REVIEW ARTICLE
Atrial Fibrillation in Congestive Heart Failure
Jens Seiler, MD, PhD, and William G. Stevenson, MD
Abstract: Atrial fibrillation (AF) and heart failure (HF) are common and
interrelated conditions, each promoting the other, and both associated with
increased mortality. HF leads to structural and electrical atrial remodeling,
thus creating the basis for the development and perpetuation of AF; and AF
may lead to hemodynamic deterioration and the development of tachycardia-
mediated cardiomyopathy. Stroke prevention by antithrombotic therapy is
crucial in patients with AF and HF. Of the 2 principal therapeutic strategies
to treat AF, rate control and rhythm control, neither has been shown to be
superior to the other in terms of survival, despite better survival in patients
with sinus rhythm compared with those in AF. Antiarrhythmic drug toxicity
and poor efficacy are concerns. Catheter ablation of AF can establish sinus
rhythm without the risks of antiarrhythmic drug therapy, but has important
procedural risks, and data from randomized trials showing a survival benefit
of this treatment strategy are still lacking. In intractable cases, ablation of the
atrioventricular junction and placement of a permanent pacemaker is a
treatment alternative; and biventricular pacing may prevent or reduce the
negative consequences of chronic right ventricular pacing.
Key Words: atrial fibrillation, heart failure, anticoagulation,
antiarrhythmic drugs, ablation
(Cardiology in Review 2010;18: 38 –50)
A trial fibrillation (AF) and heart failure (HF) have been called
the 2 epidemics of contemporary cardiovascular medicine.1 In
the United States alone, more than 2 million people have AF, and
more than 5 million suffer from HF.2,3 Each is a marker for
increased mortality and both often occur in the same patient.4 – 6
HF is a powerful risk factor for AF.6 The risk of AF increases
by 4.5- to 5.9-fold in the presence of HF.7 With increasing severity
of HF, the risk of AF increases from ⱕ5% in patients with New
York Heart Association (NYHA) functional class I to nearly 50% in
patients with functional class NYHA IV.8 Furthermore, HF is an
independent risk factor for progression from paroxysmal to perma-
nent AF.9
Approximately half of the HF population have preserved
systolic left ventricular (LV) function associated with older age,
female gender and hypertension.10 –13 AF is even more prevalent
in this patient group as compared with HF with impaired LV
function.10,12
Occurrence of AF almost doubles the risk of death compared
with age- and sex-matched controls; and the diagnosis of HF confers
a mortality rate 4 to 8 times that of the general population of the
same age.5,6 Patients with one condition, who subsequently develop
the other, have further increased mortality.4
From the Cardiovascular Division, Department of Medicine, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA.
Supported by research grant from St. Jude Medical (Switzerland) (to J.S.).
The authors have no conflicts of interest.
Correspondence: Jens Seiler, MD, PhD, Cardiovascular Division, Brigham and
Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail: jseiler@
partners.org.
