Recent Patents on Cardiovascular Drug Discovery, 2009, 4, 61-66
61
Ivabradine: Cardiovascular Effects Andrea Rognoni*, Marzia Bertolazzi, Sergio Macciò and Giorgio Rognoni Catheterization Laboratory, Division of Cardiology, Saint Andrea Hospital, 13100 Vercelli, Italy Received: September 9, 2008; Accepted: November 7, 2008; Revised: November 26, 2008
Abstract: Ivabradine (a compound of the benzocyclobutane) is a highly selective If current inhibitor acting directly on the sino-atrial node, induces a rapid, sustained and dose-dependent reduction of heart rate at rest and during exercise without a significant effect on atrio-ventricular conduction, left ventricular contraction/relaxation or vascular tissues. These properties associated with an improvement in left ventricular loading related to bradycardia resulted in an increase in stroke volume and preservation in cardiac output even during exercise. Various experimental and clinical studies showed the efficacy of ivabradine in patients with chronic stable angina, on heart rate reduction, on ventricular remodelling after acute myocardial infarction and on coronary blood flow. The safety of ivabradine has been documented in several studies and clinical trials, in contrast to beta-blockers, no significant side effects were expressed in the literature. The aim of our review is to describe ivabradine and its cardiovascular effects and outline some recent patents and the results of the most important trials.
Keywords: Ivabradine, benzocyclobutane, bradycardia, heart rate, coronary disease. INTRODUCTION Several studies show that heart rate is an independent prognostic risk factor for cardiovascular morbidity and mortality; infact a large epidemiological study, such as the Framingham Heart Study [1] showed that high resting heart rate is associated with increased all - causes of mortality. Increased heart rate is demonstrated, in the past, to be an independent risk factor for coronary and cardiovascular mortality. In a large French population study of almost 20000 individuals aged 40-69 years, heart rate superior of 100 beats/min versus inferior of 60 beats/min was associated with an age - adjusted 2 to 3 folds greater risk of mortality both in men and women [2]. Heart rate is a key determinant of coronary blood flow and myocardial oxygen consumption; a high rate induces myocardial ischemia and subsequent angina as it both increased myocardial oxygen demand and decreased myocardial perfusion, the latter by shortening the duration of diastole [3]; angina results when myocardial perfusion is insufficient to meet myocardial metabolic demand. Furthermore, increase heart rate and reduced heart rate variability have been shown to be associated with coronary plaque rupture and subclinical inflammation in healthy middle-age and elderly subjects [4, 5]. Since 1984, Beere [6] showed that lowering heat rate through ablation of the sinoatrial node in monkeys associated with an non-atherogenic diet decrease coronary atherosclerosis. Beta-blockers are effective at reducing angina by decreasing heart rate and they are usually preferred as initial therapy [7]; despite the demonstrated safety and effectiveness of beta - blockers, the use may be limited by their *Address correspondence to this author at the Catheterization Laboratory, Saint Andrea Hospital, Corso Mario Abbiate 21, 13100 Vercelli, Italy; Tel.: +39 0161 593 582; Fax: +39 0161 593 225; E-mail:
[email protected] 1574-8901/09 $100.00+.00
side effects such as fatigue, sexual dysfunction, cold extremities, depression, bronchospasm, gastrointestinal disturb and, finally, atrio-ventricular block [8, 9]. Accordingly, betablockers are contraindicated, also, in decompensated heart failure and peripheral vascular disease. These two last considerations explain why the use of some rate slowing drugs, such as beta-blockers and also, calcium channels antagonists is limited by side effects; this situation is considered by Andrikopoulos [10] to be a cornerstone of antianginal therapy. Furthermore, a broader use of calcium antagonists is limited not only by their side effects but also for the lack of convincing evidence that would strengthen the hypothesis that calcium antagonists can improve long term prognosis of patients with ischemic heart disease. Nevertheless in spite of the use of multiple anti anginal therapy and the advance in coronary surgery and coronary percutaneous revascularization, symptoms of angina continue to be experienced by up of 60% of patients [11]. Ivabradine is the first of a new class of heart rate lowering agents that act specifically on the sino-atrial node; ivabradine inhibits the If current of cardiac pacemaker cells without affecting other cardiac ionic currents [12, 13]. THE IF CURRENT IN HEART RATE MODULATION AND MOLECULAR EFFECTS OF IVABRADINE Ivabradine is a whole of the benzocyclobutane and its chemical formula is: [3-(3{[((7S)-3,4-dimethoxybicyclo [4,2,0]octa-1,3,5 trien-7-yl) methyl methylamino} propyl)1,3,4,5-terahydro-7,8-dimethoxy-2H-3-benzazepin-2-one] Fig. (1) [10]. In the sino-atrial node, several cellular mechanisms contribute to spontaneous activity. An important role in generation of diastolic depolarization, and hence repetitive activity, is played by the If current Fig. (2) [14].
