Cardiac Energy Metabolism in Heart Failure

描述(申请人提供)：尽管艾滋病流行，但在南非，心血管疾病(CVD)是相对年轻的人(35-44岁)的主要死亡原因。有人提出，心血管疾病发病率的急剧上升可能是由于加速的城市化和相关的生活方式变化(例如，脂肪摄入量增加和久坐不动的生活方式)。这些令人担忧的预测，加上南非国内在心血管疾病领域有限的研究能力，导致埃索普博士的研究团队将重点放在高脂肪饮食在心血管疾病发病机制中心脏代谢变化的作用上。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生。一种新的假说表明，心脏代谢的紊乱在心肌肥厚的发展和向心力衰竭的过渡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，心力衰竭患者血浆游离脂肪酸(FFA)水平的升高与心脏富集解偶联蛋白(UCPs)的表达呈正相关，特别是UCP2和UCP3。有鉴于此，我们假设心力衰竭是一种高肾上腺素能状态，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所致。为了验证这一假设，将使用Essop博士开发的具有良好特征的低氧诱导的适应性右心室肥厚模型。FIRCA赠款的具体目的是：1)评估心肌线粒体增加的影响！脂肪酸氧化(由高脂饮食引起)对右室心输出量和线粒体效率的影响，以及2)是否对心输出量和线粒体产生不利影响！线粒体增加所产生的能量！脂肪酸氧化可以通过给予特定的治疗药物抑制心肌线粒体来逆转！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