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Ivabradine: Cardioprotection By and Beyond Heart Rate Reduction

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Abstract

Ivabradine inhibits hyperpolarization-activated cyclic nucleotide-gated channels in the sinus node, thereby reducing heart rate, and heart rate reduction improves regional myocardial blood flow and contractile function in ischemic myocardium. Accordingly, ivabradine reduces anginal symptoms in patients with stable coronary artery disease but does not improve their clinical outcome. Heart rate reduction with ivabradine in patients with symptomatic heart failure reduces symptoms, attenuates remodeling, and improves clinical outcome. In pigs and mice, ivabradine reduces infarct size from myocardial ischemia/reperfusion, even when heart rate reduction is abrogated by atrial pacing. Improved viability is also observed in isolated ventricular cardiomyocytes subjected to simulated ischemia/reperfusion. These beneficial effects are attributed to reduced reactive oxygen species formation from the mitochondria. There is also evidence for a heart rate-independent benefit from ivabradine in the vasculature of mice and humans, and in left ventricular contractile function of pigs. Finally, in mice, ivabradine also has anti-aging potential.

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References

  1. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I f current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757–65.

    Article  CAS  PubMed  Google Scholar 

  2. Borer JS. Drug insight: I f inhibitors as specific heart-rate-reducing agents. Nature. 2004;1:103–9.

    CAS  Google Scholar 

  3. Custodis F, Reil JC, Laufs U, Bohm M. Heart rate: a global target for cardiovascular disease and therapy along the cardiovascular disease continuum. J Cardiol. 2013;62:183–7.

    Article  PubMed  Google Scholar 

  4. Roubille F, Tardif JC. New therapeutic targets in cardiology: heart failure and arrhythmia: HCN channels. Circulation. 2013;127:1986–96.

    Article  PubMed  Google Scholar 

  5. Tanaka N, Nozawa T, Yasumura Y, Futaki S, Hiramori K, Suga H. Heart-rate-proportional oxygen consumption for constant cardiac work in dog heart. Jpn J Physiol. 1990;40:503–21.

    Article  CAS  PubMed  Google Scholar 

  6. Heusch G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol. 2008;153:1589–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Custodis F, Schirmer SH, Baumhäkel M, Heusch G, Böhm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010;56:1973–83.

    Article  CAS  PubMed  Google Scholar 

  8. Colin P, Ghaleh B, Monnet X, Hittinger L, Berdeaux A. Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther. 2004;308:236–40.

    Article  CAS  PubMed  Google Scholar 

  9. Heusch G, Yoshimoto N, Müller-Ruchholtz ER. Effects of heart rate on hemodynamic severity of coronary artery stenosis in the dog. Basic Res Cardiol. 1982;77:562–73.

    Article  CAS  PubMed  Google Scholar 

  10. Flameng W, Wüsten B, Winkler B, Pasyk S, Schaper W. Inluence of perfusion pressure and heart rate on local myocardial flow in the collateralized heart with chronic coronary occlusion. Am Heart J. 1975;89:51–9.

    Article  CAS  PubMed  Google Scholar 

  11. Neill WA, Oxendine JM, Phelps NC, Anderson RP. Subendocardial ischemia provoked by tachycardia in conscious dogs with coronary stenosis. Am J Cardiol. 1975;35:30–6.

    Article  CAS  PubMed  Google Scholar 

  12. Heusch G, Yoshimoto N. Effects of heart rate and perfusion pressure on segmental coronary resistances and collateral perfusion. Pflügers Arch. 1983;397:284–9.

    Article  CAS  PubMed  Google Scholar 

  13. Heusch G, Skyschally A, Gres P, van Caster P, Schilawa D, Schulz R. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction. Eur Heart J. 2008;29:2265–75.

    Article  PubMed  Google Scholar 

  14. Buck JD, Hardman HF, Warltier DC, Gross GJ. Changes in ischemic blood flow distribution and dynamic severity of a coronary stenosis induced by beta blockade in the canine heart. Circulation. 1981;64:708–15.

    Article  CAS  PubMed  Google Scholar 

  15. Heusch G, Deussen A. The effects of cardiac sympathetic nerve stimulation on the perfusion of stenotic coronary arteries in the dog. Circ Res. 1983;53:8–15.

    Article  CAS  PubMed  Google Scholar 

  16. Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross J Jr. Intracoronary a2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res. 1988;62:436–42.

    Article  CAS  PubMed  Google Scholar 

  17. Heusch G. α-Adrenergic mechanisms in myocardial ischemia. Circulation. 1990;81:1–13.

    Article  CAS  PubMed  Google Scholar 

  18. Heusch G, Baumgart D, Camici P, Chilian W, Gregorini L, Hess O, et al. α-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation. 2000;101:689–94.

