(Circulation. 1997;96:4246-4253.)
© 1997 American Heart Association, Inc.
Articles |
Exaggerated Reactivity to Mental Stress Is Associated With Exercise-Induced Myocardial Ischemia in an Asymptomatic High-Risk Population
From the Division of Cardiology and the Center for Health Promotion, the Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to Diane M. Becker, Johns Hopkins Medical Institutions, Center for Health Promotion, 1830 E Monument St, Room 8033, Baltimore, MD 21205. E-mail dbecker{at}welchlink.welch.jhu.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background This study was done to determine whether cardiovascular reactivity to mental stress is associated with exercise-induced occult ischemia in an asymptomatic population at high risk for premature coronary heart disease (CHD).
Methods and Results One hundred fifty-two siblings of persons with premature CHD underwent mental stress testing. Exercise thallium tomography and 24-hour Holter monitoring were also performed. Hemodynamic changes were monitored during both stressors. Siblings positive for exercise-induced ischemia were offered cardiac catheterization. During mental stress, siblings with an abnormal exercise ECG and/or thallium scan (n=15) had greater maximal increases in systolic blood pressure (SBP, P=.0004) and diastolic blood pressure (DBP, P=.05) and had greater heart rate variability in the normalized low frequency domain of an analysis of Holter monitor recordings, compared with siblings without exercise-induced ischemia. Coronary arteriography confirmed coronary atherosclerosis in 85% of siblings with exercise-induced ischemia. Regression analyses showed that occult ischemia during exercise was a strong independent predictor of maximal change in SBP and DBP during mental stress. A multivariate logistic model demonstrated that siblings with exercise-induced occult ischemia were 21 times more likely to be "hot" responders (top quartile of change in SBP and DBP) during mental stress.
Conclusions An exaggerated cardiovascular response to mental stress is associated with exercise-induced myocardial ischemia in persons with preclinical coronary heart disease.
Key Words: stress • ischemia • blood pressure • nervous system, autonomic
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Persons with atherosclerosis and increased reactivity to laboratory-induced mental stress may demonstrate a generalized exaggerated response to everyday life stresses1 and be at greater risk for myocardial ischemia and coronary heart disease (CHD) events. Mental stress produces transient sympathetic arousal that varies in intensity, depending on both the mental stressor being applied and poorly defined individual characteristics.2,3 People who have the most intense responses, with greater increases in heart rate and/or blood pressure, termed "hot" responders,4 are known to develop chronic hypertension.5–8 In case-control studies, "hot" responders are differentially represented among persons with documented cardiovascular disease events compared with people who have not experienced an event.4 In patients with manifest clinical CHD events, mental stress is associated with both silent and symptomatic myocardial ischemia.9–11 Patients with known CHD who develop ischemia during mental stress have greater increases in heart rate, blood pressure, and systemic vascular resistance, suggestive of a greater sympathetic response.12 In addition, stress caused by mental arithmetic has been shown to produce coronary artery constriction in patients with documented CHD rather than dilatation as found in normal individuals.13
Prior findings have suggested that atherosclerotic vessels react differently to sympathetic stimuli than do normal vessels, with a greater degree of vasoconstriction.14,15 Animal models have demonstrated that chronic sympathetic arousal is associated with endothelial injury, which can be prevented by ß-adrenergic–blocking agents.16–18 Abnormal coronary vasomotor responses have been observed in apparently healthy people during sympathetic stimulation produced by cold pressor testing.19,20 These considerations suggest that sympathetic arousal can lead to generalized vasoconstriction and potentially to myocardial ischemia in persons with atherosclerosis, including those with preclinical CHD.
In this study, we examined the hypothesis that high-risk persons without clinical CHD but with exaggerated cardiovascular reactivity to mental stress testing would be more likely to have silent myocardial ischemia during exercise. We selected a population at risk for coronary atherosclerosis but without clinical CHD. This was done to (1) avoid the potentially confounding effects of drug treatment or cardiac symptoms on sympathetic reactivity, (2) provide sufficient numbers of individuals both with and without exercise-induced silent myocardial ischemia to allow comparisons between the two groups, and (3) access only individuals with relatively early coronary atherosclerosis without severe fixed coronary lesions in whom coronary vasoconstriction might be playing a greater pathophysiological role. We studied apparently healthy 30- to 59-year-old siblings of persons with documented CHD before the age of 60 years. Siblings are known to bear a high risk for development of premature clinical CHD themselves.21 Our prior prospective studies in siblings have shown a high prevalence of positive exercise tests that predict future clinical CHD events.22
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sample and Recruitment
The Johns Hopkins Sibling Study is a prospective investigation of coronary risk factors in asymptomatic, apparently healthy siblings of persons with documented CHD before the age of 60 years. The sample was identified through hospitalized index patients less than 60 years of age, with documented myocardial infarction or angina, accompanied by angiographic evidence of at least one 50% diameter stenosis in one or more coronary arteries. Index patients were identified through daily hospital "sweeps" in six Baltimore hospitals. Permission to speak with index cases was obtained from the attending physician. Index cases were asked for access to all siblings between 30 and 59 years of age who had no known history of CHD.
