PROJECT SUMMARY/ABSTRACT Despite marked declines, atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. Fatal or non-fatal acute myocardial infarction (MI) remains the initial presentation in at least half of these patients. In recent years, reflective of the greater understanding of the many diverse causes of myocardial injury, international consensus definition now includes non-ischemic causes of myocardial injury and several etiologically distinct subtypes of myocardial injury, including subtypes of MI. However, the basic epidemiology of MI subtypes and non-ischemic myocardial injury and how risk factors differ between these categories is conspicuously lacking and critically needed. A fundamental understanding of the epidemiology of myocardial injury events, including differential relationship of traditional and nontraditional risk factors to the different MI subtypes, is needed to advance the prediction, prevention, and treatment of these leading causes of death. The Multi-Ethnic Study of Atherosclerosis (MESA) is a gender balanced contemporary NHLBI cardiovascular cohort with extensive baseline participant phenotyping and event surveillance. In this proposal, we aim to systematically re-adjudicate more than 18,000 clinical events collected in MESA over 14 years. We have developed innovative tools to enhance accuracy and efficiency of the adjudication process. We will use this data to ascertain the incidence of specific acute MI subtypes. We will delineate the size and strength of association between baseline traditional and novel cardiovascular risk factors with individual acute MI subtypes and acute non-ischemic myocardial injury. In addition to analyzing the impact of individual risk factors on specific myocardial injury subtypes, we will utilize factor analyses to leverage information gained from how multiple risk factors within a domain (e.g., thrombogenicity, atherosclerosis and myocardial damage) interact with each other to impact specific myocardial injury subtype. Successful completion of the proposed study will define the type and frequency of acute MI events in a cohort representative of the US target prevention population. By first characterizing and quantifying the risk factor profile, we expect the findings of this project to enable development of more specific individual patient risk prediction and effective tailoring of prevention efforts (precision medicine). Such knowledge will result in the evaluation of more judicious application of current therapies—e.g., limiting aggressive anti-thrombotic therapy for those at greatest risk for Type 1 versus Type 2 MI to maximize benefit and limit risk while more efficiently utilizing healthcare resources. Furthermore, identification of new risk factors will support exploration of novel therapeutic avenues that specifically target individual myocardial injury subtypes.