Copyright © 2009 by Lippincott Williams & Wilkins
ISSN: 1061-5377/10/1801-0038
DOI: 10.1097/CRD.0b013e3181c21cff
38 | www.cardiologyinreview.com Cardiology in Review • Volume 18, Number 1, January/February 2010
CONGESTIVE HEART FAILURE LEADS TO ATRIAL
FIBRILLATION
The mechanisms by which HF promotes AF are incompletely
understood. Generally, AF results from a complex interplay of
initiating triggers and an atrial substrate capable of maintaining the
arrhythmia; and it seems likely that different mechanisms may
initiate and contribute to sustaining AF in different patients. Fur-
thermore, the mechanisms and substrate may evolve as the patient
progresses from paroxysmal AF to persistent AF.14 –16 There seem
to be trigger- and substrate-dominant mechanisms, and atrial fibrosis
appears to play a key role in the development of a substrate for AF
in HF.17,18
Atrial Fibrosis–The Structural Substrate for Reentry
in Heart Failure
Structural atrial remodeling in HF has been extensively studied
in animal models. HF in canine models induces atrial fibrosis, which
promotes AF by increasing the heterogeneity of conduction due to
discrete areas of slow conduction.19,20 These conduction disturbances
may promote AF by stabilizing reentry.20 Activation mapping data,
and the observation that the class III antiarrhythmic drug dofetilide,
but not the calcium channel blocker flunarizine, terminated and
prevented the reinduction of AF in HF dogs, support the hypothesis
of macro-reentry as a mechanism of AF in these HF models.21
Prevention of fibrosis with the drug pirfenidone significantly reduces
the remodeling process and vulnerability to AF.19
Inflammation and oxidative stress have been implicated in the
genesis of HF and of AF.22–26 Local angiotensin II production,
activation of MAP kinases, tissue apoptosis and necrosis as well as
leukocyte infiltration precede the development of atrial fibrosis in
experimental HF. Angiotensin converting enzyme inhibition par-
tially suppresses this process suggesting angiotensin-dependent and
independent pathways.27 HMG-CoA reductase inhibitors (statins)
have well established anti-inflammatory and antioxidant effects.28,29
Simvastatin treatment reduced atrial fibrosis and conduction heter-
ogeneity as well as the duration of induced AF in a HF model.30
Recovery from HF in dogs leads to normalizing or near normalizing
of left atrial function and size, respectively, but the fibrosis and
conduction abnormalities remain; the duration of induced AF de-
creases, but the atria remain vulnerable to AF, consistent with the
persistence of structural substrate.31
Observations in humans support the relevance of animal
studies. Atrial remodeling in a man with congested heart failure
(CHF) is characterized by left atrial dilation, areas of scar and slow
atrial conduction velocities as well as prolonged atrial refractoriness
and a prolonged sinus node recovery time. AF in HF patients is more
often inducible, and the episodes are more likely sustained than in
subjects without HF.32
Triggers of Atrial Fibrillation and Fibrillatory
Conduction in Heart Failure
Stambler et al demonstrated marked mitochondrial changes
consistent with cytosolic calcium overload, and delayed afterdepo-
larizations in atrial myocytes from dogs with HF.33 Delayed after
depolarization-induced triggered activity resulting from intracellular
calcium overload may cause atrial tachycardias that initiate or
perpetuate AF.33 Such focal atrial tachycardias were observed orig-
Cardiology in Review • Volume 18, Number 1, January/February 2010
inating from the crista terminalis and near or within the pulmonary
veins in this canine model.34
Furthermore, canine models provided evidence that discrete
stable atrial high frequency drivers that may be automatic or reen-
trant can potentially maintain AF.35,36 With very rapid focal firing,
wavefronts propagating away from the focus encounter refractory
tissue and break up creating fibrillatory conduction.35,36 The rele-
vance of this mechanism for sustained AF in humans is not clear.