Eligible siblings were sent a description of the study and a refusal postcard to return if they preferred not to be contacted. Siblings were called within 2 weeks and invited to participate in a comprehensive cardiovascular screening. The absence of a clinical CHD event was verified with the primary physician. Siblings were excluded from the study if they had functional status limitations that precluded exercise treadmill testing, if they were receiving chronic or recent glucocorticosteroid therapy, or had any comorbidity for which life expectancy was judged to be 5 years or less. This recruitment process yielded a total sample of 152 siblings. The study was approved by the Johns Hopkins Joint Committee on Clinical Investigation, and all participants gave informed consent.
Baseline Maximal Graded Exercise Testing
All siblings underwent a maximal graded treadmill test using a
modified Bruce protocol.22 Exercise was continued
until the subject had to stop because of maximal effort (n=124),
fatigue with musculoskeletal pain (n=11), dyspnea (n=11), dizziness
(n=1), chest pain (n=0), leg weakness or pain (n=4), or extreme
ST-segment changes 
7 mm (n=1).
In men, a positive stress test was defined as horizontal or downsloping
ST-segment depression of 1 mm over baseline at 0.06 seconds
after the J-point in three or more consecutive beats at any time during
the exercise test or during the first 3 minutes of recovery after
exercise. In women, to reduce the frequency of known high rates of
false-positive tests,23 an abnormal response was
defined as 2 mm flat or downsloping ST-segment depression over
baseline in leads II, III, or aVF or 1.5 mm ST-segment
depression in any other lead. Two cardiologists, who were blinded to
the risk factor status of the sibling and to the results of mental
stress testing, determined whether the exercise test was positive or
negative for ischemia. A consensus reading was
recorded.
Baseline Stress Thallium Scintigraphy
Thallium-201 scintigraphy was performed in
conjunction with the maximal exercise treadmill test. One minute before
the end of exercise, 3 mCi thallium-201 was injected
intravenously and tomographic imaging was performed as
previously described.22 Three hours later,
delayed imaging was performed without reinjection of thallium.
Images were reconstructed by filtered back projection using a ramp filter after prefiltering of the projection images with a two-dimensional Fourier (Weiner) filter and correction for translational motion.24,25 Image interpretation was performed visually by an experienced nuclear cardiologist without knowledge of the subject's identity, exercise test results, or the results of mental stress testing. A positive thallium tomogram was defined by a segmental perfusion defect on the immediate postexercise images in at least two contiguous tomographic slices and two image orientations, with definite improvement or normalization on the delayed images. We have previously shown, using receiver operating curve analysis, that visual interpretation using these criteria provides a sensitivity for detection of coronary disease of 95% at a false-positive rate of 10%.26 In patients without previous infarction, the sensitivity was 87%.26
Baseline Physical Examination and Baseline Blood Pressure
Assessment
A physical examination was performed and blood was obtained for
fasting plasma levels of total cholesterol, high-density
lipoprotein cholesterol, and triglycerides.
Low-density lipoprotein cholesterol was estimated with the
Friedewald formula27 for persons with
triglyceride levels up to 400 mg/dL. Measurements of height
and weight were recorded and body mass index was calculated.
National Center for Health Statistics (NCHS) Standards were used to
determine obesity separately for men and
women.28
An initial blood pressure reading was obtained during the physical
examination with a standard sphygmomanometer, following American Heart
Association guidelines.29 Measurements were
repeated before the exercise test, after the redistribution imaging,
and preceding psychometric testing. The mean of these three readings
was used as the baseline resting blood pressure. Hypertension was
defined, according to the Joint National Committee on Detection,
Evaluation, and Treatment of Hypertension (JNC IV and
V),29 as having a high baseline blood pressure
(systolic 140 or diastolic 90 mm Hg)
or currently taking blood pressure medication.
Ambulatory Monitoring for Myocardial Ischemia
A calibrated amplitude-modulated ambulatory electrocardiographic
(AECG) monitor (Spacelabs ambulatory ECG model 90205) with modified
bipolar lead V5 and modified bipolar lead
V3 was attached to siblings after the completion
of the thallium study and before psychometric testing to detect silent
ischemia during mental stress. Silent ischemia was
defined by the presence of ST-segment depressions of 1 mm from
baseline, lasting continuously for >1 minute in either lead.
Psychometric Testing: The Stroop Color Word Test
Mental stress was induced by a computerized version of the
Stroop Color Word Test (Data Instruments, Inc). All responses were
timed by the computer, and the speed of the test increased with the
accuracy and response speed of the subject. The test is generally
thought to be independent of culture and requires minimal literacy
skills. Siblings were seated in a quiet room with a closed door. After
a standardized verbal explanation of the test and a 30-second practice
period, an ARTRAC 7000 Continuous Noninvasive Blood Pressure Monitor
was applied, with the cuff placed on the nondominant arm. Blood
pressure and heart rate measurements were recorded 1 minute before
the administration of the test, every minute during the 3-minute test,
and for 1 minute thereafter. Maximal blood pressure and heart rate
changes were calculated as the absolute difference between the highest
value attained during the test and the value at 1-minute pretest.
