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Circulation. 1997;96:4246-4253

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(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

Brian G. Kral, BA; Lewis C. Becker, MD; Roger S. Blumenthal, MD; Thomas Aversano, MD; Lee A. Fleisher, MD; Raphael M. Yook, MSPH; ; Diane M. Becker, ScD, MPH

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
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 *Abstract
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 down arrowResults
 down arrowDiscussion
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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
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 *Introduction
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 down arrowDiscussion
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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
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 *Methods
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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 {chi}2 statistic were applied for categorical variables. Multivariate analyses, including linear and logistic regression techniques, were used to predict outcomes.


*    Results
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 *Results
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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 {chi}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 1Down 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).


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  		Table 1. Maximal Blood Pressure and Heart Rate Changes During Exercise and Mental Stress

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 1Up).

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 2Down). 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).


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  		Table 2. Multiple Linear Regressions for Maximal Change in Hemodynamic Variables From Baseline During Mental Stress

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 3Down). 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 FigureDown.


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  		Table 3. Multiple Logistic Regression Predicting "Hot" Responders1 During Mental Stress



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  		Figure 1. Results from a 56-year-old white male sibling who was classified as a "hot" responder. A, Composite of computer-averaged ECGs at rest, during peak exercise, and during recovery. Note ischemic-type ST-segment depression in leads III, aVF, and V5-V6 at peak exercise and downsloping ST-segment depressions in leads II, III, aVF, and V3-V6 during the recovery phase. B, Selected tomographic slices from stress and delayed exercise thallium scans (short axis [SA] from mid and basal areas of the left ventricle and long axis [LA]) Note reversible inferior and inferoseptal perfusion defect that redistributes on delayed images (see arrows). C, Selected frames from arteriograms of right (RCA) and left (LCA) coronary arteries. Note significant 45% stenosis of the proximal right coronary artery (RCA arrow) and minimal lesions in the left anterior descending and left main diagonal arteries (LCA arrows). D, Blood pressure and heart rate preceding, during, and after mental stress testing. Note increases in systolic blood pressure (32 mm Hg) and diastolic blood pressure (35 mm Hg) during mental stress. Heart rate increases by 8 bpm. Power spectral analysis of heart rate variability during mental stress demonstrated an increase of normalized low frequency power and no change in normalized high frequency power, consistent with sympathetic arousal.

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 4Down. 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.


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  		Table 4. Spectral Analysis of Heart Rate Variability in the Frequency Domain During Mental Stress


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
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.


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 up arrowAbstract
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 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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