Clinical and Metabolic Signature of Recovered Myocardium in Human Heart Failure Summary: Remarkable improvements in myocardial structure and function have been reported in some advanced heart failure (HF) patients undergoing “mechanical unloading” induced by left ventricular assist devices (LVAD). Unlike other HF therapies, which have also been associated with significant myocardial improvement, this tractable and specific LVAD population provides us access to pre-treatment myocardial tissue from both responders and non- responders which has enabled us to start probing the “signature” of myocardium that has the potential to improve. Our central hypothesis is that refining this “signature” will lead to a rational therapeutic approach in severe HF and will reveal broader recovery principles applicable to all stages and severity of HF. Achieving and defining “response” in LVAD patients requires a battery of diagnostic and therapeutic protocols and, as shown in the real world of advanced HF multicenter registries, this is challenging. Thus, there is a critical need for a selection process that can reliably predict who will and who will not “respond” to LVAD therapy. This program will also enable us to develop such a predictive model in addition to our studies of the mechanisms driving myocardial recovery. First we will provide a clinically relevant ‘signature’ of failing hearts with the potential for recovery. Following a derivation- validation approach we will develop a myocardial recovery score using myocardial structural and/ or functional parameters together with clinical characteristics. This score will create a precise algorithm for selection of patients likely to recover prior to LVAD intervention, enrich the criteria for device explantation and sustained recovery following LVAD intervention and likely increase the real world incidence and sustainability of LVAD enabled recovery. Second, we hypothesized that specific metabolic adaptations drive myocardial recovery. Our preliminary data after examining myocardial tissue from normal donors and LVAD patients suggests a post- LVAD mismatch in glycolytic versus mitochondrial intermediates that might indicate increased flux through the cardioprotective pentose phosphate pathway. We have developed methodology and will employ novel and powerful in vivo metabolic flux studies using stable isotopes, mitochondrial respiratory measurements and additional metabolic assays to test this hypothesis. This project offers a rare opportunity to closely integrate clinical function, structure and in vivo mechanistic studies in human HF and recovery. The physiological insights derived are providing clinical characteristics and biomarkers that will impact our practice in advanced HF patients. They are also revealing novel biological insights that inform both our clinical and basic science understanding of myocardial recovery applicable to all stages and severity of HF.