© 1997 American Heart Association, Inc.
Articles |
Behaviorally Elicited Heart Rate Reactivity and Atherosclerosis in Ovariectomized Cynomolgus Monkeys (Macaca fascicularis)
From the Behavioral Physiology Laboratory, University of Pittsburgh, Pittsburgh, Penn (S.B.M., J.M.M.) and the Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC (M.R.A., J.R.K.).
Correspondence to Stephen B. Manuck, PhD, Behavioral Physiology Laboratory, 506 EH, 4015 O'Hara Street, University of Pittsburgh, Pittsburgh, PA 15260. E-mail manuck{at}vms.cis.pitt.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract It has been hypothesized that atherogenesis is accelerated among individuals who exhibit heightened cardiovascular reactions to psychologic stress. We have reported previously that the coronary atherosclerosis of cholesterol-fed, male and reproductively intact (premenopausal) female cynomolgus monkeys was exacerbated in animals that experienced the largest heart rate (HR) reactions to a fear-eliciting laboratory stressor. In this article, we report a similar relationship among 20 female monkeys that were rendered estrogen-deficient (by ovariectomy) and subsequently treated with replacement of both estrogen and progesterone. At the beginning of a 30-month study period, animals were fitted with ECG telemetry devices, and their HRs were recorded under baseline and stressed conditions. Stress HR measurements were obtained during a standard challenge involving threatened capture and physical handling of the animals. As part of a related experiment, monkeys were then ovariectomized and, for the remainder of the study, administered 17ß-estradiol (continuously) and progesterone (cyclically) by subcutaneous Silastic implant (Dow Corning). Animals consumed a cholesterol-containing diet throughout, and HR measurements were repeated in the 24th month. At necropsy, the magnitude of animals' HR responses to stress correlated significantly with intimal area measurements in the left anterior descending and circumflex coronary arteries (r=.59 and r=.57, respectively; P<.009). This association was due to a marked exacerbation of coronary atherosclerosis in animals comprising the upper third of the reactivity distribution. Although total and HDL cholesterol concentrations also covaried with HR reactivity, the greater atherosclerosis of "high" HR reactors persisted after statistical adjustment for concomitant variability in plasma lipids. HR reactivity was unrelated to blood pressure, body weight, or social behavior.
Key Words: atherosclerosis • behavior • cardiovascular reactivity • stress
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
People vary greatly in their cardiovascular reactivity to behavioral stimuli. Some individuals show a characteristic hyperresponsivity of heart rate (HR) and blood pressure when performing difficult, aversive, or interpersonally threatening tasks, for instance, whereas others exhibit little or no cardiovascular arousal under the same stimulus conditions. In addition, it has been proposed that coronary disease risk may be elevated in persons whose physiologic reactions to stress entail marked increases in HR, blood pressure, or other parameters of circulatory response (eg, elevated cardiac output or peripheral resistance).1 Consistent with such speculation, previous research has shown an enhanced reactivity to be associated with (1) putative behavioral markers of coronary risk (eg, traits of anger and hostility, type A behavior)2,3; (2) the presence of coronary disease in selected patient samples4; (3) episodes of myocardial ischemia evoked by mental stress in persons with existing coronary disease5; and (4) subsequent cardiovascular events among survivors of acute myocardial infarction (reference 6, but also see reference 7).
We have hypothesized that cardiovascular responses to behavioral stimuli also potentiate atherogenesis in susceptible—that is, hyperreactive—individuals, possibly because of disturbances of blood flow near predilection sites for lesion development or effects of concomitant sympathoadrenal activation on related pathogenic processes (eg, platelet aggregation, mobilization of lipids).4,8 In two previous studies using an animal model of atherosclerosis, we observed that cynomolgus monkeys (Macaca fascicularis), similar to humans, differ in the magnitude of their cardiac reactions to behavioral provocation—viz, their HR responses to stylized threats of capture.9,10 When fed a cholesterol-containing diet, moreover, animals whose HRs increased most appreciably in response to this stimulus (high HR-reactive monkeys) developed more extensive coronary artery atherosclerosis than did animals showing a less pronounced cardiac responsivity to stress. This reactivity-atherosclerosis association was observed in both male and reproductively intact (premenopausal) female monkeys.
