Acute myocardial infarction (MI) is a major cause of death in American women as it is in men, but despite recent scientific advances, it is unclear whether its pathophysiology differs between women and men. Young and middle-aged (but not older) women have higher mortality and complication rates after an MI compared with men of similar age. The reasons for these differences are unknown; they are not explained by traditional risk factors, comorbidity or treatments, and occur despite that women have less coronary atherosclerosis than men. These findings remain an unsolved issue in the epidemiology of ischemic heart disease in women. Women have a larger burden of psychosocial risk factors. For example, depression is 2 times more frequent in younger (<60 years old) women with MI that than in other groups, affecting up to 40% of this population. Therefore, we hypothesize that psychological stress is a major risk factor in young women with MI and may explain sex differences in MI pathophysiology and prognosis. In about half of patients with ischemic heart disease, myocardial ischemia can be induced by a psychological challenge; this mental stress ischemia provides a useful model for the study of psychological stress on cardiac function. In this project we will evaluate sex differences in the prevalence, mechanisms and consequences of mental stress ischemia in young survivors of MI. We will compare 150 women and 150 men <60 years of age who were hospitalized for MI in the previous 6 months. We will also compare the MI patients with 60 female and 60 male community controls without MI. We will test the hypothesis that, among young subjects with MI, mental stress ischemia is a stronger risk factor in women than men, due to heightened physiological and behavioral responses to stress in women with MI relative to men with MI and relative to women without MI. The aims of this study are: (1) Using single photon emission tomography (SPECT) [Tc-99m]sestamibi imaging of myocardial perfusion, compare myocardial perfusion at rest, during mental stress and during exercise stress between women and men less than 60 years old who were hospitalized for a confirmed MI in the previous 6 months. (2) Compare acute vascular and inflammatory responses to stress between young women and men with MI, and between young women and men with MI and their respective community controls. We will examine changes between rest and mental stress in peripheral vascular function, systemic inflammation and immune function measures, and, secondarily, changes in neuroendocrine and behavioral measures. (3) Compare long-term (6-month) vascular and inflammatory outcomes in young women and men with MI. Our proposal will fill a significant gap. Younger women with an MI remain an understudied group despite their higher rate of adverse events compared with men, and may be especially vulnerable to psychological stress. Investigation of this group will provide critical information for the pathophysiology and prevention of ischemic heart disease in women. PUBLIC HEALTH RELEVANCE: Ischemic heart disease is the major cause of death in American women and yet, much remains to be learned about the unique characteristics of this disease in women. Young and middle-aged women have a higher unexplained mortality after an acute myocardial infarction (MI) compared with men of similar age; they also have a higher burden of psychosocial risk factors. In this project, we will 1) evaluate whether young women who have recently had an MI are more susceptible to myocardial ischemia due to psychological stress relative to men; 2) examine the mechanisms underlying ischemia due to psychological stress in women relative to men; and 3) assess whether ischemia due to psychological stress is implicated in the worse prognosis of women with MI compared with men.