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REVIEW

Atrial Fibrillation in Heart Failure: A ComprehensiveReviewPrakash C. Deedwania, MD, a,b Joel A. Lardizabal, MD ca Department of Medicine, University of California, San Francisco School of Medicine, San Francisco; b Department of Cardiology,Veterans Affairs Medical Center, Fresno, Calif; c Division of Cardiology, University of California, San Francisco School of Medicine,Fresno Medical Education Program, Fresno.

ABSTRACT

Chronic heart failure and atrial brillation are 2 major disorders that are closely linked. Their coexistenceis associated with adverse prognosis. Both share several common predisposing conditions, but their

interaction involves complex ultrastructural, electrophysiologic, and neurohormonal processes that gobeyond mere sharing of mutual risk factors. Rate control approach remains the standard therapy for atrialbrillation in heart failure because current strategies at rhythm control have so far failed to positivelyimpact mortality and morbidity. This is largely because of the shortcomings of current pharmacologicanti-arrhythmic agents. Surgical and catheter-based therapies are promising, but long-term data are lacking.The role of non-anti-arrhythmic therapeutic agents also is being explored. Further progress towardimproved understanding the complex relationship between atrial brillation and heart failure shouldimprove management strategies.Published by Elsevier Inc. The American Journal of Medicine (2010) 123, 198-204

KEYWORDS:Arrhythmia; Atrial brillation; Cardiomyopathy; Heart failure

Chronic heart failure and atrial brillation are major cardio-vascular disorders that are frequently associated with eachother. They have common risk factors, and each compli-cates the course of the other. Both are associated withsignicant morbidity and mortality, creating a serious pub-lic health burden. A closer understanding of the intricaterelationship between these 2 disorders would certainly im-prove the approach to their management.

EPIDEMIOLOGYChronic heart failure aficts 5.3 million adult Americanswith an equal sex distribution. It is associated with over a

million hospitalizations and 3.4 million outpatient visitsannually, with total costs estimated at $35 billion. Thelifetime risk of developing heart failure is 1 in 5 after age 40years, 1 with an annual mortality of 20%.

Atrial brillation, the most common clinically signicantarrhythmia, has a prevalence of over 2.2 million in theUnited States. It accounts for nearly a half million hospi-talizations yearly, at an estimated cost of $7312 per dis-charge. 2 The lifetime risk of developing atrial brillation is1 in 4 after age 40 years, 3 and based on Framingham data,atrial brillation accounts for 14% of early deaths within therst 4 months of its diagnosis in patients with heart failure. 4

With a steady incidence of both atrial brillation andchronic heart failure in the setting of an aging global pop-ulation where more and more people survive to an agewhere these conditions occur with increased frequency, theprevalence of heart failure and atrial brillation will con-tinue to increase to epidemic proportions.

PREDICTORS OF ATRIAL FIBRILLATION INCHRONIC HEART FAILUREIn the Framingham Study, heart failure was the strongestpredictor for the development of atrial brillation, with a

Funding: None.Conict of Interest: Dr Lardizabal does not have any relationship with

industry and nancial associations that might pose a conict of interest. DrDeedwania was a consultant and speaker and has been on the AdvisoryBoard of Sano-Aventis.

Authorship: Both authors were signicantly involved in all steps of the writing process, including the conception, design, drafting and criticalrevision of the manuscript, as well as nal approval for its submission.

Requests for reprints should be addressed to Prakash C. Deedwania,MD, Division of Cardiology, VA Medical Center, 2615 E Clinton Avenue,Fresno, CA 93703.

E-mail address: [email protected]

0002-9343/$ -see front matter Published by Elsevier Inc.doi:10.1016/j.amjmed.2009.06.033
mailto:[email protected]:[email protected]


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nearly 5-fold risk in men and 6-fold in women. 5 The prev-alence of atrial brillation in patients with preexisting heartfailure is associated with increasing heart failure severity. Inchronic heart failure clinical trials, the preval ence of atrialbrillation was 4% in functional class I patients, 6 10%-27% inthose with functional class II-III, 7-10

and 50% in those with functional

class IV.11

In a registry of heart failure pa-tients in everyday clinical prac-tice, 12 the overall prevalence of atrial brillation was 21%. Preva-lence of atrial brillation increasedwith age, up 29% in patients over70 years compared with 15% inthose younger than 70 years. Non-ischemic cardiomyopathy was asso-ciated with a 3-fold probability of atrial brillation compared with

ischemic etiologies. Atrial brilla-tion was more prevalent amongheart failure patients with preservedsystolic function, where diastolicdysfunction, hypertension, or valvu-lar defects are presumed to be theprimary etiologies of the heartfailure.