    Article  CAS  PubMed  Google Scholar 

  19. Simon L, Ghaleh B, Puybasset L, Giudicelli J-F, Berdeaux A. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther. 1995;275:659–66.

    CAS  PubMed  Google Scholar 

  20. Guth BD, Heusch G, Seitelberger R, Ross J Jr. Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs. Circ Res. 1987;60:738–46.

    Article  CAS  PubMed  Google Scholar 

  21. Colin P, Ghaleh B, Monnet X, Su J, Hittinger L, Giudicelli J-F, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284:H676–82.

    Article  CAS  PubMed  Google Scholar 

  22. Berdeaux A, Peres da Costa C, Garnier M, Boissier JR, Giudicelli JF. Beta adrenergic blockade, regional left ventricular blood flow and ST-segment elevation in canine experimental myocardial ischemia. J Pharmacol Exp Ther. 1978;205:646–56.

    CAS  PubMed  Google Scholar 

  23. Matsuzaki M, Patritti J, Tajimi T, Miller M, Kemper WS, Ross J Jr. Effects of β-blockade on regional myocardial flow and function during exercise. Am J Physiol. 1984;247:H52–60.

    CAS  PubMed  Google Scholar 

  24. Johannsen UJ, Mark AL, Marcus ML. Responsiveness to cardiac sympathetic nerve stimulation during maximal coronary dilation produced by adenosine. Circ Res. 1982;50:510–7.

    Article  CAS  PubMed  Google Scholar 

  25. Baumgart D, Ehring T, Kowallik P, Guth BD, Krajcar M, Heusch G. The impact of a-adrenergic coronary vasoconstriction on the transmural myocardial blood flow distribution during humoral and neuronal adrenergic activation. Circ Res. 1993;73:869–86.

    Article  CAS  PubMed  Google Scholar 

  26. Giudicelli JF, Berdeaux A, Tato F, Garnier M. Left stellate stimulation: regional myocardial flows and ischemic injury in dogs. Am J Physiol. 1980;239:H359–64.

    CAS  PubMed  Google Scholar 

  27. Berkenboom GM, Abramowicz M, Vandermoten P, Degre SG. Role of alpha-adrenergic coronary tone in exercise-induced angina pectoris. Am J Cardiol. 1986;57:195–8.

    Article  CAS  PubMed  Google Scholar 

  28. Gregorini L, Marco J, Kozàkovà M, Palombo C, Anguissola GB, Marco I, et al. α-Adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation. 1999;99:482–90.

    Article  CAS  PubMed  Google Scholar 

  29. Baumgart D, Haude M, Goerge G, Liu F, Ge J, Große-Eggebrecht C, et al. Augmented α-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999;99:2090–7.

    Article  CAS  PubMed  Google Scholar 

  30. Gregorini L, Marco J, Farah B, Bernies M, Palombo C, Kozakova M, et al. Effects of selective α1- and α2-adrenergic blockade on coronary flow reserve after coronary stenting. Circulation. 2002;106:2901–7.

    Article  CAS  PubMed  Google Scholar 

  31. Heusch G. The paradox of alpha-adrenergic coronary vasoconstriction revisited. J Mol Cell Cardiol. 2011;51:16–23.

    Article  CAS  PubMed  Google Scholar 

  32. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic effects of ivabradine, an I f inhibitor, in stable angina. Circulation. 2003;107:817–23.

    Article  PubMed  Google Scholar 

  33. Ruzyllo W, Ford IF, Tendera MT, Fox KF. Antianginal and antiischaemic effects of the If current inhibitor ivabradine compared to amlodipine as monotherapies in patients with chronic stable angina. Randomised, controlled, double-blind trial. Eur Heart J. 2004;25:A878.

    Google Scholar 

  34. Tardif J-C, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I f inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529–36.

    Article  CAS  PubMed  Google Scholar 

  35. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007;67:393–405.

    Article  CAS  PubMed  Google Scholar 

  36. Lopez-Bescos L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology. 2007;108:387–96.

    Article  CAS  PubMed  Google Scholar 

  37. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807–16.

    Article  CAS  PubMed  Google Scholar 

  38. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J. 2009;30:2337–45.

    Article  CAS  PubMed  Google Scholar 

  39. Heusch G. A BEAUTIFUL lesson: ivabradine protects from ischaemia, but not from heart failure: through heart rate reduction or more? Eur Heart J. 2009;30:2300–1.

    Article  PubMed  Google Scholar 

  40. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371:1091–9.

