Cardiac Energy Metabolism in Heart Failure

该计划项目资助解决了心力衰竭（HF）病理生理学的代谢机制，旨在确定预防和治疗HF的新代谢方法。HF中代谢功能障碍的后果知之甚少，但有强有力的证据表明能量代谢可影响收缩功能和进行性左心室重构。该转化研究项目使用复杂的HF动物模型来评估将心脏代谢的各个方面与临床相关结果联系起来的新机制。本申请将调查有关HF的病理生理学的基本问题，以及操纵能量代谢对心脏功能和HF进展的影响。该计划项目由四个项目组成：项目1：“大量营养素摄入对心力衰竭的影响”。将研究膳食脂肪、蛋白质和碳水化合物组成对HF进展的影响。项目2：“心率控制、心肌能量学和心力衰竭进展”。本研究将探讨心率在心力衰竭患者心脏能量异常、左室扩张和功能障碍进展中的作用。项目3：“心力衰竭中的底物选择和氧化应激”。将探讨HF中能量底物代谢改变与氧化应激之间的因果关系。项目4：“心力衰竭中的线粒体功能障碍”。本项目研究心衰患者心脏和骨骼肌线粒体氧化磷酸化减少的分子机制。此外，将有4个核心（管理、大型动物/组织学、代谢和线粒体/质谱）。

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).