Role of ICaL in the cardiac arrythmogenesis associated to acquired pathophysiological states
Myocardial ischemia and ventricular fibrillation
Ventricular fibrillation (VF) and myocardial ischemia are inseparable. In general terms, myocardial ischemia is defined as disequilibrium between myocardial oxygen demand versus supply, which episodes can trigger serious and fatal arrhythmic events. Thus, in the clinical setting around 80% of all sudden cardiac deaths (SCD) are due to myocardial ischemia. The most common sequence of events leading SCD appears to be the degeneration of ventricular tachycardia (VT) into ventricular fibrillation (VF) (Rubart & Zipes, 2005). VF is thought as a disorganized cardiac activation in which electrical waves propagate through the ventricles haphazardly and unpredictably (Jalife, 2000). The last consequence of this disorganized process is strong alteration in the adequate contractions of the ventricles that fail to eject blood effectively as a consequence of a strong electrical dysfunction, which is detected in the heart even during the first minutes after acute myocardial ischemia (usually lasting for 30 min) where abundant arrhythmogenesis is detected. During acute ischemia, in the border zone between the ischemic and normal tissue the excitability is increased resulting in spontaneous activation of Purkinje fibers initiating VT. During reperfusion the rapid inhomogeneous improvement in tissue excitability contributes to arrhythmogenesis again (Opthof et al., 1993; Luqman et al., 2007).
At intracellular level, an important ionic imbalance occurs during myocardial ischemia. This electrophysiological imbalance is characterized by the opening of ATP-sensitive potassium channels (IKATP) and causes acidosis and hypoxia of myocardial cells together with an aberrant intracellular Ca2+ handling that is determinant to trigger arrhythmias. Because ICaL constitutes the first trigger for the EC coupling necessary for each beat in the heart, a lot of attention has been focused in the involvement of ICaL in the conversion of VT to VF. With myocardial ischemia, the abrupt cessation of blood flow provokes a new distribution of a number of ions. The abnormal increase in the intracellular Na+ concentration ([Na+]i) consequently results in an increase in the intracellular Ca2+ concentration ([Ca2+]i) due to an increase in the Ca2+ influx via the Na+/Ca2+ exchanger (NCX) working in the reverse manner and also via depolarization-activated LTCCs. These events induce cellular Ca2+ overload (as a consequence of cellular Na+ overload) favoring the presence of spontaneous (non-voltage dependent) diastolic Ca2+ release as Ca2+ waves that induce depolarization of myocyte membrane triggering DAD and finally DAD-related arrhythmias (Schlotthauer & Bers, 2000). The presence of DADs also can trigger abnormal electrical activity with the wavebreak causing VF (Koretsune & Marban, 1989; Lakatta & Guarnieri, 1993). It is important to point out that cardiac ischemia is also characterized by a significant increase in circulating and tissue cathecholamine levels, which increase the probability of VT and SCD (Dorian, 2005). In the presence of P-adrenergic receptor (P-AR) stimulation and hypoxic conditions, a significant increase in Ca2+ influx through ICaL is able to prolong APD and also triggers EADs (Gaur et al., 2009), which in ventricular myocytes appear not to be due to spontaneous regional increase in [Ca2+]i or propagating Ca2+ waves. These results can be explained by the increase in the sensitivity of LTCC due to changes in gating properties by the modification of the phosphorylated state or by the modification of thiol groups of the channel, since the presence of dithiothreitol or catalase mimics the effect of acute hypoxia on ICaL (Hool, 2000; Hool & Arthur, 2002; Tanskanen et al., 2005). Alterations in ICaL have been also detected in simulated experimental ischemic-like conditions in single pacemaker cells isolated from the rabbit sinoatrial node (SAN). In contrast to ventricular myocytes, ICaL is declined under metabolic inhibition or ischemic conditions in SAN cells (Vinogradova et al., 2000; Ju & Allen, 2003). However, it has been reported that in vitro ischemic conditions enhanced ICaL significantly at potentials between -30 and +30 mV suggesting that the greater ICaL could account for a 6 mV increase in the AP overshoot (Du & Nathan, 2007a). This is related to an increase in the GCaL and a positive shift of the fc curve and reduction of inactivation, likely due to a H+- increased of ICaL (Du & Nathan, 2007b).