In this article, we present results of a third study of the relationship between behaviorally induced HR reactivity and atherosclerosis in cholesterol-fed monkeys, but in this study, we used animals with the intention of modeling the experience of postmenopausal women undergoing sex hormone replacement therapy. Specifically, we evaluated fear-elicited HR reactivity as a predictor of atherosclerosis in monkeys that were rendered estrogen-deficient by surgical ovariectomy and subsequently treated by replacement of both estrogen and progesterone. Results again support the hypothesis that a heightened cardiac responsivity to stress confers added risk for the development of coronary atherosclerosis.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
Study animals were 20 female cynomolgus macaques, imported as adults from Indonesia (Primate Imports). These animals comprised one experimental condition of a previously published study evaluating the antiatherogenic effects of hormone replacement in ovariectomized monkeys.11 In that experiment, animals were randomized to one of three study conditions: untreated controls, estrogen replacement only, or estrogen plus progesterone replacement. As noted above, the data reported here regarding the association between behaviorally induced HR reactivity and atherosclerosis were collected from the 20 animals administered both estrogen and progesterone replacement.
Experimental Procedures
At the beginning of a 30-month study period, all animals began
consumption of a moderately atherogenic diet containing 0.25 mg of
cholesterol/C and 40% of calories derived from fat.
Because of apparent attenuation of the
hypercholesterolemic response to this diet, the amount
of dietary cholesterol was increased by 50% at month 18.
The hypercholesterolemic effect of this change was
greater than expected, and, therefore, the cholesterol
content of the diet was reduced to the original amount at month 26. The
monkeys were housed socially in groups of five animals each, and all
groups occupied identical pens measuring 2.0x3.2x2.5 m. All
experimental procedures were conducted in compliance with state and
federal laws, standards of the Department of Health and Human Services,
guiding principles of the American Physiological
Society, and guidelines of the Institutional Care and Use
Committee.
Baseline HR measurements and HR responses to behavioral stimulation were recorded in all animals using a standard protocol (as described next), in months 1 to 2 and 24. In the fifth month of the study period, all monkeys were ovariectomized after being anesthetized with ketamine hydrochloride (10 mg/kg) and xylazine (0.6 mg/kg) administered intramuscularly. Beginning in the sixth month, sex hormones were administered by subcutaneous Silastic implants (Dow Corning) to mimic the physiologic concentrations of circulating estrogen and progesterone. Animals were implanted with Silastic tubing (0.335 cm inner diameter, 0.465 cm outer diameter), which was 3.0 cm in length and filled with crystalline 17ß-estradiol (Steraloids Inc). An identical Silastic tubing, 3.5 cm in length and filled with crystalline progesterone (Steraloids Inc), was also implanted subcutaneously. The estrogen implants remained in place for the entire 25-month treatment period, and the progesterone was administered only during alternate 28-day periods (ie, every 28 days, implants were either inserted or removed).
Measurement of HR Under Baseline and Stressed Conditions
For HR evaluations, animals were first anesthetized
(ketamine hydrochloride) and fitted with portable ECG (EKG)
telemetry units (Keuffel & Esser, Model TM-7 patient monitors); these
devices were secured beneath nylon mesh monkey jackets and maintained
in place for several days. HRs were monitored in a laboratory space
removed from the animals, and a permanent recording of the EKG
was made on a strip chart recorder (Keuffel & Esser, Model 110
portable cardiac monitor).
