Will warfarin soon be passé? New approaches to stroke prevention in atrial fibrillation

Atrial fibrillation (AF) is the most common cause for thromboembolic stroke. Oral anticoagulation with warfarin is still the most effective therapy in patients with AF, who are at an increased risk for stroke. Nevertheless, warfarin therapy has several limitations; therefore, new anticoagulants like warfarin analogs, thrombin inhibitors, or factor Xa inhibitors have been developed. Some of them are currently being tested in phase III trials in patients with AF. Furthermore, the pathophysiology of prothrombotic endocardial remodeling in fibrillating atria suggests that angiotensin II increases prothrombotic expression of vascular adhesion molecules at the atrial endocardium. Thus, novel anticoagulants or hybrid therapy with a combination of anticoagulants with inhibitors of endocardial remodelling like angiotensin II receptor blockers appear to be attractive future perspective approaches.     

Pharmacological strategies for prevention of postoperative atrial fibrillation

Atrial fibrillation (AF) complicating cardiac surgery continues to be a major problem that increases the postoperative risk of stroke, myocardial infarction, heart failure and costs and can affect long-term survival. The incidence of AF after surgery has not significantly changed over the last two decades, despite improvement in medical and surgical techniques. The mechanism and pathophysiology underlying postoperative AF (PoAF) is incompletely understood and results from a combination of acute and chronic factors, superimposed on an underlying abnormal atrial substrate with increased interstitial fibrosis. Several anti-arrhythmic and non-anti-arrhythmic medications have been used for the prevention of PoAF, but the effectiveness of these strategies has been limited due to a poor understanding of the basis for the increased susceptibility of the atria to AF in the postoperative setting. In this review, we summarize the pathophysiology underlying the development of PoAF and evidence behind pharmacological approaches used for its prevention in the postoperative setting.     

Drug therapy for atrial fibrillation

Although the maintenance of sinus rhythm would be the ideal scenario for patients with atrial fibrillation (AF), recent randomised trials have questioned the value of this approach. A careful interpretation of their results showed the limited efficacy of currently available antiarrhythmic drugs in maintaining sinus rhythm, as well as their potentially serious side effects. Therefore, it is imperative to develop safer and more effective drugs for AF. Based on our improved understanding of the pathophysiology of AF and the mechanism of action of antiarrhythmic drugs, significant efforts are being made to develop new antiarrhythmic agents that would prevent electrophysiological remodelling, would be selective for the atria and, therefore, would not prolong ventricular repolarisation, thus lacking any proarrhythmic effect.     

Drug therapy for atrial fibrillation

Although the maintenance of sinus rhythm would be the ideal scenario for patients with atrial fibrillation (AF), recent randomised trials have questioned the value of this approach. A careful interpretation of their results showed the limited efficacy of currently available antiarrhythmic drugs in maintaining sinus rhythm, as well as their potentially serious side effects. Therefore, it is imperative to develop safer and more effective drugs for AF. Based on our improved understanding of the pathophysiology of AF and the mechanism of action of antiarrhythmic drugs, significant efforts are being made to develop new antiarrhythmic agents that would prevent electrophysiological remodelling, would be selective for the atria and, therefore, would not prolong ventricular repolarisation, thus lacking any proarrhythmic effect.     

Atrial fibrillation: the nonpharmacologic strategy

Pharmacologic treatment has been used for decades for conversion and prevention of recurrent atrial fibrillation (AF). But the use of antiarrhythmic drugs is associated with substantial side effects and mortality in some patients. Accordingly, it is not surprising that nonpharmacologic techniques have been developed for the management of AF, including the use of atrial defibrillators, atrial pacing methods, and several surgical and radiofrequency catheter ablation procedures. The atrial defibrillator has been found to detect and treat atrial and ventricular arrhythmias appropriately, with successful termination of spontaneous AF through low energy shocks. Although these devices are promising, the factor which limits their widespread use is not safety or efficacy, but patient comfort. Several studies suggest that atrial-based cardiac pacing may have a beneficial effect in decreasing and preventing AF episodes in patients with sick sinus syndrome. Palliative ablative procedures also available for the treatment of atrial fibrillation include AV junctional modification and AV nodal ablation with permanent pacing, the latter technique being associated with improvements in ejection fraction. Two potentially curative procedures are the surgical MAZE and endocardial catheter ablation. These techniques are based on placing strategically located lesions in the atrium to disrupt the conduction pathway(s). Recent studies have focused on ablative therapies aimed at the area of the pulmonic veins. The main therapy for maintaining sinus rhythm after conversion is predominantly pharmacologic. Similarly, in the absence of heart block, if conversion to sinus rhythm is not successful, pharmacologic modalities may be required to control ventricular rate. In any case, planning a treatment regimen for the management of AF should include evaluation of the risks inherent in the use of various drugs as well as more invasive strategies.     

