© Borgis - Postępy Nauk Medycznych 8/2015, s. 580-587
Anna Wysocka1, 2, Marta Karaś-Głodek1, *Andrzej Wysokiński1
Leczenie antyarytmiczne chorych z migotaniem przedsionków
Antiarrhythmic therapy in patients with atrial fibrillation
1Chair and Department of Cardiology, Medical University, Lublin
Head of Department: prof. Andrzej Wysokiński, MD, PhD
2Chair of Internal Medicine and Department of Internal Medicine in Nursing, Medical University, Lublin
Head of Department: prof. Jadwiga Daniluk, MD, PhD
Migotanie przedsionków pozostaje najczęściej występującą, lecz jedną z najtrudniej poddających się leczeniu farmakologicznemu arytmią. Leki antyarytmiczne służą przywróceniu rytmu zatokowego oraz zapobieganiu nawrotom arytmii, ale leczenie farmakologiczne ogranicza się do kilku dostępnych preparatów ze względu na niewystarczającą skuteczność terapii oraz poważne działania niepożądane. U pacjentów z migotaniem przedsionków bez strukturalnej choroby serca można przeprowadzić kardiowersję farmakologiczną podając flekainid, propafenon, ibutylid lub wernakalant, u chorych ze strukturalną chorobą serca, możliwe jest zastosowanie wyłącznie amiodaronu. Przewlekłe leczenie antyarytmiczne zwiększa nie tylko prawdopodobieństwo utrzymania rytmu zatokowego, ale również ryzyko wystąpienia niekorzystnych objawów ubocznych. Kluczowym problemem pozostaje wybór pomiędzy strategią przywrócenia i utrzymywania rytmu zatokowego, a pozostawieniem utrwalonego migotania przedsionków i optymalizacją kontroli częstości rytmu komór. Ostatnio podkreśla się również znaczenie leczenia wspomagającego. Wiele oczekiwań wiąże się z badaniami mającymi na celu wprowadzenie nowych leków antyarytmicznych o korzystnym profilu skuteczności i bezpieczeństwa. Jednak pomimo niewątpliwego rozwoju kardiologii i farmakologii zarówno doświadczalnej, jak i klinicznej, leczenie migotania przedsionków wciąż stanowi poważne wyzwanie.
Atrial fibrillation is the most frequent arrhythmia, that still remains one of the most diffficult to pharmacological management. Antiarrhythmic drugs have been widely used to restore sinus rhythm and to prevent reccurence of arrhythmia, but pharmacological therapy is limited to several available agents, because of insufficient efficiacy and the significant risk of serious adverse effects. In patients with atrial fibrillation without structural heart disease, it is possible to perform pharmacological cardioversion due to flekainid, propafenon, ibutilid or vernakalant administration, but in patients with structural heart disease, there is possible only amiodarone using. Long-lasting antiarrhythmic therapy increases not only probability of the sinus rhythm maintainig, but also the risk of adverse side effects occuring. The key problem determines a choice between the rhythm control strategy or the rate control in patients with sustained atrial fibrillation. Recently, also it has been emphasized upstream therapy importance. There is a lot of expectations reffering to reaserches aimed at introducing new antiarrhythmic drugs with favorable efficiacy and safety profile. However, despite undoubted development of clinical and experimental pharmacology and cardiology, antiarrhythmic drug therapy of atrial fibrillation remains an important challenge.
Although, atrial fibrillation (AF) is the most common arrhythmia occurring in general population, incomplete knowledge of the etiology and complexity of the previously known causes of atrial fibrillation makes it still one of the most difficult arrhythmias to treat. Factors responsible for the occurrence of atrial fibrillation and necessary for its perpetuation were presented by a well-known French electrophysiologist Coumel in the form of a triangle (fig. 1) (1). Removal or modification of many described factors allows for an arrhythmia elimination, and if this is not possible, a lot of targets for the use of drug therapy can be found.
Fig. 1. Coumel's triangle – factors influencing the onset and maintenance of atrial fibrillation.
First attempts to found an effective drug preventing the occurrence of atrial fibrillation date back to the first description of arrhythmia in animals presented by William Harvey in 1628 and to the observations, made in subsequent years, which revealed that the incidence of irregular pulse in patients is associated with unfavourable prognosis. In 1785 the beneficial effects of digitalis in patients with heart failure were described, and a quinidine (2), which was introduced for the treatment of AF in the nineteenth century, is considered to be the first typical antiarrhythmic drug. In subsequent years, next antiarrhythmic drugs were synthesized and introduced into clinical practice and their classification made in 1969 by Vaughan Williams after a few modifications it is still used today (tab. 1) (3).
