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international Heart and Vascular Disease Journal Volume 2, Number 4, November 2014
Journal of the Cardioprogress Foundation
LEADING ARTICLE
Antiarrhythmic therapy in patients
with paroxysmal and persistent atrial fibrillation: prediction and prevention of progression to permanent form of arrhythmia
State Budget Educational Institution of Higher Professional Education «Kuban State Medical University» of the Ministry of Healthcare of the Russian Federation, 350 063, Russia, Krasnodar, 4 Sedin Street
Author:
Sergey G. Kanorskiy, MD, Professor, Head of the Department of Therapy № 2 of Faculty of Advanced Training and Professional Retraining of Specialists of the State Budget Educational Institution of Higher Professional Education «Kuban State Medical University» of the Ministry of Healthcare of the Russian Federation, Krasnodar, Russia
A realistic objective for treatment of patients with paroxysmal and persistent atrial fibrillation (AF) should be to prevent its progression to a permanent form of arrhythmia, which is associated with an increased risk of complications and worsening prognosis. This review presents easily identifiable predictors of AF progression, reviews available treatment options, and their efficacy and safety. Early and active measures to restore and maintain sinus rhythm by pharmacological and non-drug methods will prevent the development of arrhythmia substrate; inhibit the progression from paroxysmal to permanent AF, with potentially beneficial effects on prognosis.
Keywords
Atrial fibrillation, progression, treatment
Kanorskiy S.G.
*
Summary
* Corresponding author. Tel: +7 918 355 82 81. Fax: +7 (861) 268 17 95. E-mail: [email protected]
Between 1990 and 2010, the prevalence of AF worldwide, and its associated morbidity and mortality, increased about two times despite the best efforts of medical science and health care [1]. According to epidemiological studies conducted in Western Europe, AF is already detected in 2.0-4.7% of cases in the general population [2]. According to forecasts, by 2050 the number of patients with AF may increase more than two times [3]. AF is a major cause of stroke and congestive heart failure (HF). Even in AF patients under the age of 65 years without concomitant diseases, there is a two-fold increase in mortality compared with general population [4].
In six randomized clinical trials (PIAF, AFFIRM, RACE, STAF, HOT CAFÉ, AF CHF), treatment strategies in AF patients to restore and maintain sinus rhythm did not reduce mortality compared with the tactics of shortening the ventricular rate while maintaining AF. This result is associated with a lack of efficacy and safety of modern anti-arrhythmic drugs, and with the limitations of design of research studies [5]. In those studies, elderly patients with late-stage development of an AF substrate in atria and considerable stability arrhythmia were included. Meanwhile, even in those studies a decrease in symptoms and improvement in quality of life has been convincingly demonstrated while maintaining sinus rhythm, as well as a significant reduction in total mortality by 47% (P<0.0001) in the actual maintenance of normal sinus rhythm during observation period [6].
In general, the results of AF treatment are far from desired, which is often attributed to an inadequate understanding of the mechanisms of its development. At the same time, cellular and molecular mechanisms of AF initiation have been well studied [7]. It has been established that aging, hypertension, valve disease, HF, myocardial infarction, obesity, smoking, diabetes, thyroid dysfunction and intense physical endurance training contribute to structural remodeling of the atria [8]. With regard to clinical practice, special attention is drawn to the concept of AF progression from paroxysmal to a permanent clinical form [9].
Paroxysmal AF may take up to 7 days, but differs by spontaneous termination, usually within the first 48 hours. In paroxysmal AF lasting more than 48 hours, the probability of spontaneous termination of arrhythmia is low, but the risk of systemic thromboembolism significantly increases, which requires consideration of initiating antithrombotic therapy. Persistent AF, unlike paroxysmal, does not stop by itself, continues for more than 7 days, and medication or electrical cardioversion may be useful in resolving
the problem. Prolonged persistent AF is diagnosed when AF continues for a year or more, and the strategy of sinus rhythm restoration and conservation using anti-arrhythmic drugs and/or ablation in the left atrium are chosen. Permanent AF is diagnosed in cases when a patient and a doctor consider possible to preserve arrhythmia, or when previous attempts of cardioversion or cardiac surgery treatments have been unsuccessful [10,11].
