Abstract
Background
Heart failure with preserved ejection fraction (HFpEF) is common, yet there is a lack of effective treatments. In this meta-analysis, we assessed the efficacy and safety of inorganic nitrate in patients with HFpEF.
Methods and Results
We systematically searched PubMed, Embase, and the Cochrane Library from the inception of the database through March 2020. We included randomized controlled trials that compared the efficacy and safety of inorganic nitrate with a placebo in the treatment of patients with HFpEF. The primary outcome of the meta-analysis was exercise capacity (measured as a change in peak oxygen uptake). We also assessed the effect of inorganic nitrate on diastolic function (measured as changes in E/A and E/e’, assessed by echocardiography), quality of life (estimated using the Kansas City Cardiomyopathy Questionnaire), and rest and exercise hemodynamics (measured by invasive cardiac catheterization). In the pooled data analysis, there were no significant differences in peak oxygen uptake (mL/kg/min) [mean difference (MD), 0.25; 95% CI, − 0.07 to 0.57], diastolic function [E/A–standardized mean difference (SMD), 0.51; 95% CI, − 0.17 to 1.20; or E/e’–SMD, 0.02; 95% CI, − 0.23 to 0.27], or quality of life. However, a significant change was observed in the rest and exercise hemodynamics between the inorganic nitrate and placebo treatment in HFpEF patients. No study has reported the effect of inorganic nitrate on hospitalization and mortality of patients with HFpEF.
Conclusions
In patients with HFpEF, the use of inorganic nitrate is not associated with improvements in exercise capacity, diastolic function, and quality of life but is associated with significant changes in rest and exercise hemodynamics.
Similar content being viewed by others
References
Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF registry. J Am Coll Cardiol. 2007;50(8):768–77.
Meta-analysis Global Group in Chronic Heart F. The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J. 2012;33(14):1750–7.
Guazzi M, Myers J, Arena R. Cardiopulmonary exercise testing in the clinical and prognostic assessment of diastolic heart failure. J Am Coll Cardiol. 2005;46(10):1883–90.
Reddy YNV, Olson TP, Obokata M, Melenovsky V, Borlaug BA. Hemodynamic correlates and diagnostic role of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. JACC Heart Fail. 2018;6(8):665–75.
Lam CSP, Voors AA, de Boer RA, Solomon SD, van Veldhuisen DJ. Heart failure with preserved ejection fraction: from mechanisms to therapies. Eur Heart J. 2018;39(31):2780–92.
Borlaug BA. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction. Circ J. 2014;78(1):20–32.
Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010;56(11):845–54.
Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006;114(20):2138–47.
Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan TM, et al. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol. 2014;306(9):H1364–70.
Haykowsky MJ, Kouba EJ, Brubaker PH, Nicklas BJ, Eggebeen J, Kitzman DW. Skeletal muscle composition and its relation to exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Cardiol. 2014;113(7):1211–6.
Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263–71.
Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, et al. Isosorbide Mononitrate in heart failure with preserved ejection fraction. N Engl J Med. 2015;373(24):2314–24.
Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008;7(2):156–67.
Patel JN, Shah SJ. Inorganic vs. organic nitrates for heart failure with preserved ejection fraction: it's not all in your head! Eur J Heart Fail. 2017;19(11):1516–9.
Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, et al. One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. JACC: Heart Fail. 2016;4(6):428–37.
Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, et al. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015;131(4):371–80.
Zamani P, Tan V, Soto-Calderon H, Beraun M, Brandimarto JA, Trieu L, et al. Pharmacokinetics and pharmacodynamics of inorganic nitrate in heart failure with preserved ejection fraction. Circ Res. 2017;120(7):1151–61.
Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, et al. Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: the INDIE-HFpEF randomized clinical trial. Jama. 2018;320(17):1764–73.
Shaltout HA, Eggebeen J, Marsh AP, Brubaker PH, Laurienti PJ, Burdette JH, et al. Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction. Nitric Oxide Biol Chem. 2017;69:78–90.
Borlaug BA, Koepp KE, Melenovsky V. Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2015;66(15):1672–82.
Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res. 2016;119(7):880–6.
Londono-Hoyos F, Zamani P, Beraun M, Vasim I, Segers P, Chirinos JA. Effect of organic and inorganic nitrates on cerebrovascular pulsatile power transmission in patients with heart failure and preserved ejection fraction. Physiol Meas. 2018;39(4):044001.
Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, et al. Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight. 2016;1(18):e89620.
Reddy YNV, Andersen MJ, Obokata M, Koepp KE, Kane GC, Melenovsky V, et al. Arterial stiffening with exercise in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol. 2017;70(2):136–48.
Chirinos JA, Londono-Hoyos F, Zamani P, Beraun M, Haines P, Vasim I, et al. Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction. Eur J Heart Fail. 2017;19(11):1507–15.
Lim SL, Benson L, Dahlstrom U, Lam CSP, Lund LH. Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2017;10(4):e003534.
Tsujimoto T, Kajio H. Use of nitrates and risk of cardiovascular events in patients with heart failure with preserved ejection fraction. Mayo Clin Proc. 2019;94(7):1210–20.
Miller GD, Marsh AP, Dove RW, Beavers D, Presley T, Helms C, et al. Plasma nitrate and nitrite are increased by a high-nitrate supplement but not by high-nitrate foods in older adults. Nutr Res. 2012;32(3):160–8.
Santos M, Opotowsky AR, Shah AM, Tracy J, Waxman AB, Systrom DM. Central cardiac limit to aerobic capacity in patients with exertional pulmonary venous hypertension: implications for heart failure with preserved ejection fraction. Circ Heart Fail. 2015;8(2):278–85.
van Empel VP, Mariani J, Borlaug BA, Kaye DM. Impaired myocardial oxygen availability contributes to abnormal exercise hemodynamics in heart failure with preserved ejection fraction. J Am Heart Assoc. 2014;3(6):e001293.
Vanderpool R, Gladwin MT. Harnessing the nitrate-nitrite-nitric oxide pathway for therapy of heart failure with preserved ejection fraction. Circulation. 2015;131(4):334–6.
Andersen MJ, Olson TP, Melenovsky V, Kane GC, Borlaug BA. Differential hemodynamic effects of exercise and volume expansion in people with and without heart failure. Circ Heart Fail. 2015;8(1):41–8.
Abudiab MM, Redfield MM, Melenovsky V, Olson TP, Kass DA, Johnson BD, et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail. 2013;15(7):776–85.
Funding
This study was funded by the grant from the National Natural Science Foundation of China (Nos. 81672264 and 81871858).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights
This article does not contain any studies with human participants performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gui, Y., Chen, J., Hu, J. et al. Efficacy and Safety of Inorganic Nitrate Versus Placebo Treatment in Heart Failure with Preserved Ejection Fraction. Cardiovasc Drugs Ther 34, 503–513 (2020). https://doi.org/10.1007/s10557-020-06980-4
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10557-020-06980-4