Table 1. Vaughan-Williams Classification of Antiarrhythmic Drugs (3).
|Class IA||disopyramide, procainamide, quinidine|
|Class IB||lidocaine, mexiletine|
|Class IC||flecainide, propafenone|
|Class III||amiodarone, dofetilide, ibutilide, sotalol|
|Class IV||non-dihydropyridine blockers of calcium channels (verapamil, diltiazem)|
For the present, there is no perfect drug, allowing for prevention of atrial fibrillation occurrence and for effective maintenance of sinus rhythm. List of antiarrhythmic drugs recommended for use in patients with atrial fibrillation rather shortens than lengthens. This particularly concerns IA class drugs (quinidine and disopyramidum), which are characterized by potential pro-arrhythmic effect (risk of QT prolongation and the occurrence of torsade de pointes type ventricular tachycardia) and IC class, contributing by their pro-arrhythmic potential especially in patients with heart failure, to unfavorable prognosis, as it was demonstrated in the CAST study published in 1989 and evaluating the efficacy of moricizine, encainide and flecainide in patients after myocardial infarction, with reduced ejection fraction and ventricular extrasystoles (4).
In currently available guidelines of the European Society of Cardiology concerning the treatment of patients with atrial fibrillation, published in 2010 and updated in 2012, antiarrhythmic drugs were divided into drugs used to restore sinus rhythm and drugs used for long – term sinus rhythm maintaining (5, 6).
Drugs used to restore sinus rhythm
In patients with atrial fibrillation of recent onset (< 48 hours), for whom the strategy for maintaining sinus rhythm was chosen or for whom other medical indications for the restoration of sinus rhythm exist (for example, clinical symptoms persisting despite adequate control of ventricular rate), it is possible to carry out pharmacological cardioversion by administration of antiarrhythmic drug as an intravenous bolus. According to the current ESC guidelines in the first class of recommendations for patients in whom pharmacological cardioversion is preferred and there is no structural heart disease, an intravenously flecainide, propafenone, ibutilide or vernakalant should be used and in patients with structural heart disease an amiodarone should be used. ESC experts emphasize the need for continous medical supervision and electrocardiogram monitoring during and directly after intravenous drug administration because of the risk of ventricular arrhythmias, sinus arrest or atrioventricular block. In selected patients with atrial fibrillation of recent onset and without significant structural heart disease, according to the ESC guidelines, an outpatient pharmacological cardioversion by oral administration of high single dose of flecainide or propafenone (IIa class of recommendations) should be considered. The “pill-in-the-pocket” approach and pharmacological outpatient self-cardioversion is possible, if its safety was previously demonstrated in the hospital. It should be offered to patients suffering from severe symptoms of AF, with infrequent reccurence of arrhythmia and after the careful consideration all the indications and contraindications for the use of these drugs. Both flecainide and propafenone belong to Vaughan Williams Ic class and act by inhibiting the intracellular fast sodium current and slowing the conduction. Furthermore, flecainide inhibits the opening of potassium channels, particularly fast current component K (IKr), extending the action potential duration in atria and ventricles cells. In contrast, within the Purkinje fibers, flecainide shortens the action potential duration due to an inhibition of the Na channel. Recent studies suggest that flecainide also blocks the opening of ryanodine receptor (RyR), thus reducing the spontaneous calcium release from the sarcoplasmic reticulum, which can potentially cause late depolarization and triggered activity (7). Due to weak blocking of beta – adrenergic receptors propafenone should not be administered to patients with severe obstructive lung disease. IC class drugs are discouraged in patients with significant structural heart disease, as they may prolong the QT interval and widen QRS complexes, creating the risk of ventricular proarrhythmia, as well as unintentionally accelerate the ventricular fibrillation due to conversion of atrial fibrillation to atrial flutter with ventricular conduction 1:1. Described percentage of this type of pro-arrhythmic action of flecainide vary from 3.5 to 5.0% (8). In order to reduce the risk of rapid conduction of supraventricular arrhythmia to ventricles, along with propafenone or flecainide there should be administered drugs that inhibit atrioventricular conduction (for example, beta-blockers, verapamil or diltiazem). However, in one study it was demonstrated that propafenone and flecainide can be safely taken in outpatient cardioversion (1/569 episode of converting to atrial flutter with rapid ventricular rhythm), and their effectiveness is quite high (94%). The return of sinus rhythm after oral administration of propafenone (450-600 mg) and flecainide (200-300 mg) was observed after 2-6 hours (9). In a recently performed large randomized FLEC-SL study the efficacy of oral flecainide therapy for prevention of atrial fibrillation recurrence was proved. It has been shown that a short-term (4 weeks) treatment with flecainide after the conversion to sinus rhythm in patients with persistent atrial fibrillation is not worse than the long-term treatment (6 months), and the drug is more efficient than placebo (10).
