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Cardiovascular Research 2002 54(2):259-269; doi:10.1016/S0008-6363(01)00529-6
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Cellular electrophysiology of atrial fibrillation

Ralph F Boscha,* and Stanley Nattelb,c,d

aDepartment of Cardiology, University of Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
bResearch Center and Department of Medicine, Montreal Heart Institute, Montreal, QC, Canada
cDepartment of Medicine, University of Montreal, Montreal, QC, Canada
dDepartment of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada

* Corresponding author. Tel.: +49-7071-298-3196; fax: +49-7071-294-121 ralph.bosch{at}uni-tuebingen.de

Received 28 August 2001; accepted 29 October 2001

KEYWORDS Arrhythmia (mechanisms); Ion channels; Membrane currents; Remodeling; Supraventr. arrhythmia


   1. Introduction
Top
 1. Introduction
2. How can cellular...
 3. Cellular and molecular...
 4. Functional consequences and...
 5. Conclusions
 References
 
Atrial fibrillation (AF) is presently the most common cardiac arrhythmia in clinical practice. Its treatment is inadequate. Maintenance of normal sinus rhythm (SR) is obviously the optimal approach, but is difficult to achieve without drugs that have the potential to cause ventricular proarrhythmia and increase mortality. Non-pharmacological therapy is attractive, but to date has not reached the same level of efficacy as in the treatment of arrhythmias other than AF. In order to improve therapeutic approaches, it is important to understand the detailed pathophysiology of the arrhythmia. A key component to the pathophysiology of any cardiac arrhythmia is the cellular milieu in which it occurs. Changes in ion transport processes, including pumps, channels and exchangers, are central to alterations in action potential properties that govern the occurrence of arrhythmias like AF. Action potential duration (APD) determines the refractory period and is therefore a key determinant of the likelihood of reentry. Maximum Na+-current (INa) governs phase 0 upstroke velocity, determining conduction velocity (CV) and contributing to the likelihood of reentry. Delayed and early afterdepolarizations produce abnormal activity that can in themselves produce tachyarrhythmias and can trigger reentrant arrhythmia.

This paper reviews these aspects of the cellular electrophysiology of AF, attempting to summarize what is known, what remains to be explored and what this information can teach us about why AF occurs and how to treat it.


   2. How can cellular electrophysiology be altered to produce AF?
Top
 1. Introduction
 2. How can cellular...
3. Cellular and molecular...
 4. Functional consequences and...
 5. Conclusions
 References
 
The identification of the molecular structure of many ion channels involved in cardiac excitability and their functional correlation with native ionic currents have made it possible to study the effects of pathophysiological conditions, like AF, at different levels from genes to ionic currents. The different steps underlying the expression of an ion channel are depicted in Fig. 1 and have recently been reviewed by Roden and Kupershmidt [1]. A DNA sequence containing the genetic code for an ion channel subunit is transcribed into a pre-mRNA in the nucleus. This pre-mRNA is modified in different manners. The non-coding (intronic) sequences are excised, a process termed RNA splicing. Different splice variants have been described for several ion channels, including Kv4.3 (the pore-forming ({alpha}) subunit of the transient outward current, Ito), KvLQT1 (the {alpha}-subunit of the slow delayed-rectifier IKs) and HERG (the {alpha}-subunit of the rapid delayed-rectifier IKr) [2–5]. Single bases can be replaced during mRNA maturation by RNA editing enzymes, and RNA can be destabilized to control the rate of protein expression. The final mRNA product of this process is transferred out of the nucleus into the endoplasmic reticulum (ER) where it is translated into a protein in a polyribosome at a relatively constant rate. The nascent protein also undergoes a variety of modifications via a post-translational processing. The post-translational processing may take place in the ER and the Golgi complex, as well as during insertion of the protein into the cell membrane. Although our knowledge about post-translational modification has increased substantially over the past few years, the role of the various potential mechanisms for the control of ion channel expression, even under physiological conditions, is incompletely understood. Once the pore-forming {alpha}-subunits of the ion channels are processed and trafficked to the membrane, they can coassemble with auxillary subunits that can importantly change the biophysical or pharmacological properties of the channel, or can act as chaperones and direct membrane trafficking [6–10]. Finally, functional channels in the membrane underlie a variety of regulatory processes. Intrinsic and extrinsic agonists can alter channel function by direct binding to an ion channel linked receptor or by binding to a receptor that is coupled to an ion channel via a second messenger (e.g., G-protein) pathway. AF could modulate channel function by interacting with and/or altering any of the many steps governing ion channel expression and function, from DNA transcription through to agonist regulation of function.


