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I_f modulation: perspectives in clinical medicine

Michael R. Rosen^1,2,*, Annalisa Bucchi¹ and Richard B. Robinson¹

¹ Department of Pharmacology, Columbia University Medical Center, Columbia University, PH 7W-321, 630 West 168 Street, New York, NY 10032, USA
² Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA

^* Corresponding author. E-mail address: mrr1{at}columbia.edu

	Abstract

Top Abstract Introduction Mechanisms of normal pacemaker... Mechanism of action of... The advantages of heart... Conclusions Acknowledgements References

 
As opposed to a number of other pharmacological agents, ivabradine expresses high selectivity and specificity for its target. Ivabradine exerts a unique action on cardiac pacemaker activity, based on its block of the hyperpolarization-activated, cyclic nucleotide-gated channels that pass the pacemaker current, I_f. In doing so, it suppresses but does not stop the sinoatrial pacemaker's rate of firing. In the following pages, we will review the mechanisms of normal pacemaker activity in the heart, discuss ivabradine's mechanism of action, and then review the advantages of heart rate reduction in clinical settings as well as other potential applications of the drug.

Key Words: Ivabradine • Pacemaker current • Angina pectoris • Heart rate

	Introduction

Top Abstract Introduction Mechanisms of normal pacemaker... Mechanism of action of... The advantages of heart... Conclusions Acknowledgements References

 
It is rare, in medicine, to find a drug that is selective and specific. The usual expectation is that drugs that initially manifest a unique action are discovered in time to have other effects, sometimes desirable, as with the statins,¹ and sometimes undesirable, as with a variety of anti-arrhythmics.^2,3 In this presentation, we shall focus on ivabradine, a drug that has been developed to manifest a unique action on cardiac pacemaker activity.^4,5 In doing so, we shall first review the mechanisms of normal pacemaker activity in the heart, then consider the mechanism of action of ivabradine, and finally consider the potential advantages of heart rate reduction without other haemodynamic effects in comparison with other molecules.

	Mechanisms of normal pacemaker activity in the heart

Top Abstract Introduction Mechanisms of normal pacemaker... Mechanism of action of... The advantages of heart... Conclusions Acknowledgements References

 
In the normal heart, impulses are initiated in the sinoatrial node (SAN) and propagate from that structure to activate the atria, and then—via the atrioventricular (AV) node and His-Purkinje system—the ventricles. Figure 1 provides a summary of the characteristics of the pacemaker potential.⁶ As opposed to normal fibres of the myocardium, cells in the sinus node spontaneously depolarize during electrical diastole, producing an automatic rhythm that in the normal heart is the only self-initiating and self-sustained rhythm. This same property of automaticity resides in other cells of the cardiac specialized conducting system, but in normal hearts such rhythms are usually expressed only when the sinus rate is markedly reduced or there is sinoatrial arrest or block and/or AV block.

View larger version (45K): [in this window] [in a new window]   Figure 1 The role of If in the generation of pacemaker potentials in the SAN. (A) Pacemaker potentials in the SAN under control conditions, and after ß-adrenergic stimulation with NE. The four major currents that control the generation of the pacemaker potential are indicated: If current (produced by HCN channels), T-type (ICaT) and L-type (ICaL) calcium currents, and repolarizing K currents (IK). (B) Scheme of a SAN cell showing the regulation of the HCN channel by up- or down-regulation of cellular cAMP. M2, type-2 muscarinic receptor; AC, adenylyl cyclase; Gi, G-protein subunit (inhibits AC); Gß, G-protein ß subunit; ß1-AR, type-1 ß-adrenergic receptor; Gs, G-protein subunit (stimulates AC); V, shift of the voltage dependence of HCN channel activation induced by increase or decrease of cAMP. Reprinted with permission from Biel et al.6

