Antiarrhythmic therapy in atrial fibrillation

Pharmacology & Therapeutics 128 (2010) 129–145

Contents lists available at ScienceDirect

Pharmacology & Therapeutics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h a r m t h e r a

Associate editor: O. Binah

Antiarrhythmic therapy in atrial fibrillation Ursula Ravens ⁎ Department of Pharmacology und Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307 Dresden

a r t i c l e

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Keywords: Atrial fibrillation Electrical remodelling Atrial ion channels Atrial-selective drugs IKur blockers Constitutively active IK,ACh

a b s t r a c t Currently available antiarrhythmic drugs for the management of AF are not sufficiently effective and are burdened with cardiac and extracardiac side effects that may offset their therapeutic benefits. Better knowledge about the mechanisms underlying generation and maintenance of AF may lead to the discovery of new targets for pharmacological interventions. These could include atrial-selective ion channels (e.g. atrial INa, IKur and IK,ACh), pathology-selective ion channels (constitutively active IK,ACh, TRP channels), ischemiauncoupled gap junctions, proteins related to malfunctioning intracellular Ca2+ homeostasis (e.g., “leaky” ryanodine receptors, overactive Na+,Ca2+ exchanger) or risk factors for arrhythmias (“upstream” therapies). The review will briefly summarize the current pathophysiological and therapeutic concepts of AF. A description of recently developed antiarrhythmic drugs and their proposed pharmacological action will follow. The final section will speculate about some putative targets for antiarrhythmic drug action in the context of the remodelled atria. © 2010 Elsevier Inc. All rights reserved.

Contents 1. Introduction . . . . . . . . . . 2. Pathophysiological considerations 3. Therapeutic principles . . . . . . 4. Therapeutic Interventions . . . . 5. New Drugs . . . . . . . . . . . Acknowledgments . . . . . . . . . . References . . . . . . . . . . . . . .

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1. Introduction Atrial fibrillation (AF) is a common supraventricular arrhythmia associated with old age and cardiac diseases such as valvular abnormalities, hypertension, ischemic heart disease, myocardial infarction and cardiothoracic surgery (Heeringa et al., 2006; Kannel et al., 1998), but may also occur with no obvious clinical cause (“lone” AF). Based on the demographic development in Western societies, AF prevalence in the general population may increase from presently 0.4–1% (Fuster et al., 2006) to more than 3 fold when projected to the year 2050, and the incidence of AF in patients over 85 years of age may scale up from presently 7.1% to more than 20% (Murphy et al., 2007). AF is associated with increased morbidity and mortality, and effective

⁎ Tel.: +49 351 4586300; fax: +49 351 4586315. E-mail address: [email protected]. 0163-7258/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2010.06.004

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therapy is warranted in order to prevent stroke (Benjamin et al., 2009). Thus, AF is becoming an increasing public health problem. Current therapeutic strategies include pharmacological, electrophysiological and surgical interventions (Fuster et al., 2006; Liu et al., 1992), all of which are limited by insufficient long-term efficacy. Especially antiarrhythmic drugs are burdened with cardiac and extracardiac side effects that may offset their benefits. Therefore new drugs for effective and safe pharmacological management of AF are needed. Discovery of new drug targets and development of innovative drugs require a thorough understanding of normal impulse formation and conduction and of the pathophysiology of AF. 1.1. Action potential and ion channels The shape of the cardiac action potential is determined by voltageand time-dependent opening and closing of distinct ion channels that pass depolarising (inward) and repolarising (outward) current (see

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Fig. 1). The inward rectifier K+ current IK1 maintains the resting membrane potential. When external pulses depolarise the membrane potential beyond threshold Na+ channels will rapidly activate and inactivate, giving rise to the large inward INa during the upstroke (phase 0) of the regenerative action potential. The initial rapid repolarisation (phase 1) is caused by the transient outward current Ito. The plateau (phase 2) is maintained by a delicate balance of depolarising Ca2+ influx (L-type Ca2+ current ICa,L) and repolarising outwardly directed K+ currents. The latter include the ultrarapidly activating current IKur, the rapidly and the slowly activating delayed rectifier current IKr and IKs. Evidence is accumulating that a small depolarising current either flowing through unselective cation channels (“leak” channels) or through non-inactivating Na+ or Ltype Ca2+ channels (INa,late; ICa,L,late) also contributes to maintenance of the plateau (Liu et al., 1992). During phase 3 of the rapid final repolarisation, K+ currents such as the background inward rectifier current IK1, and IKr which will increase again due to rapid recovery from inactivation allow the membrane potential to return to resting values (phase 4). Additional inward rectifying, ligand-activated channels also contribute to final repolarisation and resting membrane potential, i.e., the acetylcholine-activated inward rectifier IK,ACh or the ATP-dependent inward rectifier IK,ATP. The concentration gradients for Na+ and K+ across the plasmalemma are restored by the energy consuming Na+ pump, the (Na+, K+)-ATPase, which extrudes 3 Na+ in exchange for 2 K+. By this electrogenic nature the (Na+, K+)ATPase contributes hyperpolarising outward current to the resting membrane potential. Calcium entering the cell during the plateau phase is removed by the Na+, Ca2+ exchanger (NCX1) (Sipido et al., 2006). Due to its stoichiometry of 3 Na+ being exchanged for 1 Ca2+ the NCX provides depolarising current at resting potential. 1.2. Refractoriness and conduction Cardiomyocytes remain refractory until inactivated cation channels (especially Na+ channels) have recovered from inactivation during diastole and become available again for activation. Recovery of Na+ channels from inactivation is faster and more complete at more negative voltage. The effective refractory period (ERP) is determined

by the action potential duration (APD) and the speed of Na+ channel recovery after full repolarisation. Propagation of action potentials between adjacent cardiomyocytes requires low resistance current pathways called gap junctions and the generation of a current large enough to depolarise the neighbouring cells beyond threshold for regenerative action potentials. Therefore, conduction velocity within myocardial tissue is a function of membrane excitability which depends on Na+ channel availability, and of cell-to-cell coupling via gap junctions. 2. Pathophysiological considerations The electrophysiological mechanisms of arrhythmias include perturbation of physiological impulse formation (ectopic activity), impaired impulse conduction, or disturbed electrical recovery (refractoriness). Ectopic automaticity develops under conditions of metabolic and mechanical stress, but can also arise from sarcoplasmic reticulum (SR) Ca2+ overload (Bers, 2002) or abnormal SR Ca2+ release (Dobrev and Nattel, 2008; Vest et al., 2005). Physiologically, Ca2+ influx via L-type Ca2+ channels triggers the release of Ca2+ for contractile activation from the SR via Ca2+ release channels. This Ca2+ is pumped back into the SR during diastole. High Ca2+ load of the SR causes spontaneous opening of the Ca2+ release channels without prior excitation. The resulting cytosolic Ca2+ increase activates the plasmalemmal (Na+, Ca2+)-exchanger (NCX) that produces the transient inward current underlying delayed afterdepolarisations [DADs (Dobrev, 2010)]. On the other hand, critical prolongation of the AP plateau phase can give rise to early afterdepolarisations (EADs), because inactivated Na+ and/or Ca2+ channels may re-open and provide extra depolarising current (Luo and Rudy, 1994). Impulse conduction is compromised by electrical decoupling of cells and by impaired excitability at depolarised membrane potential because of reduced availability of Na+ channels. Gap junction uncoupling can alter conduction pathways. Long refractoriness and rapid impulse conduction safeguard cardiomyocytes against premature excitation and the development of reentry (Jalife, 2000). Reentry occurs when an excitation wave front returns to its origin and encounters tissue that is no longer refractory. The reentry circle requires a size that is at least as large as the wave

Fig. 1. Typical action potentials from human right atrial trabeculum (left) and left ventricular papillary mucle (right), measured with sharp electrodes at physiological temperature (37 °C). Stimulation frequency 1 Hz. The numbers indicate the phases of the action potential. the curves underneath are cartoons of current flow through the various ion channels during the time course of an action potential. See text for further explanation. Redrawn from “The Sicilian Gambit” (1991).