Torsades de Pointes (TdP) is a polymorphic type of VT also associated to acquired QT prolongation and maintained bradycardia that potentially leads to SCD (Jackman et al., 1988). Several studies carried out in rabbits and dogs prone to spontaneous TdP as a consequence of the chronic atrioventricular block (AVB) showed important alterations in the control of Ca2+ (Sipido et al., 2000; Antoons et al., 2007; Qi et al., 2009). For example, AVB in dogs resulted in an increase in the SR Ca2+ content which improved Ca2+ release from SR as Ca2+ transients (Sipido et al., 2000). Although, the overall density-voltage relationship of ICaL is unchanged, a depolarizing shift in the f„ curve resulted in an increased window current (Antoons et al., 2007). The CaM activation of CaMKII has been proposed to underlie this effect, as well the induced EADs (Qi et al., 2009).
Atrial fibrillation
Among supraventricular tachyarrhythmias, atrial fibrillation (AF) is the most common. Its prevalence is considerably increased with age, and thus AF is now classified as an epidemic (Lip et al., 2007). The cellular and molecular bases of AF electrophysiology and the underlying mechanisms have been extensively investigated (Hatem et al., 2010). The definition of the latest report of the American College of Cardiology/ American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines for AF is limited to a description of the pattern of irregular atrial waveforms on the electrocardiogram (ECG) as a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with a replacement of consistent P waves by rapid oscillations or fibrillatory waves (Fuster et al., 2011). At the cellular level, AF is characterized by strong alterations in the cardiac electrophysiology. The repolarizing currents such as Ito is almost suppressed and the voltage-gated K+ current (IKur) is decreased by around 50% (Le Grand et al., 1994; Van Wagoner et al., 1997). While upon the onset of AF, an increase in the intracellular Ca2+ load is observed, in persistent AF the intracellular Ca2+ load is restored to normal levels. There is a consensus in the drastic reduction in ICaL (around 70%) that is observed during experimental and clinical AF. Because this current is the main depolarizing current that activates during plateau phase of the AP, its reduction contributes greatly to the shortening of the AP, reducing atrial effective refractory period with a loss of physiological rate adaptation and finally favouring the formation of re-entrant circuits during AF (Le Grand et al., 1994; Van Wagoner et al., 1997; Yue et al., 1997). Several authors have postulated a significant decrease in the number of Ca2+ channels subunits Cav1.2 associated with AF (Brundel et al., 2001; Shinagawa et al., 2003). In fact, experiments carried out in cultured adult canine atrial myocytes subjected to in vitro model of atrial tachycardia by continuous tachypacing have demonstrated that during the first hours of pacing exist a Ca2+ overload involved in the activation of the phosphatase (PP) calcineurin (Cn) that allows the translocation of the transcriptor factor NFAT into the nucleus. This rapid Ca2+ overload induces the activation of the Ca2+-dependent CaM-Cn-NFAT system to cause the transcriptional downregulation of a1C subunit mRNA expression and also in the levels of Cav1.2 protein expression that is observed from 8 hours of pacing (Qi et al., 2008). These results are in conflict with others demonstrating no changes in mRNA and protein levels of the pore-forming a1C and the regulatory p2A subunits in atrial myocardium from patients with chronic AF (Schotten et al., 2003). Nevertheless, the reduction of ICaL can also be the result of changes in gating properties of the channel (Bodi et al., 2005), due to alterations in the phosphorylation state of the LTCC. Indeed, it has been observed that the maximum of the current-voltage relationship of ICaL is rightward shifted to more positive potentials in AF, suggesting phosphorylation-dependent changes in the channel regulation more than changes in its expression (Christ et al., 2004). In addition, it has been also described a high sensitivity of ICaL to p-adrenergic agonists during AF, suggesting that LTCCs are in a dephosphorylated and silent state (Boixel et al., 2001; Schotten et al., 2003; Dinanian et al., 2008; Hatem et al., 2010). Moreover, the activity of CaMKII is increased in AF (Neef et al., 2010). However, increased CaMKII activity in AF seems to be offset by an increased PP activity, because CaMKII inhibitor KN-93 reduce ICaL in control cells, while it did not affect ICaL in AF cells (Greiser et al., 2007; Greiser et al., 2011). Moreover, the PP inhibitor, okadaic acid, increased ICaL to almost normal levels in human atrial myocytes from AF patients (Christ et al., 2004; Greiser et al., 2011). In conclusion, in AF the ratio between protein kinase/phosphatase is altered in favor of increased PP activity, suggesting that the basal phosphorylation of the Ca2+ channel is reduced which induces lower basal ICaL activity. It seems clear that the abnormal atrial electrical remodeling associated to AF contributes to perpetuation of the arrhythmia and has profound effects on intracellular Ca2+ handling (Greiser et al., 2011). Contractile force of atrial tissue strips from patients with AF is also reduced around 75% and exposure to high extracellular Ca2+ concentration is able to restore atrial functions (Schotten et al., 2001; Schotten et al., 2004). In a sheep model of persistent AF, even with only a slight reduction in ICaL (around 24%), its efficiency to highly reduced CICR (Lenaerts et al., 2009). In the presence of Ca2+ chelators, ICaL was unchanged in AF conditions while it is increased in control cells. These results are well-matched with a possible reduction in the CDI of ICaL.
