calibration of the radial tonometry during the recording of CNIBP. Al was

obtained from measuring the pressure waveform with a radial applanation

tonometer applied to the right arm.

Before testing a 30-minute adaptation and resting period was employed to

accustom the subject to the laboratory environment. Subjects were instructed to

relax in the seated position with their eyes open for the 30-minute adaptation and

resting period. A 6-minute baseline period was followed by the 6-minute SCWT.

After a brief introduction to the test the subject performed the SCWT. A 6-minute

recovery period followed the SCWT.

Blood pressure waves were continuously recorded with the CNIBP radial

tonometry coupled with a computerized data acquisition system during the 6-

minute baseline period, the SCWT test period, and the 6-minute recovery period.









The peak and valley of each BP wave were captured and transformed into

numerical data using a computerized data browsing system (WINDAQ, Dataq

Instruments, Akron, Ohio). The average BP and standard deviation for each

period were then calculated.

Multiple measurements of impedance and Al were obtained before,

during, and after the SCWT. Three to four sitting impedance measurements

during the baseline period, one measurement during each page of the SCWT

(three during the stress period), and three to four measurements during the

recovery period were obtained by a trained research assistant.

Likewise, three to four sitting Al measurements during the baseline period,

one measurement during each page of the SCWT (three during the stress

period), and three to four measurements during the recovery period were

obtained by the investigator. The investigator made sure that each impedance

measurement was obtained simultaneously with each Al measurement. A list of

the variables measured or calculated during the laboratory session is provided in

Table 3.

Ambulatory Blood Pressure Monitoring Protocol

The subject was 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 workday or school

day.

Subjects were fitted with an ABP monitor and familiarized with its

operation. The monitor was programmed to measure blood pressure over a 24-









hour period at the frequency of every 30 minutes during the day and evening (6

AM to 10 PM) and every 60 minutes during the sleep time (10 PM to 6 AM). A

cuff of the proper size, determined by upper arm circumference was placed on

the subject's nondominant 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 was not too tight. The monitor was then strapped to the patient on

the hip.

Rigorous calibration of the equipment was made prior to ABP monitoring.

A calibration procedure comprised of 3 calibration readings in the seated

position, each taken with the ABP monitor and a mercury column simultaneously

by means of a "T" connector between two instruments. Readings for both SBP

and DBP agreed within 5 mm Hg on all 3 attempts.

The monitor emits a series of alarm sounds 5 seconds prior to cuff

inflation. 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 patient was instructed

to keep the level of the cuff near the heart level. Subjects were given a diary and

asked to record their activities each time the monitor recorded a pressure.

Subjects were asked to return the monitor and the diary to the investigator after a

minimum elapsed time of 24 hours. The 24-hour data for each subject were then

downloaded, printed out, and compared with the subject's diary entries. The









individually defined periods of sleep and wake time indicated on the diary were

used to compute the subject's nocturnal blood pressure reduction.


Table 3
Maior Variables Measured or Calculated During the Laboratory Session


Instrument
ColinTM
CNIABP


SphygmoCorTM
PWA System




Minnesota
Impedance
Cardiograph


Variables
Systolic BP (SBP)
Diastolic BP (DBP)
Pulse Pressure (PP)
Mean Arterial Blood
Pressure (MAP)


Aortic augmentation index
(Al)
First systolic shoulder (Ps)
Second systolic shoulder
(Pi)

Resistivity of blood (p)

EKG
HR

Basal impedance (Zo)
Distance between the two
inner electrodes (L)
Left ventricle ejection time
(VET)
First derivative of thoracic
impedance (dZ/dt)
Stroke volume (SV)

Cardiac output (CO)
Body Surface Area (BSA)

Cardiac Index (CI)
Total peripheral resistance
(TPR)


Measured or Calculated
Measured
Measured
PP = SBP DBP
MAP = (SBP +2DBP) + 3


Al (%) = (Ps Pi) + (SDB -
DBP)X 100
Measured
Measured


Calculated from blood
hematocrit
Measured
Calculated from R-R interval
on EKG
Measured
Measured over chest

Measured

Measured

SV (ml) = p x (L / Zo)2 x
(VET) x (dZ / dt)
CO (L) = (SV x HR)+ 1,000
BSA (m2) = (H 0.725) x (W
0.425) x (0.007184)
CI (L / m2) = CO + BSA
TPR= (MAP + CO) x 80
dvnes-seccm5









Methods of Statistical Analyses

Data were analyzed using SAS (SAS Institute Inc, Cary, North Carolina).

