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 If 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 If 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 If 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.
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.
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.
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: 736–49PubMedGoogle Scholar
Kannel WB, Kannel C, Paffenbarger RS, et al. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J 1987; 113: 1489–94PubMedCrossRefGoogle Scholar
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: 172–7PubMedCrossRefGoogle Scholar
Mensink GB, Hoffmeister H. The relationship between resting heart rate and all-cause, cardiovascular and cancer mortality. Eur Heart J 1997; 18: 1404–10PubMedCrossRefGoogle Scholar
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: 116–24PubMedCrossRefGoogle Scholar
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: 495–500PubMedCrossRefGoogle Scholar
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: 284–5PubMedCrossRefGoogle Scholar
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: 1294–9PubMedCrossRefGoogle Scholar
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: 1148–54PubMedCrossRefGoogle Scholar
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: 2313–21Google Scholar
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: 1483–8PubMedCrossRefGoogle Scholar
Seccareccia F, Pannozzo F, Dima F, et al. Heart rate as a predictor of mortality: the MATISS Project. Am J Public Health 2001; 91: 1258–63PubMedCrossRefGoogle Scholar
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: 20–4CrossRefGoogle Scholar
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-9FCrossRefGoogle Scholar
Hjalmarson A. Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol 1998; 21 (12 Suppl. II): II3–7PubMedGoogle Scholar
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: 1428–33PubMedCrossRefGoogle Scholar
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: 738–46PubMedCrossRefGoogle Scholar
Simonsen S, Ihlen H, Kjekshus JK. Haemodynamic and metabolic effects of timolol (Blocadren) on ischaemic myocardium. Acta Med Scand 1983; 213: 393–8PubMedCrossRefGoogle Scholar
Purcell H. Heart rate as a therapeutic target in ischaemic heart disease. Eur Hear J Suppl 1999; 1 Suppl. H: H58–63Google Scholar
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: 92–100Google Scholar
Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science 1984; 226: 180–2PubMedCrossRefGoogle Scholar
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: 1245–53PubMedCrossRefGoogle Scholar
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: 609–16PubMedCrossRefGoogle Scholar
Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 2001; 104: 1477–82PubMedCrossRefGoogle Scholar
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: 489–97PubMedCrossRefGoogle Scholar
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: 1403–8PubMedGoogle Scholar
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: 151–70Google Scholar
Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 2000; 47: 658–87PubMedCrossRefGoogle Scholar
Biel M, Schneider A, Wahl C. Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc Med 2002; 12: 206–13PubMedCrossRefGoogle Scholar
Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 2003; 65: 453–80PubMedCrossRefGoogle Scholar
Ulens C, Tytgat J. Functional heteromerization of HCN1 and HCN2 pacemaker channels. J Biol Chem 2001; 276(9): 6069–72PubMedCrossRefGoogle Scholar
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: 347–59PubMedCrossRefGoogle Scholar
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: 43781–6PubMedCrossRefGoogle Scholar
Accili EA, Robinson RB, DiFrancesco D. Properties and modulation of If in newborn versus adult cardiac SA node. Am J Physiol 1997; 272: H1549–52PubMedGoogle Scholar
Yasui K, Liu W, Opthof T, et al. If current and spontaneous activity in mouse embryonic ventricular myocytes. Circ Res 2001; 88: 536–42PubMedCrossRefGoogle Scholar
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: 441–8PubMedCrossRefGoogle Scholar
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: 498–503PubMedCrossRefGoogle Scholar
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: 1–8PubMedGoogle Scholar
Schulze-Bahr E, Neu A, Friederich P, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 2003; 111: 1537–45PubMedGoogle Scholar
DiFrancesco D. Some properties of the UL-FS 49 block of the hyperpolarization-activated (if) current in SA node myocytes. Pflügers Arch 1994; 427: 64–70PubMedCrossRefGoogle Scholar
Van Bogaert PP, Pittoors F. Use-dependent blockade of cardiac pacemaker current (If) by cilobradine and zatebradine. Eur J Pharmacol 2003; 478: 161–71PubMedCrossRefGoogle Scholar
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: 343–9PubMedCrossRefGoogle Scholar
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: 43–51PubMedCrossRefGoogle Scholar
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: 1–13Google Scholar
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: 1051–7PubMedCrossRefGoogle Scholar
Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node If channels by ivabradine. J Gen Physiol 2002; 120: 1–13PubMedCrossRefGoogle Scholar
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: 688–96CrossRefGoogle Scholar
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: 1133–9PubMedGoogle Scholar
Monnet X, Colin P, Ghaleh B, et al. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Eur Heart J 2004; 25: 579–86PubMedCrossRefGoogle Scholar
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: 236–40PubMedCrossRefGoogle Scholar
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: H676–82PubMedGoogle Scholar
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: H672–9PubMedGoogle Scholar
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: 83–9PubMedCrossRefGoogle Scholar
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: 149–55PubMedCrossRefGoogle Scholar
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: 817–23PubMedCrossRefGoogle Scholar
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): 89–97PubMedCrossRefGoogle Scholar
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.): 20CrossRefGoogle Scholar
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: 1674–9PubMedCrossRefGoogle Scholar