    Article  PubMed  Google Scholar 

  41. Neumann T, Ravens U, Heusch G. Characterization of excitation-contraction coupling in conscious dogs with pacing-induced heart failure. Cardiovasc Res. 1998;37:456–66.

    Article  CAS  PubMed  Google Scholar 

  42. Mahler F, Yoran C, Ross J Jr. Inotropic effects of tachycardia and poststimulation potentiation in the conscious dog. Am J Physiol. 1974;227:569–75.

    CAS  PubMed  Google Scholar 

  43. Heusch G. Heart rate and heart failure. Circ J. 2011;75:229–36.

    Article  PubMed  Google Scholar 

  44. Miura T, Miyazaki S, Guth BD, Kambayashi M, Ross J Jr. Influence of the force–frequency relation on left ventricular function during exercise in conscious dogs. Circulation. 1992;86:563–71.

    Article  CAS  PubMed  Google Scholar 

  45. Eising GP, Hammond HK, Helmer GA, Gilpin E, Ross J Jr. Force–frequency relations during heart failure in pigs. Am J Physiol. 1994;267:H2516–22.

    CAS  PubMed  Google Scholar 

  46. Heinzel FR, Luo Y, Dodoni G, Boengler K, Petrat F, Di Lisa F, et al. Formation of reactive oxygen species at increased contraction frequency in rat cardiomyocytes. Cardiovasc Res. 2006;71:374–82.

    Article  CAS  PubMed  Google Scholar 

  47. Hasenfuss G, Holubarsch C, Hermann HP, Astheimer K, Pieske B, Just H. Influence of the force–frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J. 1994;15:164–70.

    Article  CAS  PubMed  Google Scholar 

  48. Neumann T, Heusch G. Myocardial, skeletal muscle, and renal blood flow during exercise in conscious dogs with heart failure. Am J Physiol Heart Circ Physiol. 1997;273:H2452–7.

    CAS  Google Scholar 

  49. Heusch G, Neumann T. Calcium responsiveness in canine pacing-induced heart failure. J Mol Cell Cardiol. 1998;30:1605–13.

    Article  CAS  PubMed  Google Scholar 

  50. Neumann T, Vollmer A, Schaffner T, Hess OM, Heusch G. Diastolic dysfunction and collagen structure in canine pacing-induced heart failure. J Mol Cell Cardiol. 1999;31:179–92.

    Article  CAS  PubMed  Google Scholar 

  51. Moe GW, Armstrong P. Pacing-induced heart failure: a model to study the mechanism of disease progression and novel therapy in heart failure. Cardiovasc Res. 1999;42:591–9.

    Article  CAS  PubMed  Google Scholar 

  52. McLaran CJ, Gersh BJ, Sugrue DD, Hammill SC, Seward JB, Holmes DR Jr. Tachycardia induced myocardial dysfunction. A reversible phenomenon? Br Heart J. 1985;53:323–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Packer DL, Bardy GH, Worley SJ, Smith MS, Cobb FR, Coleman RE, et al. Tachycardia-induced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J Cardiol. 1986;57:563–70.

    Article  CAS  PubMed  Google Scholar 

  54. Nerheim P, Birger-Botkin S, Piracha L, Olhansky B. Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia. Circulation. 2004;110:247–52.

    Article  PubMed  Google Scholar 

  55. Custodis F, Roggenbuck U, Lehmann N, Moebus S, Laufs U, Mahabadi AA, et al. Resting heart rate is an independent predictor of all-cause mortality in the middle aged general population. Clin Res Cardiol. Epub 23 Jan 2016.

  56. Böhm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376:886–94.

    Article  PubMed  Google Scholar 

  57. Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Lopez Sendon JL, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823–30.

    Article  PubMed  Google Scholar 

  58. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol. 2008;101:865–9.

    Article  CAS  PubMed  Google Scholar 

  59. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875–85.

    Article  CAS  PubMed  Google Scholar 

  60. Tardif JC, O’Meara E, Komajda M, Bohm M, Borer JS, Ford I, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J. 2011;32:2507–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Heusch G. Pleiotropic action(s) of the bradycardic agent ivabradine: cardiovascular protection beyond heart rate reduction. Br J Pharmacol. 2008;155:970–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kleinbongard P, Gedik N, Witting P, Freedman B, Klocker N, Heusch G. Pleiotropic, heart rate-independent cardioprotection by ivabradine. Br J Pharmacol. 2015;172:4380–90.

    Article  CAS  PubMed  Google Scholar 

  63. Herrmann S, Layh B, Ludwig A. Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart. J Mol Cell Cardiol. 2011;51:997–1006.