Vernakalant is a drug, which has been used to pharmacological cardioversion in patients with atrial fibrillation of recent onset (IA class of recommendations), patients with atrial fibrillation with a duration time < 7 days and with moderate structural heart disease or < 3 days after cardiac surgery (IIb class of recommendation, level of evidence B). The drug acts mainly in the atria, inhibiting several ion channels and leading to a prolongation of refraction and the slowing of conduction in the atria. The influence of vernakalant on conduction in the ventricles is limited. The efficacy of this drug was evaluated in several clinical studies. In ACT study (I-IV, a medium-sized randomized placebo-controlled studies) it was demonstrated the superiority of vernakalant in comparison with placebo in restoring sinus rhythm in patients with atrial fibrillation lasting < 7 days. In the CRAFT study the efficacy of different vernakalant doses restoring sinus rhythm were evaluated, showing the percentage of conversion of AF to sinus rhythm of 61% with a vernakalant dosage of 2 mg/kg for the first dose + 3 mg/kg in the next dose. In ACT, AVRO and Scene2 studies an infusion of 1 mg/kg within 10 minutes was administered, and then a bolus of 2 mg/kg, if AF was present 15 minutes after the first infusion. In the majority of patients (75-82%), sinus rhythm returned after the first dose (11-13). In a direct comparison (AVRO study) vernakalant more effectively than amiodarone restored sinus rhythm after 90 minutes (51.7 vs 5.2%; p < 0.0001) and 4 hours after infusion (54.4 vs 22.6%; p < 0.0001).
In the subgroups of patients with cardiovascular diseases (coronary heart disease, including myocardial infarction or hypertension) the efficacy of the drug was similar to the control group (45.7 vs 47.3%), and the incidence of adverse events (blood pressure decrease, bradycardia or ventricular arrhythmia) did not increase significantly, with the exception of patients with heart failure, which were less likely to benefit from the drug. As was proved, vernakalant is ineffective in restoring sinus rhythm in patients with atrial fibrillation lasting more than 7 days and in patients with atrial flutter (14, 15). Among the significant adverse events observed in patients, who were treated with vernakalant, compared with patients receiving placebo, the most commonly observed (5-7%) were transient hypotension, bradycardia, which, however, did not cause the need of drug withdrawal and short nsVT episodes, were the most commonly observed (7.3 vs 1.6% in the placebo group). Adverse effects more often occured in patients with the heart failure, but in spite of QTc prolongation (from 20 to 25 msec), there was no arrhythmia of torsade de pointes type. Mentioning the above-cited clinical studies, ESC experts in the current guidelines have formulated recommendations to use vernakalant, as safe and effective agent in patients with minimal or moderate heart disease, but a special caution was recommended in patients with heart failure I and II NYHA class, due to the increased risk of hypotension and ventricular arrhythmias. Contraindications to the use of vernakalant involve: systolic blood pressure < 100 mmHg, acute coronary syndrome within the previous 30 days, severe heart failure in III and IV NYHA class and significant aortic stenosis.
In patients with AF of recent onset and structural heart disease the only drug that can be administered for pharmacological cardioversion is amiodarone (IA class of recommendations). Sinus rhythm after intravenous injection of amiodarone was able to restore within 24 hours in 80-90% of patients in comparison with return of sinus rhythm in 40-60% of subjects treated with placebo. Amiodarone does not act effectively in a short period of time after administration. According to the guidelines, for pharmacological cardioversion there should not be used drugs ineffective in converting recent onset AF to sinus rhythm in patients with atrial fibrillation. ESC experts included to this group: digoxin, verapamil, metoprolol and other beta-blockers and ajmaline (III class of recommendations).