PATHOPHYSIOLOGIC INTERACTIONChronic heart failure and atrial brillation are associ-

ated with common predisposing conditions such as hy-pertension, diabetes, coronary artery disease, and valvu-lar heart disease. Recent data reveal complex cellular,extracellular, neurohormonal, and electrophysiologic pro-cesses that allow signicant interaction between these 2conditions that go beyond the mere sharing of mutual risk factors.

Chronic Heart Failure Predisposes to AtrialFibrillationHeart failure induces changes in the atrial structure andphysiology that promote and maintain development of ar-

rhythmias. Increased atrial volume and pressure in heartfailure results in mechanical stretching of the atrium. Inanimal studies, this tissue stretch is associated with height-ened atrial irritability and increased frequency of sustainedand nonsustained atrial tachyarrhythmias by shortening theatrial refractory period, prolonging the atrial co nduct iontimes, and increasing inter-atrial conduction blocks. 13,14 In-creased intra-atrial pressure in heart failure can intensify therate and or ganization of wavelet foci that perpetuate atrialbrillation. 15

Neurohormonal changes that accompany heart failure,including activation of the renin-angiotensin-aldosterone

system (RAAS), also contribute to the development andmaintenance of atrial brillation. Patients with heart fail-

ure have a higher level of catecholamines, which is as-sociated with rapid ventricular response. Increased an-giotensin II expression in heart failure promotes atrialinterstitial brosis and structural remodeling that createareas of slowed conduction and heterogeneity in repolarization,

serving as substrates f or atrial -brillation generation. 16 Activa-

tion of the sympathetic nervoussystem causes abnormalities of atrial action potentials and automa-ticity that can trigger arrhythmias aswell. 17

In the failing atrium, ion channelremodeling and calcium dysregula-tion at the cellular level have beenshown to enhance arrhythmogen-esis. Heart failure causes profoundabnormalities in calcium handlingand regulatory proteins within the

atrial cardiomyocyte that promotestriggered activity in atrial brilla-tion.18 The atrial cellular electro-physiological remodeling seen inheart failure, responsible for ar-rhythmogenic afterdepolarizationsand action potential alterations, isdistinct from that caused by atrialtachycardia. 19

Atrial Fibrillation Predisposes to ChronicHeart FailureChronic or incessant atrial tachyarrhythmia is known toproduce a reversible type of severe biventricular systolicdysfunction, termed tachycardia-induced cardiomyopa-thy. 20 In animal models, the severity of heart failureprogresses with increasing heart rates and duration of tachycardia. 21 High heart rates and recurrent tachycardia,as seen in atrial brillation, reduces myocardial compli-ance and impedes ventricular lling, resulting in short-ened lling times and rapidly progressive heart failure.Ultrastructural changes that occur in this setting includecytoskeletal alterations (increased actins and tubulins),

disruption of matrix metalloproteinases (gelatinase, col-lagenase, and stromolysin), and depletion of high energystores. Abnormal calcium handling also occurs, alongwith reduction in myobrillar calcium ATPase, sodium-potassium ATPase, and cardiac glycoside binding activ-ities. The remodeling process results in neurohormonalderangements that include increased epinephrine and nor-epinephrine levels. Rate or rhythm control results inreversal of cardiac dysfunction, but recurrence of thetachyarrhythmia causes abrupt decline in left ventricularfunction and increases risk of sudden death. 22 Even withnormalization of ejection fraction, negative remodeling

and ventricular dilatation may persist after treatment of tachycardia-induced cardiomyopathy. 23

CLINICAL SIGNIFICANCE

Atrial brillation and chronic heart fail-ure frequently coexist because of com-mon risk factors and closely linkedpathophysiological processes.

Pharmacologic rate-control strategy re-mains the standard of care, mainly be-cause of the limitations of the currentanti-arrhythmic agents used in rhythmcontrol therapy.

