Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial

Konstantin Schwarz, Satnam Singh, Satish K Parasuraman, Amelia Rudd, Lee Shepstone, Martin Feelisch, Magdalena Minnion, Shakil Ahmad, Melanie Madhani, John Horowitz, Dana K Dawson, Michael P Frenneaux, Konstantin Schwarz, Satnam Singh, Satish K Parasuraman, Amelia Rudd, Lee Shepstone, Martin Feelisch, Magdalena Minnion, Shakil Ahmad, Melanie Madhani, John Horowitz, Dana K Dawson, Michael P Frenneaux

Abstract

Background: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina.

Methods and results: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] μmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation.

Conclusions: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication.

Clinical trial registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.

Keywords: angina; exercise; inorganic nitrate; ischemia; nitrite; randomized trial.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
CONSORT diagram. DSE indicates dobutamine stress echocardiogram; ETT, electrocardiogram treadmill test; LBBB, left bundle branch block; LVEF, left ventricle ejection fraction; STD, ST segment depression.
Figure 2
Figure 2
Exercise treadmill test. Columns display mean±SEM time until either STD or chest pain and duration of exercise. STD indicates ST segment depression.
Figure 3
Figure 3
Plasma levels of (A) nitrate, (B) nitrite, (C) VEGF, and (D) sFlt‐1. Data are displayed as mean±SEM. sFlt indicates soluble fms‐like tyrosine kinase receptor; VEGF, vascular endothelial growth factor.

