Current Medicinal Chemistry, 2011, 18, 3675-3694 3675

0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

Atrial Remodeling and Novel Pharmacological Strategies for Antiarrhythmic

Therapy in Atrial Fibrillation

N. Jost*,a,c

, Z. Kohajdac, A. Kristóf

c, P.P. Kovács

a, Z. Husti

a, V. Juhász

a, L. Kiss

b, A. Varró

a,c, L. Virág

a and

I. Baczkóa

aDepartment of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Szeged, Hungary cDivision of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary

Abstract: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. It can occur at any age, however, it becomes ex-

tremely common in the elderly, with a prevalence approaching more than 20% in patients older than 85 years. AF is associated with a

wide range of cardiac and extra-cardiac complications and thereby contributes significantly to morbidity and mortality. Present therapeu-

tic approaches to AF have major limitations, which have inspired substantial efforts to improve our understanding of the mechanisms un-

derlying AF, with the premise that improved knowledge will lead to innovative and improved therapeutic approaches. Our understanding

of AF pathophysiology has advanced significantly over the past 10 to 15 years through an increased awareness of the role of “atrial re-

modeling”. Any persistent change in atrial structure or function constitutes atrial remodeling. Both rapid ectopic firing and reentry can

maintain AF. Atrial remodeling has the potential to increase the likelihood of ectopic or reentrant activity through a multitude of potential

mechanisms. The present paper reviews the main novel results on atrial tachycardia-induced electrical, structural and contractile remodel-

ing focusing on the underlying pathophysiological and molecular basis of their occurrence. Special attention is paid to novel strategies

and targets with therapeutic significance for atrial fibrillation.

Keywords: Atrial fibrillation, atrial remodeling, antiarrhythmic drugs.

1. INTRODUCTION

In spite of being the most common cardiac disorder, atrial fib-rillation (AF) rarely induces sudden/arrhythmogenic cardiac death, however, considering its clinical course it cannot be considered as a benign heart disease at all. It is estimated that AF affects 4.5 million people in the EU and about 2.5 million people in the USA [1, 2]. The increasingly aging population, the high prevalence of predis-posing factors and diseases leading to AF induction (hypertension, diabetes mellitus, obesity, cardiometabolic syndrome, sys-tolic/diastolic heart failure, apnea/hypopnea syndrome) may at least double this number by 2050 in economically developed and devel-oping countries [2].

The coordinated electromechanical heart function in sinus rhythm (SR) is changed to uncoordinated atrial activity in AF char-acterized by extremely high frequencies (400-800/min), rendering the atria unable to perform regular muscle contractions. The de-creased ventricular filling due to the lack of a proper atrial systole, the irregular ventricular depolarizations and contractions caused by erratic impulse conduction from the atria all lead to a 10-25% re-duction in cardiac output. In case left ventricular systolic function is impaired, the reduction in cardiac output and ventricular ejection is more pronounced [3].

During AF not only regular atrial electrophysiological activity ceases but contractile function is usually also impaired [4]. Due to atrial stasis (pooling) of blood, the increase in the formation of prothrombotic agents and the decrease of endogenous anticoagu-lants will develop thrombi, often causing ischaemic cerebrovascular thromboembolia (stroke). Of all AF, 20% of cases are diagnosed only after stroke [5]. This is an alarming fact since with early diag-nosis of the arrhythmia followed by initiation of proper antithrom-botic therapy, stroke could be prevented in many cases. One of the main lessons learnt from recent clinical trials is that the risk of stroke is similar in paroxysmal, persistent and permanent AF [5]. Therefore the prophylactic antithrombotic therapy is compulsory in all forms of AF. Importantly, 44 % of young and middle age

*Address correspondence to this author at the Division of Cardiovascular Pharmacol-

ogy, Hungarian Academy of Sciences and Department of Pharmacology & Pharma-cotherapy, Faculty of Medicine, University of Szeged, Dóm tér 12, P.O. Box 427, H-

6701 Szeged, Hungary; Tel: (36-62) 546885; Fax: (36-62) 545680;

E-mail: jost@phcol.szote.u-szeged.hu

patients with even anatomically normal hearts may have latent hy-pertension [6]; therefore the diagnosis of lone AF can be performed only on a basis of careful and repeated cardiological examinations. The proper choice of anticoagulant therapy is based on stroke risk estimation expressed by the CHADS2 risk score (Cardiac Failure, Congestive heart failure, Hypertension, Age, Diabetes, Stroke risk score), with which every medical practitioner should be familiar with [7].

Wide application of ECG monitoring and archiving devices made it possible to detect and identify the asymptomatic, lone form of AF, generally found in patients under 60 years of age [8]. These measurements made clear that AF is a progressive, gradually wors-ening disease. It seems that even the monthly performed 24 hour Holter ECG monitoring is still not enough, since in this way we may record only maximum 30-50 % of the AF episodes [9]. Proba-bly becoming the golden standard for continuous rhythm recording is the one year continuous recording using a subcutaneously in-serted loop-recorder (Reveal XT™), which detects, records and saves (for later analysis) arrhythmias even if they cause no com-plaints to the patient [10].

In paroxysmal AF, the shorter-longer persisting episodes termi-nate spontaneously and are not sustained beyond 7 days. The in-creasing number and time course of these sponte sua interrupting attacks - due to the development of atrial remodeling - will cause the arrhythmia to become persistent, and only medical (pharmacol-ogical or electrical) interventions can convert AF to SR. The prob-ability of long-time preservation of the SR is greater if the patient scarcely had AF attacks before the diagnosis is made and vice versa: if AF persisted for a long time, the stable SR probability is significant lower [11].

After two weeks of persistent AF the success ratio of pharma-cological cardioversion may drop, and after more than one year duration of AF – except for some special cases as mitral valve de-fect, myocardial ischaemia recovery via PCI and CABG, thyroid hormone recovery of hyperthyroid patients - even the combined therapy of hybrid DC-electrocardioversion (electrical cardioversion facilitated with antiarrhythmic drugs) is usually already ineffective: patient and physician are forced to accept that AF has become stabi-lised, permanent.

In a landmark study, Allessie and co-workers demonstrated in a goat model that high frequency burst electrical pulses generated by

3676 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Jost et al.

a fibrillation pacemaker induced and maintained AF, which usually terminated after switching off the stimulator. When AF was main-tained artificially, they found that the time course of the newly in-duced AF depended on the length of the preceding AF. The Maas-tricht group characterized the autogenerative nature of this perpetu-ated arrhythmia (Fig. (1)) with the now widely known sentence: “atrial fibrillation begets atrial fibrillation” [12].

During the last 10-15 years there has been significant progress in revealing the pathophysiological changes that develop in AF. The mentality of researchers and clinicians was strongly affected by the paradigm-changing concept of atrial remodeling by Allessie and co-workers [13, 14]. Today all functional and/or structural changes that lead to AF and create a substrate for repetitive renewal of the arrhythmia contribute to “atrial remodeling”, including: a) the func-tional and morphological injuries of atrial myocytes (sarcolemmal ion channels, signalling and functioning proteins), cell-surface ad-hesion molecules and coupling structures (gap-junctions), the ex-tracellular matrix, and the endocardial endothelium; b) the dysfunc-tion of neurohumoral systems - especially elements of autonomic nervous system and renin-angiotensin-aldosterone system (RAAS).

These factors altogether form a pleiomorf pathophysiological vicious circle that will continuously promote the renewal, stabiliza-tion and permanent nature of AF. Lloyd and Landberg wittily com-pared AF to the Greek mythological hydra near Lerna: Hercules wanted to cut down the nine heads of the monster with his mace, however, he failed because after knocking down one head, two new heads grew in the place of the original [15].

The most significant electrophysiological changes occurring during AF are presented on Fig. (2A) [16]. The arrhythmia in most cases is induced by an atrial extrasystole (ES). First, only a solitaire ES, later by coupled, then shorter-longer ES series or even atrial tachycardia attacks. Holter monitoring revealed that the AF initiat-ing atrial ES occurs often during extreme bradycardia or following a long pause (postpausal ES) [17]. The AF maintaining reentry

activity is based on anatomical and/or functional conductivity block(s), the coexistence of at least or more than 5-6 small or large activating wavefronts (multiple wavelets) rotating in the inexcit-able/refractory heart regions [18].

In some patients it was shown the extrasystoles originating from the pulmonary vein sleeves (described by Zipes and Knope in 1972) played an important role not only in initiating AF but they significantly contribute to the maintenance of the arrhythmia [19]. However, the current notion is that trigger extrasystoles are rather the initiators [20]. The predisposing factors of the recurrence and stabilisation of the dysrhythmia are mainly hypertonia/left ventricu-lar hypertrophy, coronary and/or heart muscle disease, ageing, fi-brosis induced atrial electrophysiological and/or (ultra)structural impairment, i.e. the presence of an anatomical/histopathological substrate [15]. In case the interstitial or the replacement (to recover necrotic myocytes) (micro)fibrosis of the atrial muscle is severe, the atrial muscle remodeling is irreversible and AF becomes perma-nent.

2. MAIN ELEMENTS OF THE PATHOMECHANISM OF

ATRIAL REMODELING

Fig. (2B) is a schematic illustration of pathophysiological changes that probably play a role in the induction of AF. We know since 1920 that fast and irregularly activating extrasinoatrial pace-maker foci may fire and maintain AF. The main representative of the “focal activity” theory was David Sherf (1899-1977), who based his hypothesis on the observation that atrial epicardial applied aco-nitine, acetylcholine or BaCl2 may produce local foci or ES, ES-series, atrial flutter (AFlu). He suggested that the pulses started from high frequency depolarizing heterotopic pacemaker foci may be blocked or might even perish when they arrive at atrial myocar-dial muscle fibres which have such a long refractory period that are unable to conduct the stimulus 1:1 [21]. Sherf’s hypothesis was in contrast with Lewis’s “circus movement” (reentry) concept, how-

Fig. (1). AF begets AF”. Representative recordings from instrumented conscious goat experiments by Wijffels and Allessie. Prolongation of the duration of

electrically induced atrial fibrillation (AF) episodes was observed after maintaining AF for 24 hours and 2 weeks, respectively. The three traces show single

atrial electrograms recorded from the same goat during induction of AF by a 1-second burst of stimuli (50 Hz, 4 times threshold). In the upper trace the goat

has been in sinus rhythm all the time and atrial fibrillation self-terminated within 5 seconds. The second trace was recorded after the goat had been connected

to the fibrillation pacemaker for 24 hours showing a clear prolongation of the duration of AF to 20 seconds. The third trace was recorded after 2 weeks of

electrically maintained atrial fibrillation. After induction of AF this episode became sustained and did not terminate. From Ref [12], with permission.