HR measurements were obtained under two conditions, termed "baseline" and "stress," on a day after the animals' recovery from anesthesia. Baseline HRs were recorded during an interval of relative quiet, when no human beings were visible to the monkeys. "Stress" HR measurements were collected immediately after the baseline recordings. As in previous studies,9,10 the stress-period procedure involved a standard challenge in which the experimenter displayed prominently and threateningly before the target animals a large "monkey glove"; this maneuver was conducted in a stylized manner, mimicking encounters typically preceding capture and physical handling of the animals.
The two measurement periods—"baseline" and "stress"—lasted 15 minutes each and were divided into six 2.5-minute recording blocks. Because the monkeys were evaluated in groups of up to five animals, 30-second HR recordings were obtained from each animal on six occasions during each measurement period; this was achieved by monitoring a different EKG telemetry channel (one for each animal) in successive 30-second intervals. The 30-second HR recordings were also randomized across animals within each 2.5-minute recording block.
Quantification of HR involved summation of all R waves detected within each 30-second sample. The baseline HR of each animal (in bpm) was calculated as the mean of the six 30-second HR recordings obtained during the baseline interval. Animals' stress-period HRs were expressed as the peak (highest) of the six 30-second readings recorded during the behavioral challenge. Peak HRs were calculated, rather than the mean of all readings, based on prior work showing this measure to be more highly associated with endpoints of interest (eg, coronary atherosclerosis) than the average of all stress measurements obtained.10
Because HR was evaluated similarly in months 1 to 2 and 24, the two occasions of measurement are referred to hereafter as time-1 and time-2, respectively. When peak stress-period HRs at time-1 are expressed as a percentage increase above baseline measurements, about one third of the animals showed HR increases of less than 50%; another one third showed HR changes from baseline of 50% to 85%, and the remainder experienced HRs greater than 85% above baseline measurements. A similar distribution of HR responses was observed at time-2. Thus, the experimental stressor elicited a pronounced HR acceleration, and among the animals tested, there existed a considerable range of individual differences.
Measurement of Atherosclerosis
At necropsy, the animals' coronary arteries were
perfusion-fixed with 10% neutral buffered formalin under a pressure of
100 mm Hg. After pressure fixation, five serial blocks each
were taken from the left anterior descending, the left circumflex, and
the right coronary arteries. One section from each block was
stained with Verhoeff-Van Gieson stain; the stained sections were then
projected, and the area occupied by intima and/or intimal lesion
(ie, the area between the internal elastic lamina and lumen of the
artery) was measured with a digitizer. Extent of
atherosclerosis was expressed as the mean intimal
(plaque) area (in mm2) of the five sections digitized
from each of the three coronary arteries.
The carotid arteries were opened longitudinally and were immersion-fixed in 10% buffered formalin. At the carotid bifurcation, one standard cross section was taken for microscopic evaluation from both the right and left carotid arteries. Three serial sections were also taken from each common carotid, and the mean intimal area was again determined from each by use of the digitizer.
Behavioral and Other Physiologic Variables
Each week, 30-minute observations were made of each social group
to evaluate behavior. All aggressive, submissive, and affiliative
behaviors occurring within a social group were recorded on an
electronic data recording device (Tandy TRS model 100) using an
ad libitum sampling technique.12 After collection, the data
were transmitted to a VAX computer for calculation of the rate (per
hour) of aggressive and submissive acts, grooming behavior, and the
percentage of time spent in passive affiliation (eg, body contact,
close proximity to another monkey) for each animal. In addition, social
dominance was determined from the outcomes of each animal's aggressive
encounters with all other monkeys housed within the same social
group.13 Monkeys that defeated all other group members were
identified as first-ranking; animals that defeated all but the
first-ranked monkey were labeled second-ranking, and so forth. For
purposes of analysis, social dominance was expressed as the
mean rank attained by each animal across all observations made during
the course of the experiment.14
At 2- to 3-month intervals, blood samples were obtained for determination of total plasma cholesterol (TPC) and HDL cholesterol (HDLC) concentrations. Lipid determinations were made in the Lipid Analytic Laboratory of the Bowman Gray School of Medicine, which is in compliance with the Cooperative Lipid Standardization Program of the US Department of Health and Human Services. Systolic and diastolic blood pressures were recorded at 6-month intervals with the use of a Doppler ultrasound apparatus (Arteriosonde 1010).