 
Families of inward and outward ionic currents generate the action potential and influence the slope of diastolic depolarization. It is beyond the scope of this review to enumerate all of them, but it is important to emphasize those that contribute to the potential of the pacemaker. As shown in Figure 1A, both inward sodium and calcium currents contribute to the sinus node action potential. Phase 4 depolarization is initiated by I_f, the so-called ‘funny current’, that activates on hyperpolarization of the membrane resulting in an inward flow of Na ions, which carries the membrane potential to more positive voltages.^7,8 Inward Ca currents also contribute to the latter portion of phase 4 as well as to the upstroke of the action potential. Counteracting the inward currents are outward currents carried by potassium that hyperpolarize the membrane and tend to maintain it at negative levels. Finally, membrane pumps and exchangers also play a role here, with the Na/Ca exchanger being a prime operative, which can also account for membrane depolarization.⁹

To sum up, multiple currents contribute to phase 4 depolarization, but it appears that I_f is the current critical to the initiation of the pacemaker potential. It is important conceptually to understand the multiplicity of currents that play a role here. In effect, they provide a safety factor; even if one were to ‘dial down’ the role of one current considerably, the others would continue to play a role ensuring the continuation of some pacemaker activity. This would lead to the expectation that one could effectively turn I_f off and still expect to see pacemaker activity, albeit at a slower rate, because of the contributions of the other currents.

Figure 1A makes another important point regarding pacemaker activity. That is, its profound autonomic responsiveness, which is essential in maintaining a normal range of responses of the heart to the demands of exercise, emotion, and other stresses. As shown, in the presence of norepinephrine (NE), the slope of phase 4 depolarization increases and the rate of pacemaker firing increases. Importantly, this ß-adrenergic action of NE is counteracted by the muscarinic agonist acetylcholine (ACh), which alone will slow down pacemaker rate and in the presence of NE will brake the increase in pacemaker rate induced by the latter. These effects of the two neurohormones are the basis for the sympathetic and parasympathetic effects exerted by autonomic stimulation on the heart in situ.

Because I_f initiates the pacemaker potential and also because ivabradine acts to block I_f and slow pacemaker rate, it is useful to spend a bit more time understanding the structural make up of the channel that carries pacemaker activity. The channels are designated as the hyperpolarization-activated, cyclic nucleotide gated (HCN) family.⁸ The nomenclature reflects the fact that I_f is activated on hyperpolarization of the membrane, passing inward current at that time, and that cyclic adenosine monophosphate (cAMP), a key second messenger of sympathetic—specifically ß-adrenergic—input, binds to the channel and shifts it to more positive voltages, resulting in more rapid onset of passage of current. There are four isoforms of the HCN channel, designated HCN1–4. HCN3 is not present in the heart; the major isoform in sinus node is HCN4 and HCN1 is present as well. HCN2 predominates in the His-Purkinje system and ventricle.

Functional HCN channels are tetramers and, as shown in Figure 1B, each subunit has six transmembrane spanning domains, with the cAMP binding site residing near the carboxy terminus. Catecholamine binding to the ß-1 adrenergic receptor operates via a guanosine triphosphate (GTP)-sensitive protein (Gs) to increase activation of the enzyme adenylyl cyclase, increasing breakdown of adenosine triphosphate to cAMP. With more cAMP available to bind to its channel site and alter voltage dependence and kinetics, the result is faster initiation of current, an increased slope of phase 4 depolarization, and a faster heart rate. ACh binds to a muscarinic receptor and, operating through the GTP-sensitive protein Gi, has a braking effect on the ß-adrenergic component. This counteracts the action of ß-1 agonist to increase cAMP synthesis, and as a result, slows rate. In addition, ACh can operate directly to suppress cAMP synthesis and therefore I_f and pacemaker rate.