Measurements of Autonomic Tone
A computerized system (SpaceLabs FT3000a) was used to determine
changes in heart rate variability during mental stress. The peak of
each QRS was identified by a computer algorithm, and beat
identification was confirmed by an investigator. Periods of poor beat
identification were excluded from analysis. Power spectrum
analysis was performed by a modification of Berger et
al,30 as previously
described.31 Initially, a time series of interest
was reviewed to ensure stationariness. Sequential RR intervals were
plotted as a function of length in milliseconds and resampled at 4 Hz
(with the use of a cubic spline function) to obtain an evenly spaced
series of 2 minutes of instantaneous heart rates (four instantaneous
heart rates per second). The mean heart rate was then subtracted and a
Hanning window was applied.
Power spectral density plots were obtained by plotting the square of the amplitude of the fast Fourier transformation of the time series against frequency (Hz) for 2-minute data sets immediately before, during, and 30 minutes after mental stress testing. Normalized power (ms2/bandwidth) in high-frequency (0.125 to 0.5 Hz) and low-frequency (0.05 to 0.125 Hz) bands was determined by integrating the appropriate area under the power spectral density plots and dividing by the total power.32 High-frequency power has been shown to reflect vagal tone, whereas low-frequency power is believed to reflect both vagal and sympathetic stimulation.33 Therefore increases in normalized low-frequency power, with an unchanged or a decreased normalized high-frequency power, has been suggested as a robust marker of sympathetic arousal.33
Cardiac Catheterization
In all siblings with a positive ETT and/or thallium scan,
coronary arteriography was offered to verify the existence of
coronary atherosclerosis. Arteriography was
done with standard 6F left and right Judkins diagnostic
catheters. Images in multiple views were recorded on
cineangiographic film at a rate of 30 frames/s, and the severity and
extent of stenosis were graded visually by an experienced
angiographer blinded to the results of mental stress testing, exercise
testing, and risk factor status. Lesions were marked on the
cineangiogram film and computerized algorithms were used to
further quantify the severity of
stenosis.34
Statistical Analysis
All risk factors were examined for distributions with the use of
standard univariate techniques. For continuous
variables, frequencies, means, and standard deviations were
examined. Bivariate relationships were examined. Student's
t test and ANOVA were used to test the significance of mean
differences among continuous variables; contingency table arrays
and the 
2 statistic were applied for
categorical variables. Multivariate
analyses, including linear and logistic regression techniques,
were used to predict outcomes.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sample Characteristics
The study included 152 siblings identified from 85 successive index cases. The sample was 70% white (55 men, 52 women) and 30% African American (9 men, 36 women). The mean age of participants was 45±7 years (range, 30 to 59). There was a high prevalence of traditional coronary risk factors: mean LDL cholesterol was 153±52 mg/dL; mean HDL cholesterol was 50±15 mg/dL; 46% of the population was hypertensive, 33% were current smokers, and 53% were obese.
Detection of Myocardial Ischemia
Occult ischemia during exercise occurred in 15 of the 152
siblings. No individual had chest pain or other potentially
ischemic discomfort on the treadmill. Seven had occult
ischemia by ECG only, 4 had a reversible perfusion defect on
thallium scan only, and 4 had both ECG and scan abnormalities. Using
means and t tests, as well as 2
analyses for prevalences, there were no significant differences
in levels of LDL cholesterol, HDL cholesterol,
triglycerides, body mass index, blood pressure, or smoking
prevalence, hyperlipidemia, or hypertension between
siblings who had occult ischemia during exercise and those who
did not. This is congruent with our prior studies in a larger
sample.22 No evidence of ischemia was
found in any sibling on AECG (Holter) during mental stress testing or
for the 24 hours thereafter. Four of the siblings with exercise-induced
occult ischemia were taking a single antihypertensive
medication at the time of screening (3 were taking calcium channel
blockers and 1 was on a diuretic). None were taking
ß-blockers.
Coronary Arteriography
Thirteen of the 15 siblings with evidence of occult
ischemia on the treadmill underwent coronary
arteriography (2 refused). Eleven of 13 (85%) had evidence of
coronary disease. Six had a maximum stenosis of 50%
of the artery diameter, 3 had extensive diffuse coronary
lesions, and 2 had mild focal stenoses. Seven of the 11
siblings with diseased coronary arteries had involvement of 2
vessels.
Reactivity During Physical Stress
Before exercise testing, baseline levels of blood pressure and
heart rate were similar between siblings with and without
exercise-induced ischemia. Table 1
shows changes
in maximal blood pressure and heart rate during treadmill exercise in
subjects with and without occult ischemia. There were no
significant differences between the two groups in maximal change of
systolic blood pressure, diastolic blood pressure,
or heart rate during or after exercise by an analysis of means
and t tests. Multivariate linear regressions
were modeled to predict the change in each of these
parameters. Variables included in each regression were
sex, race, age, baseline blood pressure, obesity, smoking status, and
the presence of occult ischemia. For systolic blood
pressure change, male sex (P<.001) and African American
race (P=.01) were the only significant predictors. For
diastolic blood pressure change, African American race
(P<.001) was the only significant independent predictor.
