DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE MINUTES OF THE SPECIAL EMPHASIS PANEL (SEP) ON MENTAL STRESS AND MYOCARDIAL ISCHEMIA JANUARY 31, 1996 The meeting of the Mental Stress and Myocardial Ischemia SEP was convened on January 31, 1996 at 8:30 a.m., at 6701 Rockledge Drive, Room 7111, Bethesda, Maryland. The meeting was open to the public from 8:30 a.m. to 3:00 p.m. Dr. Carl Pepine presided as Chair. OPEN MEETING I. CALL TO ORDER Dr. Peter Kaufmann of the National Heart, Lung, and Blood Institute (NHLBI)/DECA called the meeting to order at 8:30 AM and welcomed all present. Dr. Cutler reviewed the purpose of Special Emphasis Panels. This Panel was convened to review current knowledge concerning the relationship between mental stress and myocardial ischemia, and to advise the NHBLI regarding the most fruitful directions for future research. The entire meeting was open to the public. II. REVIEW OF CONFIDENTIALITY AND CONFLICT OF INTEREST PROCEDURES Dr. Lawrence Friedman, Division Director, explained policies and procedures regarding confidentiality and avoidance of conflict of interest situations. III. DISCUSSION OF MENTAL STRESS AND MYOCARDIAL ISCHEMIA During the morning session, Panel members reviewed evidence from clinical and basic research showing that mental stress is an effective trigger of myocardial ischemia, conditions under which ischemia occurs, and possible interventions designed to reduce frequency of myocardial ischemia in coronary heart disease (CHD) patients. During the afternoon session, panel members discussed whether current knowledge in the field is sufficient for application to clinical questions related to diagnosis, treatment, or prognosis, and reached consensus regarding research needed in order to realize the most immediate clinical benefits of progress in this field. A. Clinical Manifestations of Myocardial Ischemia Clinical studies of mental stress and myocardial ischemia were reviewed by Drs. Krantz, Sheps, Burg, and Blumenthal. Mental stress as a trigger of ischemic events. It is well known that physical exertion can lead to myocardial ischemia when flow through diseased coronary vessels fails to meet increasing myocardial demand. In the past 10-15 years, it has become clear that mental stress can also trigger episodes of myocardial ischemia in both laboratory and field settings. In most studies, ischemia was evoked almost as readily by mental stress as by physical stress, even though myocardial oxygen demand remained lower during the mental stress episodes than demand during exercise. However, most episodes of mental stress ischemia are silent, rather than symptomatic. Asymptomatic ischemia is present in the majority of CHD patients, with as many as 70% of episodes thought to be asymptomatic. Many investigators believe that most episodes of silent ischemia are in response to mental stress, which could occur in everyday life at a much higher frequency than physical stress, particularly since CHD patients are likely to moderate their physical activity due to fatigue or symptoms resulting from their illness. Mental stress is more difficult to control, since its source can be entirely external to the patient. Identification of risk. Although the mechanisms through which mental stress provokes ischemia are not well understood, characteristic changes in sympathetic response and in the circulation have been described under controlled conditions. These changes are hemodynamically different from changes observed during exercise stress testing, and may help to identify patients who are at risk for cardiac events triggered by mental stress. Whether or not a given patient is susceptible to mental stress- provoked ischemia (MSI) is not simply related to the amount of coronary atherosclerosis defined by angiography, but may be related to the extent of coronary endothelial dysfunction. For example, hemodynamic changes observed in (CHD) patients during bicycle exercise do not predict their responses under a protocol to provoke mental stress. Catecholamine levels reached in response to mental stress are, on average, similar to those seen shortly after acute myocardial infarction (MI), and are associated with hemodynamic effects similar to those seen after intravenous infusion of comparable amounts of epinephrine and norepinephrine. Although circulating catecholamines resulting from mental stress may provide a background against which other influences exert their effects, circulating catecholamines do not appear to be the most important factor determining susceptibility. Results from the Psychophysiological Investigations of Myocardial Ischemia study (PIMI) and other research studies show that CHD pathophysiology can be influenced by psychological characteristics of CHD patients, particularly those related to negative emotions such as anger, hostility, anxiety, and depression. Gender differences in susceptibility to mental stress-provoked myocardial ischemia are also thought to be important. Gender differences in cardiovascular reactivity are well documented, but not well understood. In part, these are the result of neuroendocrine influences, but could also be related to differences in receptor density or