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(Circulation. 1996;94:2402-2409.)
© 1996 American Heart Association, Inc.

Articles

Ischemic, Hemodynamic, and Neurohormonal Responses to Mental and Exercise Stress

Experience From the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI)

A. David Goldberg, MD; Lewis C. Becker, MD; Robert Bonsall, PhD; Jerome D. Cohen, MD; Mark W. Ketterer, PhD; Peter G. Kaufman, PhD; David S. Krantz, PhD; Kathleen C. Light, PhD; Robert P. McMahon, PhD; Todd Noreuil, MD; Carl J. Pepine, MD; James Raczynski, PhD; Peter H. Stone, MD; Dawn Strother, RN; Herman Taylor, MD; David S. Sheps, MD; for the PIMI Investigators*

Henry Ford Heart and Vascular Institute, 2799 West Grand Blvd, Detroit, MI 48202.

Correspondence to A. David Goldberg, MD, Henry Ford Heart and Vascular Institute, 2799 West Grand Blvd, Detroit, MI 48202. E-mail DASH@AOL.COM.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix References

 
Background The pathophysiology of mental stress–induced myocardial ischemia, which occurs at lower heart rates than during physical stress, is not well understood.

Methods and Results The Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) evaluated the physiological and neuroendocrine functioning in unmedicated patients with stable coronary artery disease and exercise-induced ischemia. Hemodynamic and neurohormonal responses to bicycle exercise, public speaking, and the Stroop test were measured by radionuclide ventriculography, ECG, and blood pressure and catecholamine monitoring. With mental stress, there were increases in heart rate, systolic blood pressure, cardiac output, and systemic vascular resistance that were correlated with increases in plasma epinephrine. During exercise, systemic vascular resistance fell, and there was no relationship between the hemodynamic changes and epinephrine levels. The fall in ejection fraction was greater with mental stress than exercise. During mental stress, the changes in ejection fraction were inversely correlated with the changes in systemic vascular resistance. Evidence for myocardial ischemia was present in 92% of patients during bicycle exercise and in 58% of patients during mental stress. Greater increases in plasma epinephrine and norepinephrine occurred with ischemia during exercise, and greater increases in systemic vascular resistance occurred with ischemia during mental stress.

Conclusions Mental stress–induced myocardial ischemia is associated with a significant increase in systemic vascular resistance and a relatively minor increase in heart rate and rate-pressure product compared with ischemia induced by exercise. These hemodynamic responses to mental stress can be mediated by the adrenal secretion of epinephrine. The pathophysiological mechanisms involved are important in the understanding of the etiology of myocardial ischemia and perhaps in the selection of appropriate anti-ischemic therapy.

Key Words: stress, mental • ischemia • catecholamines • exercise • hemodynamics

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix References

 
Myocardial ischemia detected by ambulatory ECG or radionuclide monitoring may occur with everyday activities in patients with CAD. These episodes of ambulatory ischemia occur at HRs lower than those at which ischemia develops during exercise and frequently are asymptomatic.^{1 2 3} Studies in patients with CAD have demonstrated that myocardial ischemia can be provoked in the laboratory by psychologically stressful stimuli.^{4 5 6 7 8} Mental stress may have significant effects on systemic vascular resistance, leading to elevation of BP.^{9 10} Mental stress may affect circulating levels of neurohumoral or vasoactive substances,¹¹ affect neural systems that are important in cardiovascular regulation,¹² and influence the perception of pain.¹³ During coronary angiography, the diseased coronary artery segments as well as the microcirculation react to mental stress with constriction¹⁴ or a lack of vasodilatation.¹⁵

Although evidence exists that each of these factors influences the occurrence and severity of myocardial ischemia, the evidence is inconsistent, and the relative importance of each is not well understood. Previous studies in this area involved limited aspects of these factors and were conducted in small numbers of patients. The objective of the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) was to obtain detailed, comprehensive data on CAD patients under conditions of physical and mental stress to clarify the role of the various factors thought to contribute to the expression of symptoms during myocardial ischemia and to extend our understanding of mechanisms through which mental stress produces ischemia. Elucidation of the relation among psychological, neurological, neuroendocrine, and physiological factors in both symptomatic and asymptomatic cardiac ischemia may facilitate development of treatment and secondary prevention measures for patients with CAD.

