Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction. Reddy Yogesh N V,Stewart Glenn M,Obokata Masaru,Koepp Katlyn E,Borlaug Barry A European journal of heart failure AIMS:To determine whether inorganic nitrite improves peripheral and pulmonary oxygen (O ) transport during exercise in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS:Data from two invasive, randomized, double-blind, placebo-controlled trials with matched workload exercise of inhaled and intravenous sodium nitrite were pooled for this analysis (n = 51). Directly measured O consumption (VO ) and blood gas data were used to evaluate the effect of nitrite on skeletal muscle O conductance (Dm), VO kinetics, alveolar capillary membrane O conductance (D ), and O utilization during submaximal exercise. As compared to placebo, treatment with nitrite resulted in an improvement in Dm (+4.9 ± 6.5 vs. -0.9 ± 4.3 mL/mmHg*min, P = 0.0008) as well as VO kinetics measured by mean response time (-5.0 ± 6.9 vs. -0.6 ± 6.0 s, P = 0.03), with preserved O utilization despite increased convective O delivery through cardiac output (+0.4 ± 0.7 vs. -0.3 ± 0.9 L/min, P = 0.02). Nitrite improved D (+2.5 ± 6.3 vs. -2.0 ± 9.0 mL/mmHg*min, P = 0.05) with exercise, which was associated with lower pulmonary capillary pressures (r = -0.34, P = 0.02), and reduced pulmonary dead space ventilation fraction (-0.01 ± 0.05 vs. +0.02 ± 0.05, P = 0.02). CONCLUSION:Sodium nitrite enhances skeletal muscle Dm during exercise as well as pulmonary O diffusion, optimizing O kinetics in tandem with increased convective O delivery through cardiac output augmentation. The favourable combined pulmonary, cardiac and peripheral effects of nitrite may improve exercise tolerance in people with HFpEF and requires further investigation. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov ID NCT01932606 and NCT02262078. 10.1002/ejhf.2093

Inorganic Nitrite to Amplify the Benefits and Tolerability of Exercise Training in Heart Failure With Preserved Ejection Fraction: The INABLE-Training Trial. Mayo Clinic proceedings OBJECTIVE:To determine whether nitrite can enhance exercise training (ET) effects in heart failure with preserved ejection fraction (HFpEF). METHODS:In this multicenter, double-blind, placebo-controlled, randomized trial conducted at 1 urban and 9 rural outreach centers between November 22, 2016, and December 9, 2021, patients with HFpEF underwent ET along with inorganic nitrite 40 mg or placebo 3 times daily. The primary end point was peak oxygen consumption (VO). Secondary end points included Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS, range 0 to 100; higher scores reflect better health status), 6-minute walk distance, and actigraphy. RESULTS:Of 92 patients randomized, 73 completed the trial because of protocol modifications necessitated by loss of drug availability. Most patients were older than 65 years (80%), were obese (75%), and lived in rural settings (63%). At baseline, median peak VO (14.1 mL·kg·min) and KCCQ-OSS (63.7) were severely reduced. Exercise training improved peak VO (+0.8 mL·kg·min; 95% CI, 0.3 to 1.2; P<.001) and KCCQ-OSS (+5.5; 95% CI, 2.5 to 8.6; P<.001). Nitrite was well tolerated, but treatment with nitrite did not affect the change in peak VO with ET (nitrite effect, -0.13; 95% CI, -1.03 to 0.76; P=.77) or KCCQ-OSS (-1.2; 95% CI, -7.2 to 4.9; P=.71). This pattern was consistent across other secondary outcomes. CONCLUSION:For patients with HFpEF, ET administered for 12 weeks in a predominantly rural setting improved exercise capacity and health status, but compared with placebo, treatment with inorganic nitrite did not enhance the benefit from ET. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02713126. 10.1016/j.mayocp.2023.08.031