Curr Atheroscler Rep (2017) 19: 3 DOI 10.1007/s11883-017-0638-1

CARDIOVASCULAR DISEASE AND STROKE (S. PRABHAKARAN, SECTION EDITOR)

Early Cardioversion in Atrial Fibrillation: Earlier Is Better, but Not Always and (Maybe) Not Immediately Paloma G. Piña 1 & Alexandru B. Chicos 1

Published online: 20 January 2017 # Springer Science+Business Media New York 2017

Abstract Atrial fibrillation (AF) is the most common cardiac arrhythmia in humans. One of its important features is the tendency to become more persistent over time, even in the absence of underlying progressive heart disease. Conversion and maintenance of sinus rhythm by pharmacological or electrical methods become increasingly difficult the longer the arrhythmia persists. Electrical, mechanical, structural, and autonomic remodeling processes have been implicated in the mechanisms of AF initiation, perpetuation, and progression. Prevention or reversal of these remodeling processes can halt the progression of the disease. Cardioversion is a powerful tool and rhythm control is a widely used strategy in the management of AF. However, important questions remain unanswered regarding not only if, but also when to perform cardioversion. There are observations from past trials and clinical situations that support attempting to restore sinus rhythm, but further prospective randomized clinical trials are needed. Optimal timing of cardioversion remains somewhat uncertain, but it appears to be some time after the first few hours and before the first few months: the earlier, the better, but not always, and maybe not immediately, and it has to be tailored to the clinical situation and its many variables. This review is intended to summarize the evidence supporting early intervention for the prevention of remodeling in patients with AF.

This article is part of the Topical Collection on Cardiovascular Disease and Stroke * Alexandru B. Chicos [email protected] 1

Clinical Cardiac Electrophysiology, Bluhm Cardiovascular Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA

Keywords Atrial fibrillation . Remodeling . Early cardioversion . Rhythm control

Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia in humans. Its prevalence increases with age, affecting 25% of the general population older than 80 years [1]. AF is a source of significant morbidity and is associated with almost a doubling of the mortality risk and a fivefold to sevenfold increase in the ischemic stroke risk [2,3]. AF is a progressive arrhythmia. One of its important features is the tendency to become more persistent over time, even in the absence of underlying progressive heart disease. Conversion and maintenance of sinus rhythm by pharmacological or electrical methods become increasingly difficult the longer the arrhythmia persists [4]. The rate of progression varies with patient population and duration of follow-up, but as many as 77% of patients progress to persistent or chronic forms when followed over 14 years [5,6]. Overall, the yearly progression rate is 5%, except in young patients without underlying structural cardiovascular disease, who have predominantly paroxysmal AF. Older patients, and those with underlying heart disease, have faster progression rates. The progressive nature of AF is consistent with the occurrence of atrial remodeling, which represents an important factor in the self-perpetuation of AF. Despite studies done in experimental animal models and in humans, the pathophysiology of atrial fibrillation is still not completely understood. Electrical, mechanical, structural, and autonomic remodeling processes have been implicated in the mechanisms of AF initiation, perpetuation, and progression [7, 8•, 9–13]. Remodeling is a dynamic and progressive process, an adaptive regulatory response of cardiac myocytes that occurs

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over time in order to maintain homeostasis against external stresses [14–16, 17•, 18]. The concept of atrial remodeling encompasses changes on several main levels: electrophysiological properties (electrical remodeling); decreased contractility and dilatation (mechanical remodeling); structural and ultrastructure changes, including myocyte death and development of interstitial fibrosis (structural remodeling); and endocrine and autonomic changes.

