Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction

Yogesh N V Reddy, Glenn M Stewart, Masaru Obokata, Katlyn E Koepp, Barry A Borlaug, Yogesh N V Reddy, Glenn M Stewart, Masaru Obokata, Katlyn E Koepp, Barry A Borlaug

Abstract

Aims: To determine whether inorganic nitrite improves peripheral and pulmonary oxygen (O2 ) 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 O2 consumption (VO2 ) and blood gas data were used to evaluate the effect of nitrite on skeletal muscle O2 conductance (Dm), VO2 kinetics, alveolar capillary membrane O2 conductance (DL ), and O2 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 VO2 kinetics measured by mean response time (-5.0 ± 6.9 vs. -0.6 ± 6.0 s, P = 0.03), with preserved O2 utilization despite increased convective O2 delivery through cardiac output (+0.4 ± 0.7 vs. -0.3 ± 0.9 L/min, P = 0.02). Nitrite improved DL (+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 O2 diffusion, optimizing O2 kinetics in tandem with increased convective O2 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.

Keywords: Exercise; Heart failure; Heart failure with preserved ejection fraction; Inorganic nitrite; Skeletal muscle.

© 2021 European Society of Cardiology.

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