© 2009 Bentham Science Publishers Ltd.
62 Recent Patents on Cardiovascular Drug Discovery, 2009, Vol. 4, No. 1
O
O O N
N O
Rognoni et al.
100 mV. Thus, in the pacemaker range of voltages, If is a slow activating inward current. All these properties are suited for generation of the diastolic depolarization phased of the action potential Fig. (3) [20].
O
Fig. (1). Chemical structure of ivabradine.
Fig. (3). The If channel system.
Since the first description in the 1979, the If current appeared to be important not only in the diastolic depolarization but especially in the rate acceleration caused by sympathetic stimulation; the current was indeed up regulated by - adrenoreceptor stimulation. Fig. (2). The sino-atrial node and the conduction system of the heart. (SAN: sino-atrial node; AVN: atrio-ventricular node; RA: right atrium; LA: left atrium; RV right ventricle; LV: left ventricle).
The If current was first described by Brown in 1979 [15]; “f” stands for funny because of the unusual properties of If channels relative to other system known at time. In the heart If channels were originally described in the sino-atrial node but they are also expressed functionally in the atrio-ventricular node and, in general, in all the conduction tissue [16]. The molecular correlates of If channels are the hyperpolarization activated, cyclic nucleotide-gated (HCN) channels, of which four isoforms are known (HCN 1 - 4) [17, 18]. Of the isoform identified, the most highly expressed in the sino-atrial node is HCN 4, while weaker expression of HCN 1 or HCN 2 has been observed in the sino - atriale node of different species [19]. The basic electrophysiological properties of the If current in sino-atrial node cells are particularly. Since If is carried by both Na+ and K+ ions, it reverses at approximately -10/-20 mV and is therefore an inward current at voltages in the diastolic range. If is activated on hyperpolarization at a threshold of about - 45 mV and is fully activated at around -
Furthermore, Di Francesco and Tortora [21] and various studies in the 1990s [22, 23] showed that If channels are activated by direct binding of intracellular cAMP molecules to internal aspect of channels. This cAMP modulation has a physiological importance since it is the basis for autonomic modulation of heart rate. Infact -adrenoreceptors stimulation leads to adenylate cyclase activation, to increased intracellular levels of cAMP, and to increased If current because of a depolarizing shift in the current activation range; therefore to an increased slope of diastolic depolarization, reduced diastolic duration and increased heart rate [24, 25]. The first pharmacological studies using ivabradine in the 1990s tried to characterize its effects in vitro and to investigate its mechanism of action. In the second stage, in the middle of 1990s, the studies tested the ivabradine action in vivo to investigate its hemodynamic selectivity at rest and during exercise and compare this action to beta-blockers. Ivabradine binds with a high specificity to f-channels and blocks them in a voltage dependent way. Drug molecules are “open f-channels” blockers and need to enter the channel pore from the intracellular side to reach their binding site. An unusual characteristic of f-channel block by ivabradine is that the steep voltage dependence (it is strong in
Ivabradine: Cardiovascular Effects
depolarization and weak in hyperpolarization) reflects a “current dependence”. Furthermore, it is interesting to underline that the ivabradine block of the HCN 4 isoform has the same properties as the block of native f-channels, while that of HCN 1 has substantial differences (infact Buchi [26] showed that, in this case, block occurs essentially when HCN 1 channels are closed and not open). This information confirms that the HCN 4 subunit is the most representative of native f-channels of sino-atrial node myocites, but also that differences in HCN isoform binding properties exist and can be exploited for the development of tissue-specific HCN-blocking molecules. We can also say that ivabradines’s specific mechanism of f-channels blockade suggests that this heart rate reducing agent is likely to be a clinically viable option, even in angina patients with contraindications to beta-blockers use; ivabradine is also to be an useful therapeutic alternative to Ca++ channel antagonists in angina patients for whom decreases in blood pressure and myocardial contractility are considered inappropriate [13]. CARDIOVASCULAR EFFECTS OF IVABRADINE Coronary Blood Flow If inhibition with ivabradine does not directly interfere with coronary vasomotion because the current is not present on vascular smooth cells [27] unlike beta - blockers (they decrease the diameter