Heart rate increases were predicted by male sex (P<.001),
age >45 (P<.001), high blood pressure at screening
(P<.001), and current smoking behavior
(P<.001).
|
Reactivity During Mental Stress
Before mental stress testing, there were no significant baseline
differences between siblings with and those without evidence of occult
exercise ischemia in systolic blood pressure (136
versus 132 mm Hg, respectively), diastolic blood
pressure (87 versus 84 mm Hg), or heart rate (87 versus 83
bpm). During mental stress, significant increases occurred in blood
pressure and heart rate in all siblings. Siblings with occult
ischemia during exercise had significantly greater reactivity
in systolic and diastolic blood pressure during
mental stress (P=.0004 and P=.05, respectively)
(Table 1
).
Separate multiple linear regression analyses were performed to
investigate the predictors of maximal change in systolic blood
pressure, diastolic blood pressure, and heart rate during
mental stress (Table 2). Occult ischemia during
exercise remained a significant independent predictor of maximal
increase in systolic and diastolic blood pressure,
controlling for all other variables. It was the only variable
that was a significant predictor of both measures of blood pressure
reactivity. Age was associated with maximal increase in
systolic blood pressure, and current smoking was a significant
predictor of maximal increase in heart rate (P=.04,
P=.01, respectively).
|
To further investigate the association between increased blood pressure
reactivity during mental stress and the presence of occult
ischemia during exercise, we identified a subgroup of siblings
with exaggerated mental stress–induced blood pressure reactivity in
the top quartile of change in both systolic and
diastolic blood pressure ("hot" responders).
Multiple logistic regression analysis predicting "hot"
responders demonstrated that siblings with exercise-induced occult
ischemia were more than 21 times (95% CI, 5 to 97) more likely
to be "hot" responders than siblings without evidence of
exercise-induced ischemia, independent of all other
variables (Table 3). Siblings under the age of 45
years were also more likely to be "hot" responders, with an odds
ratio of almost 5 (95% CI, 1 to 22). The exercise test and
angiographic results in a typical "hot" responder to mental stress
are depicted in the Figure.
|
|
Ambulatory ECG and Measures of Heart Rate Variability
Heart rate variability measures before, during, and after the
Stroop Color Word test are shown in Table 4. Before
mental stress testing, there were no differences in mean normalized
low- or high-frequency power between siblings with occult
ischemia on the treadmill and those without. During mental
stress, siblings with occult ischemia during exercise had
significantly greater normalized low frequency power (0.40 versus 0.29,
P=.03), with no significant differences in normalized
high-frequency power, suggesting a shift toward higher sympathetic
arousal. During mental stress, the normalized change in low-frequency
power from baseline was significant in the siblings with
exercise-induced ischemia (P=.03). After completion
of mental stress testing, siblings with occult ischemia during
exercise returned to baseline levels of low-frequency power at levels
similar to normal siblings but demonstrated a trend toward
parasympathetic withdrawal, as captured by levels of high frequency
power (P=.06), when compared with siblings without
ischemia on the treadmill.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study of asymptomatic people at high risk for premature coronary artery disease revealed a strong association between cardiovascular reactivity during mental stress and treadmill-induced occult myocardial ischemia. This finding has not been reported in the literature. Blood pressure and heart rate changes in response to exercise were in the direction of and of a magnitude normally seen during maximal graded treadmill testing, with no differences between those with a positive stress thallium test and those without. However, maximal increases in blood pressure during mental stress were significantly greater in those individuals who developed occult ischemia during exercise than in those who did not. Linear regression analyses showed that occult ischemia during exercise was a strong independent predictor of maximal change in systolic and diastolic blood pressure during mental stress and a multivariate logistic model demonstrated that individuals who had occult ischemia during exercise were 21 times more likely to be "hot" responders during mental stress than were all other subjects. Finally, frequency domain analysis of heart rate variability suggested that subjects with exercise-induced occult ischemia had greater sympathetic arousal during mental stress.
The results of our study are consistent with our hypothesis that an exaggerated cardiovascular response to mental stress is linked to exercise-induced myocardial ischemia in persons with a high probability of preclinical coronary atherosclerosis. Impaired arterial vasodilation resulting from early atherosclerosis, combined with increased sympathetic arousal, could lead to an exaggerated systemic pressor response during mental stress, as well as contributing to myocardial ischemia during exercise.