Descriptive statistics were used to obtain the summary measures for the data.

Addressing Hypotheses 1 and 2, Repeated Measures Analysis of Variance was

performed, using a mixed linear model, to determine the changes in response

variables within subjects, between subjects, and within-subjects-by-between-

subjects interactions. Student t-test was performed to address Hypotheses 3, 4

5, and 6. Simple and multiple regression analyses were used to address

Hypotheses 7, 8, and 9. The significance level of .05 for rejecting the null

hypothesis was chosen.














CHAPTER 4
RESULTS

The primary purpose of this study was to determine the differences in

aortic reflection wave amplitude as estimated by the augmentation index (Al),

arterial compliance as estimated by the SV/PP ratio, and hemodynamic patterns

underlying pressure responses to cognitive stress in normokinetic borderline

hypertensives and age-matched normotensives. The secondary purpose was to

compare the differences in ambulatory blood pressure parameters between

borderline hypertensives and normotensives. The relation between arterial

compliance and nocturnal BP reduction was also investigated in this study.

Finally, the predictive power of pressure reactivity to stress on ambulatory BP

(ABP) parameters was examined.

This chapter will first present descriptive results, including means,

standard deviations, and frequency data for each variable. The nine hypotheses

posed in Chapter 1 will be addressed using repeated measures analyses of

variance, Student's t-test, and regressional analyses.


Descriptive Results

Subject Demographics

Over 60 potential subjects met the specific inclusion criteria in the initial

screening and were invited for a second screening to be included in the study.

However only 46 subjects actually showed up for the second screening. One









subject was excluded because she was taking antihypertensive medications.

Three subjects did not meet the BP inclusion criteria in the second screening.

A total of 42 subjects participated in this study. Nineteen subjects

comprised the normotensive control group and 23 comprised the borderline

hypertensive group. Of 23 borderline hypertensives, 20 were normokinetic and 3

were hyperkinetic.

Subject demographics expressed in numbers and percentage were

gender, race, and age, family history of hypertension, and habits of cigarette

smoking and exercise. Table 4.1 shows the subject demographics, providing a

comparison among groups. For completeness, both the borderline hypertensive

and normokinetic borderline hypertensive groups are shown. The borderline

hypertensive group includes the normokinetic borderline hypertensive group.

The normotensive group ranged in age from 20 to 63 years with a mean of

40.5 years. The age of the borderline hypertensive group ranged from 24 to 64

years with a mean of 44.4 years. The age of the normokinetic borderline

hypertensives ranged from 24 to 64 years with a mean of 46.4 years. As shown

in Table 4.1, the borderline hypertensives and normotensives were comparable

in gender, race, age, and family history of hypertension, and habits of smoking

and exercise.

Clinical Characteristics

The clinical characteristics, including weight, height, BMI, clinic BP and

heart rate of the borderline hypertensive and normotensive subjects studied are

presented in Table 4.2.









Table 4.1.
Demographic Data for the Borderline Hypertensive and Normotensive Subjects
Studied

BH (N = 23) NBH (N = 20) Normotensive
(N =19)

N % N % N %
Gender

Male 9 39 7 35 8 42
Female 14 61 13 65 11 58
Race

Asian 1 4 0 0 2 11
African-American 4 18 4 20 1 5
Hispanic 1 4 1 5 0 0
Caucasian 17 74 15 75 16 84
Age

30 and under 3 13 1 5 5 26
31-40 5 22 4 20 4 21
41-50 9 39 9 45 6 32
51 60 4 17 4 20 2 10.5
61-65 2 9 2 10 2 10.5
Family History of
Hypertension

Yes 17 74 15 75 13 68
No 6 26 5 25 6 34
Smoking

Yes 6 26 5 25 3 16
No 17 74 15 75 16 84
Regular Exercise

Yes 12 52 9 45 14 74
No 11 48 11 55 5 26

BH: borderline hypertensive, NBH: normokinetic borderline hypertensive.









