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: 8634400
• 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/8634400
• 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）： 心脏病是美国死亡的主要原因，在2010年每四人中每四人中有1次死亡，每年耗资超过3000亿美元的医疗保健，药物和生产力损失。心力衰竭（HF）是一种由于心脏病而发展的临床综合征，其特征是症状恶化，例如呼吸困难和疲劳，在劳累时统称为“运动不耐受”。出乎意料的是，运动不耐受与心脏收缩（心室）功能障碍的程度无关，这表明外周流通循环的变化可能是该队列中运动不耐受的责任。尽管有许多因素可能导致这种障碍，但与疾病相关的内皮素-1（ET-1）的增加可能是HF运动不耐受性的频段的重要因素。因此，这项小型项目在康复研究（SPIRE）提案中的总体目的是探索ET-1对HF患者慢性血管收缩的贡献，并检查对该途径的抑制是否可以提高血管舒张能力，从而在患有HF的退伍军人中行使耐受性。特定目标1将决定直接 血管内皮素-1（ET-1）对HF和年龄匹配对照中骨骼肌血管收缩的影响。 ETA亚型受体的动脉内输注将用于在休息和运动过程中与ET-1途径的药理探测有关的变化。假设与静止对照组相比，HF的ET-1介导的血管收缩将升高，因此ETA受体阻断将使HF患者的血液流量高于年龄匹配的对照。在运动过程中，我们预计与年龄匹配的对照相比，HF患者对ETA受体的抑制作用将增加骨骼肌血流，从而提高运动耐受性和该患者组的骨骼肌疲劳的降低。具体目标2将确定血管内皮素-1（ET-1）对HF和年龄匹配的对照中交感神经血管收缩的增强作用。在休息时，我们假设与年龄匹配的对照组相比，输注交感神经药（去甲肾上腺素，NE）将在HF患者中产生更大的血管收缩，这表明α-肾上腺素能受体过敏。 ETA受体的抑制作用将降低HF患者对年龄匹配对照的血管收缩的“敏感性”，从而将ET-1识别为HF中α肾上腺素能超敏的促进者。在运动过程中，与年龄匹配的对照相比，HF患者的NE介导的血管收缩将更大。抑制ETA受体将减少运动过程中NE介导的血管收缩。这将增加骨骼肌的血液流动，从而提高运动耐受性，并减少HF患者的骨骼肌疲劳。我们预计，从拟议的ET-1抑制作用中提出的发现，可以在我们对HF中骨骼肌肉血流调节和运动耐受性的理解中提供信息的“缺失联系”，最终导致该队列中的生活质量提高。