We report on hemodynamic and catecholamine responses to exercise and mental stress in a population of patients with stable CAD and exercise-induced ischemia after withdrawal from cardiac medications. To investigate further the pathophysiology of mental stress–induced ischemia, we compared the physiological characteristics of patients who develop myocardial ischemia in response to mental stress with those who do not.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix References

 
One hundred ninety-six patients with stable CAD between the ages of 40 and 75 years were recruited at the four clinical centers. Subjects were eligible if they met all of the following inclusion criteria: (1) angiographically demonstrated coronary artery stenosis of 50% in one or more major vessel or verified myocardial infarction; (2) treadmill stress test (ACIP protocol) with 1-mm ST-segment depression; (3) a 48-hour ambulatory ECG; and (4) they consented to participate.

Subjects were excluded if they (1) had a myocardial infarction or angioplasty within the past 3 months or if they had undergone thoracotomy; (2) had an ECG with an abnormality that precluded accurate interpretation of ST-segment deviation; (3) could not be withdrawn from cardiac and/or other medications, with the exception of short-acting nitrates, that could influence hemodynamic response to stress or pain perception; (4) had a neurological disease; (5) abused drugs or alcohol; (6) had indications of being unreliable; or (7) had difficulty reading or communicating in English.

Screening of potential candidates was performed during a qualifying visit that included an ACIP treadmill exercise test¹⁶ and a neurological examination.

In random order, bicycle exercise and mental stress tests were performed on separate mornings <2 weeks apart. Studies were performed after the participants ingested a light breakfast after a 12-hour fast. Blood was withdrawn for baseline neurohormonal measurement; an AECG monitor and a 12-lead ECG were attached; and a BP cuff (Dinamap) was applied for automatic recording.

Bicycle ergometry was performed with the participants in a semiupright seated position, and RVG (2-minute acquisition time) was recorded with the 40° left anterior oblique view. Symptom-limited exercise commenced at a workload of 200 kpm and increased every 3 minutes by 200 kpm to tolerance. ECG and BP were recorded at rest and at 1-minute intervals, and AECG was performed continuously during exercise. Blood samples for catecholamine determinations were drawn at rest, at 1 minute, and at the peak of exercise. RVGs were obtained at baseline and at each stage of exercise.

Subjects were prepared for mental stress testing in the same manner. After baseline RVG and 12-lead ECG with the participants in the semiupright position, two mental stress tests (the Stroop Color-Word test and a simulated public speaking task), each lasting 5 minutes, were performed in random order. During each task, two 2-minute RVG images were acquired at 30 seconds and 3 minutes after the start of the task. ECG and BP were recorded at 1-minute intervals, and blood was withdrawn for catecholamine determination at 1 minute and at the completion of the task. BP, HR, and ECG were recorded at 30-second intervals after the start of each task and every minute thereafter. AECG was performed continuously.

For the speech task, subjects were asked to speak for 5 minutes on an assigned topic, which involved a difficult interpersonal scenario, while their performance was observed and evaluated by the laboratory staff. The computerized version of the Stroop Color-Word test provided automatic titration of difficulty based on level of performance as well as standardized administration and scoring.

After each stress test, radioactivity was measured from a blood sample to estimate LV volume. Attenuation distance was calculated from a static image acquired after the study.

Radionuclide images were read at the Radionuclide Core Laboratory either directly or translated through a Sudbury Image Center (Sudbury Systems) into a Sophy NXT nuclear medical computer (Sopha Medical Systems) for analysis. Global EF was measured with a commercially available, fully automated method (Sopha Medical) as well as with a manual method. The automatic EF was accepted as correct if the manual EF was within 5 EF units. Regional wall motion was scored subjectively for each RVG by means of a four-point scale for each of four predefined segments. A new or worsened wall motion abnormality was considered to occur only if the abnormality was present in both of the 2-minute images acquired during the mental task.

Calculation of LV volumes was performed with validated methods.¹⁷ The end-diastolic rate count was measured from a manual region of interest drawn around the LV. Attenuation correction was determined individually in each subject by measuring the attenuation distance from a chest wall marker to the count center of the LV, assuming a linear attenuation coefficient equal to that of water. The LV EDV was obtained from the ratio of the attenuation-corrected end-diastolic count rate to the count rate per milliliter from a venous blood sample obtained in each subject. ESV was calculated from the measured EF and EDV. SV was calculated as the difference between EDV and ESV, and CO was the product of SV and HR measured during RVG. Measurements of cardiac volumes by this method, as well as other rate-count–based methods, have been validated under resting^{17 18} and exercise^{19 20} conditions.