distribution, hemodynamic control variables, or psychological characteristics. Females are more likely than males to evidence large changes in ejection fraction in response to mental stress, a finding reported for both disease-free women and CHD patients. Results from the PIMI Reference Group Study showed that hemodynamic responses of normal women, matched in age to female coronary disease patients, were less predictable and displayed greater variability than those of men. Preliminary studies show that susceptibility to MSI in the laboratory, combined with ambulatory monitoring, improves risk-stratification of CHD patients. Although follow-up data are available only from approximately 200 patients, patients in whom mental stress provoked myocardial ischemia in the laboratory experienced approximately a three-fold increased risk of cardiac events (deaths and reinfarctions) compared with other post-MI patients. Thus, mental stress testing potentially is useful as a diagnostic tool for identifying patients for whom special cardiac rehabilitation programs would be beneficial. Interventions to reduce risk of mental stress-provoked ischemia. An important clinical question is whether interventions can be designed which target not only the physical rehabilitation needs, but the cognitive rehabilitation needs of the post-MI patient. Dr. James Blumenthal presented newly developed evidence (submitted for publication) that a four-month stress management intervention reduced the number of cardiac events, including MI, death, and revascularization procedures, relative to usual care controls. Patients with documented coronary artery disease and evidence of exercise induced ischemia were assigned to either usual care, exercise training, or stress management. Comprehensive assessments before and following the intervention included ambulatory electrocardiographic monitoring and radionuclide ventriculography during mental and exercise stress testing. Risk factors (e.g., lipids) and psychosocial functioning were also assessed before and after treatment. Patients in the stress management group had a relative risk of only .23, compared to .70 for exercise and 1.0 for usual care. In terms of potential mechanisms, participants in the stress management group exhibited fewer ischemic events during ambulatory monitoring, showed less ischemia during mental stress testing, and achieved lower scores on measures of hostility and distress relative to usual care controls. These findings, combined with other research showing that psychosocial interventions such as cognitive behavior therapy greatly reduce psychological risk factors, suggest that specific treatments are available to provide for comprehensive rehabilitation of cardiac patients. However, such interventions have not been tested in a sufficiently large sample of patients to draw firm conclusions regarding their efficacy. B. Mechanisms of Mental Stress-Provoked Ischemia Drs. Natelson, Bairey Merz, Schneiderman, and Pepine reviewed research on mechanisms through which mental stress exerts its effects. What mediates mental stress influences on the coronary vasculature and myocardium? Direct links between parts of the central nervous system mediating cognitive and emotional behavior and components mediating autonomic regulation of cardiac function are known and their importance is recognized implicitly in all studies of mental stress and cardiovascular function. Because cardiac function also depends on adequate perfusion of the myocardium, both remote (CNS) and local (endothelium-derived) influences which affect vasomotion play an important role in maintaining flow commensurate with cardiac demand. In healthy individuals, acetylcholine stimulates coronary vasodilation through the release of endothelium-derived nitric oxide (NO). This dilation is modulated by opposing alpha- and beta-adrenergic effects, whose magnitude depends on cardiac work being performed. Diseased coronary arteries of humans and animals respond with constriction rather than normal dilation in response to acetylcholine (ACh). Thus, under conditions of increased cardiac demand in response to physical or mental stressors, vagal influences may also contribute to paradoxical vasoconstriction. An association between mental stress and ischemic events in daily life has been established in several independent studies. Episodes of ischemia are also associated with decreased vagal tone as detected by changes in high frequency heart rate variability. It is not yet clear whether vagal withdrawal is specifically related to mental stress-provoked ischemic events, includes ischemia provoked by exertion, or causally precedes the ischemic event. If the above mechanisms are causally related to myocardial ischemia, they should exhibit a circadian variation similar to the well-described circadian variation in frequency of MI and ambulatory ischemia. Indeed, coronary segments with dysfunctional endothelium exhibit an early morning exaggeration in vasomotor activity in response to acetylcholine and to nitroglycerine, while segments with normally functioning endothelium do not show circadian variations. While change in vagal tone, related in part to impaired