Table 4.2. Clinical Characteristics of the Borderline Hypertensive and
Normotensive Subjects Studied

BH Group NBH Group Control Group
(N = 23) (N = 20) (N = 19)
Weight (kg) 89.9 + 18.4** 93.0 + 17.46** 72.0 + 16.05
Height (cm) 171.7 10.5 171.60+ 11.07 171.78.34
BMI (kg / m2) 30.7 + 6.9** 31.7 + 6.80** 24.1 +3.60
SBP (mm Hg) 142.6 + 7.4** 142.4 + 7.4** 117.3 +9.2
DBP (mm Hg) 88.2 + 9.3** 88.4 + 9.4** 69.6 + 6.7
HR (beats / min) 79.1 + 11.1** 80.3 + 10.2** 67.7 +9.5

Values are expressed as means SD. *p < .05, **p < .01, versus normotensive
controls, by t-test. BH: borderline hypertensive, NBH: normokinetic borderline
hypertensive, BMI: body mass index, SBP: systolic blood pressure, DBP:
diastolic blood pressure, HR: heart rate.


Clinic BP and HR were significantly higher in the borderline hypertensive

subjects than in the control subjects (refer to Table 4.2). The borderline

hypertensive subjects and the normotensive subjects also differed significantly in

weight and BMI. Therefore BMI was treated as a covariate in the repeated

measures analysis of variance.

Resting Hemodynamics

Resting hemodynamics during the baseline period are summarized in

Table 4.3.


Analytic Results for Hypotheses

For Hypotheses 1 and 5, the pattern of BP reactivity to cognitive stress

and BP reactivity during everyday life in the borderline hypertensive group was

compared to the normotensive group. For Hypotheses 2, 3, 4, hemodynamic and

arterial responses underlying BP reactivity to stress was examined in the

normokinetic borderline hypertensive subgroup and compared to the









normotensive group. For Hypothesis 6, the degree of nocturnal BP reduction in

the normokinetic borderline hypertensive subgroup was compared to the

normotensive group. Hypotheses 7 and 8 tested the predictive power of

augmentation index and arterial compliance, respectively for the day-night BP

difference in the whole study sample. Lastly, Hypothesis 9 tested the predictive

power of BP reactivity for ambulatory BP parameters in the whole study sample.


Table 4.3. Resting Hemodynamics of the Borderline Hypertensive and
Normotensive Subiects Studied

BH Group NBH Group Control Group
(N = 23) (N = 20) (N = 19)
SV (ml) 62.8 + 34.3 52.7 + 22.0** 74.3 22.2
CO (L / min) 4.5 +2.0 4.0 +1.5 4.8 +1.2
CI (L / min / m2) 2.2+ 1.1 1.9 + 0.8** 2.6 0.60
TPR(dynes-s-cm-5) 2102.2 +637.2** 2196.0 +876.1** 1298.5 + 388.0

Values are expressed as means SD. *p < .05, **p < .01, versus normotensive
controls, by t-test. BH: borderline hypertensive, NBH: normokinetic borderline
hypertensive, CO: cardiac output. CI: cardiac index, TPR: total peripheral
vascular resistance.


Hypothesis 1. Borderline hypertensives have a greater increase in BP in

response to cognitive stress (SCWT) as compared to age-matched normotensive

subjects. Repeated measures analysis of variance was performed using a mixed

linear model (PROC MIXED). A mixed linear model is a generalization of the

standard linear model. In a mixed model, the data are permitted to exhibit

nonconstant variability and correlation, thereby providing the flexibility of

modeling means, variances, as well as covariances. The mixed model is

therefore preferable to other standard linear models, because it utilizes not only









the response means but also their variances and covariances (Little, Miliken,

Stroup, & Wolfinger, 1996).