Electrical Remodeling Two independent studies in animal models [8•, 13] of AF induced by rapid atrial pacing were published in 1995 and described electrophysiological changes induced by recurrent AF (see Table 1). In 1995, Wijffels et al [8•] demonstrated in a goat model undergoing rapid atrial pacing that atrial effective refractory period (AERP) progressively decreases, resulting in an increase in the inducibility, stability, and fibrillatory rate of AF. This study introduced the important concept of “electrical remodeling” in atrial fibrillation, and, with it, the dictum “atrial fibrillation begets atrial fibrillation” was born. Morillo et al [13] demonstrated that rapid atrial pacing over 6 weeks in dogs resulted in shortening of atrial refractory periods, increased inducibility and stability of AF, decreased atrial conduction velocity, and increased P wave duration. These studies did not control ventricular rates. While changes in left ventricular function were not reported, probably the animals developed a tachycardia-mediated ventricular cardiomyopathy and congestive heart failure. Subsequent studies subsequently suggest that this is the case [19•]. Thus, the remodeling changes observed in these studies may reflect the combined effects of rapid atrial rates and of congestive heart failure (increased left atrial pressure and wall stress, stretch, neurohormonal changes, etc.) Experimental atrial electrical remodeling is complete within hours to days, whereas the development of sustained AF Table 1 pacing

Atrial electrical remodeling in animal models of rapid atrial

Atrial electrical remodeling in animal models of rapid atrial pacing • ↓AERP • ↓Conduction velocity • ↑P wave duration • ↑Inducibility and stability of AF (“AF begets AF”) • ↓Sinus node function • ↑Heterogeneity of atrial conduction and atrial refractoriness (may occur after only 24 h of rapid atrial pacing) Observed changes were caused, most likely, by the combined effects of rapid atrial rates (rapid atrial pacing, atrial fibrillation) and left ventricular dysfunction and congestive heart failure AERP atrial effective refractory period, ↓/↑ decreased/increased

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generally takes at least 1 week, suggesting that other factors must be involved. In 1996, Daoud et al. confirmed in humans that just several minutes of electrically induced AF shortens the atrial effective refractory period for up to 8 min and that this shortening correlates with an increased propensity for the induction of secondary AF [20]. In 1997, Franz and coworkers demonstrated that chronic AF and atrial flutter in humans led to quantitatively similar decreases in the right atrial action potential duration (APD) during steady state and extra-stimulus pacing a considerable time after cardioversion. This confirmed that both atrial fibrillation and flutter lead to electrical remodeling in the human atrium, with more pronounced AERP changes being manifest at longer cycle lengths, or slower rates [21]. The pathophysiology of these electrophysiological changes involves alteration in ion channels expression and function. With each action potential (AP), Ca2+ enters atrial cells; in AF, rapid atrial rates lead to increased intracellular Ca2+ loading and initiate autoprotective mechanisms that reduce Ca2+ entry: Ca2+ current inactivation and ICaL downregulation (which reduce Ca2+ entry directly) and inward rectifier K= current enhancement (both IK1 and constitutive acetylcholine-dependent current [IKAChC]) that decreases Ca2+ loading by reducing APD [22–27]. By decreasing APD, these changes stabilize atrial reentry “wavelets” or”rotors,” increasing AF vulnerability and sustainability [23–26, 28]. In addition, alterations in Ca2+ handling promote diastolic Ca2+ release and ectopic activity, which serves as a trigger for AF [24, 26]. Electrical remodeling plays an important role in the early recurrence of AF after cardioversion, as well as its tendency to progress to a more persistent state. Along with electrical remodeling, there are important structural changes that occur during AF, in particular cardiac fibrosis and atrial dilatation.

Structural Remodeling Structural remodeling such as interstitial fibrosis, left atrial enlargement, and ventricular fibrosis and change in function are important contributors to the AF substrate [9, 13, 19•, 29–32]. Changes in Atrial Structure Tissue fibrosis occurs as a reparative process to replace the degenerating myocardial parenchyma with concomitant fibrosis. Histologically, fibrillar collagen deposits are seen during this process. Atrial fibrosis may be a result of structural remodeling due to atrial fibrillation or may be part of the preexisting substrate, when occurring as a consequence of other diseases such as hypertension and heart failure. Structural remodeling has a longer time course than electrical remodeling, and uncontrolled ventricular rates accelerate it by inducing