RPP was calculated as SBPxHR. Mean arterial pressure was calculated as (SBP+[2xDBP])/3. Total SVR in dynes·s^-1·cm^-5 was calculated as (mean arterial pressurex80)/CO.

The AECG recordings were analyzed in the AECG Core Laboratory with a CardioData Mk4 playback system and modified software. An ischemic episode was defined as transient ST-segment deviation of 1.0 mm lasting 1.0 minute.

Frozen plasma samples were sent to the PIMI Biochemistry Core Laboratory for analysis. All samples from a given subject were analyzed in the same batch in duplicate. Norepinephrine and epinephrine concentrations were measured using reverse-phase, ion-pair, high-performance liquid chromatography in combination with a computer-controlled, cation-enrichment precolumn and a three-electrode electrochemical detector.

Definitions of Ischemia
Patients were considered to have ischemia during a task if they met one or more of the following three criteria: 1-mm ST-segment depression on ECG; 1-mm ST-segment depression lasting 1 minute on AECG; or on RVG (1) during exercise test, new or worsening wall motion abnormality during stress, or EF not increased by 5% or (2) during mental stress, new or worsening wall motion abnormality during both images during a task, or EF decreased by >8% in either of the two acquired images.

The EF criterion for mental stress ischemia was determined after review of EF responses to the speech and Stroop tests in a sample of 29 subjects who had no evidence of CAD by clinical history or exercise ECG.²¹

Statistical Analysis
Comparisons of responses to stress among patients with and without ischemia on a particular task were performed using the normal scores rank test.²² Comparisons among types of stress (eg, exercise versus speech) on continuous response measures within the same patient were performed with multivariate analysis (MANOVA).²³ Comparisons between tests on binary outcomes within the same patient were performed with McNemar's test. Associations among different stress responses were measured with the Pearson correlation coefficient. All calculations were carried out with the SAS statistical package.²⁴ Values of P.05 were taken as evidence of association.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Patient Characteristics and Baseline Data
Table 1 provides selected baseline characteristics of the 196 subjects who met entry criteria. The majority (87%) were men despite vigorous attempts to recruit female subjects. Most subjects (87%) were white, and the age range was 41 to 75 years. There was a history of myocardial infarction in 42% and prior coronary angioplasty in 35%; diabetes was present in 15%; and 47% gave a history of hypertension. At rest on the mental stress day, HR was 70.6±10.7 bpm, SBP was 144±20 mm Hg, DBP was 79±10 mm Hg, EF was 59±12%, and CO was 6.2±1.3 L/min. Plasma epinephrine concentration was 29.5±25.5 pg/mL, and norepinephrine was 415±228 pg/mL. All patients exhibited ST-segment depression during the qualifying exercise treadmill test.

View this table: [in this window] [in a new window]   Table 1. Selected Baseline Characteristics of Patients

Hemodynamic and Catecholamine Changes
Increases in HR and BP occurred during all three stressors (Fig 1 and Table 2). Exercise evoked a significantly greater hemodynamic change than the speech test, which produced a significantly greater change than the Stroop test (Fig 1). The increase in RPP was >50% greater during exercise than during either mental stressor. CO rose with all stressors. The calculated SVR fell with exercise but increased with the speech and the Stroop tests. Differences for changes in SVR between exercise and the mental stressors were significant (P<.001), but differences between the speech and the Stroop tests were not (P=.07). EF decreased more during both mental stressors than during exercise. During bicycle exercise, there was a small decrease in EF, and only 46 patients (24%) demonstrated a normal increase in EF of 5%. During the speech task, EF decreased >8% in 46 patients (24%), and the response to the Stroop test was similar, with a reduction of >8% in 25% of the patients. Changes in EF during the mental stress tasks were not related to the resting EF (r=-.12, P=.10 for the speech test and r=-.06, P=.38 for the Stroop test).

View larger version (19K): [in this window] [in a new window]   Figure 1. Changes in HR, SBP, DBP, RPP, CO, and SVR in response to bicycle, speech, and Stroop tests.

View this table: [in this window] [in a new window]   Table 2. Hemodynamic and Catecholamine Responses to Stressors in All Patients

Changes in EF were strongly and negatively correlated with changes in SVR during all three stressors (Fig 2) (r=-.41, -.53, and -.44 for the bicycle, speech, and Stroop tests; all P<.001) but not with changes in HR or BP.

