Blockade of calcium channels and beta adrenergic receptors for physiologic abnormalities in heart failure with preserved ejection fraction (BLOCK HFpEF)

阻断钙通道和 β 肾上腺素能受体可治疗射血分数保留的心力衰竭的生理异常（BLOCK HFpEF）

• 批准号: 10031109
• 负责人: Jordana B. Cohen
• 金额: $ 60.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10031109
• 关键词: Adrenergic Agents; Adult; Aerobic; Affect; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel; Calcium Channel Blockers; Cardiac Output; Cardiomyopathies; Cardiovascular Physiology; Cities; Clinical; Cross-Over Trials; Data; Development; Dihydropyridines; Disease; Doppler Echocardiography; EFRAC; Exercise; Exercise Physiology; Failure; Functional disorder; General Population; Goals; Gold; Guidelines; Heart failure; High Prevalence; Home environment; Hypertension; Impairment; Individual; Intervention; Investigation; Kansas; Left; Left Ventricular Ejection Fraction; Left Ventricular Function; Measurement; Measures; Mediating; Metoprolol Succinate; Morbidity - disease rate; Participant; Pattern; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacology; Physical Function; Physiological; Physiology; Public Health; Quality of life; Questionnaires; Randomized; Randomized Controlled Trials; Rest; Risk Factors; Role; Source; United States; Vasodilation; Ventricular; base; beta-adrenergic receptor; chronotropic; clinical practice; evidence base; exercise capacity; hemodynamics; hypertension control; improved outcome; modifiable risk; mortality; novel; patient population; preservation; pressure; response; symptom management; symptomatic improvement; targeted treatment; trial design

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is a critical public health problem. Heart failure (HF) affects over 5 million adults in the United States (US), and is a major source of morbidity, mortality, and impaired quality of life. Approximately half of individuals with HF have a preserved left ventricular (LV) ejection fraction (EF), termed HF with preserved EF (HFpEF). While there are several effective pharmacologic therapies for HF with reduced ejection fraction (HFrEF), none have been identified for HFpEF. There is an urgent need to identify therapies that target mechanisms of pathophysiologic progression of HFpEF. Hypertension, which is present in approximately 80% of individuals with HFpEF, is the foremost modifiable risk factor for the development and progression of HFpEF. Despite the clinical importance of hypertension in HFpEF, there is limited information on how common antihypertensive agents, particularly calcium channel blockers (CCBs) and β-blockers, effect pathophysiologic mechanisms of HFpEF. We propose a novel mechanistic investigation of the role of dihydropyridine CCBs compared to β-blockers in targeting key physiologic abnormalities in HFpEF. HFpEF is characterized by unique physiologic abnormalities that may be differentially impacted by β-blockers and CCBs. Excessive β-adrenergic stimulation may be a driver of reduced aerobic capacity in HFpEF, which may respond favorably to β-blockade. However, in HFpEF, β-blockers may reduce cardiac output, particularly during exercise, contributing to impaired cardiac output reserve and aerobic limitations. β-blockers may also have effects on the pattern of ventricular contraction and arterial load, impacting diastolic function. Similarly, CCBs may have beneficial effects related to vasodilation and reduction in late systolic load beyond their BP- lowering effect. However, CCB-induced vasodilation at rest may limit the vasodilatory reserve. Our goal is to assess the mechanisms by which CCBs and β-blockers (commonly used antihypertensive agents in clinical practice), impact aerobic capacity and quality of life in HFpEF. We will compare the impact of a dihydropyridine CCB (amlodipine besylate 5-10mg daily) vs. a β-blocker (metoprolol succinate 100-200mg daily) on arterial function, chronotropic reserve, vasodilatory reserve, and LV function, among 50 subjects with HFpEF in a randomized cross-over trial design. Participants will receive 4 weeks of each intervention, with a 1-week washout period in-between. Our mechanism-driven approach will enhance our understanding of the pathophysiology of HFpEF and characterize the physiologic potential of these common antihypertensive agents to reduce progression and improve symptom management in this disease.

项目概要 射血分数保留的心力衰竭（HFpEF）是一个严重的公共卫生问题。 影响美国超过 500 万成年人，是发病率、死亡率和死亡率的主要来源 生活质量受损。大约一半的心力衰竭患者左心室 (LV) 射血功能正常。 部分（EF），称为 HF 保留 EF（HFpEF），同时有几种有效的药理作用。 射血分数降低的心力衰竭 (HFrEF) 的治疗方法尚未确定，目前尚无针对 HFpEF 的治疗方法。 迫切需要确定针对 HFpEF 病理生理进展机制的治疗方法。 大约 80% 的 HFpEF 患者患有高血压，这是最重要的可改变风险 尽管高血压在临床上很重要，但它是 HFpEF 发生和进展的重要因素。 HFpEF，关于常见抗高血压药物，特别是钙通道的信息有限 阻滞剂（CCB）和β-阻滞剂，影响 HFpEF 的病理生理机制。 与 β 受体阻滞剂相比，二氢吡啶 CCB 在靶向关键药物方面的作用机制研究 HFpEF 的生理异常。 HFpEF 的特点是独特的生理异常，可能会受到 β 受体阻滞剂的不同影响 过度的 β-肾上腺素能刺激可能是 HFpEF 有氧能力降低的驱动因素。 可能对 β 阻滞剂有良好反应，但对于 HFpEF，β 阻滞剂可能会降低心输出量，尤其是心输出量。 运动期间，β-受体阻滞剂也可能导致心输出量储备受损和有氧限制。 对心室收缩和动脉负荷的模式有影响，从而影响舒张功能。 CCB 可能具有与血管舒张和减少超出其血压的晚期收缩负荷相关的有益作用 然而，CCB 引起的休息时血管舒张可能会限制血管舒张储备。 评估 CCB 和 β 受体阻滞剂（临床上常用的抗高血压药物）的作用机制 练习），对 HFpEF 的有氧能力和生活质量的影响 我们将比较二氢吡啶的影响。 CCB（苯磺酸氨氯地平，每日 5-10 毫克）与 β 受体阻滞剂（琥珀酸美托洛尔，每日 100-200 毫克）在动脉上的比较 一项研究中 50 名 HFpEF 受试者的功能、变时性储备、血管舒张储备和左心室功能 随机交叉试验设计，参与者将接受为期 4 周的每次干预，其中为期 1 周。 我们的机制驱动方法将增强我们对中间的清洗期。 HFpEF 的病理生理学并表征这些常见抗高血压药物的生理潜力 减少这种疾病的进展并改善症状管理的药物。