Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction

Abstract

Rationale: Abnormalities in nitric oxide signaling play a pivotal role in heart failure with preserved ejection fraction (HFpEF). Intravenous sodium nitrite, which is converted to nitric oxide in vivo, improves hemodynamics in HFpEF, but its use is limited by the need for parenteral administration. Nitrite can also be administered using a novel, portable micronebulizer system suitable for chronic use.

Objective: Determine whether inhaled nitrite improves hemodynamics in HFpEF.

Methods and results: In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF (n=26) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise before and after treatment with inhaled sodium nitrite (90 mg) or placebo. The primary end point was the pulmonary capillary wedge pressure during exercise. Before study drug administration, HFpEF subjects displayed an increase in pulmonary capillary wedge pressure with exercise from 20±6 to 34±7 mm Hg (P<0.0001). After study drug administration, exercise pulmonary capillary wedge pressure was substantially improved by nitrite as compared with placebo (baseline-adjusted mean 25±5 versus 31±6 mm Hg; analysis of covariance P=0.022). Inhaled nitrite reduced resting pulmonary capillary wedge pressure (-4±3 versus -1±2 mm Hg; P=0.002), improved pulmonary artery compliance (+1.5±1.1 versus +0.6±0.9 mL/mm Hg), and decreased mean pulmonary artery pressures at rest (-7±4 versus -3±4 mm Hg; P=0.007) and with exercise (-10±6 versus -5±6 mm Hg; P=0.05). Nitrite reduced right atrial pressures, with no effect on cardiac output or stroke volume.

Conclusions: Acute administration of inhaled sodium nitrite reduces biventricular filling pressures and pulmonary artery pressures at rest and during exercise in HFpEF. Further study is warranted to evaluate chronic effects of inhaled nitrite in HFpEF.

Clinical trial registration: This single center randomized clinical trial is registered at clinicaltrials.gov (NCT02262078).

Keywords: exercise; heart failure; hemodynamics; nitrate; nitric oxide.

Figure 1

Compared to placebo (black), nitrite administration (red) significantly lowered right atrial pressure (RA), pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (mPAP) at rest, while improving pulmonary artery compliance (PAC). Error bars indicate SEM.

Figure 2

[A] Compared to placebo (black), nitrite (red) significantly improved the primary trial endpoint of exercise pulmonary capillary wedge pressure (PCWP), [B] with effects that were observed both at rest (solid line) and during exercise (dashed line). Error bars indicate SEM.