View larger version (16K): [in this window] [in a new window]   Figure 2. Relation between change of SVR and EF during speech test.

Plasma norepinephrine and epinephrine levels (Table 2) rose significantly at 1 minute and at the peak with all stressors (all comparisons, P<.001). Plasma epinephrine increases during exercise and the speech test were similar (P=.36), but the increase during the Stroop test was significantly less.

Within individuals, the hemodynamic responses during the Stroop and the speech tests were strongly correlated (r=.55, P=.009 for HR; r=.62 for SBP; r=.48 for DBP; r=.57 for RPP; r=.51 for EF; r=.59 for CO; and r=.49 for SVR; all P<.001). However, with the exception of HR (r=.21, P=.005 for speech versus exercise; r=.19, P=.009 for Stroop versus exercise), the individual hemodynamic responses to bicycle exercise did not correlate with responses to either mental stressor (all r<.15, P.1). Individual changes in epinephrine and norepinephrine during the two mental stressors were highly correlated (r=.56, P<.001 for epinephrine; r=.75, P<.001 for norepinephrine), and correlations of epinephrine changes between exercise and mental stressors were less strong (r=.3 for speech; r=.38 for Stroop; both P<.001). Norepinephrine changes with exercise were correlated with changes during the speech task (r=.3, P<.001) but not with changes during the Stroop test (r=.12, P=NS).

During the mental stressors, the changes in plasma epinephrine were positively correlated with the changes in HR, SBP, RPP, CO, and (more weakly and negatively) SVR (Table 3). During the bicycle stress test, the changes in plasma epinephrine levels were significantly correlated only with changes in HR and RPP and, very weakly, SBP. Changes in plasma norepinephrine levels were significantly correlated with changes in HR, SBP, DBP, RPP, and CO during the speech stressor only. During bicycle exercise, there was a negative correlation between changes in norepinephrine and SVR. With this exception, there were no significant correlations between changes in plasma norepinephrine and changes in hemodynamics during bicycle or Stroop stressors.

View this table: [in this window] [in a new window]   Table 3. Correlations Between Changes in Plasma Epinephrine and Norepinephrine Levels and Changes in Hemodynamics During the Stressors

Ischemia During Tests
Bicycle exercise provoked ischemia in 175 of the patients (92%), of whom 153 (82%) showed RVG evidence. There was less incidence of ischemia during either of the mental stressors, with 77 patients (42%) developing ischemia during the speech task and 64 patients (35%) during the Stroop test. A total of 106 patients (58%) developed ischemia with either one of the mental tasks, and 35 patients (20%) had ischemia during both mental stressors. Ischemia developed during both mental stressors and exercise in 30 patients (17%).

Associated with ischemia during all three stressors was a lack of increase in SV (Table 4) and a greater increase in EDV and ESV.

View this table: [in this window] [in a new window]   Table 4. Hemodynamic and Catecholamine Responses to Exercise and Mental Stressors by Evidence for Ischemia

There were no differences in peak hemodynamics during the bicycle exercise test between those with and those without ischemia (Table 4), but patients who developed ischemia had greater increases in epinephrine and norepinephrine. The lack of ischemia during the bicycle exercise in some patients may be explained by a lower peak RPP on this test than the RPP at onset of 1-mm ST-segment depression on the qualifying visit treadmill stress test (RPP difference, -2504±6186). In contrast, patients with ischemia on the bicycle test developed a higher peak RPP than the RPP at onset of 1-mm ST-segment depression on the qualifying visit treadmill stress test (RPP difference, 852±6232). The difference between these patient groups in the change of attained RPP between the two tests was significant (P=.04). This occurred despite a longer mean duration of exercise (9.3±3.3 minutes) for the 15 patients without ischemia than the 175 patients with ischemia (7.1±2.9 minutes) (P=.006).

Development of ischemia was associated with an increase in SVR (Table 4) during the speech task (164±378) and during the Stroop test (120±295), whereas those who did not develop ischemia had no increase (differences, P<.002 and P<.001). This relation of increase in SVR was maintained when only patients with stress-induced wall motion abnormalities were compared with those without (difference, P=.03 for both speech and Stroop) (Table 5).

View this table: [in this window] [in a new window]   Table 5. Change in SVR by Presence of Wall Motion Abnormalities During Exercise, Speech, and Stroop Tests

In addition, ischemia during the speech task (Table 4) was associated with a greater increase in HR, SBP, and DBP as well as RPP. Patients who developed ischemia during the Stroop test (Table 4) showed a smaller increase in CO than those who did not.

