Mental Stress and Myocardial Ischemia after MI: Sex Differences, Mechanisms and Prognosis

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Young women with a myocardial infarction (MI) have emerged as a group in need of special study, as they have higher mortality compared with men of similar age despite less severe disease. These disparities remain unexplained and suggest sex differences in the pathophysiology, risk factors and prognostic factors of acute MI. The psychosocial sphere is a largely neglected area for the prevention of ischemic heart disease in women. In the previous funding period (R01 HL109413) we assembled a cohort of early-onset (≤60 years of age) post-MI patients, 50% women, and sex- and age-matched community controls—the Myocardial Infarction and Mental Stress (MIMS)2 study. We used a laboratory protocol to study mental stress-induced myocardial ischemia (MSI), a marker of stress vulnerability and significant prognostic factor in people with coronary artery disease. We found that young women with MI have twice the rate of MSI than men of similar age. We also found that the mechanisms of MSI differ by sex. While in men MSI is primarily due to supply-demand mismatch, in women it is driven by microvascular vasoconstriction. Despite significant progress in our previous funding period, many questions still remain. First, the clinical implications of MSI in women are unknown, since former studies have mostly examined men. Second, the pathways through which MSI contributes to adverse events are unclear. Based on our data, processes involving vascular and immune function could be especially important for women, but this has never been tested. Third, the underlying mechanisms for the higher rate of MSI in young women are unclear. In addition to differences in physiology, MSI could reflect differences in enduring daily life stressors and/or affect/emotions. Building on this previous work, the goal of this competitive renewal is to clarify sex differences in pathways of risk linking emotional stress to MSI and clinical outcomes in young post-MI patients. Within 8 months of MI, 300 new patients younger than 61 years, 50% women, will be tested in the lab for MSI using our established protocol with myocardial perfusion imaging with the same modalities as MIMS2. Subjects will be monitored at home for 1 week, and then followed for clinical events. The proposed sample (MIMS3) will augment our existing cohort (MIMS2), doubling its size to 600 patients so as to make it suitable for the assessment of clinical outcomes. The specific aims are: 1) Examine whether MSI is related to clinical outcomes in both women and men (a composite endpoint of recurrent MI, unstable angina, heart failure hospitalization and cardiovascular death). 2) Examine whether vascular responses to mental stress are related to the clinical endpoint, including endothelium-dependent and microvascular function, and peripheral vasoconstriction; in an exploratory fashion, we will also examine markers of autonomic dysregulation, inflammation, myocardial injury and repair in response to mental stress. 3) Examine sex differences in stressful events and autonomic function during daily life and their relation with MSI during one week of home monitoring.