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

项目摘要 射血分数保留性心力衰竭（HFpEF）是一个严重的公共卫生问题。心力衰竭（HF） 在美国（US）影响超过500万成年人，并且是发病率、死亡率和 生活质量受损。大约一半的HF患者左心室射血功能正常 部分（EF），称为保留EF的HF（HFpEF）。虽然有几种有效的药理学 射血分数降低的HF（HFrEF）的治疗中，没有发现HFpEF。有一个 迫切需要确定靶向HFpEF病理生理进展机制的治疗方法。 约80%的HFpEF患者存在高血压，是最重要的可改变风险 HFpEF的发展和进展的因素。尽管高血压的临床重要性， HFpEF，关于常见抗高血压药物，特别是钙通道 阻断剂（CCBs）和β-阻断剂影响HFpEF的病理生理机制。我们提出了一种新 与β受体阻滞剂相比，二氢吡啶类CCBs在靶向关键 HFpEF的生理异常。 HFpEF的特征是独特的生理异常，可能受到β受体阻滞剂的不同影响 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因素， 可能对β受体阻滞剂有良好的反应。然而，在HFpEF中，β受体阻滞剂可能会减少心输出量，特别是 在运动过程中，导致心输出量储备受损和有氧限制。β受体阻滞剂也可能 影响心室收缩模式和动脉负荷，影响舒张功能。同样地， CCB可能具有与血管舒张和收缩晚期负荷降低相关的有益作用， 降低效果。然而，静息时CCB诱导的血管舒张可能限制血管舒张储备。我们的目标是 评估CCB和β受体阻滞剂（临床常用的降压药） 实践），影响HFpEF的有氧能力和生活质量。我们将比较二氢吡啶 CCB（苯磺酸二甲双胍5- 10 mg，每日一次）与β受体阻滞剂（琥珀酸美托洛尔100- 200 mg，每日一次）对动脉 在一项研究中，对50名HFpEF受试者的心脏功能、变时储备、血管舒张储备和LV功能进行了研究。 随机交叉试验设计。参与者将接受4周的每次干预，其中1周 中间的洗脱期。我们的机制驱动的方法将提高我们对 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 药物，以减少这种疾病的进展和改善症状管理。

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.