New Models for Understanding and Treating Psychosocial Risk Factors in Patients with Coronary Heart Disease
By James Blumenthal, PhD
Coronary heart disease (CHD) is the leading cause of death for American Indians and Alaska Natives, blacks, Hispanics, and whites. In 2002, 696,947 people died of heart disease (51% of them women), accounting for 29% of all U.S. deaths. In 2005, CHD is projected to cost $393 billion, including health care services, medications, and lost productivity. In roughly half the cases the first clinical manifestations of CHD, myocardial infarction (MI) or sudden death, are catastrophic: these events are sudden, unexpected, unpredictable, and fatal. Moreover, the traditional risk factors, cigarette smoking, hyperlipidemia, diabetes, and hypertension, do not fully account for the timing and occurrence of these events.
Research from our laboratory and others has suggested that psychosocial and behavioral factors may play a significant and independent role in the development of CHD and its complications (1,2). This evidence has also provided a rationale for developing psychosocial interventions for modifying the natural history of these clinical events. However, knowledge of the role of psychosocial factors in CHD has been impeded because there have been few intervention studies that have included effective treatments with appropriate clinical endpoints. By traditional "cardiology" standards, only "hard" clinical outcomes, such as MI or death, are considered legitimate endpoints. However, these endpoints occur infrequently over relatively short follow-up periods and require large sample sizes using multiple clinical sites. Unfortunately, these large scale studies are so expensive that they are not feasible for most investigators interested in psychosocial interventions.
Technological advances have provided new opportunities to study the relationship of psychosocial factors and CHD outcomes: transient myocardial ischemia, a condition in which there is an inadequate supply of blood to the heart, has proven to be a useful surrogate marker for CHD, and has been the focus of our work for more than a decade. Ischemia can be measured easily and reliably; is prevalent among many patients with CHD (3); may be triggered by emotional stress (4-6); is associated with worse prognosis (7-10), and may be modifiable with treatment (11-13). Our research team at Duke, along with a number of collaborators including Alan Rozanski at Columbia University, David Krantz at Uniformed Services University of the Health Sciences, David Sheps at the University of Florida, and Alan Hinderliter at the University of North Carolina at Chapel Hill, have performed a series of studies that have provided new insights into the relationship of stress and CHD, which we highlight below.
Characteristics of transient myocardial ischemia during daily activities
The traditional method for the assessment of myocardial ischemia, exercise treadmill testing, is well-validated and accepted but does not typically reflect ischemia occurring outside of the laboratory setting during activities of daily life. Identification and quantification of ischemia is best accomplished by ambulatory electrographic (ECG) monitoring. Ambulatory ECG studies have noted that ischemia in daily life is subject to a variety of influences that produce a wide range of ischemic events over time: It has been shown that ischemia (a) occurs frequently, and that the majority of episodes are painless (14,15); (b) occurs at low heart rates, well below levels found to elicit ST-segment depression during exercise (15); (c) has a circadian rhythm with greatest density in the early morning hours (16-18); (d) is associated with variability over time that cannot be explained simply by changes in clinical status or fixed coronary obstruction (19); (e) frequently occurs in the absence of strenuous physical exercise and in the presence of stress both in everyday life (4,5) and in the laboratory (6,20); and (f) when induced by stress, may be an important predictor of adverse CHD events (7-10).
Characteristics of transient myocardial ischemia during laboratory testing
A number of studies have shown that myocardial ischemia is inducible in the laboratory during mental stress testing in a substantial subset of patients with CHD. The typical stress protocol requires patients to undergo a series of "mental stress" tasks such as performing mental arithmetic, outlining the shape of a star from its refection in a mirror, or giving an extemporaneous speech on a current events topic. We studied 132 CHD patients who underwent radionuclide ventriculography (or nuclear imaging of the heart) during exercise and mental stress testing (20). In this population, almost two thirds of patients exhibited evidence of ischemia in response to a battery of mental stressors. Interestingly, patients who displayed mental stress-induced ischemia in the laboratory were more likely to exhibit ischemia during daily life. These patients also were followed over a period of more than 3.5 years in which 28 patients suffered at least one cardiac event, such as fatal and non-fatal MI, or revascularization procedure such as coronary angioplasty or coronary bypass surgery. Patients who exhibited ischemia during at least one of the mental stress tasks were 3 times more likely to suffer a subsequent coronary event compared to patients who did not exhibit ischemia during the mental stress testing (10). Similar findings have now been reported by a number of other investigative teams (7-9). These findings suggest that ischemia induced by mental stress is associated with increased rates of adverse events in patients with CHD and may help to identify a subgroup of cardiac patients who may be especially appropriate for psychosocial intervention efforts.