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myocardial dysfunction [33]. Cardiomyocyte–fibroblast interactions consequent to sustained atrial tachycardia also promote fibrosis [34]. Table 2 summarizes structural changes described in detail by Ausma et al [31] in goats artificially maintained in AF for 9 to 23 weeks. Changes in Atrial Size and Contractility During fibrillation, the atria develop what is, in effect, a tachycardia-mediated myopathy, characterized by decreased contractility and marked dilatation. These mechanical changes can also reflect, in part, the effects of any concomitant left ventricular systolic and/or diastolic dysfunction associated with rapid and irregular rates and loss of atrial “kick.” There is an association between AF and atrial dilatation, and it is often unclear whether atrial dilatation is a cause or a consequence of the arrhythmia; frequently, both are true. Atrial dilatation predicts the development of AF, and atrial diameters further increase when AF is present and often decrease after conversion of AF to sinus rhythm. The Framingham Study showed that left atrial size is an independent risk factor for the development of AF (hazard ratio 1.39 for every 5-mm incremental increase in the left atrial size) [35, 36]. Atrial fibrillation results in the absence of atrial contraction, which only reappears gradually after conversion of long-term AF, after gradual recovery from what has been termed atrial “stunning,” but which might be better described as a tachycardia-mediated atrial myopathy. Atrial contractility has been noted to be impaired after only a few minutes of experimental AF, but contractile function continues to worsen over several weeks. After sinus rhythm is restored, the recovery of atrial contractility can take weeks to months, and is related to the duration of the episode of AF. This is similar to what is seen in the tachycardia-mediated myopathy of the ventricle. In a dog model of AF combined with CHF (due to tachycardia-mediated ventricular cardiomyopathy) induced and allowed to persist for ∼5 months, followed by ∼4 months of recovery in sinus rhythm, Avitall et al. found diffuse atrial fibrosis, with a marked increase in the connective tissue (2 to 4 times, compared to controls) [19•]. Along with diffuse fibrosis, there was a marked increase in the atrial susceptibility Table 2

Atrial structural and ultrastructural changes in AF. [31]

Atrial structural remodeling • Loss of myofibrils • Accumulation of glycogen • Changes in mitochondrial shape and size • Fragmentation of sarcoplasmic reticulum • Dispersion of nuclear chromatin • Cells seemed to have changed to a fetal phenotype

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even after 4 months of recovery and reverse remodeling in sinus rhythm, despite complete recovery of the left ventricular ejection fraction and substantial but incomplete improvement of left atrial dilatation. In the same study [19•], a group of dogs that underwent AV node ablation and right ventricular pacing for ventricular rate control, the left ventricular systolic function remained normal. However, AF in the absence of CHF still caused marked left atrial enlargement and decreased contractility. Despite 4 months of reverse remodeling in sinus rhythm, with complete recovery of LA size and function, these dogs showed significant atrial fibrosis and continued marked susceptibility to AF. Atrial fibrosis was not as extensive as in the group with combined AF and CHF, but it was significant when compared to healthy controls. A more recent study showed that atrial fibrosis, as estimated by delayed enhancement magnetic resonance imaging, was associated with recurrent arrhythmia after radiofrequency ablation for AF. [37, 38] Studies comparing the recovery of electrical remodeling in paroxysmal versus more persistent AF have shown that complete recovery of electrical remodeling is possible, even if an extended time is spent in AF prior to cardioversion [39, 40]. However, structural changes are likely to become permanent. Studies done in experimental animal models and humans have demonstrated only partial structural and functional recovery after cardioversion [19•, 41, 42]. Thus, irreversible changes occur in the atria during fibrillation sustained for several months, despite optimal ventricular rate control and even in the absence of CHF. The persistent, probably permanent, atrial fibrosis is associated with a markedly increased susceptibility to AF despite extensive time allowed for reverse remodeling. Extrapolating these observations to clinical practice would suggest that if the aim is to restore and maintain sinus rhythm, AF should optimally not be allowed to persist for weeks or months, and restoration of sinus rhythm should be performed early [19•].