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length, i.e., the product of ERP and conduction velocity, in order to continuously propagate through the tissue. Reentry can also be conceived as a spiral wave where the wavefront is rotating around a central core (“rotor”) (Vaquero et al., 2008). The rotor will turn faster and in a more stable position the higher the excitability and the shorter the refractory period (“stabilisation of rotor”). For theoretical background of the concepts of “leading circle” and “rotors” and a comparison of their role in AF the reader is referred to an excellent review (Comtois et al., 2005). 2.1. Initiation and maintenance of AF Atrial fibrillation is initiated when ectopic activity triggers reentry in a vulnerable substrate. Instable membrane potentials either at the AP plateau or resting level (EADs, DADs) can serve as triggers for ectopic activity. In human AF, rapidly firing ectopic foci are typically located in the pulmonary veins (Haissaguerre et al., 1998). Fibrillatory activity evolves when the excitation waves break up into multiple wavelets because the surrounding atrial tissue fails to follow the ectopic pacemaker (Berenfeld et al., 2002). Periodic activity of sustained, high-frequency functional reentry sources known as “rotors” can also trigger and sustain AF (Pandit et al., 2005). As a third possibility, fibrillatory activity may result from multiple functional reentry circuits (for review see (Nattel et al., 2008)). 2.2. Electrical remodeling Animal models of AF, as for instance chronic rapid atrial pacing in dogs (Morillo et al., 1995) and repeated induction of AF in goats (Wijffels et al., 1995), result in long-tem changes in electrophysiologic and structural properties in the atria which are thought to contribute to the tendency of AF to become persistent with longer duration. The underlying cellular mechanisms are in part related to compromised cellular Ca2+ handling and altered expression and regulation of ion channels [for recent review see (Dobrev, 2010)]. As a consequence, multiple cellular functions are altered including stability of membrane potential, regulation of proteins by phosphorylation or nitrosylation, or changes in gene expression of ion channels.

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2.2.1. Ion channels The term “electrical remodeling” was introduced for the marked shortening in refractory period and loss of rate adaptation of the cardiac action potential (Wijffels et al., 1995). Human atrial action potentials from patients in sinus rhythm exhibit a typical “spike-anddome” shape, whereas action potentials from patients with chronic AF are shorter and adopt a triangular shape [see Fig. 2, (Wettwer et al., 2004)]. The individual ion channels are affected by electrical remodeling at both transcriptional and regulatory level (Dobrev and Ravens, 2003; Nattel et al., 2008). If ion channels are to serve as molecular targets for new therapeutic agents, detailed knowledge of their remodeling during AF is of great importance. Na+ current is reduced in a dog model of tachypacing (Gaspo et al., 1997), but this is not confirmed in human AF (Bosch et al., 1999). L-type Ca2+ current is smaller in animal models and human AF than in sinus rhythm, but there is some controversy whether it is downregulated at the transcriptional level or whether current amplitude is impaired due to reduced channels phosphorylation [for discussion, see (Christ et al., 2004)]. Of the repolarising currents, Ito and IK,ACh are reduced in amplitude and this is associated with a decline in mRNA for the ion conducting α-subunits Kv4.3 and Kir3.1/ Kir3.4, respectively (Brundel et al., 2001; Dobrev et al., 2001; Van Wagoner et al., 1997). The delayed rectifier currents IKr and IKs have not been determined, and data on IKur are conflicting, with reports of no change or downregulation of current, mRNA and protein of the pore forming α-subunit Kv1.5 (Bosch and Nattel, 2002; Christ et al., 2008; Van Wagoner et al., 1997). The current amplitude of background inward rectifier IK1 and mRNA for Kir2.1 are upregulated (Bosch et al., 1999; Dobrev et al., 2001; Dobrev et al., 2005). At the cellular level, increased inward rectifier hyperpolarises the RMP and shortens action potential duration and these changes reduce spontaneous activity. However, at the cardiac tissue level, hyperpolarisation and short action potentials are conditions for stabilising rotors (Pandit et al., 2005). 2.2.2. Gap junctions Gap junctions are located at the intercalated discs where each of the adjacent cells contributes one hemi-channel or connexon. One

Fig. 2. Structural (left) and electrical remodeling (right) in right atrial tissue from patients in sinus rhythm (SR) and atrial fibrillation (AF). The histological section from the patient in AF contains clearly more collagen than the one from the patient in sinus rhythm. Please note the triangulation of the action potential in chronic AF. Electrophysiological data rearranged from (Dobrev and Ravens, 2003).

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connexon is composed of six proteins of the connexin family, each connexin consisting of four transmembrane spanning stretches with intracellular N and C terminus. In human atria, the most abundantly expressed connexin isoform is Cx40, however, the major ventricular isoform Cx43 is also strongly expressed, whereas very little Cx45 is found (Severs et al., 2008). Phosphorylation of the connexins by different signal transduction cascades regulates their function including protein trafficking, gap junction assembly and channel gating (Lampe and Lau, 2004). Cell-to-cell communication via gap junctions critically determines conduction velocity, whereas downregulation of connexins, and lateralization or uncoupling of gap junctions support and maintain reentry. Heart disease and ischemia are known to decouple gap junctions (Lampe and Lau, 2004; Peters et al., 1993; Severs et al., 2008). Increasing evidence suggests an association between metabolic stress and AF (Carnes et al., 2001; Korantzopoulos et al., 2007), linking abnormal cell-to-cell coupling to perpetuation of AF (Nattel et al., 2007). Concerning gap junction remodeling in AF, reports are conflicting: in a dog model of AF, Cx43 was upregulated and lateralised (Sakabe et al., 2005), referring to expression of connexins at the transverse sides of the cells instead of at the longitudinal ends. In goats with AF no change or down-regulation of connexins with and without lateralisation was reported (Ausma et al., 2003; van der Velden et al., 2000). The situation appears even more diverse in human AF, with reports on up-regulation and down-regulation or no change in Cx-40 and/or Cx-43 and controversial findings with respect to lateralisation of gap junctions (Duffy and Wit, 2008; Kostin et al., 2002; Li et al., 2004; Nattel et al., 2007; Polontchouk et al., 2001). The functional state of these lateral connexins is unknown, but it has been emphasised that a substantial degree of heterogeneity between Cx40 distribution at the intercalated discs or the lateral sarcolemmal membrane is observed even in normal human atria (Severs et al., 2008). While gap junction remodeling appears to be a key contributor to ventricular arrhythmias, its role in AF is still controversial.

also demonstrated the importance of preexisting structural abnormalities for the development of AF (for review see (Goette and Lendeckel, 2004)). The developing atrial fibrosis provides a morphologic substrate for reentry and hence supports persistence of AF (Li et al., 1999). Besides interstitial fibrosis, hallmarks of AF include fibroblast proliferation, abnormal collagen accumulation and distribution, and hypertrophy, all of which have been associated pathophysiologically with stretch, oxidative stress, inflammation and ischemia (Kourliouros et al., 2009; Nattel et al., 2008; Van Wagoner, 2008a; Van Wagoner, 2008b). Irregular, high frequency electrical excitation in AF stimulates the renin-angiotensin system, imposes oxidative stress and alters cell metabolism (Burstein and Nattel, 2008). Post-operative AF in particular has been associated with inflammation as evidenced by elevated cytokines (Tselentakis et al., 2006). 2.4. Genetic contribution Analysis of the Framingham cohort revealed a genetic disposition for general AF; i.e., patients who have one parent with AF have a twofold higher 4-year risk of acquiring AF than the general population, even after adjustment for risk factors of AF such as cardiovascular disease or diabetes mellitus (Fox et al., 2004). In rare cases, familial AF has been associated with distinct genetic abnormalities most of which relate to mutations in genes encoding for ion channels [see (Lubitz et al., 2009)] for recent review). Mutations in K+ channel genes usually result in gain of function (IKr, IKs, IK1). The associated abbreviation of APD and ERP reduce wave length and hence support reentry. However, one loss of function mutation (IKur) was also reported (Olson et al., 2006). In that case excessively prolonged atrial APD leads to EAD that can trigger episodes of AF. Na+ channel mutations are occasionally found in AF patients underscoring the genetic heterogeneity in AF (Ellinor et al., 2008). In addition, several gene polymorphisms enhance susceptibility to AF without causing the arrhythmia (Lubitz et al., 2009). In a recent genome-wide association study, common single nucleotide polymorphisms associated with lone AF were detected, that lie within the gene encoding the calciumactivated K+ channel of small conductance SK3 (Ellinor et al., 2010). Interestingly, this channel appears to contribute to pacing-induced shortening of APD in rabbit pulmonary veins (Ozgen et al., 2007).