References

    1. Manolis AJ, Poulimenos LE, Ambrosio G, Kallistratos MS, Lopez‐Sendon J, Dechend R, Mancia G, Camm AJ. Medical treatment of stable angina: a tailored therapeutic approach. Int J Cardiol. 2016;220:445–453.
    1. Lundberg JO, Weitzberg E, Gladwin MT. The nitrate‐nitrite‐nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008;7:156–167.
    1. Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim‐Shapiro DB, Schechter AN, Cannon RO III, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003;9:1498–1505.
    1. Maher AR, Milsom AB, Gunaruwan P, Abozguia K, Ahmed I, Weaver RA, Thomas P, Ashrafian H, Born GVR, James PE, Frenneaux MP. Hypoxic modulation of exogenous nitrite‐induced vasodilation in humans. Circulation. 2008;117:670–677.
    1. Ingram TE, Pinder AG, Bailey DM, Fraser AG, James PE. Low‐dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite. Am J Physiol Heart Circ Physiol. 2010;298:H331–H339.
    1. Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley‐Usmar VM, Kerby JD, Lang JD Jr, Kraus D, Ho C, Gladwin MT, Patel RP. Hypoxia, red blood cells, and nitrite regulate NO‐dependent hypoxic vasodilation. Blood. 2006;107:566–574.
    1. Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO III, Schechter AN, Gladwin MT. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation. 2007;116:1821–1831.
    1. Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, DiMenna FJ, Wilkerson DP, Tarr J, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of low‐intensity exercise and enhances tolerance to high‐intensity exercise in humans. J Appl Physiol. 2009;107:1144–1155.
    1. Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise. Free Radic Biol Med. 2010;48:342–347.
    1. Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, Weitzberg E. Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell Metab. 2011;13:149–159.
    1. Hoon MW, Johnson NA, Chapman PG, Burke LM. The effect of nitrate supplementation on exercise performance in healthy individuals: a systematic review and meta‐analysis. Int J Sport Nutr Exerc Metab. 2013;23:522–532.
    1. Muggeridge DJ, Howe CC, Spendiff O, Pedlar C, James PE, Easton C. A single dose of beetroot juice enhances cycling performance in simulated altitude. Med Sci Sports Exerc. 2014;46:143–150.
    1. Burwell LS, Brookes PS. Mitochondria as a target for the cardioprotective effects of nitric oxide in ischemia‐reperfusion injury. Antioxid Redox Signal. 2008;10:579–599.
    1. Nadtochiy SM, Burwell LS, Brookes PS. Cardioprotection and mitochondrial S‐nitrosation: effects of S‐nitroso‐2‐mercaptopropionyl glycine (SNO‐MPG) in cardiac ischemia‐reperfusion injury. J Mol Cell Cardiol. 2007;42:812–825.
    1. Nadtochiy SM, Tompkins AJ, Brookes PS. Different mechanisms of mitochondrial proton leak in ischaemia/reperfusion injury and preconditioning: implications for pathology and cardioprotection. Biochem J. 2006;395:611–618.
    1. Dezfulian C, Shiva S, Alekseyenko A, Pendyal A, Beiser DG, Munasinghe JP, Anderson SA, Chesley CF, Vanden Hoek TL, Gladwin MT. Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I. Circulation. 2009;120:897–905.
    1. Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X, MacArthur PH, Shoja A, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ, Gladwin MT. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med. 2007;204:2089–2102.
    1. Rammos C, Hendgen‐Cotta UB, Sobierajski J, Bernard A, Kelm M, Rassaf T. Dietary nitrate reverses vascular dysfunction in older adults with moderately increased cardiovascular risk. J Am Coll Cardiol. 2014;63:1584–1585.
    1. Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension. 2008;51:784–790.
    1. Kapil V, Milsom AB, Okorie M, Maleki‐Toyserkani S, Akram F, Rehman F, Arghandawi S, Pearl V, Benjamin N, Loukogeorgakis S, MacAllister R, Hobbs AJ, Webb AJ, Ahluwalia A. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite‐derived NO. Hypertension. 2010;56:274–281.
    1. Siervo M, Lara J, Ogbonmwan I, Mathers JC. Inorganic nitrate and beetroot juice supplementation reduces blood pressure in adults: a systematic review and meta‐analysis. J Nutr. 2013;143:818–826.
    1. Zuckerbraun BS, Shiva S, Ifedigbo E, Mathier MA, Mollen KP, Rao J, Bauer PM, Choi JJW, Curtis E, Choi AMK, Gladwin MT. Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase‐dependent nitric oxide generation. Circulation. 2010;121:98–109.
    1. Baliga RS, Milsom AB, Ghosh SM, Trinder SL, MacAllister RJ, Ahluwalia A, Hobbs AJ. Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. Circulation. 2012;125:2922–2932.
    1. Hendgen‐Cotta UB, Luedike P, Totzeck M, Kropp M, Schicho A, Stock P, Rammos C, Niessen M, Heiss C, Lundberg JO, Weitzberg E, Kelm M, Rassaf T. Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation. 2012;126:1983–1992.
    1. Heiss C, Meyer C, Totzeck M, Hendgen‐Cotta UB, Heinen Y, Luedike P, Keymel S, Ayoub N, Lundberg JO, Weitzberg E, Kelm M, Rassaf T. Dietary inorganic nitrate mobilizes circulating angiogenic cells. Free Radic Biol Med. 2012;52:1767–1772.
    1. Kumar D, Branch BG, Pattillo CB, Hood J, Thoma S, Simpson S, Illum S, Arora N, Chidlow JH Jr, Langston W, Teng X, Lefer DJ, Patel RP, Kevil CG. Chronic sodium nitrite therapy augments ischemia‐induced angiogenesis and arteriogenesis. Proc Natl Acad Sci USA. 2008;105:7540–7545.
    1. Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high‐dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010;375:2161–2167.
    1. Schwarz K, Singh S, Parasuraman SK, Bruce M, Shepstone L, Feelisch M, Minnion M, Ahmad S, Horowitz J, Dawson DK, Frenneaux MP. A randomized double‐blind placebo‐controlled crossover trial of sodium nitrate in patients with stable angina INAS. Future Cardiol. 2016;12:617–626.