of large coronary arteries and blood flow through the combined blockage of vascular receptors and unopposed vasomotor tone). Furthermore, ivabradine promotes a redistribution of transmural coronary blood flow by limiting the reduction in subendocardial flow during myocardial ischaemia; this effect is due especially to the reduction in heart rate and to the prolongation of diastolic perfusion time of the coronary vascular bed [28]. There is, also an important difference between ivabradine and beta - blockers on diastolic perfusion time because ivabradine can reduce heart rate without significant changes in myocardial inotropy whereas beta blockers cannot. Infact, in 2003, Colin showed, in conscious dog during a treadmill exercise, that ivabradine increased diastolic perfusion time by 10% more than atenolol; these increased induced by ivabradine was totally blunted by atrial pacing whereas a significant reduction in diastolic perfusion time persisted when the reduction in heart rate induced by atenolol was abolished by atrial pacing [29]. These different effects between ivabradine and atenolol on diastolic perfusion time as on oxygen consuming is relevant only during exercise when sympathetic tone are at maximal levels. Heart Rate Reduction Ivabradine reduces heart rate in a dose dependent manner and it is independent of the pathophysiological status, since this heart rate slowing effect remains unchanged in animals or humans with reduced myocardial contractility or relaxation, such as in congestive heart failure.
Recent Patents on Cardiovascular Drug Discovery, 2009, Vol. 4, No. 1
63
Because If channels are activated by a use - dependent mechanism by hyperpolarization and by direct binding of cAMP, the reduction in heart rate induced by ivabradine is more marked at higher than at lower heart rates. This reduction, as showed by Vilaine [27], is limited to 18%-20% of basal heart rate either during rest or exercise even thought ivabradine reduced heart rate in a dose - dependent manner when it is given in the range of therapeutic dose. Furthermore, ivabradine can reduce heart rate in patients in whom beta-blockers are ineffective and this reduction is an additive effect when concomitantly administered with beta - blockers, at least when a residual sympathetic tone is still significant in these patients [30]. Ivabradine does not induce a significant prolongation of the QT interval and does not modify the PR interval at doses that clearly reduce heart rate. Myocardial Ischaemia, Endothelial Dysfunction
Myocardial
Infarction
and
Monnet [31] in an experimental animal model of myocardial ischaemia, induced by a combination of a coronary stenosis and physical exercise on treadmill, showed that, even beta blocker (atenolol) an ivabradine at doses that reduced heart rate, redistributed myocardial flow towards the subendocardium and reduced myocardial dysfunction during the ischemic time; nevertheless while atenolol worsened myocardial stunning during the recovery period, ivabradine decreased the severity and duration of stunning in the same conditions. The main difference between these two drugs was related to the 1 adrenergic blockade - mediated negative inotropic effect of atenolol. On the contrary ivabradine reduces myocardial stunning through its ability to reduce heart rate selectivity as well as its inability to alter myocardial inotropy. An important effect of reduction in heart rate on myocardial structure is the effect of ivabradine on prevention of loss of coronary vessels within the remaining viable part of the failing myocardium, a property that is probably closely linked to the observed angiogenesis in healthy animals receiving long - term treatment with a drug that decreases heart rate [32]. Mulder showed that a mechanism involved in this prevention of coronary rarefaction could be the augmented levels of hypoxia - inducible factor 1 and associated growth factors through the increase in left ventricular diastolic diameter and thus in myocardial stretch, which is a trigger for multiple factors involved in angiogenesis. This effect of long - term heart rate reduction with ivabradine can preserve (or improve) the coronary reserve associated with a decrease in perivascular collagen in the surviving myocardium thus preventing the progressive degradation of the cardiac function in heart failure [33]. Furthermore ivabradine, different from beta-blockade, has the unique property of not only improving ischaemic and postischemic regional myocardial function but also reversing post-ejection wall thickening (a typical sign of asynchrony of ventricular contraction and relaxation) to wall thickening during ejection and thus making this contraction available for cardiac output [34].
