THE INORGANIC NITRATE FOR EXERCISE IN HEART FAILURE (INIX-HF) TRIAL

摘要 射血分数降低的心力衰竭（HFrEF）在美国影响大约300万人，并且是致命的， 病态疾病。HFrEF损害患者锻炼和进行日常生活活动的能力。虽然 心脏泵血能力弱明显导致与HFrEF相关的慢性残疾，骨骼异常 HFrEF患者的肌肉也是一个关键的衰弱因素。因此，骨骼肌是一个重要的目标， 治疗HFrEF。无机硝酸盐提高有氧运动能力和肌肉力量的初步研究 HFrEF患者的研究。我们研究的总体目标（以及后续随机临床试验） [RCT]）的目的是确定无机硝酸盐是否提供了一种新的，安全有效的治疗方法， 因HFrEF而致残。本研究的具体目的是：1）确定无机硝酸盐的最佳用量 对于HFrEF患者; 2）确定最佳主要终点（有氧能力或肌肉力量）和 RCT所需的患者数量;以及3）建立所需的基础设施和手册 在多个医疗中心标准化RCT方案的性能。对于目标1， 10 mmol和20 mmol KNO 3与安慰剂对血流动力学、硝酸盐和亚硝酸盐血液水平以及呼吸的影响 将测量NO并记录任何副作用。在目标2中，一项2周KNO 3的小型II期临床试验 在一项随机、安慰剂对照、非交叉设计研究中， 执行。该目标的终点将是有氧能力（峰值耗氧量-VO 2峰值）， 在跑步机运动期间使用代谢推车测量，并且使用 Biodex机器在目标3中，将建设RCT所需的所有基础设施。一个RedCAP™ 将创建用于所有RCT研究中心数据录入、存储和导出的数据库。所有核心（数据协调 中心、成像分析中心、实验室中心、运动分析中心、药学中心） 并编写操作手册。寻找一种新的、安全有效的 帮助数百万患者战胜HFrEF残疾的治疗是巨大的。

ABSTRACT Heart failure with reduced ejection fraction (HFrEF) affects roughly 3 million in the U.S. and is a mortal and morbid disease. HFrEF impairs a patient's ability to exercise and perform activities of daily living. Although weak cardiac pumping ability clearly contributes to chronic disability associated with HFrEF, abnormal skeletal muscle in patients with HFrEF is also a key debilitating factor. Skeletal muscle is therefore a vital target for treatment of HFrEF. Inorganic nitrate enhances aerobic exercise capacity and muscle power in preliminary studies of patients with HFrEF. The overarching aim of our study (and the follow-up randomized clinical trial [RCT]) is to determine whether inorganic nitrate offers a new, safe and effective treatment for ameliorating the disability due to HFrEF. The Specific Aims of this study are 1) to determine the best dose of inorganic nitrate for patients with HFrEF; 2) to determine the best primary endpoint (aerobic capacity or muscle power) and the number of patients that will be needed for the RCT; and 3) to set up the infrastructure and manuals needed for standardized performance of the RCT protocols across multiple medical centers. For Aim 1, the effects of 10mmol and 20mmol of KNO3 vs. placebo on hemodynamics, and blood levels of nitrate and nitrite and breath NO will be measured and any side effects noted. In Aim 2, a small, phase II clinical trial of 2 wk of KNO3 treatment (dose determined by Aim 1) in a randomized, placebo-controlled, non-crossover design study will be performed. The endpoints of this aim will be aerobic capacity (peak oxygen consumption – VO2peak), measured during treadmill exercise using a metabolic cart and peak quadriceps muscle power measured using a Biodex machine. In Aim 3, all of the infrastructure needed for the RCT will be constructed. A RedCAP™ database for data entry, storage, and export from all RCT sites will be created. All Cores (Data Coordinating Center, Imaging Analysis Core, Laboratory Core, Exercise Analysis Core, Pharmacy Core) for the RCT will be established and Manuals of Operation will be written. The potential impact of finding a new, safe and effective treatment that helps millions of patients beat the disability of HFrEF is enormous.