Lipid Deposition in the Right Ventricle in Pulmonary Arterial Hypertension

肺动脉高压右心室脂质沉积

基本信息

批准号：
9197665
负责人：
Anna R Hemnes
金额：
$ 51.5万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197665
关键词：
Affect Animal Model Apoptosis Autopsy CD36 Antigens CD36 gene Cardiac Cardiac Myocytes Cardiomyopathies Cause of Death Cell Culture Techniques Ceramides DNA Sequence Alteration Data Deposition Diagnosis Diet Disease Marker Enhancers Excision FDA approved Failure Fatty Acids Fatty acid glycerol esters Financial compensation Functional disorder Goals Grant Heart failure Human Human Rights Impairment Insulin Resistance Intervention Intracellular Accumulation of Lipids Lipids Magnetic Resonance Spectroscopy Measures Mediating Metabolic Metabolism Metformin Modeling Mus Muscle Cells Mutant Strains Mice Mutation Myocardial Myocardial dysfunction Myocardium Oils Patients Pharmacology Pulmonary Hypertension Pulmonary artery structure Regulator Genes Right Ventricular Dysfunction Right Ventricular Function Right Ventricular Hypertrophy Right ventricular structure Rodent Model Staining method Stains Stress Technology Testing Tissues Transgenic Organisms Translating Triglycerides Ventricular Ventricular Ejection Fractions Wild Type Mouse Work base bone morphogenic protein embryonic stem cell fatty acid oxidation fatty acid transport hemodynamics human disease improved lipid metabolism lipid transport mortality mouse model mutant promoter public health relevance pulmonary arterial hypertension receptor response thermozymocidin tool western diet

项目摘要

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.

描述（由申请人提供）：右心衰竭是肺动脉高压患者死亡率的主要原因，目前尚无逆转右心室功能障碍的疗法。他人的工作和我们自己的初步数据表明，新陈代谢的改变，包括脂肪酸氧化和脂质沉积的降低可能有助于人类肺动脉高压和与肺动脉高压相关的RV功能障碍的啮齿动脉功能障碍的右心室衰竭。我们已经确定脂肪酸氧化和脂质转运增加到心肌细胞是促进右心室脂质积累的机制。此外，在初步数据中，我们已经使用MR光谱法测量肺动脉高压患者的右心室中的脂质沉积，并且发现与对照组相比，甘油三酸酯百分比高10倍。基于这些初步数据，我们现在假设心肌细胞脂质沉积会促进肺动脉高压的RV衰竭。多种机制可能会导致右心肌脂质沉积，包括西方饮食，从而增加与脂肪酸氧化受损相关的脂质进口或遗传突变，从而导致脂肪酸代谢产物的积累，我们提出了两个特定目的，以研究导致脂质积累的机制以及对脂质积累的效果以及对右心型右心脏效果的影响。我们的第三个特殊目标将在对二甲双胍的代谢疗法的试验中转化为人类，并测试通过心脏磁共振光谱测量的脂肪酸氧化增强剂对右心室脂质的影响。我们将使用细胞培养，啮齿动物模型和人类研究来研究发生脂质沉积的机制，脂质积累的功能后果以及降低脂质积累的代谢干预措施是否会改善啮齿动物模型和人类疾病的右心室功能。这些研究的长期目标是开发有效的代谢疗法，以用于肺动脉高压症中正确的心力衰竭。