Cardiac Energy Metabolism in Heart Failure

描述（由申请人提供）：尽管艾滋病流行，但在南非，心血管疾病（CVD）是相对年轻人（35 - 44岁）的主要死亡原因。有人认为，CVD发病率的急剧上升可能是由于城市化加速和相关的生活方式改变（例如脂肪消耗增加和久坐不动的生活方式）。这些令人担忧的预测加上南非在CVD领域的研究能力有限，导致Essop博士的研究团队专注于高脂肪饮食对CVD发病机制中心脏代谢改变的作用。特别是，该项目的重点是确定心脏脂肪酸代谢升高是否有助于心力衰竭的发作。一个新兴的假说表明，心脏代谢的扰动在心脏肥大的发展和向心力衰竭的转变中起着不可或缺的作用。为了支持这些概念，最近的一项研究表明，在心力衰竭患者中，血浆游离脂肪酸（FFA）水平升高与心脏富集解偶联蛋白（UCPs）（特别是UCP2和UCP3）的表达呈正相关。鉴于此，我们假设心力衰竭是肾上腺素能亢进状态，衰竭心脏的收缩功能障碍是由于FA利用率升高和FA诱导的线粒体氧化磷酸化解偶联导致的心脏效率降低。为了检验这一假设，将采用Essop博士开发的缺氧诱导的适应性右心室肥大的良好表征模型。本FIRCA基金的具体目的是：1）评估增加心肌线粒体的影响!脂肪酸氧化（高脂喂养诱导）对右心室心输出量和线粒体效率）ATP生成的影响，以及2）确定是否对心输出量和线粒体产生不利影响!能量生产由于增加线粒体!脂肪酸氧化可以通过施用抑制心脏线粒体的特定治疗剂来逆转! FA摄取

DESCRIPTION (provided by applicant): Despite the AIDS epidemic, in South Africa cardiovascular disease (CVD) is the main cause of death in relatively young people (35-44 years). It has been suggested that the dramatic surge in CVD rates may be due to accelerated urbanization and associated lifestyle changes (e.g. increased fat consumption and sedentary lifestyle). These alarming projections together with the limited research capacity within South Africa in the CVD field, have led to Dr. Essop's research team to focus on the role of a high fat diet on altered cardiac metabolism in the pathogenesis of CVD. In particular, the focus of this project is to ascertain whether elevated cardiac fatty acid metabolism contributes to the onset of heart failure. An emerging hypothesis suggests that perturbations in cardiac metabolism plays an integral role in the development of cardiac hypertrophy and the transition to heart failure. In support of these concepts, a recent study demonstrated a positive correlation between increased plasma free fatty acid (FFA) levels and the expression of cardiac-enriched uncoupling proteins (UCPs), specifically UCP2 and UCP3, in heart failure patients. In light of this, we hypothesize that heart failure is a hyperadrenergic state and that contractile dysfunction in failing hearts is due to reduced cardiac efficiency as a consequence of elevated FA utilization and FA-induced uncoupling of mitochondria) oxidative phosphorylation. To test this hypothesis, a well- characterized hypoxia-induced model of adaptive right ventricular hypertrophy developed by Dr. Essop will be employed. Specific Aims of this FIRCA Grant are to: 1) Assess effects of increased cardiac mitochondria! fatty acid oxidation (induced by high fat feeding) on right ventricular cardiac output and efficiency of mitochondria) ATP production, and 2) Determine whether detrimental effects on cardiac output and mitochondria! energy production as a result of increased mitochondria! fatty acid oxidation can be reversed by administration of specific therapeutic agents inhibiting cardiac mitochondria! FA uptake