sinoatrial node. Cardiac pacemaker cells generate the spontaneous slow diastolic depolarisation that drives the membrane voltage away from a hyperpolarised ...
Drugs 2004; 64 (16): 1757-1765 0012-6667/04/0016-1757/$34.00/0
LEADING ARTICLE
2004 Adis Data Information BV. All rights reserved.
Heart Rate Lowering by Specific and Selective If Current Inhibition with Ivabradine A New Therapeutic Perspective in Cardiovascular Disease Dario DiFrancesco1 and John A. Camm2 1 Dipartimento di Scienze Biomolecolari e Biotecnologie, Universit`a di Milano, Milan, Italy 2 The Medical School, St George’s Hospital, London, UK
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 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
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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.
An association between elevated resting heart rate and both cardiovascular and all-cause mortality has been known for many years, based on the results of large-scale epidemiological studies, including industry-based studies in Chicago, Illinois, USA,[1] the Framingham Study[2] and the National Health and Nutrition Examination Survey (NHANES) I Follow-up Study.[3] More recent studies have confirmed this association in the general population[4-7] and also in specific populations such as the elderly,[8,9] and in individuals with particular medical conditions including hypertension,[10-12] myocardial infarction,[13] diabetes mellitus[14] and after coronary artery bypass graft surgery.[15] The association is present even among relatively young, low-risk individuals,[16] and is not restricted to those with a frankly elevated heart rate; a graded increase in risk has been suggested for heart rates above approximately 60 bpm.[7] The mortality benefit associated with therapy with agents such as β-adrenoceptor antagonists (βblockers) and some calcium channel antagonists appears to be related in part to their effects on heart rate, in both ischaemic heart disease[13,17-20] and chronic heart failure.[21] Indeed, there is evidence that much of the anti-ischaemic benefit of β-blockade can be prevented by the abolition of their effect on heart rate using atrial pacing, both in conscious dogs[22] and in patients with angina pectoris.[23] Therefore, heart rate reduction has been proposed as a therapeutic target in patients with ischaemic heart disease.[20,24] There are several mechanisms by which a low or reduced heart rate could be of benefit. Myocardial ischaemia occurs when coronary perfusion is insufficient to satisfy myocardial oxygen demand and heart rate is an important determinant of myocardial 2004 Adis Data Information BV. All rights reserved.
oxygen demand. Heart rate may also affect myocardial perfusion. Unless the normal heart rate-diastolic time relation is disturbed, a reduction in heart rate will increase the duration of diastole relative to cardiac cycle length, thus allowing more time for effective left ventricular perfusion. In this way, a reduction in heart rate should improve both aspects of myocardial oxygen balance. An obvious example of the relationship between heart rate and myocardial ischaemia is provided by angina pectoris. Symptoms of chest pain in stable angina are commonly triggered by an increase in heart rate in response to physical exercise or emotional stress. Similarly, most episodes of asymptomatic or silent myocardial ischaemia are also preceded by a period of increased heart rate, and the efficacy of different medications in preventing such episodes has been related to their efficacy in reducing heart rate.[25] In addition to its short-term effects on myocardial ischaemia, heart rate has also been implicated in the progression of atherosclerosis, in both experimental monkeys[26,27] and patients with coronary heart disease.[28] A high heart rate has also been associated with coronary plaque disruption in patients, independently of blood pressure, possibly as a result of increased haemodynamic stress.[29] Finally, in patients with impaired left ventricular function, a slow heart rate will prolong diastolic filling time, and thus may improve ventricular filling and stroke volume. Taken together, these mechanisms are predictive that slowing the heart rate would improve myocardial pumping performance and efficiency; improvements which in turn should lead to a reduction in sympathetic drive to the heart. Therefore, drugs that reduce heart rate should be of benefit in a range of cardiovascular conditions. However, current heart rate-reducing drugs are nonDrugs 2004; 64 (16)
Specific If Current Inhibition with Ivabradine
specific and have a range of actions on the cardiovascular and other systems, which both complicate the interpretation of the effects of heart rate lowering, and may be harmful, at least in some patients. For example, the use of β-adrenoceptor antagonists is limited mainly by contraindications and physician concerns relating to effects they produce other than on heart rate, such as a negative inotropic action and respiratory system effects.[30,31] More specific heart rate-lowering agents could, therefore, be of interest in a range of cardiovascular conditions. 1. Role of Pacemaker Currents Spontaneous electrical pacemaker activity may occur in several regions of the heart, including the sinoatrial node, the atrioventricular node, the bundle of His and the Purkinje fibres. However, under normal physiological conditions, the intrinsic pacemaker rhythm is fastest in the sinoatrial node, which therefore determines the overall heart rate. Pacemaker cells in the heart have the unique ability to spontaneously generate slow diastolic depolarisation that drives the membrane voltage away from the hyperpolarised level reached at the completion of one action potential towards the threshold level for initiating a subsequent action potential. The rhythmic action potentials thus generated propagate through the conducting systems of the heart and trigger myocardial contraction. Pacemaker activity involves the interplay between several ionic currents that influence the spontaneous diastolic depolarisation of the sinoatrial node. They include the If current and the calcium currents ICaL (long-lasting) and ICaT (transient).[32] The details of the mechanism vary between species, between pacemaker regions and even among different cells within the sinoatrial node.[33] The If current has several distinctive properties directly relevant to pacemaking and plays a central role in the process (reviewed by DiFrancesco[34] and Accili et al.[35]). If current activation at the termination of an action potential determines the slope of the slow diastolic depolarisation, which in turn controls the time interval between successive action potentials (figure 1) and, hence, the heart beating rate. 2004 Adis Data Information BV. All rights reserved.