Cardiac hypertrophy and heart failure
Following a pathological stress, the heart can adapt by developing cardiac hypertrophy, which improves contractile force as an adaptative mechanism to meet the new body demands. In this case, the cardiac hypertrophy is "compensated", as in physiologic cardiac hypertrophy by exercise or during the pregnancy. When the stimulus is prolonged, cardiac hypertrophy can "decompensate" toward heart failure (HF) with compromised pump function (Benitah et al., 2010). One of the best documented changes in hypertrophy and HF, both in animal models and in humans, is the prolongation of the AP, which is highly significant in the production of ventricular arrhythmias. Important abnormalities of intracellular Ca2+ handling has been showed in the hypertrophic and failing myocytes: reduced SERCA function, enhanced NCX function and enhanced SR Ca2+ leak contributing to the reduced SR Ca2+ load (Bers et al., 2003). It is also well known that changes in ICaL in the hypertrophic and failing heart can also contribute to the electrical instability. Although the different degrees in the severity of pathological stresses as well as the variability among different models appear to influence the regulation of ICaL, the amplitude of ICaL is increased in hypertrophied and failing myocytes while its density (normalized to cell capacitance, as an indirect measure of cell surface) is unchanged (Benitah et al., 2002a; Benitah et al., 2003; Song et al., 2005; Loyer et al., 2008). In an early analysis of a pressure-overloaded cardiac hypertrophy model, ICaL was augmented in non-hypertrophic cells (Keung, 1989). It was thus suggested that ICaL could be increased before the cellular hypertrophy and then, as the cell grows, ICaL density would regain control values and even decrease in models of overt HF (Aimond et al., 1999; Benitah et al., 2002b). This process involves, at least partly, the cardiac mineralocorticoid pathway (Perrier et al., 2004; Benitah et al., 2010). Although most reports agree with the idea that ICaL density is normal in failing hearts, its kinetic seems to be significantly altered (Ryder et al., 1993; Bito et al., 2008). Thus, the decay of the whole-cell ICaL and its CDI have been found to be slowed, causing a reduction in the peak of the [Ca2+]i transients producing less Ca2+-induced inactivation of ICaL. Thus, the maintained ICaL density together with a slowing of its inactivation would at the end increase the total account of Ca2+ entry through the channel (Aimond et al., 1999; Benitah et al., 2010). Such slowing of the decay of the current has a direct effect on the EC-coupling and is involved in the prolongation of APD favoring EADs observed in failing conditions (Tomaselli & Rose, 2000). An increase in Po and availability of LTCCs in human failing myocardium have been reported (Schroder et al., 1998), suggesting that the failing myocytes has fewer but more active channels. Hence, the response of ICaL to cAMP is reduced in ventricular myocytes from failing hearts (Chen et al., 2002). The attenuated increase of ICaL by P-adrenergic stimulation is consistent with a reduction in the maximal number of channels, which have a higher activity (Bito et al., 2008). This is related to the concept of "defective EC coupling" in HF (Gomez et al., 1997): The failing myocytes had a significant reduction in triggered Ca2+ release from the SR despite unaltered ICaL, which could be due to structural alteration in the relation between LTCCs and ryanodine receptors, related to important structural changes as a loss of T-tubules density in human and experimental HF (He et al., 2001; Balijepalli et al., 2003; Louch et al., 2004; Lyon et al., 2009; Horiuchi-Hirose et al., 2011). The increased basal activity at the single Ca2+ channel levels is also consistent with changes in the phosphorylation state of the channel. Thus, both increases in PKA and CaMKII-dependent phosphorylation of LTCC have been described in failing myocytes (Schroder et al., 1998; Chen et al., 2008; Wang et al., 2008). PKA activation through P-adrenergic stimulation leads to increase ICaL, as well as the CaMKII-dependent phosphorylation of both pore-forming a1C and P2 subunits, which also increased ICaL CDF (Yuan & Bers, 1994; Hudmon et al., 2005; Grueter et al., 2006). In cardiac hypertrophy with prolongation of APD, these features are important since ICaL can be inappropriately reactivated and contribute to EADs triggered arrhythmia (Wu et al., 2002; Anderson et al., 2011). Moreover, CavP2 expression is downregulated in the compensated phase of cardiac hypertrophy, while an upregulation is observed in failing states, which could explain the increase in the activity of LTCCs observed in single channel studies (Hullin et al., 2007).
