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

项目摘要 射血分数正常的心力衰竭（HFpEF）约占心脏的一半 失败的人群，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在运动期间峰值摄氧量降低。 运动，迄今为止，针对中心心脏限制的治疗总是未能改善峰值VO2， 生活质量或HFpEF的生存率。我们实验室的新证据表明骨骼肌减少 氧化能力可能导致HFpEF患者的运动不耐受。然而，机制 导致外周代谢效率低下的原因尚不清楚。血流量减少（氧气输送），以及 缓慢的氧摄取动力学（O2利用率）可能是骨骼肌减少的主要原因 氧化能力，并导致产生已知激活肌肉传入神经的代谢物， 刺激反射增加肌肉交感（血管收缩）神经系统活动（MSNA）。升高 MSNA可反过来导致运动期间血流动力学控制的进一步损害。但迄今 还没有专门研究外周血管、代谢和 HFpEF患者运动能力降低的神经损伤。该提案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损害。为了实现这一点， 我们将测量动态血流反应（氧输送）和氧摄取动力学（氧 利用）在膝伸肌（KE）运动，以及MSNA在运动过程中，以表征 外周异常对HFpEF患者运动不耐受的影响第二个目标是利用 小肌肉质量KE训练，专门针对这些外周骨骼肌缺陷，以改善 有氧能力和运动耐量。我们将评估血管代谢和神经功能 在完成8周的单一KE运动训练之前和之后，结合最大运动负荷的测量， 有氧能力和功能能力。孤立的KE训练方法将最大限度地减少中央 全身运动的血液动力学应激，同时针对骨骼肌功能， 提高HFpEF患者运动耐量。重要的是，这一建议将促进我们对基本问题的理解。 HFpEF运动不耐受的病理生理学考虑到血管功能、氧化能力和 a MSNA是心力衰竭患者死亡率的独立预测因子， 功能性标记物可能对HFpEF的治疗具有重要意义，HFpEF是一种 目前没有已知的疗法来降低发病率和死亡率。

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.