Figure 1
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  		Fig. 1 The way from gene to a functional ion channel. The synthesis and assembly of ion channels includes many steps in which pathophysiological conditions, like AF, can modulate channel function. ([AF]) indicates processes which are known to be affected by AF or by predisposing clinical conditions, ([?]) depicts those known to be important for normal synthesis or function, but whose role in electrical remodeling is not known and ([G]) indicates G-proteins.

 
We are only beginning to understand the mechanisms by which AF-related electrical remodeling alters atrial electrophysiology. Yue et al. were the first to provide evidence that transcriptional downregulation of the channel {alpha}-subunit is an important contributor to the reduced current densities of ICa,L and of Ito in rapid atrial pacing (RAP) [11,12], findings subsequently confirmed in human AF [13,14]. Two groups have reported decreased Kv1.5 protein expression in patients with AF [15,16], whereas mRNA has been reported to be unchanged [14]. The reasons for the differences remain speculative at the moment. For some currents, like IK1, no data on mRNA or protein expression are available and for other channels, data from human AF suggest an alteration in ion channel mRNA and protein expression [15], while functional data are lacking due to technical limitations of patch clamp techniques. For a better understanding of the fundamentals of electrical remodeling, it is crucial to combine methods of in vivo and cellular electrophysiology, molecular biology, protein biochemistry and morphology as discussed below.


   3. Cellular and molecular electrophysiology of atrial fibrillation — experimental considerations
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 1. Introduction
 2. How can cellular...
 3. Cellular and molecular...
4. Functional consequences and...
 5. Conclusions
 References
 
The cellular and molecular basis of AF has been a field of enormous interest over the past few years and the results have substantially improved our understanding of the pathophysiology of the arrhythmia. The effects of atrial tachycardia-remodeling on ion currents and channels were investigated in several animal models and in human tissues. Data from animal models are very important, as they allow for the isolation of the specific condition(s) of interest. However, extrapolation of the findings to humans must be very cautious, and several limitations have to be taken into account. The expression of ion channels and pumps controlling impulse propagation and repolarization show significant interspecies variation, and even currents that display similar phenotypes may differ in biophysical properties and molecular basis [17–20]. Finally, experimental models may fail to replicate the complex pathophysiology of clinical forms of the disease, although the changes observed in most well-selected models and in human preparations correspond well in many aspects.

Studies in preparations obtained from patients undergoing cardiac surgery or from explanted hearts are therefore crucial. Findings in human preparations are limited by the fact that they always represent a combination of conditions that can hardly be controlled: concomitant cardiac and extracardiac diseases, abnormalities in ventricular function, variability in medications and variable age. Additionally, technical considerations, like extensive fibrosis in some preparations or limitations of the cell isolation procedure for patch clamp experiments [21] might influence the results. Optimal cell isolation is obtained from fresh tissues subjected immediately to coronary artery perfusion for delivery of enzymes for cell dissociation. Human tissue samples are often small and must be dissociated by the ‘chunk’ method, and significant time lapses may occur from the time of tissue excision until cell isolation. For the optimal definition of mechanisms, a synthesis of the results in animal models and in humans is essential.