There was a significant change in SBP within subjects across

experimental periods with the SCWT (F = 9.86 p = .0001) and a significant

difference in SBP between the two groups (F = 97.60, p < .0001). However, the

pattern of change in SBP was similar between the borderline hypertensive and

normotensive control group (i.e., no time and group interaction, F = 0.42, p =

.6580). The effect of BMI on SBP was statistically significant (F = 11.61, p =

.0009).

Likewise, there was a significant difference in DBP between the two

groups (F = 41.07, p < .0001) and a significant change in DBP within subjects (F

= 4.21, p = .0165) with the SCWT. However, there was no time and group

interaction effect on DBP (F = 0.41, p = .6667).

There was a significant difference in PP between the two groups (F =

20.95, p < .0001). However, there was no time effect (F = 2.02, p = .01281) and

no time and group interaction effect on PP (F = 0.09, p = .9121). The effect of

BMI on PP was significant (F = 3.2, p = 0.0765).

Furthermore, there was a significant difference in MAP between the two

groups (F = 67.64, p < .0001) and a significant change in MAP within subjects

with the SCWT (F = 7.28, p = .001). In addition, the effect of BMI on MAP was

statistically significant (F = 6.23, p = .0139). Again, there was no time and group

interaction effect on MAP (F = 0.32, p = .7284).









The means and standard deviations of BP during each experimental

period are summarized in Table 4.4. Analysis revealed that all baseline BP

measurements, including SBP, DBP, MAP, and PP were significantly higher in

the borderline hypertensive group than the normotensive group. Both groups had

significant increases in SBP, DBP, MAP, and PP from baseline to stress. SBP

and MAP decreased significantly from stress to recovery in both groups. DBP

and PP decreased significantly from stress to recovery in the normotensive group

but not in the borderline hypertensive group. The changes in SBP, DBP, and PP

across the three experimental periods in the two study groups are graphically

presented in Figure 4.1, 4.2 and 4.3.

Hypothesis 2. Normotensives and normokinetic borderline hypertensives

differ significantly in their responses in HR, SV, and TPR to cognitive stress. For

Hypothesis 2, repeated measures analysis of variance was performed using

PROC MIXED. There was a significant difference in SV between the two groups

(F = 9.84, p < .0001). However, there was no significant change in SV within

subjects (F = 0.12, p = .8851) and no time and group interaction effect on SV (F

= 0.01, p = .9920).

There was a significant difference in HR between the two groups (F =

5.06, p < .0265) and a significant change in HR within subjects with the SCWT (F

= 12.62, p < .0001). Additionally, the effect of BMI on HR was significant (F =

3.95, p = .0497). Again, there was no time and group interaction effect on HR (F

= 1.18, p = .3112). The change in HR across the three experimental periods in

the two study groups is presented in Figure 4.4.









Lastly, there was a significant difference in TPR between the two groups

(F = 6.18, p = .0145). In addition, the effect of BMI on TPR was significant (F =

14.71, p = .0002). However, there was no significant change in TPR within

subjects with the SCWT (F = 1.95, p = .1475) and no time and group interaction

effect on TPR (F = 0.48, p = .6185).

Hypothesis 3. Normotensives and normokinetic borderline hypertensive

subjects differ significantly in wave reflection amplitude as indexed by Al.

Student t-test was used to address Hypothesis 3. The resting Al was

16.9% + 16.8% in the normotensive subjects and 22.1% + 11.9% in the

normokinetic borderline hypertensive subjects. The difference in Al between

these two study groups was not statistically significant (t = -1.10, p = .28).


