Introduction:
Prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, especially among older adults. HFpEF is commonly associated with exercise intolerance and skeletal muscle weakening which likely contribute to functional decline. We studied the utility of nitrite (NO
2
) supplementation with the aim to augment skeletal muscle mitochondrial respiration.
Hypothesis:
NO
2
administered via oral supplements would be associated with improved mitochondrial respiration. Whereas prior studies with other oral and inhaled nitrate and NO
2
therapy in HFpEF patients have been inconsistent, we used novel NO
2
capsules that we hypothesized would achieve higher serum levels of nitrite and nitrate, and greater cellular and clinical benefits.
Methods:
A randomized, placebo-controlled pilot trial to study the utility of oral sodium (Na) NO
2
over 4 weeks in an older population (≥70 years) was done. Participants received 20 or 40 mg Na-NO
2
supplements 3 times daily based on their hemodynamic responses. Pre- and post-NO
2
intervention participants underwent biopsies of the vastus lateralis muscle with associated assessments of mitochondrial respiration in permeabilized fibers and also completed cardiopulmonary exercise test.
Results:
15 participants were randomized and 13 completed the interventions (n=6 on NO
2
, n=7 on placebo, 69% men, mean age 75.7 years, range 70-91). Post-intervention serum NO
2
level increased (+0.61±0.67 μmol on NO
2,
+0.25±0.15 on placebo). Ex-vivo analysis of mitochondrial respiration showed increased O
2
consumption in muscle (+27.1±27.4 pmol/(s*mg) on NO
2
, -11.7±11.3 on placebo). Rated perceived exertion during steady-state walking decreased (-1.2±2.0 on NO
2,
+0.2±1.6 on placebo). Peak oxygen uptake (VO
2
) increased (+1.4±5.2 ml/kg/min on NO2, -3.4±5.2 on placebo).
Conclusion:
Our study demonstrated efficacy and potential clinical utility of oral NO
2
supplementation in older HFpEF patients with an internally consistent physiologic composite of improved skeletal muscle mitochondrial respiration in association with improved cardiorespiratory fitness and diminished perceived exertion during steady-state walking. Clinical implications are auspicious and further research is indicated.
Sarcopenic Obesity and the Pathogenesis of Exercise Intolerance in Heart Failure with Preserved Ejection Fraction