endothelial function, is likely to be one of the factors which influence susceptibility of the myocardium to mental stress-provoked myocardial ischemia, numerous other influences undoubtedly are involved, either alone or in combination. These include changes in sensitivity to circulating or locally released neuroactive substances and local endothelial effects in the presence of atherosclerotic heart disease. None of these are well understood. Evidence of coronary vasomotion provoked by stimulation of specific central nervous system sites is available from a small number of studies in animal models, and from recent studies in humans showing evidence of thalamic activation during myocardial ischemia. However, central nervous system influences are perhaps the least well-understood aspect of the control of vascular tone and vasomotion. Influence of gender on development of CHD. Several gender differences exist in CHD patients, including effects mediated by estrogen at several levels of coronary pathophysiology, interactions of the patient with the psychosocial environment, and response to physical exertion. The extent and severity of exercise-induced cardiac ischemia and ambulatory ischemia is related to psychological test scores of hostility in female, but not male CHD patients. Women also experience higher rates of depression and have significantly different care-giver status compared with men, thus also have different social support relationships. All three attributes: high hostility, depression, and low social support have been linked with increased risk of CHD, although the mechanisms remain speculative. Finally, women have higher cardiovascular reactivity than men, a trait associated with increased rate of atherosclerotic disease. Elevated cardiovascular reactivity in women results in more frequent and greater ejection fraction decrements in response to mental stress. Insulin metabolic syndrome. Epidemiological studies have identified a relationship between a constellation of factors (consisting of central obesity, hypertension, hyperglycemia, dyslipidemia) and risk of CHD. These risk factors are associated with aspects of insulin metabolism and cluster in individuals at much higher frequencies than predicted by chance. There is good evidence that lifestyle contributes to the syndrome: excess dietary fat, carbohydrate, and alcohol can lead to obesity, and reducing obesity is associated with decreased blood pressure, decreased hyperinsulinemia, and decreased insulin resistance. Decreased blood pressure and plasma insulin are intercorrelated after aerobic exercise training even when body weight remains unchanged. Other evidence suggests a relationship between insulin metabolism and increased activation of the sympathetic nervous system (SNS) and the hypothalamo-pituitary-adrenal axis, leading to accelerated development of the disease process. A possible relationship between the insulin metabolic syndrome and SNS activation is particularly interesting, because the latter is also often cited as a link between behavioral factors and CHD. Genetic influences on risk of coronary heart disease. After taking into consideration all risk factors present in an individual, a history of CHD in the family adds a statistically significant additional amount of risk, suggesting a strong genetic influence. The Asymptomatic Cardiac Ischemia Pilot study showed that the presence of ambulatory ischemia on treatment imparts an additional 22% risk of a coronary event at one year, while presence of family history before age 55 is greater: increasing risk by 87%. The role of three candidate genetic influences were described by Dr. Pepine: a deficiency in the enzyme cystathionine beta- synthase, leading to high plasma homocysteine concentrations and atherosclerosis; an insertion/deletion polymorphism of the angiotensin-converting enzyme gene which is also associated with CHD; and the Lewis (a-b-) phenotype, which occurs at a higher frequency in people of African descent than in Caucasians, and has been associated with a twofold risk of CHD. The Lewis (a-b-) phenotype is particularly interesting because it is determined by genes in the proximity of several genes involved in LDL receptor regulation and insulin resistance. Insulin resistance is believed to be influenced by neuroendocrine changes in response to activation of the hypothalamo-pituitary-adrenal axis, especially through adrenaline, noradrenaline, and cortisol, which are known to have a counter-regulatory effect on glucose metabolism. Links with increased very low density lipoprotein and decreased HDL cholesterol as well as increased plasma fibrinogen have also been described. C. Discussion of Research Recommendations When it became clear that risk in CHD patients was associated with the degree of left ventricular dysfunction, the mechanisms were not understood, nor was it clear that it would be possible to intervene to improve function or to reduce risk. Today, a similar situation exists in connection with mental stress- provoked myocardial ischemia. There is conclusive evidence that MSI, and preliminary evidence that susceptibility to MSI provides prognostic information beyond that provided by exercise