Ionic Atrial Remodeling in Heart Failure
HF leads to changes in transmembrane ionic currents that
may promote AF.37,38 Reductions in ionic transmembrane currents
ICaL, Ito and IKs and an increase in the Na⫹/Ca2⫹ exchanger current
(INCX) occur. The atrial action potential duration is normal at slow
heart rates, but prolonged at faster heart rates.37 The increase in the
NCX current may be important in generating arrhythmogenic de-
layed afterdepolarizations.38 Atrial tachycardia can trigger AF, and
chronic atrial tachycardia, mimicked by rapid pacing, can induce
persistent AF in animal models. Interestingly, the presence of HF
alters the ionic remodeling that occurs in response to rapid pac-
ing.39,40 In CHF, atrial tachycardia does not change the Ito, IKs and
INCX currents beyond the effect seen with HF alone, decreases ICaL
slightly, but does not change ICaL and IK1 to the extent seen in atrial
tachycardia alone. In HF, the decrease in refractory period produced
by tachycardia is blunted.39,40
ATRIAL FIBRILLATION PROMOTES HEART FAILURE
Acute Hemodynamic and Neurohumoral Effects of
Atrial Fibrillation
AF is associated with further hemodynamic deterioration in
HF patients.41 An inappropriately fast and irregular ventricular
response, the loss of mechanical atrial function and loss of atrio-
ventricular (AV) synchrony may have acute negative hemodynamic
consequences.42– 44
Diastolic ventricular filling is impaired by an inappropriately
rapid ventricular response due to the short cardiac cycle length and
the loss of atrial function.42 In a canine model with AV block and
regular ventricular pacing, development of AF reduced cardiac
output by 18%; irregular ventricular pacing further reduced the
cardiac output by 9% and mitral regurgitation was also observed.43
Similar observations were made in patients undergoing AV node
ablation for AF; irregular ventricular pacing led to a reduction in
cardiac output by 15% as compared with regular ventricular pacing
at the same cycle length. However, a worsening of pre-existing
mitral regurgitation by irregular pacing was seen in only 1 of 10
echocardiographically evaluated patients.44
Sympathetic activation is related to prognosis in HF.45 There
is controversy whether AF increases sympathetic activity in this
patient population. In a series of 8 patients (4 of them with impaired
LV function), induced AF increased the sympathetic tone, in part,
because of the irregular ventricular response.46 However, in a larger
study of 133 patients with HF, 25 of whom were in AF and 108 in
sinus rhythm, patients with AF did not appear to have a heightened
sympathetic tone in comparison to those with sinus rhythm.47
Tachycardia-Mediated Cardiomyopathy
A chronic fast ventricular response— especially with ventric-
ular rates in excess of 100 beats per minute (bpm)—may lead to
tachycardia-mediated cardiomyopathy, which may cause or exacer-
bate HF.48,49 Tachycardia-mediated cardiomyopathy is character-
ized by LV dilation and systolic as well as diastolic dysfunction.
Recovery occurs after termination of the tachycardia, leading to
improvement of the systolic function, but diastolic dysfunction
persists and LV hypertrophy develops.50 Proposed mechanisms
© 2009 Lippincott Williams & Wilkins
Atrial Fibrillation in Congestive Heart Failure
include abnormalities of cardiac calcium handling, myocyte and
extracellular matrix remodeling, impaired coronary flow reserve,
and myocardial energy depletion.48,49
IMPACT OF ATRIAL FIBRILLATION ON OUTCOME
IN HEART FAILURE
AF may adversely affect survival through hemodynamic
effects, risk of thromboemboli, and exposure of the patient to
adverse effects of therapy for AF (antiarrhythmic drugs and antico-
agulation). There is controversy, however, as to whether AF is an
independent risk factor for mortality in HF patients, or only a marker
of a more advanced heart disease.
Data from the HF trials V-HeFT I, V-HeFT II, and PRIME-II
did not show an impact of AF on survival in a multivariate
model.51,52 Similarly, AF was not associated with the occurrence
of the combined end point of death, heart transplantation or
implantation of a LV assist device in a study of patients with
advanced HF referred for heart transplantation evaluation.53
However in the COMET study, AF at baseline was a risk factor
for mortality in a univariate, but not in a multivariate analysis,
and new-onset AF was an independent risk factor for mortality.54
Likewise, the EuroHeart Failure Survey on patients admitted to the
hospital with HF suggests that new onset AF, but not preexisting AF, is
a predictor for in-hospital mortality.55 In the SOLVD and DIAMOND
trials, however, the presence of AF was associated with increased
mortality in a multivariate analysis.56,57
The impact of AF on mortality is likely greater in less severe
HF, and the occurrence of AF in severe HF may contribute little or
none to the overall poor prognosis. In a single center study, AF was
an independent risk factor for mortality in advanced HF, especially
in patients with lower filling pressures on vasodilator and diuretic
therapy, but not in patients with a high pulmonary capillary wedge
pressure.58 This observation was supported by data of the CHARM
study, where the presence of AF was associated with increased
mortality, with a greater impact in patients with preserved LV
function than in patients with a low ejection fraction.59
MANAGEMENT OF ATRIAL FIBRILLATION IN HEART
FAILURE
Stroke Prevention
In the Framingham Heart Study, AF increases the risk of
stroke by 4.8-fold, and HF increases the stroke risk by 4.3-fold. AF
occurring in HF almost doubles the risk of stroke in men and almost
triples it in women.60
The overall annual stroke risk in patients aged 65 to 95 years
with nonrheumatic AF and without warfarin therapy is 4.4% accord-
ing to the National Registry for Atrial Fibrillation.61 The CHADS2
index, derived from clinical data, provides an estimate of the
individual stroke risk that is used to guide antithrombotic therapy.
