Autophagy in Myocardial Recovery and Remission

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ABSTRACT Therapeutic interventions that favorably impact the untoward natural history of heart failure (HF) either slow or reverse left ventricular (LV) remodeling. In some patients with HF with a reduced ejection fraction (HFrEF) reverse LV remodeling is associated with freedom from future clinical HF events (“myocardial recovery”), whereas in the great majority of patients the initial stabilization of LV structure/function is followed by progressive LV remodeling and untoward clinical outcomes (“myocardial remission”). Thus, although recovery of LV structure and function are associated with stabilization of the clinical course of HF, as well as reversal of many aspects of the HF phenotype, it is not associated with freedom from future HF events. Understanding the clinical and biological features of “compensated” HF patients, who have normalized or partially normalized LV structure and function, but remain vulnerable to hemodynamic/neurohormonal stress, represents a major unmet need in the field of heart failure. The long term goal of this research initiative is to delineate the mechanisms responsible for the functional instability of hearts that have undergone reverse LV remodeling with recovery of LV function, and to develop new therapies that will address this unmet clinical need. To explore the biological basis for the clinical phenomenon of “myocardial remission,” we have developed a clinically relevant pre-clinical model of “reversible heart failure” that combines moderate aortic constriction (TAC) and distal LAD ligation (MI), which are the major comorbidities that cause HFrEF in industrialized nations. To “reverse” the HF phenotype, the TAC + MI mice are hemodynamically unloaded by surgically removing the aortic constriction, resulting in the normalization of LV structure and function. Germane to the present proposal, when the de-banded TAC + MI mice (“HF-DB” mice) are exposed to a neurohormone stress, they develop increased LV hypertrophy and increased LV dysfunction, analogous to what is observed in HFrEF patients who develop functional instability following recovery of LV structure and function. Based on our preliminary observations that the autophagy-lysosome system is dysregulated during the development and recovery from HF, we prose to test the following three hypotheses: (1) autophagic flux is impaired during the development of HF and, although flux is relatively improved following hemodynamic unloading, flux remains “inefficient” (Aim1); (2) autophagic flux is required for effective reverse LV remodeling (Aim 2); and (3) insufficient autophagic flux is responsible, at least in part, for the functional instability that develops in reverse LV remodeled hearts that are exposed to neurohormonal stress (Aim 3). Specific Aims 1-3 will provide definitive information with respect to the potential role of autophagy in the recovery of LV structure and LV function following hemodynamic unloading, as well as the functional instability of reverse LV remodeling in a pathophysiologically relevant model of reversible HF.