When the Mind Controls the Fate of the Heart

Paco E. Bravo, MD; Thomas P. Cappola, MD, ScM

Coronary heart disease (CHD) is the leading cause of mortality globally, and patients who have chronic forms of CHD experience substantial morbidity, including high rates of recurrent cardiac events and eventual onset of heart failure.1,2 Further research to identify vulnerable populations, improve risk stratification, and understand nontraditional risk factors is essential to reduce the public health burden of CHD.

In this context, sufficient evidence now suggests that mental stress can trigger myocardial infarction,3,4 reversible cardiomyopathy,5 and sudden cardiac death in susceptible individuals.6 The link between mental stress and CHD was first described over a century ago7 and has become an important topic of research over the past 40 years.3,4 In a meta-analysis of 20 studies involving 3164 individuals with CHD, mental stress provoked in a controlled environment (eg, public speaking, mental arithmetic, anger recall) was associated with inducing myocardial ischemia in 32% of patients with CHD in the form of either transient regional wall motion abnormalities on echocardiography, ST-segment deviation on electrocardiography, or reversible defects on myocardial perfusion imaging with single-photon emission computed tomography (SPECT).4 Another meta-analysis of 5 studies involving 555 individuals suggested that presence of so-called mental stress–induced myocardial ischemia in patients with CHD was associated with increased risk of recurrent cardiac events and mortality compared with individuals with CHD but without mental stress–induced myocardial ischemia, with absolute rates of these outcomes of 34% vs 14%, respectively.3

Although suggestive, these prior studies were limited by small sample sizes (largest single outcomes study, n = 182), lack of racial, ethnic, and gender diversity, and use of relatively less sensitive techniques to detect ischemia (mainly echocardiography and electrocardiography).3 Therefore, it is unclear whether the increased risk of cardiac events associated with mental stress–induced myocardial ischemia can be generalized to larger populations with CHD.8 Moreover, the underlying mechanisms of and the interplay between mental stress ischemia and conventional stress ischemia induced during exercise or pharmacological stress have not been sufficiently explored.

In this issue of JAMA,9 Vaccarino and colleagues present the largest (n = 918) and most diverse (34% women, 40% Black individuals) observational study investigating the association between mental stress ischemia, conventional stress ischemia, and future cardiac events in patients with known CHD using contemporary myocardial perfusion SPECT imaging. The study consisted of a pooled analysis of 2 parallel prospective studies, with similar protocols, involving patients with established CHD: the Mental Stress Ischemia Prognosis Study (MIPS; n = 618) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2; n = 300). After enrollment, all participants underwent both mental stress testing with public speaking challenge and conventional stress testing with either exercise (69%) or pharmacologic SPECT (31%) to provoke ischemia.

Overall, mental stress ischemia was observed in 16% of participants, conventional stress ischemia in 31%, and both in 10%. After a median 5-year follow-up, the primary end point of cardiovascular death or myocardial infarction occurred in 17% of study participants, and a secondary end point that also included heart failure hospital admission occurred in 35%. In all models tested; presence of mental stress ischemia showed significant associations with both the primary (pooled adjusted hazard ratio [HR], 2.5; 95%CI, 1.8-3.5) and secondary (pooled adjusted HR, 2.0; 95%CI, 1.5-2.8) end points. Presence of conventional stress ischemia showed similar associations with primary (adjusted HR, 2.0; 95% CI, 1.3-2.0) and secondary (adjusted HR, 1.6; 95%CI, 1.3-2.0) end points. However, analyses based on the specific ischemia phenotype demonstrated that participants with evidence of both phenotypes had the strongest Association with the primary end point (HR, 3.8; 95%CI, 2.6-5.6), followed by individuals with mental stress ischemia only (HR, 2.0; 95%CI, 1.1-3.7). In contrast, conventional stress ischemia alone was not significantly associated with the primary outcome (HR, 1.4; 95%CI, 0.9-2.1) when compared with individuals without myocardial ischemia by either intervention. Similar associations were apparent for the secondary end point.

The results of the study by Vaccarino et al largely confirm prior observations from smaller studies and extend the generalizability of the findings to women, Black individuals, and younger individuals with stable CHD, populations that are often underrepresented in biomedical research. In addition, this study reports for the first time the complex interplay that seems to exist between inducible ischemia by mental stress and conventional stress testing, which can result in distinct ischemia phenotypes that may have different risk profiles. In particular, it is remarkable that mental stress ischemia (without conventional stress ischemia) appears to be a stronger risk factor than conventional stress ischemia (without concomitant mental stress ischemia) for cardiovascular death, nonfatal myocardial infarction, or heart failure hospital admission.

From a pathophysiological perspective, mental stress ischemia and conventional stress ischemia appear to arise through different mechanisms. Mental stress may lead to an From a pathophysiological perspective, mental stress ischemia and conventional stress ischemia appear to arise through different mechanisms. Mental stress may lead to an adrenergic surge, but unlike exercise-induced ischemia, mental stress ischemia typically occurs at a lower cardiac workload and is not associated with angiographic CHD severity.10 Moreover, mental stress ischemia ensues independent of hemodynamic changes, implying that myocardial oxygen demand and CHD burden play relatively minor roles. Invasive studies have shown that in mental stress ischemia, coronary blood flow decreases while the coronary diameter does not significantly change at the site of atherosclerotic disease, suggesting an impairment in the coronary microcirculation. Patients with mental stress ischemia also have an impaired vasodilatory response to intracoronary acetylcholine infusion, in keeping with coronary endothelial dysfunction.8 By comparison, vasodilators used to induce conventional stress ischemia increase coronary blood flow through endothelium-independent mechanisms11 and exercise mainly induces endothelium-dependent changes in coronary flow.12

Thus, presence of mental stress ischemia as assessed through SPECT appears to be primarily a marker of coronary endothelial dysfunction, whereas presence of conventional stress ischemia is a more mixed picture that encompasses impaired endothelium-independent vasoreactivity, endothelial dysfunction, degree of coronary atherosclerosis, and increased myocardial oxygen demand. These underlying differences may account for the discrepancies in outcome associated with both types of ischemia, and may also help explain the relatively higher risk observed in patients with mental stress ischemia only than in patients with conventional stress ischemia only. For example, emerging evidence indicates that patients with CHD and coronary endothelial dysfunction have generally worse outcomes than their counterparts with endothelium-independent dysfunction.13 Consequently, it is plausible that coexistence of endothelium-dependent and endothelium-independent microvascular dysfunction, as elicited by mental stress ischemia and conventional stress ischemia, respectively, may portend the highest risk as suggested by the current study.9

In summary, the study by Vaccarino and colleagues provides compelling evidence demonstrating a strong association between mental stress ischemia and the risk of future cardiac events and mortality among individuals with stable CHD. However, several clinically relevant questions remain for future studies, including the following: To what extent is mental stress ischemia therapeutically modifiable? Can screening for and treatment of mental stress ischemia lead to improved outcomes? Is mental stress testing reproducible and feasible in clinical practice? Are there additional at-risk populations in whom mental stress ischemia testing should be considered? Answers to these important questions will help determine whether mental stress should become an actionable clinical item in the management of individuals with known or suspected CHD.

Article Information

Corresponding Author: Paco Bravo, MD, Hospital of the University of Pennsylvania, 3400 Civic Center Blvd, 11-154 South Pavilion, Philadelphia, PA 19104 (

Conflict of Interest Disclosures: None reported.


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