    1. Bondonno CP, Liu AH, Croft KD, Considine MJ, Puddey IB, Woodman RJ, Hodgson JM. Antibacterial mouthwash blunts oral nitrate reduction and increases blood pressure in treated hypertensive men and women. Am J Hypertens. 2015;28:572–575.
    1. Ghosh SM, Kapil V, Fuentes‐Calvo I, Bubb KJ, Pearl V, Milsom AB, Khambata R, Maleki‐Toyserkani S, Yousuf M, Benjamin N, Webb AJ, Caulfield MJ, Hobbs AJ, Ahluwalia A. Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential. Hypertension. 2013;61:1091–1102.
    1. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, Pepine CJ, Wang W, Nelson JJ, Hebert DA, Wolff AA. Anti‐ischemic effects and long‐term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–1382.
    1. Schnaack SD, Siegmund P, Spes CH, Tammen AR, Theisen K, Angermann CE. Transpulmonary contrast echocardiography: effects on delineation of endocardial border, assessment of wall motion and interobserver variability in stress echocardiograms of limited image quality. Coron Artery Dis. 2000;11:549–554.
    1. Ingram TE, Fraser AG, Bleasdale RA, Ellins EA, Margulescu AD, Halcox JP, James PE. Low‐dose sodium nitrite attenuates myocardial ischemia and vascular ischemia‐reperfusion injury in human models. J Am Coll Cardiol. 2013;61:2534–2541.
    1. Siddiqi N, Bruce M, Neil CJ, Jagpal B, Maclennon G, Cotton SC, Papadopoulo SA, Bunce N, Lim P, Schwarz K, Singh S, Hildick‐Smith D, Horowitz JD, Madhani M, Boon N, Kaski J‐, Dawson D, Frenneaux MP. Protocol: does sodium nitrite administration reduce ischaemia‐reperfusion injury in patients presenting with acute ST segment elevation myocardial infarction? Nitrites In Acute Myocardial Infarction (NIAMI). J Transl Med. 2013;11:116.
    1. Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, Fihn SD. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol. 1995;25:333–341.
    1. Dunselman PHJM, Van Kempen LHJ, Bouwens LHM, Holwerda KJ, Herweijer AH, Bernink PJLM. Value of the addition of amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade. Am J Cardiol. 1998;81:128–132.
    1. Knight CJ, Fox KM. Amlodipine versus diltiazem as additional antianginal treatment to atenolol. Am J Cardiol. 1998;81:133–136.
    1. Tardif JC, Ponikowski P, Kahan T. Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta‐blocker therapy: a 4‐month, randomized, placebo‐controlled trial. Eur Heart J. 2009;30:540–548.
    1. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291:309–316.
    1. Thadani U, Smith W, Nash S, Bittar N, Glasser S, Narayan P, Stein RA, Larkin S, Mazzu A, Tota R, Pomerantz K, Sundaresan P. The effect of vardenafil, a potent and highly selective phosphodiesterase‐5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease. J Am Coll Cardiol. 2002;40:2006–2012.
    1. Halcox JPJ, Nour KRA, Zalos G, Mincemoyer R, Waclawiw MA, Rivera CE, Willie G, Ellahham S, Quyyumi AA. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol. 2002;40:1232–1240.
    1. Fox KM, Thadani U, Ma PT, Nash SD, Keating Z, Czorniak MA, Gillies H, Keltai M; CAESAR I (Clinical American and European Studies of Angina and Revascularization) investigators . Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. Eur Heart J. 2003;24:2206–2212.
    1. Senn S. Cross‐Over Trials in Clinical Research, 2nd ed Chichester: John Wiley & Sons; 1993.
    1. Campeau L. Letter: grading of angina pectoris. Circulation. 1976;54:522–523.
    1. Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia‐Ocana A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT. SIRT3‐AMP‐activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction. Circulation. 2016;133:717–731.
    1. Coggan AR, Leibowitz JL, Anderson Spearie C, Kadkhodayan A, Thomas DP, Ramamurthy S, Mahmood K, Park S, Waller S, Farmer M, Peterson LR. Acute dietary nitrate intake improves muscle contractile function in patients with heart failure: a double‐blind, placebo‐controlled, randomized trial. Circ Heart Fail. 2015;8:914–920.
    1. 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. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015;131:371–380; discussion 380.
    1. Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr. 2009;90:1–10.
    1. Butler AR, Feelisch M. Therapeutic uses of inorganic nitrite and nitrate: from the past to the future. Circulation. 2008;117:2151–2159.
    1. Gilchrist M, Winyard PG, Aizawa K, Anning C, Shore A, Benjamin N. Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes. Free Radic Biol Med. 2013;60:89–97.
    1. Lara J, Ogbonmwan I, Oggioni C, Zheng D, Qadir O, Ashor A, Brandt K, Mathers JC, Siervo M. Effects of handgrip exercise or inorganic nitrate supplementation on 24‐h ambulatory blood pressure and peripheral arterial function in overweight and obese middle age and older adults: a pilot RCT. Maturitas. 2015;82:228–235.
    1. Pechanova O, Varga ZV, Cebova M, Giricz Z, Pacher P, Ferdinandy P. Cardiac NO signalling in the metabolic syndrome. Br J Pharmacol. 2015;172:1415–1433.
    1. Pinheiro LC, Montenegro MF, Amaral JH, Ferreira GC, Oliveira AM, Tanus‐Santos JE. Increase in gastric pH reduces hypotensive effect of oral sodium nitrite in rats. Free Radic Biol Med. 2012;53:701–709.
    1. Montenegro MF, Lundberg JO. Letter by Montenegro and Lundberg regarding article, “Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine”. Circulation. 2014;129:e426.
    1. Pinheiro LC, Amaral JH, Tanus‐Santos JE. Letter by Pinheiro et al. regarding article, “unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine”. Circulation. 2014;129:e427.
    1. Montenegro MF, Sundqvist ML, Larsen FJ, Zhuge Z, Carlstrom M, Weitzberg E, Lundberg JO. Blood pressure‐lowering effect of orally ingested nitrite is abolished by a proton pump inhibitor. Hypertension. 2017;69:23–31.
    1. Machha A, Schechter AN. Inorganic nitrate: a major player in the cardiovascular health benefits of vegetables? Nutr Rev. 2012;70:367–372.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir