Coronary artery disease remains the leading cause of morbidity and mortality in the Western society and is expected to be the leading cause of morbidity and mortality worldwide. It becomes apparent that in order to attenuate the disease process, clinical investigation into the mechanism, diagnosis and treatment of early coronary atherosclerosis is crucial. Early coronary atherosclerosis is associated with altered coronary endothelial function prior to the development of significant atherosclerotic disease. This disease stage is characterized by coronary vasoconstriction and reduction or attenuated coronary vasorelaxant response to the endothelial-dependent vasodilators such as acetylcholine and is associated with myocardial perfusion defects consistent with myocardial ischemia and an increase in cardiac events. Thus, the current K-24 application seeks to support the principal investigator to devote time to patient-oriented research and to act as a mentor for beginning clinical investigators in the area of early coronary atherosclerosis and endothelial function in humans. The exceptional patient-oriented research environment at the Mayo Clinic further optimized by the auspices of the Mayo Clinic Cardiac Catheterization Laboratory constitutes a unique resource to address these questions thereby providing a rich experience in patient oriented research to junior investigators. Thus, building on methods implemented during the P.I.?s R01 grant, in conjunction with novel and prospective approaches, the objective of this K24 application is to develop a program to mentor future investigators in patient-oriented research. The broad scientific aims of this application are: 1) to determine the role of endothelial humoral regulation of the coronary circulation with a specific focus upon endothelin and oxidative stress in early coronary atherosclerosis and endothelial dysfunction in humans; 2) to examine the associations between conventional and non-conventional risk factors as well as genetic predisposition and coronary endothelial function; 3) to develop novel non-invasive tests as well as peripheral markers for early diagnosis of coronary endothelial dysfunction; 4) to assess the relationship between coronary endothelial function and structure in humans with early coronary atherosclerosis; and 5) to address prospectively the prognosis of coronary endothelial function in humans. The success of this program has the potential to further both the research and mentoring endeavors of patient-oriented investigation and mentoring the next generation of patient-oriented researchers.