Autonomic Remodeling It is now known that autonomic remodeling also contributes to the AF-induced arrhythmia substrate [43]. AF causes changes in the autonomic nervous system, such as atrial nerve sprouting [44–46]. Previous studies demonstrated that hyperactivity of the cardiac autonomic nervous system (ANS) is critical in the initiation and maintenance of AF. In a canine model for paroxysmal AF simulated by rapid atrial pacing (RAP), the neural activity in the cardiac ganglionated plexi increased progressively as RAP continued [44, 47, 48]. Even relatively short periods of atrial tachycardia (3 h) increase discharge rates in the intracardiac ganglionated plexi [41]. Ablation of the intracardiac autonomic ganglia blunts tachycardia-induced shortening of refractoriness and AF susceptibility, demonstrating a role for autonomic tone in AF-

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induced remodeling [41]. Spatially heterogeneous sympathetic hyper-innervation results from longer-lasting AF [42].

Clinical Implications It would then seem logical that early rhythm control can be beneficial in preventing and reversing remodeling and, thus, in maintaining sinus rhythm (SR) and ultimately improving outcomes in AF. However, clinical trials available to date have failed to show benefit for a rhythm control strategy compared to rate control [49–55]. These trials have a number of limitations, including that most reflect a clinical practice that largely ignores the effects of atrial remodeling. Patients with vastly different or unknown burden of AF and atrial remodeling were enrolled and were generally grouped together and managed similarly (see Table 3). Extensive evidence suggests that complex atrial remodeling occurs and is needed for the initiation and maintenance of AF. Electrical remodeling is seen as early as 4 h after AF was induced [48]. Autonomic remodeling occurs in the first 24 h of AF initiation [48]. Atrial dilatation and decreased contractility occur and peak within days to weeks. Atrial fibrosis was demonstrated after as few as 6 weeks of rapid atrial stimulation [17•,19•,32]. We also know that reverse remodeling is possible when sinus rhythm is restored early. In 2001, the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) showed that patients who maintained sinus rhythm, either with or without antiarrhythmic therapy, had a superior mortality prognosis compared with patients with continued AF. [56] In 2004, a post hoc analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial according to actual treatment revealed that presence of sinus rhythm was associated with a considerable reduction in the risk of death [14,57•]. More recently, in 2009, the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study showed improvement in AF-specific quality of life scores when compared to a rate control group in patients with paroxysmal AF [58]. These findings suggest that there is actually a benefit in maintaining sinus rhythm. The question remains, in humans, when is restoration of sinus rhythm too late in the disease process? In a recent study, a total of 126 patients with persistent AF were randomly assigned to a transesophageal echocardiogram followed by early direct current cardioversion (DCCV) or to a conventional treatment with dabigatran-etexilat for 3 weeks followed by DCCV. AF was stratified as <60 days and >60 days. Patients in the AF <60 days group with early intervention cardioversion had a significant reduction in AF recurrence, AF-related hospitalizations, and the number of outpatient visits compared with the conventional treatment [59]. In a subgroup analysis from the AFFIRM trial, Damluji et al. presented evidence that patients assigned to a rhythm control