2.2.3. Ca2+ handling proteins The 6- to 8-fold higher rate of electrical activation in AF than in sinus rhythm goes along with elevated Ca2+ load of myocardial cells, which in turn is instrumental to multiple adaptation processes (Dobrev and Nattel, 2008). Despite reduced ICa,L during individual action potentials due to electrical remodeling, the cardiomyocytes are loaded with Ca2+ because of the high atrial frequency. This Ca2+ load must be balanced by extrusion mainly via NCX1 or by uptake into intracellular stores via the sarcoplasmic reticulum Ca2+ ATPase (SERCA-2). Indeed, increased expression of NCX1 in AF was reported (El Armouche et al., 2006) although maximum NCX1 rates after brief caffeine exposure were similar in sinus rhythm and AF (Hove-Madsen et al., 2004). When operating in the Ca2+-extrusion mode near the resting membrane potential, the NCX1 can give rise to delayed afterdepolarisations, that may serve as triggers for maintaining AF. Ca2+ uptake into the SR is increased because phospholamban becomes phosphorylated and no longer inhibits of SERCA-2. In addition, the open probability of the Ca2+ release channels of the SR, the ryanodine receptors (RyR2), is increased due phosphorylationdependent dissociation of calstabin2(FKBP12.6)-RyR2 complex [see (Dobrev, 2010) for review]. “Leaky” RyR2 channels may give rise to spontaneous Ca2+ release during diastole, further facilitating delayed afterdepolarisation due to NCX1 activity (Vest et al., 2005). This concept is supported by a recent report that increased susceptibility to AF is due to an enhanced diastolic SR calcium leak (Sood et al., 2008).

By intuition restoration of normal sinus rhythm, i.e. rhythm control, would be the optimal therapeutic goal in atrial fibrillation, however, rate control was shown to be equivalent with respect to mortality (Wyse et al., 2002). The two strategies were also equivalent in patients with AF and congestive heart failure, despite the clinical evidence that AF appears to be a predictor for death and its suppression might provide a benefit with respect to cardiovascular or all cause mortality in heart failure . Whilst rhythm control usually requires a combination of pharmacological and non-pharmacological treatments, rate control involves prolongation of atrioventricular nodal refractoriness and slowing of atrioventricular nodal conduction by different classes of drugs like β-blockers, calcium channel blockers or amiodarone. Interestingly, there is no benefit in outcome when strict rate control defined as resting heart rate below 85 beats per minute (bpm) is compared with more lenient control where resting rates could be between 90-100 bpm (Van Gelder et al., 2010).

2.3. Structural remodeling

3.2. Removal of ectopic trigger

Increasingly frequent episodes of AF induce structural and ultrastructural changes in atrial tissue (“structural remodeling”) (Ausma et al., 1997). In addition to AF-induced alterations, recent studies have

Suppression of hyperexcitability of pulmonary veins or atrial tissue can terminate AF by eliminating ectopic triggers and hence support rhythm control. Antiarrhythmic drugs used to reach this goal include

3. Therapeutic principles 3.1. Rhythm versus rate control

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Na+ channel blockers or multiple ion channel blockers such as amiodarone.

3.3. Disruption of reentry According to the leading circle concept (Allessie et al., 1977), short refractoriness and slow conduction will increase the likelihood of reentry. Theoretically, the reentry circuits can be interrupted when conduction is enhanced and refractoriness prolonged so that the reentrant wavefront will reach tissue that is still in the refractory state. Available antiarrhythmic drugs can prolong refractoriness but will slow instead of enhance conduction via block of Na+ channels. Nevertheless, such treatment causes re-entry wavelets to collapse and terminate AF, probably because block of Na+ channels not only slows down conduction but also reduces excitability.

3.4. Prevention A recent European consensus conference on research perspectives in AF has expressed the need for deeper insight into pathophysiological mechanisms that take place long before the first arrhythmic episode in order to prevent the burden of AF including its complications (Kirchhof et al., 2009). Unfortunately, apart from antithrombotic therapy to reduce the risk of stroke we presently do not have the means for efficient prevention, although targeting signaling pathways that are involved in structural remodeling may provide promising “nonchannel drug targets” in patients with AF” (Goette and Lendeckel, 2004; Goette et al., 2007; Nattel et al., 2002). Novel strategies include prevention of risk factors and suppression of secondary responses by influencing “upstream targets” (Savelieva et al., 2010).

4. Therapeutic Interventions 4.1. Electrical cardioversion, defibrillators, atrial pacing Electrical cardioversion is a recommended therapeutic option (Fuster et al., 2006) although the rate of AF recurrence is rather high and maintenance of sinus rhythm is low. Electrical defibrillators did not become widely accepted for use in AF because the large number of shocks required is not tolerated by the patients. Nevertheless, a hybrid between pharmacological and electrical defibrillators could be an attractive strategy for treatment of AF. Moreover, early administration of antiarrhythmic drugs could stabilise electric properties and thereby reduce the need for shock application. By self-medication with propafenone, patients with therapy-resistant, recurrent AF and an implanted atrial defibrillator could indeed reduce the need for shocks by 50% (Schwartzman et al., 2006). Based on extensive data-logging capacities of implanted pacemakers, occurrence of AF was shown to be preceded by repetitive, self-terminating atrial arrhythmias (Hoffmann et al., 2006). These repetitive episodes might be suppressed by overdrive pacing or shock application, but the efficacy of such concept remains unclear.

4.2. Ablation Discovery of ectopic pacemaker activity in the pulmonary veins (Haissaguerre et al., 1998) has led to the concept of surgical or catheter-based ablation. This therapeutic principle aims at electrically isolating rapid ectopic foci from the rest of the atria so that the sinus node can take over again. Lines of controlled tissue damage are inflicted around foci originating predominately in the pulmonary vein or left atria (Delacretaz, 2006; Haissaguerre et al., 2000).

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4.3. Antiarrhythmic drugs The current guidelines for treatment of AF (Fuster et al., 2006) recommend the use of flecainide, dofetilide, propafenone, ibutilide, and amiodarone for pharmacological conversion; however the efficacy and safety of conventional antiarrhythmic agents is far from satisfactory. In order to avoid adverse side effects of long-term prophylactic treatment, the “pill-in-the pocket” approach has been designed and tested. As soon as palpitations occur, a high oral dose of propafenone or flecainide is taken for conversion of AF episode at the earliest possible time in order to prevent the remodeling process (Alboni et al., 2004). 4.3.1. Reduction of excitability and impulse propagation (Class I antiarrhythmic drugs) Class I antiarrhythmic drugs are Na+ channel blockers that reduce excitability and delay conduction leading to extinction of multiple wavelet reentry or collapse of rapidly rotating spiral waves. However, slowing of conduction velocity especially in ischemic myocardium will increase wave length and thus may actually promote reentry. This mechanism could explain the high incidence of sudden death in patients with myocardial infarction who were treated with class IC antiarrhythmic drugs (CAST study) (Echt et al., 1991). Electrophysiological differences in atria and ventricles and strong frequencydependent action of some Na+ channel blockers account for atrial selectivity of action, especially in the fibrillating atria (Burashnikov et al., 2007); see Section 5.1.3. 4.3.1.1. Flecainide, Propafenone. The two antiarrhythmic drugs flecainide and propafenone mainly block Na+ channels in a frequencydependent manner. Like other class I antiarrhythmic drugs, propafenone and flecainide also inhibit several K+ channels (Rolf et al., 2000; Tamargo et al., 2004b; Wang et al., 1995). The CAST study reported increased mortality with class IC antiarrhythmic drugs in patients with non-sustained ventricular tachycardia after myocardial infarction (Echt et al., 1991). Since then the proarrhythmic potential of flecainide and propafenone have been a major safety concern excluding from treatment patients with coronary heart disease. The incidence of ventricular arrhythmias is considered “very low”, namely, less than 3%, with orally or intravenously administered flecainide or propafenone for conversion of AF into sinus rhythm, and “minimal” with no incidences of ventricular arrhythmias reported in studies evaluating flecainide for maintenance of sinus rhythm after successful conversion of AF (McNamara et al., 2003; Naccarelli et al., 2003; Tamargo et al., 2004a). In a large meta-analysis, flecainide caused increased withdrawals due to adverse effects but did not increase proarrhythmia (Lafuente-Lafuente et al., 2006). Therefore, the two drugs flecainide and propafenone can be considered as relatively safe provided that the contraindications can be respected. 4.3.2. Prolongation of refractory period (Class III antiarrhythmic drugs) 4.3.2.1. Amiodarone. Originally noted for its antianginal effects (Charlier et al., 1968), amiodarone is currently the most effective antiarrhythmic drugs with respect to treatment of AF. The antiarrhythmic activity after acute administration has first been associated with an action potential-prolonging effect, yet moderate depression of upstroke velocity (as a surrogate for Na+ current) (Singh and Vaughan Williams, 1970). After 6 weeks of daily treatment of rabbits with amiodarone, 20 mg/kg, the ex-vivo cardiac electrophysiological effects are strikingly similar to those following thyroidectomy, i.e. stable resting membrane potential, use-dependent reduction in maximum rate of rise of AP and profound APD prolongation (Freedberg et al., 1970; Singh and Vaughan Williams, 1970). Incidentally, these characteristics lent themselves to the original definition of class III action for antiarrhythmic drugs (Vaughan Williams, 1975). Detailed electrophysiological analysis