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The molecular mechanisms underlying the distinctive properties of the If current have been intensively investigated and have been the subject of several recent reviews.[35-38] The channels responsible for the If current are known as HCN (hyperpolarisation-activated, cyclic nucleotide-gated) channels. Four distinct isoforms (HCN1–4) have been identified and their encoding genes have been cloned. The experimental evidence indicates that HCN channels are tetramers,[39] like the voltagegated, 6-transmembrane-domain potassium (Kv) channels. In the heart, native pacemaker channels are likely to be heteromultimers composed of different HCN subunits, as indicated by comparing the properties of cotransfected HCN isoforms and native channels.[40,41] The different HCN isoforms vary in their properties and in their distribution in different tissues. In the mouse and rabbit sinoatrial node, HCN4 is the predominant isoform, with HCN1 and HCN2 expressed at much lower levels. The expression of HCN channels and If current density in the heart changes during development,[42,43] in disease states[44] and in response to 0
500
msec
mV −50
pA −50 50
If
IK ICaL −50 ICaT −50 INaCa −50 25 Ip
Fig. 1. Computer simulation of ion currents flowing in a spontaneously active sinoatrial node cell. The If current represents the largest contribution to diastolic depolarisation except in its late fraction (reproduced from Robinson and DiFrancesco,[32] with permission from Marcel Dekker). ICaL = long-lasting calcium current; ICaT = transient calcium current; IK = potassium current; INaCa = sodium/ calcium exchange current; Ip = pump current; mV = millivolt; pA = picoampere.
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thyroid hormones.[45,46] Recently, idiopathic sinus node dysfunction, with bradycardia at rest and chronotropic incompetence during exercise in a patient, was attributed to the expression of mutant HCN4 channels that were insensitive to intracellular cyclic adenosine monophosphate.[47] Thus, the role and clinical importance of the If current in a range of situations involving physiological and pathological changes in heart rate and its regulation are becoming progressively clearer. 2. The If Current as a Pharmacological Target The growing evidence for the potential clinical benefits of pure heart rate-lowering drugs, together with the primary role of the If current in the control of heart rate demonstrated by recent progress in the understanding of cardiac automaticity, prompted the search for specific heart rate-lowering agents targeting this current. Ivabradine is currently undergoing regulatory approval in Europe. Other agents such as zatebradine, cilobradine and ZD 7288 have been investigated,[48-50] but there is no information that their development is continuing. In isolated rabbit sinoatrial node, the spontaneous firing rate of the pacemaker cells was reduced by ivabradine. Over the large range of concentrations tested (0.3–10 µmol/L), the slope of slow diastolic depolarisation was reduced, while maximum diastolic potential or threshold potential of activation remained unaffected[51,52] (figure 2).
40
Control Ivabradine 0.3 µmol/L
mV
20 0 0.5
sec
−20 −40 −60 Fig. 2. Spontaneous action potential in rabbit sinoatrial node in the absence (control) or presence of ivabradine 0.3 µmol/L (reproduced from DiFrancesco,[52] with permission). mV = millivolt.
2004 Adis Data Information BV. All rights reserved.
Further patch clamp studies in rabbit sinoatrial node cells showed that ivabradine specifically blocks f-channels in a concentration-dependent manner. The block occurs when the drug enters the channel pore from the intracellular side and binds to a site within the ion permeation pathway[53,54] (figure 3). Binding and unbinding of ivabradine at this site can only occur when the channel is in the open state; the block is therefore use dependent, which may enhance the rate of block at high heart rates and may be advantageous in a clinical setting. Ivabradine is a selective antagonist of the If current, as it significantly inhibits the current and produces substantial reduction in the rate of spontaneous action potential firing in rabbit sinoatrial node cells at concentrations that have no effect on other ionic currents, in particular T- and L-type calcium currents and delayed-rectifier potassium current (table I).[53] Several experimental studies have been published recently that clarify the different beneficial effects that may be associated with pure heart rate reduction when using ivabradine. In a model of exercise-induced regional myocardial ischaemia in pigs, ivabradine and propranolol were equipotent in reducing tachycardia during exercise and reducing ST-segment shift, but ivabradine, unlike propranolol, did not reduce left ventricular contractility and it preserved systolic shortening fraction in the ischaemic region to a greater degree.[55] In a model of ischaemic left ventricular contractile dysfunction in dogs, recovery of contractility was significantly more rapid with ivabradine than with atenolol.[56,57] In chronically instrumented conscious dogs, heart rate lowering with ivabradine dose-dependently increased diastolic time and reduced myocardial oxygen consumption (MVO2), with a linear relationship between heart rate and MVO2.[58] In contrast, the negative inotropic action of atenolol led to a prolonged ejection time and, consequently, a smaller increase in diastolic time for the same reduction in heart rate than with ivabradine.[59] Additionally, ivabradine, unlike atenolol, did not depress the physiological exercise-induced acceleration of left ventricular diastolic relaxation in dogs; thus, Drugs 2004; 64 (16)
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Closed
Open
Blockade
Extracellular
Intracellular Na+
K+
Ivabradine
Fig. 3. Schematic representation showing that ivabradine specifically blocks f-channels by entering the channel pore from the intracellular side and binding to a site within the ion permeation pathway.