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strategy were more likely to remain in sinus rhythm if they had new onset AF (<48 h) versus longer duration (>48 h) [60]. It is possible that ablation might perform better than medical therapy. Walters et al. published an observational study that showed that 38 patients managed medically for paroxysmal atrial fibrillation had a significant progression of left atrium remodeling over a 12-month period, in contrast to patients who underwent AF ablation and had a negligible burden of AF, who demonstrated significant reverse remodeling [61]. Can Cardioversion be too Early? It is possible that performing cardioversion very early may be less effective. Oral et al. assessed the immediate recurrence of AF (IRAF) after cardioversion, defined as 60 s after restoration of sinus rhythm, in patients with implantable atrial defibrillators. In this study, restoration of sinus rhythm less than an hour after the onset of atrial fibrillation was associated with higher rate of immediate recurrence when compared with patients cardioverted after 24 h of onset [62]. These findings have been further supported by other studies such as the one published in 2005 by Schwartzman et al. where patients with implantable cardioverter defibrillators were randomized to cardioversion by the device as soon as possible versus delayed a day after AF was detected. This study showed that the delayed strategy was associated with less early recurrence of AF when compared to shocks delivered within a few hours of AF onset [63]. Moreover, in a larger retrospective study assessing electrical cardioversions performed for acute (<48 h) AF, a shorter duration (<12 h) of AF prior to cardioversion was a significant predictor of unsuccessful cardioversion [64]. Therefore, other factors might play a role in the onset and maintenance of AF and very early cardioversion in those situations might not be the answer. It is possible that the initial trigger of AF, such as altered autonomic state, persists in the first few hours of AF and can cause recurrence if cardioversion is performed immediately. Specific Clinical Situations In some clinical situations, early or even immediate cardioversion might be justified: when AF with rapid ventricular rate is poorly tolerated hemodynamically; when rate control medications are not tolerated due to hypotension (however, one must consider the option of a more lenient approach to ventricular rates and verify that rate control is required for solid reasons, such as hemodynamic difficulties); selected patients with decompensated systolic or diastolic dysfunction that might benefit from restoration of atrial contraction (HCM, cardiac amyloidosis etc.). In these situations, cardioversion should not be a reflex response to the presence of AF with or without rapid ventricular rates, but a plan of care chosen after weighing all treatment options and careful, individualized clinical judgment.

506

OD Pedersen 2001

DG Wyse 2002

IC Van Gelder 2002

J Carlsson 2003

G Opolski 2004

DIAMOND [56] (2001)

AFFIRM [52] (2002)

RACE [51] (2002)

STAF [50] (2003)

HOTCAFE [54] (2004)

205

200

522

4060

252

S. Hohnloser 2000

First author/year No. of patients publication

1.7 +/−0.4 years

19.6 +/−8.9 months

Mean follow-up 2.3+/−0.6 years

Mean follow-up 3.5 years

1 year

1 year

Duration follow-up

Rate versus rhythm control: a summary of major trials

PIAF [49] (2000)

Table 3

Class I antiarrhythmic agents or sotalol in the absence of CHD and normal LV function. Patients with CHD or an impaired LV function received a beta-blocker and/or amiodarone. In case of a recurrence, repeated DCCV was performed Serial cardioversion supported by a predefined stepwise AAD regimen (disopyramide,

DCCV + sotalol, if recurrence flecainide or propafenone + DCCV, if recurrence amiodarone load then DCCV

Amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, and combinations of these drugs. Dofetilide was used when available +/−DCCV

Dofetilide

Amiodarone + DCCV

Rhythm control intervention

Management of AF with the rhythm control strategy offers no survival advantage over the rate control strategy, and there are potential advantages, such as a lower risk of adverse drug effects, with the rate control strategy. Anticoagulation should be continued in this group of high-risk patients Rate control is not inferior to rhythm control for the prevention of death and morbidity from cardiovascular causes and may be an appropriate therapy in patients with a recurrence of persistent atrial fibrillation after electrical cardioversion No differences between rate vs. rhythm control in all end points except hospitalizations. Data suggested that there was no benefit in attempting rhythm control in these patients with a high risk of arrhythmia recurrence No significant differences in major in composite end point all-cause mortality, number of thromboembolic events, or major

Rate versus rhythm control yielded similar clinical results with respect to symptomatic improvement in AF. Exercise tolerance is better with rhythm control, although hospital admission is more frequent Dofetilide is safe, increases the probability of obtaining and maintaining SR in patients with structural heart disease. Study suggests that restoration of SR is associated with improved survival

Conclusion

Limitations

-Low maintenance SR -Anticoagulation stopped when sinus rhythm obtained and this arm with higher occurrence strokes -Mostly persistent AF -Newer AAD underused -Small study -PAF patients were excluded -Low maintenance SR

-Small study -Low-rate anticoagulation use in SR -Newer AAD not used

-RCT -Long-term follow-up

-RCT Percentage maintenance SR was significant

-Study mainly aimed to compare dofetilide vs. placebo in maintaining sinus rhythm -Short follow-up -Study population differs from the US population -No stratification by specific rhythm, AF/AFL studied together -Mostly older patients -Majority of patients in stroke with subtherapeutic INR or not on anticoagulation -Patients mostly in persistent AF -Symptoms not taken into account -Patients placed on two AAD -Newer AAD underused -RCT -Representative population of AF patients

