The Association of Metabolic Disease and Pulmonary Hypertension

项目摘要/摘要 肥胖是一种紧迫的医疗需求：在美国，三分之一的成年人患有肥胖症，超过80%的人患有肥胖症 糖尿病是指超重或肥胖。在动物模型中，多条与肥胖相关的途径导致 肺动脉高压，包括胰岛素抵抗、炎症、氧化应激和脂肪因子 发信号。很少有研究研究人类代谢功能障碍与PH值之间的关系。我们 假设肥胖相关的代谢性疾病导致肺血管功能障碍，并可能代表 向心力衰竭过渡的早期表型。人们认识到代谢性疾病会导致内皮细胞 功能障碍；当局限于肺循环时，肺内皮细胞功能障碍是一个不可或缺的驱动因素 关于PH的病理生物学。我们假设代谢性疾病可能导致肺动脉内皮细胞 细胞(PAEC)功能障碍是PH的驱动因素。我们建议对250名肥胖的非糖尿病患者进行研究 劳力性呼吸困难。为了进一步深入了解肥胖相关的PH的潜在机制，我们将继续 三条相关的调查路线：在目标1中，我们将调查代谢性疾病与 受试者肺动脉内皮细胞表型与肺血流动力学的关系。vbl.使用 一种在右心导管术时分离新鲜人肺血管内皮细胞的新技术，我们将对其进行轮廓分析 表型包括内皮胰岛素信号转导(胰岛素介导的内皮型一氧化氮合酶 磷酸化)和一磷酸腺苷激活的蛋白激酶的激活。在目标2中，我们将研究 代谢性疾病患者心肺运动试验的动态肺血管反应。肺 血管功能将在休息时和在自行车功率运动测试中进行精确表征 同步血流动力学监测评价多点肺动脉压-心脏 PH的产出关系和毛细管前、后成分。在目标3中，我们将进行一项随机的 干预研究：比较二甲双胍与安慰剂对肺血管功能和肺功能的影响 肥胖者的PAEC表型。这项计划利用了一个独特的多学科团队的协作者 在心血管和代谢疾病、内皮生物学、PH、运动生理学、 内分泌学和生物统计学。这些研究有可能为 代谢性疾病中PH的驱动机制，并将为未来专注于疾病的研究奠定基础 肥胖相关心血管疾病的预防和最佳治疗。

Project Summary/Abstract Obesity is a pressing medical need: it affects one-third of adults in the US, and more than 80% of people with diabetes mellitus are overweight or obese. In animal models, multiple obesity-related pathways lead to pulmonary hypertension (PH), including insulin resistance, inflammation, oxidative stress, and adipokine signaling. Few studies have examined the association of metabolic dysfunction and PH in humans. We postulate that obesity-related metabolic disease leads to pulmonary vascular dysfunction, and may represent an early phenotype in the transition to heart failure. It is recognized that metabolic disease leads to endothelial dysfunction; when localized to the pulmonary circulation, pulmonary endothelial dysfunction is an integral driver of the pathobiology of PH. We hypothesize that metabolic disease may lead to pulmonary artery endothelial cell (PAEC) dysfunction as a driver of PH. We propose to study 250 obese non-diabetic individuals with exertional dyspnea. To gain further insights into underlying mechanisms of obesity-related PH, we will pursue three related lines of investigation: In Aim 1, we will investigate the association of metabolic disease and pulmonary artery endothelial cell (PAEC) phenotype with pulmonary hemodynamics in human subjects. Using a novel technique to isolate fresh human PAECs at the time of right heart catheterization, we will profile PAEC phenotypes including endothelial insulin signaling (insulin-mediated endothelial nitric oxide synthase phosphorylation) and adenosine monophosphate-activated protein kinase activation. In Aim 2, we will study the dynamic pulmonary vascular responses to cardiopulmonary exercise testing in metabolic disease. Pulmonary vascular function will be precisely characterized at rest and during cycle ergometry exercise testing with simultaneous hemodynamic monitoring in order to evaluate multi-point pulmonary artery pressure-cardiac output relationships and pre- and post-capillary components of PH. In Aim 3, we will conduct a randomized intervention study, to examine the effect of metformin versus placebo on pulmonary vascular function and PAEC phenotype in obese individuals. This proposal leverages a unique multidisciplinary team of collaborators with expertise in cardiovascular and metabolic disease, endothelial biology, PH, exercise physiology, endocrinology, and biostatistics. These studies have the potential to provide important insights into mechanisms driving PH in metabolic disease, and will lay the foundation for future studies focused on disease prevention and optimal therapies in obesity-related cardiovascular disease.