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Drug Insight: If inhibitors as specific heart-rate-reducing agents

Nature Clinical Practice Cardiovascular Medicine volume 1, pages 103–109 (2004)Cite this article

An Erratum to this article was published on 01 April 2006

Abstract

Heart rate is determined primarily by spontaneously repeating net inward current carried by sodium ions and potassium ions through hyperpolarization-activated cyclic-nucleotide-gated channels. Within the heart, these channels are found most abundantly in sinoatrial cardiomyocytes. The channels open in response to membrane hyperpolarization, modulated by local cAMP concentrations. They permit activation of the If current, which can be blocked specifically by molecules characterized by linked benzazepinone and benzocyclobutane rings, and which are devoid of effects on cardiac conduction, inotropy or peripheral vascular tone. The resulting heart-rate reduction has been effective in angina prevention in clinical trials involving 4,000 patients, using the prototype If inhibitor, ivabradine. No serious adverse events have been attributed to the treatment; the most prominent side-effect is dose-related, always reversible and often transient visual symptoms that seldom result in voluntary drug discontinuation.

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Figure 1: Main properties of f-channel inhibition by ivabradine
Figure 2: Effect of ivabradine on time to angina sufficient to limit continued bicycle exercise among 257 protocol-compliant patients with coronary artery disease
Figure 3: Changes in heart rate in the different treatment groups during double-blind dose-ranging

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References

  1. Habib G (2001) Is heart rate a risk factor in the general population? Dialogues Cardiovasc Med 6: 25–31

    Google Scholar 

  2. Goldberg R et al. (1996) Factors associated with survival to 75 years of age in middle-aged men and women: The Framingham Study. Arch Intern Med 156: 505–509

    Article  CAS  Google Scholar 

  3. Gillum R (1988) The epidemiology of resting heart rate in a national sample of men and women: association with hypertension, coronary artery disasse, blood pressure, and other cardiovascular risk factors. Am Heart J 116: 163–174

    Article  CAS  Google Scholar 

  4. Singh BN (2004) Impact of heart rate on cardiovascular disorders: focus on chronic stable angina. In Selective and Specific If Channel Inhibition in Cardiology, 25–36 (Ed., Fox K), London: Science Press Ltd

    Google Scholar 

  5. Kjekshus J and Gullestad L (1999) Heart rate as a therapeutic target in heart failure. Eur Heart J 1 (Suppl H): H64–H69

    Google Scholar 

  6. Kjekshus JK (1986) Importance of heart rate in determining beta-blocker efficacy in acute and long-term myocardial intervention trials. Am J Cardiol 57: 43F–49F

    Article  CAS  Google Scholar 

  7. Levine HJ (1997) Rest heart rate and life expectancy. J Am Coll Cardiol 30: 1104–1106

    Article  CAS  Google Scholar 

  8. DiFrancesco D (2004) If current inhibitors: properties of drug-channel interaction. In Selective and Specific If Channel Inhibition in Cardiology, 1–13 (Ed., Fox K), London: Science Press Ltd

    Google Scholar 

  9. DiFrancesco D (1985) The cardiac hyperpolarizing-activated current, If: origins and developments. Prog Biophys Molec Biol 46: 163–183

    Article  CAS  Google Scholar 

  10. DiFrancesco D (1986) Characaterization of single pacemaker channels in cardiac sino-atrial node cells. Nature 324: 470–473

    Article  CAS  Google Scholar 

  11. Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. (1997) Eur Heart J 18: 394–413

  12. Gibbons RJ et al. (1999) ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. Circulation 99: 2829–2848

    Article  CAS  Google Scholar 

  13. Williams SV et al. (2001) Guidelines for the management of patients with chronic stable angina: diagnosis and risk stratification. Ann Intern Med 135: 530–547

    Article  CAS  Google Scholar 

  14. Pepine CJ et al. (1994) Characteristics of a contemporary population with angina pectoris: TIDES Investigators. Am J Cardiol 74: 226–231

    Article  CAS  Google Scholar 

  15. Brown HF et al. (1979) How does adrenaline accelerate the heart? Nature 280: 235–236

    Article  CAS  Google Scholar 

  16. DiFrancesco D and Tortora P (1991) Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351: 145–147

    Article  CAS  Google Scholar 

  17. Ludwig A et al. (1998) A family of hyperpolarization-activated mammalian cation channels. Nature 393: 587–591

    Article  CAS  Google Scholar 

  18. DiFrancesco D and Tromba C (1988) Inhibition of the hyperpolarization activated current (If) induced by acetylcholine in rabbit sino-atrial node myocytes. J Physiol (Lond) 405: 477–491

    Article  Google Scholar 

  19. DiFrancesco D (1991) The contribution of the “pace-maker” current (If) to generation of spontaneous activity in rabbit sino-atrial node myocytes. J Physiol 434: 23–40

    Article  CAS  Google Scholar 

  20. Colin P et al. (2003) Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol 284: H676–H682

    Article  CAS  Google Scholar 

  21. Colin P et al. (2004) Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther 308: 236–240

    Article  CAS  Google Scholar 

  22. Heidland UE and Strauer BE (2001) Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 104: 1477–1482

    Article  CAS  Google Scholar 

  23. Colin P et al. (2002) Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation during exercise. Am J Physiol Heart Circ Physiol 282: H672–H679

    Article  CAS  Google Scholar 

  24. Simon L et al. (1995) Coronary and haemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther 275: 659–666

    CAS  PubMed  Google Scholar 

  25. Mulder P et al. (2004) Long-term heart rate reduction induced by the selective I(f) current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation 109: 1674–1679