The risk factors for stroke in this index are: recent CHF, history of
hypertension, age ⱖ75 years, diabetes mellitus, and history of stroke
or transient ischemic attack. The CHADS2 score is calculated by
adding 1 point for each risk factor except for the history of stroke or
transient ischemic attack, for which 2 points are added. The annual
stroke risk varies from 1.9% at a CHADS2 score of 0 points to
18.2% at the maximum CHADS2 score of 6 points (Fig. 1).61
Recent meta-analyses found that dose-adjusted warfarin re-
duces the risk of stroke in AF by 64% to 67%.62,63 In contrast, the
antiplatelet agents aspirin and dipyridamole reduce the stroke risk
only by 22%.63 The ACTIVE A and ACTIVE W studies compared
the combination of clopidogrel and aspirin with aspirin or dose-
adjusted warfarin, respectively, in patients with AF at risk for
stroke.64,65 The ACTIVE A study showed an absolute risk reduction
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Seiler and Stevenson Cardiology in Review • Volume 18, Number 1, January/February 2010
FIGURE 1. The CHADS2 index. Panel A, the
CHADS2 index estimates the annual stroke risk on
the basis of the following clinical risk factors: re-
cent congestive heart failure, history of hyperten-
sion, age of 75 years or older, diabetes mellitus,
and prior stroke or transient ischemic attack. The
CHADS2 score is calculated by adding 1 point for
each risk factor except for stroke or transient isch-
emic attack, for which 2 points are added. Panel
B, the annual risk of stroke increases gradually
from 1.9% at a CHADS2 score of 0 points to
18.2% at a CHADS2 score of 6 points. (Data from
Reference 61).
for stroke for the addition of clopidogrel to aspirin compared with
aspirin alone by approximately 0.9% per year at the cost of an
increase in major bleeding by approximately 0.7% per year, and no
difference in mortality between the 2 groups.64 The ACTIVE W
study was stopped because it demonstrated the superiority of dose-
adjusted warfarin over the combination of aspirin and clopidogrel.
The relative risk of reaching the combined primary end point of
stroke, noncerebral systemic embolism, myocardial infarction and
vascular death was 1.44 for the combination of aspirin and clopi-
dogrel when compared with the warfarin group.65
The risk stratification and therapeutic recommendation for
stroke prevention according to the guidelines for the management of
AF is based on the CHADS2 index.66 HF and a left ventricular
ejection fraction (LVEF) ⱕ35% are considered moderate risk fac-
tors for thromboembolic events. Dose-adjusted warfarin or aspirin is
recommended in the presence of one moderate risk factor (according
to a CHADS2 score ⫽ 1), and dose-adjusted warfarin is warranted
in the presence of 2 or more moderate or any high risk factors
(CHADS2 score ⱖ2, mitral stenosis and/or prosthetic heart valve).66
The current guidelines for the management of patients with HF
recommend dose-adjusted warfarin in all patients with HF and a
history of AF.67
Patients with HF do appear to be at increased risk from
bleeding during anticoagulation therapy. In the AFFIRM study,
major bleeding occurred in approximately 2% of the total anticoag-
ulated patients per year; HF increased the risk of major bleeding by
the factor 1.4. However, in patients with AF and HF and/or other
risk factors for stroke, the risk of stroke is usually higher than the
risk of bleeding.68
Left atrial appendage occlusion devices– currently under clin-
ical evaluation–are a potential alternative to long-term warfarin
therapy in selected patients (see below).