An exaggerated response to mental stress in the laboratory may be indicative of increased reactivity to daily life stressors.1 An irruptive pattern of blood pressure, including multiple daily episodes of hypertension, may potentially lead to more severe atherosclerosis.35 The presence of more frequent exercise-induced ischemia in people with an exaggerated response to mental stress may possibly represent more severe atherosclerosis in these individuals. Although we found evidence of coronary atherosclerosis in 11 of 13 siblings undergoing coronary angiography for an abnormal exercise test or thallium scan, we do not know that these individuals in fact had more severe coronary atherosclerosis than the 137 other siblings who had normal exercise test results and did not undergo angiography. Ethical considerations relative to performing angiography in completely asymptomatic persons with normal exercise studies precluded angiography in the stress test and thallium scan negative persons. Thus the angiogram was used to demonstrate that most subjects with abnormal stress thallium tests had significant coronary atherosclerosis, although it is clearly possible that mechanisms other than severe alterations in coronary anatomy, such as exercise-induced coronary vasoconstriction or microvascular disease, may in part have been responsible for the stress thallium results. Because those siblings without a positive test may have had preclinical disease, we can only conclude that siblings demonstrating increased reactivity during mental stress had a greater propensity to manifest myocardial ischemia during exercise (possibly through vasoconstrictive mechanisms). Our prior work provides strong support for the positive stress thallium tests being indicative of preclinical CHD.22 We have shown that the single strongest predictor of a clinically manifest event (myocardial infarction, sudden death event, or severe stenoses with revascularization) at 6-year follow-up in a group of 264 apparently healthy siblings is a positive stress thallium test at baseline; 13 of 73 persons with a positive ECG or thallium test had an event whereas only 6 of 191 siblings with a negative ECG and thallium test had an event.22 Thus it is probable that the siblings with a positive stress thallium test have true preclinical disease and it is unlikely that these are false-positive tests.
Our findings on AECG of altered heart rate variability are strongly supportive of increased sympathetic tone in siblings with the greatest increments in reactivity during mental stress. The sympathetic nervous system response during mental stress differs from the sympathetic response during physical stress in that with mental stress, there is a relatively greater increase in plasma epinephrine than norepinephrine,36–38 a more rapid rise in blood pressure, and a smaller increase in heart rate.37 Increased sympathetic nervous system activity or diminished parasympathetic nervous system activity are likely to be primarily responsible for increased mental stress-induced reactivity39,40 while being only one of many factors inducing blood pressure and heart rate changes during physical stress. There is an established relationship between sympathetic drive and vascular damage, attributed to both altered hemodynamics and the direct effect of circulating catecholamines released by sympathetic nerves. Sympathetic activity increases blood flow velocity, flow turbulence,41,42 and arterial wall shear stress,43 which may cause diffuse thickening of the arterial intima42 and may increase endothelial permeability and endothelial cell turnover.43–46 Sympathetic nerves release neurohumoral agents, which elicit the release of endothelium-dependent relaxing factor from the endothelium but also exert a direct vasoconstrictor effect on vascular smooth muscle.47,48 Unopposed interaction with smooth muscle by such agents, due to loss of endothelial function, could lead to exaggerated vasoconstriction of the affected vessels and, subsequently, increased blood pressure responses to mental stress, as well as coronary vasoconstriction and resulting myocardial ischemia during physical stress. Intact endothelium may also inhibit the release of norepinephrine from sympathetic nerves, which would reduce the tendency for vasoconstriction.49 Animal studies have also shown that norepinephrine can directly induce medial hypertrophy and cell polyploidization of aortic smooth muscle.50
The degree and direction of coronary vasomotion in response to sympathetic stimulation is intimately related to the integrity of endothelial function.51 Vita et al52 demonstrated that patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion have increased constrictor effects of catecholamines. Furthermore, paradoxical vasoconstriction in atherosclerotic coronary arteries may occur at a very early stage in the disease process, even before the formation of detectable atherosclerotic plaque by coronary angiography.53–55
Conclusions
We found evidence that occult myocardial ischemia during
physical stress in asymptomatic people at risk for CHD is
related to an exaggerated blood pressure rise during mental stress.
Sympathetic activity during mental stress, assessed by heart rate
variability, was higher in siblings with exercise-induced occult
ischemia than those without, providing a possible explanation
for the greater pressor response during mental stress. The association
between mental stress reactivity and physically induced myocardial
ischemia may be mediated by interactions between increased
sympathetic tone and atherosclerosis-related vascular
endothelial dysfunction.
|
Acknowledgments |
|---|
This study was supported by grant HL-4976202 from the National Heart, Blood, and Lung Institute and by grant NR-0224103 from the National Institute of Nursing Research and supported in part by the General Clinical Research Center NIH-NCRR, OPD-GCRC grants MO1-RR00035 and MO1-RR00722. This research was also supported by grant 5RO1HL-4976202 from the National Heart, Blood, and Lung Institute, grant 5RO1-NR0224103 from the National Institute of Nursing Research and General Clinical Research Center Grants MO1-RR00035 and MO1-RR00722 from the National Center for Research Resources and the National Institutes of Health, Bethesda, Md. We would like to express our thanks to Sinai Hospital, University of Maryland Medical Center, Mercy Hospital, Liberty Medical Center, and Union Memorial Hospital for continued support in subject recruitment.
Received April 10, 1997; revision received August 11, 1997; accepted September 1, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Fredrikson M, Tuomisto M, Melin B. Blood pressure in healthy men and women under laboratory and naturalistic conditions. J Psychosom Res. 1990;34:675–686.[Medline] [Order article via Infotrieve]
2. Nestel PJ. Blood pressure and catecholamine excretion after mental stress in labile hypertension. Lancet. 1969;1:692–694.[Medline] [Order article via Infotrieve]
3.
