NHLBI Workshop
Optimizing Stress Reduction Interventions for
Cardiovascular Disease Risk

Executive Summary

The National Heart, Lung, and Blood Institute (NHLBI) convened a Workshop on September 27-28, 2010 in Bethesda, Maryland to provide recommendations to the NHLBI to inform decisions on research priorities and directions in the field of stress reduction interventions for cardiovascular disease risk.  The participants included national experts in clinical trials methodology, basic and translational science as well as in cardiac rehabilitation, electrophysiology and cardiac arrhythmias, cardiovascular epidemiology, clinical cardiology, medical psychology, and behavioral medicine. These experts were asked to:

• Assess the current state of knowledge to identify readiness for the development and conduct of rigorous randomized controlled trials testing stress management interventions for cardiovascular risk and outcomes.  Review definitions and assessments of stress.
• Evaluate existing stress management interventions and their components to identify the most promising approaches for coronary heart disease patients.
• Consider the knowledge base from animal and human literature on stress and its role in the etiology of cardiovascular disease to inform interventions.

Overview

The workshop focused on bringing key decision leaders together to consider the state of the science concerning the role of psychosocial stress reduction on cardiovascular disease risk, and providing recommendations regarding conceptualization, measurement, and design strategies for conducting rigorous research in this area.  Detailed discussion included animal models of stress; experimental studies in humans of the mechanisms through which stress influences cardiovascular function; epidemiological evidence of associations between stress and cardiovascular risk; and key randomized controlled trials of stress reduction for decreasing cardiovascular morbidity and relevant clinical endpoints. A substantial discussion ensued of design considerations for an adequately-powered study of stress management interventions for cardiovascular disease (CVD) endpoints.

Discussion

Significant evidence has accumulated that psychosocial stress contributes to the etiology and pathogenesis of coronary artery disease.  In addition to direct influences through the nervous, endocrine, and immune systems, stress reduces the adoption and maintenance of a healthy lifestyle and adherence to medical care (1).  Epidemiological evidence is compelling; several large and international studies have shown that individuals reporting high levels of psychosocial stress have significantly elevated risk of cardiovascular diseases.  Most notably, the INTERHEART study demonstrated that among more than 30,000 individuals, those who reported elevated stress had odds ratios for myocardial infarction of 2.5 (2).  High work demands and daily stress have also been associated with coronary heart disease (CHD) morbidity and mortality, with carotid artery intima-media thickness progression, and with recurrent events.  The most recent addition to this literature was the finding in the prospective Women’s Health Study that women with high job-related stress were at nearly twice the risk of myocardial infarction of those with lower job-related stress, and were 43 percent more likely to undergo heart surgery.  These findings are similar to several earlier reports of job strain predicting recurrent MI in both men and women (3), as well as with studies in humans and non-human primate investigations that identified a number of specific biologic and behavioral pathways through which stress promotes the progression of cardiovascular disease.

Despite these compelling findings, few randomized controlled trials have been conducted to evaluate the potential of stress management interventions to reduce cardiovascular events. Those data that are available have reported reductions in CVD risk factors, rehospitalization and cardiac events (4).  However, small sample sizes and variation in the patient population, eligibility criteria and components of the interventions prevent a definitive causal conclusion regarding the role of stress management in the prevention or treatment of cardiovascular disease.

Knowledge Base

Each Workshop participant led an empirically-focused overview and discussion regarding the evidence in specific areas of the literature, each related to psychosocial stress, cardiovascular disease risk, prevention, and clinical endpoints.   The studies covered the range of knowledge from epidemiological investigations, to animal models of stress and CVD, to mechanistic studies identifying the biologically relevant changes that occur during psychosocial stress and stress reduction.  The most important findings include:

• Although considerable variation exists among patients regarding the sources, measurement, and intensity of mental stress, those that report high stress levels in observational studies show significantly increased risk of cardiovascular events.
• Conceptual overlaps between mood, stress, affect, and depression notwithstanding, valid diagnostic instruments for stress exist and can be effectively used to evaluate progress in clinical and research contexts. 
• New technologies are now available and well-validated that can provide additional and uniform metrics of mental stress.
• Several biological and behavioral mechanisms through which stress affects cardiovascular risk have been identified.   Stress management interventions may influence more than one of these at any given time. 
• Self-reported psychological stress is highly prevalent in the general population as well as among CVD patients.  The clinical importance of establishing whether the inclusion of stress management strategies into cardiac care improves clinical outcomes will have significant public health relevance.
• Prominent gender differences identified in animal and human studies have provided a better understanding of the physiological mechanisms of the relationships between stress and CVD (5).
• Particularly promising research in this area has demonstrated a reduced incidence of major adverse cardiac events in patients enrolled in a stress management program, compared to a traditional cardiac rehabilitation program (6).  Biomarkers showed similar improvements with exercise and stress management (7). The Working Group noted that the cardiac rehabilitation setting seems to be ideal for testing the separate and combined effects of stress management and exercise on clinical outcomes.
• Notably, the Working Group did not make specific recommendations on uniform definitions and a single measure of stress.  Rather, it recommended that each research study carefully define the construct under study and apply valid measures.

Recommendations

The participants recommended that research continue and expand on all aspects of the relationships between stress and cardiovascular outcomes.  Because of the dearth of knowledge regarding the potential of stress management to improve clinical outcomes, the most urgent need is for additional clinical research in cardiovascular patients.  Most importantly, the Working Group recommended that the NHLBI launch a multi-site clinical trial, preferably in a setting of cardiac rehabilitation, to evaluate whether including a stress management intervention improves clinical outcomes.  Interdisciplinary collaboration would be key for success in this trial.  The use of technologies that can capture essential components of the measures of interest should be exploited.  The primary endpoint of this study initially should be a composite of MAJOR ADVERSE CARDIAC EVENTS (MACE), including unstable angina, re-infarction, hospitalization, and cardiovascular death.

NHLBI Contacts

Catherine M. Stoney, PhD
Division of Cardiovascular Sciences
Stoneyc@mail.nih.gov

Peter Kaufmann, PhD
Division of Cardiovascular Sciences
kaufmannp@mail.nih.gov

Workshop Members

Chair

James Blumenthal, PhD
Duke University Medical Center
Blume003@mc.duke.edu

Members

• Jonathan Davidson MD – Seabrook Island, SC
• Susan Folkman, PhD - University of California, San Francisco
• Kenneth E. Freedland, PhD – Washington University School of Medicine
• William Gerin, PhD – Pennsylvania State University
• David S. Goldstein, MD, PhD – NINDS (Intramural), NIH
• Thomas W. Kamarck, PhD – University of Pittsburgh School of Medicine
• David S. Krantz, PhD – Uniformed Services University
• Rachel Lampert, MD -  Yale University School of Medicine
• Karen Matthews, PhD – University of Pittsburgh School of Medicine
• Deborah Olster, PhD – Office of Behavioral and Social Sciences Research, NIH
• Joseph Schwartz, PhD – State University of New York, Stony Brook
• David Sheps, MD – Emory University School of Medicine
• Carol Shively, PhD – Wake Forest University School of Medicine and Primate Center
• Jerry Suls, PhD – University of Iowa

Appendices

• Meeting Agenda ( 63KB)

References

• Kuhl EA et al., Relation of anxiety and adherence to risk-reducing recommendations following myocardial infarction. American Journal of Cardiology, 2009, 1629-1634.
• Rosengren A et al., Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.  Lancet, 2004, 364: 953-962.
• Laszlo KD et al., Job strain predicts recurrent events after a first acute myocardial infarction: The Stockholm Heart Epidemiology Program, Journal of Internal Medicine, 2010, 267: 599-611.
• Jones DA & West RR.  Psychological rehabilitation after myocardial infarction: Multicentre randomized controlled trial.  BMJ, 1996, 313: 1517-1521.
• Low CL et al., Psychosocial factors in the development of heart disease in women: Current research and future directions. Psychosomatic Medicine, 2010, 72: 842-854.
• Blumenthal JA, et al., Stress management and exercise training in cardiac patients with myocardial ischemia. Effects on prognosis and evaluation of mechanisms. Archives of Internal Medicine, 1997, 157:2213-23.
• Blumenthal JA et al., Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: A randomized controlled trial. JAMA, 2005, 1626-34.

Last Updated: January 2011