In recent years, antithrombotic therapy in patients with AF has become the most popular, which actually changes the prognosis for patients. It is emphasized that the risk of stroke depends not on the form of AF (paroxysmal, persistent or permanent), but on other clinical factors, summarized by scales, CHADS2 and more modern CHA2DS2-VASc, designed to assess stroke risk [10,11]. Indeed, according to the ACTIVE W study, the incidence of stroke in patients with paroxysmal (n=1,202, the average score CHADS2 1.79±1.03), persistent and permanent AF (n=5,495, the average score CHADS2 2.04±1.12, P <0.00001) was not significantly different (P=0.496), even after adjusting for baseline clinical differences (P=0.755) [12]. One might think that in paroxysmal AF a shorter period of blood stagnation in the atria during fibrillation takes place, but the rapid restoration of mechanical atrial systole contributes to dislocation of fresh blood clots into the arterial system. In persistent/permanent AF, long/continuous stagnation of blood in the atria creates a constant environment for thrombus formation in the atria, but long-term/permanent absence of mechanical atrial systole allows blood clots to organize, to grow together with the wall of the atrium and even dissolve by the fibrinolytic system in the body.
However, in a large modern study, ARISTOTLE, the frequency of stroke or systemic embolism was significantly higher in patients with persistent or permanent AF (n=15,412) than in patients with paroxysmal AF (n=2,786) (1.52% vs. 0.98%, P=0.003, adjusted for baseline clinical differences P=0.015). There was also a tendency towards higher mortality in patients with persistent or permanent AF (3.90% vs. 2.81%, P= 0.0002, adjusted P=0.066) [13].
K. Imai et al. [14] recently developed and tested a scale assessing the risk of severe HF in New York Heart Association (NYHA) functional class III or IV patients with non-valvular AF - ARC2H. According to this scale, a patient gains 1 point if he/she is 72 years and older, has heart rate of 80 beats per minute or more, hypertension, and he/she gains 2 points if there is previously established HF.
The annual risk of severe HF ranged from 0.8% to 35% in patients with 0 and 5.4 points according to ARC2H, respectively. In the largest study, AFFIRM, which compared the tactics of restoring and maintaining sinus rhythm with the tactics of shortening of ventricular rate while maintaining AF, the long duration of AF was directly related to the high prevalence of symptoms of chronic HF [15].
According to S. Taillandier et al. [16], among 1,906 patients with a combination of AF and chronic HF, 55% of patients had persistent or paroxysmal and 45% -permanent form of arrhythmia. During an about 1.9 years of follow-up, the risk of hospitalization for decompensation of HF was significantly higher in patients with permanent AF, especially in a subgroup of individuals with preserved left ventricular ejection fraction.
The presented data confirm the known position [17] - slowing the progression of AF to its more prolonged forms may be considered as one of the goals of its therapy that can mitigate a risk of thromboembolism, HF and mortality. Modern ideas about the factors of such AF progression necessarily include structural and electrical remodeling of the atria. Sustained AF can cause an inflammatory reaction that leads to activation of myofibroblasts and the release of cytokines, such as transforming growth factor-B and platelet-derived growth factor, and also profibrotic proteins. Activation of signaling cascades involving the latter is essential for the development of fibrosis. It leads to dysfunction of ion channels, apoptosis of cardiomyocytes and growth of extracellular matrix, which contributes to both electric and structural remodeling - the basis for preservation of AF [18,19].