3.1 Cellular abnormalities in conditions associated with AF
3.1.1 Congestive heart failure (CHF)
Conditions involving chronic atrial volume and/or pressure overload, such as CHF and mitral valve disease, are among the most common clinical causes of AF. In two models of chronic atrial enlargement associated with AF, Boyden et al. noted only minor changes in action potential morphology [22,23]. In Langendorff-perfused rabbit hearts, an acute increase in atrial pressure caused a marked shortening of atrial refractoriness and an increased susceptibility to AF [24,25]. Results in dogs have been variable: two studies showed that an acute increase in atrial pressure and stretch prolongs AERP and monophasic action potential duration [26,27] while another reported shortening of the AERP [28]. Data on the effects of acute dilatation in humans are also inconsistent [29,30]. In cats with cardiomyopathy and atrial tachyarrhythmias, dilated left atria displayed an increased percentage of inexcitable cells with low resting membrane potentials, as well as decreased phase 0 depolarization and reduced action potential amplitude [31]. In dilated atria, norepinephrine also caused abnormal automaticity and triggered activity due to delayed afterdepolarizations. Repolarization was not altered in the right atria and only moderately prolonged in the most dilated left atria. Recent studies of pacing-induced heart failure in dogs clearly demonstrated an association between congestive heart failure (CHF) and an increased susceptibility to AF [32]. In contrast to tachycardia-remodeling, CHF did not alter atrial ERP, ERP heterogeneity or overall conduction velocity. There was, however, a strong increase in heterogeneity of conduction, due to discrete regions of slow conduction, potentially creating conditions for microreentry. At the cellular level, CHF decreased the densities of ICa,L, Ito and IKs [33], and increased the Na+/Ca2+ exchanger (NCX) current and protein expression. The balanced changes in inward and outward currents may explain the relatively small APD changes in CHF, whereas the increased NCX may promote delayed afterdepolarization-induced ectopic activity. A preliminary report in rabbits also demonstrated a reduction in ICa,L in pacing-induced heart failure [34]. T-type calcium currents were higher in CHF than in controls in that model.

The effects of CHF and atrial dilatation have also been investigated in human atrial myocytes. However, the currently available data are conflicting. For ICa,L, Le Grand et al. and Ouadid et al. both reported a decrease [35,36] whereas another group did not see any alteration [37]. Ito was reduced in dilated and in diseased atria [35,38], whereas a more recent study observed an increase in Ito densities in atria of failing hearts [39]. Finally, Kuomi et al. showed that the classical (IK1) and the acetylcholine-activated (IKACh) inward rectifier potassium currents are both reduced in CHF [40], whereas Le Grand and co-workers [35] did not observe an effect of atrial dilation on IK1. The contradictory results may be due to varying clinical characteristics of the patient populations. For example, in the study by Le Grand et al. [35], a considerable percentage of patients with atrial dilatation suffered from AF, which certainly contributes to the reduction in ICa,L and in Ito and might also have influenced IK1 densities [16,41,42]. On the other hand, some of the opposing results remain unresolved at this time. These data show the limitations of studies in human tissue and highlight the necessity to combine data from human experiments with those from animal models.

3.1.2 Hyperthyroidism
Hyperthyroidism is a common clinical condition that is associated with an increased incidence of AF [43,44], and the likely mechanism is an acceleration of atrial repolarization. Studies in the early 1970s reported shortening in AERP and multicellular action potential duration in hyperthyroid rabbits [45,46]. In humans, atrial monophasic action potentials are prolonged by hypothyroidism [47] and normalized by thyroid hormone replacement [48]. Atrial cellular action potentials are shortened in hyperthyroid guinea pigs that have increased IKs and ICa,L with unchanged IKr and IK1 [49]. The mRNA expression of KvLQT1, and the {alpha}1-subunit of L-type calcium channels were unaffected by hyperthyroidism. A potential mechanism of thyroid action is presented by thyroid effects on the adrenergic nervous system. Hyperthyroidism upregulates the expression of atrial β1- and β2-adrenergic receptors [50], and both IKs and ICa,L are substantially increased by β-adrenergic activation [51–53]. Patients with latent hyperthyroidism were found to have increased peak ICa,L single-channel activity along with increased {alpha}1c-subunit protein expression [54].

3.1.3 Thoracic surgery
Thoracic surgery (including, but not only, open-heart surgery) substantially increases the risk of AF. Predisposing factors have also been defined at the cellular level. Van Wagoner et al. reported that patients who were in SR at the time of cardiac surgery but subsequently develop AF, have a larger atrial ICa,L than those who stay in SR [42]. Patients that develop postoperative AF also display increased Cx40 expression [55]. The distribution of Cx40 was heterogeneous with regions of up to several millimeters with little staining adjacent to regions with intense staining. A stronger expression of Cx40 might be associated with increases in spatial heterogeneity of conduction properties, thereby creating a substrate that favors the occurrence of AF.

From the available data on electrical remodeling in conditions associated with AF, it is obvious that different entities causing AF cause different forms of ionic remodeling. Thus, there is no single ‘pathological profile’ of ion channel abnormalities that causes AF; rather, the ionic mechanisms that govern AF occurrence vary according to the clinical context. More needs to be understood about the role of ionic mechanisms in each form of clinical AF, and the specific ionic substrate needs to be considered in optimizing antiarrhythmic drug therapy.

