Abnormal Vascular, Metabolic, and Neural Function During Exercise in Heart Failure with Preserved Ejection Fraction

射血分数保留的心力衰竭患者运动期间血管、代谢和神经功能异常

• 批准号: 9327726
• 负责人: Christopher M Hearon
• 金额: $ 5.67万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2020-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327726
• 关键词: Acetylene; Activities of Daily Living; Aerobic; Blood Vessels; Blood flow; Cardiac; Cardiac Output; Clinical; EFRAC; Educational Intervention; Exercise; Exercise Tolerance; Exercise stress test; Extensor; Failure; Functional disorder; Gases; Goals; Heart failure; Human; Impairment; Ischemia; Kinetics; Knee; Lung; Measurement; Measures; Mediating; Metabolic; Methodology; Morbidity - disease rate; Muscle; Muscle Contraction; Muscle function; Nervous system structure; Neurophysiology - biologic function; Outcome; Oxygen; Patients; Peripheral; Population; Production; Quality of life; Reflex action; Rest; Skeletal Muscle; Speed; Stress; Techniques; Testing; Training; Treatment Efficacy; Treatment Failure; United States; Vasoconstrictor Agents; Walking; Work; afferent nerve; design; exercise capacity; exercise intervention; exercise intolerance; exercise training; experience; hemodynamics; improved; insight; mortality; muscle form; novel; patient population; peroneal nerve; persistent symptom; relating to nervous system; response; targeted treatment; uptake; vascular abnormality

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of the heart failure population in the United States, and the primary chronic symptom experienced by these patients is severe exercise intolerance. Exercise intolerance is quantified as reduced peak oxygen uptake during exercise, and to date, therapies targeting central cardiac limitations have invariably failed to improve peak VO2, quality of life, or survival in HFpEF. Emerging evidence from our lab suggests reduced skeletal muscle oxidative capacity may contribute to exercise intolerance in HFpEF patients. However, the mechanisms responsible for peripheral metabolic inefficiency remain unclear. Reduced blood flow (oxygen delivery), and slowed oxygen uptake kinetics (O2 utilization), may be primary contributors to reduced skeletal muscle oxidative capacity and result in the production of metabolites known to activate muscle afferent nerves and stimulate reflex increases in muscle sympathetic (vasoconstrictor) nervous system activity (MSNA). Elevated MSNA can in turn, result in further impairments in hemodynamic control during exercise. However, to date there have been no studies specifically investigating the contribution of peripheral vascular, metabolic, and neural impairments to reduced exercise capacity in HFpEF. The first goal of this proposal will be to identify impairments in peripheral vascular, metabolic, and sympathetic neural function in HFpEF. To accomplish this, we will measure the dynamic blood flow response (oxygen delivery) and oxygen uptake kinetics (oxygen utilization) during knee extensor (KE) exercise, as well as MSNA during exercise to characterize the contribution of peripheral abnormalities to exercise intolerance in HFpEF. The second goal will be to utilize small muscle mass KE training, specifically targeting these peripheral skeletal muscle deficiencies, to improve aerobic capacity and exercise tolerance in HFpEF. We will assess vascular, metabolic, and neural function before and after completing 8 weeks of single KE exercise training, in conjunction with measures of maximal aerobic capacity and functional capacity. The isolated KE training approach will minimize the central hemodynamic stress of whole body exercise, while simultaneously targeting skeletal muscle function to improve exercise tolerance in HFpEF. Importantly, this proposal will advance our understanding of the basic pathophysiology of exercise intolerance in HFpEF. Considering that vascular function, oxidative capacity, and a MSNA are independent predictors of mortality in heart failure patients, strategies aimed at improving these functional markers may have important implications for the treatment of HFpEF, a condition for which there are currently no known therapies to reduce morbidity and mortality.

项目摘要 心力衰竭，保留的射血分数（HFPEF）约占心脏的一半 美国的失败人群以及这些患者经历的主要慢性症状是 严重的运动不耐受。运动不耐受被量化为减少的峰值氧气吸收 锻炼和迄今为止，针对中央心脏限制的疗法总是无法改善峰值VO2， HFPEF的生活质量或生存。来自我们实验室的新兴证据表明骨骼肌减少了 氧化能力可能有助于HFPEF患者的运动不耐受。但是，机制 负责外围代谢效率低下的效率仍不清楚。血流减少（氧递送），并且 减慢氧气吸收动力学（O2利用率），可能是减少骨骼肌肉的主要因素 氧化能力，并导致已知激活肌肉传入神经的代谢产物的产生 刺激肌肉交感神经（血管收缩）神经系统活性（MSNA）的反射增加。高架 MSNA又可以在运动过程中进一步导致血液动力学控制进一步损害。但是，迄今为止 没有专门研究周围血管，代谢和 神经障碍可降低HFPEF运动能力。该提议的第一个目标是确定 HFPEF中外周血管，代谢和交感神经功能的障碍。为此， 我们将测量动态血流反应（氧递送）和氧气吸收动力学（氧气 膝盖伸肌（KE）运动中的利用）以及运动过程中的MSNA以表征 外周异常对在HFPEF中行使不耐受的贡献。第二个目标是利用 小肌肉质量训练，专门针对这些外围骨骼肌缺陷，以改善 HFPEF中有氧能力和运动耐受性。我们将评估血管，代谢和神经功能 在完成8周的单个KE运动训练之前和之后，结合最大程度的措施 有氧能力和功能能力。孤立的KE训练方法将使中央 全身运动的血液动力学压力，同时将骨骼肌功能靶向 提高HFPEF的运动耐受性。重要的是，该提议将促进我们对基本的理解 HFPEF运动不耐受的病理生理学。考虑到血管功能，氧化能力和 MSNA是心力衰竭患者死亡率的独立预测指标，旨在改善这些病人 功能标记可能对HFPEF的治疗有重要影响 目前尚无降低发病率和死亡率的已知疗法。