Lipid Deposition in the Right Ventricle in Pulmonary Arterial Hypertension

描述(申请人提供)：右心衰竭是肺动脉高压患者死亡的主要原因，目前还没有逆转右心功能障碍的治疗方法。Other的工作和我们自己的初步数据表明，代谢的改变，包括脂肪酸氧化和脂肪沉积的减少，可能导致人类肺动脉高压和与肺动脉高压相关的右室功能障碍的啮齿动物模型的右室衰竭。我们发现脂肪酸氧化和增加向心肌细胞的脂类转运是促进右室脂类蓄积的机制。此外，在初步数据中，我们使用磁共振波谱测量了一名肺动脉高压患者右室的脂肪沉积，发现甘油三酯百分比比对照组高10倍。基于这些初步数据，我们现在假设，心肌细胞脂质沉积促进了肺动脉高压患者的RV衰竭。多种机制可能导致右室心肌细胞脂质沉积，包括西方饮食导致脂质输入增加或与脂肪酸氧化受损相关的基因突变，从而导致脂肪酸代谢物积累，我们提出两个特定的目标来研究导致脂质堆积的机制和沉积对右室功能不全的影响。我们的第三个特定目标是将这些发现翻译到人类身上，用于二甲双胍治疗右心衰竭的代谢治疗试验，并测试这种脂肪酸氧化增强剂对心脏磁共振波谱测量的右室脂肪的影响。我们将利用细胞培养、啮齿动物模型和人类研究来研究脂肪沉积发生的机制，脂肪堆积的功能后果，以及减少脂肪堆积的代谢干预是否会改善啮齿动物模型和人类疾病的右室功能。这些研究的长期目标是开发有效的代谢疗法来治疗肺动脉高压所致的右心衰竭。

DESCRIPTION (provided by applicant): Right ventricular failure is the primary cause of mortality in patients with pulmonary arterial hypertension and there currently are no therapies to reverse right ventricular dysfunction. Other's work and our own preliminary data have suggested altered metabolism including decreased fatty acid oxidation and lipid deposition may contribute to right ventricular failure in both human pulmonary arterial hypertension and in rodent models of RV dysfunction associated with pulmonary arterial hypertension. We have identified both fatty acid oxidation and increased lipid transport into cardiomyocytes as mechanisms that promote right ventricular lipid accumulation. Moreover, in preliminary data we have used MR spectroscopy to measure lipid deposition in the right ventricle of a patient with pulmonary arterial hypertension and found 10 fold higher percent triglyceride compared with controls. Based on these preliminary data, we now hypothesize that cardiomyocyte lipid deposition promotes RV failure in pulmonary arterial hypertension. Multiple mechanisms may result in right ventricular myocyte lipid deposition including Western diet resulting in increased lipid import or genetic mutations associated with impaired fatty acid oxidation with resultant accumulation of fatty acid metabolites and we propose two specific aims to study the mechanisms leading to lipid accumulation and the effect of deposition on right ventricular dysfunction. Our third specifi aim will translate these findings to humans in a trial of metabolic therapy for right ventricular failure with metformin and test the effect of this fatty acid oxidation enhancer on right ventriculr lipid measured by cardiac magnetic resonance spectroscopy. We will use cell culture, rodent model and human studies to study the mechanisms by which lipid deposition occurs, the functional consequences of lipid accumulation and if metabolic interventions to decrease lipid accumulation will improve right ventricular function in both rodent models and human disease. The long-term goal of these studies is to develop effective metabolic therapy for right heart failure in pulmonary arterial hypertension.