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Efficacy of Potassium Nitrate in Heart Failure with Preserved Ejection Fraction

硝酸钾治疗射血分数保留的心力衰竭的疗效

基本信息

批准号：
8963158
负责人：
JULIO ALONSO CHIRINOS MEDINA
金额：
$ 63.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-11 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8963158
关键词：
Adult Aerobic Affect African American Back Bicycling Biochemistry Blood Blood Vessels Blood flow Cardiac Output Cardiomyopathies Chemicals Chronic Disease Cities Clinical Clinical Trials Consumption Cross-Over Trials Data Disease Doppler Echocardiography Dose Double-Blind Method EFRAC Echocardiography Endothelium Enrollment Exercise Exercise Physiology Exercise Tolerance Exercise stress test Flexor Functional disorder Gender Genetic Crossing Over Heart Heart failure Hypoxia Image Intervention Kansas Kinetics Left Left Ventricular Ejection Fraction Left Ventricular Function Left Ventricular Remodeling Link Magnetic Resonance Imaging Maps Measures Mediating Methods Mitochondria Morbidity - disease rate Muscle Muscle function Myocardial Nitrates Nitric Oxide Nitrites Oral Oral Administration Oral cavity Oxygen Consumption Pathway interactions Patients Perfusion Peripheral Peripheral Resistance Pharmacology Phosphorus Physiological Adaptation Plasma Population Potassium Chloride Public Health Quality of life Questionnaires Race Randomized Recovery Resolution Rest Risk Sampling Site Skeletal Muscle Source Spectrum Analysis Spin Labels Stress Supplementation Techniques Testing Therapeutic Therapeutic Intervention Time Travel Vasodilation Vasodilator Agents Ventricular Woman Workload aged arterial tonometry clinically relevant control trial dietary nitrate effective therapy hemodynamics improved mortality muscle metabolism novel placebo controlled study potassium nitrate pressure public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Approximately 50% of patients with HF have a normal ejection fraction (HF with preserved ejection fraction, HFpEF). There are currently no effective pharmacologic interventions available for HFpEF. Given the enormous burden of HFpEF, finding effective therapies for this condition is a top priority. Exercise intolerance is the hallmrk of HFpEF and greatly impairs quality of life. Recent evidence links abnormalities in peripheral vasodilation to exercise intolerance in HFpEF. Inorganic circulating nitrite constitutes an important source of the potent vasodilator nitric oxide (NO), which operates preferentially in situations of hypoxia, as occurs in exercising muscle. Dietary nitrates also exert mitochondrial effects in skeletal muscle. In addition to these exercise-related effects, dietary nitrates exert peripheral effects that have the potential for chronic "disease-modifying" benefits in HFpEF, particularly a reduction in late systolic load, which appears to promote left ventricular remodelin and diastolic dysfunction. Our preliminary data from a double-blinded cross-over placebo-controlled trial demonstrates that a single dose of inorganic nitrate improves aerobic capacity, the peripheral vasodilator response to exercise, skeletal muscle mitochondrial oxidative function and left ventricular late systolic load. We propose a pilot randomized cross-over double-blind controlled trial to compare the effects of potassium nitrate (6 mEq orally three times daily) administered over 6 weeks on: (1) Clinical Endpoints: Exercise capacity (peak oxygen consumption [VO2], during a maximal exercise test) and quality of life (assessed with the Kansas City Cardiomyopathy Questionnaire). (2) Specific physiologic adaptations to exercise : a. Systemic vasodilator response to exercise (assessed via the change in systemic vascular resistance during maximal effort supine-bicycle exercise) b. Muscle tissue blood flow during exercise and muscle oxidative capacity: measured with arterial MRI spin labeling, phosphorus MRI spectroscopy and chemical exchange saturation transfer MRI techniques during a standardized plantar flexor exercise test. c. LV diastolic filling parameters (measured with echocardiography at rest and peak exercise) and myocardial strain (assessed with speckle-tracking echocardiography). (3) Late systolic LV load (assessed via time-resolved LV wall stress and aortic pressure-flow relations, using arterial tonometry and Doppler echocardiography). If our mechanistically-targeted intervention improves exercise capacity, exercise vascular and muscle reserve and arterial hemodynamics, it would establish a new, readily implementable therapeutic paradigm in HFpEF.

描述（由申请人提供）：约50%的HF患者射血分数正常（HF伴射血分数保留，HFpEF）。目前尚无有效的药物干预措施可用于HFpEF。考虑到HFpEF的巨大负担，寻找有效的治疗方法是当务之急。运动不耐受是HFpEF的标志，极大地损害了生活质量。最近的证据将外周血管舒张异常与HFpEF的运动不耐受联系起来。无机循环亚硝酸盐构成了有效的血管扩张剂一氧化氮（NO）的重要来源，其优先在缺氧的情况下起作用，如在运动肌肉中发生的。饮食中的硝酸盐也对骨骼肌产生线粒体效应。除了这些运动相关的影响，饮食中的硝酸盐发挥外周效应，有可能在HFpEF中获得慢性"疾病改善"益处，特别是收缩晚期负荷的减少，这似乎促进了左心室重塑和舒张功能障碍。我们的双盲交叉安慰剂对照试验的初步数据表明，单剂量的无机硝酸盐改善有氧能力，外周血管扩张剂对运动的反应，骨骼肌线粒体氧化功能和左心室收缩晚期负荷。我们提出了一个初步的随机交叉双盲对照试验，比较硝酸钾（6 mEq口服，每日三次）的影响，超过6周：（1）临床终点：运动能力（峰值耗氧量[VO2]，在最大运动试验）和生活质量（评估与堪萨斯城心肌病问卷）。(2)对运动的特殊生理适应：a.全身血管舒张剂对运动的反应（通过最大努力仰卧自行车运动期间全身血管阻力的变化评估）B.运动过程中的肌肉组织血流量和肌肉氧化能力：在标准化跖屈肌运动试验期间，采用动脉MRI自旋标记、磷MRI光谱和化学交换饱和转移MRI技术进行测量。 C.左室舒张充盈参数（在静息和峰值运动时用超声心动图测量）和心肌应变（用斑点追踪超声心动图评估）。(3)收缩晚期LV负荷（通过时间分辨LV壁应力和主动脉压力-血流关系，使用动脉张力测定和多普勒超声心动图进行评估）。如果我们的机械靶向干预可以改善运动能力、运动血管和肌肉储备以及动脉血流动力学，那么它将在HFpEF中建立一种新的、易于实施的治疗模式。