The final insight needed before proceeding with a discussion of ivabradine can be obtained from Figure 2. Panel A (left) shows the native I_f current that is transmitted through a single rabbit SAN cell, as recorded using the patch clamp technique. A two-step protocol was used to first impose a voltage in the physiological range, near the midpoint of the I_f activation curve, and then to impose a more negative voltage that fully activates the current. When isoproterenol is added, the current at the less negative voltage is increased, whereas that at the more negative voltage is unchanged, because isoproterenol shifts the activation curve to more positive voltages without increasing maximal conductance. The magnitude of the voltage shift can be estimated by shifting the holding potential positive during successive test sweeps to effectively reduce the size of the initial voltage step. If the holding potential is reduced by an amount that equals the actual shift in voltage dependence caused by isoproterenol, then the isoproterenol trace will overlie the control trace. In the example shown in Figure 2, the measured shift was 8.5 mV. The result is more current flow at physiologic voltages. This results in an increased slope of diastolic depolarization and faster spontaneous rate, as seen in Figure 2A (right), in which spontaneous action potentials were recorded in a separate cluster of SAN cells. In Figure 2B, a similar experiment is shown, but in this case the preparation being newborn rat ventricular cells in culture that have been infected with an HCN2-expressing adenovirus to overexpress HCN2 channels and create an HCN-based pacemaker. An identical pattern of results is observed. The current carried by the HCN2 channel is increased by isoproterenol, at physiological voltages, because of a 10 mV shift in voltage dependence, and the rate and diastolic slope of the spontaneous action potentials are increased. In summary, this figure demonstrates that for both native I_f current in the SAN and for a genetically engineered HCN2-based pacemaker, altering pacemaker current at physiologic voltages will modify spontaneous rate.

View larger version (24K): [in this window] [in a new window]   Figure 2 Effect of ß-adrenergic stimulation on pacemaker current and spontaneous rate. (A) Native pacemaker current in rabbit SAN cells. Left: Pacemaker current If was recorded in an isolated myocyte during a two-step voltage clamp from a holding potential of –35 mV to voltages of –70 and –135 mV in control (black trace), and during superfusion with 1 µM isoproterenol (gray trace). The current at the less negative voltage increased, reflecting a positive shift in the voltage dependence of the pacemaker channels, and this shift was separately measured (by holding potential adjustment) to be 8.5 mV in this cell. Right: Spontaneous action potentials were recorded in a small cluster of SAN myocytes during control and isoproterenol (1 µM) superfusion. Isoproterenol increased the slope of diastolic depolarization and spontaneous rate. (B) Expressed HCN2 channel in neonatal rat ventricle cells. Left: HCN2 current was recorded in an isolated myocyte during a two-step voltage clamp from a holding potential of –25 mV to voltages of –70 and –35 mV in control (black trace) and during superfusion with 1 µM isoproterenol (gray trace). The current at the less negative voltage increased because of a measured shift of 10 mV. Right: Spontaneous action potentials were recorded in a monolayer of myocytes during control and isoproterenol (1 µM) superfusion. Isoproterenol increased the slope of diastolic depolarization and spontaneous rate.

 

	Mechanism of action of ivabradine and its novelty

Top Abstract Introduction Mechanisms of normal pacemaker... Mechanism of action of... The advantages of heart... Conclusions Acknowledgements References

 
There are many drugs that affect heart rate: obvious examples are ß-blockers which slow sinus rate by antagonizing the actions of catecholamine to increase the activation of I_f; L-type calcium-channel blockers that decrease inward Ca current (Figure 1); many anti-arrhythmic drugs, which exert effects on a combination of inward Na and Ca currents. However, none of these drugs is selective and specific for the pacemaker current, and it is here that ivabradine achieves its novelty.

There has been interest for some time in the development of drugs having a unique effect to slow heart rate. Indeed, in 1985, Kobinger¹⁰ proposed the use of heart rate slowing as a therapy for angina pectoris. Likely, the first drug studied because of its unique bradycardic properties was alinidine.^11,12 Snyders and Van Bogaert¹³ demonstrated that alinidine decreased the slope of phase 4 depolarization in sheep Purkinje fibres. The mechanism was a decreased current density and a shift of activation into more negative voltages. However, the effect of alinidine was not sufficiently specific: perhaps most worrisome was its effect of prolonging action potential duration.¹⁴ This type of effect, attributed to a blockade of K channels⁸ together with a slowing of heart rate, is known to be proarrhythmic.

