Effect of Inorganic Nitrate on Exercise Capacity in Heart Failure With Preserved Ejection Fraction
Open accessAbstract
Background—: Inorganic nitrate (NO 3 − ), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide in the setting of hypoxia. We tested the hypothesis that NO 3 − supplementation improves exercise capacity in heart failure with preserved ejection fraction via specific adaptations to exercise. Methods and Results—: Seventeen subjects participated in this randomized, double-blind, crossover study comparing a single dose of NO 3 -rich beetroot juice (NO 3 − , 12.9 mmol) with an identical nitrate-depleted placebo. Subjects performed supine-cycle maximal-effort cardiopulmonary exercise tests, with measurements of cardiac output and skeletal muscle oxygenation. We also assessed skeletal muscle oxidative function. Study end points included exercise efficiency (total work/total oxygen consumed), peak o 2 , 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 nitric oxide metabolites (median, 326 versus 10 μmol/L; P =0.0003), peak o 2 (12.6±3.7 versus 11.6±3.1 mL O 2 ·min −1 ·kg −1 ; P =0.005), and total work performed (55.6±35.3 versus 49.2±28.9 kJ; P =0.04). However, efficiency was unchanged. NO 3 − led to greater reductions in systemic vascular resistance (−42.4±16.6% versus −31.8±20.3%; P =0.03) and increases in cardiac output (121.2±59.9% versus 88.7±53.3%; P =0.006) with exercise. NO 3 − reduced aortic augmentation index (132.2±16.7% versus 141.4±21.9%; P =0.03) and tended to improve mitochondrial oxidative function. Conclusions—: NO 3 − increased exercise capacity in heart failure with preserved ejection fraction by targeting peripheral abnormalities. Efficiency did not change as a result of parallel increases in total work and o 2. NO 3 − increased exercise vasodilatory and cardiac output reserves. NO 3 − also reduced arterial wave reflections, which are linked to left ventricular diastolic dysfunction and remodeling. Clinical Trial Registration—: URL: www.clinicaltrials.gov . Unique identifier: NCT01919177.
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Dietary nitrate has been shown to improve exercise tolerance in heart failure patients (~65-69-year-olds) with preserved ejection fraction.
“in heart failure patients (∼65-69-year-olds) with preserved ejection fraction (39,171)”
From Dietary Nitrate and Physical Performance (2018) · cites this paper as [171]
In patients with heart failure and preserved ejection fraction, nitrate supplementation increased exercise duration, total work, peak oxygen extraction and cardiac output.
“for patients with HF and preserved ejection fraction, nitrate supplementation increased exercise duration, total work and increased both peak oxygen extraction and cardiac output (Zamani et al. 2015).”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Zamani et al. 2015
In heart failure and cardiomyopathy, dietary nitrate improves left ventricular function in mice and overall cardiac contractility and exercise performance in humans.
“Additionally, in the setting of heart failure and cardiomyopathy, dietary nitrate improves left ventricular function in mice[133] and overall cardiac contractility and exercise performance in humans[134–137]”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [137]
In a population of individuals with HFpEF, there was a 14% increase in cardiopulmonary exercise testing performance in 17 patients after a single dose of beetroot juice (12.9 mmol nitrate).
“Further, in a population of individuals with HFpEF, there was a 14% increase in cardiopulmonary exercise testing performance in 17 patients after a single dose of beetroot juice (12.9 mmol nitrate)[137]”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [137]
Clinically, nitrate supplementation improves exercise performance in patients with heart failure and HFpEF.
“improved exercise performance in patients with heart failure and HFpEF[135,137,151].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [137]
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Bailey, S. J., Gandra, P. G., Jones, A. M., Hogan, M. C., & Nogueira, L. (2019) · The Journal of Physiology · doi:10.1113/jp278494 · Cited by 51 · see citing works
Nitric oxide, aging and aerobic exercise: Sedentary individuals to Master's athletes
Shannon, O. M., Clifford, T., Seals, D. R., Craighead, D. H., & Rossman, M. J. (2022) · Nitric Oxide · doi:10.1016/j.niox.2022.06.002 · Cited by 51 · see citing works
Siervo, M., Oggioni, C., Jakovljevic, D. G., Trenell, M., Mathers, J. C., Houghton, D., Celis-Morales, C., Ashor, A. W., Ruddock, A., Ranchordas, M., et al. (2016) · Nutrition Research · doi:10.1016/j.nutres.2016.11.004 · Cited by 37 · see citing works
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Dietary Nitrate and Skeletal Muscle Contractile Function in Heart Failure
Coggan, A. R., & Peterson, L. R. (2016) · Current Heart Failure Reports · doi:10.1007/s11897-016-0293-9 · Cited by 20 · see citing works
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- Authors
- Zamani, P., Rawat, D., Shiva-Kumar, P., Geraci, S., Bhuva, R., Konda, P., Doulias, P.-T., Ischiropoulos, H., Townsend, R. R., Margulies, K. B., Cappola, T. P., Poole, D. C., & Chirinos, J. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R...
- ORCID
- Venue
- Circulation
- Published
- 2015-01-27
- Volume
- 131
- Issue
- 4
- Pages
- 371-380
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC5823250
- OpenAlex
- W2000501615
- Cited by
- 307
- References
- 53
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 16 · 2023: 14 · 2022: 22 · 2021: 15 · 2020: 24 · 2019: 31 · 2018: 42 · 2017: 50 · 2016: 37 · 2015: 27 · 2014: 1
- FWCI
- 82.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL54926, HL110338, R21HL113777, HL105993, HL113777, R01HL054926, R01HL105993, U10HL110338)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- inorganic nitrate, nitrate supplementation, beetroot juice, heart failure with preserved ejection fraction, exercise capacity, nitric oxide, nitrite, exercise efficiency, peak oxygen uptake, systemic vascular resistance, cardiac output, augmentation index, arterial wave reflection, left ventricular diastolic dysfunction, left ventricular remodeling, dietary nitrate
- MeSH terms
- Aged, Double-Blind Method, Exercise Test, Female, Heart Failure, Humans, Male, Middle Aged, Nitrates, Oxygen Consumption, Stroke Volume, Treatment Outcome, Exercise Tolerance, Cross-Over Studies
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