The tachycardia-induced dog model of atrial fibrillation. clinical relevance and comparison with other models

In the past, investigators have relied extensively on acute in vivo models of atrial fibrillation (AF), in which AF was induced either pharmacologicly or by vagal stimulation. More recently, there is a need and desire for more clinically relevant models that can only be achieved with the use of chronically instrumented animals. One of these models is the atrial tachycardia-induced AF dog model, which is the main focus of this review. The model produces a persistent AF in 80% of animals paced at 400 beats/min for 6 weeks. Atrial tachycardia also induces various pathophysiologic and ultrastructural changes that often resemble electrical remodeling of atria in patients that have a high susceptibility to AF. This model can also be used to evaluate drug efficacy with respect to attenuation of AF duration or conversion of AF to sinus rhythm. The model may therefore be used to provide further insights into the discovery of new therapeutic approaches to modifying this atrial arrhythmic disorder in man.     

Current Management of Symptomatic Atrial Fibrillation

Atrial fibrillation (AF) is the most commonly encountered sustained arrhythmia. Heart rate control, reduction of symptoms, and prevention of embolism are major goals of treatment. Whether the strategy of cardioversion with subsequent maintenance of sinus rhythm has an advantage over heart rate control is under active investigation. Digoxin, non-dihydropyridine calcium channel antagonists, β-adrenoceptor antagonists (β-blockers), and amiodarone are the pharmacologic agents most commonly used to achieve rate control. In patients with drug-resistant AF, atrioventricular nodal ablation (or modification) with implantation of a permanent pacemaker is an alternative therapy. Conversion to sinus rhythm can best be achieved by electrical cardioversion. In selected patients, pharmacologic cardioversion can also be attempted. The use of antiarrhythmic drugs for the maintenance of sinus rhythm depends on several factors: (i) the nature of the arrhythmia (first attack, paroxysmal AF with frequent attacks, paroxysmal AF with infrequent attacks, or persistent AF); (ii) the associated symptoms; and (iii) the risk of severe adverse effects associated with the chosen drug. If the administration of an antiarrhythmic drug is appropriate, the choice of the drug must be tailored to the specific characteristics of the given patient. In lone AF, class Ic antiarrhythmic drugs are the best tolerated. These agents should be combined with a calcium channel antagonist or a β-blocker to prevent rapid ventricular response in the case of conversion of AF to atrial flutter. In this situation, catheter ablation of atrial flutter at the isthmus (hybrid therapy) should be performed. All class I antiarrhythmic agents should be avoided in patients with structural heart disease. Alternative approaches that may be used if sinus rhythm cannot be maintained with drug therapy include: (i) the ablation of arrhyth-mogenic pulmonary veins; (ii) the implantation of an atrial defibrillator; (iii) the use of specific pacing sites; or (iv) pacing modes. Whether these approaches will reach clinical relevance merits further investigation. Intraoperative catheter ablation or surgical ablation (maze procedure) seems a promising approach for curing AF in patients undergoing cardiac surgery. Among all of the available treatment options, the most consistent proof of efficacy in reducing mortality and morbidity from AF exists for antithrombotic treatment.     

IKur/Kv1.5 channel blockers for the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia. Anti-arrhythmic drugs remain the mainstay of therapy, but the available class I and III anti-arrhythmic drugs are only moderately effective in long-term restoring/maintaining sinus rhythm (SR) and can produce potentially fatal ventricular pro-arrhythmia. In an attempt to identify safer and more effective anti-arrhythmic drugs, drug discovery efforts have focused on ‘atrial selective drugs’ that target cardiac ion channel(s) that are exclusively or predominantly expressed in the atria. The ultra-rapid activating delayed rectifier K⁺ current (I_Kur), carried by Kv1.5 channels, is a major repolarizing current in human atria, but seems to play no role in the ventricle. This finding offers the possibility of developing selective I_Kur blockers to restore and maintain SR without a risk of ventricular pro-arrhythmia. Several I_Kur blockers are now being developed but clinical data are still limited, so the precise role of these agents in the treatment of AF remains to be defined. In this review we analyze the possible advantages and disadvantages of the developmental I_Kur blockers as they represent the first step for the development of potential atrial selective drugs for a more effective and safer treatment and prevention of AF.     

