Skip to main content
SpringerLink
Log in

Heart Rate Lowering by Specific and Selective I f Current Inhibition with Ivabradine

A New Therapeutic Perspective in Cardiovascular Disease

  • Leading Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Resting heart rate is associated with cardiovascular and all-cause mortality, and the mortality benefit of some cardiovascular drugs seems to be related in part to their heart rate-lowering effects. Since it is difficult to separate the benefit of heart rate lowering from other actions with currently available drugs, a ‘pure’ heart rate-lowering drug would be of great interest in establishing the benefit of heart rate reduction per se.

Heart rate is determined by spontaneous electrical pacemaker activity in the sinoatrial node. Cardiac pacemaker cells generate the spontaneous slow diastolic depolarisation that drives the membrane voltage away from a hyperpolarised level towards the threshold level for initiating a subsequent action potential, generating rhythmic action potentials that propagate through the heart and trigger myocardial contraction. The I f current is an ionic current that determines the slope of the diastolic depolarisation, which in turn controls the heart beating rate.

Ivabradine is the first specific heart rate-lowering agent to have completed clinical development for stable angina pectoris. Ivabradine specifically blocks cardiac pacemaker cell f-channels by entering and binding to a site in the channel pore from the intracellular side. Ivabradine is selective for the I f current and exerts significant inhibition of this current and heart rate reduction at concentrations that do not affect other cardiac ionic currents. This activity translates into specific heart rate reduction, which reduces myocardial oxygen demand and simultaneously improves oxygen supply, by prolonging diastole and thus allowing increased coronary flow and myocardial perfusion. Ivabradine lowers heart rate without any negative inotropic or lusitropic effect, thus preserving ventricular contractility.

Ivabradine was shown to reduce resting heart rate without modifying any major electrophysiological parameters not related to heart rate. In patients with left ventricular dysfunction, ivabradine reduced resting heart rate without altering myocardial contractility. Thus, pure heart rate lowering can be achieved in the clinic as a result of specific and selective I f current inhibition.

Two randomised clinical studies have shown that ivabradine is an effective anti-ischaemic agent that reduces heart rate and improves exercise capacity in patients with stable angina. Ivabradine was shown to be superior to placebo in improving exercise tolerance test (ETT) criteria (n = 360) and, in a 4-month, double-blind, controlled study (n = 939), ivabradine 5 and 7.5mg twice daily were shown to be at least as effective as atenolol 50 and 100mg once daily, respectively, in improving total exercise duration and other ETT criteria, and reducing the number of angina attacks.

Experimental data indicate a potential role of pure heart rate lowering in other cardiovascular conditions, such as heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Table I
Fig. 4

Similar content being viewed by others

References

  1. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol 1980; 112: 736–49

    PubMed  CAS  Google Scholar 

  2. Kannel WB, Kannel C, Paffenbarger RS, et al. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J 1987; 113: 1489–94

    Article  PubMed  CAS  Google Scholar 

  3. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologie Follow-up Study. Am Heart J 1991; 121: 172–7

    Article  PubMed  CAS  Google Scholar 

  4. Mensink GB, Hoffmeister H. The relationship between resting heart rate and all-cause, cardiovascular and cancer mortality. Eur Heart J 1997; 18: 1404–10

    Article  PubMed  CAS  Google Scholar 

  5. Kristal-Boneh E, Silber H, Harari G, et al. The association of resting heart rate with cardiovascular, cancer and all-cause mortality: eight year follow-up of 3527 male Israeli employees (the CORDIS Study). Eur Heart J 2000; 21: 116–24

    Article  PubMed  CAS  Google Scholar 

  6. Reunanen A, Karjalainen J, Ristola P, et al. Heart rate and mortality. J Intern Med 2000; 247: 231–9

    Article  PubMed  CAS  Google Scholar 

  7. Fujiura Y, Adachi H, Tsuruta M, et al. Heart rate and mortality in a Japanese general population: an 18-year follow-up study. J Clin Epidemiol 2001; 54: 495–500

