HL-Inorganic Nitrite to Enhance Benefits from Exercise Training in Heart Failure with preserved Ejection Fraction

 描述（由申请人提供）：资助机会HL-132提供了一种解决射血分数保留性心力衰竭（HFpEF）状况的机制，该疾病困扰着数百万美国老年人，并与运动不耐受、生活质量（QOL）降低、医疗保健费用高和死亡率增加相关。HFpEF患者显示心脏充盈压增加，心输出量储备不足，无法在运动期间向身体输送血液。许多证据表明，一氧化氮-环磷酸鸟苷（NO-cGMP）信号传导异常在促进这些异常中起着关键作用。虽然目前尚无有效的HFpEF治疗方法，但已证明运动训练（ET）可改善该人群的有氧能力和生活质量。然而，ET通过外周效应提供益处，而不针对心脏局限性。本研究的长期目标是根据对其病理生理学的详细了解，确定HFpEF的新型治疗方法。本申请的具体目的是确定除ET外，亚硝酸钠（NO2-）治疗是否可以改善HFpEF患者的运动能力、慢性活动水平和QOL。指导性假设是，在运动期间优先增强心脏和外周中的NO-cGMP信号传导将改善HFpEF中的功能能力和症状，超过单独ET所见。在HFpEF患者的低水平运动过程中，组织缺氧和酸中毒会增强NO2-向生物活性NO的转化，因此预计这种干预将优先针对这些患者在最需要时运动过程中出现的心脏限制。 这一假设将通过追求两个具体目标来检验：（1）确定与ET安慰剂相比，ET + NO2-治疗12周是否改善HFpEF患者的运动能力和血流动力学储备，以及（2）确定ET + NO2-治疗12周是否增加慢性日常活动水平和QOL，并减少ET期间的努力不耐受症状。在第一个目标下，将在休息和运动期间进行呼气分析、惰性气体（C2H2）再呼吸和超声心动图检查，以测量在使用NO2-进行ET 12周完成前后与使用安慰剂进行ET相比的耗氧量、心输出量反应和对最大努力运动的中心血流动力学。在第二个目标下，受试者将使用外部佩戴的加速计设备来量化12周研究期间的慢性日常体力活动，QOL将通过问卷进行评估，ET耐受性将通过ET期间报告的感知努力和呼吸困难评分进行测量。这一建议是创新性的和重要的，因为它将允许更大的利用 并通过使用一种新型药物增强HFpEF患者从ET中获益，我们已经证明，这种药物优先针对日益增长的美国老年人中运动引起的心脏异常，而这些老年人目前几乎没有可用的治疗方案。

 DESCRIPTION (provided by applicant): Funding opportunity HL-132 provides a mechanism to address the condition of heart failure with preserved ejection fraction (HFpEF), which afflicts millions of older Americans and is associated with exercise intolerance, reduced quality of life (QOL), high health care costs, and increased mortality. People with HFpEF display increased cardiac filling pressures and inadequate cardiac output reserve to deliver blood to the body during exercise. Numerous lines of evidence have implicated abnormalities in nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling as playing a key role in promoting these abnormalities. While there is currently no proven effective medical treatment for HFpEF, exercise training (ET) has been shown to improve aerobic ca- pacity and QOL in this population. However, ET provides benefits through peripheral effects without targeting the cardiac limitations. The long-term goal of this research is to identify novel treatments for HFpEF based upon detailed understanding of its pathophysiology. The specific objectives of this application are to determine whether treatment with sodium nitrite (NO2-) in addition to ET can improve exercise capacity, chronic activity levels, and QOL in people with HFpEF. The guiding hypothesis is that enhancing NO-cGMP signaling in the heart and periphery preferentially during exercise will improve functional capacity and symptoms in HFpEF above and beyond what is seen with ET alone. Conversion of NO2- to biologically active NO is enhanced during tissue hypoxia and acidosis, which develop during low-level exercise in HFpEF, so it is expected that this intervention will preferentially target the cardiac limitations that develop during exercise i these patients at the time of greatest need. This hypothesis will be tested by pursuing two specific aims: (1) Determine whether treatment with NO2- in addition to ET for 12 weeks improves exercise capacity and hemodynamic reserve in people with HFpEF as compared to placebo with ET, and (2) Determine whether treatment with NO2- in addition to ET for 12 weeks increases chronic daily activity levels and QOL, and reduces symptoms of effort intolerance during ET. Under the first aim, expired gas analysis, inert gas (C2H2) rebreathe and echocardiography will be performed at rest and during exercise to measure oxygen consumption, cardiac output responses and central hemodynamics to maximal effort exercise before and after completion of 12 weeks of ET with NO2- as compared to ET with placebo. Under the second aim, subjects will use externally-worn accelerometer devices to quantify chronic daily physical activity over the 12-week study, QOL will be assessed by questionnaire, and ET tolerability will be measured by perceived effort and dyspnea scores reported during ET sessions. This proposal is innovative and significant because it will allow for greater utilization and enhanced benefit from ET in people with HFpEF by using a novel class of medicine that we have shown to preferentially target cardiac abnormalities developing with exercise in a growing population of older Americans for whom there are few current treatment options available.