Stress Management Training in CHD patients
There is now growing evidence that psychosocial interventions, independent of medical therapies, offer considerable benefit to patients with CHD (21). In a meta-analysis almost 10 years ago by Wolfgang Linden (22), 2024 patients who received psychosocial interventions and 1156 control subjects who received standard medical therapy and usually some form of exercise training were compared. Relative to controls, psychosocially treated patients showed greater clinical improvement not only in psychological distress, but also in lower blood pressure, heart rate, and cholesterol levels. More importantly, Linden et al. also concluded that patients who received psychosocial interventions were over 40% less likely to die and 65% less likely to have a recurrent coronary event than controls over a two year follow-up period. Although changes in cardiac risk factors were observed in the treatment group, the mechanisms by which the interventions reduced the event rates could not be determined.
One mechanism by which psychosocial interventions might contribute to improved outcomes is alterations in ischemic activity. In an initial study (11) we showed that, compared to usual care, patients in stress management showed greater improvements in wall motion abnormalities (detected by nuclear imaging) during mental stress testing and exhibited fewer ischemic episodes during ambulatory ECG monitoring. Stress management patients also showed clinically significant improvements in diary-reported chest pain and negative emotions, as well as improvements in perceived health and well-being. In addition, follow-up data suggested that the stress management intervention also had an impact on clinical prognosis. Twenty-two (21%) of the 107 patients who participated in the trial experienced at least one event: only 9% of the patients in the stress management group suffered an event, compared to 21% in exercise training and 30% in usual medical care. Thus, the stress management intervention not only modified the occurrence of ischemia, but also had a significant impact on longer-term clinical outcomes. A more extended follow up of participants revealed that the clinical benefits of stress management training were maintained over a period of 5 years, and there also was a significant reduction in medical expenses compared to usual care controls (12).
Because our study was not fully randomized, there remained lingering doubts about the significance of our findings. Consequently, we undertook a fully randomized controlled trial comparing exercise or stress management training compared to usual care in a sample of CHD patients with exercise-induced ischemia (13). CHD patients completed a comprehensive assessment of a number of biomarkers of risk including measures of vascular endothelial function, heart rate variability, and baroreflex sensitivity. They also completed a psychometric test battery including measures of depression and general psychiatric symptoms. After a 4-month treatment program, patients were re-assessed.
Results of our study showed that compared to Usual Care, patients in both active treatment groups exhibited lower post-treatment depression and reduced distress. Patients in both active treatment groups also exhibited smaller reductions in LVEF during mental stress testing and increased flow mediated dilation (FMD), which reflects improved vascular functioning. In a subgroup of participants, Stress Management patients showed improved baroreflex sensitivity (BRS), which measures the ability to buffer the blood vessels from large surges in blood pressure, and significant increases in heart rate variability (HRV), an index of autonomic nervous system function, compared to Usual Care controls.
These findings collectively demonstrate that behavioral treatments provide added benefits to routine medical management of CHD patients. In our latest research at Duke, patients who underwent four months of either aerobic exercise or stress management training exhibited greater improvements in psychosocial functioning, including less emotional distress and lower levels of depression compared to usual care controls. Moreover, we observed reductions in ischemic activity during mental stress, and improvements in FMD, HRV and BRS. Although “hard” clinical endpoints are widely considered to be the “gold standard” in evaluating the effectiveness of treatment, such studies invariably require large samples of 3000 patients or more. Because such studies are often prohibitively expensive, newer models are needed to evaluate effective and innovative therapies. As shown in the figure below, the use of surrogate endpoints such as myocardial ischemia offers considerable promise for furthering our understanding of stress and CHD. We conclude that behavioral interventions such as exercise and stress management provide additional benefits to CHD patients over-and-above routine medical management. Ultimately the long term effects of these behavioral interventions will need to be evaluated prospectively with respect to mortality and morbidity in larger samples of CHD patients. However, the present findings suggest that these interventions offer considerable promise to patients with stable CHD, not only in terms of improving their quality of life, but in improving important surrogate risk markers that could result in improved clinical outcomes.
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I am grateful to a number of valued colleagues at Duke University Medical Center for their commitment to our research program. I am especially indebted to Andy Sherwood, Michael Babyak, Lana Watkins, Robert Waugh, Edward Coleman, Michael Hanson, Junichiro Hayano, Salvatore Borges-Neto, Jiang Wei, Elizabeth Gullette, Anastasia Georgiades, and Simon Bacon for their contributions to the studies described in this review.
About the Author
James Blumenthal is Professor of Medical Psychology in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center and Professor of Psychology: Social and Health at Duke University. He received his Ph.D. from the University of Washington in Clinical Psychology and is board certified from the American Board of Professional Psychology in Clinical Psychology. He completed his pre-doctoral internship training and a postdoctoral fellowship in Aging and Human Development at Duke University Medical Center, where he later joined the faculty. Dr. Blumenthal is the recipient of several awards including an honorary doctorate from Uppsala University, the Michael L. Pollock Established Investigator Award for his work in cardiac rehabilitation, and the Outstanding Contributions to Health Psychology award from Division 38 of the American Psychological Association. He is a founding fellow of the American Association of Cardiopulmonary Rehabilitation and holds fellowship status in the American Psychological Association, the Society of Behavioral Medicine, and the Academy of Behavioral Medicine Research. He also is former President of the American Psychosomatic Society and Division 38 (Health Psychology) of the American Psychological Association.