Statistical Analysis
To quantitate individual differences in HR reactivity, mean
baseline and stress-period HRs were used to compute a residualized (or
baseline-free) HR change score for each monkey.15 The
residualized change ("reactivity") reflects the extent to which an
animal's actual HR, when exposed to the behavioral challenge, was
either greater or less than that predicted by linear regression from
the overall association between baseline and stress-period HRs for the
sample as a whole (ie, adjusted for influences of initial values).
HR-reactivity scores, calculated separately for time-1 and time-2,
correlated significantly between the two occasions of measurement
(r=.75, P<.0003). Baseline and peak
stress-period HRs at time-1 averaged 159.7 (SD=28.9) and 259.5
(SD=13.0) bpm, respectively, across all animals; the substantial
difference in HR between these two conditions was highly significant
(t=14.8, df=19, P<.0001).
Corresponding baseline and peak stress HRs at time-2 were quite
similar, at 153.8 (SD=23.6) and 254.9 (SD=16.2) bpm (t=15.8,
df=18, P<.0001). Although peak HR responses to
the experimental stressor averaged +100 bpm, data of individual monkeys
varied appreciably; for instance, time-1 HR elevations ranged from +15
to +140 bpm. To perform a "prospective" analysis of the
relationship between HR reactivity and atherosclerosis,
only time-1 measurements are reported in the following statistical
analyses. As might be expected from the high retest reliability
of our reactivity index, however, study results are nearly identical
when performed using the end-of-experiment (ie, time-2) reactivity
scores.
Pearson correlation coefficients were calculated to evaluate the
association between HR reactivity and artery-specific indices of
atherosclerosis, as well as measures of behavior,
plasma lipids, blood pressure, and body weight. To reduce skewness in
the distributions of atherosclerosis measurements,
these data were first subjected to square-root transformation of the
form X' = 
+
.16,17
Analyses were also performed to compare subsets of animals that
were clearly differentiated with respect to the magnitude of their HR
reactivity. As in previous studies,9,10 we partitioned
time-1 reactivity scores to derive tertiles of the distribution
(labeled high, intermediate, and low HR reactors). Group differences in
the major dependent variables were then evaluated by ANOVA or
ANCOVA, with pairwise comparisons conducted using Tukey's HSD
procedure.18 Two-tailed tests of significance are reported
for all statistical analyses.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Correlations of HR reactivity with all dependent variables are summarized in Table 1
. The reactivity
index covaried in the predicted direction for each measure of
atherosclerosis, reaching statistical significance for
the left anterior descending and the left circumflex coronary
arteries, the left carotid artery bifurcation, and the right common
carotid artery.* HR reactivity was not associated with
behavioral attributes of the animals, body weight, or blood pressure
but did correlate significantly with TPC and (inversely) with HDLC
concentrations. Compared with less reactive monkeys, therefore, animals
that exhibited the largest cardiac responsivity to stress developed
greater atherosclerosis at several arterial
sites and showed a more atherogenic lipid profile.
|
ANOVAs conducted on grouped data (ie, high, intermediate, and low HR
reactors) suggest a "threshold" effect in the relationship between
HR reactivity and atherosclerosis. As summarized in
Table 2, these analyses revealed
significant group main effects for the left anterior and the left
circumflex arteries, as well as the left carotid bifurcation and right
common carotid artery. In the coronary arteries, pairwise
contrasts showed high HR reactors to differ significantly from both
intermediate and low reactors (P<.05), whereas lesion
extent was virtually identical in the latter groups. This relationship
is also illustrated in Fig 1, in which
plaque area (averaged across the left anterior descending and the left
circumflex coronary arteries) is depicted for each animal
within the three reactor groups. In contrast to the coronary
arteries, atherosclerosis at the left carotid
bifurcation was similar for high and intermediate reactors, with each
of these groups differing significantly from low HR reactors
(P<.05). The pattern of atherosclerosis in
the right common carotid artery is similar but only differed
significantly between high and low HR reactor groups
(P<.05).
