Targeting Wave Reflections in Heart Failure with Preserved Ejection Fraction

描述(由申请人提供)：心力衰竭(HF)影响约2%的西方人口和约10%的75岁人群。心力衰竭不仅已经是一种流行病，而且随着人口老龄化，其流行率预计将进一步大幅上升。大约50%的心衰患者射血分数正常(射血分数保留)，通常被称为“舒张期”心衰。对于射血分数降低的心力衰竭，有许多治疗措施可用，但目前还没有有效的干预措施可用于HFpEF。鉴于HFpEF的巨大公共卫生、临床和社会负担，寻找有效的治疗方法是该领域的首要任务。基于一系列 在动物实验和人体观察研究中，动脉波反射与异常的左心室松弛、左心室重构(肥厚)和心力衰竭风险有关，我们建议进行一项试点随机双盲对照临床试验，旨在评估在42例HFpEF患者中，使用消心痛或联合应用硝酸异山梨酯和肼丙嗪24周，减少动脉波反射是否会改善舒张期功能、左室重构和临床相关终点(体能、生活质量)。因此，我们的目标是：1)测试长期的硝酸盐治疗(24周)是否对HFpEF患者的波形反射产生持续的影响，以及合用肼是否增强了硝酸盐治疗对HFpEF患者的波形反射的影响。2)测试长期应用硝酸酯类药物和肼类药物的血管活性疗法是否能使HFpEF患者的左室肥厚(左心室重量减少)和左室纤维化消退。3)评估硝酸盐+肼类药物治疗是否改善了HFpEF患者的舒张期。4)评估硝酸盐+肼安定治疗是否能改善HFpEF患者与临床直接相关的终点(身体健康和生活质量)。我们还将评估血管活性治疗对左室重构、舒张期松弛、体能和生活质量的影响是否可以通过减少动脉波反射来解释。如果我们的介入改善了心室重构、舒张期功能和身体健康，这将在该领域引入一种新的范式，并为证明、设计和推动更明确的硬终点驱动临床试验奠定基础，在该试验中，这种方法将被测试为改善HFpEF患者预后的一种策略。

DESCRIPTION (provided by applicant): Heart Failure (HF) affects ~2% of the western population and ~10% of individuals aged >75 years. Not only is HF already an epidemic, but with the aging of the population, a dramatic further increase in its prevalence is expected. Approximately 50% of patients with HF have a normal ejection fraction (HF with preserved ejection fraction, HFpEF), often called "diastolic" HF. Many therapeutic interventions are available for HF with reduced ejection fraction, but there is currently no effective intervention available for HFpEF. Given the enormous public health, clinical and societal burden of HFpEF, finding effective therapies for this condition is a top priority in the field. Based on a series of animal experimental and human observational studies that link arterial wave reflections to abnormal left ventricular relaxation, left ventricular remodeling (hypertrophy) and HF risk, we propose a pilot randomized double-blind controlled clinical trial designed to assess whether reducing arterial wave reflections with either isosorbide dinitrate or the combination of isosorbide dinitrate and hydralazine administered for 24 weeks will improve diastolic function, LV remodeling and clinically-relevant endpoints (physical fitness, quality of life) among 42 patients with HFpEF. We therefore aim to: 1) Test whether prolonged nitrate therapy (24 weeks) exerts sustained effects on wave reflections and whether the addition of hydralazine enhances the effect of nitrate therapy on wave reflections in patients with HFpEF. 2) Test whether long-term vasoactive therapy with nitrates + hydralazine results in regression of LV hypertrophy (reduction in LV mass) and LV fibrosis in patients with HFpEF.3) Assess whether nitrate + hydralazine therapy improves diastolic relaxation in patients with HFpEF. 4) Assess whether nitrate + hydralazine therapy results in an improvement in endpoints with immediate clinical relevance (physical fitness and quality of life) in patients with HFpEF. We will also assess whether the effects of vasoactive therapy on LV remodeling, diastolic relaxation, physical fitness and quality of life can be explained by a reduction in arterial wave reflections. If our interventin improves ventricular remodeling, diastolic function and physical fitness, this would introduce a new paradigm in the field and provide a foundation for justifying, designing and powering a more definitive hard endpoint-driven clinical trial in which this approach will be tested as a strategy o improve the outcomes of patients with HFpEF.