Table 4.4. Summary of Beat-to Beat Radial Blood Pressure During the Stress
Protocol

Group / BP mm Hg Baseline Stress Recovery
BH Group
SBP 133.7 +12.3 144.2 +13.0 138.1 + 11.5
DBP 72.6+ 10.4 78.5+ 11.0* 75.5 +10.5
MAP 93.4 +10.7 101.2 +11.0 96.5 + 10.1*
PP 61.1 + 10.0 65.7 + 12.7** 62.5+ 10.0
Control Group
SBP 105.0+11.9 117.1 +13.6 106.2+ 13.6
DBP 56.6 +10.0 63.9 + 11.5** 57.0 + 12.0*
MAP 72.8 + 9.5 82.0 + 11.4** 73.6 + 12.2*
PP 48.4 +9.4 53.3 + 9.5 49.5 + 9.1

Values are expressed as means + SD, p < .01 versus control group, p < .01
versus baseline, p < .01 versus stress, by t-test. BH: borderline hypertensive,
SBP: systolic blood pressure, DBP: diastolic blood pressure, MAP: mean arterial
blood pressure, PP: pulse pressure.























150,




140 **
I
E
E

Z 130,
U)


o
0 120,

C)

U)
CO 110, *** Baseline

Stress

100 N M Recovery
NC BH

Figure 4.1. Systolic blood pressure changes across the three experimental
periods. NC: normal controls, BH: borderline hypertensives. p < .01
versus baseline, p < .01 versus stress, by t-test.





















80






E
E70,




o
0

0 60,


0o Baseline

Stress

50, Recovery
NC BH

Figure 4.2. Diastolic blood pressure changes across the three
experimental periods. NC: normal controls, BH: borderline hypertensives.
p < .01 versus baseline, p < .01 versus stress, by t-test.
























70





0)
60
E
E





_. 50
0-




W Baseline

Stress

40 Recovery
NC BH

Figure 4.3. Pulse pressure changes across the three experimental
periods. NC: normal controls, BH: borderline hypertensives. p < .01
versus baseline, p < .01 versus stress, by t-test.
























90








80
E


(D
-Q
(**




70
(D

E Baseline

Stress

60 Recovery
NC NBH

Figure 4.4. Heart rate changes across the three experimental
periods. NC: normal controls, NBH: normokinetic borderline
hypertensives. p < .01 versus baseline, p < .01 versus stress,
by t-test.









Hypothesis 4. Normotensive and normokinetic borderline hypertensive

subjects differ significantly in arterial compliance as indexed by SV/PP.

Student t-test was used to test Hypothesis 4. The resting arterial

compliance was 2.25 + 0.85 (ml/mm Hg) in the normotensive group and 1.18 +

0.48 (ml/mm Hg) in the normokinetic borderline hypertensive subjects (See

Figure 4.5). The normotensive group had significantly higher arterial compliance

than the normokinetic borderline hypertensive group (t = 4.9, p < .0001).

Hypothesis 5. Borderline hypertensives exhibit a greater ABP variability as

determined by a greater standard deviation of the average 24-hour BP, as

compared to the age-matched normotensives.

Student t-test was used to address Hypothesis 5. The results of the

comparison of 24-hour, daytime, nighttime BP parameters and BP variability

measures between the two groups using a t-test are shown in Table 4.5.

The standard deviations for 24-hour and daytime SBP were significantly

higher in the borderline hypertensives than in the control group. The standard

deviations for 24-hour, daytime, and nighttime DBP were significantly higher in

the borderline hypertensives than in the control group. Likewise, the standard

deviations for 24-hour, daytime, and nighttime MAP were significantly higher in

the borderline hypertensives than in the control group. In addition to the

variability measures, the two groups differed significantly in all the BP measures

as shown in Table 4.5. Of course if the Bonferroni method of controlling the

overall error was used, the new level of significance will be .003. Based on this









new level of significance, none of the ABP variabilities were different between

groups.

Hypothesis 6. Normotensives exhibit a significantly greater day-night BP

difference as compared to normokinetic borderline hypertensives. Student t-test

was used to test Hypothesis 6.