|
|
As indicated in Table 2
, groups did not differ in social rank, rates of
aggressive and submissive behavior, the percentage of time spent in
affiliation (ie, grooming or in passive body contact), body weight, or
blood pressure. Corroborating the correlational findings (Table 1), an
ANOVA showed significant group main effects for TPC and HDLC
concentrations. TPC varied linearly with HR reactivity but differed
significantly only between high and low HR reactors
(P<.0.01). HDLC concentrations were similar among
intermediate and low reactors, and in each of these groups, HDLC
concentrations were significantly greater than among high HR-reactive
animals (P<.05). Finally, because HR reactivity was
predictive of both coronary atherosclerosis and
plasma lipids, we sought to determine whether the accelerated
atherogenesis of high-reactive monkeys persisted after statistical
adjustment for the covariation in animals' TPC and HDLC
concentrations. For this purpose, lesion area in the left anterior
descending and the left circumflex arteries was averaged for each
animal (as in Fig 1) and subjected to ANCOVA, entering as covariates,
TPC and HDLC. To preserve degrees of freedom, high HR reactors were
evaluated relative to the combined intermediate- and low-reactive
groups. This analysis revealed a significant group main effect
(F=4.46, df=1,16, P=.05), with plaque
area among high HR reactors again exceeding that of their less
responsive counterparts; covariance-adjusted group means,
back-transformed to intimal area measurements, were 0.24
mm2 among high HR reactors and 0.09 mm2
among intermediate-and low-reactive animals. We conclude, therefore,
that the HR reactivity-atherosclerosis relationship
cannot be attributed entirely to the concomitant association between
reactivity and plasma lipids.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
It has been hypothesized that behavioral factors contribute to the pathogenesis of coronary disease, including coronary atherosclerosis, through associated sympathoadrenal or hemodynamic reactions to psychologic stress. A corollary of this hypothesis is that persons who exhibit such responses in greatest magnitude are at correspondingly higher risk for coronary disease. In two previous studies of cynomolgus monkeys, cholesterol-fed animals showing the largest HR reactions to a fear-eliciting stimulus (threatened capture) also exhibited accelerated atherogenesis when compared with less reactive animals.9,10 In each of those studies, however, the measurement of animals' cardiac responsivity to stress occurred on a single occasion near the time of necropsy. Hence, it is conceivable that the higher stress-elicited HRs of high-reactive animals were a consequence of their exacerbated atherosclerosis rather than a response characteristic predating (and therefore potentially promoting) lesion development. In contrast, time-1 HR measurements in the current study were obtained in the first 2 months of the 30-month experiment, before animals had consumed an atherogenic diet for any appreciable period and, thus, before the acquisition of significant disease (also note that in the absence of a moderate hyperlipoproteinemia induced by diet, cynomolgus monkeys develop negligible lesion). Thus, the findings presented here offer the first demonstration that heightened cardiac reactions to stress, as seen among the high HR-reactive animals, predict the development of atherosclerosis, unconfounded by the presence of disease at the time of reactivity assessment.
It is also noteworthy that HR measurements obtained after 24-months' consumption of the experimental diet (ie, time-2) were comparable to those recorded at the beginning of the study; indeed, mean elevations in HR between corresponding baseline and stress periods at time-1 and time-2 were nearly identical, at +100 and +101 bpm, respectively. Response differences among individuals were also stable over time, as demonstrated by their substantial retest reliability over 2 years (r=.75). Hence, individual differences in HR response to this standardized laboratory stressor denote an enduring characteristic of the monkeys, which is not appreciably altered by the passage of time, ovariectomy and subsequent hormone replacement, or the development of atherosclerosis. It is probable, then, that our two previous studies showing end-of-experiment reactivity assessments to correlate significantly with atherosclerosis reflect the same association that is demonstrated prospectively in the investigation presented here.