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provided clear evidence for frequency-dependent INa depression (class I action), block of L-type Ca2+ current and inhibition of K+ currents including Ito, IKur, IKr, IKs, IK1, and IK,ACh in addition to α- and βadrenoceptor blocking effects [for review see (Kodama et al., 1997)]. The major metabolite desethylamiodarone has a similar activity profile. Chronic treatment with amiodarone may cause antiarrhythmic remodeling of cardiac cells through modulation of gene expression of ion channels most likely mediated by antagonism with triiodothyronine (T3) at the level of the cardiomyocytes. Amiodarone exhibits little propensity for inducing torsades-depointes arrhythmias despite its well-documented QT-interval prolongation (Lazzara, 1989). This favourable cardiac safety is suggested to be due to atrial selectivity of INa block [(Maltsev et al., 2001), see also Section 5.1.3]. Nevertheless, amiodarone is burdened with severe non-cardiac side effects including pulmonary fibrosis, photosensitivity, thyroid dysfunctions and neurological disorders (Brendorp et al., 2002). 4.3.2.2. Dofetilide. As an alternative strategy for obtaining antiarrhythmic compounds devoid of proarrhythmic events in patients with ischemic or structural heart disease, highly selective K* channel blockers have been developed in the past. Dofetilide is a pure IKr/ hERG channel blocker (Carmeliet, 1992) and prolongs both atrial and ventricular APD (Tande et al., 1990). Experimentally, it is more effective against AF associated with chronic heart failure than with burst atrial pacing (Li et al., 2000). The initial promising results that dofetilide effectively converts AF and prevents its recurrence (Prystowsky et al., 2003; Singh et al., 2000) could not be reproduced with other IKr/IKs blockers. The mixed IKr channel and β-adrenoceptor blocker sotalol is not effective in conversion and not superior to a “pure” β-adrenoceptor blocker in prevention of AF recurrence (Kuhlkamp et al., 2000; Plewan et al., 2001). Moreover, attenuation of electrophysiologic actions of class III drugs in the chronically remodeled human atrium may serve as an explanation for their low efficacy to prevent early AF recurrence after electrical cardioversion (Tse and Lau, 2002). 4.3.2.3. Ibutilide. Though ibutilide is similar to sotalol in chemical structure, it has a unique class III action by prolonging the APD not only via hERG channel block but also via activation of a slow inward current carried by Na+ (Lee, 1992; Lee and Lee, 1998; Yang et al., 1995). This dual mode of action is associated with QT prolongation and enhanced risk of torsades-de-pointes arrhythmias (Murray, 1998; Stambler et al., 1996). When used intravenously for pharmacological conversion of AF (Vos et al., 1998) the risk can be greatly reduced by administering simultaneously the short acting β-adrenoceptor blocker esmolol (Fragakis et al., 2009). Selective hERG channel blockers inhibit IKr in both atria and ventricles and prolong action potential duration and refractoriness (Sanguinetti and Tristani-Firouzi, 2006). These drugs can give rise to EADs, torsades-de-pointes arrhythmias and even sudden cardiac death, especially when combined with other hERG channel blocking compounds given for non-cardiac indications, such as antibiotics, antihistaminics, antipsychotics, and lipid lowering drugs. From a conceptual point of view, proarrhythmic effects should be avoided with atrialselective drugs which preferentially block K+ channels that are predominantly expressed in the atria and are absent in ventricles. Although hERG channels blockers are claimed to exhibit some selectivity for atrial over ventricular potassium channels (see chapter 5.1.3) safety concerns and lack of efficacy do not render them first line drugs in treatment of AF. In fact, multiple channel blockers are probably most effective in converting to and maintaining sinus rhythm.

and safety. An ideal drug against AF should suppress atrial triggers and disrupt atrial reentry circuits by prolonging atrial refractoriness and slowing intraatrial conduction; by being atrial selective it should not cause any ventricular proarrhythmic effect; it should be devoid of organ toxicity and be safe in patients with concomitant cardiovascular disease, in particular coronary artery disease and heart failure.Novel compounds can block specific or multiple ion channels, preferably in an atrial-selective manner, and they can be directed at non-ion channel targets including upstream inflammatory or infiltrative processes. 5.1. Ion channel blockers 5.1.1. New IKr blockers with extended profile 5.1.1.1. Azimilide (IKr, IKs). This drug was designed to lack the typical reverse frequency-dependent action of hERG channels blockers by targeting also IKs (Lombardi and Terranova, 2006; Nishida et al., 2007). Clinically, azimilide is claimed to prevent AF recurrence, but shows only modest efficacy compared with placebo and is significantly inferior to sotalol due to severe side effects (Pratt et al., 2004; Kerr et al., 2006). Several opinion leaders doubt that azimilide will become available for treatment of AF (Levy, 2006). 5.1.1.2. AZD7009 (IKr, INa). The pharmacological profile of AZD7009 includes block of IKr (IC50 0.6 μM in a heterologous expression system) and rate-dependent block of INa with an IC50 4.3 μM at 10 Hz. The compound also blocks other repolarising currents albeit with different IC50 values, i.e. Ito (IC50 23.7 μM) and IKur (IC50 27.0 μM), whereas IKs is affected only at very high concentrations (IC50 193 μM) (Persson et al., 2005a; Persson et al., 2005b). In dog atria, AZD7009 increases effective refractory period in a concentration-dependent manner without significant change in ventricular QT-interval despite its high affinity for hERG channels (Carlsson et al., 2006). AZD7009 also increases effective refractory period, prevents AF induction and restores sinus rhythm in rabbit dilated atria (Lofberg et al., 2006), a model that is particularly vulnerable to stretch-induced AF (Bode et al., 2001). The kinetic characteristics of AZD7009-ion channel interactions endow this antiarrhythmic compound with strong atrial selectivity (see 5.1.3). 5.1.2. New multichannel blocking drugs As outlined above, combination of block of different ion channels may produce the most favourable electrophysiological profile. 5.1.2.1. Dronedarone. Dronedarone is structurally related to amiodarone but lacks the iodine groups that are considered to be responsible for the pulmonary, thyroid, hepatic and ocular toxicity of amiodarone. The acute and chronic electrophysiological effects of dronedarone in rabbit atrial and ventricular tissue are similar to those of amiodarone, although dronedarone appears to be more potent (Sun et al., 1999; Sun et al., 2002). Evidence from a comparative study in human cardiomyocytes suggests, that the iodine moiety is not required for the Na+ channel blocking activity (Lalevee et al., 2003). Like amiodarone, dronedarone also inhibits INa in a frequency-dependent manner ICa,L, various K+ currents (Ito, IKr, IKs) and β1-adrenoceptors (Chatelain et al., 1995; Gautier et al., 2003). In dog ventricular myocardium, dronedaroene frequency-dependently reduces maximum upstroke velocity, and blocks ICa,L and IKr (Varro et al., 2001). In guinea pig atria, dronedarone is 100 times more potent in blocking of IK,ACh than amiodarone (Guillemare et al., 2000). Dronedarone is supposed to have less side effects, but in clinical studies it also seems to be less effective (Patel et al., 2009).