3.2 Significance and cellular mechanisms of atrial tachycardia-induced remodeling
The clinical course of atrial fibrillation (AF) is very often characterized by paroxysmal episodes that become more frequent and are of longer duration to finally progress into sustained AF. The pathophysiological substrate is provided by a variety of electrophysiological, mechanical and structural alterations caused by the arrhythmia itself. This process is termed ‘electrical remodeling’. The electrophysiological changes that are the consequence of AF and facilitate the induction and perpetuation of the arrhythmia were first described by Wijffels et al. in 1995 [56]. Since then, many groups have systematically characterized these alterations in a variety of models (for reviews, see [57–60]). It is now evident that AF is associated with a marked shortening, a decreased rate adaptation and an increased spatial heterogeneity in atrial refractoriness, as well as a slowing of intra-atrial conduction.

Different electrophysiological parameters are altered in specific time domains over the course of the arrhythmia. Atrial repolarization and refractoriness abbreviate within a few minutes of atrial tachycardia onset [61,62], with changes at a maximum within 30 min. Over the next hours and days, a gradual decline in atrial effective refractory period (AERP) and in AERP rate-adaptation occurs, reaching near-maximum within 2–7 days [56,61,63,64]. AERP shortening is associated with an increased inducibility and duration of AF episodes. These early changes in repolarization were noted in a variety of different animal models and in human AF. The effects of AF on intraatrial conduction are less clear and only a limited number of studies are available. In the RAP dog model, a slowing of intra-atrial conduction is seen, but it develops much more slowly than AERP shortening. Conduction velocity is preserved within the first week of RAP, but slows significantly after 42 days [63]. In contrast, no changes in intraatrial conduction velocities were observed even after long periods of AF in the goat model [65]. Finally, after weeks to months, other aspects of remodeling, like structural alterations, may become important for the further stabilization of the arrhythmia.

3.3 Cellular and molecular mechanisms of atrial tachycardia/AF induced remodeling in experimental models
Alterations in action potentials and ion current and channel function have mostly been investigated in the dog rapid pacing model and have substantially improved our knowledge about the mechanisms of atrial remodeling. Yue et al. [11] were the first to demonstrate that single cell action potentials (AP) of dogs subjected to atrial tachycardia had properties comparable to those of patients in AF. APs lost their plateau, acquiring a triangular shape, were substantially shortened and showed impaired rate adaptation. Blocking ICa,L of a control cell with nifedipine led to an AP morphology comparable to that of atrial-tachycardia animals and addition of BayK 8644 (to increase ICa,L) restored a more normal AP morphology to cells from chronically paced dogs, pointing to a pivotal role of ICa,L in remodeling. These changes in AP properties have been confirmed in other experimental AF studies [66,67]. AP from dogs with nonsustained and sustained AF were further investigated in a study by Hara and coworkers, who showed that restitution curves were flattened in AF and adaptation of repolarization to abrupt changes in rate was altered [67].

In the study of Yue et al., the effects of atrial tachycardia on ionic currents involved in repolarization were also characterized [11]. In paced dogs, ICa,L density progressively decreased by about 70% over 42 days. Ca2+-independent transient outward current (Ito) was reduced similarly, whereas all other currents, including the T-type Ca2+ current (ICa,T), delayed rectifier (IKs, IKr, IKur,d) and inward rectifier (IK1) potassium currents and the Ca2+-dependent Cl– current, were not altered. In a subsequent study, atrial tachycardia was found to decrease mRNA expression of the L-type Ca2+ channel {alpha}1c-subunit and of Kv4.3, suggesting transcriptional downregulation of channel {alpha}-subunits as the mechanism underlying the reduced densities of ICa,L and Ito [12]. The number of dihydropyridine receptors was reduced in dogs with rapid pacing, indicating a decreased number of functional L-type Ca2+-channels in the membrane [68]. In sustained AF in the goat, the mRNA expression of the L-type Ca2+ channel {alpha}1c-subunit and of Kv1.5 were also reduced, but the expression Kv4.3 and Kv4.2 were not altered [66]. To our knowledge, no functional information on ionic currents in the goat atrium are available, impeding the interpretation of these data. Very limited information is available on changes in ion pumps and exchangers caused by atrial tachycardia. No effects were seen in the expression of mRNA encoding the Na+/Ca2+-exchanger [12,66], but data on corresponding currents are not available.

