The Association of Metabolic Disease and Pulmonary Hypertension

项目总结/摘要 肥胖是一个迫切的医疗需求：它影响了美国三分之一的成年人，超过80%的人患有肥胖症。 糖尿病患者超重或肥胖。在动物模型中，多种肥胖相关途径导致 肺动脉高压（PH），包括胰岛素抵抗、炎症、氧化应激和脂肪因子 信号很少有研究检查了人类代谢功能障碍和PH的关联。我们 假设肥胖相关的代谢疾病导致肺血管功能障碍，并可能代表 心力衰竭转变的早期表型人们认识到，代谢性疾病导致内皮细胞 功能障碍;当局限于肺循环时，肺内皮功能障碍是一个不可或缺的驱动因素， 我们假设代谢性疾病可能导致肺动脉内皮细胞 细胞（PAEC）功能障碍作为PH的驱动因素。我们建议研究250名肥胖的非糖尿病个体， 劳力性呼吸困难为了进一步了解肥胖相关PH的潜在机制，我们将继续研究 三条相关的研究路线：在目标1中，我们将研究代谢性疾病与 肺动脉内皮细胞（PAEC）表型与人类受试者的肺血流动力学。使用 在右心导管插入术时分离新鲜人PAEC的新技术，我们将分析PAEC 表型包括内皮胰岛素信号传导（胰岛素介导的内皮一氧化氮合酶 磷酸化）和腺苷一磷酸活化的蛋白激酶活化。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踏车测力运动试验期间精确表征， 同步血流动力学监测，以评估多点肺动脉压-心脏 输出关系和前和后毛细血管成分的PH值。在目标3中，我们将进行随机 干预研究，检查二甲双胍与安慰剂相比对肺血管功能的影响， 肥胖个体中的PAEC表型。该提案利用了一个独特的多学科合作者团队 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。这些研究有可能提供重要的见解， 代谢性疾病中驱动PH的机制，并将为未来的疾病研究奠定基础 预防和最佳治疗肥胖相关的心血管疾病。

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.