5. New Drugs Currently available antiarrhythmic drugs for treatment of AF are far from being ideal, and impose serious concerns regarding efficacy

5.1.2.2. Tedisamil. Tedisamil is a heterocyclic compound that was originally developed as an antiischemic and bradycardic drug. It is a non-selective blocker of the cardiac K+ currents Ito, IKur, IKr, IKs and IK,ATP

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(Dukes and Morad, 1989; Dukes et al., 1990; Wettwer et al., 1998). The resulting prolongation in action potential duration observed in isolated human atrial and ventricular myocardium (Ohler and Ravens, 1994; Nemeth et al., 1997) is the proposed mechanism for termination of supraventricular tachycardia (Opie, 2003; Fischbach et al., 1999). The clinical efficacy of tedisamil for cardioversion of AF has been recently demonstrated in a clinical trial (Hohnloser et al., 2004). 5.1.3. Atrial-selective drugs A novel strategy for anti-AF agents devoid of proarrhythmic effects is the development of so-called atrial-selective drugs. This concept exploits the electrophysiological differences as well as differences in expression pattern of ion channels between atrial and ventricular myocytes (see Fig. 1). Na+ channel blockers display atrial selectivity when their effects are strongly voltage dependent and steady-state block in atria is larger than in ventricles. In addition, there is a diseasespecific component of atrial-selectivity due to the high atrial rate in AF, which further enhances block of atrial over ventricular Na+ channels (Burashnikov et al., 2007). In heart failure, ischemia or certain forms of Long QT-syndrome a small fraction of ventricular Na+ channels will not inactivate (INa,late). The resulting prolongation of APD is associated with an increased risk of torsades-de-pointes arrhythmias. It is not known whether such channels are also present in diseased human atria. In any case, high affinity of mixed ion channel blockers to INa,late will indirectly constitute atrial selectivity by counteracting the proarrhythmic risk of K+ channel block. Block of ventricular late INa, which is observed in certain forms of Long-QT syndrome, and also occurs in heart failure or ischemia (Shryock and Belardinelli, 2008), provides for atrial selectivity because such drugs exert antiarrhythmic effects in atria, and at the same time reduce the proarrhythmic effects in ventricles by counteracting excessive APD prolongation (Burashnikov and Antzelevitch, 2010). There is also experimental evidence that atrial over ventricular selectivity can be achieved to some extent with K+ channel blockers by targeting of single or a mix of K+ channel subtypes (Baskin and Lynch, 1998). Last but not least, ion channels that are more abundantly expressed in atria than in ventricle, for example, IKur (Nerbonne, 2000) and IK,ACh (Dobrzynski et al., 2001) are also targets for potential atrialselective compounds. 5.1.3.1. INa blockers. Class IA antiarrhythmic drugs have long been recognized to display preferential binding to open (activated) or closed (inactivated; resting) states of the Na+ channel [“modulated receptor hypothesis” (Hondeghem and Katzung, 1984) versus “guarded receptor hypothesis” (Starmer et al., 1984)]. Atrial selectivity of Na+ channel blockers (Burashnikov et al., 2007) is due to slightly more depolarized resting membrane potential and a more negative potential for half-maximum inactivation of INa in atrial than in ventricular cardiomyocytes. Since recovery from inactivation depends on membrane potential, less Na+ channels recover during diastole in atria than in ventricles. Therefore, Na+ channel blockers that bind preferentially to the inactivated channel state and also have a fast dissociation rate will exhibit atrial selectivity, because steadystate drug binding and consequently channel block will be larger in atria than in ventricles. At the less negative atrial resting membrane potential a greater fraction of Na+ channels remains in the inactivated, drug-binding state, whereas at more negative ventricular resting membrane potential, most Na+ channels recover and allow drug dissociation (Burashnikov and Antzelevitch, 2010). 5.1.3.1.1. Ranolazine. During its initial development as an antianginal drug, ranolazine was noted to suppress ventricular EAD and to reduce transmural dispersion of APD (Antzelevitch et al., 2004). At the ion channel level, ranolazine blocks IKr and IKs, late INa and possibly also L-type ICa (Antzelevitch et al., 2004; Schram et al., 2004). Compared with amiodarone, ranolazine binds to inactivated channels

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and has similar rapid kinetics of recovery from block so that both drugs can be considered as atrial selective antiarrhythmic agents (Antzelevitch and Burashnikov, 2009). Clinical studies suggest putative protection against supraventricular tachycardia and new onset AF (Scirica et al., 2007). In dog experiments, ranolazine blocks peak INa with strong atrial selectivity in cardiomyocytes and suppresses ACh-induced AF (Burashnikov et al., 2007). When tested in anesthetized pigs, ranolazine slows conduction and prolongs right and left atrial effective refractory period (ERP) 2 times more than in the ventricle. Moreover, ranolazine significantly reduces dominant frequencies in the left atrium (Kumar et al., 2009). 5.1.3.1.2. Vernakalant (RSD1235). This antiarrhythmic drug was designed as an atrial-selective blocker targeting IKur and was developed for early conversion of AF to sinus rhythm [(Kozlowski et al., 2009) see below], but with additional block of INa and atrial-selective IK,ACh (Fedida et al., 2005). Preferential binding of vernakalant to inactivated Na+ channels and rapid dissociation kinetics contribute to atrial selectivity (Fedida, 2007). Na+ channel block by vernakalant is enhanced at high heart rates and in depolarised tissue, due to rateand voltage-dependent block. Since these features are the hallmarks of AF, vernakalant is also claimed to be a “disease-specific” drug (Fedida et al., 2005; Orth et al., 2006). Vernakalant was recently approved by the FDA for intravenous conversion of AF and is expected to become available in late 2010. 5.1.3.1.3. AZD7009. Because of its Na+ channel blocking activity, AZD7009 has been interpreted as an atrial-selective ion channel blocker (Goldstein et al., 2004). Since INa block increases at high heart rates, AZD7009 is expected to be particularly effective in fibrillating atria. Indeed, results from recent clinical studies indicate that intravenous infusion of AZD7009 is effective in converting episodes of persistent AF and has apparently a low risk of proarrhythmia (Geller et al., 2009; Crijns et al., 2006), supporting effectiveness and safety of the drug. AZD7009 potently and predominantly increases atrial refractoriness, with actions mediated by combined effects on and the Na+ current system and low proarrhythmic potential in animals and humans. 5.1.3.2. IKur blockers (”ARDAs” - atrial repolarisation-delaying agents). The ultrarapidly activating, delayed outward rectifier current IKur has been considered an extremely useful drug target because blockers of IKur prolong the ERP in atria only without much effect on ventricular ERP and without prolongation of the QT interval. Therefore, a large number of compounds directed at selective IKur block has been synthesised in the past decade (Ford and Milnes, 2008). Despite mRNA and protein expression of Kv1.5 channels in atria and ventricles of rodents, dog and man (Nerbonne, 2000; Gaborit et al., 2005; Fedida et al., 2003), IKur-like current is virtually absent in ventricular myocytes of man (Amos et al., 1996) and dog, but not entirely so in rat (Lagrutta et al., 2006). The concept of atrial selective IKur block in dog has been recently challenged, because ventricular action potentials are clearly prolonged in the presence of a low, IKur-selective concentration of 4-aminopyridine [4-AP;(Sridhar et al., 2007)]. Low concentrations of 4-AP which selectively block IKur elevate the plateau of human artial action potentials, but produce opposite effects on atrial APD depending on the patients’ history of supraventricular arrhythmia, with shortening of APD and ERP in tabeculae from patients in SR but prolongation of these parameters in AF (Christ et al., 2008; Wettwer et al., 2004). 5.1.3.2.1. AVE0118, AVE1231. The biphenyl derivative AVE0118 blocks IKur (IC50 1.1 μM) in expression systems and in native atrial myocytes with additional effects on Ito and IK,ACh in a similar concentration range, whereas cloned hERG channels are blocked at higher concentrations (IC50 10 μM) (Decher et al., 2006; Gogelein et al., 2004). AVE0118 effectively reduces IKur in myocytes from patients in SR, whereas in myocytes from patients in chronic AF, IKur becomes resistant to the compound, despite absence of reduced current amplitude or downregulation of mRNA expression of Kv1.5 (Christ