Inherited channelopathies or genetically determined ion-channel disorder
The critical role of LTCCs in cardiac cells has led many to suggest that inherited defects of LTCCs could be incompatible with life. This view dramatically changed in the 2004 when the CaCNA1C gene was found to show genetic linkage to life-threatening arrhythmias associated with Timothy syndrome (Splawski et al., 2004). Since, we witnessed an explosion of information linking LTCC genes mutations (more than 25 mutations identified in the past decade) with a wide variety of inherited arrhythmia syndromes (Napolitano & Antzelevitch, 2011).
LQT8 or Timothy syndrome
Identified in the 1990s (Marks et al., 1995), Timothy syndrome, or syndactyly-associated LQTS or LQT8, is a dominantly inherited genetic condition characterized by multisystem dysfunction, with severe arrhythmic disorders including: QT prolongation; 2:1 atrioventricular block (due to delayed ventricular repolarisation); T-wave alternans, polymorphic VT, and TdP; and abnormal changes in multiple organs (heart, skin, eyes, teeth, immune system, brain, and dysmorphism, such as syndactyly). Patients with LQT8 may also have episodic hypoglycaemia, which can trigger arrhythmias, and structural heart anomalies, including patent ductus arteriosus, patent foramen ovale, ventricular septum defect, and tetralogy of Fallot. Prognosis is very poor and SCD often occurs during childhood.
Gain-of-function mutations in CACNA1C, localized at the end of IS6 segment that is important for the regulation of channel inactivation and the binding of the Cavp subunit, have been associated with Timothy syndrome (Splawski et al., 2004; Splawski et al., 2005). A missense mutation G406R in the minor alternatively splice exon 8 of CACNA1C gene, as been first identified in all probands analysed (Splawski et al., 2004). Later, two other Gly mutations in the mutually exclusive major spliced exon 8a (G402S and G406R) were shown to cause a very similar syndrome but without the syndactyly (Splawski et al., 2005). These mutations exert powerful effect on inactivation, slowing the VDI irrespective of auxiliary p subunits, while through a proposed low-Po gating shift speeding the kinetics of CDI (Barrett & Tsien, 2008), which was previously reported unchanged (Splawski et al., 2005). Moreover, the mutation did not affect closed-state VDI, which might explain absence of hypertension associated with LQT8, and along with impaired open-state VDI, slowed activation and deactivation (Yarotskyy et al., 2009). The later is in part consistent with spontaneous increased occurrence of mode 2 gating at single channel level, which has been associated with the generation of a consensus phosphorylation site for CaMKII (Erxleben et al., 2006). Indeed, on isolated rat cardiomyocytes infected with dihydropyridine-resistant G406R Cav1.2 channel, CaMKII autophosphorylation is increased, which mediated enhanced ICaL facilitation, AP prolongation, increased Ca2+ spark frequency and afterdepolarizations (Thiel et al., 2008). The impaired inactivation of LTCC leads to sustained Ca2+ influx, AP prolongation, and Ca2+ overload, which promotes EADs and DADs (Jacobs et al., 2006; Sicouri et al., 2007). Roscovitine, a compound that increases the VDI, rescues the electrophysiological and Ca2+ homeostasis properties of Timothy syndrome cardiomyocytes (Yazawa et al.). Ca2+ channel blockade (eg, by verapamil and diltiazem) can control arrhythmias without affecting the QT interval, and is a possible treatment (Napolitano et al., 2006).
