PROJECT SUMMARY/ABSTRACT Cardiogenic shock (CS) is a highly morbid condition (50% mortality) that occurs in 160,000 Americans each year, often as a complication of acute myocardial infarction. The use of veno-arterial extracorporeal membrane oxygenation (VA ECMO) is a promising therapy that can provide full cardiopulmonary support to these patients, enabling survival. VA ECMO may also paradoxically cause harm to the failing heart by flowing 5+ liters per minute of blood retrograde up the aorta against the normal flow of blood out of the heart. The optimal way to manage patients on VA ECMO for CS is not yet known. The addition of a second device to unload or decompress the left ventricle of the heart, such as an intra-aortic balloon pump (IABP), has been shown in observational studies to improve survival these patients. Future mortality trials are necessary to confirm this finding, but prior to a mortality trial, the physiologic pathway whereby LV unloading could mediate this survival benefit needs to be determined—as this is unknown. Preliminary data suggest that LV unloading causes multiple physiologic effects, including improvements in cardiopulmonary congestion, acute cardiovascular function, and possibly durable myocardial recovery. These findings have direct implications on the clinical use of LV unloading and on future trial design, but are limited by sample size, selection bias and confounding. This R01 proposal will use randomization and high-volume centers to overcome these limitations and accomplish the following goals: (Aim 1) determine the physiologic effects of adding LV unloading to VA ECMO on cardiopulmonary congestion; (Aim 2) determine the effects of adding LV unloading to VA ECMO on acute cardiovascular function; (Exploratory Aim 3) determine whether adding LV unloading to VA ECMO improves biomarkers predictive of durable myocardial recovery. These data will define the physiologic effect of LV unloading on cardiopulmonary congestion, cardiovascular function and biomarkers of long-term recovery, directly informing optimal design for a mortality outcome trial of LV unloading during VA ECMO for CS. This is an application for a R01 award for Dr. Joseph Tonna, an emergency medicine trained intensivist at the University of Utah, who was recently promoted to Associate Professor and awarded Tenure. Dr. Tonna is a young investigator in his last year of a NIH NHLBI Career Development Award (1K23HL141596) who is establishing himself as a clinical trialist in the application and validation of rescue therapies such as ECMO. This R01 award uses pragmatic outcomes and an innovative and rigorous design to mechanistically answer the question of how LV unloading works; the results will define the physiologic pathways by which LV unloading affects the observed outcome differences from observational studies. To achieve these goals, Dr. Tonna has assembled a diverse and complementary team comprising experts in critical care, cardiogenic shock, myoca...