This Program Project Grant addresses the metabolic mechanisms underlying the pathophysiology of heart failure (HF), and aims to identify novel metabolic approaches to prevent and treat HF. The consequences of metabolic dysfunction in HF are poorly understood, but there is strong evidence that energy metabolism can effect contractile function and progressive left ventricular remodeling. This translational research project uses sophisticated animal models of HF to evaluate novel mechanisms that link various aspects of cardiac metabolism to clinically relevant outcomes. This application will investigate fundamental questions about the pathophysiology of HF, and the effects of manipulating energy metabolism on cardiac function and HF progression. This Program Project is composed of four projects: Project 1: Impact of Macronutrient Intake in Heart Failure. The effects of dietary fat, protein and carbohydrate composition on progression of HF will be investigated. Project 2: Heart Rate Control, Myocardial Energetics and Progression of Heart Failure. This project will dissect the role of heart rate in abnormalities of cardiac energetics and progression of LV dilation and dysfunction in HF. Project 3: Substrate Selection and Oxidative Stress in Heart Failure. Causal relationships will be explored between altered energy substrate metabolism and oxidative stress in HF. Project 4: Mitochondrial Dysfunction in Heart Failure. This project investigates the molecular mechanisms for the decrease in oxidative phosphorylation found in heart and skeletal muscle mitochondria in HF. In addition, there will be four Cores (Administrative, Large Animal/Histology, Metabolism, and Mitochondria/Mass Spec).