Atrial Remodelling and Therapy of AF Current Medicinal Chemistry, 2011 Vol. 18, No. 24 3677

ever, it was reborn in the 1990s: currently it is largely known that in the pulmonary sleeve veins and in some vestigial anatomical struc-tures (auriculum, Marshall-bundles, crista terminalis) cell types exist that qualify for spontaneous automaticity/pacemaker activity.

For the initiation and maintenance of the “single-circuit reen-try” AF, one larger reentry circuit, the “central or mother wave” is responsible. The randomly fast and fibrillatory waves arise and leave in centrifugal directions and the dominant circuit disorganizes atrial electrical activity, consequently producing AF (Fig. (2B)).

In other cases, at least or more than 5-6 simultaneously present reentry depolarizing wavefronts (“multiple circuit wavelets”) main-tain the chaotic/fragmented atrial electrical activity [18]. The pathogenetic role of the circus movement in AFlu/AF was demon-strated in 1920 by Sir Thomas Lewis (1881-1945), who used his own and other researchers’ (Alfred Goldsborough Mayer (1868-

1922), George Ralph Mines (1886-1914) and Walter Garrey (1874-1951)) observations. Later in the 1950s, Gordon Kenneth Moe (1915-1989) improved the reentry concept with the help of compu-tational and mathematical modelling methods [22]. He developed a theory called “multiple wavelet” theory (1959), that later in the 1970s was undoubtedly demonstrated by Maurits Allessie group’s multielectrode mapping experiments in rabbit atrial muscle. They were the first to point out that not only lasting tachycardia (>30s) exists, that is based on an anatomical substrate (fibrotic focus, scar) and induces more or less stable reentry circuits (with fixed cycle length), but other tachyarrhythmias also exist, which arise from different large size reentry circuits (“leading circles”) [18]. These types of reentry may cause lone or paroxysmal AF.

Fig. (3) shows the relation between the ectopic stimulation, the reentry circuit and AF. The activating wavefront stimulated by an

Fig. (2). Panel A. Main factors that induce and maintain AF. Panel B. AF is initiated by an extrasystole started from a pacemaker region (usual left upper

pulmonary vein), created by atrial tachycardia remodelling (APD shortening). The electrical perpetuator may be a single/mother wave and/or multiple

wave/circuit reentry. Atrial ischaemia and inflammation are known reentry facilitators. The key factors of structural/morphological remodelling are atrial myo-

cardial (micro)fibrosis and left atrial dilation. (AF = atrial fibrillation; RA = right atrium; LA = left atrium; EAD = early afterdepolarization; DAD = delayed

afterdepolarization; PVs = pulmonary veins; APD = action potential duration; RP = refractory period; WL = wavelength). Modified from Ref [16] with per-

mission.

DAD

EAD

Abnormal automaticity

Atrial dilation

Acute ischemia Inflammation

Fibrosis

A. Ectopic focus

B. Single circuit reentry C. Multiple-circuit reentry

Substrate Trigger

SubstrateTriggerTachycardia

APD

Atrial dilationAcute ischemia

Inflammation

RP WL

A

B

Substrate Trigger Ectopic activity

Atrial fibrillation

Reentry

Remodelling

3678 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Jost et al.

ES impacts on a part of the myocardium in absolute refractory pe-riod and blows out in one direction (unidirectional block), but may spread in another direction, then also in the retrograde way depolar-izes the myocardium “behind” the functional block that, in the meantime also recovers from refractoriness, thus completing the circle.

Allessie should also be credited for the wavelength (WL) theory [18, 23, 24]. He designated the refractoriness wavelength ( =lambda) a myocardial circuit/distance, that is activated by the depolarizing pulse during the refractory period duration. WL is thereby the product of the effective refractory period (ERP) and the conduction velocity (CV) ( = ERP x CV). Taken this definition into consideration, we may say that the condition for maintenance of reentry is that the wavelength of the pulse to be shorter than the length of the circuit (Figs. (3A) and (3B).

The shorter ERP and the slower CV are, the smaller their prod-uct WL becomes. Short ERP and/or slow conduction velocity in-crease the probability of the arriving pulse of the reentry circuit to reactivate the myocytes. All factors that shorten WL decrease the reentry circuits’ size, and increase the number of wavelets, and the possibility for reentry activity. For example, Na-channel blockers that do not or only moderately lengthen ERP and strongly depress stimulation conduction, may facilitate reentry formation, and espe-cially in partially depolarized cardiac muscle strongly decrease CV and consequently WL [25].

The shape and duration of the action potential (APD) are de-termined by the equilibrium between the relative intensity of the inward sarcolemmal ionic currents (especially by the inward L-type Ca

2+ current at the early phase of the plateau) and of the outward

repolarizing K+ currents (Fig. (3C)).

The essence of tachycardia-induced electrical remodeling is that atrial ERP (AERP) and APD within minutes after the initiation of

AF shortens, and the AP shape becomes even more triangularized (Figs. (3C) and (4)). The AERP shortening is due mainly to the loss of function (downregulation) of the L type Ca

2+ current, together

with the increase (upregulation) of several K+ current densities

and/or membrane permeability [26, 27].

Swedish authors found that the duration of the monophasic ac-tion potential (MAP) recordings conducted from right endocardial atrial myocardium to be significant shorter than from the controls (either persons, which were converted from AF to SR or arrhythmia free persons). Using the MAP registration technique with electrodes in humans, Bertil Olsson’s group (1971) was thereby the first to report shortened MAPD as the most important element of AF elec-trical remodeling. They also observed that if MAPD remained short, AF would recur within 3 months [28].

The other significant element of atrial electrical remodeling is that the atrial AERP duration during interparoxysmal SR can not accommodate to modifications in cardiac frequency. In normal conditions, tachycardia is associated with adaptive AERP shorten-ing (the normal rate adaptation mechanism of the refractoriness to cardiac frequency). Specifically in AF induced electrical remodel-ing this adaptive disorder remains after SR is restored: AERP doesn’t adapt to heart rate (ERP mismatch – maladaptation). This phenomenon was first described by Attuel and co-workers in 1982, however, at that time they didn’t consider that their observations can be explained by one of the components of electrical remodeling [29].

The slowing of atrial impulse propagation is induced by the dysfunction and/or ultrastructural alterations of the sarcolemmal Na

+-channels, and/or intercellular gap-junctions (Fig. (3D)). The

energy source of the fast depolarization (phase 0 of the AP) is given by the large conductance Na

+-channels that are open for 1-3 ms. In

normal myocardium, the electrical resistance and energy dissipation is rather low. The electrochemical coupling (tight junction) of the

Fig. (3). Main factors determining reentry. A premature beat is blocked in the anterograd direction in still refractory cardiac tissue (unidirectional block, panel

A), but in the other direction (retrograde direction) propagates and may pass through all tissue already in refractory state (panel B). Panel C. Mechanisms

involved in atrial fibrillation inducing shortening of effective refractoriness. Panel D. Two principal mechanisms of remodelling-induced conduction slowing.

Panel E. Remodelling-induced atrial dilation promotes AF by increasing circuit path space so that larger reentry circuits can be supported (left) and/or a larger

number of circuits can be maintained (right). RP = refractory period. SR=sinus rhythm, AF= atrial fibrillation, APD90=action potential duration at 90 % repo-

larization. Modified from Ref [16] with permission.

Decreased inward currents (Ca2+)Increased outward currents (K+)

Factors determining reentry

Circuit time: has to be longer than RP

Normal conduction

Slowed conduction(Decreased source current (INa)

C D EShortened refractory periods

Normal sized atrium

Increased circuit path-space

Dilated atria

Impaired connexin function fibrosis

Favoured by: short refractory periods slow conduction long pathways available

BA

How does remodelling promote reentry?

Atrial Remodelling and Therapy of AF Current Medicinal Chemistry, 2011 Vol. 18, No. 24 3679

neighbouring cells is based on these small resistance, high conduc-tance (which allow fast impulse propagation) gap-junction chan-nels.

The gap-junction channels unlike other sarcolemmal cation-channels are complex membrane protein channels with special properties, and are composed of two connexon units strongly cou-pled in the intercellular gap. The connexons are composed from six connexin protein subunits. Usually they form direct electrical and chemical contact at the end of the neighbouring cell (“end-to-end”): due to their low resistance they are capable of an extremely fast longitudinal impulse propagation, which enables the myocytes to concurrent, synchronized depolarization (electrical synapses) and contraction (syncytium theory). Gap junctions also favour chemical communication and signalling, since typically less than 1-2 kDa small molecules (mostly secondary messenger molecules, cAMP, Ca

2+) can get through the 1.2-2 nm i.d. channels by passive diffu-

sion. In case of ischaemia or any other myocardial injury intracellu-lar Ca

2+ and H

+ concentrations (acidosis) of cardiomyocytes ab-

normally increase, gap junction channels, as part of a protective mechanism close, and the cells diverge form each other. This un-coupling is arrhythmogenic as a consequence of slowed conduction [30].

