Efficacy of Potassium Nitrate in Heart Failure with Preserved Ejection Fraction

 描述(申请人提供)：大约50%的心衰患者射血分数正常(射血分数保留)。目前还没有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的特征，极大地损害生活质量。最近的证据将外周血管扩张异常与HFpEF的运动不耐受联系起来。无机循环中的亚硝酸盐是一种强有力的血管扩张剂一氧化氮(NO)的重要来源，它在低氧情况下优先发挥作用，就像在锻炼肌肉时一样。饮食中的硝酸盐也对骨骼肌中的线粒体起作用。除了这些与运动有关的影响外，饮食硝酸盐还会产生外周影响，有可能在HFpEF中产生慢性“疾病修正”益处，特别是减少收缩晚期负荷，这似乎会促进左心室重塑和舒张期功能障碍。我们来自双盲交叉安慰剂对照试验的初步数据表明，单剂量无机硝酸盐可以改善有氧能力、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。我们提出了一项试验性随机双盲对照试验，以比较硝酸钾(每天三次口服6mEq)在6周内对以下方面的影响：(1)临床终点：运动能力(最大运动试验期间的最大氧耗[VO2])和生活质量(使用堪萨斯城心肌病问卷进行评估)。(2)对运动的特殊生理适应：a.全身血管扩张剂对运动的反应(通过最大努力仰卧自行车运动时全身血管阻力的变化来评估)b.运动中的肌肉组织血流量和肌肉氧化能力：在标准化的足底屈肌运动测试中，采用动脉MRI自旋标记、磷MRI光谱和化学交换饱和转移MRI技术测量肌肉氧化能力。C.左心室舒张期充盈参数(静息和高峰运动时用超声心动图测量)和心肌应变(用斑点跟踪超声心动图评估)。(3)收缩晚期LV负荷(通过动脉血压计和多普勒超声心动图，通过时间分辨的LV壁应力和主动脉压力-流量关系来评估)。如果我们的机械靶向干预改善了运动能力、运动血管和肌肉储备以及动脉血流动力学，它将在HFpEF中建立一种新的、易于实施的治疗范例。

 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.