Nonpharmacologic approaches to ther-apy using invasive and catheter-basedmodalities are showing promise in thetreatment of atrial brillation in heartfailure.

199Deedwania and Lardizabal Atrial Fibrillation in Chronic Heart Failure


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Atrial systole can contribute up to 25% of the cardiacoutput, and even up to 50% in patients w ith preexistingvalvular disease or ventricular dysfunction. 24,25 The onsetof atrial brillation produces adverse hemodynamic effects,including reductions in cardiac output, peak oxygen uptake,and exercise tolerance. Atrial brillation may reduce cardiacoutput by several mechanisms, including loss of the atrial

contribution to left ventricular lling, valvular regurgitation,and increased ventricular rate, leading to inadequate leftventricular lling time. Left ventricle ejection fraction andstroke volume signicantly improve immediately after car-dioversion as a result of enhanced left ventricular diastoliclling from increased cycle length and restoration of theatrial booster pump function. 26-28 Irregular ventricular re-sponse in itself has been shown to decrease cardiac output,increase pulmonary capillary wedge pressure, and increaseright atrial pressure, independent of heart rate. 29

PROGNOSISEven with optimal medical therapy for heart failure, theonset of atrial brillation is often accompanied by cardiacdecompensation as well as functional class deterioration.Peak oxygen consumption and cardiac index markedly de-crease, while the severity of valvular regurgitation and car-diac chamber dim ensions increase shortly after the onset of atrial brillation. 30 Whether atrial brillation directly af-fects prognosis or is merely a marker for heart failureseverity is still under debate.

In patients with asymptomatic and symptomatic heart fail-ure, the Studies of Left Ventricular Dysfunction (SOLVD) trial

showed that atrial brillation was independently and signi-cantly associated with all-cause mortality, mostly from deathsdue to progressive pump failure. 31 The Candesartan in Heartfailure-Assessment of Reduction in Mortality (CHARM) trial,which enrolled heart failure patients with either low or pre-served systolic function, showed that atrial brillation wasassociated with increased risk of mortali ty and cardiovascularmorbidity regardless of ejection fraction. 32

These studies, along with many others, have demon-strated adverse outcomes associated with atrial brillationin patients with heart failure. However, there are other trialsthat refute such prognostic effect. Analysis of data from the

Vasodilator-Heart Failure Trial (V-HeFT) concluded that inpatients with mild to moderate heart failure, atrial brilla-tion did not increase cumulative mortality, sudden deat h,hospitalization rate, or major cardiovascular morbidity. 10

Data from the Prospective Randomized Study of Ibopamineon Mortality and Efcacy (PRIME-II) also showed thatafter adjustment for other variables such as age, ejectionfraction, New York Heart Association class, renal function,and blood pressure, the presence or the development of atrial brillation was no longer independently related to anadvers e outcome in patients with moderate to severe heartfailure. 33 Post hoc analysis of the Carvedilol Or Metoprolol

European Trial (COMET) showed that while the prognosticvalue of preexisting atrial brillation diminished after adjust-

ment for other variables in patients with heart failure, the onsetof new atrial brillation remained an independent predictor of subsequent all-cause mortality in patients with sinus rhythm atbaseline. 34

THERAPEUTIC APPROACHES

Beta-blockers are rst-line agents common to the manage-ment of both atrial brillation and heart failure. Bisoprolol,metoprolol succinate, and carvedilol have been shown tohave signicant mortality benet in heart failure 35 and alsoare effective for rate-control in atrial brillation as well.Anticoagulation is the cornerstone of therapy for strokeprophylaxis in atrial brillation, and atrial brillation is theprimary indication for anticoagulation in heart failure. Inaddition, patients with heart failure require warfarin therapyin the presence of previous thromboembolic events, leftventricle thrombus, extensive ischemic regional wall mo-tion abnormalities, and symptomatic heart failure with ejec-

tion fraction 35%. Digoxin is another agent common toboth atrial brillation and heart failure therapies, although itis not considered a rst-line agent in either condition. 36

Digoxin is given to patients with systolic dysfunction (ejec-tion fraction 40%) who are symptomatic despite treatmentwith angiotensin-converting enzyme (ACE) inhibitors andbeta-blockers. In patients with atrial brillation who areunable to tolerate beta-blockers and other rate-modulatingagents, digoxin remains a viable option for rate control.