Cellular changes related to atrial conduction alterations caused by rapid atrial rates are less clear. INa and gap junctions are major determinants of conduction velocity in the heart [69,70]. Atrial conduction velocity and INa current density are reduced if atrial tachycardia persists for more than 7 days in the dog [71]. Na+-channel {alpha}-subunit mRNA and protein expression are also decreased, suggesting transcriptional downregulation [12]. In contrast, Na+-channel mRNA expression is unaffected in the goat model of AF-remodeling [66] in which no disturbances of intra-atrial conduction are observed [56].

Gap junctions are intercellular connections formed by the assembly of two connexin (Cx) hemichannels, of which Cx40 and Cx43 seem to be the predominant forms in the atria [70]. Cx40 is distributed homogeneously in atria of goats with SR, but with prolonged AF smaller zones with reduced Cx40 expression are imbedded in larger areas with uniform Cx40 distribution [72]. Cx43 distribution is unchanged, resulting in a reduced Cx40/Cx43 ratio [73]. An earlier study in the RAP dog model reported elevated Cx43 protein expression and a redistribution of Cx43 protein towards side-to-side connections of neighboring myocytes [74]. At the moment, functional data on gap junctions in AF are not available and further investigations are needed to clarify the role of these channels in the pathophysiology of AF.

Chronic atrial tachycardia also leads to profound changes in cellular Ca2+ handling. Dogs subjected to RAP for more than 1 week show a decreased amplitude and slowed kinetics of Ca2+-transients, leading to decreased contractility [75]. AF-related alterations in the APD response to abrupt rate changes are reduced by ryanodine, suggesting an involvement of sarcoplasmic Ca2+ release channels [67].

3.4 Cellular and molecular remodeling in human AF
A shortening and decreased rate adaptation of the AERP in human AF was first reported by Attuel et al. [76]. A subsequent microelectrode study described triangular action potentials with marked abbreviation and decreased APD rate-adaptation in tissues of AF patients [77]. Similar changes in AF were later observed in single atrial myocytes of AF patients [41]. ICa,L has been shown to be a central determinant of APD and rate-dependence of repolarization in the human atrium [78]. Chronic AF decreases ICa,L densities by ~60–75% [41,79,42,80] whereas paroxysmal AF seems to have little effect on ICa,L [79]. A major mechanism of reduced ICa,L appears to be transcriptional downregulation of the pore-forming {alpha}1c-subunit [81–83], although some studies did not observe a change in mRNA [14] or protein [84] expression of this subunit. ICa,L β-subunits importantly modulate the amplitude of ICa,L [85], gene expression of the βb/βc and of the {alpha}2/{delta} subunit are strongly decreased in human AF [14], thereby contributing to the reduction in ICa,L.

Ito is also reduced in cells from AF patients [16,41,80], and Grammer et al. have shown a decreased transcription of Kv4.3, but not of Kv1.4 subunits, in AF [13]. Conflicting data exist on the effect of AF on the sustained outward current (Isus), in man largely carried by the ultrarapid delayed-rectifier current, IKur [86], composed of Kv1.5 subunits [87]. Several groups have not observed Isus changes in AF [41,80], whereas an initial study had reported a reduction of the current [16]. The mRNA expression of Kv1.5 is unchanged [13,15] or decreased [88], whereas protein expression, analyzed by Western- or slot-blotting, is reduced in two studies [15,16]. Given the potential importance of IKur/Kv1.5 as a target for atrial-selective antiarrhythmic drugs [19], the issue of changes of this component in AF bears resolution. IK1 and the acetylcholine-activated inward-rectifier IKACh are increased in patients with AF [41]. The outward component of these currents is important in the terminal phase of repolarization and increased current can therefore contribute to the AP shortening in AF. Brundel et al. reported a downregulation of the Kir3.1 mRNA and protein content in AF [15]. At the moment, nothing is known about the effects of AF on other {alpha}-subunits underlying the inward rectifier potassium channels nor on auxillary subunits or associated receptors (i.e., ACh receptors).

