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: 10251265
• 负责人: Jordana B. Cohen
• 金额: $ 63.8万
• 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/10251265
• 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; 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.

项目摘要 保留的射血分数（HFPEF）的心力衰竭是一个关键的公共卫生问题。心力衰竭（HF） 在美国（美国）影响超过500万成年人，是发病率，死亡率和 生活质量受损。大约一半的HF个体具有左心室（LV）弹出 分数（EF），称为HF，保留EF（HFPEF）。虽然有几种有效的药理学 射血分数降低（HFREF）的HF疗法，没有针对HFPEF确定的。有一个 迫切需要确定针对HFPEF病理生理进展机制的疗法。 高血压在大约80％的患有HFPEF的个体中呈现为最重要的风险 尽管高血压在 HFPEF，关于常见的降压药，尤其是钙通道的信息有限 阻滞剂（CCB）和β受体阻滞剂，影响HFPEF的病理生理机制。我们提出了一本小说 二氢吡啶CCB的作用与β受体阻滞剂在靶向钥匙中相比 HFPEF的生理异常。 HFPEF的特征是独特的生理异常，可能受到β受体阻滞剂的影响 和CCB。过度的β-肾上腺素能刺激可能是HFPEF中有氧能力降低的驱动力，这 可能对β受体阻滞有利。但是，在HFPEF中，β受体阻滞剂可能会减少心脏输出，特别是 在锻炼过程中，有助于心脏输出储备和有氧限制受损。 β受体阻滞剂也可能 对心室收缩和动脉负荷的模式产生影响，从而影响舒张功能。相似地， CCB可能具有与血管舒张和减少的收缩期负荷相关的有益作用，超出其BP- 降低效果。但是，CCB诱导的静止血管舒张可能会限制血管舒张储备。我们的目标是 评估CCB和β受体阻滞剂的机制（临床中常用的抗高血压剂 实践），影响HFPEF的有氧运动能力和生活质量。我们将比较二氢吡啶的影响 CCB（每天5-10毫克的氨氯地平）与动脉上的β受体阻滞剂（每天100-200mg） 功能，计时储备，血管舒张储备和LV功能，在50位HFPEF的受试者中 随机交叉试验设计。参与者将接受每次干预的4周，为期1周 冲洗期之间。我们机制驱动的方法将增强我们对 HFPEF的病理生理学并表征了这些常见降压的生理潜力 降低进展并改善该疾病症状管理的药物。