Rate Control
Pharmacologic Approaches
Rate control is extremely important in HF to mitigate acute
negative hemodynamic effects and to prevent the development of
tachycardia-mediated cardiomyopathy. Pharmacologic approaches
with AV nodal blocking agents may be chosen either as a first-line
strategy, or when attempts to restore and maintain sinus rhythm fail.
The goal is a heart rate of 60 to 80 bpm at rest, and a heart rate of
90 to 115 bpm during moderate exercise, but these parameters may
vary according to the age of the patient.66,67
Digoxin has limited effect on heart rate when sympathetic
tone is elevated, such as during exercise, but continues to have a role
for rate control in patients with HF.66 The Digitalis Investigation
Group study showed that digoxin is safe in patients with HF and sinus
rhythm, with no effect on overall mortality and a reduced rate of
hospitalizations.69 Posthoc analysis revealed that higher serum digoxin
concentrations increase all-cause and cardiovascular mortality, but not
40 | www.cardiologyinreview.com
mortality due to worsening HF, suggesting inotropic-associated in-
creases in oxygen consumption and arrhythmogenesis at higher digoxin
concentrations are responsible for this effect.70 Further posthoc analysis
of that data showed that women with HF receiving digoxin may have
an increased risk of death, possibly by interaction with hormone
replacement therapy increasing the serum digoxin levels.71
Beta blockers are effective rate controlling agents that have
also been shown to decrease mortality in HF, and are indicated in all
patients with stable HF, but should be initiated at a low dose
followed by a gradual increase, because negative inotropic effects
may cause fluid retention and worsening of HF.67,72–74
The combination of digoxin and beta-blockers may be more
effective than one agent alone. Farshi et al compared multiple
regimens of AV blocking agents including digoxin 0.25 mg daily,
the beta-blocker atenolol 50 mg daily, and the combination of both.
There was no difference between digoxin and atenolol in the mean
24-hour heart rate, but less effective rate control during exercise
with digoxin as compared with atenolol or the combination of both
drugs. Furthermore, the combination of both drugs achieved a lower
mean 24-hour heart rate then either drug alone.75 In an observational
study in unselected patients with AF and HF, treatment with beta
blockers or the combination of beta blockers with digoxin was
associated with a similar reduction in the risk of death.76
Amiodarone does slow the ventricular rate and has been used for
pharmacologic rate control when other medications are contraindicated
or unsuccessful, but the considerable potential for noncardiac toxicity
warrants avoidance of use for rate control alone.66,67,77,78
The nondihydropyridine calcium channel blockers verapamil
and diltiazem may induce or worsen HF in patients with a low
ejection fraction because of their negative inotropic effect.79,80
These drugs are not recommended and should be avoided for rate
control in patients with HF and depressed systolic ventricular
function.66,67 However, diltiazem or verapamil should be considered
for rate control in patients with AF and HF with preserved ejection
fraction, in whom beta blockers have been proven inadequate
because of intolerance.81
When rate control is needed acutely during exacerbation of
HF, digoxin or amiodarone, administered intravenously, are recom-
mended. The intravenous administration of beta-blockers and non-
dihydropyridine calcium channel blockers should be avoided due to
negative inotropic effects that can precipitate hemodynamic deteri-
oration in this setting.66
Ablation of the Atrioventricular Junction and
Permanent Pacing
The Ablate and Pace Approach in Patients With Heart Failure
Ablation of the AV junction to create heart block and perma-
nent pacing achieves rate control and regulates heart rate without the
need for AV nodal suppressing drugs. This approach may improve
© 2009 Lippincott Williams & Wilkins
Cardiology in Review • Volume 18, Number 1, January/February 2010
LV function, exercise duration and quality of life in patients with
medically refractory AF.82 In the absence of underlying heart
disease, survival is comparable to the expected survival in the
general population.83
However, right ventricular (RV) pacing results in dysschro-