Rhythm versus Rate ControlThe major clinical trials on atrial brillation therapy ( Table )

have shown that pharmacologic rhythm control is not supe-rior to rate control in terms of morbidity and mortality. 37-40

Under-represented in these trials, however, were patientswith heart failure who are thought to benet the most from

Table Comparison of Outcomes with Rate Control and RhythmControl Strategies in the Major Atrial Fibrillation Studies

Rate Control Rhythm Control P Value

AFFIRM37

Death 25.9% 26.7% .08

Major adverse events 32.7% 32% NSRACE38

Death 7% 6.8% NSMajor adverse events 17.2% 22.6% NS

HOT CAFE39

Death 1% 2.9% NSMajor adverse events 8% 31% .05

STAF 40

Death 8% 4% NSMajor adverse events 10% 9% NS

AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Man-agement; NS not signicant; RACE Rate-Control Efcacy in Perma-nent Atrial Fibrillation study; HOT CAFE Polish How to Treat Chronic

Atrial Fibrillation study; STAF Strategies of Treatment of Atrial Fibril-lation study.

200 The American Journal of Medicine, Vol 123, No 3, March 2010


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the hemodynamic improvement associated with conversionto sinus rhythm. Subgroup analysis of patients with heartfailure in the Rate-Control Efcacy in Permanent AtrialFibrillation (RACE) study pointed towards a favorable out-come if sinus rhythm was maintained after cardioversionfrom atrial brillation. 41

In the Congestive Heart Failure : Survival Trial of Anti-

arrhythmic Therapy (CHF-STAT),7

the subgroup of heartfailure patients with atrial brillation who converted tosinus rhythm with amiodarone treatment had signicantlylower mortality than those who remained in atrial brilla-tion. The same result was seen in a substudy of the DanishInvestigations of Arrhythmia and Mortality on Dofetilide(DIAMOND), where patients with atrial brillation andheart failure who maintained sinu s rhythm with dofetilidetreatment had improved survival. 8 In a small prospectivestudy, the CAFE-II trial found that restoration of sinusrhythm with amiodarone was associated with signicantimprovement in cardiac functio n and quality of life com-

pared with rate control strategy. 42The landmark Atrial Fibrillation in Congestive Heart

Failure (AF-CHF) trial, 43 however, showed no mortalityor morbidity benet of rhythm control over rate control(Figure ). This was a large multicenter prospective random-ized trial that compared current strategies for rhythm controlfor atrial brillation, specically in patients with heart fail-ure. Like the previous trials in the general atrial brillationpopulation, the AF-CHF study found no clear evidence torecommend a routine rhythm control approach in patientswith atrial brillation and heart failure. It further impliedthat the negative prognostic features associated with heart

failure make atrial brillation more likely, but atrial bril-lation per se may not have an independent effect on out-comes. The different result seen in the AF-CHF trial com-pared with the previous studies might be explained byimproved overall heart failure therapy in the AF-CHF trial,including a higher frequency of beta-blocker use (88%).

A notable observation in these studies is the suboptimalefcacy of pharmacologic agents in maintaining sinusrhythm (conversion to sinus rhythm in only 66% in CAFE-II, 51% in Congestive Heart Failure: Survival Trial of An-tiarrhythmic Therapy, and 44% in Danish Investigations of Arrhythmia and Mortality on Dofetilide, with 58% atrial

brillation recurrence in AF-CHF). The toxicity of anti-arrhythmic drugs increases morbidity, and this may havereduced the overall benet of rhythm control in the AF-CHFstudy. Anti-arrhythmic drug therapy, especially Class Iagents like quinidine and disopyramide, increases the risk of death from car diac and arrhythmic etiologies in the settingof heart failure. 44 Although safer agents for atrial brillationlike amiodarone, dofetilide, and azim ilide do not increasemortality in patients with heart failure, 45 they are still asso-ciated with increased morbidity, as reected by higher h os-pitalization rates due to anti-arrhythmic-related toxicity. 43

