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提供了一种机制，以解决射血分数保留(HFpEF)心力衰竭的状况，这种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、医疗成本高和死亡率增加有关。患有HFpEF的人在运动过程中表现出心脏充盈压增加，心输出量储备不足，无法将血液输送到身体。大量证据表明，一氧化氮-环磷酸鸟苷(NO-cGMP)信号的异常在促进这些异常中起着关键作用。虽然目前还没有被证实有效的治疗HFpEF的药物，但运动训练(ET)已被证明可以改善这一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，而不针对心脏限制。这项研究的长期目标是在详细了解HFpEF的病理生理学的基础上，确定新的治疗方法。这项应用的具体目标是确定在ET的基础上加用亚硝酸钠(NO2-)治疗是否可以改善HFpEF患者的运动能力、慢性活动水平和生活质量。指导性假说是，在运动中优先增强心脏和外周的NO-cGMP信号将改善HFpEF的功能能力和症状，超过单独使用ET的情况。在HFpEF的低水平运动期间，组织缺氧和酸中毒会促进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的时候运动时出现的心脏局限性。这一假说将通过追求两个具体目标来验证：(1)确定与服用安慰剂的ET相比，接受NO2-+ET治疗12周的HFpEF患者的运动能力和血流动力学储备是否得到改善，以及(2)确定在ET治疗的同时接受NO2-治疗12周是否提高了慢性日常活动水平和生活质量，并减少了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，以测量在使用NO2的ET和使用安慰剂的ET完成12周之前和之后最大努力运动的耗氧量、心输出量反应和中心血流动力学。在第二个目标下，受试者将在12周的研究中使用外部佩戴的加速度计设备来量化长期的日常体力活动，生活质量将通过问卷调查进行评估，ET的耐受性将通过在ET治疗期间报告的感知努力和呼吸困难分数来衡量。这项建议具有创新性和重要意义，因为它将允许更高的利用率 通过使用一种新的药物类别，我们已经证明，这种药物优先针对随着运动而发展的心脏异常，在日益增长的美国老年人口中，目前几乎没有可用的治疗选择，从而增强了ET对HFpEF患者的好处。

 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.