testing, ambulatory electrocardiographic monitoring, and myocardial perfusion tests, although the mechanisms through which MSI is provoked or how this imparts risk for cardiovascular events is not known. Furthermore, data from some studies suggests that exercise and stress management training can reduce the frequency of MSI and the number of cardiac events. However, more research is needed to determine which kinds of interventions or rehabilitation programs reduce susceptibility to MSI. Several recommendations for research that would lead to a better understanding of the mechanisms that influence susceptibility to MSI, or that govern triggering of myocardial ischemia by mental stress were made: 1. Basic Behavioral Neurosciences a. The role of elevated circulating catecholamines in response to stress is not understood, in part because cardiac events, some of which are asymptomatic and thus are not detected, also cause elevated plasma catecholamines. Larger studies are needed with repeated assays to evaluate the dynamics of circulating catecholamines in the CHD patient, as well as the effects of diverse neurotransmitter substances released into the circulation during anxiety, pain, and stress. b. Although work is progressing at an increased pace, much additional research is needed to define gender differences in hemodynamic changes due to mental stress, including effects caused by redistribution of blood flow through different peripheral vascular beds, and to understand how sex hormones affect coronary reactivity to local neurohormones (ACh, catecholamines) and to neural activation. c. Neural control of vasomotion in normal coronary arteries is understood much better than neural control of diseased coronary vessels. It is not known whether vagal activation produces the same effects as infusion of ACh, whether sympathetic fibers retain their original effectiveness; the role of fibers releasing other neurotransmitter substances is also not known. While animal models do not necessarily replicate human CHD, study of diseased endothelium will provide badly needed insight into principles of interaction between overlapping systems. d. In connection with the insulin metabolic syndrome, research is needed to determine why some individuals with similar levels of insulin resistance may develop hypertension, others NIDDM or dyslipidemias. e. Although research in nonhuman primates has demonstrated that emotional stressors can interact with diet to promote coronary risk, the role played by insulin metabolism and the SNS has not been clarified. Nonhuman primate models have been used successfully to study the effects of emotional stress on atherosclerosis. They should continue to be developed. f. Further studies are needed to assess the contribution of coronary vasomotion and endothelial dysfunction to mental stress ischemia. 2. Clinical Research Mental stress clearly triggers ischemia in both laboratory and ambulatory settings. It is not known whether interventions designed to reduce MSI would alter the disease process itself. Ideally, a greater understanding of the mechanistic role played by mental stress in coronary artery disease would enable design of interventions that serve to reduce ischemia while also altering the course of disease. New technology enables direct pathophysiologic investigation of the impact of stress on atherosclerotic risk factors (clinical and serologic), atherosclerosis severity (Intima-Media Thickness), endothelial function (brachial ultrasonography), and autonomic function (heart rate variability, baroreflex sensitivity), as well as myocardial ischemia. a. A comprehensive longitudinal study which evaluates the role of increased but transient natural environmental stress (>4 months) on risk factors, serologic parameters of plaque rupture, endothelial function, myocardial ischemia and autonomic function would further this end. Study of genetic phenotypes thought to influence SNS activity and other stress-related risk factors would also be of interest. Study power requirements are likely to dictate a multicenter study to enable rapid accrual of a sufficient number of patients. Sample size calculations should consider including morbidity and mortality endpoints. b. Plausibly important psychosocial and physiological differences have been identified between male and female CHD patients. Elucidating their significance is likely to benefit patients of both genders, since some of the differences may have gender-specific importance, but others represent fundamental commonalities underlying the atherosclerotic disease process. Future work should include study of the action of estrogen on vascular/endothelial function, both directly and by influencing the action of other risk factors. c. Knowledge concerning the prognostic value of mental stress testing should be extended and refined and integrated with other medical risk factors. d. Little is known regarding whether MSI predicts vulnerability to a specific class of triggers of acute cardiac events. Such information could be helpful for refining clinical interventions. 