Very limited information is available regarding AF effects on rapid (IKr) and slow (IKs) components of IK. These currents have been described in the human atrium [89,90], but are difficult to record. Brundel and coworkers found that mRNA and protein expression of HERG and of minK, an auxillary subunit of IKs, are reduced in AF [15]. Another study also reported mRNA downregulation of HERG and of KvLQT1 (KCNQ1) [88]. In the latter study however, mRNA expression of minK was increased in AF patients.

Very little data are available on the effects of AF on the determinants of intraatrial conduction in humans. In contrast to the rapid pacing model in dogs [71], densities and biophysical properties of INa were found to be unaltered in patients with chronic AF [41] and mRNA expression of the Na+-channel {alpha}-subunit was also identical in SR and AF [15]. Almost nothing is known about the remodeling of connexins in AF, although a preliminary report in humans describes reduced Cx43 expression in patients with AF [91].

Several studies report changes in cellular Ca2+-handling proteins in patients with AF. AF decreases sarcoplasmic reticulum Ca2+-ATPase mRNA and protein levels [81,82,92] and inhibitory guanine nucleotide binding protein i{alpha}2-mRNA [83]. Expression of other proteins, like ryanodine receptors, calsequestrin, phospholamban and the Na+/Ca2+ exchanger, is comparable in SR and in AF patients. Recent work by Schotten et al. points to normal function of the sarcoplasmic reticulum in patients with chronic AF and reduced atrial contractility [93].

3.5 Cellular changes in early phases of remodeling
Remodeling is likely to be composed of a series of responses to maintain cell integrity in the face of tachycardia-induced Ca2+-overload, starting immediately upon tachycardia onset and developing in different time domains as long as the arrhythmia persists [58]. Early stages of the remodeling process are probably mostly reversible. If the arrhythmia persists, more slowly-reversible and possibly even irreversible changes develop. Possible mechanisms involved in early phases of electrical remodeling include functional adaptations of ion channels, regulatory processes and alterations in ion channel expression. Intact ICa,L is crucial for short-term rate-adaptive shortening of atrial APD [78], likely via a combination of voltage- and Ca2+i-dependent inactivation at rapid rates [94,95]. Dogs subjected to a few hours of atrial tachycardia display AERP shortening and histologic abnormalities that are compatible with intracellular Ca2+-overload [61]. In isolated atrial myocytes, an acute increase in rate is associated with significant [Ca2+]i increases that persist for up to 50 min after the onset of rapid stimulation [96]. This rise in [Ca2+]i decreases ICa,L by Ca2+-dependent inactivation [97,98], preventing Ca2+-overload. Changes in metabolic state may also contribute to ICa,L reduction via alterations of the channel redox state [99] or by decreasing local pO2 [100].

Knowledge about changes in ion currents and channels in the very early phases of remodeling is still limited. Recent data indicate that transcriptional changes of channel subunits start as early as a few hours after the onset of atrial tachycardia. Atrial tachycardia in the rat reduced gene expression of Kv4.2 and Kv4.3 within 8 h, whereas Kv1.5 mRNA was transiently increased and returned to baseline levels after [101]. The increase in Kv1.5 mRNA was paralleled by a rise in Kv1.5 protein expression, whereas the decrease in Kv4.2 and Kv4.3 mRNA was not accompanied by a reduction in protein levels. All other potassium channels studied, including Kv1.2, Kv1.4, Kv2.1, ERG, KvLQT1 and minK, were not altered by short-term atrial tachycardia. In an in vivo rabbit model of rapid pacing, atrial ICa,L started to decline after 12 h, whereas Ito current densities were first reduced after 24 h. Alterations in ICa,L mRNA transcription were noted even earlier, with downregulation of the {alpha}1c-subunit after 12 h and all β-subunits at 6 h [102]. Kv4.3 and Kv1.4 mRNA downregulation started at 6 h. In a similar isolated rabbit heart model, atrial tachycardia-induced changes were suppressed by the protein kinase C (PKC) inhibitor bisindolylmaleimide, but not by a calpain I inhibitor, pointing to a potentially important role of PKC as a mediator [103].