    Article  PubMed  CAS  Google Scholar 

  8. Benetos A, Thomas F, Bean K, et al. Resting heart rate in older people: a predictor of survival to 85. J Am Geriatr Soc 2003; 51: 284–5

    Article  PubMed  Google Scholar 

  9. Chang M, Havlik RJ, Corti MC, et al. Relation of heart rate at rest and mortality in the Women’s Health and Aging Study. Am J Cardiol 2003; 92: 1294–9

    Article  PubMed  Google Scholar 

  10. Gillman MW, Kannel WB, Belanger A, et al. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J 1993; 125: 1148–54

    Article  PubMed  CAS  Google Scholar 

  11. Palatini P, Thijs L, Staessen JA, et al. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med 2002; 162: 2313–21

    Google Scholar 

  12. Imai Y, Hozawa A, Ohkubo T, et al. Heart rate measurement and outcome. Blood Press Monit 2003; 8: 53–5

    Article  PubMed  Google Scholar 

  13. Hjalmarson A, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol 1990; 65: 547–53

    Article  PubMed  CAS  Google Scholar 

  14. Singh N. Diabetes, heart rate, and mortality. J Cardiovasc Pharmacol Ther 2002; 7: 117–29

    Article  PubMed  Google Scholar 

  15. Fillinger MP, Surgenor SD, Hartman GS, et al. The association between heart rate and in-hospital mortality after coronary artery bypass graft surgery. Anesth Analg 2002; 95: 1483–8

    Article  PubMed  Google Scholar 

  16. Seccareccia F, Pannozzo F, Dima F, et al. Heart rate as a predictor of mortality: the MATISS Project. Am J Public Health 2001; 91: 1258–63

    Article  PubMed  CAS  Google Scholar 

  17. Gundersen T, Grottum P, Pedersen T, et al. Effect of timolol on mortality and reinfarction after acute myocardial infarction: prognostic importance of heart rate at rest. Am J Cardiol 1989; 58: 20–4

    Article  Google Scholar 

  18. Kjekshus JK. Importance of heart rate in determining betablocker efficacy in acute and long-term acute myocardial infarction intervention trials. Am J Cardiol 1986; 57: 43F-9F

    Article  Google Scholar 

  19. Kjekshus J. Heart rate reduction: a mechanism of benefit? Eur Heart J 1987; 8 Suppl. L: 115–22

    Article  PubMed  Google Scholar 

  20. Hjalmarson A. Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol 1998; 21 (12 Suppl. II): II3–7

    PubMed  CAS  Google Scholar 

  21. Lechat P, Hulot J-S, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation 2001; 103: 1428–33

    Article  PubMed  CAS  Google Scholar 

  22. Guth BD, Heusch G, scitelberger R, et al. Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischaemia in conscious dogs. Circ Res 1987; 60: 738–46

    Article  PubMed  CAS  Google Scholar 

  23. Simonsen S, Ihlen H, Kjekshus JK. Haemodynamic and metabolic effects of timolol (Blocadren) on ischaemic myocardium. Acta Med Scand 1983; 213: 393–8

    Article  PubMed  CAS  Google Scholar 

  24. Purcell H. Heart rate as a therapeutic target in ischaemic heart disease. Eur Hear J Suppl 1999; 1 Suppl. H: H58–63

    Google Scholar 

  25. Andrews TC, Fenton T, Toyasaki N, et al. Subsets of ambulatory myocardial ischemia based on heart rate activity: circadian distribution and response to anti-ischemic medication. The Angina and Silent Ischemia Study Group (ASIS). Circulation 1993; 88: 92–100

    CAS  Google Scholar 

  26. Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science 1984; 226: 180–2

    Article  PubMed  CAS  Google Scholar 

  27. Beere PA, Glagov S, Zarins CK. Experimental atherosclerosis at the carotid bifurcation of the cynomolgus monkey: localization, compensatory enlargement, and the sparing effect of lowered heart rate. Arterioscler Thromb 1992; 12: 1245–53

