Cardiac Energy Metabolism in Heart Failure

描述(申请人提供)：衰竭的心脏不能有效地将食物燃烧产生的化学能转化为收缩功。代谢功能障碍在心力衰竭中的后果知之甚少，但有强有力的证据表明，能量代谢受损会导致收缩功能障碍和进行性左室重构，这是心力衰竭状态的特征。该计划项目的主题是识别心力衰竭时发生的心肌能量底物代谢异常，以及这些异常对左心功能和重塑的影响，以及疾病的进展。 该方案由四个项目和三个核心设施组成。这些项目包括： 项目1：“心力衰竭中的代谢调节” 项目2：“心力衰竭进展过程中的脂肪酸氧化” 项目3：“心力衰竭中的代谢表型转换” 项目4：“心力衰竭中的线粒体功能障碍” 所有四个项目的目标都是确定在心力衰竭过程中发生的代谢变化的调节机制，并阐明这些代谢变化对收缩功能和心力衰竭进展的影响。所有项目都解决了共同的问题，涉及导致心力衰竭代谢表型变化的机制，以及这些变化对心功能和疾病进展的影响。所有研究将在成熟的大型心力衰竭动物模型中进行，并将使用对底物代谢的短期和长期操作来阐明能量代谢在心力衰竭病理生理学中的确切后果。该计划的主要优势是结合了对心脏功能和新陈代谢的体内研究，以及对心脏表型和能量底物代谢的生化调节的详细评估。

DESCRIPTION (provided by applicant): The failing heart is unable to transfer effectively the chemical energy from the combustion of foodstuffs to contractile work. The consequences of metabolic dysfunction in heart failure are poorly understood, but there is strong evidence that impaired energy metabolism contributes to contractile dysfunction and to the progressive left ventricular remodeling that are characteristic of the heart failure state. The theme of this Program Project is the identification of abnormalities of myocardial energy substrate metabolism that occur with heart failure, and the effects of these abnormalities on left ventricular function and remodeling, and the progression of the disease. This Program consists of four projects and three core facilities. The projects are: Project 1: "Metabolic Regulation in Heart Failure" Project 2: "Fatty Acid Oxidation in Heart Failure Progression" Project 3: "Metabolic Phenotype Switch in Heart Failure" Project 4: "Mitochondrial Dysfunction in Heart Failure" The goal of all four projects is to identify the mechanisms regulating the metabolic changes that occur over the course of heart failure, and to elucidate the effects of these metabolic changes on contractile function and the progression of heart failure. Common questions are addressed by all projects regarding the mechanisms responsible for the alterations in metabolic phenotype in heart failure, and the consequences of these changes on cardiac function and progression of the disease. All studies will be performed in well-established large animal models of heart failure, and short and long-term manipulations of substrate metabolism will be used to elucidate the precise consequences of energy metabolism in the pathophysiology of heart failure. The major strength of this Program is the combination of in vivo studies on cardiac function and metabolism with the detailed assessment of biochemical regulators of cardiac phenotype and energy substrate metabolism.