ivabradine does not show the negative lusitropic effects associated with β-blockade.[60] 3. Clinical Experience with Ivabradine Several clinical studies have documented the effects and benefits of the pure heart rate-lowering action of ivabradine in humans. 3.1 Studies Examining the Effects of Specific If Blockade on Cardiac Electrophysiology and Myocardial Contractility
In an uncontrolled study in 14 patients needing cardiac electrophysiological investigation or catheter radiofrequency ablation for supra-ventricular arrhythmia, but with normal electrophysiology at study baseline, a single intravenous administration of ivabradine (0.2 mg/kg corresponding to approximately 10mg twice daily orally) reduced resting heart rate by approximately 14 bpm, but did not induce any change in major electrophysiological parameters other than those related to heart rate. The QT interval was prolonged as the heart rate was
slowed by ivabradine, raising the possibility that the use of ivabradine might encourage ventricular arrhythmias. However, the QT interval corrected for heart rate (QTc) was not prolonged by ivabradine, thus providing reassurance that such arrhythmias are unlikely. The PR and QRS intervals, as well as the conductivity and refractoriness of the atrium, atrioventricular node, His-Purkinje system and ventricles were not modified by ivabradine.[61] In a randomised, placebo-controlled study in 44 patients with left ventricular dysfunction, a single intravenous infusion of ivabradine 0.2–0.3 mg/kg reduced resting heart rate by over 17%, but did not alter left ventricular ejection fraction, fractional shortening or stroke volume as determined by echocardiography.[62] The absence of effects on myocardial contractility and cardiac electrophysiology are attributable to the lack of effect of ivabradine on cardiac ion currents other than the If, and demonstrate that pure heart rate lowering can be achieved in the clinic as a result of specific and selective If current inhibition.
Table I. Inhibition (%) of sinus node ion currents by ivabradine, as determined using the patch-clamp technique on rabbit sinoatrial node cells[53] Ion current (n)
Concentration of ivabradine (µmol/L) [mean ± SE] 0.03
0.3
1
3
5.5 ± 1.0
19.5 ± 2.2
32 ± 3
59 ± 2
80 ± 2
ICaT (8)
0
0
0
ICaL (8)
0
0
18 ± 1
If (10)
10
IK (12) 0 0 16 ± 1 ICaL = long-lasting calcium current; ICaT = transient calcium current; IK = potassium current; SE = standard error of the mean.
2004 Adis Data Information BV. All rights reserved.
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3.2 Studies in Patients with Stable Angina Pectoris
An area where pure heart rate lowering should be of direct benefit is the prevention of symptoms and myocardial ischaemia in stable angina pectoris. This would be through the reduction of oxygen needs resulting from reduced cardiac work and the improvement of coronary artery perfusion resulting from the prolongation of diastole. The efficacy of ivabradine in patients with stable angina has been evaluated in two large-scale clinical studies. The first study was a randomised, placebo-controlled, dose-ranging study in 360 patients with stable angina and documented coronary artery disease.[63] Patients (mean age 58.5 years) were randomised to receive placebo or one of three oral doses of ivabradine (2.5, 5 or 10mg twice daily) for 2 weeks. Efficacy was evaluated using standardised, symptom-limited bicycle exercise tolerance tests (ETT). At the trough of drug activity (i.e. 12 hours after the last drug administration), ivabradine produced dose-dependent reductions versus placebo in heart rate at rest and during exercise of approximately 15 and 14 bpm, respectively, with the 10mg twice-daily dose. These reductions in exercise heart rate were associated with significant, dose-dependent anti-ischaemic and anti-anginal efficacy (measured by increases in time to 1mm ST-segment depression and time to limiting angina, respectively) during ETT. There were also significant reductions in the frequency of angina attacks reported by patients in their daily lives with ivabradine treatment. The only adverse events linked to ivabradine treatment were visual symptoms, reported by approximately 15% of patients receiving the 10mg twicedaily dose, and fewer than 2% of patients in the 2.5 and 5mg twice-daily groups, in the double-blind phase. These symptoms consisted of transient enhanced brightness in limited areas of the visual field and were commonly associated with abrupt changes in light intensity. They were generally mild and well tolerated, causing