Currently at least 20 connexin (Cx) isoforms are known, and each of them is composed of 4 domains. In the atria and the specific impulse conducting system mostly Cx40 and Cx45 are expressed, while in the ventricles Cx43 is the dominant gap-junction protein [31]. Atrial tachycardia downregulates Cx40 expression, while immunochemical studies demonstrated that the amount and distri-bution of the different Cx isoforms are also altered in AF [31].

In a dog model the several week-long and experimentally main-tained atrial tachycardia (stimulated tachypaced atrial dog model) causes electrical remodeling. In this model, the downregulation of

Na+-channels was observed [32]. Electrical remodeling is followed

by structural changes, especially by interstitial and replacement fibrosis. The side-to-side formed (micro)fibrotic bundles between the cardiac cells further delay transversal (which is already 3-5 fold slower than the longitudinal) impulse propagation. The significant difference between the transversal and longitudinal impulse propa-gation in impaired atrial tissue will further increase the CV dispar-ity, and the fibrillation disposition of the atria (anisotropic reentry). It was demonstrated in dogs that as a consequence of atrial dilation the endocardial cardiac muscle will become hypertrophic, where reentry circuits can form easier at a later stage (Fig. (3E) [33, 34].

3. REMODELING AND VENOATRIAL ECTOPIC ACTIVI-

TY (ATRIAL EXTRASYSTOLES)

The mechanisms responsible for the induction atrial ectopic ac-tivity and extrasystoles are summarized on Fig. (5). Spontaneous phase 4 depolarizations occur following repolarization in the rest-ing/diastolic phase, with a rate depending on the slope of the upris-ing curve. When the membrane potential increase caused by the spontaneous diastolic depolarization reaches the threshold potential, a new action potential arises. In case the resting potential of the working cell before the spontaneous diastolic depolarization was in a physiological range (–85 to –90 mV), the activity is considered normal automaticity, however, when it develops at more positive voltage range (to about –50 to –40 mV, i.e the myocyte is partially depolarized) pathological/abnormal automaticity is considered.

In case the stimulation of the atria is slower than the rate dic-tated by the Keith-Flack node (sinus node), ectopic beats/ES cannot occur: the heart rate is (over)controlled by the physiological pace-maker sinus node. On the other hand, if the slope of the spontane-ous diastolic depolarization upstroke curve is substantially in-

Fig. (4). Transmembrane ionic currents determining atrial action potential in sinus rhythm (SR) and in atrial fibrillation (ion channel remodelling). Left col-

umn depicts ionic current densities, while middle and right columns show the changes in the expression of the main current subunit putative proteins and

genes, respectively. Pictograms present current amplitude and time course more or less considering real size ratios. n.d.: no data available.

GeneMain subunit(protein)

Current

n.d.

n.d. n.d.

n.d.

n.d.

3680 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Jost et al.

creased in any extrasinoatrial region of the atria, extrasystoles and focal atrial tachycardia can freely occur (Fig. (5A)). It has been demonstrated that in atrial ectopic tachycardia the expression of the funny current (If) - known as the main responsible current for phase 4 depolarization - is upregulated [35].

Atrial cellular Ca2+-overload and sarcoplasmic reticular Ca2+

-homeostasis defects may induce secondary, non-selective transient depolarizing currents (Na

+ and/or Ca

2+) and delayed afterdepolari-

zations (DADs) [36]. These are small “dome” shaped transient depolarisations on the transmembrane action potential or in situ monophasic action potential registrations (Fig. (5B), which occur during the electrical diastolic phase. The electropathogenesis of DADs is different than that of phase 4 depolarizations (normal or pathologic automaticity). When the amplitude of the DAD is large enough and it reaches threshold potential, a solitaire ES may be induced, while a series of DADs may induce repeated extrasystoles or atrial tachycardia. A clinical example for DAD initiated multifo-cal atrial tachycardia with AV block can be observed in digitalis intoxication [37]. During each action potential (including AF with 400-800/min frequency) Ca

2+ enters (via L-type Ca

2+ channels) into

the cells: [Ca2+

]i increases and may lead to DAD-induced tachycar-dia/tachyarrhythmia. DADs can be often observed in congestive heart failure also because the intracellular Ca

2+ concentration is

higher in this disease [38, 39]. This type of arrhythmogenesis is called triggered activity.

In summary, three arrhythmogenic factors may cause venoatrial extrasystoles and consequently AF via: 1) increased automaticity; 2) reentry; 3) triggered activity. The latter may be caused by DADs and so-called early afterdepolarizations (EADs). EADs occur when the APD is extremely prolonged. As a result of the repolarization lengthening, the already closed L-type Ca

2+ channels re-open, and

this reactivated ICaL induces single or repeated depolarizations, EADs (Fig. (5C)). EADs most often occur in Purkinje fibres and/or in midmyocardial cells (M cells, where the APD in physiological conditions is already longer), mostly in congenital or acquired (e.g. by drugs) long QT syndrome [40].

In patients with long QT the EAD triggered escalated ventricu-lar extrasystoles may induce VT/VF [41]. For a long time it has been suggested that extremely lengthened repolarization (QTU interval) based EADs represent a triggered mechanism specific only for the ventricles. However, Satoh and Zipes demonstrated in dog experiments that intravenous application of the potassium channel blocker cesium (Cs) induced extreme repolarization lengthening both in the atria and the ventricles, and consequently they observed not only EAD induced ventricular but also atrial chaotic “Torsades de Pointes” tachycardia, that also degenerated into AF [42]. Cur-rently it is known that some forms of atrial tachyarrhythmias are clearly EAD-dependent [42, 43]. Kirchoff and co-workers using MAP studies clearly demonstrated the presence of EAD initiated chaotic tachycardia, which turned into AF in congenital long QT patients [44].

Chen et al. reported that in canine PV ostium and sleeve myo-cytes they observed not only EAD/DAD triggered activity but a spontaneous reentry type mechanism similar to that of already shown in patients with AF [45]. Schlotthauer and Bers showed that the activation of the reverse (depolarizing) mode of the Na

+/Ca

2+-

exchanger (NCX) contributes to Ca2+

-overload and/or EAD/DAD triggered activity [46]. The atrial and ventricular (STU) repolarizing alternants are caused also by Ca

2+-overload and mishandling, and

they are usually the forecasters of persistent polymorphic tachycar-dia/tachyarrhythmia [47-49].

4. TACHYCARDIA/TACHYARRHYTHMIA INDUCED ION

CHANNEL REMODELING

As already mentioned, the main result of tachycardia induced atrial remodeling (ATR) is the shortening of APD/ERP (Figs. (3)

and (4) [50]. This is caused mainly by the downregulation of the L-type Ca

2+-current (ICaL), [51, 52] and by the upregulation and/or

gain on function of the background current type inward rectifier K+-

channel (IK1) [50], and exclusively in permanent AF, the constitu-tively active ACh-dependent potassium channel (IK,Ach), [27, 50, 53]. The frequency of atrial activation becomes extremely high in AF (400-800/min), therefore in spite of the shorter APD plateaus, the amount of Ca

2+ entering the myocytes significantly increases

leading to impaired intracellular Ca2+

homeostasis (“Ca2+-mishandling”) [54]. The elevated Ca

2+-influx increases the activa-

tion of ryanodine receptors (“Ca2+-release”[RyR2]-channel) lead-ing to a higher number of arrhythmogenic Ca

2+ sparks [55]. The

cells respond to Ca2+

-overload by reducing the expression of Ca2+

-channels (downregulation), that within a relatively short time sig-nificantly shortens APD [14]. Impaired Ca

2+ homeostasis also

manifests in deterioration of contractile and diastolic function of the atria as well as consequent wall stiffness and increased stretch that after a longer duration will cause left atrial dilation. The dilation and geometric deformation of the atria are the most important pathomorphologic factors determining the propensity for AF recur-rence (structural remodeling), and may predict the impossibility of AF conversion in the clinical setting [4, 33, 54].

4.1. Fast Sodium Current (INa)

The available literature discussing the possible electropa-thopysiological role of INa in atrial electrical remodeling is rather controversial. It was reported following the investigation of atrial biopsy samples from patients with permanent AF that neither the density of the INa current [56], nor the mRNA expression of the main subunit [SCNA5, 57] was altered. Conversely, others found INa-channel density reduction (loss of function) or INa upregulation (gain on function) in AF [32, 58, 59]. However, INa downregulation would cause impulse propagation (CV) deceleration, which facili-

Fig. (5). Cellular mechanisms responsible for the induction of premature

venoatrial/ectopic beats (extrasystoles): enhanced automaticity (A); DAD,

delayed afterdepolarization (B); and EAD, early afterdepolarization (C).

Modified from Ref [16] with permission.

Threshold potentialSpontaneous phase 4 depolarization

C

B

A

Atrial Remodelling and Therapy of AF Current Medicinal Chemistry, 2011 Vol. 18, No. 24 3681

tates reentry formation. On the other hand, the gain on function of the channel increases the excitability of the myocardium [60]. Taken in consideration the authors concluded that the observed slowed conduction was caused by both gap-junction and fast Na channel function impairment. Further studies are required to answer this question.

4.2. L-Type Inward Ca2+

-Current (ICaL)

The main transmembrane current during the plateau phase of the action potential is the L-type inward Ca

2+-current (ICaL). Since

in AF the number of action potentials within a given time period is markedly larger, the high atrial frequency will significantly enhance Ca

2+-influx. As an adaptive/autoprotective mechanism, atrial myo-

cytes will decrease up to 60-70 % the density/magnitude of ICaL-current within a few minutes following AF onset [52, 61, 62]. This current function downregulation is also associated with the reduc-tion of the expression of the main ICaL-current subunit 1c protein [52, 57, 63] and mRNA [CACNA1C, 52, 64] levels. The current reduction can also be explained by the 1c protein dephosphorila-tion induced signal transduction disorders and by cGMP-independent mechanisms (increase in S-nitrosylation and direct effects on G proteins) [52, 65]. Several studies reported the down-regulation of the expression of ICaL-current 1, 2a, 2b, 3 és 2 2 auxiliary subunits [59, 66, 67]. Downregulation of the ICaL-current seems to be the most important mechanism responsible for increas-ing the reentry/AF predisposing to APD and WL shortening [4].