-RCT -Large study -Population representative of most AF patients

-RCT -Specific subset population (HF) -High percentage maintenance SR

-RCT -Amiodarone sole AAD -Mainly symptoms -Low maintenance SR (23%) outcomes as endpoints -Short-term follow-up -Mostly men

Strengths

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823

J-RHYTHM [58] (2009)

Mean follow-up was 37 ±19 months

Duration follow-up

Pilsicainide, cibenzoline, propafenone, disopyramide, bepridil, flecainide, aprindine, pirmenol, amiodarone

DCCV + amiodarone (drug of choice). Dofetilide or sotalol used if required

propafenone, sotalol, and amiodarone)

Rhythm control intervention

Strengths

bleeding between the rate control -Symptoms and group and the rhythm control echocardiographic group criteria as part of endpoints -Included patients with first episode AF -Younger patient population -Long-term follow-up In patients with AF and CHF, a -RCT routine strategy of rhythm -Large study control does not reduce the rate -Shorter duration AF at of death from cardiovascular baseline (<12 months) causes, as compared with a rate -Subset patients with AF control strategy studied -Long-term follow-up -Representative patient population Rhythm control was associated with -RCT fewer primary endpoints -PAF patients (composite of total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure, or physical/psychological disability requiring alteration of treatment strategy) than rate control. However, mortality and cardiovascular morbidity were not affected by the treatment strategy

Conclusion

-Study therapeutics were not blinded to physicians or patients -Most patients without structural heart disease -Population differs from the USA -AAD different than used in the USA

-Majority of patients on amiodarone -No catheter ablation used -Significant crossover between arms -AF only assessed by EKG at follow-up

Limitations

DCCV direct current cardioversion, AF atrial fibrillation, RCT randomized controlled trial, AAD antiarrhythmic drug, HF heart failure, SR sinus rhythm, AFL atrial flutter, CHD coronary heart disease, LV left ventricle, PAF paroxysmal atrial fibrillation, CHF congestive heart failure, EKG electrocardiogram

S Ogawa 2009

1376

Rhythm D Roy 2008 control vs. rate control for AF and HF [53] (2008)

First author/year No. of patients publication

Table 3 (continued)

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On the other hand, there are instances in which early cardioversion may not be appropriate. There are more or less obvious clinical situations associated with AF onset that might favor waiting for a short period, such as alcohol or stimulant drugs abuse, illness, surgery, other high adrenergic states, or other unknown activators of AF triggers. The patients in atrial fibrillation presenting with acute embolic stroke present a particular challenge, as there might be an increased risk for repeat embolization. However, these patients are often felt to be poor candidates for anticoagulation due to the risk of hemorrhagic transformation of their recent cerebral infarct. This precludes them from being candidates for early cardioversion, given the increased thromboembolic risk in the following days and weeks, presumably because of persistence of prothrombotic factors, such as low atrial blood flow velocities, dilatation, and poor contractility, concomitantly with gradual recovery atrial contractility, which might play a role in dislodging some of these thrombi. As of now, indications for cardioversion in a specific subset of patients such as patients with acute stroke are not clearly stated in our current guidelines. As we know, the current AF guidelines recommend cardioversion, either electrical or pharmacological when pursuing a rhythm control strategy or when a rapid ventricular response to AF or atrial flutter does not respond promptly to pharmacological therapies and contributes to ongoing myocardial ischemia, hypotension, or heart failure. Other indications for cardioversion include patients with AF or atrial flutter and pre-excitation when tachycardia is associated with hemodynamic instability [55]. Our current practice recommendations are listed in Table 4.