In Polish conditions, only propafenone and amiodarone are the drugs commonly available in clinical practice. In many centers the drug commonly used to restore sinus rhythm is phenazolinum, which does not have place in the current ESC guidelines. Phenazolinum belongs to antihistamines (H1-receptor antagonist) with anti-allergic effect. Because of the anticholinergic and cell membrane stabilizing effects, phenazolinum is included to Vaughan Williams class IA drugs (similar to quinidine). The agent prolongs the duration and decreases the amplitude of the action potential and the resting potential of phase 4. The efficacy of phenazolinum in restoring sinus rhythm is estimated at 52-70% in comparison with the complete effectiveness of pharmacological cardioversion of approx. 62% (16). In the absence of a recommendation for the drug in current guidelines, phenazolinum use in restoring sinus rhythm should be treated with adequate reserve, albeit soon there will be published the results of a randomized study on the effectiveness of phenazolinum that may affect the justification for the increased use of the drug.
Drugs used to maintain sinus rhythm
Initiation of treatment aimed at maintaining sinus rhythm should be justified by the presence of persistent symptoms associated with atrial fibrillation episodes in patient. The updated guidelines on atrial fibrillation, taking into account the results of meta-analyzes and review papers confirming the efficacy of antiarrhythmic therapy, as well as emerging reports associated with adverse effects (17-19), underline the leading role of the principle of “safety first”. Therefore, it was considered as a valuable observation that in some patients, for example in those with increased risk connected with treatment, a short-term antiarrhythmic drug therapy (4 weeks after cardioversion) can be used. It is also emphasized that the choice of the antiarrhythmic drug should be based more on the predicted safety of its use, rather than on the expected efficacy, although it is known that the probability of maintaining sinus rhythm by using the antiarrhythmic drug increases about 2 times. In a large meta-analysis of studies comparing antiarrhythmic drugs with placebo, no treatment or administration of heart rate controlling drugs, it was confirmed that drugs being both sodium antagonists with rapid (quinidine, disopyramide) and slow (propafenone, flecainide) binding kinetics, potassium channels inhibitors (dofetilide) and influencing on potassium channels and beta-adrenergic receptors (sotalol), as well as drugs affecting many ion channels with simultaneous inhibition of the sympathetic nervous system (amiodarone) significantly reduce the rate of recurrence of atrial fibrillation (20).
The choice of the antiarrhythmic drug should obviously be adapted to the patient’s clinical condition. In patients without structural heart disease as the first choice of antiarrhythmic drugs dronedarone, flecainide, propafenone or sotalol are recommended (I class of recommendations, drugs given in alphabetical order), while in case of their ineffectiveness amiodarone should be given. In patients with adrenergically stimulated atrial fibrillation (an paroxysm associated with physical exertion or mental distress) or with hyperthyroidism beta-blockers should be first taken into consideration, both in order to maintain sinus rhythm and ventricular rate control in case of recurrence of AF (IIa class of recommendations). In patients with AF caused by increased vagal nerve tone, disopyramide, a drug with a significant anticholinergic impact may be considered (IIb class of recommendations). In patients with a structural cardiovascular disease (left ventricular hypertrophy, ischemic heart disease or congestive heart failure), there are established contraindications to the use of particular antiarrhythmic groups of drugs. This group of patients has acutely high risk of pro-arrhythmic and negative inotropic effects of these drugs. The risk of pro-arrhythmic effect of sotalol results from QT prolongation or from bradycardia, which may result in the occurrence of tachycardia of torsade de pointes type. Particularly at risk of pro-arrhythmic drug effect are patients with significant left ventricular hypertrophy and with heart failure. Whereas, in the study SAFE-T in patients with coronary artery disease, the benefits from the use of sotalol comparable to that of amiodarone with a relatively good safety profile was found. The QT interval should be monitored in patients treated with sotalol and if it exceeds 500 ms, the drug should be discontinued. In addition to patients with left ventricular hypertrophy, those with significant bradycardia, hypokalemia or hypomagnesemia and women are more likely to be exposed to pro-arrhythmic effect of sotalol. The last meta-analysis of studies on drugs for maintaining sinus rhythm after cardioversion indicates that the use of sotalol is associated with higher all-cause mortality compared to the control group (20-22).
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1. Coumel P, Leenhardt A: Mental attivity, adrenergic modulation and cardiac arrhythmias in patients with heart dissease. Circulation 1991; 83: 1158-1170.
2. Snellen HA: History of cardiology. Donker Acadeic Publications, Rotterdam 1984.
3. Vaughan Wiliams EM: A classification of antiarrhythmic actions reassesed after a decade of new drugs. J Clin Pharmacol 1984; 24: 129-147.