The two groups did not differ significantly in the day-night SBP difference

(t = -0.90, p = .3765), day-night DBP difference (t = -0.90, p = .3765), and day-

night MAP difference (t = -1.46, p = .1539). Additionally, the day-night HR

difference was not significantly different between the two groups (t = -0.44, p =

.6599). The results of the day-night BP and HR difference are shown in Table

4.6.

Hypothesis 7. Aortic wave reflection amplitude as indexed by Al is

predictive of the day-night BP difference. Regression analysis was used to

address Hypothesis 7.

There was no significant relationship between Al and the day-night SBP

difference (R2 = .0010, p = .8417). Additionally, Al did not explain the variations

in the day-night DBP difference (R2 = .0006, p = .8793) and day-night MAP

difference (R2 = .0018, p = .7930).

Hypothesis 8. Arterial compliance as indexed by SV/PP is predictive of the

day-night BP difference. Regression analysis was used to address Hypothesis 8.

The SV/PP ratio did not explain the variations in the day-night SBP

difference (R2 = .205, p = .197). Likewise, the variations in the day-night DBP

difference was not explained by the level of SV/PP (R2 = .121, p = .452).







80
















3.5



3.0



I 2.5
E
E

S2.0


0--
0
C
E 1.5



1.0



.5
N 19 20
NC NBH

Figure 4.5. A comparison of arterial compliance between the normotensive
control group and the normokinetic borderline hypertensive group. NC:
normal controls, NBH: normokinetic borderline hypertensives. Values
expressed as means + SD, p < .01 versus normal controls, by t-test.









Table 4.5. Group Comparison of Ambulatory
Measures


Blood Pressure and Variability


ABP and Variability Control Group BH Group t p-value
Parameters (mm Hg) (N = 19) (N = 23)
Mean + SD Mean + SD
24-hour SBP 118.0+9.4 136.6 +10.4 -5.92 < .0001
24-hour SBPV 10.5 +3.1 13.5 +3.2 -3.00 .0046
Daytime SBP 121.2 + 9.4 140.4 +10.4 -6.02 < .0001
Daytime SBPV 7.6 + 1.9 11.0 +2.6 -2.09 .0433
Nighttime SBP 108.2 +9.9 122.6 +13.4 -3.80 .0005
Nighttime SBPV 7.4 +2.3 12.3+ 14.6 -1.56 .1330
24-hour DBP 71.3 + 5.9 83.2 + 9.9 -4.82 < .0001
24-hour DBPV 9.4 +2.3 11.8 +2.9 -2.83 .0073
Daytime DBP 74.4 + 6.3 86.9 + 9.7 -4.95 < .0001
Daytime DBPV 7.6+ 1.9 9.5 +3.2 -2.32 .0260
Nighttime DBP 61.7 +4.5 70.9 11.4 -3.53 .0014
Nighttime DBPV 6.7 +2.8 9.1 +3.2 -2.55 .0149
24-hour MAP 87.0 +5.8 101.5 +9.6 -5.64 < .0001
24-hour MAPV 9.2 +2.6 12.0 +3.0 -3.15 .0031
Daytime MAP 89.9 +6.5 105.2 + 9.5 -6.30 < .0001
Daytime MAPV 9.2 +2.6 9.7 + 3.1 -2.26 .0295
Nighttime MAP 78.0 + 5.5 88.5 +11.5 -3.85 .0005
Nighttime MAPV 6.9 + 2.4 9.0 + 3.4 -2.27 .0288

ABP: ambulatory blood pressure, BH: borderline hypertensive, SBP: systolic
blood pressure, DBP: diastolic blood pressure. MAP: mean arterial pressure,
SBPV: systolic blood pressure variability, DBPV: diastolic blood pressure
variability. MAPV: mean arterial pressure variability. p < .05, p < .003.