Mills PJ, Dimsdale JE, Nelesen RA, Jasiewicz J,
Ziegler MG, Kennedy B. Patterns of adrenergic receptors and adrenergic
agonists underlying cardiovascular responses to a
psychological challenge. Psychosom Med. 1994;56:70–76.
4. McKinney ME, McIlvain HE, Hofschire PJ, Collins RE, Somers JA, Ruddel H, Buell JC, Eliot RS. Cardiovascular changes during mental stress: correlations with presence of coronary risk factors and cardiovascular disease in physicians and dentists. J Hum Hypertens. 1987;1:137–145.[Medline] [Order article via Infotrieve]
5. Saab PG, Schneiderman N. Biobehavioral stressors, laboratory investigation, and the risk of hypertension. In: Blascovich J, Katkin ES, eds. Cardiovascular Reactivity to Psychological Stress and Disease. Washington, DC: American Psychological Association; 1993.
6. Loyke HF. Cold pressor test as a predictor of the severity of hypertension. South Med J. 1995;88:300–304.[Medline] [Order article via Infotrieve]
7.
Manuck SB, Olsson G, Hjemdahl P, Rehnqvist N. Does
cardiovascular reactivity to mental stress have
prognostic value in postinfarction patients? A pilot study.
Psychosom Med. 1992;54:102–108.
8.
Matthews KA, Woodall KL, Allen MT.
Cardiovascular reactivity to stress predicts future
blood pressure status. Hypertension. 1993;22:479–485.
9. Rozanski A, Bairey CN, Kranz DS, Friedman J, Resser KJ, Morell M, Hilton-Chalfen S, Hestrin L, Bierendorf J, Berman DS. Mental stress and the induction of silent myocardial ischemia in patients with coronary artery disease. N Engl J Med. 1988;318:1005–1012.[Abstract]
10.
Legault SE, Freeman MR, Langer A, Armstrong PW.
Pathophysiology and time course of silent myocardial ischemia
during mental stress: clinical, anatomical, and
physiological correlates. Br Heart
J. 1995;73:242–249.
11.
Kranz 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.
12.
Goldberg AD, Becker LC, Bonsall R, Cohen JD, Ketterer,
Kranz DS, Light KC, McMahon RP, Noreuil T, Pepine CJ, Raczynski J,
Stone PH, Strother D, Taylor H, Sheps DS. Ischemic,
hemodynamic, and neurohormone responses to mental and
exercise stress: experience from the
Psychophysiological Investigations of Myocardial
Ischemia (PIMI). Circulation. 1996;94:2402–2409.
13. Yeung AC, Vekshtein VI, Krantz DS, Vita JA, Ryan TJ Jr, Ganz P, Selwyn AP. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med. 1991;325:1551–1556.[Abstract]
14. Maseri LA, Severi S, De Nes M, L'Abbate A, Chierchia S, Marzilli M, Ballestra AM, Parodi O, Biagini A, Distante A. `Variant' angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia: pathogenetic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients. Am J Cardiol. 1978;42:1019–1035.[Medline] [Order article via Infotrieve]
15. Maseri LA, L'Abbate A, Baroldi G, Chierchia S, Marzilli M, Ballestra AM, Severi S, Parodi O, Biagini A, Distante A. Coronary vasospasm as a possible cause of myocardial infarction: a conclusion derived from the study of `preinfarction' angina. N Engl J Med. 1978;299:1271–1277.[Abstract]
16.
Pettersson K, Bejne B, Bjork H, Strawn WB, Bondjers G.
Experimental sympathetic activation causes endothelial
injury in the rabbit thoracic aorta via B1-adrenoceptor activation.
Circ Res. 1990;67:1027–1034.
17. Ablad B, Bjorkman JA, Gustaffson D, Hansson G, Ostlund-Lindquist AM, Pettersson K. The role of sympathetic activation in atherogenesis: effects of beta-blockade. Am Heart J. 1988;116:322–327.[Medline] [Order article via Infotrieve]
18. Pettersson K, Ablad B. Metoprolol inhibits platelet deposition at arterial bifurcations in rabbits with sympathetic activation. J Fed Am Soc Exp Biol. 1988;2:A1580. Abstract.
19. Zeiher AM, Drexler H, Wollschlaeger H, Saurbier B, Just H. Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium. J Am Coll Cardiol. 1989;14:1181–1190.[Abstract]
20. Dubois-Rande J, Dupouy P, Aptecar E, Bhatia A, Teiger E, Hittinger L, Berdeaux A, Castaigne A, Geschwind H. Comparison of the effects of exercise and cold pressor test on the vasomotor response of normal and atherosclerotic coronary arteries and their relation to the flow-mediated mechanism. Am J Cardiol. 1995;76:467–473.[Medline] [Order article via Infotrieve]
21. Hunt SC, Williams RR, Barlow GK. A comparison of positive family history definitions for defining risk of future disease. J Chron Dis. 1986;39:809–812.[Medline] [Order article via Infotrieve]
22.
