The cardiac influence of chronic ethanol (EtOH) consumption in humans is dictated by the frequency of ethanol ingestion. Whereas moderate consumption (i.e. 1-2 alcoholic drinks/day) imparts a cardiac benefit to patients by reducing adverse cardiovascular event (ACE) occurrences, consumption below or beyond these moderate levels significantly increases the incidence of ACEs. Despite these observations, little is known regarding the functional impact of chronic EtOH consumption on post-myocardial infarct repair or the cellular mechanisms involved in this process. Thus, we investigated the post-AMI functional consequences of chronic ethanol consumption in mice. Mice received chronic ethanol via the Lieber-DeCarli paradigm (i.e. 0%, 1% (moderate) or 5% (high) ethanol v/v) in an isocaloric fashion for 8 weeks. After 8 weeks, mice underwent a 60-minute ischemic/reperfusion injury and the subsequent assessment of their cardiac function for 4 weeks post-AMI. As early as two weeks post-AMI, mice fed the 1% EtOH displayed modest yet significant improvements in ejection fraction and systolic ventricular volumes as compared to control mice. Conversely, the 5% EtOH diet group displayed diminished ejection fraction and increases in both systolic chamber volume and infarct size. To explore the cellular basis of these observed functional changes, primary cardiac cell types (fibroblasts and endothelial cells) treated chronically (5 days) with ethanol in vitro (i.e. 0%, 0.1% (moderate) or 0.5% (high) ethanol v/v) displayed robust changes in their epigenetic histone-modification profiles indicating a high likelihood for changes in cell specific gene expression. In addition, conditioned media from ethanol treated primary cardiac fibroblasts (PCFBs) altered the tube forming capacity of endothelial cells in a matrigel tube-formation assay in a dose pattern akin to what was observed in vivo. This data suggests that chronic ethanol directly invokes epigenetic changes in PCFBs that can modify their contribution to cardiac repair processes following AMI. Lastly, we are actively investigating whether ethanol-induced changes to endothelial cell epigenetic patterns alter the cells responses in the face of an ischemic insult.