Table 4 Recommendations for rhythm control strategy and cardioversion in atrial fibrillation

Summary

AF atrial fibrillation, HCM hypertrophic cardiomyopathy

Cardioversion is a powerful tool and rhythm control is a widely used strategy in the management of AF. However, important questions remain unanswered regarding not only if, but also when to cardiovert. There are observations from past trials and clinical situations that support attempting to restore sinus rhythm, but further prospective randomized clinical trials are needed. The timing of cardioversion depends on the clinical situation and its many variables. Complex processes of atrial remodeling are caused by AF itself and, when associated, by CHF. If a clinical decision is made that restoring and maintaining sinus rhythm is a reasonable strategy, it is apparent that cardioversion is more likely to be successful if it is performed earlier, and restoration of sinus rhythm should be performed before irreversible changes occur in the atrium. There is data suggesting that cardioversion may be less effective (due to early recurrence of AF) if performed in the first few hours of AF, possibly due to persistence of the factors that triggered AF in the first place. If performed after the first few hours, electrical remodeling has occurred and reaches its peak

after ∼24 h, rendering the atrium more susceptible to AF. However, most cardioversions are successful in these patients. In the first few days to weeks, there is continued mechanical remodeling, with progressive atrial dilation and decreasing contractility. The atrial substrate becomes progressively more susceptible to AF, making its recurrence more likely. The use of short-term antiarrhythmic drugs for suppression of AF triggers (atrial ectopic activity) and modulation of the electrical properties of the atrial myocardium has the potential to be helpful in selected cases, under expert care. Irreversible structural changes follow a longer timeline, but it is likely that significant atrial fibrosis develops after at most 2–3 months, even if ventricular rates are optimally controlled and in the absence of CHF. Subsequent efforts to restore and maintain sinus rhythm will have to overcome the additional burden of irreversible remodeling caused by AF itself, in addition to any pre-existing structural changes that led to the initial AF event.

Situations when a rhythm control strategy and cardioversion should be considered: -Initial episode of persistent AF -AF caused by a reversible trigger: illness, thyrotoxicosis -Symptoms: palpitations, fatigue, low energy, exertional dyspnea •Can be subtle, the patient may have adjusted to a new “normal” -Congestive heart failure: systolic, diastolic (with preserved ejection fraction) •Frequently difficult to distinguish cause and effect -Inability to adequately control ventricular rate •Medication dosage often limited by hypotension, bradycardia, other side effects -Tachycardia-mediated cardiomyopathy caused by uncontrolled rapid ventricular rate -Tachycardia-bradycardia syndrome (when adequate rate control is difficult due to bradycardia) -Certain patients may be particularly dependent on “atrial kick”: hypertrophic cardiomyopathy, cardiac amyloidosis, diastolic dysfunction -Patients with CHF and cardiac resynchronization therapy (who may have a suboptimal percentage of biventricular pacing because of AF) Clinical situations when early or even immediate cardioversion might be justified: -Hemodynamically unstable or poorly tolerated AF with rapid ventricular rate -Rate control medications not well tolerated due to hypotension -Selected patients with decompensated systolic or diastolic dysfunction that might benefit from restoration of atrial contraction (HCM, cardiac amyloidosis etc.) Clinical situations when immediate cardioversion might not be appropriate: -Acute AF caused by a reversible trigger alcohol or stimulant drugs abuse, illness, surgery, other high adrenergic states, thyrotoxicosis -Acute embolic stroke when the risk of hemorrhagic transformation is deemed significant

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Conclusion AF is the most common arrhythmia, its prevalence increasing with the aging of the population. It causes significant morbidity and can have devastating implications, such as stroke, even at the initial presentation. Electrical cardioversion is a safe and widely used procedure used to restore sinus rhythm, with a success rate ranging from 66 to 98% depending on the duration of the arrhythmia [65,66•]. Electrical, mechanical, structural, and autonomic remodeling are important factors in the initiation, perpetuation, and recurrence of AF. Prevention or reversal of these remodeling processes can halt the progression of the disease. The optimal timing of cardioversion remains somewhat uncertain, but it appears to be some time after the first few hours and before the first few months: the earlier, the better, but not always and maybe not immediately.

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12. Compliance with Ethical Standards Conflict of Interest Paloma G. Piña and Alexandru B. Chicos declare that they have no conflict of interest.

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Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Papers of particular interest, published recently, have been highlighted as: • Of importance 1.

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