   4. Functional consequences and clinical implications of electrical remodeling
Top
 1. Introduction
 2. How can cellular...
 3. Cellular and molecular...
 4. Functional consequences and...
5. Conclusions
 References
 
Electrical remodeling in AF is a synthesis of changes that predispose to the development and perpetuation of the arrhythmia, as illustrated schematically in Fig. 2. On one hand, electrical remodeling can be a result of preexisting pathophysiological conditions that create triggers or a substrate to favor AF induction and/or persistence as was discussed in previous sections. On the other hand, electrical remodeling can be a consequence of the arrhythmia per se. It has long been known that longer lasting AF is more refractory to pharmacological cardioversion [58]. D-Sotalol, a predominant IKr blocker, exerted a marked class III effect in normal goat atria, but no longer delayed repolarization after 48 h of experimentally-maintained AF [104], a lack of response maintained in chronically-remodeled atria [105,106]. This could be a consequence of decreased HERG expression as reported in the goat [66] and human remodeled atria [88]. Although dofetilide is highly effective in prolonging repolarization and terminating AF induced in the setting of experimental CHF, the drug is totally ineffective in tachycardia-remodeled AF [115]. These differences may be due to a relatively more important role of IKr in the remodeled CHF dog atria (in which IKs is downregulated [33]) and/or to differences in the underlying arrhythmia mechanism [107]. In a mathematical model that simulates the human atrial AP, IKur block prolonged repolarization in the remodeled but not the normal AP [108], making it an interesting target for an atrium-selective antiarrhythmic drug for AF.


Figure 2
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  		Fig. 2 Electrical remodeling in atrial fibrillation. For remodeling that is a consequence of AF, different levels of evidence are indicated by different gray scales: ([Results from a single study / modeling work]); ([Results confirmed in several studies and / or different models]); ([Several studies from different models, but conflicting or incomplete data]). APD=Action potential duration, AERP=atrial effective refractory period, CV=conduction velocity.

 
Prevention of electrical remodeling is an attractive therapeutic target by which the vicious circle of self perpetuation of AF can be interrupted. Besides primary prevention, i.e., optimal treatment of predisposing epidemiological risk factors and clinical conditions like CHF, valve disease, arterial hypertension or coronary artery disease, measures of ‘secondary’ prevention, once the arrhythmia has started, should prevent development of the remodeling cascade. There is evidence that cellular Ca2+-overload is an initiating signal for the remodeling process [61,96], and several studies in humans and in different animal models have reported that administration of Ca2+-channel blockers prevents short term atrial remodeling [61,109–111]. In contrast, Ca2+-channel blockade is not effective in preventing long-term electrical remodeling or inducibility of AF [112,113]. The most likely explanation for the discrepant findings in short- and long-term remodeling are different underlying mechanisms; short-term effects being primarily functional, whereas altered gene expression are important in long-term remodeling [113]. Fareh and coworkers demonstrated in their dog model that the T-type channel blocker mibefradil is highly effective in preventing electrical remodeling caused by atrial tachycardia [113,114], possibly because of a more important role of ICa,T in remodeled atria compared to normal. A recent study suggests that vitamin C (possibly because of its anti-oxidant properties) might be useful to prevent early-phase remodeling [115].


   5. Conclusions
Top
 1. Introduction
 2. How can cellular...
 3. Cellular and molecular...
 4. Functional consequences and...
 5. Conclusions
References
 
An enormous amount has been learned about the cellular substrate underlying AF over the past few years. Many areas remain relatively unexplored, including the cellular basis of other forms of AF, the mechanisms of activity in specific tissue zones of great pathophysiological importance, like the pulmonary veins, the determinants of antiarrhythmic drug action in different pathophysiological settings, and the signal transduction mechanisms leading to atrial tachycardia remodeling. Combining the novel findings of cellular and molecular studies on AF with important recent clinical concepts [116], as well as with rapid progress in pharmacological, molecular and technical therapeutical applications, should enable us to develop more efficacious and safer strategies to combat the increasing burden of AF in the future.

Time for primary review 23 days.


   Acknowledgements
 
This work was supported by the Deutsche Forschungsgemeinschaft (Bo1396/3-1); Bundesministerium für Bildung und Forschung (BMBF)/University of Tübingen (IZKF) (Fö. 01KS9602); Franz–Loogen–Stiftung, Düsseldorf, Germany and the Pinguin-Stiftung, Düsseldorf, Germany for RFB. SN was supported by the Canadian Institutes of Health Research and the Quebec Heart and Stroke Foundation.


   References
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 1. Introduction
 2. How can cellular...
 3. Cellular and molecular...
 4. Functional consequences and...
 5. Conclusions
 References
 

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