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

项目总结 心力衰竭伴保留射血分数(HFpEF)是一个严重的公共卫生问题。心力衰竭(HF) 在美国影响着500多万成年人，是发病率、死亡率和 生活质量受损。大约一半的心衰患者的左心室射血功能保持不变。 分数(EF)，称为保留EF的HF(HFpEF)。虽然有几种有效的药理作用 射血分数(HFrEF)降低的HF的治疗方法，目前还没有针对HFpEF的治疗方法。有一个 迫切需要确定针对HFpEF病理生理进展机制的治疗方法。 高血压在大约80%的HFpEF患者中存在，是最重要的可修改风险 HFpEF的发展和进展的因素。尽管高血压在中国的临床重要性 HFpEF，关于常见的降压药，特别是钙通道的信息有限 受体阻滞剂(CCB)和β受体阻滞剂影响高血压性肺间质纤维化的病理生理机制。我们提议写一部小说 二氢吡啶类CCBS与β受体阻滞剂靶向关键点作用的机制研究 HFpEF的生理异常。 HFpEF的特征是独特的生理异常，这些异常可能会受到β阻滞剂的不同影响。 和CCBS。过度的β-肾上腺素能刺激可能是HFpEF有氧能力降低的一个驱动因素， 可能会对β-BLOCKED做出积极回应。然而，在HFpEF中，β阻滞剂可能会减少心输出量，尤其是 在运动过程中，会导致心输出量储备受损和有氧限制。β阻滞剂还可以 对心室收缩模式和动脉负荷产生影响，从而影响舒张期功能。同样， CCBS可能具有与血管扩张和降低收缩晚期负荷有关的有益作用。 降低效果。然而，CCB诱导的静息血管扩张可能会限制血管扩张储备。我们的目标是 评估CCBS和β阻滞剂(临床上常用的降压药)的作用机制 练习)，影响HFpEF的有氧能力和生活质量。我们将比较二氢吡啶的影响 β阻滞剂(丁二酸美托洛尔每天100-200 mg)与CCB(苯磺酸氨氯地平每天5-10 mg)对动脉的作用 50例高血压性心功能受试者的功能、变时性储备、血管扩张储备和左心功能 随机交叉试验设计。参与者将接受为期4周的干预，每次干预为期1周 其间的冲洗期。我们以机制为主导的方法，将加强我们对 HFpEF的病理生理机制及其常用抗高血压药物的生理潜力 药物以减缓进展和改善这种疾病的症状管理。

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.