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%的西方人群和约10%的年龄>75岁的个体。HF不仅已经是一种流行病，而且随着人口老龄化，预计其患病率将进一步急剧增加。大约50%的HF患者射血分数正常（HF伴射血分数保留，HFpEF），通常称为“舒张期”HF。许多治疗性干预可用于射血分数降低的HF，但目前没有有效的干预可用于HFpEF。考虑到HFpEF的巨大公共卫生、临床和社会负担，找到有效的治疗方法是该领域的首要任务。基于一系列 将动脉波反射与异常左心室舒张、左心室重构联系起来的动物实验和人体观察研究（肥大）和HF风险，我们提出了一项初步的随机双盲对照临床试验，旨在评估使用硝酸异山梨酯或硝酸异山梨酯和肼苯哒嗪联合给药24周减少动脉波反射是否会改善舒张功能，42例HFpEF患者的LV重构和临床相关终点（身体健康、生活质量）。因此，我们的目标是：1）测试延长的硝酸盐治疗（24周）是否对HFpEF患者的波反射产生持续影响，以及添加肼苯哒嗪是否增强硝酸盐治疗对HFpEF患者的波反射的影响。2)测试硝酸盐+肼苯哒嗪长期血管活性治疗是否导致HFpEF患者的LV肥大（LV质量减少）和LV纤维化的消退。3）评估硝酸盐+肼苯哒嗪治疗是否改善HFpEF患者的舒张期舒张。 4)评估硝酸盐+肼苯哒嗪治疗是否可改善HFpEF患者的直接临床相关终点（身体健康和生活质量）。我们还将评估血管活性药物治疗对左室重构、舒张期舒张、体能和生活质量的影响是否可以通过动脉波反射的减少来解释。如果我们的干预措施能够改善心室重塑、舒张功能和身体健康，这将在该领域引入一个新的范例，并为证明、设计和支持一个更明确的硬终点驱动的临床试验提供基础，在该临床试验中，这种方法将作为改善HFpEF患者结局的策略进行测试。

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.