Atrial tachycardia induces remodelling of muscarinic receptors and their coupled potassium currents in canine left atrial and pulmonary vein cardiomyocytes

BACKGROUND AND PURPOSE: Both parasympathetic tone and atrial tachycardia (AT) remodelling of ion channels play important roles in atrial fibrillation (AF) pathophysiology. Different muscarinic cholinergic receptor (mAChR) subtypes (M2, M3, M4) in atrial cardiomyocytes are coupled to distinct K+-currents (called IKM2, IKM3, IKM4, respectively). Pulmonary veins (PVs) are important in AF and differential cholinergic current responses are a potential underlying mechanism. This study investigated AT-induced remodelling of mAChR subtypes and K+-currents in left-atrial (LA) and PV cardiomyocytes. EXPERIMENTAL APPROACH: Receptor expression was assayed by western blot. IKM2, IKM3 and IKM4 were recorded with whole-cell patch-clamp in LA and PV cardiomyocytes of nonpaced control dogs and dogs after 7 days of AT-pacing (400 bpm). KEY RESULTS: Current densities of IKM2, IKM3 and IKM4 were significantly reduced by AT-pacing in LA and PV cardiomyocytes. PV cardiomyocyte current-voltage relations were similar to LA for all three cholinergic currents, both in control and AT remodelling. Membrane-protein expression levels corresponding to M2, M3 and M4 subtypes were decreased significantly (by about 50%) after AT pacing. Agonist concentration-response relations for all three currents were unaffected by AT pacing. CONCLUSIONS AND IMPLICATIONS: AT downregulated all three mAChR-coupled K+-current subtypes, along with corresponding mAChR protein expression. These changes in cholinergic receptor-coupled function may play a role in AF pathophysiology. Cholinergic receptor-coupled K+-currents in PV cardiomyocytes were similar to those in LA under control and AT-pacing conditions, suggesting that differential cholinergic current properties do not explain the role of PVs in AF.     

心房不同部位起搏对阵发房颤患者心房激动时间的影响

目的　比较右心耳 (RAA)、冠状窦远端 (DCS)、右房双部位 (右心耳加冠状窦口 ,DSA)和双房 (右心耳加冠状窦远端 ,BiA)起搏对阵发房颤 (PAf)患者心房激动时间的影响。方法 2 2例接受心脏电生理评价试验的PAf患者在窦性心律下行心房不同部位起搏 ,同步记录 12 -导心电图 ,测量最大P波时限。结果与窦性P波时限相比 ,RAA起搏明显延长P波时限 (P <0 0 1) ,DCS、DSA及BiA起搏则明显缩短P波时限 (P <0 0 1)结论DCS、DSA及BiA起搏明显缩短心房激动时间 ,减少心房电活动的离散度 ,有利于PAf的防治     

Virtual tissue engineering of the human atrium: modelling pharmacological actions on atrial arrhythmogenesis

Computational models of human atrial cells, tissues and atria have been developed. Cell models, for atrial wall, crista terminalis, appendage, Bachmann's bundle and pectinate myocytes are characterised by action potentials, ionic currents and action potential duration (APD) restitution. The principal effect of the ion channel remodelling of persistent atrial fibrillation (AF), and a mutation producing familial AF, was APD shortening at all rates. Electrical alternans was abolished by the modelled action of Dronedarone. AF induced gap junctional remodelling slows propagation velocity at all rates. Re-entrant spiral waves in 2-D models are characterised by their frequency, wavelength, meander and stability. For homogenous models of normal tissue, spiral waves self-terminate, due to meander to inexcitable boundaries, and by dissipation of excitation. AF electrical remodelling in these homogenous models led to persistence of spiral waves, and AF fibrotic remodelling to their breakdown into fibrillatory activity. An anatomical model of the atria was partially validated by the activation times of normal sinus rhythm. The use of tissue geometry from clinical MRI, and tissue anisotropy from ex vivo diffusion tensor magnetic resonance imaging is outlined. In the homogenous model of normal atria, a single scroll breaks down onto spatio-temporal irregularity (electrical fibrillation) that is self-terminating; while in the AF remodelled atria the fibrillatory activity is persistent. The persistence of electrical AF can be dissected in the model in terms of ion channel and intercellular coupling processes, that can be modified pharmacologically; the effects of anatomy, that can be modified by ablation; and the permanent effects of fibrosis, that need to be prevented.     

Pharmacotherapy of atrial fibrillation

Atrial fibrillation (AF) remains a widespread health problem and the drugs available for its treatment suffer from several drawbacks, including potentially lethal proarrhythmia, serious non-cardiac toxicity and limited efficacy. The evidence for efficacy of currently available anti-arrhythmic agents for sinus rhythm restoration and maintenance is reviewed, with emphasis on randomised trials when available. The current approach to thromboembolism prophylaxis in AF is summarised.     

