Peripheral and pulmonary effects of <scp>inorganic nitrite</scp> during exercise in heart failure with preserved ejection fraction
Yogesh N.V. Reddy, Glenn M. Stewart, Masaru Obokata, Katlyn E. Koepp, Barry A. Borlaug
Abstract
Abstract Aims To determine whether inorganic nitrite improves peripheral and pulmonary oxygen (O 2 ) 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 2 consumption (VO 2 ) and blood gas data were used to evaluate the effect of nitrite on skeletal muscle O 2 conductance (Dm), VO 2 kinetics, alveolar capillary membrane O 2 conductance (D L ), and O 2 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 2 kinetics measured by mean response time (−5.0 ± 6.9 vs. −0.6 ± 6.0 s, P = 0.03), with preserved O 2 utilization despite increased convective O 2 delivery through cardiac output (+0.4 ± 0.7 vs. −0.3 ± 0.9 L/min, P = 0.02). Nitrite improved D L (+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 2 diffusion, optimizing O 2 kinetics in tandem with increased convective O 2 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.