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

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 (D_L ), 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 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 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.