Studies of modern pharmacological types of treatment of underlying disease (upstream therapies) to prevent electric (blockers of slow calcium channels) and structural remodeling, fibrosis (renin-angioten-sin system blockers, statins, omega-3 fatty acids), revealed contradictory, mostly negative results [20,21]. Despite this, one of the objectives of treating AF patients should be regression of left ventricular hypertrophy. Multivariate data analysis of the AFFIRM project has shown that thickening of the left ventricular wall, especially the interventricular septum, is an independent predictor for overall mortality (1.46 relative risk (RR), 95% confidence interval (CI), from 1.14 to 1.86, P=0.003) and stroke (1.89 RR, 95% CI, from 1.17 to 3.08, P=0.01). Concentric left ventricular hypertrophy was associated with the highest overall mortality (1.53 RR, 95% CI, from 1.11 to 2.12, P=0.009) [22]. It is
known that the presence of left ventricular hypertrophy increases the risk of death because of ventricular tachyarrhythmia, including instigated antiarrhythmic therapy.
Moreover, left ventricular hypertrophy predisposes to the resumption of AF during a therapy to maintain sinus rhythm. In a cohort of 1,088 participants of the AFFIRM study, the median time of AF recurrence in patients with concentric left ventricular hypertrophy was 13.3 months (95% CI, from 8.2 to 24.5) versus 28.3 months (95% CI, from 20.2 to 48.6) in patients without hypertrophy. Concentric type of hypertrophy was an independent predictor of AF recurrence (1.49 RR, 95% CI, from 1.10 to 2.01, P=0.01) [23].
R. Chung et al. [24] selected 537 AF patients with left ventricular hypertrophy where the wall thickness s1.4 cm (mean age 67.5±11.7 years, left ventricular ejection fraction (LVEF) 48.3±13.3%), some not receiving antiarrhythmic drugs and some receiving amiodarone or other antiarrhythmic agents to maintain sinus rhythm. Amiodarone therapy was associated with lower survival (P=0.001), even after age adjustment, LVEF and the presence of coronary artery disease (CAD) (P=0.023). These data do not support expert opinion that treatment of persistent AF in patients with left ventricular hypertrophy should be conducted with amiodarone due to the fact that, compared to it, other antiarrhythmic drugs increase mortality [25].
According the Euro Heart Survey registry [26] and J-RHYTHM II study [27], within one year 10-15% of patients have progression from paroxysmal to persistent AF. It is shown that old age, organic heart disease, hypertension, AF lasting more than 3 months, tactics of shortening ventricular rate contribute to progression to more sustainable forms of AF, but restoration and maintenance of sinus rhythm, left atrial dilatation and obesity do not [28]. Also, the HATCH score was suggested, according to which a patient gets 2 points for the presence of HF and history of transient ischemic attack / stroke, and 1 point for the age over 75 years, hypertension, chronic obstructive pulmonary disease [17]. If the total score is from 5 to 7 the risk of progression from paroxysmal to persistent AF on the background of a drug therapy can reach 35-50%, and at 0 points - about 6%.
It is important to note that psychological status of AF patients deteriorates as arrhythmia progresses. In a study conducted by A.F. von Eisenhart Rothe et al. [29], after eliminating the influence of gender, age and other relevant factors, major depressive disorder occurred 44% more often (P=0.007) at persistent AF compared to paroxysmal.
Antiarrhythmic drugs, despite their well-known shortcomings, remain the only widely available means for the effective suppression of AF, i.e. implementation of tactics of maintaining sinus rhythm. Are they able to slow the progression of this arrhythmia to its permanent form? In AF patients with maintaining sinus rhythm, the left atrium decreases in size and left ventricular systolic function improves. Both of these indicators are important factors associated with progression of AF [30]. However, in a study conducted by S.B.de Vos et al. [31], only class IC antiarrhythmic medications significantly (P=0.0013) inhibited the progression of AF during a year of observation.
The most dangerous, though rare, side effect of class I drugs is a ventricular tachyarrhythmia. Its harbinger is an expansion of the QRS complex on the electrocardiogram (ECG). In the AFFIRM study, to maintain sinus rhythm it was allowed to use drugs of class IA (disopyramide, procainamide, quinidine) and class IC (moricizine, propafenone, flecainide). The QRS duration s 120 ms was associated with a significant (1.61 RR, 95% CI, from 1.29 to 2.03, P<0.001) increase in the risk of death (all-cause, cardiovascular and arrhythmic) and hospitaliza-tion (1.14 RR, 95% CI, from 1.07 to 1.34, P=0.043). Increased mortality (P=0.03) was also observed among patients with QRS duration 90-119 ms and concomitant HF [32].