3. Pilot Clinical Trial The Panel considered a full range of research possibilities that would lead to clinical benefits. In particular, the Panel discussed in considerable detail the possibility of interventions for patients with MSI, and concluded unanimously that a randomized clinical trial would be of great value to optimize treatment and rehabilitation programs for CHD patients. An additional benefit of a clinical trial would be that some of the questions related to mechanisms, discussed earlier, might be answerable through substudies. The rationale for a clinical trial is grounded in early data suggesting that susceptibility to MSI significantly raises risk of MI, while an intervention that provides stress management reduces the number of cardiac events, including death, MI, and revascularization procedures. Indirect evidence comes from studies showing that exercise rehabilitation decreases cardiovascular reactivity, which is linked with MSI. Patients susceptible to MSI can be identified with presently available methods. Since mental stress is a common occurrence of everyday life and because of the increased risk associated with MSI, effective interventions could make a significant impact on the total ischemic burden including ischemia-related adverse clinical outcomes of the coronary patient. Thus, the Panel concluded unanimously that a randomized pilot clinical trial should be conducted to determine whether a multimodal intervention can be implemented to reduce recurrent MI and death in CHD patients at high risk of MSI. The objectives of a pilot study would be to assess ability to identify and recruit patients at risk of MSI, and to refine a multifactorial intervention comprised of a combination of exercise and stress management, against a background of usual medical care. Such a clinical trial should consider the additional lifestyle and risk factor change interventions currently available. For example, evidence suggests that dietary fat reduction promotes regression of coronary atherosclerosis, and that stress-management promotes adherence to dietary regimens. Thus, the clinical trial design might incorporate aggressive dietary management as one of its components. The primary endpoint for assessing efficacy of interventions should be the number of cardiovascular deaths and re-infarction. Response variables for the pilot trial should include frequency and duration of ambulatory ischemia, ischemia provoked by mental stress in the laboratory, cardiovascular reactivity, lifestyle risk factor change, and serum lipid levels. A full-scale clinical trial (and, to a lesser extent, the pilot study) would enable developing hypotheses regarding the mechanisms through which MSI, or interventions which reduce MSI, affect clinical outcomes. ADJOURNMENT The meeting was adjourned at 3:00 p.m. on January 31, 1996. CERTIFICATION I hereby certify that the foregoing minutes are accurate and complete. ____________________________________ Carl Pepine, M.D. Chair SEP on Mental Stress and Myocardial Ischemia ____________________________________ Peter G. Kaufmann, Ph.D. Federal Official SEP on Mental Stress and Myocardial Ischemia Attachment: Panel Roster Note: A complete set of handouts are available from the Executive Secretary. NATIONAL HEART, LUNG, AND BLOOD INSTITUTE SPECIAL EMPHASIS PANEL (SEP) ON MENTAL STRESS AND MYOCARDIAL ISCHEMIA PARTICIPANT LIST JANUARY 31, 1996 BETHESDA, MARYLAND CHAIR: Carl J. Pepine, M.D. Professor of Medicine Co-Director, Division of Cardiovascular Medicine University of Florida College of Medicine 1600 Archer Road/P.O. Box 100277 Gainesville, FL 32610-0277 PARTICIPANTS: C. Noel Bairey Merz, M.D. Assistant Clinical Professor of Medicine, UCLA School of Medicine Medical Director, Preventive and Rehabilitative Cardiac Center Cedars-Sinai Medical Center 444 S. San Vicente Blvd., Suite 901 Los Angeles, CA 90048 James A. Blumenthal, Ph.D. Professor of Medical Psychology Department of Psychiatry Duke University Medical School - Box 3119 Durham, NC 27710 Matthew M. Burg, Ph.D. Assistant Clinical Professor of Medicine Section of Cardiovascular Medicine Yale University School of Medicine 135 College Street New Haven, CT 06510-8056 David S. Krantz, Ph.D. Professor of Psychiatry Georgetown University Medical Center 3800 Reservoir Road Washington, DC 20007 Benjamin H. Natelson, M.D. Professor of Neurosciences New Jersey Medical School 88 Ross Street East Orange, NJ 07018 Neil Schneiderman Ph.D. Professor of Psychology, Medicine, and Biomedical Engineering Department of Psychology University of Miami Coral Gables FL 33124 David S. Sheps, M.D., M.S.P.H. Professor of Medicine Division of Cardiology University of North Carolina at Chapel Hill Chapel Hill, NC 27599-7075 NHLBI PROGRAM STAFF: Jeffrey Cutler, M.D. Director, Clinical Applications and Prevention Program Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute II Rockledge Center 6701 Rockledge Drive, MSC 7936 Bethesda, MD 20892-7936 Lawrence Friedman, M.D. Director, Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Bldg. II, MSC 7938 Bethesda, MD 20892-7938 FEDERAL OFFICIAL: Peter Kaufmann, Ph.D. Group Leader, Behavioral Medicine Research Group Clinical Applications and Prevention Program Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Bldg. II, MSC 7936 Bethesda, MD 20892-7936