The Effect of Inorganic Nitrate on Exercise Capacity in Heart Failure with Preserved Ejection Fraction
Background—Inorganic nitrate (NO3-), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide (NO) in the setting of hypoxia. We tested the hypothesis that NO3- supplementation improves exercise capacity in HFpEF via specific adaptations to exercise.
Methods and Results—Seventeen subjects participated in this randomized, double-blind, cross-over study comparing a single-dose of NO3-rich beetroot juice (NO3-:12.9 mmoles) versus an identical nitrate-depleted placebo. Subjects performed supine-cycle maximal-effort cardiopulmonary exercise tests, with measurements of cardiac output (CO) and skeletal muscle oxygenation. We also assessed skeletal muscle oxidative function. Study endpoints included exercise efficiency (total work/total oxygen consumed), peak VO2, total work performed, vasodilatory reserve, forearm mitochondrial oxidative function, and augmentation index (a marker of arterial wave reflections, measured via radial arterial tonometry). Supplementation increased plasma NO-metabolites (median 326 μM versus 10 μM; P=0.0003), peak VO2 (12.6±3.7 vs. 11.6±3.1 mL O2/min/kg; P=0.005), and total work performed (55.6±35.3 vs. 49.2±28.9 kJ; P=0.04). However, efficiency was unchanged. NO3- led to greater reductions in SVR (-42.4±16.6 vs. -31.8±20.3%; P=0.03) and increases in CO (121.2±59.9 vs. 88.7±53.3%; P=0.006) with exercise. NO3- reduced aortic augmentation index (132.2±16.7 vs. 141.4±21.9%, P=0.03) and tended to improve mitochondrial oxidative function.
Conclusions—NO3- increased exercise capacity in HFpEF by targeting peripheral abnormalities. Efficiency did not change due to parallel increases in total work and VO2. NO3- increased exercise vasodilatory and cardiac output reserves. NO3- also reduced arterial wave reflections, which are linked to left ventricular diastolic dysfunction and remodeling.
Clinical Trial Registration Information—www.clinicaltrials.gov.Identifier: NCT01919177.
- Received August 24, 2014.
- Revision received November 2, 2014.
- Accepted November 5, 2014.