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et al., 2008). In anesthetized pigs, AVE0118 prolongs effective refractory period more in left than in right atria (Knobloch et al., 2004; Wirth et al., 2007). AVE0118 reduces atrial vulnerability against AF induced by an extra stimulus in rabbit and dog models. Like other IKur blockers, AVE0118 shortens APD and ERP in atrial trabeculae from patients in SR whereas it prolongs APD and ERP in AF (Christ et al., 2008; Wettwer et al., 2004). In a goat model of AF, AVE0118 effectively prevents inducibility of AF episodes and is in this respect superior to dofetilide (Blaauw et al., 2004). Conversion rate of AF is significantly higher with AVE0118 than with dofetilide and ibutilide, yet QT-prolongation as with the other two compounds is absent. AVE0118 effectively induces sinus rhythm in goats with chronic AF (de Haan et al., 2006), whereas it appears to be less successful in patients with AF. By virtue of the AP plateau elevating effect, AVE0118 enhances contractility in animal and human atrial preparations (Christ et al., 2008; de Haan et al., 2006; Schotten et al., 2007). Alleviation of AFinduced contractile dysfunction could reduce the risk for thrombus formation. For undisclosed reasons, clinical development of AVE0118 has been abandoned. A putative drawback of IKur blockers could relate to the remodeling of Kv1.5 channels in chronic AF. Myocytes from patients in AF exhibit a strong AVE0118-resistant fraction of what appears IKur (Christ et al., 2008). If this peculiar resistance of IKur to block is not confined to AVE0118 and presents as a more general phenomenon, IKur may be of limited value as a drug target for treatment of chronic AF. The situation may be different in recent onset of AF, depending on how rapidly Kv1.5 channels develop resistance to the drug. In animal models of atrial tachypacing, which reproduce electrical remodeling, downregulation of K+ channels occurs within hours of initiation of high-frequency stimulation (Bosch et al., 2003). However, nothing is known about the time course of development of channel resistance towards AVE0118. Clearly more experimental data are required. AVE1231 is an orally available IKur blocker analogue of AVE0118. It blocks hKv1.5 and IKur with IC50 values of 3.6 and 0.9 μM, respectively. Ito, IK,ACh and hERG channels are also blocked, albeit at higher concentrations, i.e. with IC50 values of 3.3, 8.4 and 30 μM, respectively (Wirth et al., 2007). Concentrations of upto 10 μM AVE1231 do not block hERG channels (Gogelein et al., 2004). After oral dosage in anesthetized pigs, left atrial ERP is prolonged, left atrial vulnerability decreases by 86% and QTc interval remains constant (Gogelein et al., 2004; Wirth et al., 2007). Nevertheless, AVE1231 is less effective than AVE0118 in the goat model of atrial fibrillation (Linz et al., 2007). 5.1.3.2.1. S9947, S20951. These two compounds were studied in the search of selective IKur blockers. S9947 blocks hKv1.5 with an IC50 value of 0.42 μM in a strong positive frequency-dependent manner, the respective IC50 values for IKur block are 0.96 μM in rat ventricle and 0.07 μM in human atrial cardiomyocytes (Bachmann et al., 2001). Selectivity for IKur is excellent: rat IK1, and rat and human Ito are blocked by ~20% by 10 μM of S9947, and essentially similar results are obtained with S20951. In an in-vivo model of anesthetized pigs, S9947 and S20951 - like other IKur blockers - prolong left atrial ERP to a larger extent than right atrial ERP. In addition, left atrial vulnerability against AF induced by pre-mature stimuli is almost completely suppressed (Knobloch et al., 2002). Similar profiles are found for the IKur blockers AVE0118 and AVE1231, whereas the IKr blockers included for comparative purposes, i.e. dofetilide, azimilide, ibutilide, and d,l-sotalol induce a stronger prolongation of right over left atrial ERP and are significantly less effective in reducing atrial vulnerability (Knobloch et al., 2002). 5.1.3.2.2. Diphenylphosphine oxide. In this group of novel IKur blockers the compound DPO-1 has been studied most extensively. In isolated human atrial myocytes DPO-1 blocks IKur with increasingly lower IC50 values the higher the stimulation frequency; IC50 of 30 nM at 3.0 Hz, and the same IC50 for expressed channels (Lagrutta et al., 2006). Selectivity of block is high, since no block of Ito is detectable with concentrations as high as 1.0 μM. In guinea-pig ventricular

myocytes very little block of other cardiac K+ currents is observed; 3 μM DPO-1 reduce IK1 by 15%, IKr by 3 % and IKs by 25% of control. Action potential duration is prolonged by 120% at APD50 and by 20% at APD90 in human atrial but not in ventricular myocytes. Like 4-AP, DPO-1 produces plateau elevation and shortening (SR) and prolongation (AF) of APD in human atrial tissue, but is devoid of any significant effect in human ventricular action potentials. In-vivo studies show that DPO-1 increases both atrial and ventricular ERP in rats, but only atrial ERP in primates (Regan et al., 2006). In a dog model of atrial flutter, DPO-1 significantly increases atrial APD and refractoriness but lacks similar effects in ventricles (Lagrutta et al., 2006). For comparison, the selective IKr blockers MK499 and ibutilide significantly increased both atrial and ventricular absolute and relative refractoriness in antiarrhythmic doses (Stump et al., 2005). Despite these favourable results in animal studies, lack of oral bioavailability probably precludes further clinical development. 5.1.3.2.3. Vernakalant (RSD1235). Vernakalant produces a strong, positive frequency-dependent IKur block with an IC50 of 13 μM at 1 Hz when measured in stably expressed hKv1.5 channels, whereas 3-fold higher concentrations are required for open-channel block of Nav1.5. Block of IKur is larger than block of Ito or IKr, when studied in expression systems (Fedida et al., 2005). In rat ventricular myocytes, vernakalant prolongs APD at 50% of and at higher concentrations elevates the plateau phase. This latter effect was attributed to Ito block. However, our own preliminary data in human atrial trabeculae suggests that unlike selective Kv1.5 blocking concentrations of 4-AP, vernakalant does not elevate plateau potential or rhythm-specifically modulate APD, neither in preparations from SR nor AF patients. Nevertheless, vernakalant is reported to convert AF rapidly and safely (Roy et al., 2008). 5.1.3.3. IK,ACh blockers. Enhancement of vagal activity may initiate paroxysms of AF (Chen et al., 1998). Activation of IK,ACh by vagal stimulation shortens atrial refractoriness and increases Na+ channel availability thereby creating a substrate for reentry through dispersion of atrial repolarisation and stabilisation of high frequency rotors, which promotes the duration of AF episodes (Nattel et al., 2002). Since knockout mice lacking IK,ACh channels are resistant to acetylcholineinduced AF (Kovoor et al., 2001), blocking IK,ACh may be a promising therapeutic strategy. Indeed, tertiapine, a selective IK,ACh channel blocking peptide, prolongs canine atrial action potentials and suppresses inducible AF episodes (Cha et al., 2006; Hashimoto et al., 2006). Whole cell current in atrial cardiomyocytes from AF patients is blocked by tertiapin with higher potency than in cells from patients with sinus rhythm (Dobrev et al., 2005). Mori et al. were first to suggest that inhibition of ligand-operated K+ channels by class III antiarrhythmic dugs can contribute to their potential usefulness for prevention and termination of AF (Mori et al., 1995). In guinea-pig atrial myocytes the hERG channel blockers d,lsotalol, E4031 and MS-551 also concentration-dependently reduce muscarinic-receptor activated current IK,ACh. In order to exclude that the effects are mediated by upstream block of muscarinic receptors, the antiarrhythmic compounds have also been tested after channel activation via adenosine (A1) receptors or by applying GTPγS. Under these conditions, high concentrations of MS-551 and E4031, but not d, l-sotalol reduces IK,ACh suggesting that the former 2 agents (MS-551 and E4031) can act also by direct depression of K+ channel function or by interfering with G proteins. Based on early measurements in bullfrog atrial myocytes showing a similarity in current-voltage relations and in sensitivity to block by Ba2+ and Cs+, it was suggested that acetylcholine-activated current might flow through the same channels as IK1 - albeit with altered kinetics (Hartzell, 1988; Momose et al., 1984). In human atrial myocytes whole cell recordings with ramp pulses also results in IK1 and IK,ACh of similar voltage dependence [see for instance (Dobrev et al., 2001)], but the two channels can be clearly distinguished in

