Project Summary/Abstract Sepsis results when the host response to infection—comprising both immune and stress responses—leads to organ dysfunction, centrally cardiovascular dysfunction. The resulting sepsis-associated hypotension is lethal; how best to treat it is currently unknown. The two main treatments—intravenous fluid and catecholamine vasopressor infusions—both have toxicities, including direct effects on the heart, thus contributing to what is often termed septic cardiomyopathy. A large NIH/NHLBI-funded clinical trial, Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS), randomizes patients to competing strategies for treating sepsis-associated hypotension: liberal fluids (≥5L fluids before vasopressors) or early vasopressors (immediate vasopressors without additional fluids). CLOVERS represents an ideal laboratory for understanding the effects of management strategies on the evolution of septic cardiomyopathy, the relative contributions of right ventricular (RV) and left ventricular (LV) impairment to outcomes from septic cardiomyopathy, and the implications of baseline echocardiographic findings for the effect of treatments in certain groups of people. The Study of Treatment’s Echocardiographic Mechanisms (CLOVERS-STEM) is a prospective observational ancillary study within CLOVERS. Study subjects (N=210) will undergo speckle-tracked echocardiograms at enrollment and 24 hours later. Three integrated aims employ robust echocardiographic measures to assess the evolution of septic cardiomyopathy and differential susceptibility to treatment. Aim 1 assesses whether the early vasopressor treatment leads to LV impairment at 24 hours, as measured by global longitudinal strain. Aim 2 assesses whether the early vasopressor treatment leads to RV impairment, as measured by the ratio of RV to LV end-diastolic areas and RV free wall longitudinal strain. These two aims will also explore the contributions of LV and RV impairment to clinical endpoints. Aim 3 uses a validated continuous surrogate outcome—the change in multiple organ dysfunction on day 3—to explore possible heterogeneity of treatment effect based on the baseline echocardiographic results. This project innovates in multiple respects to dramatically advance our understanding of a major cause of global morbidity and mortality.