These recently published data require consideration when choosing between available in Russian class IC antiarrhythmic drugs allapinin, propafenone and etatsizin. When used in normal dosages allapinin the least expands the QRS complex, which ensures the highest safety of therapy, but does not at least inferior to propafenone and etatsizin efficiency. According to our data, in comparable groups of patients with highly symptomatic persistent AF (Table 1), allapinin in dose of 67±12 mg/day caused widening of the QRS complex by 14% in average, propafenone - 385±44 mg/ day - 19%, and etatsizin - 126±20 mg/day - 23%, respectively.
To prevent such side-effect of class IC antiarrhythmic drugs as atrial flutter with a high frequency of impulses to the ventricles, to achieve a therapy of high anti-relapse activity for AF even at lower doses of drugs it is appropriate to take them in combination with sotalol or amiodarone [33]. According to the latest data of the PREFER registry [34], in 461 centers of 7 European countries frequently AF patients, in order to maintain sinus rhythm, are assigned amiodarone (24.1% of cases), flecainide or propafenone (13.5%), sotalol (5.5%), and dronedarone (only 4.0%, respectively). Similar statistics from 9 European countries was presented by the authors of the EORP-AF registry [35]. Before starting treatment with amiodarone and every 6-12 months of therapy, it is required to monitor the lungs, liver and thyroid. The ORBIT-AF registry in the US [36] showed that among 10,061 AF patients, the majority of them (often elderly people with hypertension, HF, previous stroke, and minimally symptomatic arrhythmias) received therapy which slows down the ventricular rate. Of course, this treatment strategy does not provide reverse remodeling of the heart and enhances morphological changes in the atria that perpetuate the arrhythmia [37].
Currently, the EAST study, in order to prevent stroke and other adverse events by early therapy of preserving sinus rhythm, includes patients with newly emerging AF and a CHA2DS2-VASc score of 2 or more [38]. It is assumed that preservation of sinus rhythm from the early detection of AF will keep the structure and function of the atria more effectively than the standard treatment (transition to the restoring and maintaining sinus rhythm in case of continued symptoms with effective reduction of ventricular contractions on the background of AF). The EAST project suggests using not only antiarrhythmic drug therapy of AF, but also catheter ablation in the left atrium.
In 2012, two authoritative expert groups expanded indications for radiofrequency catheter ablation to maintain sinus rhythm in patients with AF [25,39].
Parameter Allapinin (n=28) propafenone (n=24) Etatsizin (n=25)
Age, years, (M±m) 59.5±5.3 57.7±4.8 56.8±4.9
Men/Women 14/14 11/13 13/12
Hypertension,% 78.6% 83.3% 76.0%
Idiopathic AF, % 10.7% 4.6% 12.0%
CAD,% 10.7% 12.5% 12.0%
Functional class of chronic HF, (M±m) 1.50±0.33 1.43±0.26 1.58±0.29
Anteroposterior diameter of the left atrium, mm (M±m) 43.6±2.1 44.2±2.3 43.8±2.0
LVEF, % (M±m) 60.5±4.2 58.6±3.8 62.1±4.5
Table 1. Baseline characteristics of patients with persistent AF
Recently, the first results of the multicenter, prospective, randomized SARA study of 146 patients with persistent AF were published, it established the superiority of catheter ablation in the maintenance of sinus rhythm compared with antiarrhythmic drug therapy. From 3 to 12 months after initiation of the therapy, there were no records of episodes of AF or atrial flutter lasting more than 24 hours in 70.4% of patients who underwent ablation, and in 43.7% of patients treated with class IC or III antiarrhythmic drugs (P=0.002) [40].
Regression of dilatation and remodeling of the left atrium was observed in AF patients after catheter isolation of pulmonary veins [41]. As a result of sinus rhythm restoration and maintenance, initially decreased LVEF significantly increases, exercise tolerance and quality of life improves compared with the tactics of shortening of ventricular rate while maintaining AF [42,43].
