Autonomic Dysfunction in Patients with HFpEF

HFpEF 患者的自主神经功能障碍

• 批准号: 10587484
• 负责人: MARKUS AMANN
• 金额: $ 69.65万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587484
• 关键词: Acceleration; Activities of Daily Living; Address; Adrenergic Agents; Affect; American; Autonomic Dysfunction; Baroreflex; Blood; Blood Pressure; Blood Vessels; Blood flow; Brain; Buffers; Cardiopulmonary; Cardiovascular system; Characteristics; Circulation; Clinical; Development; Disease; Dissociation; Dyspnea; EFRAC; Exercise; Exercise Tolerance; Exertion; Fatigue; Feedback; Functional disorder; Heart failure; Impairment; Infusion procedures; Knowledge; Limb structure; Mediating; Methodology; Muscle; Organ; Pathologic; Pathway interactions; Patients; Peripheral; Phenotype; Phentolamine; Physical activity; Play; Prevalence; Prognosis; Quality of life; Reflex action; Regulation; Regulatory Pathway; Research; Resistance; Rest; Signal Transduction; Skeletal Muscle; Sympathetic Nervous System; Symptoms; Translating; Treatment Failure; Vasomotor; Work; alpha-adrenergic receptor; antagonist; cardiovascular risk factor; clinical care; design; exercise intolerance; heart function; hemodynamics; improved; innovation; insight; mortality; neuromuscular; neurovascular; pharmacologic; premature; preservation; public health relevance; response; success; treatment strategy; vasoconstriction

PROJECT SUMMARY: Heart failure with preserved ejection fraction (HFpEF) accounts for greater than 50% of the 6 million HF cases nationwide, and the prevalence relative to heart failure with reduced ejection fraction (HFrEF) continues to rise at a rate of 1% per year, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. The clinical presentation of HFpEF is defined by dyspnea upon exertion and severe exercise intolerance, symptoms that are likely due, at least in part, to disease-related changes in the peripheral circulation. While the mechanisms responsible for the loss of peripheral vascular control in HFpEF have not been established, sympathetic nervous system (SNS) overactivity is likely to play a key role. In the peripheral circulation, sympathetic vasomotor outflow causes vasoconstriction via activation of alpha-adrenergic receptors located on the skeletal muscle vasculature, which serves to constrain limb blood flow, both at rest and during physical activity. In the presence of pathologic elevations in SNS activity, exaggerated vasoconstriction may therefore result in insufficient delivery of blood to the exercising muscle, resulting in exercise intolerance and premature neuromuscular fatigue. As the regulation and functional consequences of excess sympathoexcitation on vascular control have not been examined in patients with HFpEF, this proposal seeks to address a significant knowledge gap in our understanding of HFpEF pathophysiology. Specific Aim 1 is designed to evaluate disease-related changes in the arterial baroreflex, which is a key regulator of SNS activity. It is hypothesized that that both cardiovagal and sympathetic baroreflex sensitivity will be reduced, at rest and during exercise, in patients with HFpEF compared to healthy controls. Both cardiopulmonary and carotid baroreflex responses will be assessed to delineate the impact of HFpEF on overall arterial baroreflex function. Specific Aim 2 focuses on the transduction of sympathetic outflow in the peripheral circulation, with the hypothesis that changes in arterial blood pressure and vascular conductance in response to bursts of SNS activity will be exaggerated in patients with HFpEF. Specific Aim 3 will evaluate the functional consequences of SNS overactivity at the end organ, utilizing pharmacologic inhibition of alpha- adrenergic receptors via intra-arterial Phentolamine infusion to block expression of SNS activity. For this Aim, it is hypothesized that regional alpha adrenergic receptor antagonism will normalize resting and exercising muscle blood flow, and subsequently improve exercise tolerance and neuromuscular fatigue resistance, in patients with HFpEF. Upon completion, findings from the proposed work hold the promise of offering new mechanistic insight regarding HFpEF pathophysiology that may provide a pathway to improved clinical care and, ultimately, better prognosis in this patient group.

项目摘要：保留的射血分数（HFPEF）的心力衰竭占50％以上 全国600万例HF病例，相对于心力衰竭的患病率减少了 （HFREF）继续以每年1％的速度上升，这迫在眉睫，需要进一步研究 这种普遍疾病的病理生理学。 HFPEF的临床表现由呼吸困难定义 劳累和严重的运动不宽容，至少部分归因于疾病有关的症状 周围循环的变化。而造成周围血管损失的机制 HFPEF中的控制尚未建立，交感神经系统（SNS）过度活动可能会发挥 关键角色。在外周循环中，交感神经输血流出通过激活引起血管收缩 位于骨骼肌脉管系统上的α-肾上腺素能受体，这可以约束肢体血液 在休息和体育锻炼期间的流动。在SNS活性中存在病理升高的情况下， 因此 导致运动不耐受和过早的神经肌肉疲劳。作为调节和功能 在患者中尚未检查过过多交感神经对血管控制的后果 HFPEF，该建议旨在解决我们对HFPEF的理解中的一个重大知识差距 病理生理学。特定的目标1旨在评估动脉压力反射的疾病相关变化， 这是SNS活动的关键调节剂。假设心脏和富有同情心 与健康对照组相比，HFPEF患者的静止和运动过程中的敏感性将降低。 将评估心肺和颈动脉降压反应，以描绘HFPEF的影响 总体动脉压力反射功能。特定目标2的重点是在 外围循环，假设动脉血压和血管电导的变化 HFPEF患者对SNS活性爆发的反应将被夸大。特定目标3将评估 SNS在末端器官中过度活动的功能后果，利用α-的药理抑制作用 肾上腺内苯丙胺输注以阻断SNS活性的表达，肾上腺素能受体。为了这个目标 假设区域性α肾上腺素能受体拮抗作用将使静止和锻炼正常 血液流动，随后提高运动耐受性和神经肌肉疲劳性的耐药性，患有 HFPEF。完成后，提议的工作的发现有望提供新的机械洞察力 关于HFPEF病理生理学，可能为改善临床护理提供途径，最终更好 该患者组的预后。