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

HL-无机亚硝酸盐可增强心力衰竭运动训练的益处并保留射血分数

• 批准号: 9459406
• 负责人: Barry A. Borlaug
• 金额: $ 58.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9459406
• 关键词: Accelerometer; Acidosis; Activities of Daily Living; Address; Adherence; Aerobic; American; Arteries; Biological; Blood; Cardiac; Cardiac Output; Cardiovascular system; Chronic; Combined Modality Therapy; Coupling; Cyclic GMP; Development; Devices; Disease; Dyspnea; EFRAC; Echocardiography; Elderly; Exercise; Failure; Fatigue; Functional disorder; Funding Opportunities; Gases; Goals; Health Care Costs; Heart; Heart Abnormalities; Heart failure; Homeostasis; Hospitalization; Hypotension; Hypoxia; Inhalation; Intervention; Knowledge; Life; Measures; Medical; Medicine; Mission; Morbidity - disease rate; Multiple Abnormalities; Nitrates; Nitric Oxide; Nitrites; Noble Gases; Older Population; Outcome Assessment; Oxygen Consumption; Pathway interactions; Patients; Peripheral; Phase III Clinical Trials; Physical Exercise; Physical activity; Placebos; Play; Population; Public Health; Pulmonary artery structure; Quality of life; Questionnaires; Reporting; Research; Rest; Series; Signal Transduction; Sodium Nitrite; Stress; Symptoms; Testing; Time; Tissues; Training; Treatment Failure; United States; United States National Institutes of Health; Weight; Work; Workload; base; burden of illness; digital; disability; effective therapy; exercise capacity; exercise intolerance; exercise prescription; exercise training; experimental study; hemodynamics; improved; innovation; mortality; new therapeutic target; novel; novel strategies; novel therapeutics; pressure; public health relevance; reduce symptoms; response

 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.

 描述（由申请人提供）：资助机会 HL-132 提供了一种机制来解决射血分数保留型心力衰竭 (HFpEF) 的问题，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) 下降、医疗保健成本高昂和死亡率增加有关。患有 HFpEF 的人在运动期间表现出心脏充盈压升高和向身体输送血液的心输出量储备不足。大量证据表明一氧化氮-环磷酸鸟苷 (NO-cGMP) 信号异常在促进这些异常中发挥着关键作用。虽然目前尚无有效的治疗 HFpEF 的药物，但运动训练 (ET) 已被证明可以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，但没有针对心脏限制。这项研究的长期目标是在详细了解 HFpEF 病理生理学的基础上确定新的治疗方法。本申请的具体目标是确定除 ET 之外使用亚硝酸钠 (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。指导性假设是，在运动期间优先增强心脏和外周的 NO-cGMP 信号传导将改善 HFpEF 的功能能力和症状，其效果优于单独使用 ET 所见的效果。 NO2- 向生物活性 NO 的转化在 HFpEF 低水平运动期间发生的组织缺氧和酸中毒过程中得到增强，因此预计这种干预措施将优先针对这些患者在最需要的时候在运动过程中出现的心脏限制。 该假设将通过追求两个具体目标进行检验：(1) 确定与安慰剂加 ET 相比，NO2- 加 ET 治疗 12 周是否可以改善 HFpEF 患者的运动能力和血流动力学储备，以及 (2) 确定 NO2- 加 ET 治疗 12 周是否会增加慢性日常活动水平和生活质量，并减少 ET 期间努力不耐受的症状。第一个目标是，在休息和运动期间进行呼出气体分析、惰性气体 (C2H2) 再呼吸和超声心动图检查，以测量在完成 12 周 NO2- ET 之前和之后与安慰剂 ET 相比，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，受试者将使用外部佩戴的加速计设备来量化为期 12 周的研究中的长期日常体力活动，通过问卷评估生活质量，并通过 ET 疗程期间报告的感知努力和呼吸困难评分来衡量 ET 耐受性。该提案具有创新性且意义重大，因为它将提高利用率 通过使用一类新型药物，增强 ET 对 HFpEF 患者的益处，我们已证明这种药物优先针对日益增长的美国老年人群中因运动而出现的心脏异常，而对于这些老年人来说，目前几乎没有可用的治疗选择。