The Efficacy of Nitrite Therapy for the Treatment of Heart Failure: A Meta-Analysis of Randomized Controlled Trials
DOI:
https://doi.org/10.1532/hsf.3215Keywords:
nitrite therapy, heart failure, randomized controlled trials, meta-analysisAbstract
Introduction: The efficacy of nitrite therapy for the treatment of heart failure remains controversial. We conducted a systematic review and meta-analysis to explore the impact of nitrite therapy on heart failure.
Methods: We searched the PubMed, EMbase, Web of Science, EBSCO, and Cochrane Library databases through November 2019 for randomized controlled trials (RCTs) assessing the effect of nitrite therapy on heart failure. This meta-analysis was performed using the random-effect model.
Results: Three RCTs are included in the meta-analysis. Overall, compared with the control group for heart failure, nitrite therapy is associated with significantly reduced PCWP (Std. MD=-1.22; 95% CI=-1.81 to -0.63; P < 0.0001) and improved PAC (Std. MD=0.71; 95% CI=0.16 to 1.27; P = 0.01), but reveals no substantial influence on peak VO2 (Std. MD=-0.19; 95% CI=-0.49 to 0.11; P = 0.21), systolic BP (Std. MD=-3.98; 95% CI=-8.24 to 0.28; P = 0.07), mean BP (Std. MD=-1.53; 95% CI=-3.37 to 0.31; P = 0.10), or heart rate (Std. MD=0.40; 95% CI=-0.14 to 0.94; P = 0.15).
Conclusions: Nitrite therapy may show some benefits to heart failure.
References
Andersen MJ, Olson TP, Melenovsky V, Kane GC, Borlaug BA. 2015. Differential hemodynamic effects of exercise and volume expansion in people with and without heart failure, Circ Heart Fail. 8(1) 41-8.
Bhushan S, Kondo K, Polhemus DJ, Otsuka H, Nicholson CK, Tao YX, Huang H, Georgiopoulou VV, Murohara T, Calvert JW, Butler J, Lefer DJ. 2014. Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling, Circ Res. 114(8) 1281-91.
Borlaug BA. 2014. The pathophysiology of heart failure with preserved ejection fraction, Nature reviews. Cardiology. 11(9) 507-15.
Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, Givertz MM, Felker GM, LeWinter MM, Mann DL. 2018. 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. 320(17) 1764-1773.
Borlaug BA, Koepp KE, Melenovsky V. 2015. Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction, Journal of the American College of Cardiology. 66(15) 1672-1682.
Borlaug BA, Melenovsky V, Koepp KE. 2016. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction, Circulation research. 119(7) 880-886.
Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. 2010. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction, Circulation: Heart Failure. 3(5) 588-595.
Borlaug BA, Paulus WJ. 2011. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment, Eur Heart J. 32(6) 670-9.
Dorfs S, Zeh W, Hochholzer W, Jander N, Kienzle RP, Pieske B, Neumann FJ. 2014. Pulmonary capillary wedge pressure during exercise and long-term mortality in patients with suspected heart failure with preserved ejection fraction, Eur Heart J. 35(44) 3103-12.
Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, Rejeski J, Kitzman DW. 2016. 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 Failure. 4(6) 428-437.
Eisman AS, Shah RV, Dhakal BP, Pappagianopoulos PP, Wooster L, Bailey C, Cunningham TF, Hardin KM, Baggish AL, Ho JE. 2018. Pulmonary capillary wedge pressure patterns during exercise predict exercise capacity and incident heart failure, Circulation: Heart Failure. 11(5) e004750.
Ergatoudes C, Schaufelberger M, Andersson B, Pivodic A, Dahlström U, Fu M. 2019. Non-cardiac comorbidities and mortality in patients with heart failure with reduced vs. preserved ejection fraction: a study using the Swedish Heart Failure Registry, Clinical Research in Cardiology. 1-9.
Felker GM, Shaw LK, O'Connor CM. 2002. A standardized definition of ischemic cardiomyopathy for use in clinical research, Journal of the American College of Cardiology 39(2). 210-8.
Francis GS, Tang WW. 2019. Pathophysiology of congestive heart failure, Reviews in cardiovascular medicine. 4(S2) 14-20.
Greene SJ, Gheorghiade M, Borlaug BA, Pieske B, Vaduganathan M, Burnett Jr. JC, Roessig L, Stasch JP, Solomon SD, Paulus WJ, Butler J. 2013. The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction, Journal of the American Heart Association. 2(6) e000536.
Guazzi M, Myers J, Arena R. 2005. Cardiopulmonary exercise testing in the clinical and prognostic assessment of diastolic heart failure, Journal of the American College of Cardiology. 46(10) 1883-1890.
Higgins JP, Thompson SG. 2002. Quantifying heterogeneity in a meta-analysis, Statistics in medicine. 21(11) 1539-58.
Houstis NE, Eisman AS, Pappagianopoulos PP, Wooster L, Bailey CS, Wagner PD, Lewis GD. 2018. Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O2 pathway analysis, Circulation. 137(2) 148-161.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ. 1996. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Controlled Clinical Trials. 17(1) 1-12.
Kjaergard LL, Villumsen J, Gluud C. 2001. Reported Methodologic Quality and Discrepancies between Large and Small Randomized Trials in Meta-Analyses, Annals of Internal Medicine. 135(11) 982-989.
