Abstract Cardiovascular disease (CVD) continues to be a leading cause of disability and premature mortality in the United States and globally, Recently, young women have been found to be disproportionately affected by CVD with rising incident of myocardial infarctions raising concerns for potentially novel disease mechanisms and risk factors. Psychosocial stress is believed to play a role in the pathogenesis of coronary artery disease and myocardial infarction among this vulnerable patient population. At the same time, recent studies have shown that stress might be implicated in the differential pattern of CVD among men and women as they may have different incidence and mechanisms of cardiovascular proclivity to stress. However, key sex-related differences in biomarkers and mechanisms remain elusive. Therefore, the identification of differences in the pattern of myocardial ischemia during mental and physical stress will allow for the better characterization of at-risk populations and may facilitate understanding mechanisms of myocardial ischemia during mental stress and its relation to non-obstructive coronary artery disease. In this application, we will develop and use a novel algorithm applied to rest/stress myocardial perfusion imaging studies in conjunction with coronary angiography results from the Myocardial Infarction and Mental Stress 2 (MIMS-2) database to quantify regional homogeneity of myocardial ischemia. Aim 1 will compare the pattern of myocardial ischemia (focal vs diffuse) in men and women and during mental and physical stress. In Aim 2, we will investigate the association of diffuse mild myocardial ischemia as quantified by the novel algorithm with adverse cardiovascular outcomes. The proposed analyses will provide plausible evidence to understand the effects of diffuse myocardial ischemia on coronary artery function and myocardial blood flow at the levels of blood vessel segments and its association with adverse cardiovascular outcomes. Additionally, this research will provide a context to use in our interpretations of subjects improve our understanding of susceptibility to myocardial ischemia and the relationship between myocardial ischemia, mental stress and coronary artery disease.