Despite these positive data directly indicating preferred tactics of sinus rhythm control, the left atrial catheter ablation in terms of its implementation requires further research [44]. It is still carefully studied and evaluated the frequency of such immediate complications of this invasive procedure as pericardial effusion, cardiac tamponade, pulmonary vein stenosis, ulcers or esophageal perforation with the atrio-esophageal fistula formation, stroke/transient ischemic attack, phrenic nerve injury, arteriovenous fistula in a puncture on the hip [45].
No one denied the presumption of a possible deterioration of atrial function in years after ablation. H. Cochet et al. [46] studied the structure and function of the left atrium in 26 patients with persistent AF 80±15 months after radiofrequency catheter ablation. According to magnetic resonance imaging (MRI), contractility and compliance of the left atrium noticeably deteriorated after 5 years of successful ablation of persistent AF in direct relation to scar size.
Radiofrequency catheter ablation appears to be the most appropriate in paroxysmal AF. Observation of 889 patients with paroxysmal or persistent/long-lasting persistent AF for an average of 64 months after catheter ablation in the left atrium (pulmonary vein isolation and linear effects) showed an early advantage of such procedure. AF progression to its permanent form was significantly more frequently observed in patients with persistent (10%) or long-lasting persistent AF (14.6%) than in patients with paroxysmal AF (2.7%, P<0.001) [47].
The ongoing big CABANA and EAST projects will help in the future answer the remaining questions,
including the long-term efficacy of catheter ablation and the impact of the underlying disease on treatment outcomes.
During open heart surgery, some surgical effects can be performed on the atria to eliminate AF. According to the results of 7 comparative studies of surgical ablation on the epicardial surface and radio-frequency ablation on the endocardial surface of the left atrium, the first procedure usually eliminates AF during a year (74% versus 43% of patients; 3.91 RR, 95% CI, from 2.38 to 6.42, P<0.00001). However, the surgical ablation often required pacemaker implantation, and the number of neurological complications and cardiac tamponade appeared to be comparable to those in the group of catheter ablation [48].
A tolerant attitude toward asymptomatic AF is erroneous. K.Senoo et at. [49] observed 1,176 patients with paroxysmal AF in average for 1,213±905 days, noting the progress of arrhythmia toward its permanent form with a frequency of 6% per year. In 468 asymptomatic, at the first examination, patients, even at low levels of risk, a more frequent progression of AF was noted compared to patients who had arrhythmia symptoms. This paradoxical result, according to the authors, is due to less intensive drug treatment and rare use of radiofrequency ablation to maintain sinus rhythm.
Management of the known risk factors may also be useful. According to a 16-year observation of 34,720 female participants in the Women's Health Study project who did not initially have AF and cardiovascular disease, obesity and elevated levels of hemoglobin A1c contribute to the occurrence of persistent and permanent AF. It is expected that reduction of overweight and glycemic control can reduce the proportion of people with persistent AF [50].
Conclusion
Large clinical investigations have not yet shown prognostic benefits of rhythm control compared with ventricular rate control during persistent AF, but they included patients in the late stages of the disease. It is likely that only intervention at an early stage of AF progression will be more effective. Early and active measures to detect AF, restoration and maintenance of sinus rhythm by pharmacological and non-drug methods will prevent the development of arrhythmia substrate, inhibit the progression from paroxysmal to persistent AF with potentially beneficial effects on prognosis. Therefore, for relatively young patients and/or for patients with severe symptoms of AF, restoration and maintenance of sinus rhythm is preferred.
Conflict of interest: None declared References
1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: A Global Burden of Disease 2010 Study. Circulation. 2014;129:837-47.
2. Davis RC, Hobbs FD, Kenkre JE, et al. Prevalence of atrial fibrillation in the general population and in high-risk groups: the ECHOES study. Europace. 2012;14:1553-9.
3. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119-25.
4. Olsson LG, Swedberg K, Lappas G, et al. Trends in mortality after first hospitalization with atrial fibrillation diagnosis in Sweden 1987 to 2006. Int J Cardiol. 2013;170:75-80.