Angina was reported by 68 patients (35%) during bicycle exercise stress and by 11 patients (6%) during mental stress. Nine of the 11 patients with angina during mental stress also had angina during bicycle exercise (P<.01); of the 2 who did not, 1 had angina on the qualifying visit treadmill exercise test.

ECG ST-segment depression was observed in 124 patients (64%) during bicycle exercise but in only 6 (3%) during the speech task and 3 (2%) during the Stroop test.

Patients Positive on All Three Tasks
In a comparison of the hemodynamic and catecholamine data for the 30 patients who developed ischemia during all three tasks (Table 6), we found that ischemia during the speech task occurred at the same changes in BP but at lower HR, RPP, SV, EDV, CO, and norepinephrine levels than during bicycle exercise. Ischemia during the Stroop task occurred at an even lower HR and BP than ischemia that occurred during the speech task. SVR was similarly elevated by both mental stressors.

View this table: [in this window] [in a new window]   Table 6. Maximum Hemodynamic and Catecholamine Changes From Resting Values in Response to Stressors for Patients With Ischemia on All Three Tests Only

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
Our results confirm that mental stress in the laboratory causes clinically significant hemodynamic and neurohormonal changes that are associated with myocardial ischemia in susceptible patients with CAD and exercise-induced myocardial ischemia. The hemodynamic and neurohormonal responses to the selected mental stressor tasks differed from the corresponding responses to exercise. Ischemia during mental stress was associated with a less marked increase in HR, SBP, DBP, CO, and norepinephrine than during physical exercise. SVR rose during mental stress, whereas it fell during exercise. Responses to the mental stressors were similar and highly correlated but of a greater magnitude during the speech task than the Stroop task. However, the hemodynamic changes in each individual during the bicycle exercise did not predict the responses of that individual to mental stress.

The hemodynamic and catecholamine changes that we observed during mental stress are similar to those seen in our reference group of control subjects.²¹ Thus, the presence of stable CAD does not alter the responses to mental stressors seen in a normal age-matched population.

Myocardial ischemia developed in a majority of our patients during mental stress. Most of the patients demonstrated RVG abnormalities with a fall in EF and/or wall motion abnormalities. Even though all patients had ischemic ECG changes on a qualifying exercise stress test and 42% had ischemia during 48 hours of AECG monitoring during routine outpatient daily activities, similar ECG changes were uncommon during mental stress testing.

Others^{6 7 25 26 27 28 29} have found similar frequencies of ischemia induced by mental stressors, although the methods used to detect and the criteria to define ischemia differ among the studies. Our definition of RVG ischemia was based on a study of volunteers who had a low probability for CAD and were age matched with this cohort.¹⁵ In that study, with the criteria of a fall in EF of >8% or a new wall motion abnormality, the specificity for ischemia was 93% for men and 67% for women.

It is of interest that individual patients did not respond in the same way to each of the tests. Although all patients had a positive ECG treadmill test, <20% demonstrated ischemia on bicycle exercise as well as both mental stress tests. Mental stress ischemia was provoked in 5% who had no ischemia during bicycle exercise. Although more patients had ischemia with the speech task than the Stroop test, 15% had ischemia with the Stroop test but not with the speech task, suggesting that neither task alone provides adequate information.

Patients who developed ischemia with mental stress had a significantly greater increase in SVR. During both mental stressors, there was a strong inverse relation between change in SVR and EF, suggesting that RVG myocardial ischemia may be due to an excessive increase in SVR, although our data could not rule out alternative explanations of this association. During the speech stressor, there was in addition a greater increase in HR than that occurring during the Stroop test, perhaps accounting for the greater occurrence of ischemia during that test. Excessive reactivity as a cause of ischemia has been previously suggested by Specchia et al,⁹ who reported a greater increase in BP and HR in patients developing ECG evidence of ischemia in response to mental stress. Krantz et al¹⁰ classified their patients according to their hemodynamic responses to three different mental stressors. The severely ischemic group had greater SBP reactivity than the moderately ischemic and nonischemic groups. Legault et al²⁷ did not find any differences in BP and HR in patients developing ischemia in response to mental stress compared with those who did not. In contrast, during the bicycle exercise, we found there was no difference in hemodynamic responses between those who did and did not develop ischemia, although the number of patients without exercise-induced ischemia was very small.