ioaL and LQT syndrome
The QT interval is an electrocardiographic index of ventricular repolarization and a measure of the duration of the ventricular AP. Ca2+ influx through LTCC plays a significant role in maintaining the plateau phase of AP and hence contributes importantly to APD and QT interval. Therefore, administration of CCB is a logical strategy in all types of LQTS. In the clinical study involving recording of monophasic AP (MAP) in eight patients with LQTS, verapamil effectively abbreviated MAP duration and suppressed epinephrine-induced EADs (Shimizu et al., 1995). At the bench side, verapamil effectively abbreviates QT interval and suppresses TdP in models of congenital and acquired LQTS (LQT1+ LQT2) (Aiba et al., 2005). In a rabbit model of drug-induced LQT2, the increased ICaL at the base of hearts, attributable to gender and regional difference in Cav1.2 expression, is an important determinant of the arrhythmia phenotype (Sims et al., 2008). This echoes clinical reports suggesting that Ca2+ channel antagonists might be appropriate as adjunctive therapy for arrhythmia suppression in LQT1, LQT2 and even LQT3 (Shimizu et al., 2005). Hence, an anti-arrhythmic effect of the specific LTCC antagonist nifedipine has been reported in mice with targeted disruption of the Na+ channel gene (Thomas et al., 2007), as well as in intact hearts from LQT5 mice model (Balasubramaniam et al., 2003).
J wave syndromes
Because they share a common arrhythmic platform and similarities in ECG characteristics, clinical outcomes and risk factors, congenital and acquired forms of Brugada (BrS) and early repolarization (ERS) syndromes have been grouped together under the heading of J wave syndromes (Antzelevitch & Yan, 2010). Recent studies have implicated loss of function mutations in all 3 subunits of the cardiac LTCC in the generation and accentuation of electrocardiographic J waves associated with these syndromes (Antzelevitch et al., 2007; Cordeiro et al., 2009); (Burashnikov et al.).
Short QT syndrome
Although QT prolongation has long been known to increase the risk of SCD and overall cardiac mortality among patients with a variety of underlying etiologies, a shorter than normal QT interval could also be detrimental leading to the concept of a new clinical entity, the short QT syndrome, associated with AF and SCD (Gussak et al., 2000). Since more than 30 patients with SQTS have been reported (Schulze-Bahr et al., 1997; Gaita et al., 2003; Schimpf et al., 2005; Giustetto et al., 2006).
SQT4 and SQT5 are associated with mutations in CACNA1C and CACNB2B (Antzelevitch et al., 2007). These mutations reduce ICaL, shorten QT, and are associated with asymmetrical T waves, attenuated QT-heart rate relations, and AF. More recently, a new variant of SQTS at a heterozygous state caused by a mutation in the CACNA2D1 gene has been reported (Templin et al., 2011). This mutation leads also to a decreased ICaL, without modification in the Cav1.2 expression suggesting alteration of some of the biophysical single channel properties of channel.
Brugada syndrome
Brugada syndrome (BrS), an inherited cardiac arrhythmia syndrome associated with a relatively high risk of VF, was first described as a new clinical entity in 1992 (Brugada & Brugada, 1992). The ECG features of the Brugada patient includes an accentuated J wave displaying a real or apparent right branch bundle block and ST segment elevation in the right precordial leads. Although the BrS has thus far been linked to mutations that impede Na+ channel expression or function, alterations in ICaL current with CCBs have been implicated in the development of BrS both clinically (Shimizu, 2005) and experimentally (Fish & Antzelevitch, 2004).
Recently, novel mutations of the cardiac LTCC genes responsible for shortening of the QT interval in families characterized by SCD, AF and a BrS type I ECG pattern have been reported (Antzelevitch et al., 2007). Functional analyses revealed loss-of-function missense mutations of the CACNA1C (A39V in the N-terminus and G490R in the I-II domain linker) and CACNB2 (S481L). These mutations reduce ICaL amplitude (due to trafficking defect for A39V), shorten QT, and are associated with asymmetrical T waves, attenuated QT-heart rate relations, and AF. Some patients also have tall, peaked T waves. These patients can also have BrS-type ST elevation in the right precordial leads with or without drug provocation, suggesting that the same reduction in ICaL underlies both SQTs and BrS. More recently, a novel missense mutation (T11L) in CACNB2B has been associated with BrS (Cordeiro et al., 2009). Characterized in heterologous expression system, this mutation induced faster inactivation kinetics and hyperpolarized shift in the steady-state inactivation without any other alteration in ICaL, resulting in a reduced depolarizing current in response to epicardial AP waveform.