nous ventricular activation with impairment of mechanical contrac-
tion and relaxation that can be adverse in some patients, associated
with worsening HF and increased mortality.84,85 Unfavorable ven-
tricular remodeling may occur over time.84,86 AV node ablation and
RV pacing can cause or aggravate mitral regurgitation, and cause
hemodynamic deterioration in some patients with preexisting ven-
tricular dilation.87,88
Ozcan et al examined the effect of AV node ablation and RV
pacing on long-term survival in 56 patients with drug-refractory AF
and a LVEF of ⱕ40% out of a series of 350 patients undergoing the
procedure. The mean LVEF improved from 26% to 34%. The subset
of patients with near normalization of LV function had long-term
survival compared to normal subjects, but the majority of patients
with a persistent low EF had high mortality rate.89
The adverse effects of RV pacing may be mitigated by
effective biventricular pacing.90 In patients undergoing AV node
ablation and pacemaker implantation for medically refractory AF
with rapid ventricular rates, Doshi et al found that patients with
NYHA II/III symptoms or a baseline LVEF of ⱕ45% experienced
functional improvement from biventricular pacing compared with
RV pacing.91 In an observational series of patients who had severe
HF, and who had previously undergone AV node ablation and
implantation of a RV pacing system, revising the pacing system to
add biventricular pacing improved NYHA functional class, LV
dimensions, LVEF, and quality of life.92
According to current guidelines, AV node ablation and pace-
maker implantation may be warranted in patients with medically
refractory AF, in whom sinus rhythm cannot be maintained and
adequate rate control is not possible.66,67,78 Implantation of a biven-
tricular system should be considered in patients with HF or de-
pressed LV function. Patients with persistent HF after ablation of the
AV junction and implantation of a RV pacing system should be
considered for an upgrade to a biventricular system.66
However, limitations of the ablate and pace approach are the
persistent need for anticoagulation, the loss of AV synchrony, and
lifelong pacemaker dependency.66 Early after AV junction ablation,
patients are transiently vulnerable to polymorphic ventricular tachy-
cardia causing ventricular fibrillation and sudden death. Mechanisms
responsible for the transient vulnerability to ventricular arrhythmias
are bradycardia and pacing-related prolongation of repolarization,
the change in the ventricular activation sequence, increased disper-
sion of repolarization, and increased sympathetic tone; HF, female
gender and hypokalemia may increase risk.93 Geelen et al observed
this complication in 6% of patients, mostly occurring at slow
ventricular escape rhythms or during slow ventricular pacing. Pacing
at 90 bpm for 1 to 3 months after the AV node ablation prevented
these complications.94
Whether restoration of sinus rhythm is preferable to biven-
tricular pacing is not clear. The PABA-CHF study compared AV
node ablation and biventricular pacing with catheter ablation of AF
in 81 patients with HF and drug-refractory AF. Catheter ablation of
AF was superior to AV node ablation and biventricular pacing with
regard to quality of life, exercise capacity, and LV function after a
follow-up period of 6 months.95
Cardiac Resynchronization Therapy in Patients With Atrial
Fibrillation
Cardiac resynchronization therapy in HF patients with AF
confers benefit similar to patients in sinus rhythm, and is considered
reasonable treatment when eligibility criteria are met.67,96 –101 Ef-
© 2009 Lippincott Williams & Wilkins
Atrial Fibrillation in Congestive Heart Failure
fective implementation of LV pacing requires that AV nodal con-
duction be adequately suppressed to allow for initial LV capture. AV
junction ablation is sometimes required to achieve biventricular
pacing. However, whether routine use of AV node ablation im-
proves outcomes of cardiac resynchronization therapy in AF is not
clear.102 AV node ablation had a functional and prognostic benefit in
studies by Gasparini et al, but Tolosana and others found no
difference in the degree of functional improvement and reverse
remodeling.97,99,100
Rhythm Control
Pharmacologic Rhythm Control
Drug options for maintenance of sinus rhythm in HF have
been extensively studied. Pharmacologic options have important
limitations, particularly in HF populations.