Table 4.6. Group Comparison of Nocturnal Blood Pressure and Heart Rate
Reduction

Day-Night Difference Control Group NBH Group t p-value
(mm Hg) (N= 19) (N = 20)
Mean + SD Mean + SD
SBP 13.0 +6.5 15.6 +11.2 -0.90 .3765
DBP 12.8 +5.3 14.7 +7.5 -0.93 .3605
MAP 11.8 6.0 15.2 8.0 -1.46 .1539
HR 10.5 6.5 11.3 4.2 -0.44 .6599

NBH: normokinetic borderline hypertensive, SBP: systolic blood pressure, DBP:
diastolic blood pressure. MAP: mean arterial pressure









Hypothesis 9. Pressure reactivity is predictive of the average 24-hour and

daytime BP. The reactivity score was calculated by subtracting the baseline from

the stress score. The recovery score was calculated by subtracting the recovery

from the stress score. Multiple regressions were used to test Hypothesis 9. Each

ambulatory BP measure was regressed on all reactivity and recovery measures,

clinic BP and HR, and BMI. The stepwise regression procedure in multiple

regression analysis was performed to determine the optimal number of variables

necessary to account for explaining the maximum variance in the response

variables.

Daytime SBP was significantly explained by DBP reactivity (p = .0073),

DBP recovery (p < .0001), MAP reactivity (p = .0045), MAP recovery (p < .0001),

HR reactivity (p = .0494), SV reactivity (p = .0201), CI recovery (p = .0112), and

clinic SBP (p < .0001) with an R2 of .87.

Daytime DBP was significantly explained by DBP recovery (p = .0002),

MAP reactivity (p = .0337) and recovery (p = .0001), clinic DBP (p < .0001) and

BMI (p = .0126) with an R2 f .86.

In addition, the variation in daytime MAP was explained by DBP recovery

(p < .0001), MAP reactivity (p = .0286) and recovery (p < .0001), clinic SBP (p =

.0002) and DBP (p = .0003), and BMI (p = .0262) with a R2of .86.

Furthermore, the variations in 24-hour SBP were significantly explained

(R2 = .86) by reactivity (p = .0458) and recovery DBP (p < .0001), reactivity (p =

.0284) and recovery MAP (p < .0001), and clinic SBP (p < .0001). The variations

in 24-hour DBP were significantly explained (R2 = .86) by recovery DBP (p =









.0458), reactivity (p < .0001) and recovery MAP (p = .0284), clinic DBP (p <

.0001), and BMI (p < .0001). The variations in 24-hour MAP were significantly

explained (R2= .84) by recovery DBP (p < .0001), reactivity (p = .0473) and

recovery MAP (p < .0001), clinic SBP (p = .0027) and DBP (p = .0001).

Additional Findings

Augmentation index. A gender comparison of resting Al was performed

using the t-test. Female subjects had significantly higher (t= -2.46, p = 0.019) Al

values than male subjects (24.6% + 14.5% and 13.7 % + 13.8 %, respectively).

Further analysis revealed that female subjects had significant lower body height

than male subjects (t = 8.11, p < 0.0001). There was no difference in resting Al

between subjects with and without family history of hypertension (t = 1.023, p =

.313). Again, the difference in resting Al between regular exercisers and

nonexercisers was not statistically significant (t = 0.320, p = .750).

Correlational analyses were performed to examine possible correlates of

Al. Age significantly correlated with resting Al (r = .58, p < .0001). Height and Al

had a weak but significant inverse relationship (r = -.33, p = .036). SV and Al was

inversely correlated (r = -.40, p = .008). The correlation between the resting HR

and Al was not statistically significant (r= -.03, p = .835). However, the correlation

between resting HR and Al was barely significant in the normokinetic borderline

hypertensive subjects (r = -.43, p = .056). Figure 4.6 shows the correlation

between Al and age. Figure 4.7 shows the correlation between Al and height.

The correlation between SV and Al is presented in Figure 4.8. The gender

comparison of Al is presented in Figure 4.9.









The study subjects were further divided into dippers (the day-night MAP

difference equal to or greater than 10 mm Hg) versus nondippers (the day-night

MAP difference less than 10 mm Hg). Thirty-one subjects were categorized as

dippers (74%) and 11 subjects were categorized as nondippers (26%). A

comparison of resting Al between the dippers and nondippers was performed

using a t-test. There was no significant difference in Al between the dippers and

nondippers (t = 0.43, p = .6664).