4.3. Na+/Ca

2+-Exchanger

During diastole, the large amount of intracellular Ca2+

is partly sequestered by the sarcoplasmatic reticulum (SR), while the re-maining Ca

2+ is mainly extruded by the sarcolemmal Na

+/Ca

2+-

exchanger (NCX). NCX is an electrogenic ionic pump: it exchanges three Na

+ to one Ca

2+ [68], which means that during Ca

2+ extrusion

may cause a DAD or EAD inducing depolarizing current [69]. It has been reported that the protein expression of the main NCX forming subunit is significantly upregulated in AF patients [70]. Since we still lack highly selective NCX blockers, we are not able to characterise the real physiological and pathophysiological role of NCX in the arrhythmogenesis leading to AF.

4.4. Pacemaker-Current (If)

The non-selective hyperpolarisation activated cation (mixed Na

+/K

+) pacemaker current (funny current If), which is responsible

for the diastolic depolarization during phase 4, has been detected not only in the sinus node but also in other atrial regions as well (auricle, crista terminalis, left atrium). In AF patients, the upregula-tion of mRNA levels of the main If subunits was reported [HCN2/HCN4, 35], which means that If may contribute to initiation of AF inducing triggered extrasystoles [26].

On the other hand, Yeh et al observed in atrial tachypaced re-modelled (ATR) dogs that the sinus node recovery time was in-creased. They have demonstrated the HCN2/HCN4 gene and If current downregulation determine the sinus node-remodeling, and they concluded that tachycardia induced sinus node remodeling most probable contributes to the development of excessive sinus-bradycardia and supraventricular tachyarrhytmias (“tachy-brady syndrome”) in sinus node syndrome [71].

4.5. Inward Rectifier Potassium Currents

The resting membrane potential of the cardiomyocytes is re-established by the “background” inward rectifier potassium cur-rents. In AF, the resting membrane potential is more negative than in SR [50, 53, 72]. The main resting membrane potential regulating current is the inward rectifier K

+-current [IK1, 73]. IK1 is formed by

the co-expression of several Kir2.x family members (Kir2.1-Kir2.4). A number of studies have reported that IK1 current density [50, 53, 56, 61, 74], channel proteins [50, 59] and gene mRNA [50, 53, 59, 61, 74] are upregulated in human permanent AF. In atrial myocytes, unlike in ventricular ones, a special inward rectifier po-tassium current has been identified that requires ligand stimulation for activation, named the acetylcholine-dependent inward rectifier potassium current [IK,ACh, 75]. Acetylcholine (ACh) released fol-lowing parasympathetic/vagal stimulation bind to atrial muscarinic-2 receptors, and activate IK,ACh through a G-protein coupled mecha-nism [76, 77]. Until recently it was considered that without direct ligand stimulation (ACh binding) IK,ACh channels were in a closed state [53]. However, it has been known for more than a decade that from efferent vagal nerve terminals in different atrial regions differ-ent amount of ACh is released that causes repolarization disparity and APD and ERP inhomogeneity, consequently further increasing atrial repolarization dispersion [78].

In 1978, Philippe Coumel, the recently deceased brilliant French cardiologist described a special form of vagal paroxysmal AF - later named after him. This type of AF most commonly occurs in 30-50 year-old men who have macro-anatomically intact heart at night, during sleep or rest following meals [79]. The Coumel AF has a unique clinical feature: the AF episode is usually pre-ceded/induced by sinus bradycardia and/or other sort of vagomimetic event or manoeuvre (for example cough, swallow, belch, vagotonic episode of sleep, carotid compression, Valsalva experiment) [80]. When Coumel AF develops, ventricular fre-quency is usually not too high (bradyarrhythmic AF). Therefore, the logical question arises whether the remodeling of IK,ACh can modu-late the occurrence and/or stabilization of AF.

In 2001, Dobrev et al reported that the upregulation of IK1 was associated with the downregulation of GIRK4, the main IK,ACh subunit protein in AF. Therefore, at that time the electrical remodel-ing induced APD shortening was explained only by IK1 up- and ICaL downregulation [50]. Later the same group reported that during atrial tachyarrhythmia induced permanent AF via a not fully eluci-dated signal-transduction mechanism [81], IK,ACh channels were constitutively open and active without any direct ligand stimulation [53, 82]. It was the first in vitro study demonstrating that IK,ACh may by active without ligand stimulation and in this special pathophysi-ological condition, permanent AF may induce an outward K

+-

current. Therefore, it was hypothesized that in permanent AF con-stitutively active IK,ACh may contribute to the APD abbreviation and triangularization, thereby enhancing the propensity of reentry in the atria. According to this hypothesis, selective blockade of constitu-tively active IK,ACh current may have antiarrhythmic/antifibrillatory effects [53, 82]. Based on this concept, the synthesis of new inves-tigational, selective IK,ACh compounds, such as NIP 142 and NIP 151, was initiated. Preliminary in vitro and in vivo preclinical stud-ies with these compounds yielded promising results [83, 84].

We may summarize that, according to our current knowledge, the three most likely components of atrial electrical remodeling (APD shortening and triangularization, Fig. (4) are as follows: 1) downregulation of ICa,L; 2) upregulation of IK1; 3) activation of the constitutive (ligand independent) IK,ACh.

Adenosine-triphosphate (ATP) sensitive potassium channels (IK,ATP) provide a direct link between cellular metabolism and membrane excitability that open as a result of acute myocardial ischaemia induced intracellular ATP depletion [85]. It was demon-strated that AF upregulates IK,ATP density, a finding that is in good correlation with the observation that there is a relative ischaemia in AF: at high frequencies the arterial blood flow is not sufficient in the atria even when coronary function is intact [86]. However, the downregulation of KATP channels were also reported in atrial myo-cytes isolated from patients with chronic AF [87].

Data regarding the exact molecular composition of IK,ATP channel subunits present

3682 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Jost et al.

in the atria are also incomplete [63, 88], however, a recent study indicated that SUR1 was an essential component of mouse atrial, but not ventricular, KATP channels [89]. Whether similar chamber specific differences in KATP channel composition exist in humans will be determined by future studies.

4.6. Voltage Dependent K+-Currents

4.6.1. The Transient Outward K+-Current (Ito)

The main current responsible for the early phase of the repolari-zation (phase 1) is the fast activating and relatively fast inactivating depolarization activated transient K

+ current, the Ito. Ito current den-

sity has large transmural heterogeneity, since in epicardial myo-cytes current amplitude is significantly larger than in endocardial cells [90, 91]. This heterogeneity explains the known transmural differences in APD and why the notch is larger in epicardial cells. Ito current amplitude/density is significantly depressed in AF [56, 92-94]. This downregulation was demonstrated for the Kv4.3 pro-tein [57, 58, 88] and also for KCND3 mRNA levels [57, 88, 95]. The consequences of Ito current loss of function downregulation are not clear yet. Ito is a fast activating current, which counterbalances the depolarizing effect of the fast Na

+ current during the upstroke

phase of the AP. Theoretically, Ito downregulation may increase the AP amplitude, which either may increase CV, or indirectly offset conduction delay caused by other pathological changes.

4.6.2. The Ultrarapid Delayed Rectifier Potassium Current (IKur)

The available data in the literature regarding IKur are controver-sial [51, 56, 92, 96]. Regan et al showed that the newly synthesised IKur blocker isoquinoline derivates (ISQ-1) in dog and African green monkey lengthened specific only atrial but not ventricular ERP; iv application of the drug prevented the AFlu induced by fast electri-cal (tachy)pacing [97]. On the other hand biopsy sample (originat-ing from patients in permanent AF) showed IKur downregulation of IKur current [51, 56, 92, 94]. IKur current is a atrial specific current that is expressed only in atrial myocardium, which means that theo-retically would be an ideal atrial selective antiarrhythmic drug tar-get [98, 99]. Since in AF the main IKur current subunit Kv1.5 pro-tein and KCNA5 gene mRNA levels downregulates [92, 94], the additive pharmacologically blockade of the channel seems be ques-

tionable. Inhibition of the channel may pathologically shorten AERP/APD, and consequently may be ideal substrate of AF. Wett-wer et al analysed the effect of AVE0118 on the atrial APD in hu-man atrial samples from patients in permanent AF: they found ei-ther APD lengthening or shortening. They explained this surprising result with the severity of the disease, i.e. the level of the electrical remodeling [100]. On the other hand the amplitude of IKur strongly depends on the shape of the action potential, which means that the current amplitude may increase if the APD is shortened, or become triangularized, for example like in AF remodelled APD [100, 101]. These results strongly questioned the hypothesis raised by Nattel and co-workers in the mid 1990s, which said the selective IKur blockers, may be atrioselective powerful and proarrhythmia free new antiarrhythmics for treating AF.

4.6.3. The Rapid and Slow Delayed Rectifier Potassium Currents

(IKr and IKs)

Due to technical complications native IKr and IKs current densi-ties were not detected until now in healthy or AF remodelled atrial tissue. Some studies reported that IKr and IKs proteins and mRNA levels were reduced in permanent AF [57, 59, 102]. However, without proper functional current data, it is difficult to evaluate the clinical significance of these molecular biological investigations [51]. A very recent paper reported that IKs current upregulated, and IKr current density remained unchanged in human atrial myocytes following AF, however, the detected average current was extremely low in these experiments [94].

