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%的年龄在50 - 75岁之间的个体。心衰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急剧上升。大约50%的HF患者有正常的射血分数（保留射血分数的HF， HFpEF），通常称为“舒张期”HF。许多治疗性干预措施可用于射血分数降低的心衰，但目前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。基于一系列的

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.