Current antiarrhythmic strategies and ICaL
Current therapy to prevent cardiac arrhythmia is multidimensional and complicated. The conventional antiarrhythmic drugs have limited efficacy and safety. In the case of the most common cardiac arrhythmia, AF, treatment strategies can be pharmacological or interventional (e.g. catheter ablation techniques) but are also complicated by the presence of co-morbidities such as hypertension, diabetes, and/or pre-existing cardiovascular diseases (HF or coronary artery disease) (Prystowsky et al., 2010). Within the pharmacological strategies there are several groups of drugs including p-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), lipid-lowering and antithrombotic agents, spironolactone, among others, which have also demonstrated its efficacy in the prevention of SDC (Alberte & Zipes, 2003). From among all of them, the greatest reduction in cardiovascular mortality has been demonstrated with the treatment of p-blockers (Dorian, 2005). However, these drugs most likely exert their antiarrhythmic potential indirectly by affecting "upstream events" that contribute to the development of electrophysiological instability (Rubart & Zipes, 2005).
It has been demonstrated that the direct blockade of ICaL with dihydropyridine Ca2+ channel blockers (CCBs) produces a strong shortening in the APD. So, blocking ICaL is a potent means of suppressing VF. In Langendorff-perfused rabbit hearts, verapamil decreased the frequency of arrhythmia and changed it from disorganized VF into more organized VT (Samie et al., 2000). Similar results were also obtained using nifedipine (Choi et al., 2002). Therefore, CCBs could be considered promising antiarrhythmic drugs. However, the effects of these drugs have not emerged as unequivocally favorable in all clinical studies. Thus, verapamil and diltiazem can, in some cases, prevent episodes of acute ischemia VF in human, but they do not demonstrated to have as much of a beneficial effect on overall mortality as p-blockers or angiotensin-converting enzyme (ACE) inhibitors (Bodi et al., 2005). The problem observed with the direct blockade of ICaL using CBBs is that, at the same time that VT is prevented, the contractility could be suppressed, precluding their clinical usefulness as antifibrillatory drugs. Therefore, in the last years it has been proposed that only modifying ICaL kinetic properties, instead of blocking ICaL, could produce equivalent anti-fibrillatory effects without impairing EC coupling (Mahajan et al., 2008). In the clinical setting it is well established that the improvement in the current approach to treat AF is completely necessary. Amiodarone is the most effective antiarrhythmic drug for maintaining sinus rhythm in patients with AF. However, the extra-cardiac side effects have been a limiting factor, especially during chronic use, and may offset its benefits. Dronedarone is a new antiarrhythmic drug similar to amidarone that has been developed to provide rhythm and rate control in AF patients with fewer side effects. Dronedarone is considered as a potent blocker of multiple ion currents, including ICaL, and also exhibits antiadrenergic effects. In myocytes from several experimental animals, it has been demonstrated that the effect of dronedarone on ICaL consists in 76% block at dose of 10 ^M with IC50=0.18 ^M (Varro et al., 2001; Gautier et al., 2003). Dronedarone has also important antiarrhythmic effects. Intravenous administration of dronedarone shortened ventricular APD, suppressed EADs, ectopic beats and also TdP (Verduyn et al., 1999). Moreover, intravenous dronedarone was able to prevent VF in a rat model of ischemia and reperfusion-induced arrhythmias (Manning et al., 1995). Similarly, several clinical trials have demonstrated that dronedarone is able to maintain sinus rhythm and control ventricular rate in AF, reducing the number of cardiovascular hospitalizations and mortality in patients with high-risk of AF (Singh et al., 2007; Davy et al., 2008; Hohnloser et al., 2009). The current DIONYSOS clinical trial has demonstrated that in a short-term, dronedarone was less effective than amiodarone in decreasing AF recurrence and maintaining normal sinus rhythm, but had a better safety profile, specifically with regard to thyroid and neurologic events and a lack of interaction with oral anticoagulants (Le Heuzey et al., 2010). However, the ANDROMEDA clinical trial has showed that dronedarone is also contraindicated in severe or deteriorating HF (K0ber et al., 2008). The reason of that is because of a negative inotropic effect of dronedarone resulting from inhibition of ICaL that could have contributed to worsening of severe HF, increasing its mortality (Gautier et al., 2003; Zimetbaum, 2009). Therefore, dronedarone is still under clinical studies and has to demonstrate its real antiarrhythmic potency and effectiveness over other antiarrhythmic as well as its possible effects in the management of additional arrhythmias, e.g. VT.