The significant relation between the changes in plasma epinephrine and the HR, SBP, and CO changes during the mental stressors suggests a causal relation. The present findings in our middle-aged and elderly subjects with CAD are similar to those seen in young, healthy subjects^{30 31} as well as in hypertensives^{32 33} and type 1 diabetic subjects.³⁴ Similar changes in hemodynamics can be seen during graduated doses of epinephrine infusion in normal volunteers.³⁵ Further evidence that epinephrine has a direct role in modulating the cardiovascular responses is provided by the effects of ß-blocker therapy,^{27 28} which attenuates the changes in HR and SVR. Thus, the adrenal release of epinephrine during mental stress appears to play an important role in mediating the hemodynamic changes occurring in patients with CAD, an effect that can be attenuated with medical therapy. However, development of ischemia during mental stress was not predicted by the increases in catecholamines during the test.

In this study, we were not able to measure coronary artery tone. Epicardial coronary artery constriction occurs in atherosclerotic arteries in response to mental stress^{14 36} and acetylcholine infusion. In addition, there is a lack of normal microvascular vasodilatation¹⁵ that is restored with infusion of the -adrenergic–blocker phentolamine. Although the increase in SVR may be sufficient to explain the observed myocardial ischemia in our patients, the same pathophysiological process, if generalized, could be responsible for simultaneously increasing coronary artery resistance.

As in most previous studies, few symptoms accompanied mental stress ischemia. Only 6% of our patients developed angina-like symptoms during the mental testing. This is comparable to studies of ambulatory patients in whom most episodes of ST-segment depression are silent.

Similar to previous studies, few patients with mental stress–induced ischemia had ECG changes.^{5 26 29} This suggests that the RVG method is more sensitive than the ECG for detection of ischemia. During episodes of ischemia, either spontaneous³⁷ or induced by angioplasty³⁸ or ergonovine infusion,³⁹ a sequence of events is initiated, with the delay to ST-segment depression by 6 minutes and the time to chest pain (which follows ST-segment depression by 3 minutes⁴⁰ ) by 9 minutes. The lack of pain and ECG changes may reflect that we were unable to maintain a stimulus for the time and intensity sufficient for these changes to occur. Sheps et al⁸ did not observe chest pain in any of their 26 patients using a protocol requiring 15 minutes of public speaking. An alternative explanation is that the RVG is nonspecific. Reduction in EF of 12% can occur in young, normal subjects in response to mental stress,⁴¹ and we²¹ observed such changes in a small minority of women in our middle-aged and elderly control population subjects.

Study Limitations
It is possible that a more uniform response to the speech stressor could have been obtained by determining an individual rather than a standardized topic for all patients. The amount of psychological discomfort that can be inflicted on a research subject is limited, and it is likely that most patients experience more stress in their everyday activities.

Unfortunately, there is no simple way to identify an ischemic response in all patients. The accuracy of RNA has been previously validated^{17 18 19 20} but has limitations due to motion artifact, noise from low counts, etc. By comparing our results, especially in the patients with normal resting LV EF, with those in the reference group of volunteers,²¹ we are confident that the reduction in EF is most likely to be an ischemic rather than a nonspecific result of elevation in SVR. The use of new technologies in future studies may cast light on this problem.

It should be recognized that the derived variable SVR is obtained from measures of LV volumes that are themselves correlated with EF and even uses the same volumes in the calculation. The association between changes in EF and SVR, although making physiological sense, could nevertheless be spurious in whole or in part. No independent measure of change in afterload was available in this study. This study did not measure the mental stress–induced changes in coronary artery tone, which may have contributed to the manifestations of myocardial ischemia.

Clinical Implications
Many patients with CAD and a positive ECG exercise stress test have a low threshold for stress-induced myocardial ischemia. Mental and exercise stress produce different hemodynamic and catecholamine responses that may cause myocardial ischemia via different mechanisms. The pathophysiological mechanisms involved are important in the understanding of the etiology of ischemia in patients with stable CAD and perhaps in selecting appropriate anti-ischemic therapy.⁴²

	Selected Abbreviations and Acronyms

 

AECG = ambulatory ECG BP = blood pressure CAD = coronary artery disease CO = cardiac output DBP = diastolic blood pressure EDV = end-diastolic volume EF = ejection fraction ESV = end-systolic volume HR = heart rate LV = left ventricular, ventricle RPP = rate-pressure product RVG = radionuclide ventriculogram, ventriculography SBP = systolic blood pressure SV = stroke volume SVR = systemic vascular resistance