5. STRUCTURAL REMODELING, FIBROSIS

In an editorial entitled “A paradigm shift in treatment of atrial fibrillation: from electrical to structural therapy ?” in 2003, Heid-büchel drew attention to the importance of upstream/non-channel targeting therapy as being the most relevant element in AF preven-tion [79]. The most problematic element in the clinical evolution of AF is not electrical remodeling that develops within a relatively short time frame, but the irreversible changes leading to structural remodeling that occurs mainly after 3-4 months. The main patho-morphologic contributor to structural remodeling is microfibrosis of the atrial myocardium [103]. Structural remodeling is a key factor

Fig. (6). Illustration of microfibrosis-induced myocyte uncoupling. Panel A. In normal myocardium myocytes are electrically coupled primarily in an end-to-

end fashion by intercellular gap-junctional complexes. Panel B. The activation of fibroblasts causes reactive/interstitial fibrosis and the increase of the ex-

tracellular matrix (ECM). Panel C. Reparative/replacement fibrosis replaces degenerating myocytes following apoptosis or necrosis by creating swollen colla-

gen fibres.

Cardiomyocytes

Connexins

Fibrosis

Normal tissueA B

C

Reactive fibrosis

Reparative/replacement fibrosis

Atrial Remodelling and Therapy of AF Current Medicinal Chemistry, 2011 Vol. 18, No. 24 3683

responsible for the deteriorating nature (paroxysmal persistent permanent) of AF [104]. The main elements of structural remod-

eling are as follows: fibrosis of atrial myocardium, activation of fibro(myo)blasts, accumulation and deposition of collagens [104]. In the dilated, deformed, fibrotic myocardium AF will become permanent first of last. Myocyte loss, either by apoptosis or necro-sis, is observed in parallel with the onset of fibrosis [105, 106]. Reparative fibrosis replaces degenerating myocardial cells, whereas co-existing reactive fibrosis causes interstitial expansion between bundles of myocytes, as shown in Fig. (6). Pathologically produced collagen differs from that in the normal myocardium, with altered ratios of collagen subtypes [13]. Dense and disorganized collagen fibres physically separate remaining myocytes, and can create a barrier to impulse propagation [107].

The fibrosis therefore is a multifactorial process and effective but currently non-existent antifibrotic therapeutic modalities would probably represent a major step toward the prevention of AF [108]. In lone AF, collagen deposition and morphological alterations typi-cal for myocardial inflammation were also observed [109]. The mechanisms responsible for the remodeling of extracellular matrix are not fully understood. Microfibrosis is definitely affected by the increased activity of the renin-angiotensin-aldosterone system (RAAS), the transforming growth factor- 1, inflammation [110-112] and oxidative stress [113].

6. CONTRACTILE REMODELING

The terms mechanical or contractile remodeling refers to the impairment of atrial contractile function eventually leading to atrial dilation. Echocardiographic investigations demonstrated that atrial contractile dysfunction correlated with AF duration, and following cardioversion required at least 3-4 weeks or more for full recovery of systolic atrial function [114, 115]. The mechanisms of postfibril-lation atrial dysfunction (stunning) are not clearly elucidated. Pre-viously it was thought to be the result of electrical cardioversion [116], but later similar stunning was found after pharmacological or even spontaneous conversion of AF [117, 118]. Both experimental and clinical studies revealed that verapamil pre-treatment prevented in short time paroxysmal AF the atrial systolic dysfunction dura-tion, leading to the conclusion that Ca

2+ overload may be the cause

of post-conversion stunning [119, 120]. In a six-week atrial tachy-cardia model the downregulation of L-type Ca

2+ channels was re-

ported, with significant changes in Ca2+

transients and cell contrac-tility [51, 54]. Since ICaL is the main factor for Ca

2+ release from the

SR, it was concluded that the downregulation of ICaL was the main pathogenetic factor for AF induced contractile remodeling. In summary, the loss of atrial myocardial contractility is mainly due to ICaL reduction and impaired Ca

2+-homeostasis. In addition, de-

creased contractility leads to atrial dilation, thereby “electrical and contractile remodeling go hand in hand” [4].

6.1. Relation between Electrical, Contractile, and Structural

Remodeling

The rapid electrical and contractile remodeling occur within minutes to hours, while exist a long time electrical and contractile remodeling that develops on a time scale of days or weeks [4]. However, both electrical and contractile remodeling are fully re-versible after conversion to AF. Conversely, the development of structural remodeling is a much slower process; however, it may cause irreversible morphological alterations within 3-4 months. Primarily (micro)fibrosis and left atrial dilation are the changes that will hamper the pharmacological conversion of AF and/or the main-tenance of SR. Fig. (7) presents three cascade processes of electri-cal, contractile and structural remodeling [13].

7. THE PREVENTION AND THERAPY OF ATRIAL

REMODELING

7.1. Therapeutic Principles, Treatment Options

7.1.1. Restoration of Sinus Rhythm Versus Rate Control

By intuition, restoration of normal sinus rhythm, i.e. rhythm control, would be the optimal therapeutic goal in atrial fibrillation. Whilst rhythm control usually requires a combination of pharma-cological and non-pharmacological treatments, rate control involves other mechanisms including prolongation of atrioventricular nodal refractoriness, slowing of AV node conduction. This can be achieved by several classes of antiarrhythmic drugs, including -blockers, calcium channel blockers or amiodarone [121]. However, Van Gelder in a recent paper reported no benefit in outcome when

Fig. (7). Three proposed positive feedback-loops of atrial remodelling in AF. The main cause for electric and contractile remodelling is the downregulation of

L-type Ca2+-channels. Stretch of the atrial myocardium, which is the result of loss of contractility and increase in compliance of the fibrillating atria, is hy-

pothesized to act as a stimulus for structural remodeling of the atria. The resulting electro-anatomical substrate of AF consists of enlarged atria allowing intra-

atrial circuits of small size, due to a reduction in wavelength (shortening of refractoriness and slowing of conduction) and increased non-uniform tissue anisot-

ropy (zig-zag conduction). From Ref [13], with permission.

3684 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Jost et al.

strict rate control defined as resting heart rate below 85 beats per minute (bpm) was compared with more lenient control where rest-ing rates could be between 90-100 bpm [122].

7.1.2. Removal of Ectopic Triggers and Disruption of Re-Entry

Suppression of hyper-excitability of pulmonary veins or atrial tissue can terminate AF by eliminating ectopic triggers and hence support rhythm control. Classical antiarrhythmic drugs used to reach this goal include Na

+ channel blockers or multiple ion chan-

nel blockers such as amiodarone [108]. According to the leading wavelet concept [18, 23, 24], short refractoriness and slow conduc-tion will increase the likelihood of re-entry. Theoretically, the re-entry circuits can be interrupted when conduction is enhanced and refractoriness prolonged so that the re-entrant wavefront will reach tissue that is still in the refractory state. Available antiarrhythmic drugs can prolong refractoriness but will slow instead of enhancing 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.

7.2. Novel Pharmacological Drugs/Compounds Combating for

the Treatment AF

Currently available antiarrhythmic drugs approved for the treatment of AF are far from being ideal, and impose serious con-cerns regarding efficacy and safety. An ideal drug against AF should suppress atrial triggers and disrupt atrial re-entry circuits by prolonging atrial refractoriness and slowing intra-atrial conduction; its atrial selectivity should minimize its ventricular proarrhythmic effects. This is called the atrial selective drug concept, i.e. drugs that affect currents abundant in the atria but not, or rarely present in the ventricles. Moreover, new drugs 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, pref-erably in an atrial-selective manner, and they can be directed at non-ion channel targets including upstream inflammatory or infil-trative processes or they may influence gap-junctions (the latter is considered the most modern pharmacological therapeutic approach of AF) (Fig. (8)).

7.3. Specific and Multiple Ion Channel Blocker Drugs

Numerous class III or repolarization-delaying compounds have been partly developed and then abandoned, largely because of the

risk of torsades de pointes brought about by their detrimental ef-fects on ventricular repolarization.

Azimilide (Procter & Gamble, specific IKr and IKs blocker, Fig. (9)). The drug was designed having typical Class III antiarrhythmic effects as a result of Sanguinetti’s hypothesis, which presumed that IKs blockers would be devoid of reverse rate dependency. Azimilide blocks both IKr and IKs currents and it is expected to be particularly effective during high rates associated with AF compared to pure IKr blockers, since during rapid heart rates, the contribution of IKr to repolarization is functionally diminished because of the enhanced contribution of other currents, such as IKs, which accumulate at faster rates as a result of incomplete deactivation [Sanguinetti’s hypothesis, 123]. Azimilide, however, also exerts calcium and use-dependent sodium channel block like amiodarone [124, 125].

Although initial studies in AF were encouraging [126, 127], later post-cardioversion maintenance of sinus rhythm studies and maintenance programmes showed less impressive results, moreo-ver, several opinion leaders doubt that azimilide will become avail-able for treatment of AF [128]. The ALIVE (AzimiLide Post-Infarct SurviVal Evaluation) trial of 3717 patients with recent myo-cardial infarction and left ventricular dysfunction has found a neu-tral effect of azimilide on all-cause mortality, including patients with a significantly reduced ejection fraction. Fewer patients who started the trial in sinus rhythm developed AF on azimilide and there was a trend to higher pharmacological conversion rates in the azimilide arm than in the placebo arm (26.8 vs. 10.8%) [129]. Sev-eral studies in patients with persistent AF, A-STAR (Supraventricu-lar TachyArrhythmia Reduction), and A-COMET I and II (Car-diOversion MaintEnance Trial) have failed to show any antiar-rhythmic benefit of azimilide and some unveiled a torsadogenic potential [130]. The marginal efficacy, which was restricted to pa-tients with structural heart disease seen with azimilide, is a limita-tion and hence it is doubtful that azimilide will claim a place for the treatment of AF.

IKs blockers (HMR-1556, Fig. (9)). As mentioned before, San-guinetti’s hypothesis [123] turned the attention of the pharmaceuti-cal industry to IKs blockers. Due to the lack of selective IKs block-ers, the anti-arrhythmic potential of IKs inhibition could not be in-vestigated for a long time. A chromanol derivative agent, HMR1556, is perhaps the only selective IKs blocker whose effects have been studied in atrial preparations and in animal models of AF. HMR1556 has 1000-fold selectivity for IKs over IKr, but at higher concentration also inhibits Ito, the sustained outward current Isus, and ICaL currents [131]. In a canine model of vagal AF,

Fig. (8). Current prominent investigational strategies for rhythm control of AF.