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single-channel recordings due to marked differences in their gating properties; for instance, inwardly rectifying K+ channels have a long open time (~100 ms) while the open times of the acetylcholineactivated K+ channels are very short (~1 ms) (Clark et al., 1990). Selective IK,ACh blockers are in development. 5.1.3.3.1. NIP-142, NIP-151. The benzopyrane derivative NIP-142, prevents acetylcholine-induced action potential shortening (Matsuda et al., 2006). Current flow via channels expressed in HEK293 cells is blocked by NIP-142 in the following order of potency IK,ACh N IKur N IKs N IKr N N Ito (Tanaka and Hashimoto, 2007). High concentrations of NIP-142 also reduced L- and T-type Ca2+ current, by 80% and 20%, respectively at 10 μM. The congener NIP-151 is even more potent and more selective than its parent compound, and blocks IK,ACh with an IC50 of 1.6 nM while more than 4000 fold concentrations are required for block of IKr. In dogs, NIP-151 significantly prolongs atrial but not ventricular ERP, and successfully terminates vagally- and aconitineinduced AF, with 6-fold higher doses required for the latter (Hashimoto et al., 2008). 5.1.3.3.2. Constitutively active IK,ACh channels. In atrial myocytes of several species, IK,ACh channels have been noted to open spontaneously in the absence of agonist [rabbit: (Kaibara et al., 1991), dog: (Ehrlich et al., 2004), human: (Dobrev et al., 2005; Voigt et al., 2008)] with the smallest agonist-independent, constitutive activity in human atria. Interestingly, in human chronic AF, electrical remodeling reduces muscarinic receptor-mediated activation of IK,ACh and the expression of the channel subunit Kir3.4 declines in patients with chronic AF (Dobrev et al., 2001). Nevertheless electrical remodeling induces IK,ACh channels to develop constitutive activity (Dobrev et al., 2005). The agonist-independent, constitutive activity of IK,ACh contributes to the enhanced basal rectifier current observed in chronic AF (Dobrev et al., 2001; Voigt et al., 2007). Some class I and IV antiarrhythmic drugs inhibit IK,ACh by (i) direct block of ligand-operated K+ channels; (ii) block of muscarinic receptors; (iii) GTP binding proteins and many conventional antiarrhythmic drugs and newly developed agents block IK,ACh in expression systems or native cardiomyocytes. An ideal therapeutic agent should selectively suppress constitutively active IK,ACh without any effect on agonist-activated IK,ACh because the latter current modulates conduction through the sino-atrial node and its suppression may leave sympathetic increase of AV-conduction unopposed leading to enhanced ventricular rate. In a recent study with antiarrhythmic drugs in human cardiomyocytes we have observed that block of muscarinic receptor-activated IK,ACh and constitutively active IK,Ch are not necessarily linked to each other [see Fig. 3.1 and 3.2 taken from (Voigt et al., 2010)]. While all 4 compounds tested, flecainide, AVE0118 propafenone and dofetilide, concentrationdependently suppress receptor-activated IK,ACh, only the first two are able to reduce also constitutively active channels. From the characteristics of the single channel openings in cell-attached cardiomyocytes (Fig. 4) it can be concluded that there is indeed constitutive activity of IK,ACh channels in AF, and that this activity is blocked by flecainide. It could be speculated, that compounds that block both agonist-stimulated and constitutively active IK,ACh would be safer with respect to ventricular tachycardia. 5.2. NCX1 modulators Since DADs elicited by NCX1 activity can trigger AF, block of the exchanger has been proposed as a useful antiarrhythmic mechanism. Indeed, many antiarrhythmic drugs (e.g., amiodarone, dronedarone, bepridil and aprindine,) inhibit NCX1, only amiodarone does so within the therapeutic concentration range of 0.1 to 10 μM [cited in (Iwamoto et al., 2007)]. Reducing NCX1 activity may be a double edged sword, unless drugs exhibit selectivity for the reverse mode of activity. Blocking NCX1 in its “reverse mode” during the initial phase of the action potential will reduce Ca2+ entry and alleviate the

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proarrhythmic propensity of cellular Ca2+ load. On the other hand, inhibition of the exchanger in the “forward mode” at resting membrane potential will suppress Ca2+ extrusion and thereby directly remove the electrogenic transport mechanism that causes proarrhythmic DADs, however, this takes place only at the expense of worsening Ca2+ overload. 5.2.1. KB-R7943, SEA0400 Several benzyloxyphenyl analogues that block NCX1 activity were synthesized in the past decade, including KB-R7943, SEA0400, SN-6 and YM-244769 (Iwamoto et al., 2007). These compounds have antiarrhythmic potential in some models of ischemia-reperfusion related arrhythmias induced by Ca2+ overload (Takahashi et al., 2003). SEA0400 is considered to be a more selective blocker of NCX1 than KB-R7943, but there are also controversial reports (Reuter et al., 2002). KB-R7943 and SEA0400 preferentially inhibit the reverse mode of NCX1 with potencies of 0.32 μM and 78 nM, respectively, whereas inhibition of the forward mode exchange activity required 10–50 times higher concentrations (Lee et al., 2004; Watano et al., 1996), though some authors cannot support thgis finding (Birinyi et al., 2005). It should be noted, however, that selective inhibition of reverse mode of exchanger has been refuted for thermodynamic reasons, since experimental conditions are different when the exchanger operates in Ca2+-entry or Ca2+-efflux mode and the drug effects strongly depend on intracellular Na+ (Noble and Blaustein, 2007). Concerning atrial fibrillation, there might be some benefit from NCX1 inhibition. In rabbit pulmonary veins, KB-R7943 can prolong APD, reduce ectopic firing rate and decrease the incidence of DADs (Wongcharoen et al., 2006). Although the suppression of ectopic automaticity in pulmonary veins could also be due to block of Ca2+ or Na+ channels, the putative therapeutic suppression of AF by NCX1 inhibition is worth investigating with blockers more selective for the exchanger than KB-R7963. 5.3. Gap junction modulators 5.3.1. Antiarrhyhtmic peptides (APP10) Facilitating conduction via gap junctions is an important new antiarrhythmic principle (Dhein et al., 2010). Based on the discovery of antiarrhythmic peptides [AAP; (Aonuma et al., 1980)], Dhein et al. have synthesised modulated AAPs that were able to restore compromised conduction by re-establishing intercellular gap-junctional communication, with APP10 being the most effective compound of this series (Dhein et al., 1994; Muller et al., 1997). APP10 was shown to increase intercellular communication in HeLa cells expressing Cx43 and to a lesser extent Cx40, as evidenced by fluoresent dye transfer, and protein kinase C activity was involved in AAP10 action (Easton et al., 2009; Jozwiak and Dhein, 2008). In a rat model of AF, however, AAP10 was ineffective (Haugan et al., 2004). 5.3.2. Rotigaptide (ZP123) The recently developed stable hexapeptide rotigaptide [ZP123; (Kjolbye et al., 2003)] selectively improves intercellular coupling in Cx43-, but not in Cx32- or Cx26-expressing cells (Clarke et al., 2006). Rotigaptide prevents slowing of conduction in metabolically stressed rat atria, yet has minor affinity for a multitude of ion channels and receptors (Haugan et al., 2005). When the effects of rotigaptide are compared in a dog heart failure model and a chronic mitral regurgitation model of AF, vulnerability to arrhythmia induction is reduced only in the latter model (Guerra et al., 2006). Though rotigaptide enhances conduction in various other AF models, the arrhythmia is only suppressed in the ischemic substrate (ShiroshitaTakeshita et al., 2007). As a possible mechanism of action in ventricular arrhythmias, rotgaptide is suggested to prevent ischemia-induced loss

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Fig. 3. Upper 4 panels: Effects of antiarrhythmic drugs on muscarinic receptor-stimulated IK,ACh. IK,ACh was measured as the difference between basal current and peak current amplitude in response to 2 min of exposure to 2 μM carbachol in the absence and presence of antiarrhythmic agent in various concentrations (one concentration per cell). Lower four panels: Effects of propafenone, flecainide, dofetilide, and AVE 0118 on constitutively active IK,ACh measured as basal current in human atrial myocytes from patients in sinus rhythm and chronic AF. From Voigt et al. 2010, with kind permission of the publisher.

of phosphorylation at 2 specific sites in Cx43 (Kjolbye et al., 2008), but it is still unknown whether this also applies to atrial connexins in AF and under gap junction decoupling conditions not related to metabolic stress.

5.3.3. GAP-134 The orally available dipeptide GAP-134 has been selected recently for further drug development because it was most effective in a mouse model of cardiac conduction block (Butera et al., 2009). When studied

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Fig. 4. Single channel recordings of constitutively active IK,ACh channels at –100 mV from a human right atrial cardiomyocyte from a patient in chronic AF. A) Consecutive tracings in an cell-attached patch showing burst opening of probably 2 channels (open arrow heads indicate the 2 distinct conductance levels) under control conditions and recorded with a pipette containing 10 μM flecainide. B) Open probability in the absence (BL) and presence of 10 μM flecainide. C) Average single channel current amplitude indicated that there is no change in channel conductance. (By courtesy of Niels Voigt, unpublished result).