窦性冲动疏导术治疗心房颤动的长期随访研究

目的 观察窦性冲动疏导术治疗心房颤动的长期疗效.方法 1996年5月至2002年6月,9例患者接受了窦性冲动疏导术,消除多子波折返激动.其中7例同时进行二尖瓣置换.术后对9例患者进行不定期随访,随访过程中,患者接受心电图,彩色超声心动图检测.结果 2例于随访l后及1.5年后失访,其他7例患者随访7 ～13年.术后1年内心功能Ⅰ级5例,Ⅱ级4例；窦性心律2例,类窦性心律7例；Ⅲ度AV-B并发症1例,心肌病进展1例,肾功能不全1例；心房A/E峰为0.3者2例,0.4者4例,0.5者2例,0.6者1例.有6例于术后1～2周内先后出现过早搏、阵发性室上性心动过速等心律失常,未服用抗心律失常药自行恢复规律的心律.结论 窦性冲动疏导术是一种可以有效消除心房多子波折返激动的术式,消除了多子波折返激动就可以消除心房颤动.但是得到的却是一种永久性的室上心律.如果对这种单一的室上心律起搏点进行消融,失去了异位起搏点后可以得到的应该是窦性心律.     

Effects of selective mineralocorticoid receptor antagonism on atrial ion currents and early ionic tachycardia-induced electrical remodelling in rabbits

Over the past years, the importance of the renin–angiotensin–aldosterone system in atrial fibrillation (AF) pathophysiology has been recognised. Lately, the role of aldosterone in AF pathophysiology and mineralocorticoid receptor (MR) antagonism in “upstream” AF treatment is discussed. Hypothesising that selective MR antagonism might also influence atrial ion currents (L-type calcium current [I _Ca,L], transient outward potassium current [I _to], sustained outward potassium current [I _sus]) and their tachycardia-induced remodelling, the effects of an eplerenone treatment were studied in a rabbit model. Six groups each with four animals were built. Animals of the control group received atrial pacing leads, but in contrast to the pacing groups, no atrial tachypacing (600 per minute for 24 and 120 h immediately before heart removal) was applied. Animals of the eplerenone groups were instrumented/paced as the corresponding control/pacing groups, but were additionally treated with eplerenone (7 days before heart removal). Atrial tachypacing was associated with a reduction of I _Ca,L. I _to was decreased after 24 h of tachypacing, but returned to control values after 120 h. In the absence of rapid atrial pacing, MR antagonism reduced I _Ca,L to a similar extent as 120 h of tachypacing alone. Based on this lower “take-off level”, I _Ca,L was not further decreased by high-rate pacing. I _to and its expected tachycardia-induced alterations were not influenced by MR antagonism. In our experiments, selective MR antagonism influenced atrial I _Ca,L and its tachycardia-induced alterations. As changes of I _Ca,L are closely linked with atrial calcium signalling, the relevance of these alterations in AF pathophysiology and, accordingly, AF treatment is likely and has to be further evaluated.     

Recurrent atrial fibrillation in a patient with ulcerative colitis treated with azathioprine: case report and review of the literature

We present a clinical case report regarding recurrent atrial fibrillation in a patient with ulcerative colitis treated with azathioprine. Atrial fibrillation represents the most common sustained cardiac arrhythmia, occurring in 1-2% of the general population and characterized by seemingly disorganized atrial depolarizations without effective atrial contraction. Several mechanisms determine this arrhythmia; in particular remodelling (structural, mechanical and electrical alteration related to atrial fibrillation). The pro-arrhythmic effect of azathioprine may be evaluated during immunosuppressive therapy to be aware of this serious but reversible adverse effect.     

蝙蝠葛碱对家兔急性房颤连接蛋白40重构的影响及其机制

目的　观察快速心房起搏所致急性心房颤动 (房颤 )对家兔心房肌组织Ca2 + 含量和连接蛋白 4 0 (Connexin 4 0 ,Cx4 0 )重构的影响以及钙通道阻滞剂蝙蝠葛碱 (DAU)的干预作用 ,并对其作用机制进行探讨。方法　 32只家兔随机分为 3组 :对照组 (n =8)、房颤组 (n =12 )、DAU组 (n =12 )。经颈内静脉将电极置入右心房 ,对照组不予心房起搏 ,另外两组以 6 0 0beat·min-1行快速心房起搏以诱发房颤 ,并且DAU组于快速起搏前 30min按 5mg·kg-1静脉给予DAU ,其余两组则给予等量的生理盐水。用生化方法检测右心耳组织Ca2 + 含量 ,并分别用Westernblot和免疫荧光标记激光共聚焦显微镜检测Cx4 0的含量和分布。结果　房颤组心房组织Ca2 + 含量高于对照组 ,Cx4 0含量低于对照组 (P均 <0 0 1) ,房颤组Cx4 0分布不均一 ;蝙蝠葛碱组Ca2 + 、Cx4 0含量分别低于和高于房颤组 (P均 <0 0 5 ) ,Cx4 0分布不均一的程度较房颤组减轻。结论　快速心房起搏诱发急性房颤可引起家兔心房肌Ca2 + 含量升高、Cx4 0含量降低和分布不均一 ,蝙蝠葛碱能有效抑制Ca2 + 含量升高、减轻Cx4 0重构 ,钙超载可能参与房颤Cx4 0重构。     

