Drug Therapy in Atrial Fibrillation Management: Where Do We Stand in 2010? Sodium channel characteristics are different between the atrium and ventricle, and selective sodium channel blocking is another specific strategy for the management of AF.53 Vernakalant is an atrial-selective agent that can block sodium and potassium channels in the atrium and has little effect on the other channels.54 Vernakalant prolongs the atrial-effective refractory period.55 Roy et al. showed that an IV administration of RSD1235 (Vernakalant) was effective in the termination of recent onset AF (50-60% vs 4 - 5% compared with placebo).56, 57 The drug is infused at 2.25 - 4.5 mg/kg in 35 minutes.56 This drug has a small effect on sinus node recovery time (SNRT), atrioventricular node (AVN) refractoriness, and intraventricular conduction.55 Phase II trials have shown that oral vernakalant 300 - 600 mg twice daily can effectively maintain sinus rhythm compared with placebo, and earlier studies demonstrated that this drug was very effective for converting new AF to sinus rhythm.58 Sneezing, nausea, dysgeusia, paresthesia, and hypotension are amongst the adverse effects that can be seen with vernakalant. Sinus arrest, atrioventricular dissociation, and ventricular fibrillation are the other effects that have been reported.58 AZD7009 is another agent that can block delayed rectifier potassium current (Ikr), sodium current (INa), and ultra rapid rectifier delayed potassium current (Ikur).59 In animal studies, it has been shown that this drug has a predominant atrial electrophysiological effect.60 It is a highly effective agent in terminating AF/AFL and maintaining sinus rhythm in animal models.59 AZD7009 can increase the atrial-effective refractory period more in the dilated atrium rather than the normal- sized atrium (probably due to INa inhibition). Therefore, it is effective in converting persistent AF to sinus rhythm.61 Nifekalant is an Ikr blocker that is used for the acute treatment of refractory ventricular tachycardia. It can prolong the atrial refractory period and can terminate atrial flutter in 75% of patients within one hour but it is not a suitable agent for converting AF to sinus rhythm.62 As was mentioned before, atrial fibrosis has a central role in pathological changes contributed to AF.63 Upstream therapy can interfere with this phenomenon. Renin angiotensin system (RAS) inhibitors, statins, and omega-3 fatty acids are the drugs used to prevent atrial fibrosis.6 Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in AF prevention in patients with hypertension, left ventricular hypertrophy, and congestive heart failure, as well as in post- myocardial infarction patients with depressed left ventricular function.42 Kalus et al. demonstrated that the use of ARBs and ACEIs for at least three months before cardiothoracic surgery could TEHRAN HEART CENTER decrease the incidence of post-operative AF.64 Serotonin (5HT4) receptor blockers (RS - 100302, SB - 207266, and CVT - 150) have no ventricular side effect and can be promising agents in the AF management because the infusion of serotonin can cause AF.42 Atrial Fibrillation and Thromboembolism Atrial fibrillation can predispose clot formation in the left atrium and consequently ischemic stroke and extra cranial thromboembolism.65, 66 If AF persists for two days, left atrium thrombosis could be seen in 5 - 14% of patients.67 It might, subsequently, become fragmented and embolize to the peripheral atrial system.68 Most thromboembolic events are manifested in the brain, but other organs can also be affected and contribute to mortality and morbidity. The annual incidence rates of ischemic stroke, acute mesenteric ischemia, and acute limb ischemia are 2.3% (lethality 30%), 0.14 (lethality 70%), and 0.4% (lethality 16%), respectively. Thromboembolic events can be reduced by warfarin and aspirin in guideline- adherent antithrombotic therapy. If thromboembolic events occur, restoring perfusion and limiting the tissue ischemia are the treatment of choice. The major goal is, however, preventing these events. In patients with valvular heart disease or high-risk individuals (according to the CHADS2 or CHA DS2VAS scoring), warfarin is the drug of choice. 2 C In low-risk conditions, aspirin can be used.69 Warfarin needs frequent dose adjustment because it has multiple interactions with food and drugs, and it requires frequent laboratory monitoring. Therefore, the rates of discontinuation are high. That is why many patients may receive inadequate anticoagulation. Dabigatran is a new, potent, direct and competitive inhibitor of thrombin. Its half-life is 12 to 17 hours, and it does not require regular monitoring. Connolly et al. demonstrated that AF patients receiving Dabigatran 110 mg twice daily had similar rates of stroke and systemic embolism compared with those using warfarin, but with lower rates of major bleeding. At a dose of 150 mg twice daily, the rate of stroke and systemic embolism is lower but the rate of major bleeding is similar to warfarin.70 Conclusion In conjunction with catheter ablation, which is a rapidly growing modality in the AF management, drug therapy of AF still has a pivotal role and is subject to striking changes and new developments. Our new concepts about the mechanisms of AF and its triggers, substrates, atrial remodeling, and related ionic channels have led investigators towards newly developed drugs which may probably be more effective The Journal of Tehran University Heart Center175