Blumenthal RS, Becker DM, Moy TF, Coresh J, Wilder LB,
Becker LC. Exercise thallium tomography predicts future clinically
manifest coronary heart disease in a high-risk
asymptomatic population. Circulation. 1996;93:915–923.
23. Myers J, Froelicher VF. Exercise testing: procedures and implementation. Cardiol Clin. 1993;11:199–213.[Medline] [Order article via Infotrieve]
24.
Links JM, Jeremy RW, Dyer SM, Frank TC, Becker LC.
Weiner filtering improves quantification of regional myocardial
perfusion with thallium-201 SPECT. J Nucl Med. 1990;31:1230–1236.
25.
Geckle WJ, Frank TL, Links JM, Becker LC. Correction
for patient and organ movement in SPECT: application to exercise
thallium-201 cardiac imaging. J Nucl Med. 1988;29:441–450.
26. Fintel DJ, Links JM, Brinker JA, Frank TL, Parker M, Becker LC. Improved diagnostic performance of exercise thallium-201 single photon emission computed tomography over planar imaging in the diagnosis of coronary artery disease: a receiver operating characteristic analysis. J Am Coll Cardiol. 1989;13:600–612.[Abstract]
27. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
28. National Institutes of Health Consensus Development Panel on the Health Implications of Obesity. Ann Intern Med. 1985;103:981–1077.
29.
Joint National Committee on Detection, Evaluation, and
Treatment of High Blood Pressure. The fifth report of the Joint
National Committee on Detection, Evaluation, and Treatment of High
Blood Pressure (JNC V). Arch Intern Med. 1993;153:154–183.
30. Berger RD, Akselrod S, Gordon D, Cohen RJ. An efficient algorithm for spectral analysis of heart rate variability. IEEE Trans Biomed Eng. 1986;33:900–904.[Medline] [Order article via Infotrieve]
31.
Fleisher LA, Frank SM, Shir Y, Estafanous M, Kelly S,
Raja SN. Cardiac sympathovagal balance and peripheral
sympathetic vasoconstriction: epidural versus general
anesthesia. Anesth Analg. 1994;79:165–171.
32.
Malliani A, Pagani M, Lombardi F, Cerutti S.
cardiovascular neural regulation explored in the
frequency domain. Circulation. 1992;84:482–492.
33.
Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R,
Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E. Power
spectral analysis of heart rate and arterial
pressure variabilities as a marker of sympathovagal interaction in man
and conscious dog. Circ Res. 1986;59:178–193.
34.
Brown GB, Bolson E, Frimer M, Dodge HT. Quantitative
coronary angiography: estimation of dimensions,
hemodynamic resistance, and atheroma mass
of coronary artery lesions using the arteriogram and digital
computation. Circulation. 1977;55:329–337.
35. Pauletto P, Scannapieco G, Pessina AC. Sympathetic drive and vascular damage in hypertension and atherosclerosis. Hypertension. 1991;17[suppl III]:III-75-III-81.
36.
Dimsdale JE, Moss J. Plasma catecholamines
in stress and exercise. JAMA. 1980;243:340–342.
37. Wennlund A, Wahreenberg H, Hagstrom-oft E, Bolinder J, Arner P. Lipolytic and cardiac responses to various forms of stress in humans. Int J Sports Med. 1994;15:408–413.[Medline] [Order article via Infotrieve]
38. Sundin O, Ohman A, Palm T, Strom G. Cardiovascular reactivity, type A behavior and coronary heart disease: comparison between myocardial infarction patients and controls during laboratory-induced stress. Psychophysiology. 1995;32:28–35.[Medline] [Order article via Infotrieve]
39.
Williams RB Jr, Lane JD, Kuhn CM, Melosh W, White AD,
Schanberg SM. Type A behavior and elevated
physiological and neuroendocrine responses to
cognitive tests. Science. 1982;218:483–485.
40. Jiang W, Hayano J, Coleman ER, Hanson MW, Frid DJ, O'Connor C, Thurber D, Waugh RA, Blumenthal JA. Relation of cardiovascular responses to mental stress and cardiac vagal activity in coronary artery disease. Am J Cardiol. 1993;72:551–554.[Medline] [Order article via Infotrieve]
41. Spence JD. Effects of antihypertensive drugs on blood velocity: implications for prevention of cerebral vascular disease. Can J Neurol Sci. 1977;4:93–87.[Medline] [Order article via Infotrieve]
42.
Roach MR, Scott M, Ferguson GC. The
hemodynamics of the geometry of bifurcations in the
circle of Willis. Stroke. 1982;3:255–270.
43. Davies PF, Remuzzi A, Gordon EJ, Forbes Dewey C, Gimbrone MA. Turbulent fluent shear stress induced vascular endothelial cell turnover in vitro. Cell Biol. 1986;83:2114–2117.
44. Hirsch EZ, Maksen JA, Gagen D. Effects of stress and propranolol on the aortic intima of rats. Arteriosclerosis. 1984;4:526a. Abstract.