    Article  PubMed  CAS  Google Scholar 

  28. Perski A, Olsson G, Landou C, et al. Minimum heart rate and coronary atherosclerosis: independent relations to global severity and rate of progression of angiographic lesions in men with myocardial infarction at a young age. Am Heart J 1992; 123: 609–16

    Article  PubMed  CAS  Google Scholar 

  29. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 2001; 104: 1477–82

    Article  PubMed  CAS  Google Scholar 

  30. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998; 339: 489–97

    Article  PubMed  CAS  Google Scholar 

  31. Rochon PA, Anderson GM, Tu JV, et al. Use of β-blocker therapy in older patients after acute myocardial infarction in Ontario. CMAJ 1999; 161: 1403–8

    PubMed  CAS  Google Scholar 

  32. Robinson RB, DiFrancesco D. Sinoatrial node and impulse initiation. In: Spooner PM, Rosen MR, editors. Foundations of cardiac arrhythmias: basic concepts and clinical approaches. New York: Marcel Dekker, 2001: 151–70

    Google Scholar 

  33. Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 2000; 47: 658–87

    Article  PubMed  CAS  Google Scholar 

  34. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993; 55: 455–72

    Article  PubMed  CAS  Google Scholar 

  35. Accili EA, Proenza C, Baruscotti M, et al. From funny current to HCN channels: 20 years of excitation. News Physiol sci 2002; 17: 32–7

    PubMed  CAS  Google Scholar 

  36. Kaupp UB, Scifert R. Molecular diversity of pacemaker ion channels. Annu Rev Physiol 2001; 63: 235–57

    Article  PubMed  CAS  Google Scholar 

  37. Biel M, Schneider A, Wahl C. Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc Med 2002; 12: 206–13

    Article  PubMed  CAS  Google Scholar 

  38. Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 2003; 65: 453–80

    Article  PubMed  CAS  Google Scholar 

  39. Ulens C, Tytgat J. Functional heteromerization of HCN1 and HCN2 pacemaker channels. J Biol Chem 2001; 276(9): 6069–72

    Article  PubMed  CAS  Google Scholar 

  40. Altomare C, Terragni B, Brioschi C, et al. Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node. J Physiol 2003; 549: 347–59

    Article  PubMed  CAS  Google Scholar 

  41. Much B, Wahl-Schott C, Zong X, et al. Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotidegated channels. J Biol Chem 2003; 278: 43781–6

    Article  PubMed  CAS  Google Scholar 

  42. Accili EA, Robinson RB, DiFrancesco D. Properties and modulation of If in newborn versus adult cardiac SA node. Am J Physiol 1997; 272: H1549–52

    PubMed  CAS  Google Scholar 

  43. Yasui K, Liu W, Opthof T, et al. If current and spontaneous activity in mouse embryonic ventricular myocytes. Circ Res 2001; 88: 536–42

    Article  PubMed  CAS  Google Scholar 

  44. Cerbai E, Sartiani L, DePaoli P, et al. The properties of the pacemaker current I(F) in human ventricular myocytes are modulated by cardiac disease. J Mol Cell Cardiol 2001; 33: 441–8

    Article  PubMed  CAS  Google Scholar 

  45. Pachucki J, Burmeister LA, Larsen PR. Thyroid hormone regulates hyperpolarization-activated cyclic nucleotide-gated channel (HCN2) mRNA in the rat heart. Circ Res 1999; 85: 498–503

    Article  PubMed  CAS  Google Scholar 

  46. Renaudon B, Lenfant J, Decressac S, et al. Thyroid hormone increases the conductance density of f-channels in rabbit sinoatrial node cells. Receptors Channels 2000; 7: 1–8

    PubMed  CAS  Google Scholar 

  47. Schulze-Bahr E, Neu A, Friederich P, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 2003; 111: 1537–45

    PubMed  CAS  Google Scholar 

  48. DiFrancesco D. Some properties of the UL-FS 49 block of the hyperpolarization-activated (if) current in SA node myocytes. Pflügers Arch 1994; 427: 64–70