Pharmacological strategies g

for AF treatment

Improvement of current antiarrhythmic Atrial selective

therapeutic agents

Upstream therapyagents Gap junction therapyagents

Multi-channel blockersAmiodarone derivates

therapeutic agents

IKurIKACh

IN , IK ?

g

Drugs affecting structural remodelling,

inflammation, Hypertrophy, i i

Gap junction therapy

Antiarrhythmic peptides affecting Cx40 and Cx43

etc. INa, IKr ? oxidative stress, etc.

Atrial Remodelling and Therapy of AF Current Medicinal Chemistry, 2011 Vol. 18, No. 24 3685

HMR1556 prolonged the atrial effective refractory period and ex-erted a modest effect on the duration of induced AF only in the presence of intact -adrenergic stimulation [132]. Intuitively, with rapidly receding interest to IKr blockers because of the modest effi-cacy and the significant proarrhythmic potential, the role of IKs inhibitors in pharmacological management of AF is also question-able. Moreover, under certain conditions, such as in long QT syn-drome 1 and in other circumstances where repolarization reserve is compromised, IKs blockade may be arrhythmogenic [133].

O

OF3C OH

NS

O

O

HMR-1556

Cl

O

N N

N

O

O

N

NAzimilide

CN

O

OH

N O N

NH

O

O

AZD7009

O

NH

S OO

O

O

N

Dronedarone

N

N

Tedisamil

Fig. (9). Chemical structures of of several specific and multiple ion channel

blocker drugs.

AZD7009 (IKr and INa blocker, Fig. (9)). The pharmacological profile of the new Astra-Zeneca compound AZD7009 includes a combined block of IKr (IC50=0.6 μM) and rate-dependent block of

INa with an IC50 4.3 μM at 10 Hz. The compound also blocks other repolarizing currents such as Ito, IKur and IKs, however, only at higher concentrations [134, 135]. In dog atria, AZD7009 concentra-tion-dependently reduced Vmax and increased APD. The ERP was increased through APD lengthening and post-repolarization refrac-toriness. The suppression of Vmax, but not APD prolongation, showed frequency-dependence [136]. In dilated rabbit atria, AZD7009 concentration-dependently increased AERP, effectively prevented AF induction, and rapidly restored sinus rhythm [137]. Several clinical trials demonstrated that favourable ion channel blocker profile of AZD7009 is successful in fast and effective SR conversion in persistent atrial fibrillation [138].

The undoubted success of amiodarone indicated that a properly chosen combination of block of different ion channels may produce the most favourable electrophysiological profile. Therefore, several new compounds and drugs with combined effects on different ion channels have recently been developed for the treatment of AF.

Dronedarone (Fig. (9)). Dronedarone is a novel drug by Sanofi-Aventis. The starting point for the molecule was amiodar-one, but dronedarone lacks the iodine groups that are considered to be responsible for the pulmonary, thyroid, hepatic and ocular toxic-ity of amiodarone [139]. The acute and chronic electrophysiological effects of dronedarone are similar to those of amiodarone, although dronedarone appears to be more potent in preclinical studies [140, 141]. In dog ventricular myocardium, dronedarone frequency-dependently reduces maximum upstroke velocity, and blocks ICa,L and IKr [139]. Due to these promising early preclinical results the antiarrhythmic potential of dronedarone has been extensively stud-ied. Several clinical trials (including ADONIS and EURIDIS) showed superiority of dronedarone over placebo, moreover dronedarone did not significantly prolong the QT interval and probably has a low potential for causing torsades de pointes [142, 143]. A phase III randomised trial, ATHENA showed encouraging results. Dronedarone significantly prolonged time to first cardio-vascular hospitalization or death from any cause (the composite primary endpoint) by 24% compared to placebo. This effect was driven by the reduction in cardiovascular hospitalizations (25%), particularly hospitalizations for AF (37%). All-cause mortality was similar in the dronedarone and placebo groups (5% and 6%, respec-tively; hazard ratio 0.84, 95% CI, 0.66–1.08, p = 0.176); however, dronedarone has lowered mortality (significantly reduced the num-ber of deaths from cardiovascular causes) despite being ineffective in terms of rhythm restoration opening a discussion about the mode of action. [144]. However, it should be emphasized that dronedar-one is not a new golden standard, and its antiarrhythmic potential is not undoubtedly superior in comparison with that of amiodarone [145, 146]. Based largely on the ATHENA trial, the United States Food and Drug Administration (FDA) approved dronedarone for the prevention of hospitalizations due to recurrent AF, a secondary endpoint. This is an unusual approval label and normally not al-lowed by the FDA. It also does not allow the drug to be marketed as a primary anti-AF agent [144]. However, the enthusiastic use of dronedarone is overshadowed by some recent cases of near fatal liver toxicity making immediate liver transplantation necessary [147].

Tedisamil (Solvay Pharma, Fig. (9)). Tedisamil is a heterocyc-lic compound that was originally developed as an anti-ischemic and bradycardic drug. It is a non-selective blocker of several cardiac K

+

currents (Ito, IKur, IKr, IKs and IKATP) and produces a negative chro-notropic effect by increasing gap junction conductance and conduc-tion velocity, which may prevent fast ventricular rates during AF recurrence [148-150]. Unlike selective IKr blockers, tedisamil is devoid of reverse use-dependency with respect to atrial refractori-ness. In a dose-efficacy study in 175 patients with little structural heart disease and recent-onset AF, tedisamil (0.4 and 0.6 mg/kg) restored sinus rhythm in 41 and 51% of the patients, respectively, compared with 7% in the placebo group. Due to this modest effi-

3686 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Jost et al.

cacy and high proarrhythmic risk (two patients developed ventricu-lar tachycardia), tedisamil is unlikely to be a useful remedy for AF, and it has not been approved by the FDA.

7.4. Atrial Selective Ion Channel Blocker Drugs

A novel strategy for development of agents against AF in order to avoid ventricular proarrhythmic effects is the development of so-called atrial selective drugs. This concept exploits the electrophysi-ological differences as well as differences in expression patterns of ion channels between atrial and ventricular myocytes. A great deal of effort has been invested into the development of atrial specific ion channel blockers to avoid ventricular arrhythmogenic effects of currently available drugs. Atrial specific targets for AF treatment include the ultra-rapid delayed rectified potassium current (IKur), the acetylcholine-regulated inward rectifying potassium current (IK,ACh), the constitutively active IK,ACh (i.e., which does not require acetylcholine or muscarinic receptors for activation), and connexin 40 (Cx40). The channels responsible for IKur and IK,ACh are exclu-sively or nearly exclusively present in atria and largely absent in the ventricles and these channels are commonly referred to as atrial specific. In addition to atrial specific ion channels, there are ion channels that are present in both chambers of the heart but the inhi-bition of these channels can produce predominant electrophysi-ological changes in atria vs. ventricles. These atrial selective or predominant targets, include sodium channels responsible for fast INa and, perhaps, channels underlying IKr. Note that atrial predomi-nant targets represent a lesser degree of atrial selectivity.

7.4.1. IKur Blockers

“IKur block for AF therapy” is the most investigated strategy among the atrial-specific approaches. The ultra-rapidly activating, delayed outward rectifier current IKur has been considered to be an extremely useful drug target because blockers of IKur prolong the ERP in atria only without significantly affecting ventricular ERP and without prolonging the QT interval. Therefore, a large number of compounds intended for selective IKur block (such as AVE0118, AVE1231, S9947, S20951, ISQ-1, DPO-1, vernakalant; AZD7009; NIP-141, NIP-142, acacetin) has been synthesised in the past dec-ade. These investigational agents are also known as atrial repolari-zation-delaying agents (ARDAs). 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) [151]. Low con-centrations of 4-AP that selectively block IKur elevate the plateau of human atrial AP, but produce opposite effects on atrial APD de-pending on the patients’ history of supraventricular arrhythmia, with shortening of APD and ERP in trabeculae from patients in SR but prolongation of these parameters in AF [100]. However, the potential efficacy of highly selective IKur blocking agents has yet to be demonstrated. There are concerns that isolated IKur blockade may not be sufficient for the prolongation of the AERP because the IKur current is responsible predominantly for the early repolarization phase I and contributes less to the plateau phase 2. Furthermore, IKur block may move the plateau to a more positive potential which in turn may activate the IKr current and accelerate phase 3 late repo-larization, thus abbreviating the action potential [100, 152].

AVE0118 (Sanofi-Aventis, Fig. (10)). 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) [153, 154]. Like

other IKur blockers, AVE0118 shortens APD and ERP in atrial tra-beculae from patients in SR whereas it prolongs APD and ERP in

AF [100, 152]. Animal studies have demonstrated the ability of AVE0118 to prolong the atrial effective refractory period and con-

vert AF to SR in a goat model with little effect on ventricular re-fractoriness and the QT interval. The greatest effect on atrial refrac-

toriness appeared to be confined to the left atrium, but was less

pronounced in the right atrium. In normal goat atria, AVE0118 similar to that of dofetilide showed a clear rate dependent effect on

atrial refractoriness. However, in remodelled atria after 48 h of continuous AF, AVE0118 unlike dofetilide, prolonged the AERP to

a pre-remodelled level and prevented induction of AF in two-thirds of experiments [155]. No clinical studies with AVE0118 have been

reported and its development has probably been terminated.

XEN-D0101 (Xention, chemical structure not disclosed). XEN-D0101 is highly selective for the Kv1.5 channels over non-target

ion channels [156]. In dogs with acute and chronic AF induced by rapid atrial pacing, XEN-D0101 selectively prolonged the atrial

effective refractory period and decreased the duration of AF [157, 158]. Clinical studies with this compound to maintain sinus rhythm

after cardioversion in patients with persistent AF are under way.