Alinidine is an imidazoline derivative of the anti-hypertensive drug clonidine.⁸ The next lead in developing bradycardic drugs came from a different family of compounds, derivatives of the calcium-channel blocker verapamil. Of the group of drugs initially developed, perhaps the most promising was zatebradine, which reduces the conductance of the f channel and with this current density, and does so in a frequency-dependent fashion.^15,16 A positive property was zatebradine's potent effect in blocking I_f accompanied by only weak effects on calcium and potassium channels.¹⁵ Yet, although it reduced heart rate during rest and exercise, it reportedly had no appreciable anti-anginal action.¹⁷ And on the negative side were reports of visual toxicity expressed both as flashes of light and as persistence of visual images.^17,18 These were found to result from a drug effect on neuronal h channels (the I_f of the nervous system).^19,20

Whereas other drugs such as cilobradine, a zatebradine congener, and ZD-7288 have been and are being studied,⁸ ivabradine is the only drug of its kind to have reached the clinic for treatment of stable angina. Ivabradine and zatebradine are reportedly equipotent in reducing automatic rate, an effect that is attributed to decreased diastolic depolarization.⁵ However, whereas zatebradine increased action potential duration by approximately 30%, equivalent doses of ivabradine had only one-third the effect of prolonging repolarization.⁵

The molecular and biophysical bases of ivabradine's action on I_f have been studied in some detail as is summarized in Figure 3. The drug is an open-channel blocker that expresses its action use dependently. Moreover, while it is an open-channel blocker preferential block is exerted when f channels deactivate during depolarization.²¹ This action is like that of zatebradine and of ZD-7288 and implies that only when the channel is open can the drug gain access to its binding site within the channel pore. However, zatebradine and ZD-7288 appear to exert block that is voltage-dependent, whereas the block induced by ivabradine appears unique in that it depends on the driving force of the current itself.²¹ Bucchi et al.²¹ attribute this to ‘I_f channels having multi-ion, single file pores (with ivabradine blocking) current flow by entering the pore from the intracellular side (of the cell membrane) and competing with permeating ions for a binding site along the permeation pathway.’

View larger version (36K): [in this window] [in a new window]   Figure 3 Properties of the If block by ivabradine. (A) If block induced by ivabradine during repetitive stimulation (–100 mV/+5 mV) is partially removed by a long hyperpolarizing step to –100 mV (compare traces a and c in inset). (B) When the same protocol is applied in the presence of Cs+, no block removal occurs, indicating that the current flow is required for block removal. (C) The voltage dependence of block shifts to more negative voltages when the external Na+ concentration is reduced, and the shift is similar to that of the If reversal potential, as measured by plotting fully activated I/V relations in the two solutions (bottom panel); also, there is a steep change of block efficiency across the reversal potentials in both conditions. This confirms that the block depends on current flow rather than on voltage per se. (D) The current dependence could be due to the interaction of ivabradine with permeating ions within the pore. Figure and legend reprinted from Baruscotti et al.8 with permission.

 
There are several aspects of the action of ivabradine that make it potentially unique for clinical use: one is its use-dependent action (implying greater effect at faster heart rates), and the second is its high affinity for f channels.⁴ This combination of effects would suggest that the drug should not induce excess bradycardia and that its channel-blocking effects should be largely confined to the primary pacemaker current, I_f.

	The advantages of heart rate reduction without other effects in comparison with ß-blockers and other molecules

Top Abstract Introduction Mechanisms of normal pacemaker... Mechanism of action of... The advantages of heart... Conclusions Acknowledgements References