Effects of a new class III antiarrhythmic drug nibentan in a canine model of vagally mediated atrial fibrillation

Nibentan, a new class III antiarrhythmic drug, is highly effective in patients with atrial flutter and fibrillation. However, its mechanism of action remains unclear. The aim of this study was to investigate the effects of nibentan using a canine model of vagally sustained atrial fibrillation (AF). Nibentan was intravenously infused to anesthetized open-chest dogs during vagally induced AF. Cumulative doses of nibentan (0.063, 0.125, and 0.250 mg/kg) successfully terminated AF in 78, 88, and 100% as well as prevented AF reinduction in 11, 63, and 90% of cases, respectively. All doses of nibentan significantly and rate-independently increased atrial effective refractory period (AERP) with and without vagal stimulation. Activation mapping (224 epicardial electrodes) during AF showed that nibentan reduced the number of simultaneously occurring reentrant wavelets. Herewith the atrial excitation slowed down until conduction failure of reentrant wavelets led to arrhythmia termination. These changes in activation patterns can be accounted for by nibentan-induced increase of AERP (55 +/- 9%, 82 +/- 12%, and 90 +/- 6%; p < 0.01) and wavelength for reentry (47 +/- 7%, 68 +/- 12%, and 72 +/- 4%; p < 0.01) at rapid atrial rates in the presence of vagal stimulation. In conclusion, the high efficacy of nibentan against AF was associated with significant rate-independent increase in AERP and in wavelength, and might be in part explained by block of both delayed rectifier (I(K)) and muscarinic I(K,ACh) currents.     

Pharmacological cardioversion of atrial fibrillation: current management and treatment options

Atrial fibrillation (AF) is the most common form of arrhythmia, carrying high social costs. It is usually first seen by general practitioners or in emergency departments. Despite the availability of consensus guidelines, considerable variations exist in treatment practice, especially outside specialised cardiological settings. Cardioversion to sinus rhythm aims to: (i) restore the atrial contribution to ventricular filling/output; (ii) regularise ventricular rate; and (iii) interrupt atrial remodelling. Cardioversion always requires careful assessment of potential proarrhythmic and thromboembolic risks, and this translates into the need to personalise treatment decisions. Among the many clinical variables that affect strategy selection, time from onset is crucial. In selected patients, pharmacological cardioversion of recent-onset AF can be a safely used, feasible and effective approach, even in internal medicine and emergency departments. In most cases of recent-onset AF, pharmacological cardioversion provides an important--and probably more cost effective--alternative to electrical cardioversion, which can then be employed as a second-line therapy for nonresponders. Class IC agents (flecainide or propafenone), which can be safely used in hospitalised patients with recent-onset AF without left ventricular dysfunction, can provide rapid conversion to sinus rhythm after either intravenous administration or oral loading. Although intravenous amiodarone requires longer conversion times, it is still the standard treatment for patients with heart failure. Ibutilide also provides good conversion rates and could be used for AF patients with left ventricular dysfunction (were it not for high costs). For long-lasting AF most pharmacological treatments have only limited efficacy and electrical cardioversion remains the gold standard in this setting. However, a widely used strategy involves pretreatment with amiodarone in the weeks before planned electrical cardioversion: this provides optimal prophylaxis and can sometimes even restore sinus rhythm. Dofetilide may also be capable of restoring sinus rhythm in up to 25-30% of patients and can be used in patients with heart failure. The potential risk of proarrhythmia increases the need for careful therapeutic decision making and management of pharmacological cardioversion. The results of recent trials (AFFIRM [Atrial Fibrillation Follow-up Investigation of Rhythm Management] and RACE [Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation]) on rate versus rhythm control strategies in the long term have led to a generalised shift in interest towards rate control. Although carefully designed studies are required to better define the role of pharmacological rhythm control in specific AF settings, this alternative option remains a recommendable strategy for many patients, especially those in acute care.