    Article  CAS  Google Scholar 

  26. Ramahi TM (2000) Beta blocker therapy for chronic heart failure. Am Fam Physician 62: 2267–2274

    CAS  PubMed  Google Scholar 

  27. Tattersfield AE (1991) Respiratory function in the elderly and the effects of beta blockade. Cardiovasc Drugs Ther 4 (suppl 6): 1229–1232

    Article  Google Scholar 

  28. Reneland R et al. (2000) Induction of insulin resistance by beta blockade but not ACE-inhibition: long-term treatment with atenolol or trandolapril. J Hum Hypertens 14: 175–180

    Article  CAS  Google Scholar 

  29. Krone W and Nagele H (1988) Effects of antihypertensives on plasma lipids and lipoprotein metabolism. Am Heart J 116: 1729–1734

    Article  CAS  Google Scholar 

  30. Lewis RV and Lofthouse C (1993) Adverse reactions with beta-adrenoceptor blocking drugs: an update. Drug Safety 9: 272–279

    Article  CAS  Google Scholar 

  31. Egstrup K (1988) Transient myocardial ischemia after abrupt withdrawal of antianginal therapy in chronic stable angina. Am J Cardiol 61: 1219–1222

    Article  CAS  Google Scholar 

  32. Frishman WH and Sica DA (2003) Calcium channel blockers. In Cardiovascular Pharmacotherapies, 2nd edn, 105–130 (Eds, Frishman WH et al.), New York: McGraw-Hill

    Google Scholar 

  33. Abrams J and Frishman WH (2003) The organic nitrates and nitroprusside. In Cardiovascular Pharmacotherapies, 2nd edn, 203–214 (Eds, Frishman WH et al.), New York: McGraw-Hill

    Google Scholar 

  34. Steering Committee, Transdermal Nitroglycerin Cooperative Study (1991) Acute and chronic antianginal efficacy in continuous twenty-four hour application of transdermal nitroglycerin. Am J Cardiol 68: 1263–1270

  35. Frishman WH et al. (1995) Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomised, double-blind, placebo-controlled, parallel-group study. J Am Coll Cardiol 26: 305–312

    Article  CAS  Google Scholar 

  36. Thollon C et al. (1994) Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea pig-cardiac preparations: comparison with UL-FS 49. Br J Pharmacol 112: 37–42

    Article  CAS  Google Scholar 

  37. Bois P et al. (1996) Mode of action of bradycardic agent, S16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol 118: 1051–1057

    Article  CAS  Google Scholar 

  38. Bucchi A et al. (2002) Current-dependent block of rabbit sino-atrial node If channels by ivabradine. J Gen Physiol 120: 1–13

    Article  CAS  Google Scholar 

  39. Monnet X et al. (2001) Effect of heart rate reduction with ivabradine on exercise induced myocardial ischaemia and stunning. J Pharmacol Exp Ther 299: 1133–1139

    CAS  PubMed  Google Scholar 

  40. Vilaine JP et al. (2003) Anti-ischemic effects of ivabradine, a selective heart rate-reducing agent, in exercise-induced myocardial ischemia in pigs. J Cardiovasc Pharmacol 42: 688–696

    Article  CAS  Google Scholar 

  41. Moore N et al. (1998) Effects of a pure bradycardic agent, S 16257, at rest and during exercise in healthy volunteers: comparison with propranolol. Br J Clin Pharmacol 45: 188–189

    Google Scholar 

  42. Manz M et al. (2003) A single intravenous dose of ivabradine, a novel I(f) inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology 100: 149–155

    Article  CAS  Google Scholar 

  43. DiFrancesco D and Camm J (2004) Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs 64: 1757–1765

    Article  CAS  Google Scholar 

  44. Borer JS Development of cardiovascular drugs: the US regulatory milieu from the perspective of a participating nonregulator. J Am Coll Cardiol, in press

  45. Borer JS et al., for the European Ivabradine Investigators (2003) Anti-anginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blinded, multicentered, placebo-controlled trial. Circulation 107: 817–823

    Article  Google Scholar 

  46. Borer JS (2004) New perspectives for the treatment of stable angina. In Selective and Specific If Channel Inhibition in Cardiology, 51–62 (Ed., Fox K), London: Science Press Ltd

    Google Scholar 

  47. Tardif JC et al., on behalf of the INITIATIVE study investigators (2003) Anti-anginal and anti-ischaemic effects of the If current inhibitor ivabradine compared to atenolol as monotherapies in patients with chronic stable angina. A 4-month randomised, double-blinded, multicenter, controlled non-inferiority trial [abstract]. Eur J Cardiol

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Authors and Affiliations

  1. Cardiovascular Medicine,

    Jeffrey S Borer

  2. Cardiovascular Pathophysiology,

    Jeffrey S Borer

  3. Howard Gilman Institute for Valvular Heart Diseases, Weill Medical College of Cornell University, New York-Presbyterian Hospital Weill Cornell Center, New York, NY, USA

    Jeffrey S Borer

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  1. Jeffrey S Borer
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Correspondence to Jeffrey S Borer.

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JS Borer serves as a paid consultant to Servier Laboratoires, Neuilly sur Seine, France.

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Borer, J. Drug Insight: If inhibitors as specific heart-rate-reducing agents. Nat Rev Cardiol 1, 103–109 (2004). https://doi.org/10.1038/ncpcardio0052

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