In premenopausal monkeys, animals that exhibit an elevated HR reactivity also experience chronic ovarian dysfunction, as indicated by frequent anovulatory menstrual cycles and, during ovulatory cycles, low luteal-phase plasma progesterone concentrations.10 At present, it is unclear whether activation of the sympathoadrenal system under stress (which may underlie an increased HR reactivity) suppresses ovarian function, thereby compromising the estrogen-dependent protection against atherosclerosis that is ordinarily observed among premenopausal females. Because estrogen and progesterone were administered by implant in the study presented here of surgically ovariectomized monkeys, however, it would appear that heightened HR reactions to stress predict atherosclerosis, at least in part, independently of effects that such reactivity might otherwise have on ovarian function, as seen among reproductively intact animals.
Logically, stress-elicited cardiac reactivity may relate to atherosclerosis in one of three ways: (1) as a marker for increased risk conferred by some third variable with which it is itself only correlated; (2) causally, by hemodynamic influences on the artery wall (eg, propagation of flow disturbances, as at vessel bends or bifurcations, with consequent endothelial dysfunction and injury); or (3) indirectly, through associated sympathoadrenal influences on other pathogenic processes.1,4 With respect to the third possibility, HR reactivity in this study was found to correlate appreciably with animals' TPC and HDLC concentrations. Similar, albeit weaker, relationships between behaviorally evoked HR reactivity and plasma lipids have been reported previously, by ourselves and others, in both monkeys and human subjects.9,19,20 Moreover, persistent pharmacologic elevations of epinephrine have been shown to produce significant increase in the TPC concentrations of cynomolgus monkeys.21 It is likely, therefore, that some portion of the reactivity-atherosclerosis association is mediated by effects of sympathoadrenal activation on aspects of lipid metabolism.
Nonetheless, ANCOVA demonstrates an exacerbation of coronary atherosclerosis among high HR-reactive monkeys, even after adjusting for concomitant variability in plasma lipids. That HR alone may modulate rates of lesion development is suggested by the observation that HR lowering, through sinoatrial node ablation, retards coronary atherogenesis in cholesterol-fed cynomolgus monkeys and does so independently of variability in lipids, blood pressure, or body weight.22 Conversely, it is conceivable that sympathetically induced hemodynamic perturbations, as might be indexed by an elevated HR under stress, promote atherogenesis. For instance, chloralose anesthesia (which produces marked sympathetic activation) causes endothelial injury in the thoracic aorta of rabbits, an effect that is mitigated by concomitant ß-adrenoreceptor blockade.23 Chloralose-induced endothelial injury also occurs primarily at circumostial locations, consistent with the hypothesis that hemodynamic concomitants of sympathetic arousal predispose to atherosclerosis by their propensity to induce flow disturbances at such sites.1,24–26 In cynomolgus monkeys, moreover, acute social stress similarly induces endothelial injury in the coronary arteries and aorta.27 This effect is also prevented by administration of a ß-receptor antagonist and occurs preferentially at sites where flow disturbances propagate most readily and that have known predilection for lesion development. Finally, such endothelial injury and resulting dysfunction may adversely affect a variety of other proatherogenic events, including vascular smooth muscle tone, permeability of the endothelium to blood-borne substances, the production of growth-regulatory molecules and cytokines, and oxidation of lipoproteins.28–31 Future research should, therefore, elucidate the mechanisms by which heightened sympathoadrenal and cardiac responsivity to stress potentiate atherogenesis, focusing on both lipid metabolic and hemodynamic processes.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This research was supported by grants HL-33492 and HL-40962 from the National Heart, Lung, and Blood Institute, National Institutes of Health.
|
Footnotes |
|---|
1 HR-reactivity measurements at time-2 correlated similarly with coronary and carotid artery atherosclerosis (left anterior descending: r=.50, P<.03; circumflex: r=.49, P<.04; right coronary artery: r=.33, NS; left carotid artery bifurcation: r=.48, P<.04; right bifurcation: r=.30, NS; left common carotid artery: r=.29, NS; right common carotid: r=.42, P=.06).