The experimental agent dronedarone, a derivative of

amiodarone with shorter half-life and devoid of iodine moi-ety, showed great promise in signicantly reducing toxicity

of anti-arrhythmic therapy in atrial brillation. The Ameri-can-Australian Trial With Dronedarone in Atrial Fibrillationor Flutter Patients for the Maintenance of Sinus Rhythm(ADONIS), and the European Trial In Atrial Fibrillation orFlutter Patients Receiving Dronedarone for the Maintenanceof Sinus Rhythm (EURIDIS) conrmed dronedarones su-perior safety prole in atrial brill ation (albeit lower ef-cacy) compared with amiodarone. 46 In patients with ad-vanced heart failure, however, the Antiarrhythmic Trial

with Dronedarone in Moderate to Severe Congestive HeartFailure Evaluating Morbidity Decrease (ANDROMEDA)

Figure KaplanMeier estimates of death from cardiovascu-lar causes ( upper graph ) and probability of the compositeoutcome of death from cardiovascular causes, stroke, or wors-ening heart failure ( lower graph ) among 1376 patients withatrial brillation and congestive heart failure who were fol-lowed for a mean of 37 months in the Atrial Fibrillation inCongestive Heart Failure trial. 43 CI condence interval. Re-printed with permission from: Roy D, Talajic M, Nattel S, et al.Rhythm control versus rate control for atrial brillation andheart failure. N Engl J Med . 2008;358:2667-2677. 43



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found that dronedarone was associated with deterioration of clinical status and increased mortality, prompting the earlytermination of the study. 47 On the other hand, the(ATHENA) trial (a placebo-controlled, double-blind, paral-lel arm trial to assess the efcacy of dronedarone 400 mgtwice a day for the prevention of cardiovascular hospital-ization or death from any cause in patients with atrial

brillation/atrial utter) found that dronedarone therapy wasassociated with reduction in cardiovascular events and mor-tality in patients with atrial brillation, 21% of whom hadheart failure with functional class II or III symptoms. Theauthors speculated that dronedarone possibly increases car-diovascular mortality among patients with advanced andrecently decompensated heart failure, but reduces cardio-vascul ar mortality in patients with less severe heartfailure. 48

The lack of benet of rhythm control over rate controlstrategies does not necessarily equate to lack of benet of restoration of atrial brillation to sinus rhythm in heart

failure. With a disappointing track record of current drug-based rhythm control strategies, attention is now focusingtowards nonpharmacologic therapies in the management of atrial brillation in heart failure.

Surgical Rhythm ControlThe Cox maze surgical procedure involves placing multipleincisions within the left and right atrial myocardium, pri-marily involving the structures around which reentry candevelop to interrupt potential reentry pathways. The proce-dure has an excellent long-term efcacy, with nearly 90%rate of freedom from atrial brillation at 10 years and 94%10-year survival. Major perioperative complications, how-ever, occur in 13% of cases, with a 1.4% early operativemortality rate. 49 Although generally avoided in patientswith heart failure, it has been shown to be safe and effectivein patients with heart failure, resulting in signicantimprovem ent in ejection fraction, functional class, andsymptoms. 50

Catheter-based AblationAs safer and less invasive alternatives to surgical ap-proaches, catheter-based ablation techniques for rhythm

control have been rapidly gaining popularity. Left atrialcatheter ablation, intended to isolate the pulmonary veinswhere arrhythmogenic foci may originate, has been shownto be safe and effective in patients with atrial brillation. Ina prospective study of patients with resistant atrial brilla-tion and coexisting systolic heart failure, electrical isolationof the pulmonary veins by radiofrequency ablation resultedin signicant improvement in cardiac function, symptoms,exercise capacity, and quality of life. Up to 78% of thesepatients with heart failure and atrial brillation were in sinusrhythm at 1-year follow-up. Co mplications were infrequentand occurred in 1% of cases. 51

In patients with atrial brillation and heart failure, theprogression of atrial brillation in the pulmonary vein an-

trum isolation vs atrioventrocular node ablation with bi-ventricular pacing for treatment of atrial brillat ion inpatients with congestive heart failure (PABA-CHF) 52 trialreported maintenance of sinus rhythm 6 months after catheter-based pulmonary vein isolation in 88% of patients receivingantiarrhythmic drugs and in 71% of patients not on anyantiarrhythmic agent. No procedure-related deaths occurred,

although 10% of patients had major complications, likepulmonary vein stenosis, pericardial effusion, and pulmo-nary edema. Compared with atrioventricular node ablationwith biventricular pacing (a form of nonpharmacologic ratecontrol), rhythm control with pulmonary vein isolation wasassociated with signicantly improved exercise tolerance,cardiac function, and quality of life. Whether or not ablationtechniques for atrial brillation will have a favorable impacton mortality, or whether the morbidity benets continue inthe long term for patients with heart failure is yet to bedetermined.