5. Angaran P, Dorian P. Antiarrhythmic drugs in atrial fibrillation: do they have a future? Can J Cardiol. 2013;29:1158-64.
6. Corley SD, Epstein AE, DiMarco JP, et al.; AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109:1509-13.
7. Voigt N, Heijman J, Wang Q, et al. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation. 2014;129:145-56.
8. Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res. 2014;114:1453-68.
9. Heijman J, Voigt N, Nattel S, Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res. 2014;114:1483-99.
10. Sulimov VA, Golitsyn SP, Panchenko YeP. Diagnostika i lecheni-ye fibrillyatsii predserdiy. Rekomendatsii RKO, VNOA i ASSKH, 2012 [Diagnosis and treatment of atrial fibrillation. Guidelines RKO, VNOA and ASSKH, 2012]. Rossiyskiy kardiologicheskiy zhurnal 2013;4(102), prilozheniye 3. Russian.
11. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology. Eur Heart J. 2010;31:2369-429.
12. Hohnloser SH, Pajitnev D, Pogue J, et al. ACTIVE W Investigators. Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W Substudy. J Am Coll Cardiol. 2007;50:2156-61.
13. Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixa-ban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J. 2013;34:2464-71.
14. Imai K, Okura H, Tamada T, et al. Prediction of congestive heart failure in patients with non valvular atrial fibrillation. Intern Med. 2014;53:7-12.
15. Guglin M, Chen R. How much atrial fibrillation causes symptoms of heart failure? Int J Clin Pract. 2014;68:453-7.
16. Taillandier S, Brunet Bernard A, Lallemand B, et al. Prognosis in patients hospitalized with permanent and nonpermanent atrial fibrillation in heart failure. Am J Cardiol. 2014;113:1 189-95.
17. de Vos CB, Pisters R, Nieuwlaat R, et al. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol. 2010;55:725-31.
18. Jalife J. Mechanisms of persistent atrial fibrillation. Curr Opin Cardiol. 2014;29:20-7.
19. Kottkamp H. Human atrial fibrillation substrate: towards a specific fibrotic atrial cardiomyopathy. Eur Heart J. 2013;34:2731-8.
20. 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 I: primary prevention. Europace. 2011;13:308-28.
21. 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;13:610-25.
22. Apostolakis S, Sullivan RM, Olshansky B, Lip GY. Left ventricular geometry and outcomes in patients with atrial fibrillation: The AFFIRM Trial. Int J Cardiol. 2014;170:303-8.
23. Shah N, Badheka AO, Grover PM, et al. Influence of left ventricular remodeling on atrial fibrillation recurrence and cardiovascular hospitalizations in patients undergoing rhythm-control therapy. Int J Cardiol. 2014;174:288-92.
24. Chung R, Houghtaling PL, Tchou M, et al. Left ventricular hypertrophy and antiarrhythmic drugs in atrial fibrillation: impact on mortality. Pacing Clin Electrophysiol. 2014 0ct;37(10): 1338-48.
25. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation-developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33:2719-47.
26. Nieuwlaat R, Prins MH, Le Heuzey JY, et al. Prognosis, disease progression, and treatment of atrial fibrillation patients during 1 year: follow-up of the Euro Heart Survey on atrial fibrillation. Eur Heart J. 2008;29:1181-9.
27. Yamashita T, Inoue H, Okumura K, et al. 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;13:473-9.
28. Tsang TS, Barnes ME, Miyasaka Y, et al. Obesity as a risk factor for the progression of paroxysmal to permanent atrial fibrillation: a longitudinal cohort study of 21 years. Eur Heart J. 2008;29:2227-33.
29. von Eisenhart Rothe AF, Goette A, Kirchhof P, et al. Depression in paroxysmal and persistent atrial fibrillation patients: a cross-sectional comparison of patients enroled in two large clinical trials. Europace. 2014;16:812-9.
30. Hagens VE, Van Veldhuisen DJ, Kamp O, et al. Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: results from the RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study. Heart Rhythm. 2005;2:19-24.