Lipinski MJ, Luger D, Epstein SE. 2017. Mesenchymal Stem Cell Therapy for the Treatment of Heart Failure Caused by Ischemic or Non-ischemic Cardiomyopathy: Immunosuppression and Its Implications, Handbook of experimental pharmacology. 243 329-353.
Lundberg JO, Weitzberg E, Gladwin MT. 2008. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics, Nature reviews. Drug discovery. 7(2) 156-67.
Maeder MT, Thompson BR, Brunner-La Rocca HP, Kaye DM. 2010. Hemodynamic basis of exercise limitation in patients with heart failure and normal ejection fraction, J Am Coll Cardiol. 56(11) 855-63.
McMurray JJ, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J. 2019. Dapagliflozin in patients with heart failure and reduced ejection fraction, New England Journal of Medicine. 381(21) 1995-2008.
Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. 2014. Right heart dysfunction in heart failure with preserved ejection fraction, Eur Heart J. 35(48) 3452-62.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, Journal of clinical epidemiology. 62(10) 1006-12.
Obokata M, Olson TP, Reddy YN, Melenovsky V, Kane GC, Borlaug BA. 2018. Haemodynamics, dyspnoea, and pulmonary reserve in heart failure with preserved ejection fraction, European heart journal. 39(30). 2810-2821.
Ormerod JO, Arif S, Mukadam M, Evans JD, Beadle R, Fernandez BO, Bonser RS, Feelisch M, Madhani M, Frenneaux MP. 2015. Short-term intravenous sodium nitrite infusion improves cardiac and pulmonary hemodynamics in heart failure patients, Circ Heart Fail 8(3). 565-71.
Paulus WJ, Tschöpe C. 2013. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation, Journal of the American College of Cardiology. 62(4) 263-271.
Pieske B, Maggioni AP, Lam CS, Pieske-Kraigher E, Filippatos G, Butler J, Ponikowski P, Shah SJ, Solomon SD, Scalise AV. 2017. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study, European heart journal 38(15). 1119-1127.
Pryzbek M, MacDonald M, Stratford P, McQuarrie A, Richardson J, McKelvie R, Tang A. 2019. Long-term enrollment in cardiac rehabilitation benefits cardiorespiratory fitness and skeletal muscle strength in men with cardiovascular disease, Canadian Journal of Cardiology.
Reddy YN, Andersen MJ, Obokata M, Koepp KE, Kane GC, Melenovsky V, Olson TP, Borlaug BA. 2017. Arterial stiffening with exercise in patients with heart failure and preserved ejection fraction, Journal of the American College of Cardiology. 70(2) 136-148.
Reddy YN, Lewis GD, Shah SJ, LeWinter M, Semigran M, Davila-Roman VG, Anstrom K, Hernandez A, Braunwald E, Redfield MM. 2017. Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction (INDIE-HFpEF): Rationale and Design, Circulation. Heart failure. 10(5).
Reddy YN, Olson TP, Obokata M, Melenovsky V, Borlaug BA. 2018. Hemodynamic correlates and diagnostic role of cardiopulmonary exercise testing in heart failure with preserved ejection fraction, JACC: Heart Failure. 854.
Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, LeWinter MM, Joseph SM, Shah SJ, Semigran MJ. 2015. Isosorbide mononitrate in heart failure with preserved ejection fraction, New England Journal of Medicine. 373(24) 2314-2324.
Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL. 2013. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial, Jama. 309(12) 1268-1277.
Shah SJ, Gheorghiade M. 2008. Heart failure with preserved ejection fraction: treat now by treating comorbidities, Jama. 300(4) 431-433.
Sharma K, Kass DA. 2014. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies, Circ Res. 115(1) 79-96.
Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, Gorcsan J III, Parsley L, Gladwin MT. 2016. Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction, JCI insight. 1(18).
Solomon SD, McMurray JJ, Anand IS, Ge J, Lam CS, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B. 2019. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction, New England Journal of Medicine. 381(17) 1609-1620.
Van der Meer P, van der Wal HH, Melenovsky V. 2019. Mitochondrial Function, Skeletal Muscle Metabolism, and Iron Deficiency in Heart Failure, Am Heart Assoc.
Vanderpool R, Gladwin MT. 2015. Harnessing the nitrate-nitrite-nitric oxide pathway for therapy of heart failure with preserved ejection fraction, Circulation. 131(4) 334-6.
Weiss K, Schär M, Panjrath GS, Zhang Y, Sharma K, Bottomley PA, Golozar A, Steinberg A, Gerstenblith G, Russell SD. 2017. Fatigability, exercise intolerance, and abnormal skeletal muscle energetics in heart failure, Circulation: Heart Failure. 10(7) e004129.
Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC, Chirinos JA. 2015. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction, Circulation. 131(4). 371-80; discussion 380.
Zamani P, Tan V, Soto-Calderon H, Beraun M, Brandimarto JA, Trieu L, Varakantam S, Doulias PT, Townsend RR, Chittams J. 2017. Pharmacokinetics and pharmacodynamics of inorganic nitrate in heart failure with preserved ejection fraction, Circulation research. 120(7) 1151-1161.