Non-anti-arrhythmic TherapyEven with improved surgical and catheter ablation tech-niques, the substrates for atrial arrhythmogenesis in heartfailure (eg, increased atrial load, dilatation, local conductiondisturbances, and brosis) may become irreversible, makingnonpharmacologic strategies for rhythm control not muchmore effective than anti-arrhythmic agents in atrial brilla-tion. Beyond just rhythm or rate control, treatment of atrialbrillation in heart failure also has started focusing on thesesubstrates as possible therapeutic targets.

Statins are implicated in lowering the rates of atrialbrillation independent of its cholesterol-lowering effect.

Statins potentially have anti-ischemic, antioxidant, anti-arrhythmic, and anti-inammatory properties that exert astabilizing effect on the cardiac membrane and prevent atrialremodeling. Fish oils are thought to reduce arrhythmiasthroug h the same anti-inammatory and membrane-stabilizingeffects. 53 In patients with heart failure, the Gruppo Italiano perlo Studio della Sopr avvivenza nellInfarto miocardico - HeartFailure (GISSI-HF) 54 trial showed that sh oil is superior toplacebo and statin in reducing mortality and hospitalization,although specic data on atrial brillation is lacking.

Atrial extracellular matrix brosis, induced by alteredneurohormonal processes and RAAS activation in heart

failure, is being increasingly recognized as an importantfactor in arrhythmogenesis. In animal models, ACE inhib-itors signicantly reduced atrial brosis in atrial brillationand heart fa ilure, an effect that was not demonstrated withvasodilators. 16 Retrospective clinical studies on RAASblockade in heart failure showed signicant reduction inincidence of atrial brillation and improved outcomes withboth ACE inhibitor and angiotensin-receptor blocker treat-ments, presumably by ret arding atrial brosis through neu-rohormonal modulation. 55 True benets also could besecondary to improvement in hemodynamics and cardiacperformance. Several studies have reported the efcacy of

ACE inhibitors and angiotensin-receptor blockers in pre-venting atrial brillation, and a meta-analysis of these trials



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found that the greatest reduction in atrial brillation was inpatients with heart failure. 56 The Atrial Fibrillation Clopi-dogrel Trial with Irbesartan for Prevention of VascularEvents (ACTIVE-I) is currently evaluating in a large dou-ble-blind, placebo-controlled study the effect of the angio-tensin-receptor blocker irbesartan on clinical outcomes inpatients with atrial brillation. 57 Preliminary results showthat irbesartan therapy reduced hospitalization from heartfailure by 14% in patients with atrial brillation. 58

Another deleterious neurohormonal response evoked inatrial brillation and heart failure is abnormal sympatheticactivation. Beta-blocker therapy effectively blunts suchmaladaptive adrenergic response, and this mechanism isthought to signicantly contribute to its benecial effects inatrial brillation and heart failure, in addition to rate controland prevention of arrhythmias. 59 In patients with atrial -brillation and heart failure, the use of beta-blockers wasassociated with a 42% reduction in mortality. 60

CONCLUSIONAtrial brillation and chronic heart failure frequently coex-ist because of common risk factors and closely linked patho-physiologic processes. Their association is correlated withadverse prognosis. Rate-control strategy remains the stan-dard of care because rhythm control therapy has yieldedmixed results in patients with atrial brillation and heartfailure. This is primarily because of the limitations of cur-rent anti-arrhythmic agents that are not that effective inmaintaining sinus rhythm and also are associated with sig-nicant toxicities. Invasive and catheter-based treatmentmodalities are promising, but their long-term efcacy andcost-effectiveness are yet to be ascertained. Recent ad-vances in understanding the complex relationship betweenatrial brillation and heart failure are paving the way to-wards better therapeutic strategies, both pharmacologic andnonpharmacologic. Although a number of questions stillremain unanswered, it is hoped that a steady progress to-wards this endeavor would ultimately provide the clinicianswith the most appropriate therapeutic strategy.

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Fibrilacion Atrial (8)

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