PROJECT SUMMARY/ABSTRACT: Acute myocardial infarction (AMI), a major cause of cardiovascular disability and death in the US, can be triggered by environmental exposures like heat, cold, and fine particulate air pollution (PM2.5). However, less is known about whether temperature variability, elevated temperature-humidity metrics, or ground-level ozone exposures could also trigger AMI, especially in young (aged 18-55 years) and older (aged ≥75 years) adults. These exposures take on increasing importance in the context of climate change. Moreover, it remains unclear whether women, persons of low socioeconomic status (SES), people with pre-existing chronic conditions, or users of certain medications have elevated vulnerability to heat-related AMI risk. Furthermore, evidence regarding whether co-exposures to extreme heat and air pollution interactively trigger AMI remains largely lacking. The overall objectives in this application are to (i) evaluate the effects of extreme heat and air pollution on AMI; and (ii) identify potential effect modification by sex, SES, medical history, and air pollution on the association between exposure to extreme heat and AMI risk. To achieve these objectives, we will use two unique US nationwide multicenter prospective observational cohort studies: VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) and SILVER-AMI (Comprehensive Evaluation of Risk Factors in Older Patients With Acute Myocardial Infarction). We will link patient-level medical record and interview data with highly spatiotemporally resolved estimates of ambient air temperature and air pollution predicted from satellite- based ensemble models and apply time-stratified case-crossover designs coupled with state-of-the-art distributed lag nonlinear models. Specifically, we aim to: (1) assess the association of AMI occurrence with short- term exposure to extreme heat, heat waves, temperature variability (both within and between days), and temperature-humidity metrics (i.e., heat index, humidex, and wet bulb temperature) and examine its sex and socioeconomic disparities; (2) determine whether medical history (pre-existing chronic conditions and medication use) modifies the association between extreme heat and risk of AMI occurrence; and (3) estimate the association of short-term co-exposure to extreme heat and air pollution (PM2.5 or ozone) with risk of AMI occurrence. The proposed research is significant because it is expected to provide strong and actionable scientific evidence on the roles of exposure to extreme heat and air pollution in AMI risk and on the roles of sex, SES, pre-existing conditions, medication intake, and air pollution in contributing to population vulnerability to heat-related AMI, thus greatly aiding clinicians, policymakers, and stakeholders to more effectively prevent adverse impacts of extreme heat and air pollution in relation to AMI risk, especially under a warming climate.