in dogs with sterile pericarditis, GAP-134 effectively prevents AF in this model for post-operative AF (Rossman et al., 2009). In dogs with simultaneous tachicardic atrioventricular pacing for two weeks, oral GAP-134 decreases AF vulnerability, but only in animals with less atrial remodeling (Laurent et al., 2009). Although the studies with gap junction modulators seem to indicate that facilitating gap junctional function might be a novel treatment strategy at least for some forms of AF, other authors have argued that blocking the remaining gap junctions may be more effective in stopping re-entry (Wit and Duffy, 2008). 5.4. Other putative targets for novel antiarrhythmic drugs 5.4.1. Ion channels with possible role in arrhythmogenesis 5.4.1.1. Two-pore-domain potassium (K2P). Multiple additional families of ion channels have been suggested to contribute to the shape of the atrial action potential (Fig. 1). Among the former, two-poredomain potassium (K2P) channels belong to a large family of background leak channels that are highly regulated and control excitability, stabilise membrane potential below firing threshold and shorten ERP (Goldstein et al., 2001). They are robustly expressed in the cardiovascular system and are involved in multiple physiological functions, including cardioprotection, regulation of cardiac rhythm and mechanical stress (Gierten et al., 2008). Block of these K+ background channels prolongs action potential duration in mouse ventricle (Putzke et al., 2007) and could contribute to arrhythmogenesis via initiation of EAD leading to torsades de pointes and fibrillation. However, it is not known whether K2P channels could be promising antiarrhythmic drug targets in AF. Human cardiac K2P3.1 (TASK-1) K+ leak channels heterologously expressed in Xenopus oocytes are blocked by amiodarone in therapeutically relevant concentrations (Gierten et al., 2010). 5.4.1.2. Transient receptor potential (TRP) channels. Increasing evidence emerges that the transient receptor potential (TRP) channels are involved in cardiac arrhythmia (Vassort and Alvarez, 2009; Watanabe et al., 2009). For example, TRP channels of the canonical

family (TRPC) contribute to abnormal Ca2+ influx under pathophysiological conditions such as hypertrophy [for recent review see, (Nishida and Kurose, 2008)]. TRPC1 and TRPC3 are expressed in human atrial myocytes from patients with diseased hearts, and protein expression of TRPC3 is increased in atrial fibrillation patients (Van Wagoner et al., 2009). The transient inward current underlying DADs is carried by the Na+,Ca2+ exchanger, but in addition, a Ca2+-activated non-selective cation current may also contribute to DADs in human atrial myocytes (Guinamard et al., 2004), whereas contribution of a Ca2+-activated Cl- current seems unlikely because these currents are absent in human atria (Koster et al., 1999). Detailed electrophysiological analysis of Ca2+-activated non-selective cation channels in freshly isolated human atrial myocytes reveal striking resemblance to the properties of TRP channels of the melastatin family TRPM4b and TRMP5 (Guinamard et al., 2004), suggesting that these channels might indeed be involved in Ca2+ overload- induced arrhythmogenesis (Guinamard et al., 2006). 5.4.1.3. Stretch-activated ion channels. Mechanical stretch is a cause of spontaneous electrical activity and arrhythmia (Kaufmann and Theophile, 1967) and has been associated with the depolarising action of stretch-activated channels belonging to the TRP family. In ventricular myocytes, for instance, TRPC6 channel activity is modulated by mechanical strain (Dyachenko et al., 2009). Moreover, stretch-activated channels appear to be involved in atrial fibrillation, because arrhythmia induction by acute atrial dilation can be suppressed with the selective stretch-activated channel blocker GsMTx4, a peptide isolated from tarantula venom (Bode et al., 2001). Modulation of stretch-activated channels as an antiarrhythmic target is worth of investigation, although effective model drugs are not known. Noteworhty that Ω3-PUFAs apparently enhance resistance to stretch-mediated changes in cardiac refractoriness (Ninio and Saint, 2008). 5.4.1.4. Ca2+-activated K+ channels. Ca2+-activated K+ channels with small conductance (SK), long known for limiting excessive Ca2+ entry in vascular smooth muscle (Ledoux et al., 2006), are also expressed in

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mouse and human hearts, and of the three channel subunits SK1-3, SK2 is selectively distributed in atria (Xu et al., 2003). In genetically engineered mice, increase in SK2 abbreviates atrial action potentials (Ozgen et al., 2007), while loss of SK2 function prolongs action potential duration and induces EAD (Li et al., 2009b). This ion channel has been proposed to be a novel contributor in atrial fibrillation remodeling (Nattel et al., 2002), however, selective SK2 channel modulators are currently not available.

aldosterone system (RAAS), improved autonomic tone, and a reduction in ventricular arrhythmias have also been demonstrated, raising the possibility of an antiarrhythmic role for statins (Kostapanos et al., 2007). Although clinical evidence points at a possible role for statins as “upstream therapy” in AF (Bachmann et al., 2008; Dawe et al., 2009; Savelieva et al., 2010), more clinical studies are required before this issue can be settled.

5.4.2. Stabilisers of sarcoplasmic reticular Ca2+ release protein complexes The 1,4-benzothiazepine JTV-519 (formerly K-201) has vasodilatory properties and was initially developed as a cardioprotective agent against Ca2+ overload-induced cell death (Kaneko, 1994), especially under conditions of ischemia-reperfusion damage (Inagaki et al., 2000). The compound also blocks various ion channels, including Na+, L-type Ca2+ and K+ channels in micromolar concentrations, but has no effect on NCX1 (Kimura et al., 1999; Kiriyama et al., 2000). JTV-519 suppresses inducibility of AF by lowering AF threshold with carbachol, and prolongs atrial ERP (Kumagai et al., 2003; Nakaya et al., 2000). In part, the beneficial effects on AF can be explained by the drug's ability to stabilise the calstabin2-RyR2 complex thereby reducing diastolic Ca2+ leak from the sarcoplasmic reticulum.

5.5.3. PUFAs (polyunsaturated fatty acids) The lower incidence of AF in populations with high fish consumption has been related to the foodstuff's high content of omega-3 polyunsaturated fatty acids (Ω3-PUFAs) (Savelieva and Camm, 2008). Ω3-PUFAs are natural constituents of cell membranes and exert membrane-stabilizing effects. By increasing membrane fluidity they affect several ion channels in animal models including INa, ICa,L and Ito (Boland and Drzewiecki, 2008; Boland et al., 2009; Xiao et al., 2005). In human atrial myocytes Ω-3 PUFAs block INa, Ito, and IKur in a concentration-dependent manner and these effects may contribute, at least in part, to the putative beneficial effects of Ω-3 PUFAs in AF (Li et al., 2009a). An ongoing randomized, blinded and placebocontrolled trial in AF patients without significant structural heart disease will assess whether regular daily intake of Ω3-PUFAs can prevent recurrent AF (Pratt et al., 2009).

5.4.3. Blockers of atrial serotonine (5-HT4) receptors The proarrhythmic potential of human atrial serotonine (5-HT4) receptors has long been recognized (Kaumann, 1994). Serotonine increases the amplitude of pacemaker current If and reduces atrial ERP (Pino et al., 1998). Since 5-HT4 receptors are present in human atria, but not in the ventricle (Jahnel et al., 1992) pharmacological suppression of 5-HT4 receptors is expected to be devoid of ventricular proarrhythmic effects. The selective 5-HT4 antagonist RS-100302 does in fact prolong atrial but not ventricular ERP (Rahme et al., 1999). The 5-HT4 antagonist piboserod (SB207266) has been clinically tested, although it was never further evaluated for treatment of AF without any specific reason (Page and Roden, 2005).

5.5.3.1. Outlook. Although during the last years considerable progress has been made in the understanding the pathophysiological mechanism of AF, the pharmacotherapy of AF is still hampered by lowly effectiveness and safety. Recent new therapeutic agents are multiple channel blockers dronedarone and vernakalant with atrial-selective and/or disease-specific components of action. Nevertheless it seems mandatory to strengthen basic research of pathophysiological concepts for AF in order to prevent initial episodes of AF and the associated electrical and structural remodeling.

5.5. Non-ion channel blockers (“Upstream Therapy”) Drugs with potential for primary or secondary prevention of AF or risk factors for AF target the renin-angiotension system, cholesterol synthase (3-hydroxy-3-methyl-glutaryl-CoA reductase) and membrane lipid composition. 5.5.1. ACE inhibitors and AT1 receptor blockers Blocking the renin-angiotensin system prevents structural remodeling including atrial dilatation, fibrosis and conduction slowing and hence may help to prevent onset of AF (Aksnes et al., 2007). Based on these findings, angiotensin converting enzyme (ACE) inhibitors and angiotensin-1 (AT1)-receptor blockers (ARB) were introduced into primary and secondary prevention (Aksnes et al., 2007; Savelieva and Camm, 2007). A meta-analysis of clinical studies with angiontensin converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARB) describes reduced incidence of AF, particularly in patients with congestive heart failure (Jibrini et al., 2008). However, a recent placebo-controlled clinical study can not confirm effectiveness for the ARB valsartan (Disertori et al., 2009). ACE inhibitors and ARB can also constitute some antiarrhythmic properties by preventing direct proarrhythmic effects of angiotensin II on ion channels (Aiello and Cingolani, 2001; Moorman et al., 1989; von Lewinski et al., 2008). 5.5.2. Statins Inhibitors of 3-Hydroxy-3-methyl-glutaryl-CoA reductase, socalled statins are used as lipid-lowering drugs that have antiinflammotory and anti-oxidant (‘pleiotropic’) effects and therefore effective in the primary and secondary prevention of cardiovascular events (Davignon, 2004). Recently, downregulation of the renin-angiotensin-

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