Received September 5, 1996; accepted January 9, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Manuck SB. Cardiovascular reactivity in cardiovascular disease: `Once more unto the breach.' Int J Behav Med. 1994;1:4-31.
2. Harbin TJ. The relationship between type A behavior pattern and physiological responsivity: a quantitative review. Psychophysiology. 1989;26:110-119.[Medline] [Order article via Infotrieve]
3. Houston BK. Personality characteristics, reactivity, and cardiovascular disease. In: Turner JR, Sherwood A, Light KC, eds. Individual Differences in Cardiovascular Responses to Stress. New York: Plenum, 1992:103-124.
4.
Manuck SB, Kaplan JR, Matthews KA. Behavioral
antecedents of coronary heart disease and
atherosclerosis.
Arteriosclerosis. 1986;6:2-14.
5.
Krantz DS, Helmers KF, Bairey CN, Nebel LE, Hedges SM,
Rozanski A. Cardiovascular reactivity and mental
stress-induced myocardial ischemia in patients with
coronary artery disease. Psychosom Med. 1991;53:1-12.
6.
Manuck SB, Olsson G, Hjemdahl P, Renqvist N. Does
cardiovascular reactivity to mental stress have
prognostic value in postinfarction patients? Psychosom Med. 1992;54:102-108.
7. Follick MJ, Ahern DK, Gorkin L, Niaura RS, Herd JA, Ewart C, Schron EB, Kornfeld DS, Capone RJ. Relation of psychosocial and stress reactivity variables to ventricular arrhythmias in the Cardiac Arrhythmia Pilot Study (CAPS). Am J Cardiol. 1990;66:63-67.[Medline] [Order article via Infotrieve]
8.
Malkoff SB, Muldoon MF, Ziegler ZR, Manuck SB. Blood
platelet responsivity to acute mental stress. Psychosom
Med. 1993;55:477-482.
9.
Manuck SB, Kaplan JR, Clarkson TB. Behaviorally
induced heart rate reactivity and atherosclerosis in
cynomolgus monkeys. Psychosom Med. 1983;45:95-108.
10.
Manuck SB, Kaplan JR, Adams MR, Clarkson TB.
Behaviorally elicited heart rate reactivity and
atherosclerosis in female cynomolgus monkeys
(Macaca fascicularis). Psychosom Med. 1989;51:306-318.
11.
Adams MR, Kaplan JR, Manuck SB, Koritnik DR, Parks JS,
Wolfe MS, Clarkson TB. Inhibition of coronary artery
atherosclerosis by 17-beta estradiol in ovariectomized
monkeys: lack of an effect of added progesterone.
Arteriosclerosis. 1990;10:1051-1057.
12. Altmann J. Observational study of behavior: Sampling methods. Behaviour. 1974;48:1-41.
13. Sade DS. Determinants of dominance in a group of free-ranging rhesus monkeys. In: Altmann SA, ed. Social Communication Among Primates. Chicago: University of Chicago Press, 1982:99-114.
14.
Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DB.
Social status, environment and atherosclerosis in
cynomolgus monkeys. Arteriosclerosis. 1982;2:359-368.
15. Manuck SB, Monroe SM, Kasprowicz A, Monroe SM, Larkin KT, Kaplan JR. Psychophysiologic reactivity as a dimension of individual differences. In: Schneiderman N, Weiss SM, Kaufmann P, eds. Handbook of Methods and Measurements in Cardiovascular Behavioral Medicine. New York: Plenum, 1989:365-382.
16. Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Math Stat. 1950;21:607-611.