A comparison of the change in Al from the baseline to the stress level was

made between the normokinetic borderline hypertensive group and the

normotensive group using the t-test. Both groups showed a nonsignificant trend

toward a decrease in Al from the resting baseline in response to the SCWT.

However, there was no significant difference in the change in Al from the

baseline to the stress level between the two groups (t = -0.98, p = .3326). The

change in Al from the stress to the recovery level was also compared between

the normokinetic borderline hypertensive group and the normotensive group.

Both groups showed a nonsignificant trend toward an increase in Al from the

stress to the recovery level. Again, no significant difference in the change in Al

from the stress to the recovery level between the two groups was found (t = -

0.52, p = .6064). Al across the three experimental periods in both groups is

displayed in Figure 4.10.

Arterial compliance. Correlational analyses were performed to identify

correlates of the SV/PP ratio. The SV/PP ratio was inversely related to age (r = -

.60, p < .0001), BMI (r = -.47, p < .002), HR (r = -.45, p = .003), and Al (-.65, p <









.0001). The SV/PP positively correlated with height (r = .34, p = .03). The

relationship between the SV/PP ratio and Al is shown in Figure 4.11. The SV/PP

ratio strongly correlated with SV (r = .83, p < .0001) and moderately inversely

correlated with aortic PP (r = -.56, p < .0001).

A comparison of the change in arterial compliance from the baseline to the

stress level was made between the normokinetic borderline hypertensive group

and the normotensive group using the t-test. There is no difference in the change

in Al between groups (t = -1.67, p = .103). Arterial compliance across the three

experimental periods in both groups is displayed in Figure 4.12.

Repeated measures analysis of variance was performed using a mixed

model to determine the difference in the pattern of change in arterial compliance

during the stress protocol. Age and BMI were adjusted in the model. The change

in Al was not significantly different within subjects (F = 2.07, p = .1311), though

there was a between-group difference (F = 26.66, p < .0001). The pattern of

change in arterial compliance was not statistically different between groups (F =

0.79, p < .4548). The effects of BMI and age on arterial compliance were

significant (F = 18.02, p < .0001 and F = 27.83, p < .0001, respectively).

Blood pressure reactivity and recovery. A comparison of the BP reactivity

and recovery scores between the borderline hypertensive group and the

normotensive group was performed using a t-test. Table 4.7 shows the BP

reactivity and recovery for the two study groups. No significant differences in the

reactivity and recovery BP scores between the two groups were found.







86

















.5* 0



.4- r= .58, p < .01
O 0

3 m



.2-


.1 I O O




D BH
0.0" am

a BH
-.1 .N
SD NC

-.2 Total
10 20 30 40 5"0 60 70


AGE (years)

Figure 4.6. Relationship between augmentation index (Al) and age
(bivariate correlation). BH: borderline hypertensive subjects, NC:
normal control subjects.







87

















.5 0
0


.4 o r=-.33, p<.05




0 0

.2 Tt


.1D
O OO










150 160 170 180 190 200
0.0 o

o BH
-.1 .
0 0 NC

-.2 Total
150 160 170 180 190 200


Height (cm)

Figure 4.7. Relationship between augmentation index (Al) and height
(bivariate correlation). BH: borderline hypertensive subjects, NC:
normal control subjects.







88

















.51 0
0


.4. 0 r= -.40, p< .01
o0





.2*
.1 I OB O
< 0





0.0. D
0
o D BH
-.1 .
D D NC

-.2 Total
20 40 6"0 80 1 20 140 160


Stroke Volume (ml)

Figure 4.8. Relationship between augmentation index (Al) and stroke
volume (bivariate correlation). BH: borderline hypertensive subjects, NC:
normal control subjects.







89


















.5



.4



.3



< .2



.1 .



0.0



-.1
N= 17 25
Males Females

Figure 4.9. Gender comparison of augmentation index (Al). Values
expressed as means + SD, p < .05 versus males, by f-test.




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