64 Recent Patents on Cardiovascular Drug Discovery, 2009, Vol. 4, No. 1
Rognoni et al.
In 2006, Langenbach [35] in a experimental animal model, after 28 days of coronary occlusion, showed that ivabradine as well as metoprolol not only preserved LV function and dilatation (with a significant reduction of brain natriuretic peptide) but also significantly reduced mortality and infarct size.
Furthermore, Ruzyllo et al. [40] recently showed, in a 3month randomized trial on 1195 patients, the non inferiority of twice daily ivabradine 7.5 mg and 10 mg with respect on amlodipine 10 mg one daily.
Thorin [36] showed that ivabradine prevented cerebrovascular endothelial dysfunction and lead to concomitant restoration of the endothelium - dependent dilatory hydrogen peroxidative pathway in dyslipidemic mice; furthermore in the same model they also demonstrated that ivabradine prevented endothelial dysfunction in renal arteries by reducing the oxidative stress. Custodis recently showed that the selective heart rate reduction may influence endothelial function and atherogenesis and tested the effect of ivabradine in apolipoprotein E-deficient mice. In this experimental model ivabradine (at the dosage of 10 mg/Kg body weight per day) significantly improved endothelial function in ApoE-/- mice almost to the levels of the control group. Instead, lower dose of ivabradine that did not affect heart rate (2 mg/kg body weight per day) did not alter endothelial function; furthermore cotreatment with ivabradine (full dosage just described) and L-NAME showed a trend toward decreased endothelial function compared with ivabradine alone, suggesting that prevention of eNOS uncoupling does not play a major role. Always in the same study, the authors demonstrated, in a histomor-phometric analysis of atherosclerotic lesion in the aortic sinus and descending aorta, that selective heart rate reduction by ivabradine significantly slows atherogenesis [37]. EXPERIENCE FROM THE CLINICAL TRIALS The first important randomized, double-blind, multicentered, placebo-controlled trial was published in 2003 [38]; in this study 360 patients with a history on chronic stable angina were assigned to receive ivabradine or placebo for two weeks followed by an open - label two or three month extension to ivabradine and one week randomized withdrawal to ivabradine or placebo (the first administration of ivabradine was 2.5, 5 or 10 mg; second one and third 10 mg). Primary efficacy criteria were changes in time to 1-mm ST depression and time to limiting angina during bicycle exercise, performed at through of drug activity. The authors showed that ivabradine produces a dose dependent improvements in exercise tolerance and time to development of ischaemia during exercise; furthermore this trial suggested that ivabradine was effective and safe in a mid - term treatment. In the INITIATIVE trial [39] (a 4-month randomized, double-blind, controlled, multicenter study of 939 patients) ivabradine at dosage of 7.5 mg and 10 mg twice daily was compared to atenolol 100 mg one daily in terms of their antianginal and antiischaemic effects. Ivabradine increased total exercise duration by 1.5 minutes at the trough of drug activity; in the ivabradine group an increase in time to 1-mm ST depression was showed and indicated that the improvement in total exercise capacity s associated with a relevant antiischaemic effect.
