The Association of Metabolic Disease and Pulmonary Hypertension

代谢疾病与肺动脉高压的关联

• 批准号: 9383518
• 负责人: Jennifer E Ho
• 金额: $ 57.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383518
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenosine Monophosphate; Adult; Affect; Animal Model; Automobile Driving; Biology; Biometry; Blood Vessels; Blood capillaries; Cardiac Catheterization Procedures; Cardiac Output; Cardiopulmonary; Cardiovascular Diseases; Defect; Development; Diabetes Mellitus; Disease; Double-Blind Method; Dyspnea; Endocrinology; Ergometry; Exercise; Exercise Physiology; Exercise stress test; Exertion; Exhibits; Experimental Models; Foundations; Functional disorder; Future; Heart failure; Human; Individual; Inflammation; Insulin; Insulin Resistance; Intervention; Intervention Studies; Intervention Trial; Investigation; Laboratories; Lead; Lung; Measurement; Mediating; Medical; Metabolic; Metabolic Diseases; Metformin; Molecular; Monitor; Morbidity - disease rate; NOS3 gene; Nitric Oxide Synthase; Non obese; Obesity; Obesity associated cardiovascular disease; Overweight; Oxidative Stress; Participant; Pathway interactions; Patients; Phenotype; Phosphorylation; Placebo Control; Placebos; Population; Positioning Attribute; Preventive; Prospective Studies; Protein Kinase; Protocols documentation; Pulmonary Capillary Wedge Pressure; Pulmonary Circulation; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary artery structure; Randomized; Research; Research Personnel; Rest; Risk; Role; Signal Transduction; Techniques; Testing; Therapeutic; Time; Vascular Diseases; Vascular remodeling; Vasodilation; adipokines; capillary; cardiovascular risk factor; cohort; disorder prevention; endothelial dysfunction; experience; hemodynamics; human subject; improved; insight; insulin signaling; metabolic phenotype; mortality; multidisciplinary; non-diabetic; novel; patient oriented; population based; post intervention; pre-clinical; pressure; public health relevance; pulmonary artery endothelial cell; response; translational study

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.

项目概要/摘要 肥胖是一项紧迫的医疗需求：它影响着美国三分之一的成年人，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，多种与肥胖相关的途径导致 肺动脉高压 (PH)，包括胰岛素抵抗、炎症、氧化应激和脂肪因子 发信号。很少有研究探讨人类代谢功能障碍与 PH 值之间的关系。我们 假设肥胖相关代谢疾病导致肺血管功能障碍，并可能代表 向心力衰竭转变的早期表型。人们认识到代谢疾病会导致内皮细胞 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 PH 的病理学。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 名非糖尿病肥胖者进行研究 劳力性呼吸困难。为了进一步了解肥胖相关 PH 的潜在机制，我们将追求 三个相关的研究方向：在目标 1 中，我们将研究代谢疾病与 人类受试者的肺动脉内皮细胞（PAEC）表型与肺血流动力学。使用 这是一种在右心导管插入术时分离新鲜人类 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）和单磷酸腺苷激活的蛋白激酶激活。在目标 2 中，我们将研究 代谢疾病中心肺运动测试的动态肺血管反应。肺部 将在休息时和自行车测力运动测试期间精确表征血管功能 同时血流动力学监测以评估多点肺动脉压力-心脏 输出关系以及 PH 的毛细血管前和毛细管后成分。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对肺血管功能的影响 肥胖个体的 PAEC 表型。该提案利用了独特的多学科合作团队 拥有心血管和代谢疾病、内皮生物学、PH、运动生理学方面的专业知识， 内分泌学和生物统计学。这些研究有可能提供重要的见解 代谢疾病中PH的驱动机制，将为未来针对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。