4. Ruskin JN: The cardiac arrhythmina suppresion trial (CAST). N Engl J Med 1989; 321: 386-388.
5. Vahanian A, Auricchio A, Bax J et al.: Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010; 12: 1360-1420.
6. Camm AJ, Lip GY, De Caterina R et al.: 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012; 33: 2719-2747.
7. Watanabe H, Chopra N, Laver D et al.: Flecainide prevents catecholaminergic polymorphic ventircular tachycardia in mice and humans. Nat Med 1009; 15: 380-383.
8. Falk RH: Proarrhythmia in patients treated for atrial fibrillation or flutter. Ann Inter Med 1992; 117: 141-150.
9. Alboni P, Botto GL, Baldi N et al.: Outpatient treatment of recent – onset atrial fibrillation with the ‘pill-in-the-pocket’ approach. N Engl J Med 2004; 351: 2384-2391.
10. Kirchof P, Andersen D, Bosch R et al.: Short-term versus long-term antiarrhythmic dru treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded end-point assesment trial. Lancet 2012; 380: 238-246.
11. Pratt CM, Roy D, Torp-Pedersen C et al.: Atrial Arrhythmia Conversion Trial (ACT-III) Investigators. Usefulness of vernakalant hydrochloride injection for rapid conversion of atrial fibrillation. Am J Cardiol 2010; 106: 1277-1283.
12. Roy D, Rowe BH, Stiell IG et al.: CRAFT Investigators. A randomized, controlled trial of RSD1235, a novel anti-arrhythmic agent, in the treatment of recent onset atrial fibrillation. J Am Coll Cardiol 2004; 44: 2355-2361.
13. Stiell IG, Roos JS, Kavanagh KM, Dickinson G: A multicenter, open-label study of vernakalant for the conversion of atrial fibrillation to sinus rhythm. Am Heart J 2010; 159: 1095-1101.
14. Camm AJ, Capucci A, Hohnloser SH et al.: AVRO Investigators. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol 2011; 57: 313-321.
15. Camm AJ, Toft E, Torp-Pedersen C et al.: Scene 2 Investigators. Efficacyand safety of vernakalant in patients with atrial flutter: a randomized, double-blind, placebocontrolled trial. Europace 2012; 14: 804-809.
16. Kuch M, Janiszewski M, Dłużniewski M, Mamcarz A: Antazolina – lek nieskuteczny czy niedoceniany w leczeniu napadowego migotania przedsionków? Pol Przegl Kardiol 2000; 2: 247-251.
17. Freemantle N, Lafuente-Lafuente C, Mitchell S et al.: Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrialfibrillation. Europace 2011; 13: 329-345.
18. Piccini JP, Hasselblad V, Peterson ED et al.: Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54: 1089-1095.
19. Sullivan SD, Orme ME, Morais E, Mitchell SA: Interventions for the treatment of atrial fibrillation: A systematic literature reviewand meta-analysis. Int J Cardiol 2013; 165: 229-236.
20. Lafuente-Lafuente C, Valembois L, Bergmann JF, Belmin J: Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2015; 3: CD005049.
21. Haverkamp W, Breithardt G, Camm AJ et al.: The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J 2000; 21: 1216-1231.
22. Singh BN, Singh SN, Reda DJ et al.: Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352: 1861-1872.
23. Gierten J, Ficker E, Bloehs R et al.: The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone. Naunyn Schmiedebergs Arch Pharmacol 2010; 381: 261-270.
24. Linz DK, Afkham F, Itter G et al.: Effect of atrial electrical remodeling on the efficacy of antiarrhythmic drugs: comparison of amiodarone with I(Kr)- and I(to)/IKur-blockade in vivo. J Cardiovasc Electrophysiol 2007 Dec; 18(12): 1313-1320.
25. Palardy M, Ducharme A, Nattel S et al.; CTAF Investigators: Absence of protective effect of renin-angiotensin system inhibitors on atrial fibrillation development: insights from the Canadian Trial of Atrial Fibrillation (CTAF). Can J Cardiol 2008; 24: 709-713.
26. Zimetbaum P: Amiodarone for atrial fibrillation. N Eng J Med 2007; 356: 935-941.
27. Le Heuzey JY, De Ferrari GM, Radzik D et al.: A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21: 597-605.
28. Hohnloser SH, Crijns HJ, van Eickels M et al.: ATHENA Investigators: Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360: 668-678.
