Contribution of Endothelin-1 to Exercise Intolerance in HF

Endothelin-1 对心力衰竭运动不耐受的影响

• 批准号: 9001841
• 负责人: D. Walter Wray
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001841
• 关键词: Accounting; Adrenergic Agents; Aerobic Exercise; Affect; Age; American; Blood Circulation; Blood Vessels; Blood flow; Cardiac; Cardiac Output; Cardiac rehabilitation; Caring; Cause of Death; Cessation of life; Chemicals; Chronic; Clinical; Complex; Diagnosis; Disease; Dyspnea; Endothelin-1; Enrollment; Exercise; Exercise Tolerance; Exertion; Fatigue; Goals; Healthcare; Heart Diseases; Heart failure; Hospitals; Hypersensitivity; Impairment; Individual; Infusion procedures; Integration Host Factors; Intra-Arterial Infusions; Link; Mediating; Metabolic; Morbidity - disease rate; Muscle; Muscle Fatigue; Norepinephrine; Pathway interactions; Patients; Perfusion; Peripheral; Pharmaceutical Preparations; Play; Production; Productivity; Quality of life; Regulation; Rehabilitation Research; Rehabilitation therapy; Research Proposals; Rest; Role; Skeletal Muscle; Smooth Muscle Myocytes; Sympathetic Nervous System; Sympathomimetics; Symptoms; Syndrome; Training; United States; Vascular Diseases; Vasoconstrictor Agents; Vasodilator Agents; Ventricular Dysfunction; Veterans; Work; adrenergic; alpha-adrenergic receptor; cohort; cost; disability; functional disability; improved; innovation; lifetime risk; meetings; mortality; muscle form; outcome forecast; patient population; programs; public health relevance; receptor; response; shear stress; vascular inflammation; vasoconstriction

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in the United States, accounting for one in every four deaths in 2010 and costing over $300 billion annually in health care, medication, and lost productivity. Heart failure (HF), a clinical syndrome that develops as a consequence of heart disease, is characterized by the worsening of symptoms, such as dyspnea and fatigue, upon exertion, collectively defined as "exercise intolerance". Surprisingly, exercise intolerance does not correlate with the degree of cardiac contractile (ventricular) dysfunction, suggesting that changes in the peripheral circulation may be to blame for exercise intolerance in this cohort. Though there are a host of factors that may contribute to this impairment, disease-related increases in circulating endothelin-1 (ET-1) may be a significant factor in the sequalae of exercise intolerance in HF. Thus, the overall purpose of this Small Projects in Rehabilitation Research (SPiRE) proposal is to explore the contribution of ET-1 to chronic vasoconstriction in HF patients, and to examine whether inhibition of this pathway could improve vasodilatory ability, and thus exercise tolerance, in Veterans with HF. Specific Aim 1 will determine the direct effect of vascular endothelin-1 (ET-1) on skeletal muscle vasoconstriction in HF and age-matched controls. Intra-arterial infusion of the ETA subtype receptor will be undertaken to pharmacologically probe disease-related changes in the ET-1 pathway at rest and during exercise. It is hypothesized that ET-1-mediated vasoconstriction will be elevated in HF compared to controls at rest, such that ETA receptor blockade will augment blood flow in HF patients to a greater degree than age-matched controls. During exercise, we anticipate that inhibition of the ETA receptor will augment skeletal muscle blood flow in HF patients compared to age-matched controls, leading to improved exercise tolerance and reduced skeletal muscle fatigue in this patient group. Specific Aim 2 will determine the potentiating effect of vascular endothelin-1 (ET-1) on sympathetic vasoconstriction in HF and age-matched controls. At rest, we hypothesize that infusion of a sympathomimetic drug (norepinephrine, NE) will produce greater vasoconstriction in HF patients compared to age-matched controls, demonstrating a hypersensitivity of the alpha-adrenergic receptors. Inhibition of the ETA receptor will reduce "sensitivity" of NE-mediated vasoconstriction in HF patients towards that of age-matched controls, identifying ET-1 as a contributor to alpha adrenergic hypersensitivity in HF. During exercise, it is anticipated that NE-mediated vasoconstriction will be greater in HF patients compared to age-matched controls. Inhibition of the ETA receptor will reduce NE-mediated vasoconstriction during exercise. This will augment skeletal muscle blood flow, leading to improved exercise tolerance and reduced skeletal muscle fatigue in HF patients. We anticipate that findings from the proposed work with ET-1 inhibition could thus provide a "missing link" of information in our understanding of skeletal muscle blood flow regulation and exercise tolerance in HF, ultimately leading to enhanced quality of life in this cohort.

描述（由申请人提供）： 心脏病是美国的首要死因，2010 年，心脏病占死亡人数的四分之一，每年在医疗保健、药物治疗和生产力损失方面造成的损失超过 3000 亿美元。心力衰竭（HF）是一种由心脏病引起的临床综合征，其特征是运动时呼吸困难和疲劳等症状恶化，统称为“运动不耐受”。令人惊讶的是，运动不耐受与心脏收缩（心室）功能障碍的程度无关，这表明外周循环的变化可能是该队列中运动不耐受的原因。尽管有许多因素可能导致这种损害，但与疾病相关的循环内皮素-1 (ET-1) 增加可能是心力衰竭运动不耐受后遗症的一个重要因素。因此，这个康复研究小型项目（SPiRE）提案的总体目的是探索 ET-1 对心力衰竭患者慢性血管收缩的贡献，并检查抑制该通路是否可以提高血管舒张能力，从而提高运动耐量，患有心衰的退伍军人。具体目标 1 将决定直接 血管内皮素-1 (ET-1) 对心力衰竭和年龄匹配对照骨骼肌血管收缩的影响。将进行 ETA 亚型受体的动脉内输注，以药理学探讨静息和运动期间 ET-1 通路与疾病相关的变化。据推测，与休息时的对照组相比，心力衰竭时 ET-1 介导的血管收缩会增强，因此 ETA 受体阻断将比年龄匹配的对照组更大程度地增加心力衰竭患者的血流量。在运动过程中，我们预计，与年龄匹配的对照组相比，ETA 受体的抑制将增加心力衰竭患者的骨骼肌血流量，从而提高该患者组的运动耐量并减少骨骼肌疲劳。具体目标 2 将确定血管内皮素 1 (ET-1) 对 HF 和年龄匹配对照的交感血管收缩的增强作用。休息时，我们假设与年龄匹配的对照组相比，输注拟交感神经药物（去甲肾上腺素，NE）会在心力衰竭患者中产生更大的血管收缩，证明α-肾上腺素能受体的超敏性。抑制 ETA 受体将降低心力衰竭患者 NE 介导的血管收缩的“敏感性”，使其与年龄匹配的对照组相比，从而确定 ET-1 是心力衰竭中 α 肾上腺素能超敏反应的一个促成因素。在运动过程中，预计与年龄匹配的对照组相比，心力衰竭患者的 NE 介导的血管收缩会更大。抑制 ETA 受体将减少运动过程中 NE 介导的血管收缩。这将增加骨骼肌血流量，从而提高心力衰竭患者的运动耐量并减少骨骼肌疲劳。我们预计，拟议的 ET-1 抑制工作的结果可以为我们理解心力衰竭的骨骼肌血流调节和运动耐量提供一个“缺失的环节”信息，最终提高该人群的生活质量。