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：射血分数保留的心力衰竭 (HFpEF) 占所有患者的 50% 以上 全国 600 万例心力衰竭病例，以及射血分数降低心力衰竭的患病率 (HFrEF) 继续以每年 1% 的速度增长，迫切需要进一步研究解决 这种普遍性疾病的病理生理学。 HFpEF 的临床表现是呼吸困难 劳累和严重的运动不耐受，这些症状可能至少部分是由疾病相关引起的 末梢循环的变化。虽然导致外周血管丧失的机制 HFpEF 的控制尚未建立，交感神经系统 (SNS) 过度活跃可能会发挥作用 关键作用。在外周循环中，交感神经血管舒缩流出通过激活 α-肾上腺素能受体位于骨骼肌脉管系统上，用于限制肢体血液 流动，无论是在休息时还是在体力活动期间。在 SNS 活动出现病理性升高的情况下， 因此，过度的血管收缩可能会导致运动肌肉的血液输送不足， 导致运动不耐受和过早的神经肌肉疲劳。由于监管和功能 交感神经过度兴奋对血管控制的影响尚未在患有以下疾病的患者中进行过研究 HFpEF，该提案旨在解决我们对 HFpEF 理解中的重大知识差距 病理生理学。具体目标 1 旨在评估动脉压力反射的疾病相关变化， 它是 SNS 活动的关键调节器。据推测，心迷走神经和交感神经压力反射 与健康对照相比，HFpEF 患者在休息和运动时的敏感性会降低。 将评估心肺和颈动脉压力反射反应，以描述 HFpEF 对 总体动脉压力反射功能。具体目标 2 侧重于交感神经流出的转导 外周循环，假设动脉血压和血管电导发生变化 HFpEF 患者对 SNS 活动爆发的反应会被夸大。具体目标 3 将评估 利用 α- 的药理学抑制，最终器官 SNS 过度活动的功能后果 肾上腺素能受体通过动脉内输注酚妥拉明来阻断 SNS 活性的表达。为了这个目标，它 假设局部α肾上腺素能受体拮抗作用将使静息和运动肌肉正常化 血流量，从而提高患者的运动耐量和神经肌肉疲劳抵抗力 HFpEF。完成后，拟议工作的结果有望提供新的机制见解 关于 HFpEF 病理生理学，可能提供改善临床护理并最终更好地治疗的途径 该患者组的预后。