Zamani Payman, Shah Sanjiv J, Cohen Jordana B, Zhao Manyun, Yang Wei, Afable Jessica L, Caturla Maria, Maynard Hannah, Pourmussa Bianca, Demastus Cassandra, Mohanty Ipsita, Miyake Michelle Menon, Adusumalli Srinath, Margulies Kenneth B, Prenner Stuart B, Poole David C, Wilson Neil, Reddy Ravinder, Townsend Raymond R, Ischiropoulos Harry, Cappola Thomas P, Chirinos Julio A
Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Northwestern University Feinberg School of Medicine, Chicago, Illinois.
JAMA Cardiol. 2025 Mar 1;10(3):284-289. doi: 10.1001/jamacardio.2024.4417.
Nitric oxide deficiency may contribute to exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Prior pilot studies have shown improvements in exercise tolerance with single-dose and short-term inorganic nitrate administration.
To assess the impact of chronic inorganic nitrate administration on exercise tolerance in a larger trial of participants with HFpEF.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter randomized double-blinded crossover trial was conducted at the University of Pennsylvania, the Philadelphia Veterans Affairs Medical Center, and Northwestern University between October 2016 and July 2022. Participants included patients with symptomatic (New York Heart Association class II/III) HFpEF who had objective signs of elevated left ventricular filling pressures. Image quantification, physiological data modeling and biochemical measurements, unblinding, and statistical analyses were completed in 2024.
Potassium nitrate (KNO3) (6 mmol 3 times daily) vs equimolar doses of potassium chloride (KCl) for 6 weeks, each with a 1-week washout in between.
The coprimary end points included peak oxygen uptake and total work performed during a maximal effort incremental cardiopulmonary exercise test. Secondary end points included the exercise systemic vasodilatory reserve (ie, reduction in systemic vascular resistance with exercise) and quality of life assessed using the Kansas City Cardiomyopathy Questionnaire.
Eighty-four participants were enrolled. Median age was 68 years and 58 participants were women (69.0%). Most participants had NYHA class II disease (69%) with a mean 6-minute walk distance of 335.5 (SD, 97.3) m. Seventy-seven participants received the KNO3 intervention and 74 received the KCl intervention. KNO3 increased trough levels of serum nitric oxide metabolites after 6 weeks (KNO3, 418.4 [SD, 26.9] uM vs KCl, 40.1 [SD, 28.3] uM; P < .001). KNO3 did not improve peak oxygen uptake (KNO3, 10.23 [SD, 0.43] mL/min/kg vs KCl, 10.17 [SD, 0.43] mL/min/kg; P = .73) or total work performed (KNO3, 25.9 [SD, 3.65] kilojoules vs KCl, 23.63 [SD, 3.63] kilojoules; P = .29). KNO3 nitrate did not improve the vasodilatory reserve or quality of life, though it was well-tolerated.
In this study, potassium nitrate did not improve aerobic capacity, total work, or quality of life in participants with HFpEF.
ClinicalTrials.gov Identifier: NCT02840799.
一氧化氮缺乏可能导致射血分数保留的心力衰竭（HFpEF）患者运动不耐受。先前的试点研究表明，单剂量和短期给予无机硝酸盐可改善运动耐量。
在一项针对HFpEF参与者的更大规模试验中，评估长期给予无机硝酸盐对运动耐量的影响。
设计、地点和参与者：这项多中心随机双盲交叉试验于2016年10月至2022年7月在宾夕法尼亚大学、费城退伍军人事务医疗中心和西北大学进行。参与者包括有症状（纽约心脏协会II/III级）HFpEF且有左心室充盈压升高客观体征的患者。图像定量、生理数据建模和生化测量、揭盲及统计分析于2024年完成。
硝酸钾（KNO3）（每日3次，每次6 mmol）与等摩尔剂量的氯化钾（KCl），各治疗6周，中间有1周的洗脱期。
共同主要终点包括最大负荷递增心肺运动试验期间的峰值摄氧量和总做功量。次要终点包括运动时的全身血管舒张储备（即运动时全身血管阻力的降低）以及使用堪萨斯城心肌病问卷评估的生活质量。
共纳入84名参与者。中位年龄为68岁，58名参与者为女性（69.0%）。大多数参与者患有纽约心脏协会II级疾病（69%），平均6分钟步行距离为335.5（标准差，97.3）m。77名参与者接受了KNO3干预，74名参与者接受了KCl干预。6周后，KNO3使血清一氧化氮代谢产物的谷值水平升高（KNO3，418.4[标准差，26.9]μM vs KCl，40.1[标准差，28.3]μM；P < .001）。KNO3并未改善峰值摄氧量（KNO3，10.23[标准差，0.43]mL/min/kg vs KCl，10.17[标准差，0.43]mL/min/kg；P = .73）或总做功量（KNO3，25.9[标准差，3.65]千焦 vs KCl，23.63[标准差，3.63]千焦；P = .29）。硝酸钾并未改善血管舒张储备或生活质量，不过其耐受性良好。
在本研究中，硝酸钾并未改善HFpEF参与者的有氧运动能力、总做功量或生活质量。
ClinicalTrials.gov标识符：NCT02840799。
