Cardiovascular Drugs and Therapy

, Volume 27, Issue 1, pp 69–77 | Cite as

Anti-Anginal and Anti-Ischemic Effects of Late Sodium Current Inhibition

  • Neil J. Wimmer
  • Peter H. Stone


The effective treatment of coronary artery disease targets two distinct goals, controlling symptomatic angina and decreasing the adverse events associated with ischemia. Traditional anti-anginal and anti-ischemic drugs function by altering the determinants of myocardial oxygen supply or demand, usually by altering loading conditions, changing the heart rate, or impacting contractility. Blockade of the late inward sodium current, late INa, offers another target for the treatment of ischemia. Blockade of late INa reduces the sodium and calcium overload that follows ischemia. This improves myocardial relaxation and reduces left ventricular diastolic stiffness, in turn enhancing myocardial contractility and perfusion. Ranolazine, a late INa inhibitor, has been shown to provide both anti-anginal and anti-ischemic benefits without significant alterations in the heart rate and blood pressure in patients with stable coronary artery disease. When evaluated in patients with acute coronary syndrome, ranolazine has been shown to decrease recurrent ischemia, but not significantly reduce the risk of death or myocardial infarction. This review will address the rationale that inhibition of the late sodium current is beneficial in reducing cardiac dysfunction during ischemia, and discuss the clinical studies supporting the use of ranolazine for its anti-anginal and anti-ischemic effects.


Ischemia Angina Sodium current Ranolazine 



Dr. Wimmer has no disclosures. Dr. Stone has no disclosures.


Dr. Wimmer receives research support from NIH T32HL007604.