29. Duray GZ, Torp-Pedersen C, Connolly SJ, Hohnloser SH: Effects of dronedarone on clinical outcomes in patients with lone atrial fibrillation: pooled post hoc analysis from the ATHENA/EURIDIS/ADONIS studies. J Cardiovasc Electrophysiol 2011 Jul; 22(7): 770-776.
30. Singh BN, Connolly SJ, Crijns H et al.; EURIDIS and ADONIS Investigators: Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter. N Engl J Med 2007; 357: 987-999.
31. Davy JM, Herold M, Hoglund C et al.; ERATO Study Investigators: Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J 2008 Sep; 156(3): 527.
32. Connolly SJ, Camm AJ, Halperin JL et al.: PALLAS Investigators: Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365: 2268-2276.
33. Savelieva I, Kakouros N, Kourliouros A, Camm AJ: Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology Guidelines. Part II: secondary prevention. Europace 2011; 13: 610-625.
34. Bianconi L, Calo L, Mennuni M et al.: n-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical cardioversion of chronic persistent atrial fibrillation: a randomized, double-blind, multicentre study. Europace 2011; 13: 174-181.
35. Kowey PR, Reiffel JA, Ellenbogen KA et al.: Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA 2010; 304: 2363-2372.
36. Goette A, Schön N, Kirchhof P et al. Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) Trial. Circ Arrhythm Electrophysiol 2012; 5: 43-51.
37. Yamashita T, Inoue H, Okumura K et al.: J-RHYTHM II Investigators: Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II study). Europace 2011; 13: 473-479.
38. Ford J, Milnes J, Wettwer E et al.: Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. J Cardiovasc Pharmacol 2013: 60: 408-415.
39. Yamamoto W, Hashimoto N, Matsuura J et al.: Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing: comparison with class Ic and III drugs. J Cardiovasc Pharmacol 2014; 63: 421-427.
40. Scirica BM, Belardinelli L, Chaitman BR et al.: Effect of ranolazine on atrial fibrillation in patients with non-ST elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 trial. Europace 2015; 17: 32-37.
41. Rosa GM, Dorighi U, Ferrero S et al.: Ranolazine for the treatment of atrial fibrillation. Expert Opin Investig Drugs 2015; 24: 825-836.
42. Gupta T, Khera S, Kolte D et al.: Antiarrhythmic properties of ranolazine: A review of the current evidence. Int J Cardiol 2015; 187: 66-74.
43. De Ferrari GM, Maier LS, Mont L et al.: RAFFAELLO Investigators (see Online Supplementary Appendix for List of Participating Centers and Investigators): Ranolazine in the treatment of atrial fibrillation: Results of the dose-ranging RAFFAELLO (Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion) study. Heart Rhythm 2015; 12(5): 872-878.
44. Yi F, Ling TY, Lu T et al.: Down-regulation of the small conductance calcium-activated potassium channels in diabetic mouse atria. J Biol Chem 2015; 290: 7016-7026.
45. Chen WT, Chen YC, Lu YY et al.: Apamin modulates electrophysiological characteristics of the pulmonary vein and the Sinoatrial Node. Eur J Clin Invest 2013; 43: 957-963.
46. Shin SY, Jo WM, Min TJ et al.: Gap junction remodelling by chronic pressure overload is related to the increased susceptibility to atrial fibrillation in rat heart. Europace 2015; 17: 655-663.
47. Qi XY, Yeh YH, Xiao L et al.: Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circ Res 2008; 103: 845-854.
48. Makary S, Voigt N, Maguy A et al.: Differential protein kinase C isoform regulation and increased constitutive activity of acetylcholine-regulated potassium channels in atrial remodeling. Circ Res 2011; 109: 1031.
49. Chiang DY, Li N, Wang Q et al.: Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation. Cardiovasc Res 2014; 103: 178-187.
50. Dobrev D, Wehrens XH: Role of RyR2 phosphorylation in heart failure and arrhythmias: Controversies around ryanodine receptor phosphorylation in cardiac disease. Circ Res 2014; 11: 1311-1319.
51. Avila G, Osornio-Garduño DS, Ríos-Pèrez EB, Ramos-Mondragón R: Functional and structural impact of pirfenidone on the alterations of cardiac disease and diabetes mellitus. Cell Calcium 2014; 56: 428-435.
52. Wang J, Wang Y, Han J et al.: Integrated analysis of microRNA and mRNA expression profiles in the left atrium of patients with nonvalvular paroxysmal atrial fibrillation: Role of miR-146b-5p in atrial fibrosis. Heart Rhythm 2015; 12: 1018-1026.