31. De Vos CB, Breithardt G, Camm AJ, et al. Progression of atrial fibrillation in the REgistry on Cardiac rhythm disORDers assessing the control of Atrial Fibrillation cohort: clinical correlates and the effect of rhythm-control therapy. Am Heart J. 2012;163:887-93.
32. Whitbeck MG, Charnigo RJ, Shah J, et al. QRS duration predicts death and hospitalization among patients with atrial fibrillation irrespective of heart failure: evidence from the AFFIRM study. Europace. 2014;16:803-11.
33. Kanorskiy SG. Sovremennaya medikamentoznaya terapiya fibrillyatsii predserdiy: vybor taktiki, antiaritmicheskikh pre-paratov i skhem lecheniya [Modern drug therapy of atrial fibrillation: selection of treatment strategy, antiarrhythmic preparations, and schemes of treatment]. Kardiologiya. 2012;9:58-63. Russian.
34. Kirchhof P, Ammentorp B, Darius H, et al. Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention oF thromboemolic events-European Registry in Atrial Fibrillation (PREFER in AF). Europace. 2014;16:6-14.
35. Lip GY, Laroche C, Dan GA, et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EuroObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace. 2014;16:308-19.
36. Steinberg BA, Holmes DN, Ezekowitz MD, et al. Rate versus rhythm control for management of atrial fibrillation in clinical practice: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Am Heart J. 2013;165:622-9.
37. Shukla A, Curtis AB. Avoiding permanent atrial fibrillation: treatment approaches to prevent disease progression. Vasc Health Risk Manag. 2014;10:1-12.
38. Kirchhof P, Breithardt G, Camm AJ, et al. Improving outcomes in patients with atrial fibrillation: rationale and design of the Early treatment of Atrial fibrillation for Stroke prevention Trial. Am Heart J. 2013;166:442-8.
39. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace. 2012;14:528-606.
40. Mont L, Bisbal F, Hernandez-Madrid A, et al. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur Heart J. 2014;35:501-7.
41. Bisbal F, Guiu E, Cabanas P, et al. Reversal of spherical remodelling of the left atrium after pulmonary vein isolation: incidence and predictors. Europace. 2014;16:840-7.
42. Hunter RJ, Berriman TJ, Diab I, et al. A randomised controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (THE CAMTAF trial). Circ Arrhythm Electrophysiol. 2014;7:31-8.
43. Nedios S, Sommer P, Dagres N, et al. Long-term follow-up after atrial fibrillation ablation in patients with impaired left ventricular systolic function. The importance of rhythm and rate control. Heart Rhythm. 2014;11:344-51.
44. Hindricks G, Packer DL. Moving catheter ablation forward from paroxysmal to persistent atrial fibrillation: progress, limitations, and surprises of the SARA trial. Eur Heart J. 2014;35:482-4.
45. Gupta A, Perera T, Ganesan A, et al. Complications of catheter ablation of atrial fibrillation: a systematic review. Circ Arrhythm Electrophysiol. 2013;6:1082-8.
46. Cochet H, Scherr D, Zellerhoff S, et al. Atrial structure and function 5 years after successful ablation for persistent atrial fibrillation: an MRI study. J Cardiovasc Electrophysiol. 2014;25:671-9.
47. Scaglione M, Gallo C, Battaglia A, et al. Long-term progression from paroxysmal to permanent atrial fibrillation following transcatheter ablation in a large single-center experience. Heart Rhythm. 2014;11:777-82.
48. Kearney K, Stephenson R, Phan K, et al. A systematic review of surgical ablation versus catheter ablation for atrial fibrillation. Ann Cardiothorac Surg. 2014;3:15-29.
49. Senoo K, Suzuki S, Otsuka T, et al. Progression to the persistent form in asymptomatic paroxysmal atrial fibrillation. Circ J. 2014;78:1121-6.
50. Sandhu RK, Conen D, Tedrow UB, et al. Predisposing factors associated with development of persistent compared with paroxysmal atrial fibrillation. J Am Heart Assoc. 2014;3:e000916.
