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）： 心脏病是美国死亡的主要原因，2010年每四例死亡中就有一例死于心脏病，每年在医疗保健、药物治疗和生产力损失方面花费超过3000亿美元。心力衰竭（HF）是一种由心脏病引起的临床综合征，其特征在于运动后症状恶化，如呼吸困难和疲劳，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。虽然有许多因素可能导致这种损害，但疾病相关的循环内皮素-1（ET-1）增加可能是HF运动不耐受后遗症的重要因素。因此，本康复研究小型项目（SPiRE）提案的总体目的是探索ET-1对HF患者慢性血管收缩的作用，并检查抑制该途径是否可以改善HF退伍军人的血管舒张能力，从而改善运动耐量。具体目标1将决定直接 血管内皮素-1（ET-1）对HF和年龄匹配对照组骨骼肌血管收缩的影响。将进行ETA亚型受体的动脉内输注，以在休息和运动期间快速探测ET-1通路中的疾病相关变化。据推测，ET-1介导的血管收缩将在HF相比，在休息时，使ETA受体阻滞剂将增加HF患者的血流量比年龄匹配的对照更大的程度。在运动过程中，我们预计，抑制ETA受体将增加骨骼肌血流量在HF患者相比，年龄匹配的控制，导致改善运动耐量和减少骨骼肌疲劳，在这个病人群体。具体目标2将确定血管内皮素-1（ET-1）对HF和年龄匹配对照组交感神经血管收缩的增强作用。在休息时，我们假设输注拟交感神经药物（去甲肾上腺素，NE）将产生更大的血管收缩HF患者相比，年龄匹配的对照，证明了α-肾上腺素能受体的超敏反应。抑制ETA受体将降低HF患者NE介导的血管收缩对年龄匹配对照的“敏感性”，确定ET-1是HF中α肾上腺素能超敏反应的贡献者。在运动过程中，预计HF患者NE介导的血管收缩将大于年龄匹配的对照组。抑制ETA受体将减少运动期间NE介导的血管收缩。这将增加骨骼肌血流量，从而改善HF患者的运动耐量并减少骨骼肌疲劳。我们预计，ET-1抑制的研究结果可以为我们理解HF中骨骼肌血流调节和运动耐量提供一个“缺失的环节”，最终提高该队列的生活质量。