Myocardial ischemia is an Important clinical marker of coronary artery disease (CAD) activity that results from an Imbalance of myocardial oxygen supply and demand. The presence of ischemia, both in- and out- of-hospital, confers significant prognostic risk of cardiac events for CAD patients. Thus, understanding of the pathophysiology and triggers of myocardial ischemia may provide a link between the asymptomatic development of CAD and the occurrence of health-damaging clinical events, and Is also potentially Important for effective efforts at prevention and risk factor stratification. The broad goal of this revised project is to assess the role of myocardial oxygen supply and demand mechanisms in interaction with mental stress triggers in accounting for individual differences In ischemic activity. Prior research indicates that mental stress and daily activities interact with the biology of CAD to trigger ischemia, and that mental stress-induced ischemia and out-of-hospital ischemia occur in a subset of patients with CAD. Similarities between characteristics of ambulant ischemia and mental stress-induced ischemia have been noted, suggesting--but not proving--that common pathophysiologic mechanisms are operative. To investigate these mechanisms, the general hypothesis is of this project Is that individual differences In ischemic activity may be accountable for by levels of mental stress and by myocardial supply and demand mechanisms that relate to dysfunction of the coronary endothelium and to cardiovascular responsiveness to stress. Using quantitative angiography during cardiac catheterization, and non-invasive techniques (echocardiography and ambulatory ECG monitoring) to quantity mental stress-induced ischemia and out-of-hospital ischemia in separate sessions' specific aims of this project are to test the following hypotheses: (1) that patients with ischemia inducible by mental stress in the lab have more severe coronary endothelial dysfunction and Increased hemodynamic responses to stress compared to patients with ischemia Inducible with exercise alone; (2) that patients with daily life ischemia also evidence more severe endothelial dysfunction and Increased cardiovascular responses to stress; (3) that mental stress Is an Important determinant of daily life ischemia in patients with endothelial dysfunction; and (4) that changes in ambulant ischemia over time will be predicted by: initial endothelial dysfunction, susceptibility to mental stress ischemia, and changes in levels of mental and physical stress. Using a combination of non-invasive and Invasive methodologies, this project will assess possible mechanisms that may link the asymptomatic development of CAD to the occurrence of health damaging clinical events.