    Article  PubMed  CAS  Google Scholar 

  49. Van Bogaert PP, Pittoors F. Use-dependent blockade of cardiac pacemaker current (If) by cilobradine and zatebradine. Eur J Pharmacol 2003; 478: 161–71

    Article  PubMed  Google Scholar 

  50. BoSmith RE, Briggs I, Sturgess NC. Inhibitory actions of ZENECA ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells. Br J Pharmacol 1993; 110: 343–9

    Article  PubMed  CAS  Google Scholar 

  51. Thollon C, Bidouard JP, Cambarrat C, et al. Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S 16257. Eur J Pharmacol 1997; 339: 43–51

    Article  PubMed  CAS  Google Scholar 

  52. DiFrancesco D. If current inhibitors: properties of drug-channel interaction. In: Fox K, editor. Selective and specific If channel inhibition in cardiology. London: Science Press, 2004: 1–13

    Google Scholar 

  53. Bois P, Bescond J, Renaudon B, et al. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol 1996; 118: 1051–7

    Article  PubMed  CAS  Google Scholar 

  54. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node If channels by ivabradine. J Gen Physiol 2002; 120: 1–13

    Article  PubMed  CAS  Google Scholar 

  55. Vilaine JP, Bidouard JP, Lesage L, et al. Anti-ischemic effects of ivabradine, a selective heart rate-reducing agent, in exercise-induced myocardial ischemia in pigs. J Cardiovasc Pharmacol 2003; 32: 688–96

    Article  Google Scholar 

  56. Monnet X, Ghaleh B, Colin P, et al. Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and stunning. J Pharmacol Exp Ther 2001; 299: 1133–9

    PubMed  CAS  Google Scholar 

  57. Monnet X, Colin P, Ghaleh B, et al. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Eur Heart J 2004; 25: 579–86

    Article  PubMed  Google Scholar 

  58. Colin P, Ghaleh B, Monnet X, et al. 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  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  60. Colin P, Ghaleh B, Hittinger L, et al. Differential effects of heart rate reduction and β-blockade on left ventricular relaxation during exercise. Am J Physiol Heart Circ Physiol 2002; 282: H672–9

    PubMed  CAS  Google Scholar 

  61. Camm AJ, Lau CP. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Drugs R D 2003; 4: 83–9

    Article  PubMed  CAS  Google Scholar 

  62. Manz M, Reuter M, Lauck G, et al. 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 2003; 100: 149–55

    Article  PubMed  CAS  Google Scholar 

  63. Borer JS, Fox K, Jaillon P, et al. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003; 107: 817–23

    Article  PubMed  Google Scholar 

  64. Demontis GC, Moroni A, Gravante B, et al. Functional characterisation and subcellular localisation of HCN1 channels in rabbit retinal rod photoreceptors. J Physiol 2002; 542 (Pt 1): 89–97

    Article  PubMed  CAS  Google Scholar 

  65. Tardif JC, Ford I, Tendera M, et al. Anti-anginal and anti-ischaemic effects of the If current inhibitor ivabradine versus atenolol in stable angina [abstract no. 186]. Eur Heart J 2003; 24 (Abstract Suppl.): 20

    Article  Google Scholar 

  66. Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation 2004; 109: 1674–9

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The preparation of this manuscript was supported by Servier. Professor Camm is the Chairman of the Ivabradine Safety Committee and is reimbursed by Servier for his time spent in this role. Professor DiFrancesco wishes to declare that Servier has provided support for research activity in his laboratory.

Author information

Authors and Affiliations

  1. Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, Milan, Italy

    Dario DiFrancesco

  2. The Medical School, St George’s Hospital, Cranmer Terrace, London, SW17 0RE, UK

    John A. Camm

Authors
  1. Dario DiFrancesco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John A. Camm
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John A. Camm.

Rights and permissions

Reprints and permissions

About this article

Cite this article

DiFrancesco, D., Camm, J.A. Heart Rate Lowering by Specific and Selective I f Current Inhibition with Ivabradine. Drugs 64, 1757–1765 (2004). https://doi.org/10.2165/00003495-200464160-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200464160-00003

Keywords

Search

Navigation