The efficacy and safety of therapy with ivabradine has been, also, demonstrated in a randomized, double blind, multi-center trial conduced with 386 patients with stable angina (already treated by nitrates or dihydropyridine calcium-channel blockers) who received ivabradine for 1 year in doses of 5 and 7.5 mg by day. Ivabradine decreased heart rate in a dose-dependent manner and the reduction was constant over one year of follow-up; the number of angina attacks reported be patients was significantly lower after the adjunction of ivabradine to therapy [41]. A small double-blind study, comparing the effect of ivabradine and propanolol on cardiac hemodynamics at rest and during exercise was conducted by Joannides et al. [42] with nine healthy volunteers receiving ivabradine or propanolol or placebo. This study demonstrated that administration of ivabradine reduced myocardial oxygen demand at the same degree as propanolol but without negative inotropic effect. The effects of ivabradine on cardiovascular morbidity and mortality were being explored in the BEAUTIFUL study [43] on more than 12000 patients and recently published. This study tested the potentially favourable effects of ivabradine in term of left ventricular remodelling and improvement in left ventricular function in patients with coronary artery disease. In recent past, Jondeau [44] in a small placebo-controlled randomized study on 65 patients with coronary artery disease and moderate left ventricular systolic dysfunction showed that ivabradine may be associated with improved left ventricular remodelling. The finally results of the BEAUTIFUL study did not yet confirmed these data; infact the authors concluded that reduction in heart rate with ivabradine does not significantly improve cardiac outcomes in all patients with stable coronary artery disease and left ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 beats or greater. All these data has been summarised in Table 1. Use of ivabradine for obtaining medicaments intended for the treatment of endothelial dysfunction has been recenty patented [45]. The Applicant has now discovered that ivabradine and its addition salts, more especially its hydrochloride, have valuable properties that allow them to be used in the treatment of endothelial dysfunction. Ivabradine, and also its addition salts with a pharmaceutically acceptable acid, and more especially its hydrochloride, and the hydrates of the said addition salts, have very valuable pharmacological and therapeutic properties, especially negative chronotropic properties (reduction of cardiac frequency), which render those compounds useful in the treatment, prevention and improvement of prognosis of various cardiovascular diseases associated with myocardial ischaemia, such as angina pectoris, myocardial infarction and associated rhythm disorders, as well as in various pathologies involving rhythm disorders, especially supraventricular rhythm disorders, and in chronic heart failure.
Ivabradine: Cardiovascular Effects
Table 1.
Recent Patents on Cardiovascular Drug Discovery, 2009, Vol. 4, No. 1
65
Clinical Studies with Ivabradine Study
Year
Aim
Conclusion
BEAUTIFUL trial [43]
2008
To evaluate the effects of ivabradine in patients with coronary artery disease and left ventricular dysfunction
Reduction in heart rate does not improve cardiac outcome in all patients; ivabradine could be used to reduce the incidence of coronary artery disease outcomes in patients with hight heart rate
INITIATIVE trial [39]
2005
To compare anti-ischemic and anti-anginal effects of ivabradien vs atenolol
Ivabradine as atenolol is effective in patients with stable angina
Borer et al. [38]
2003
To evaluate the anti-anginale effects of ivabradine
Ivabradine has a dose-dependent improvement in exercise tolerance and time to development if ischemia during exercise
Joannides [42]
2006
To compare the effects of ivabradine and propanolol on cardiac haemodynamics at rest and during exercise
Ivabradine, as propanolol, reduced myocardial oxygen demand but without negative inotropic effects
Lopez-Bscos et al. [41]
2004
To evaluate the efficacy and safety of combined therapy with ivabradine in patients treated with nitrates or dihydropiridine calcium channels blockers
After adjunction of ivabradine the number of angina attacks was significantly lower
Ruzyllo et al. [40]
2004
To evaluate anti-anginal and anti-ischemic effects of ivabradine vs amlodipine
Ivabradine as amlodipine is effective in patients with stable angina
Methods of identifying modulators of hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels have also been patented [46]. CURRENT & FUTURE DEVELOPMENTS Controlling heart rate has been particularly difficult in patients with myocardial ischemia, especially in the presence of poor tolerability to rate - slowing medications and particularly to beta - blockade therapy. Ivabradine has obtained in the recent past years the patents for lowering heart rate and improvement of stable angina in patients with coronary artery disease. Furthermore there is solid pathophysiological evidence that selective heart rate reduction by ivabradine improves blood flow to, and its redistribution within, ischemic myocardium. Different from beta blockade ivabradine does not impair isovolumic ventricular relaxation and does not exert a negative inotropic action. Therefore endothelium - mediated coronary vasodilatation and left ventricular function are better preserved than with beta - blockade. More mechanistic analyses on the benefits from ivabradine in the setting of myocardial reperfusion must be carried out [34]. Finally an appropriate pharmacological manipulation of the If channels is expected not only to provide a new therapeutic approach, but to enrich our knowledge on the molecular mechanism underlying heart rate. We hope that advanced therapeutic strategies aiming to appropriate control of heart rate would be available in the future.