 
The advantages of a highly selective action such as that of ivabradine are both theoretical and practical. Many years ago when it still seemed that the holy grail of safe, effective arrhythmic therapy might be achieved with anti-arrhythmic drugs alone, the availability of a series of molecules having unique effects on single ion channels was a goal proposed.² Yet, this was not to be, for a variety of reasons. First, drugs initially thought to be selective for individual channels were found to affect more than one channel. An example is ibutilide, initially thought uniquely to increase inward Na current during the action potential plateau to prolong repolarization and refractoriness.²² It subsequently was found to be a potent blocker of delayed rectifier (outward potassium) current as well.²³ Yes, the drug was effective, but regrettably was associated with a high incidence of proarrhythmia.²² Second, amiodarone, a drug with actions on multiple channels, was found not only to be more effective than many other anti-arrhythmic drugs, but perhaps least confounded with serious proarrhythmic actions.³ Third, the triggers and substrates for arrhythmias are now known to be so complex and varied from individual to individual that the goal of mixing single channel therapies to provide cocktails individualized for each patient appears naïve. However, for specific arrhythmias having a single trigger mechanism, such as exercise- or catecholamine-induced tachycardias, single target therapy (in this case ß-adrenergic blockade) has proven to be safe and reasonably effective.³

In other words, if one approaches the idea of drug design from the perspective of mechanism and finds that attacking a single target effectively modifies a trigger or substrate, be it arrhythmia, angina, or for that matter any disease entity, the single target approach is not only valid, but in light of the likelihood of lesser toxicity, still should be sought after. And so the question, with regard to bradycardic agents is: are they as or more effective than more broad-spectrum compounds in their therapeutic application? As angina pectoris is the major target of bradycardic therapy at present, what is to be gained with an I_f blocker that is not already satisfied by ß-adrenergic blockers? The answer is a simple one: if by inducing I_f blockade one can achieve a comparable or superior anti-anginal effect without the accompanying actions of ß-adrenergic blockade on mood, peripheral vasculature, libido, etc., then one has a drug that would be viewed as superior.

The idea of heart rate slowing is that it will reduce cardiac work and myocardial O₂ demand and increase stroke volume, coronary blood flow, and myocardial O₂ supply.^24–27 Benefit accrues especially to the subendocardium in this setting.²⁶ Among the effects of ß-adrenergic blockade not seen in the setting of I_f blockade are hypotension, depression, loss of libido, and complications of conduction system disease, chronic obstructive pulmonary disease, diabetes, and peripheral vascular disease.^28–32

Heart rate slowing can also be achieved with calcium-channel blockers, for reasons that can be appreciated by referring to Figure 1A. However, this effect comes at the expense of decreased inotropy and at times worsening of congestive failure and peripheral oedema.³³ Finally, long-acting nitrates also have a variety of side effects and are often associated with cardioacceleration.²⁶

Given that ivabradine, reduces the heart rate without negative inotropy in both animal models and in clinical studies,^24,27,34 and in large-scale clinical trials has been shown to be anti-anginal and anti-ischaemic as compared with placebo,^26,35 its absence of side effects seen with calcium-channel or ß-adrenergic blockade would appear to confer significant therapeutic advantage. This is not to say that the drug is without side effects altogether. Specifically, dose-related effects on vision have been reported in up to 18% of patients, although this occurs at dosages above the therapeutic range.³⁵ Moreover, given its action to block I_f, its use is contraindicated in patients with SAN dysfunction.

	Conclusions

Top Abstract Introduction Mechanisms of normal pacemaker... Mechanism of action of... The advantages of heart... Conclusions Acknowledgements References

 
Ivabradine exerts its anti-anginal effects via heart rate slowing, which results from a highly specific action on the pacemaker current I_f. Its clinical success, to date, provides an example of how highly targeted therapy can result in a risk/benefit advantage over other effective therapies. However, the possibilities provided by I_f blockade can far exceed the use of blocking agents as anti-anginals. Given current interest in biological pacemaking based on overexpression of HCN channels,³⁶ one might see a future use in modulating rate increases in specific patients. Moreover, given the presence and role of HCN channels in neuronal tissues, I_f blockade is being explored in seizure disorders and in pain management as well.³⁷

	Acknowledgements

Top Abstract Introduction Mechanisms of normal pacemaker... Mechanism of action of... The advantages of heart... Conclusions Acknowledgements References

 
Supported by USPHS-NHLBI grant HL28958.

Conflict of interest: Drs Rosen and Robinson receive research support from Servier.

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Top Abstract Introduction Mechanisms of normal pacemaker... Mechanism of action of... The advantages of heart... Conclusions Acknowledgements References

 

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