17. Sokol R, Rohlf FJ. Biometry. San Francisco: Freeman, 1981.
18. Kirk RE. Experimental Design: Procedures for the Behavioral Sciences. Belmont, CA: Brooks/Cole, 1968.
19. Waldstein SR, Polefrone JM, Bachen EA, Muldoon MF, Kaplan JR, Manuck SB. Relationship of cardiovascular reactivity and anger expression to serum lipid concentrations in healthy young men. J Psychosom Res. 1993;37:249-256.[Medline] [Order article via Infotrieve]
20. Jorgensen RS, Nash JK, Lasser NL, Hymowitz N, Langer AW. Heart rate acceleration and its relationship to total serum cholesterol, triglycerides, and blood pressure reactivity in men with mild hypertension. Psychophysiology. 1988;25:39-44.[Medline] [Order article via Infotrieve]
21.
Dimsdale JE, Herd J, Hartley L. Epinephrine
mediated increases in plasma cholesterol. Psychosom
Med. 1983;45:227-232.
22.
Beere PA, Glagov S, Zarins CK. Retarding effect of
lowered heart rate on coronary atherosclerosis.
Science. 1984;226:180-182.
23.
Pettersson K, Bejne B, Bjork H, Strawn WB, Bondjers G.
Experimental sympathetic activation causes endothelial
injury in the rabbit thoracic aorta via beta-1 adrenoceptor activation.
Circ Res. 1990;67:1027-1034.
24. Bondjers G, Brattand R, Bylock A, Hansson GK, Bjorkerud S. Endothelial integrity and atherogenesis in rabbits with moderate hypercholesterolemia. Artery. 1977;3:295-408.
25.
Kaplan JR, Manuck SB, Adams MR, Weingard KW, Clarkson
TB. Inhibition of coronary atherosclerosis by
propranolol in behaviorally predisposed monkeys fed an
atherogenic diet. Circulation.. 1987;76:1364-1372.
26. Spence JD, Perkins DB, Klein JR, et al. Hemodynamic modifications of aortic atherosclerosis: effects of propranolol versus hydralazine in hypertensive hyperlipidemic rabbits. Atherosclerosis. 1984;50:325-333.[Medline] [Order article via Infotrieve]
27.
Strawn WB, Bondjers G, Kaplan JR, Manuck SB, Schwenke
DC, Hansson GK, Shively CA, Clarkson TB. Endothelial
dysfunction in response to psychosocial stress in monkeys. Circ
Res. 1991;68:1070-1079.
28.
Masuda J, Ross R. Atherogenesis during low level
hypercholesterolemia in the nonhuman primate.
I. Fatty streak formation.
Arteriosclerosis. 1990;10:164-177.
29.
Masuda J, Ross R. Atherogenesis during low level
hypercholesterolemia in the nonhuman primate.
II. Fatty streak conversion to fibrous plaque.
Arteriosclerosis. 1990;10:178-187.
30. Ross R. The pathogenesis of atherosclerosis: n update. N Engl J Med. 1986;314:488-500.[Medline] [Order article via Infotrieve]
31. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. O'Donovan and B. M. Hughes Access to Social Support in Life and in the Laboratory: Combined Impact on Cardiovascular Reactivity to Stress and State Anxiety J Health Psychol, November 1, 2008; 13(8): 1147 - 1156. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Lucini, S. Riva, P. Pizzinelli, and M. Pagani Stress Management at the Worksite: Reversal of Symptoms Profile and Cardiovascular Dysregulation Hypertension, February 1, 2007; 49(2): 291 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Levy, J. M. Hausdorff, R. Hencke, and J. Y. Wei Reducing Cardiovascular Stress With Positive Self-Stereotypes of Aging J. Gerontol. B. Psychol. Sci. Soc. Sci., July 1, 2000; 55(4): P205 - P213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rozanski, J. A. Blumenthal, and J. Kaplan Impact of Psychological Factors on the Pathogenesis of Cardiovascular Disease and Implications for Therapy Circulation, April 27, 1999; 99(16): 2192 - 2217. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||