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：
9304280
负责人：
JULIO ALONSO CHIRINOS MEDINA
金额：
$ 61.87万
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/9304280
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 Failure Flexor Functional disorder Gender Heart Heart failure Hypoxia Image Impairment Intervention Kansas Kinetics Left Left Ventricular Ejection Fraction Left Ventricular Remodeling Link Magnetic Resonance Imaging Measures Mediating Methods Mitochondria Morbidity - disease rate Muscle 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 Standardization Stress Supination Supplementation Techniques Testing Therapeutic Therapeutic Intervention Time Travel Treatment Failure Vasodilation Vasodilator Agents Ventricular Woman Workload aged arterial tonometry clinically relevant control trial dietary nitrate effective therapy exercise capacity exercise intolerance 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（由适用提供）：大约50％的HF患者的射血分数正常（HF保留的射血分数，HFPEF）。目前尚无HFPEF的有效药理干预措施。鉴于HFPEF的巨大伯恩（Burnen），为这种情况找到有效的疗法是当务之急。锻炼是HFPEF的Hallmrk，并严重损害了生活质量。最近的证据将周围血管舒张的异常与HFPEF中的肠道运动联系起来。无机循环亚硝酸盐构成了潜在血管扩张剂一氧化氮（NO）的重要来源，该氧化物（NO）在缺氧的情况下优先运行，就像运动肌肉中发生的那样。饮食硝酸盐还会在骨骼肌中发挥线粒体作用。除了这些与运动相关的作用外，饮食中的硝酸盐还具有外周效应，具有慢性“改良疾病改良”益处的外围作用，尤其是晚期收缩期负荷的降低，这似乎促进了左心室重塑和舒张功能障碍。我们来自双盲安慰剂对照试验的初步数据表明，单剂量的无机硝酸盐可提高有氧运动能力，外周血管舒张剂对运动，骨骼肌线粒体氧化功能和左心室晚期的骨骼氧化功能的反应。我们提出了一项飞行员随机跨界双盲对照试验，以比较6周内硝酸钾（每天3次）每天进行3次MEQ（每天三次）的影响：（1）临床终点：运动能力（氧气消耗量[VO2]，在最大的运动测试中）和生活质量（评估了堪萨斯州城市Cardiomyopathy问题）。（2）锻炼的特定生理适应：全身血管扩张器对运动的反应（通过最大程度地努力运动在全身血管抗性的变化中评估）b。运动和肌肉氧化能力期间的肌肉组织血流：通过动脉MRI自旋标记，磷MRI光谱和化学交换饱和度转移MRI技术在标准化足底屈肌运动测试过程中测量。 c。 LV舒张期填充参数（在休息和峰值运动时用超声心动图测量）和心肌菌株（通过斑点跟踪超声心动图评估）。（3）收缩期LV载荷（通过使用动脉沟通和多普勒超声心动图评估，通过时间分辨的LV壁应力和主动脉压力流关系评估）。如果我们针对机械的干预措施可以提高运动能力，运动血管和肌肉储备以及动脉血流动力学，则将在HFPEF中建立一个新的，易于实现的治疗范式。