DPO-1 (Diphenylphosphine oxide, Fig. (10)). 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 fre-quency; IC50 of 30 nM at 3.0 Hz, and with the same IC50 for ex-

pressed channels. Selectivity of block is high, since no block of Ito

is detectable with concentrations as high as 1.0 μM. Like 4-AP,

DPO-1 produces plateau elevation and shortening (in SR) and pro-longation (in AF) of APD in human atrial tissue, and has no meas-

urable effects on human ventricular action potentials [159]. In simi-lar studies, DPO-1 terminated atrial flutter in non-human primates

and increased the AERP by 13-15% at a mean intravenous dose of 5.5+2 mg/kg.

Vernakalant (RSD1235, Cardiome and Astellas, Fig. (10)) is

in the most advanced phase of investigation and its intravenous formulation has recently been recommended for approval for phar-

macological cardioversion of AF. Although IKur current is the main target of the drug, its mechanism of action involves blockade of

several ion channels including Ito, and INa, but there is little impact on IKr or IKs currents. Vernakalant produces a strong, positive fre-

quency-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, and even higher for Ito [160]. Therefore, vernakalant, al-

though referred to as an ARDA, is in fact a multi-channel blocker. Vernakalant slows conduction velocity within the atrium and pro-

longs its recovery [161]. Because the INa blockade has fast offset kinetics, vernakalant is not likely to cause conduction disturbances

and proarrhythmias at low heart rates. Na+ channel block by verna-

kalant is enhanced at high heart rates and in depolarised tissue, due

to rate and voltage-dependent block [161]. Vernakalant has been extensively investigated in several clinical trials. In a recent phase

III study (AVRO), vernakalant demonstrated superior efficacy to amiodarone for acute conversion of recent-onset AF [162]. Verna-

kalant was recently approved by the FDA for intravenous conver-sion of AF.

7.4.2. Sodium Channel Blockers

Class IA antiarrhythmic drugs have long been recognized to display preferential binding to open (activated) or closed (inacti-

vated; resting) states of the Na+-channel (“modulated receptor hy-

pothesis”) [163]. Atrial selectivity of Na+ channel blockers is due to

the slightly more depolarized resting membrane potential and a more negative potential for half-maximum inactivation of INa in

atrial compared to ventricular cardiomyocytes. Since recovery from inactivation depends on membrane potential, fewer Na

+ channels

recover during diastole in the atria than in the ventricles, conse-quently Na

+ channel blockers that bind preferentially to the inacti-

vated channel state and also have a fast dissociation rate will exhibit atrial selectivity and larger Na

+ channel block in the atria than in

the ventricles [164, 165]. Last but not least, atrial-selectivity may

Atrial Remodelling and Therapy of AF Current Medicinal Chemistry, 2011 Vol. 18, No. 24 3687

evolve due to disease-specific processes, for instance high atrial rate or remodeling processes.

Ranolazine (Fig. (10)). Ranolazine was initially developed as an antianginal drug, however, it was soon recognized to suppress ventricular EADs and to reduce transmural dispersion of APD [166]. At the ion channel level, ranolazine blocks IKr and IKs, and possibly also L-type ICa and especially late INa [166, 167]. By pref-erentially inhibiting the late INa current, ranolazine has been shown in isolated hearts and animal models to reduce intracellular sodium and calcium overload caused by ischaemia and to suppress early afterdepolarizations. At therapeutical concentrations (2–6 mmol/L), ranolazine also affects IKr (50% inhibition at 12 mmol/L) and can potentially prolong the action potential, but this effect is offset by more potent late INa blockade. However, it still a question of debate, whether late sodium channel blockade may be effective or not in suppressing atrial fibrillation [168]. In isolated canine ventricular myocytes and wedge preparations, ranolazine prolonged the action potential duration of the epicardial layer due to its predominant IKr- blocking effects, but shortened the action potential duration of M cells due to predominant INa blockade and reduced another proar-rhythmic substrate - transmural dispersion of repolarization [169]. Recent experiments in canine isolated perfused atrial and ventricu-lar preparations have suggested that sodium channel characteristics

may differ between atrial and ventricular cells and that ranolazine shows greater affinity to sodium channels in the atria than to those in the ventricles [166]. The net effect and clinical consequence of multiple channel blockade by ranolazine is a modest increase in the mean QT interval by 2–6 ms [170].

7.4.3. Atrial Acetylcholine-Regulated Potassium Current (IK,ACh)

Inhibitors

Block of another atrial-selective current, the acetylcholine acti-vated inwardly rectifying K

+ current, IK,ACh is expected to prove

useful in vagally induced atrial fibrillation. Activation of IK,ACh by vagal stimulation shortens atrial refractoriness and increases Na

+

channel availability thereby creating a substrate for re-entry through dispersion of atrial repolarisation and stabilisation of high fre-quency rotors, which promotes the duration of AF episodes [171]. Vagal activity can contribute to the initiation of paroxysmal AF [172, 173] and thus blocking parasympathetic activity could help maintain sinus rhythm in these patients. The latter hypothesis is sustained by the observation that knockout mice lacking IK,ACh channels are resistant to acetylcholine induced AF [174], blocking IK,ACh may be a promising therapeutic strategy. IK,ACh block with tertiapin Q prolongs atrial APD and suppresses AF in experimental models [27, 83].

MeO

NH

O

HN

ON

AVE0118

P

O

DPO-1

N

O

OH

MeO

MeO

Vernakalant

HN

O

N

N

OH

O

OMe

Ranolazine

O

HN

OMeO

OH

HN

O2N

NIP142

O2N

O

S NH

NH2

KBR7943

O

O

NH2

OEt

F

F

SEA0400

Ala-Leu-Cys-Asn-Cys-Asn-Arg-Ile-Ile-Ile-Pro

His-Gln-Cys-Trp-Lys-Lys-Cys-Gly-Lys-Lys-NH2

Tertiapin Q

Fig. (10). Chemical structures of several atrial selective ion channel blocker drugs

3688 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Jost et al.

NIP-142 (Fig. (10)) and NIP-151 (chemical structure not dis-closed). The benzopyrane derivative NIP-142 is a selective blocker of IK,ACh that prevents acetylcholine-induced action potential short-ening [175]. The congener NIP-151 is even more potent and more selective than its parent compound. In dogs, NIP-151 significantly prolongs atrial but not ventricular ERP, and successfully terminates vagally- and aconitine induced AF [84].

7.4.4. Constitutively Active IK,ACh Channels (CI-IK,ACh)

Recently it was shown that in atrial tachyarrhythmia induced permanent AF, via a not fully elucidated signal-transduction mechanism [176], the IK,ACh channels are constitutively open and active without any direct ligand stimulation [53, 177]. Therefore it was hypothesised that in permanent AF constitutively active IK,ACh may contribute to APD abbreviation and triangularization, and

Fig. (11). Panel A. Original recordings of the acetylcholine sensitive potassium current (IK,ACh) activated by ramp protocols in myocytes isolated from dogs in

sinus rhythm (SR, left panels) and from tachypaced atrial fibrillating dogs (ATR, right panels) measured by patch-clamp technique at 37°C. IK,ACh was acti-

vated with cholinergic agonist carbachol (CCh) and blocked by selective IK,ACh blocker tertiapin Q. In SR could not be observed tertapin Q sensitive current

without initial cholinerg activation (not shown). In SR, CCh activated a large current either at inward or outward directions (left panels). Tertiapin Q (10 nM, a

concentration close to reported EC50, 53) blocked the CCh induced current by 57%. In ATR cells a constitutively active IK,ACh was present, which could be

blocked by 26% with 10 nM tertiapin (middle panels). However, in ATR atrial myocytes, CCh could also activate an additional and significant ligand-

dependent and tertiapin sensitive IK,ACh current (right panels). Bars represent average current levels measured at -100 mV voltage level. The inset shows the

applied voltage protocol. Panel B. Representative ECG recording of AF induced by a 10-second long 800/min frequency atrial burst in a conscious ATR dog in

control conditions and following intravenous tertiapin Q administration. Tertiapin at low concentrations fully prevented burst-induced AF in ATR dogs and in-

creased right atrial effective refractory period. Unpublished results from the present authors partially presented as meeting abstract Refs. [174,175].

Tertiapin Q

ControlAF

End of 800/min 10 sec burst

End of 800/min 10 sec burstP wave

Tertiapin 0.86 - 2.59 - 7.76 - 23.3 nM/kg; i.v.

<80 ms 80 ms 90 ms 100 ms 110 ms

Control 0.86 2.59 7.76 23.3 nM/kg

Atrial effective refractory period (AERP)

C 0.86 C C2.59 7.76 23.3

0

20

40

60

80

100

Inci

den

ce o

f A

F (

%)

B

A

Atrial Remodelling and Therapy of AF Current Medicinal Chemistry, 2011 Vol. 18, No. 24 3689

thereby to enhancing the re-entry susceptibility of the atria. Conse-quently, selective blockade of constitutively active IK,ACh current may have antiarrhythmic/antifibrillatory effects [53, 82]. Direct test of this hypothesis is not possible since at present, there are no avail-able drugs that selectively block CI-IK,ACh.

However, it must be emphasized that when we analyse the available data more carefully, this CI_IK,Ach current in the outward direction does not seem to be large enough to have substantial con-tribution to AERP shortening and to abbreviation of APD on its own [27, 53]. However, here we propose the following new con-cept. In normal conditions in vivo a background parasympathetic tone is always present, consequently it is probable that a vagally stimulated IK,ACh exists in atrial myocytes. In addition, the CI-IK,ACh can also be activated in permanent AF.