  1. 1.
    Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al. Heart disease and stroke statistics–2007 update: a report from the American heart association statistics committee and stroke statistics subcommittee. Circulation. 2007;115:e69–171.PubMedCrossRefGoogle Scholar
  2. 2.
    Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina–summary article: a report of the American college of cardiology/American heart association task force on practice guidelines (committee on the management of patients with chronic stable angina). Circulation. 2003;107:149–58.PubMedCrossRefGoogle Scholar
  3. 3.
    Heidenreich PA, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK, et al. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA. 1999;281:1927–36.PubMedCrossRefGoogle Scholar
  4. 4.
    Abrams J. Clinical practice. Chronic stable angina. N Engl J Med. 2005;352:2524–33.PubMedCrossRefGoogle Scholar
  5. 5.
    Silverman HS, Stern MD. Ionic basis of ischaemic cardiac injury: insights from cellular studies. Cardiovasc Res. 1994;28:581–97.PubMedCrossRefGoogle Scholar
  6. 6.
    Imahashi K, Kusuoka H, Hashimoto K, Yoshioka J, Yamaguchi H, Nishimura T. Intracellular sodium accumulation during ischemia as the substrate for reperfusion injury. Circ Res. 1999;84:1401–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Bers DM. Excitation-contraction coupling and cardiac contractile force. 2nd ed. Developments in cardiovascular medicine, vol 237. Dordrecht; Boston: Kluwer Academic Publishers; 2001.Google Scholar
  8. 8.
    Hale SL, Shryock JC, Belardinelli L, Sweeney M, Kloner RA. Late sodium current inhibition as a new cardioprotective approach. J Mol Cell Cardiol. 2008;44:954–67.PubMedCrossRefGoogle Scholar
  9. 9.
    Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497(Pt 2):337–47.PubMedGoogle Scholar
  10. 10.
    Undrovinas AI, Fleidervish IA, Makielski JC. Inward sodium current at resting potentials in single cardiac myocytes induced by the ischemic metabolite lysophosphatidylcholine. Circ Res. 1992;71:1231–41.PubMedCrossRefGoogle Scholar
  11. 11.
    Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol. 1997;500(Pt 3):631–42.PubMedGoogle Scholar
  12. 12.
    Brandes R, Maier LS, Bers DM. Regulation of mitochondrial [NADH] by cytosolic [Ca2+] and work in trabeculae from hypertrophic and normal rat hearts. Circ Res. 1998;82(11):1189–98.PubMedCrossRefGoogle Scholar
  13. 13.
    McCormack JG, Barr RL, Wolff AA, Lopaschuk GD. Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation. 1996;93:135–42.PubMedCrossRefGoogle Scholar
  14. 14.
    MacInnes A, Fairman DA, Binding P, Rhodes J, Wyatt MJ, Phelan A, et al. The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2003;93:e26–32.PubMedCrossRefGoogle Scholar
  15. 15.
    Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006;113:2462–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Maier LS. A novel mechanism for the treatment of angina, arrhythmias, and diastolic dysfunction: inhibition of late I(Na) using ranolazine. J Cardiovasc Pharmacol. 2009;54:279–86.PubMedCrossRefGoogle Scholar
  17. 17.
    Antzelevitch C, Belardinelli L, Wu L, Fraser H, Zygmunt AC, Burashnikov A, et al. Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent. J Cardiovasc Pharmacol Ther. 2004;9 Suppl 1:S65–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Stone PH, Chaitman BR, Stocke K, Sano J, DeVault A, Koch GG. The anti-ischemic mechanism of action of ranolazine in stable ischemic heart disease. J Am Coll Cardiol. 2010;56:934–42.PubMedCrossRefGoogle Scholar
  19. 19.
    Figueredo VM, Pressman GS, Romero-Corral A, Murdock E, Holderbach P, Morris DL. Improvement in left ventricular systolic and diastolic performance during ranolazine treatment in patients with stable angina. J Cardiovasc Pharmacol Ther. 2011;16:168–72.PubMedCrossRefGoogle Scholar
  20. 20.
    Venkataraman R, Chen J, Garcia EV, Belardinelli L, Hage FG, Heo J, et al. Effect of ranolazine on left ventricular dyssynchrony in patients with coronary artery disease. Am J Cardiol. 2012;110:1440–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Jerling M. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet. 2006;45:469–91.PubMedCrossRefGoogle Scholar
  22. 22.
    Pepine CJ, Wolff AA. A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine study group. Am J Cardiol. 1999;84:46–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Rousseau MF, Pouleur H, Cocco G, Wolff AA. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris. Am J Cardiol. 2005;95:311–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al. 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;291:309–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Sendon JL, Lee S, Cheng ML, Ben-Yehuda O. Effects of ranolazine on exercise tolerance and angina frequency in patients with severe chronic angina receiving maximally-tolerated background therapy: analysis from the Combination Assessment of Ranolazine In Stable Angina (CARISA) randomized trial. Eur J Prev Cardiol. 2012;19:952–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine In Chronic Angina) trial. J Am Coll Cardiol. 2006;48:566–75.PubMedCrossRefGoogle Scholar
  28. 28.
    Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007;297:1775–83.PubMedCrossRefGoogle Scholar
  29. 29.
    Morrow DA, Scirica BM, Sabatine MS, de Lemos JA, Murphy SA, Jarolim P, et al. B-type natriuretic peptide and the effect of ranolazine in patients with non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 (metabolic efficiency with ranolazine for less ischemia in non-ST elevation acute coronary-thrombolysis in myocardial infarction 36) trial. J Am Coll Cardiol. 2010;55:1189–96.PubMedCrossRefGoogle Scholar
  30. 30.
    Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the metabolic efficiency with ranolazine for less ischemia in non ST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation. 2007;116:1647–52.PubMedCrossRefGoogle Scholar
  31. 31.
    Pelliccia F, Pasceri V, Marazzi G, Rosano G, Greco C, Gaudio C. A pilot randomized study of ranolazine for reduction of myocardial damage during elective percutaneous coronary intervention. Am Heart J. 2012;163:1019–23.PubMedCrossRefGoogle Scholar
  32. 32.
    Mega JL, Hochman JS, Scirica BM, Murphy SA, Sloan S, McCabe CH, et al. Clinical features and outcomes of women with unstable ischemic heart disease: observations from metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromes-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36). Circulation. 2010;121:1809–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y, et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging. 2011;4:514–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Belardinelli L, Shryock JC, Wu L, Song Y. Use of preclinical assays to predict risk of drug-induced torsades de pointes. Hear Rhythm. 2005;2(2 Suppl):S16–22.CrossRefGoogle Scholar
  35. 35.
    Wu L, Shryock JC, Song Y, Li Y, Antzelevitch C, Belardinelli L. Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome. J Pharmacol Exp Ther. 2004;310:599–605.PubMedCrossRefGoogle Scholar
  36. 36.
    Song Y, Shryock JC, Wu L, Belardinelli L. Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricular myocytes. J Cardiovasc Pharmacol. 2004;44:192–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Division of Cardiovascular MedicineBrigham and Women’s HospitalBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA

Personalised recommendations