ABSTRACT / PROJECT SUMMARY Sepsis is a life-threatening condition diagnosed when dysfunction of organs results from severe infection. Sepsis affects approximately 1 million patients in the United States each year. About one-half of patients with sepsis have evidence of injury to the heart muscle called ‘myocardial injury’. Multiple pathways can lead to myocardial injury during sepsis. Even though patients with myocardial injury during sepsis have worse outcomes, there is currently little information to inform the best approach to evaluate these patients, to inform the likely pathways leading to myocardial injury in individual patients, or to guide the selection of optimal treatments. We propose the “Informing best practices for evaluation and treatment of myocardial injury during sepsis” study to provide clinically actionable information to benchmark and guide the care of patients with myocardial injury in sepsis. We will use existing longitudinal electronic health record data from two large integrated healthcare systems in the United States to efficiently determine the patterns of testing and treatment and the factors that predict the patients most likely to respond to treatments for pathways involving coronary artery disease. We will also assess the effectiveness of commonly used blood thinners for myocardial injury in sepsis. We have assembled a team with a record of collaboration and expertise in the use of electronic health record data to study sepsis outcomes, mechanisms and biomarkers of myocardial injury, and observational research methodology. Results from our proposal will inform current diagnostic and therapeutic strategies and guide the design and conduct of future randomized trials investigating optimal clinical pathways for patients with myocardial injury in sepsis.