	Acknowledgments

 
This study was funded by the National Heart, Lung, and Blood Institute (Bethesda, Md) research contracts HV-18114, HV-18119, HV-18120, HV-19121, and HV-28127. Support for ECG data collection was provided in part by Applied Cardiac Systems (Laguna Hills, Calif), Marquette Electronics and Mortara Instrument (both of Milwaukee, Wis), and Quinton Instruments (Seattle, Wash). Support for BP data collection was provided in part by the Critikon Corporation, a Johnson & Johnson Corporation. Michael Eddy (University of Pittsburgh) and Richard Lutz provided Stroop test software; Dr William Maixner provided software and design of the Marstock sensory perception test; and Dr. Kathleen Light (University of North Carolina at Chapel Hill) provided scenarios for the speech test.

	Footnotes

 
Reprint requests to PIMI Clinical Coordinating Center, Maryland Medical Research Institute, 600 Wyndhurst Ave, Baltimore, MD 21210.

The opinions and assertions contained herein are those of the authors and should not be construed as representing positions or policies of the National Heart, Lung, and Blood Institute or the US Department of Health and Human Services.

*A list of participating centers and investigators appears in the "Appendix."

	Appendix

Top Abstract Introduction Methods Results Discussion Appendix References

 
List of Participating Clinical Units, Core Laboratories, and Clinical Coordinating Center
PIMI Clinical Units
Henry Ford Hospital, Detroit, Mich: A. David Goldberg, MD*; Mark Ketterer, PhD*; Laurel Dvorak, BSN; Dawn Strother, BSN; and B.K. Ahmad, MD.

St Louis University Health Sciences Center, St Louis, Mo: Jerome D. Cohen, MD*; Robert Carney, PhD; Kenneth Freedland, PhD; Stephanie Smith, RN; and Anne Zeffert, RN.

University of Alabama at Birmingham: James Raczynski, MD*; Herman Taylor, MD; Cecil Coghlan, MD; Isabelle Joffrion, RN, MA; and Todd Noreuil, MD.

University of Florida, Gainesville: Carl J. Pepine, MD*; Barry Bertolet, MD; Linnea Lindholm, PhD; Michael Robinson, PhD; Anthony Green, PhD; and Alice Boyette.

PIMI Central Units
PIMI Study Chairman, University of North Carolina, Chapel Hill: David S. Sheps, MD.

Clinical Coordinating Center, Maryland Medical Research Institute, Baltimore, Md: Genell L. Knatterud, PhD*; Michael L. Terrin, MD, MPH; Sandra Forman, MA; Robert McMahon, PhD; Evelyn Mirenzi; Rosemary Giro; Margie Carroll; Cheryl Kelly; Lee Monroe; Judy Dotson; and Virginia Milne. Consultants: David S. Krantz, PhD; William Maixner, DDS, PhD; and Kathleen C. Light, PhD.

Ambulatory ECG Core Laboratory, Brigham and Women's Hospital, Boston, Mass: Peter H. Stone, MD*; Gail MacCallum; and Michael Smalls.

Biochemistry Core Laboratory, Emory University School of Medicine, Atlanta, Ga: Robert Bonsall, PhD*; Milburn Emery, BS.

Radionuclide Ventriculography Core Laboratory, Johns Hopkins University, Baltimore, Md: Lewis Becker, MD*; Jon Clulow.

Rest and Exercise ECG Core Laboratory, St Louis University, St Louis, Mo: Bernard Chaitman, MD*; Ihor Gussak, MD; and Karen Stocke, BS, MBA.

Project Office, Behavioral Medicine Research Group, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md: Peter G. Kaufmann, PhD*; Office of Biostatistics Research: Michael Proschan, PhD; and Nancy Geller, PhD; Division of Heart and Vascular Diseases: George Sopko, MD; and Division of Extramural Affairs: Kristee Camilletti.

Data and Safety Monitoring Board: Francis Klocke, MD (Chair); Michael Cowley, MD; Lloyd Fisher, PhD; Costas Lambrew, MD; Karen Matthews, PhD; Thomas Ryan, MD; and Harmon Smith, PhD.

*Principal investigator.

Received January 2, 1996; revision received May 22, 1996; accepted June 7, 1996.

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