REFERENCES [1] [2]
[3]
[4]
[5]
[6] [7] [8]
[9] [10]
[11]
CONFLICT OF INTEREST The authors have no conflict of interest regarding the opinion expressed in this manuscript and did not receive grants or financial support from industry or from any other source to prepare this review.
[12] [13]
Kannel WB, Kannel C, Paffenbarger RS Jr., Cupples LA. Heart rate and cardiovascular mortality: The Framingham Study. Am Heart J 1987; 113: 1489-1494. Benetos A, Rudnichi A, Thomas F, et al. Influence of heart rate on mortality in a French population: Role of age, gender, and blood pressure. Hypertension 1999; 33 (1): 44-52. Tardif JC, Ford I, Tendera M, Safar M, Guize M. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005; 26: 25292536. Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF. Increased heart rate and reduced heart rate variability are associated with subclinical inflammation in middle-age and elderly subjects with no apparent heart disease. Eur Heart J 2004; 25: 363-370. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart-rate are associated with coronary plaque disruption. Circulation 2001; 104: 1477-1482. Beere PA, GlagovS, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science 1984; 226: 180-182. North of England Stable Angina Guideline Development Group. Summary version of evidence based guideline for the primary care management of angina. Br Med J 1996; 312: 827-832. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, fatigue and sexual dysfunction. JAMA 2002; 288: 351-357. Fogari R, Zoppi A, Corradi L, et al. Sexual function in hypertensive males treated with lisinopril and atenolol: A crossover study. Am J Hypertens 1998; 11: 1244-1247. Andrikopoulos G, Dasopoulou C, Sakelliarou D, et al. Ivabradine: A selective If Inhibitor in the treatment of stable angina. Recent Patent Cardiovasc Drug Discov 2006; 1: 277-282. Henderson RA, Pocock SJ, Clayton TC, et al. Second randomized intervention treatment of angina (RITA - 2) trial participants. 7Year outcome in the RITA-2 trial: Coronary angioplasty versus medical therapy. J Am Coll Cardiol 2003; 42: 1161-1170. Camm AJ, Lau CP. Electrophysiological effects of a single intravenous administration of ivabradine (S16257) in adult patients with normal baseline electrophysiology. Drugs R D 2003; 4: 83-89. DiFrancesco D, Camm AJ. Heart rate lowering by specific and selective If current inhibition with ivabradine. Drugs 2004; 64: 1757-1765.
66 Recent Patents on Cardiovascular Drug Discovery, 2009, Vol. 4, No. 1 [14]
[15] [16] [17]
[18] [19]
[20] [21] [22]
[23] [24] [25]
[26] [27] [28]
[29] [30] [31]
[32]
Di Francesco D. The pacemaker current If plays an important role in regulating SA node pacemaker activity. Cardiovasc Res 1995; 30(2): 307-308. Brown HF, Di Francesco D, Noble SJ. How does adrenaline accelerate the heart? Nature 1979; 280(5719): 235-236. Dobzynski H, Nikolsky VP, Sambelahvilli AT, et al. Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart. Circ Res 2003; 93(11): 1102-1110. Barbuti A, Baruscotti M, Di Francesco D. The pacemaker current: From basics to the clinics. J Cardiovasc Electrophysiol 2007; 18(3): 342-347. Baruscotti M, Bucchi A, Di Francesco D. Physiology and pharmacology of the cardiac pacemaker (“funny”) current. Pharmacol Ther 2005; 107(1): 59-79. Shi W, Wymore R, Yu H, et al. Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res 1999; 85: e1-6. Di Francesco D, Borer JS. The funny current: Cellular basis for the control of heart rate. Drugs 2007; 67(2): 15-24. Di Francesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 1991; 351(6322): 145-147. Ishii T, Takano M, Xie LH, et al. Molecular characterization of the hyperpolarization-activated cation channel in a rabbit heart sinoatrial node. J Biol Chem 1999; 274: 12835-12839. Vaccari T, Moroni A, Rocchi M, et al. The human gene coding coding for HCN 2, a pacemaker channel of the heart. Biochim Biophys Acta 1999; 1446: 419-425. Di Francesco D. Pacemaker mechanism in cardiac tissue. Annu Rev Physiol 1993; 55: 455-472. Benetos A, Rudnichi A, Thomas F, et al. Influence of heart rate on mortality in a French population: Role of age, gender, and blood pressure. Hypertension 1999; 33(1): 44-52. Bucchi A, Tognati A, Milanesi R, et al. Properties of ivabradineinduced block of HCN 1 and HCN 4 pacemaker channels. J Physiol 2006; 572(2): 335-346. Vilaine JP, Thollon C, Villeneuve N, et al. Procorolan, a new selective If current inhibitor. Eur Heart J 2003; 5: G26-G35. Monnet X, Ghaleh B, Colin P, et al. Effect of heart reduction with ivabradine on exercise - induced myocardial ischaemia and stunning. J Pharmacol Exp Ther 2001; 299: 1133-1139. Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Circ Physiol 2003; 284: H676-682. Beardeaux A. Preclinical results with If current inhibition by ivabradine. Drugs 2007; 67(2): 25-33. Monnet X, Colin P, Ghaleh B, et al. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Eur Heart J 2004; 25: 579-586. Lei L, Zhou R, Zheng W, et al. Bradycardia induces angiogenesis, increases coronary reserve, and preserves function of the postinfarcted heart. Circulation 2004; 110: 796-802.
Rognoni et al. [33]
[34]
[35] [36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45] [46]
Mulder P, Thuillez C. In: Camm J, Tandera M, Eds. Heart rate slowing for myocardial dysfunction/heart failure: Rationale and preclinical studies. Heart rate slowing by If current inhibition. Adv Cardiol 2006; 43: 97-105. Neusch G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: Benefit from selective bradycardic agents. Br J Pharmacol 2008; 153: 1589-1601. Langenbach MR, Schmitz-Spanke S, Brockert M, et al. Comparison of a -blocker and an If current inhibitor in rabbits with myocardial infarction. J Cardiovasc Surg 2006; 47: 719-725. Thorin E, Drouin A, Gendro M, et al. Chronic heart rate reduction by ivabradine prevents cerebrovascular dysfunction in dyslipidemic mice. Arch Mal Coeur Vaiss 2007; 100(II): 653. Custodis F, Baumhakel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apoliprotein E-deficient mice. Circulation 2008; 117: 2377-2387. Borer JS, Fox K, Jaillon P, et al. Antianginal and antiiaschemic effect of ivabradine, an I (f) inhibitor in stable angina: A randomized, double-blind, mulcentered, placebo-controlled trial. Circulation 2003; 107: 817-823. Tardif JC, Ford I, Tendera M, et al. For the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005; 26: 2529-2536. Ruzyllo W, Tendera M, Ford I, et al. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: A 3-month randomised, double-blind, multicentre, noninferioriry trial. Drugs 2007; 67: 393-405. Lopez-Bscos L, Filpova S, Martos R. Long- term safety and antianginal efficacy of the If current inhibitor ivabradine in patients with chronic stable angina. A one-year randomized, double-blind, multicenter trial. Eur Heart J 2004; 25: 876. Joannides R, Moore N, Iacob M, et al. Comparative effects of ivabradine, a selective heart rate-lowering agent, and propanolol on systemic and cardiac hemodynamics at rest and during exercise. Br J Clin Pharmacol 2006; 61 (2): 127-137. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. On behalf of the BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular dysfunction (BEAUTIFUL): A randomized, double-blind, placebo-controlled trial. Lancet 2008; 372: 807-816. Jondeau G, Korewicki J, Vasiliauskns D. Effect of ivabradine in patients with left ventricular systolic dysfunction and coronary artery disease (abstract 2637). Eur Heart J 2004; 25: 451. Benatar, V., Lerebours-Pigeonniere, G., Tardif, J.-C., Thorin, E., Rheaume, E.: US20080200450A1 (2008). Vasylyev, D., Lu, Q., Mark, B., Edward, K., Shan, Q.: WO2008121735A1 (2008).