We hypothesize that the ligand dependent and independent IK,ACh together may be so large that indeed they may contribute to AERP/APD shortening, consequently blockade of this combined current may prevent AF. In this regard, in recent experiments we demonstrated that in atrial canine myocytes isolated from ATR dogs, either in inward but also in outward directions a substantial constitutive and ligand dependent IK,ACh also exists (Fig. (11)). Se-lective blockade of combined IK,ACh current with low concentrations of Tertiapin Q (chemical structure in Fig. (10)) successfully pre-vented burst-induced AF in conscious ATR dogs (Fig. (11)) [178, 179]. However, further investigations are required to test this hy-pothesis.

7.5. NCX Modulators

The Na+/Ca

2+ exchanger current (NCX) exchanges one intracel-

lular Ca2+

ion for three extracellular sodium ions. During rapid atrial rates caused by AF or pacing, a larger increase in intracellular sodium relative to calcium may cause the bidirectional exchanger to work in the reverse mode, bringing calcium into the cell, thus con-tributing to the shortening of the action potential. Since DADs elic-ited by NCX1 activity can trigger AF, block of the exchanger has been proposed as a useful antiarrhythmic mechanism. However, reducing NCX1 activity may be a double edged sword, unless drugs exhibit selectivity for the reverse mode. Blocking NCX1 in its re-verse mode during the initial phase of the action potential will re-duce Ca

2+ entry and reduce the proarrhythmic propensity of cellular

Ca2+

load. On the other hand, inhibition of the exchanger in the for-ward mode at resting membrane potential will suppress Ca

2+ extrusion

and thereby directly remove the electrogenic transport mechanism that causes proarrhythmic DADs, however, this takes place only at the ex-pense of worsening Ca

2+ overload.

KB-R7943 (Kanebo, Fig. (10)) preferentially inhibits the re-verse mode of the NCX. The underlying molecular mechanism for this directional specificity is not fully understood, however, KB-R7943 appears to block calcium influx irrespective of the presence or absence of extracellular calcium. The drug also blocks multiple sodium, potassium and calcium channels (Ito, IK, IK1, INa, and ICaL), and has been found to prolong the ventricular effective refractory periods [180]. In anaesthetized dogs, KB-R7943 prevented AERP shortening caused by pacing-induced AF [181].

SEA0400 (Taisho Pharmaceutical, Fig. (10)) is another NCX inhibitor which is more selective and potent than KB-R7943. In a recent study using SEA0400 it was found that NCX current was upregulated in human AF compared to SR [70]. Block of NCX by SEA0400 did not affect basal contractility or inotropic interven-tions, thereby challenging the concept that NCX regulates intracel-lular Ca

2+ in a manner relevant for contractility under steady-sate

conditions [180, 182]. Further work is needed to investigate whether the relevance of human atrial NCX is relevant for electrical stability in EC-coupling related phenomena [183]. Although the suppression of ectopic automaticity in pulmonary veins could also be due to block of Ca

2+ or Na

+ channels, the real benefit of suppression

of atrial NCX channels to prevent AF can be investigated only with NCX inhibitors more selective than KB-R7943 or SEA0400.

7.6. Gap Junction Modulators

Electrophysiological and structural remodeling of the fibrillat-ing atria involves changes in junctions at the atrial intercalated discs: fascia adherens, the desmosomes, and gap junctions and their proteins (N-cadherin, desmoplakin, and connexins). Two major isoforms of connexins with a molecular weight of 40 and 43 kDa are specific for the cardiac tissue, with connexin 40 predominantly expressed in the atrial myocardium and the conduction system. In addition, connexin 45 is also found in conductive tissue [31]. There are several studies that investigated the function of gap junctions during early acute ischemia (after 15-24 minutes of coronary artery occlusion), which provided evidence suggesting that closing of gap junctions causes conduction velocity slowing, which occurs in fi-brillating/ischemic atria [30, 184]. In acute myocardial ischemia there are several factors, including macroerg phosphate depletion, cellular acidosis, arrhythmogenic/cardiodepressing lipid accumula-tion (free fatty acids, diacyl-glycerol, lisophosphoglycerides, car-nitine-esters) that cause the closing of the gap-junctions [31]. Based on these observations, several peptides have been developed, which prevent gap junction closing, consequently offering an antiarrhyth-mic, protective effect against AF.

Rotigaptide (GAP-486, ZP123, Fig. (12)) was developed on the basis of the original AAP structure with d-isomers substituted for l-isomers and is currently under investigation. Rotigaptide in the setting of acute coronary artery occlusion induced myocardial ischaemia, probably due to keeping the gap junctions in an open state, attenuated conduction velocity slowing and ventricular ar-rhythmogenesis, but did not have effects on gap junction conduc-tion under physiological (without metabolic stress) conditions [185].

In dog models of acute myocardial ischaemia and mitral insuf-ficiency, rotigaptide prevented induction of AF by preventing slow-ing of conduction, but had no effect on AF promotion in dogs sub-jected to atrial or ventricular tachypacing [186].

GAP 134 (Fig. (12)) was designed to reduce atrial conduction velocity. In acute animal experiments it proved to be effective, however, in permanent AF had neither antifibrillatory nor AP pro-longing potential [187].

The electrophysiological effects of gap junction modulators, in situations when connexins are redistributed but their expression and function remain unaltered, have not been explored.

7.7. Other Possible Ion Channel Targets for Novel Antiar-

rhythmic Drugs

There are several attempts for targeting many other ion chan-nels modulation including two pore-domain potassium channels [K2P, 188], transient receptor channels [TRP, 189], mechanosensi-tive, stretch activated cannels [190], calcium activated K+

-channels etc. There are no or very few promising results suggesting modula-tors of these channels have beneficial effects in preventing AF.

7.8. Non ion-Channel Blockers - Upstream Therapy of AF

In addition to further developing ion channel based AF therapy, there is rapid development of non ion-channel approaches, aimed at reducing or reversing structural remodeling, inflammation, and oxidative stress injury associated with AF. These are generally referred to as “upstream therapies” [103, 191].

It has been known for some time that inflammation and oxida-tive injury promote structural remodeling, including interstitial fibrosis, fibroblast proliferation, accumulation and/or redistribution of collagen, chamber dilation, and hypertrophy. Proarrhythmic

3690 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Jost et al.

actions of atrial structural remodeling are generally related to con-duction disturbances, which promote re-entrant arrhythmias. A number of experimental and clinical studies have shown that drugs affecting structural remodeling, inflammation, and/or oxidative stress such as angiotensin-converting enzyme inhibitors, angio-tensin II receptor blockers, and statins may reduce the occurrence of AF [191-193], although some studies question the efficacy of such therapies in AF [194-196]. Successful development of “upstream therapy” depends on our ability to identify factors and signalling pathways involved in the generation of atrial structural remodeling, inflammation, and oxidative stress. A number of mediating factors have been identified such as angiotensin II, angiotensin II receptors, transforming growth factor- 1 (TGF- 1), mitogen-activated protein kinase (MAPK), platelet-derived growth factor (PDGF), perox-isome proliferator-activated receptor- (PPAR- ), Janus kinase (JAK), Rac1, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, signal transducers and activators of transcrip-tion (STAT), and calcineurin with Ang II and its angiotensin II type 1 (AT1) receptor being critically involved in the initiation of the signalling cascades involved [108, 191]. The relative roles of these mediating factors in structural remodeling, inflammation, and oxi-dative stress are poorly understood. Moreover, the relative role of structural remodeling, inflammation, and oxidative stress in devel-opment of AF is still not fully understood and varies significantly among different AF pathologies [110-113, 197].

8. CONCLUSIONS

Considerable progress has been made in understanding the mechanisms underlying atrial remodeling. These insights have po-tentially important implications for our understanding of the patho-physiology of AF and for the development of new therapeutic ap-proaches. Ongoing research aimed at the development of novel pharmacological strategies for the management of AF includes both ion channel and non ion-channel mediated approaches to therapy. Current pharmacological treatment to prevent, suppress or protect against AF are far from ideal. However, while success to date has been modest, the recent identification of atrial- and pathology-selective targets and compounds selectively modulating them hold promise for the development of effective new treatment modalities. New antiarrhythmic drugs targeting multiple ion channels or having a high affinity to the atrial myocardium are believed to have a more favourable risk/benefit ratio than traditional antiarrhythmic drugs. Agents that can prevent or reverse the AF or underlying disease induced remodeling process in atrial myocardium may play a cru-cial role in preventing or reducing the recurrence of AF. Extensive studies utilizing a wide range of such agents are currently underway with potentially promising results.

ACKNOWLEDGEMENTS

Supported by grants from the Hungarian Scientific Research Fund (OTKA CNK-77855, K-82079), Hungarian Ministry of

Health (ETT 302-03/2009 and 306-03/2009), the National Office for Research and Technology –Ányos Jedlik and Baross Pro-grammes (NKFP_07_01-RYT07_AF and REG-DA-09-2-2009-0115-NCXINHIB), European Community (EU FP7 grant ICT-2008-224381, preDiCT), the National Development Agency co-financed by the European Regional Fund (TÁMOP-4.2.2.-08/1-2008-0013 and TÁMOP-4.2.1/B-09/1/KONV-2010-0005), the Hungarian Academy of Sciences, and the János Bolyai Research Scholarship (N.J. and I.B).

ABBREVIATIONS

AF = atrial fibrillation

AFlu = atrial flutter

APD = action potential duration

AERP = atrial effective refractory period

ACh = acetylcholine

ATR = atrial tachypaced remodeling

ARDA = atrial repolarization-delaying agents

CV = conduction velocity

DAD = delayed afterdepolarization

EAD = early afterdepolarization

ERP = effective refractory period

ES = extra systole

MAP = monophasic action potential

RAAS = renin-angiotensin-aldosterone system

RyR = ryanodine receptor

SR = sinus rhythm

VT/VF = ventricular tachycardia/ventricular fibrillation

WL = wavelength

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N

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Received: April 16, 2011 Revised: July 09, 2011 Accepted: July 11, 2011