Original Investigation
Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction

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Abstract

Background

There is no effective medical treatment for heart failure with preserved ejection fraction (HFpEF). Increases in pulmonary capillary wedge pressure (PCWP) develop in patients with HFpEF during exercise coupled with impaired nitric oxide (NO) signaling. Nitrite can be reduced to bioactive NO in vivo, particularly under conditions of tissue hypoxia, as with exercise.

Objectives

This study sought to determine whether acute nitrite administration improves exercise hemodynamics and cardiac reserve in HFpEF.

Methods

In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF (N = 28) underwent invasive cardiac catheterization with simultaneous expired gas analysis at rest and during exercise, before and 15 min after treatment with either sodium nitrite or matching placebo.

Results

Before the study drug infusion, HFpEF subjects displayed an increase in PCWP with exercise from 16 ± 5 mm Hg to 30 ± 7 mm Hg (p < 0.0001). After study drug infusion, the primary endpoint of exercise PCWP was substantially improved by nitrite compared with placebo (adjusted mean: 19 ± 5 mm Hg vs. 28 ± 6 mm Hg; p = 0.0003). Nitrite-enhanced cardiac output reserve improved with exercise (+0.5 ± 0.7 l/min vs. −0.4 ± 0.7 l/min; p = 0.002) and normalized the increase in cardiac output relative to oxygen consumption. Nitrite improved pulmonary artery pressure-flow relationships in HFpEF and increased left ventricular stroke work with exercise versus placebo, indicating an improvement in ventricular performance with stress.

Conclusions

Acute sodium nitrite infusion favorably attenuates hemodynamic derangements of cardiac failure that develop during exercise in individuals with HFpEF. Prospective trials testing long-term nitrite therapy in this population are warranted. (Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction; NCT01932606)

Key Words

cardiac output
nitrate
pressure
stroke volume

Abbreviations and Acronyms

BP
blood pressure
Cao2 − Cvo2
arteriovenous oxygen content difference
cGMP
cyclic guanosine monophosphate
CO
cardiac output
HFpEF
heart failure with preserved ejection fraction
LV
left ventricular
NO
nitric oxide
PA
pulmonary artery
PCWP
pulmonary capillary wedge pressure
PVR
pulmonary vascular resistance
RAP
right atrial pressure
SV
stroke volume
SVR
systemic vascular resistance
Vo2
oxygen consumption
VE/Vco2
ventilatory efficiency

Cited by (0)

This study was supported by a grant from the Mayo Clinic Division of Cardiovascular Diseases. Dr. Borlaug receives research support from Aires Pharmaceuticals for a separate study examining the use of inhaled nitrite in patients with HFpEF. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.