    Article  CAS  PubMed  Google Scholar 

  64. Hofmann F, Fabritz L, Stieber J, Schmitt J, Kirchhof P, Ludwig A, et al. Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart. Cardiovasc Res. 2012;95:317–26.

    Article  CAS  PubMed  Google Scholar 

  65. Cerbai E, Sartiani L, DePaoli P, Pino R, Maccherini M, Bizzarri F, et al. The properties of the pacemaker current If in human ventricular myocytes are modulated by cardiac disease. J Mol Cell Cardiol. 2001;33:441–8.

    Article  CAS  PubMed  Google Scholar 

  66. Stillitano F, Lonardo G, Zicha S, Varro A, Cerbai E, Mugelli A, et al. Molecular basis of funny current If in normal and failing human heart. J Mol Cell Cardiol. 2008;45:289–99.

    Article  CAS  PubMed  Google Scholar 

  67. Steg P, Lopez-de-Sa E, Schiele F, Hamon M, Meinertz T, Goicolea J, et al. Safety of intravenous ivabradine in acute ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention: a randomized, placebo-controlled, double-blind, pilot study. Eur Heart J Acute Cardiovasc Care. 2013;2:270–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post- and remote conditioning. Circ Res. 2015;116:674–99.

    Article  CAS  PubMed  Google Scholar 

  69. Ibanez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015;65:1454–71.

    Article  PubMed  Google Scholar 

  70. Rienzo M, Melka J, Bize A, Sambin L, Jozwiak M, Su JB, et al. Ivabradine improves left ventricular function during chronic hypertension in conscious pigs. Hypertension. 2015;65:122–9.

    Article  CAS  PubMed  Google Scholar 

  71. Monnet X, Colin P, Ghaleh B, Hittinger L, Giudicelli J-F, Berdeaux A. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Eur Heart J. 2004;25:579–86.

    Article  PubMed  Google Scholar 

  72. Maranta F, Tondi L, Agricola E, Margonato A, Rimoldi O, Camici PG. Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia. Basic Res Cardiol. 2015;110:55.

    Article  CAS  PubMed  Google Scholar 

  73. Bolli R. Causative role of oxyradicals in myocardial stunning: a proven hypothesis. A brief review of the evidence demonstrating a major role of reactive oxygen species in several forms of postischemic dysfunction. Basic Res Cardiol. 1998;93:156–62.

    Article  CAS  PubMed  Google Scholar 

  74. Custodis F, Baumhäkel M, Schlimmer N, List F, Gensch C, Böhm M, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E deficient mice. Circulation. 2008;117:2377–87.

    Article  CAS  PubMed  Google Scholar 

  75. Drouin A, Gendron ME, Thorin E, Gillis MA, Mahlberg-Gaudin F, Tardif JC. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol. 2008;154:749–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Skalidis EI, Hamilos MI, Chlouverakis G, Zacharis EA, Vardas PE. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Atherosclerosis. 2011;215:160–5.

    Article  CAS  PubMed  Google Scholar 

  77. Tagliamonte E, Cirillo T, Rigo F, Astarita C, Coppola A, Romano C, et al. Ivabradine and bisoprolol on doppler-derived coronary flow velocity reserve in patients with stable coronary artery disease: beyond the heart rate. Adv Ther. 2015;32:757–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol. 1997;30:1104–6.

    Article  CAS  PubMed  Google Scholar 

  79. Gent S, Kleinbongard P, Dammann P, Neuhauser M, Heusch G. Heart rate reduction and longevity in mice. Basic Res Cardiol. 2015;110:2.

    Article  PubMed  Google Scholar 

  80. Coburn AF, Grey RM, Rivera SM. Observations on the relation of heart rate, life span, weight and mineralization in the digoxin-treated A-J mouse. Johns Hopkins Med J. 1971;128:169–93.

    CAS  PubMed  Google Scholar 

  81. Mercken EM, Carboneau BA, Krzysik-Walker SM, de Cabo R. Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res Rev. 2012;11:390–8.

    Article  PubMed  PubMed Central  Google Scholar 

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  1. West German Heart and Vascular Center, Institute for Pathophysiology, University of Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany

    Gerd Heusch & Petra Kleinbongard

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  1. Gerd Heusch
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Correspondence to Gerd Heusch.

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Gerd Heusch has served as a consultant for and on the Speakers Board of Servier. Petra Kleinbongard declares that she has no conflicts of interest that might be relevant to the content of this article.

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Heusch, G., Kleinbongard, P. Ivabradine: Cardioprotection By and Beyond Heart Rate Reduction. Drugs 76, 733–740 (2016). https://doi.org/10.1007/s40265-016-0567-2

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