45. Gordon D, Guyton J, Karnovsky N. Intimal alterations in rat aorta induced by stressful stimuli. Lab Invest. 1983;45:14–27.[Medline] [Order article via Infotrieve]
46. Hollander W, Kransch DR, Yagi S. The metabolism of norepinephrine in arteries. Trans Assoc Am Phys. 1964;72:210–217.
47.
Freiman PC, Mitchell GG, Heistad DD, Armstrong ML,
Harrison DG. Atherosclerosis impairs
endothelium-dependent vascular relaxation to
acetylcholine and thrombin in primates. Circ Res. 1986;58:783–789.
48. Cocks TM, Angus JA. Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin. Nature. 1983;305:627–630.[Medline] [Order article via Infotrieve]
49. Nabel EG, Selwyn AP, Ganz P. Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis. J Am Coll Cardiol. 1990;16:349–356.[Abstract]
50. Yamori Y, Mano M, Nara Y, Horie R. Catecholamine-induced polyploidization in vascular smooth muscle cells. Circulation. 1987;75(suppl I):I-92-I-95.
51. Zeiher AM, Drexler H, Wollschlaeger H, Saurbier B, Just H. Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium. J Am Coll Cardiol. 1989;14:1181–1190.
52.
Vita JA, Treasure CB, Yeung AC, Vekshtein VI, Fantasia
GM, Fish RD, Ganz P, Selwyn AP. Patients with evidence of
coronary endothelial dysfunction as assessed by
acetylcholine infusion demonstrate marked increase in sensitivity to
constrictor effects of catecholamines.
Circulation. 1992;85:1390–1397.
53.
Zeiher AM, Drexler H, Wollschlaeger H, Just H.
Modulation of coronary vasomotor tone in humans: progressive
endothelial dysfunction with different early stages of
coronary atherosclerosis.
Circulation. 1991;83:391–401.
54. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115.[Medline] [Order article via Infotrieve]
55. Drexler H, Zeiher AM. Progression of coronary endothelial dysfunction in man and its potential clinical significance. Basic Res Cardiol. 1991;86(suppl 2):223–232.
This article has been cited by other articles:
 |
|
 |
|
  R. Lampert, V. Shusterman, M. Burg, C. McPherson, W. Batsford, A. Goldberg, and R. Soufer Anger-induced T-wave alternans predicts future ventricular arrhythmias in patients with implantable cardioverter-defibrillators. J. Am. Coll. Cardiol., March 3, 2009; 53(9): 774 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Holmes, D. S. Krantz, W. J. Kop, A. Del Negro, P. Karasik, and J. S. Gottdiener Mental Stress Hemodynamic Responses and Myocardial Ischemia: Does Left Ventricular Dysfunction Alter These Relationships? Psychosom Med, July 1, 2007; 69(6): 495 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.C Strike and A Steptoe Systematic review of mental stress-induced myocardial ischaemia Eur. Heart J., April 2, 2003; 24(8): 690 - 703. [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Blumenthal, D. M. Becker, L. R. Yanek, T. R. Aversano, T. F. Moy, B. G. Kral, and L. C. Becker Detecting Occult Coronary Disease in a High-Risk Asymptomatic Population Circulation, February 11, 2003; 107(5): 702 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Knox, J. Hausdorff, and J. H. Markovitz Reactivity as a Predictor of Subsequent Blood Pressure: Racial Differences in the Coronary Artery Risk Development in Young Adults (CARDIA) Study Hypertension, December 1, 2002; 40(6): 914 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Lipman, P. Grossman, S. E. Bridges, J.W. Hamner, and J. A. Taylor Mental Stress Response, Arterial Stiffness, and Baroreflex Sensitivity in Healthy Aging J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2002; 57(7): B279 - 284. [Abstract] [Full Text]
|
|
|
|
|
|
A. C. King, K. Baumann, P. O'Sullivan, S. Wilcox, and C. Castro Effects of Moderate-Intensity Exercise on Physiological, Behavioral, and Emotional Responses to Family Caregiving: A Randomized Controlled Trial J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2002; 57(1): M26 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Curtis and J. H. O'Keefe Jr Autonomic Tone as a Cardiovascular Risk Factor: The Dangers of Chronic Fight or Flight Mayo Clin. Proc., January 1, 2002; 77(1): 45 - 54. [Abstract] [PDF]
|
|
|
|
 |
|
 K J Paavonen, H Swan, K Piippo, L Hokkanen, P Laitinen, M Viitasalo, L Toivonen, and K Kontula Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome Heart, July 1, 2001; 86(1): 39 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Siegman, S. T. Townsend, A. C. Civelek, and R. S. Blumenthal Antagonistic Behavior, Dominance, Hostility, and Coronary Heart Disease Psychosom Med, March 1, 2000; 62(2): 248 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Schoder, D. H. Silverman, R. Campisi, J. W. Sayre, M. E. Phelps, H. R. Schelbert, and J. Czernin Regulation of myocardial blood flow response to mental stress in healthy individuals Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H360 - H366. [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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||