Class III Antiarrhythmic Drugs
The major pharmacologic considerations for rhythm control in
HF are the class III antiarrhythmic drugs amiodarone and dofetilide.66
Amiodarone is presently the most effective pharmacologic
agent for maintaining sinus rhythm, and is recommended for this
indication in patients with AF in the presence of HF.66,103 It also
slows the ventricular response in AF (see above). It has been studied
for an effect on mortality in populations with and without AF. The
CHF-STAT study demonstrated that amiodarone did not increase
mortality in HF patients, and that it could safely be initiated in an
outpatient setting.77,104 In the SCD-HeFT study however, subgroup
analysis showed that amiodarone was associated with a higher
mortality in the group with more advanced HF (NYHA class III),
raising concerns regarding drug toxicity.105
Weinfeld et al studied the efficacy of amiodarone on cardio-
version of AF and maintenance of sinus rhythm after cardioversion
in patients with advanced LV dysfunction who underwent initiation
of amiodarone for AF during hospitalization on a HF service. The
median duration of the arrhythmia was 12 months. Five percent of
patients converted pharmacologically, and sinus rhythm was estab-
lished by pharmacologically enhanced electrical cardioversion in
70% of patients. After a follow-up of 9.5 months, 57% of patients
remained in sinus or atrial-paced rhythm.106
However, amiodarone has a significant profile of adverse
effects. In one-third of patients in the study of Weinfeld et al, drug
induced bradycardia necessitated adjustment of the concomitant
pharmacologic therapy or placement of a permanent pacemaker,
exposing patients to the potential hemodynamic risks of pacing
discussed above.106 During long-term treatment, amiodarone has to
be discontinued in 8% of patients after 1 year and 30% after 5 years.
Noncardiac toxicities including skin-discoloration, lung toxicity,
hepatitis, neurologic toxicity, and hyper- or hypothyroidism are the
most common reasons for discontinuation.107
The effects of dofetilide in patients with HF and LV dysfunc-
tion were studied in the DIAMOND-CHF trial. Dofetilide did not
influence total mortality.108 Dofetilide can be effective in the con-
version of AF to sinus rhythm, and in maintaining sinus rhythm.57 In
the DIAMOND-CHF study, 12% of patients with AF at baseline
converted pharmacologically to sinus rhythm after 1 month, as
opposed to 1% in the placebo group. Once sinus rhythm was
restored, treatment with dofetilide was associated with lower risk of
recurring of AF (hazard ratio 0.35).108
Dofetilide prolongs the QT interval due to blockade of the IKr
current. It caused torsade de pointes in 3.3% of patients in the
DIAMOND-CHF study, despite amendments of the study protocol
to prevent this complication, ie, dose adjustment to the renal func-
tion and QT interval. Seventy-six percent of the torsade de pointes
cases occurred within the first 3 days after initiation of dofetilide
therapy, thus monitored in-hospital initiation of this drug is
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Seiler and Stevenson Cardiology in Review • Volume 18, Number 1, January/February 2010

warranted.108 For both dofetilide and sotalol (below) implantable
cardioverter-defibrillators provide pacing to prevent additional
QT prolongation from bradycardia, and defibrillation that should
reduce the risk of death from proarrhythmia.
To date, there is no head-to-head comparison of the efficacy
in maintaining sinus rhythm between amiodarone and dofetilide.
Sotalol, another class III antiarrhythmic drug with nonselec-
tive beta blocking and IKr blocking activity similar to dofetilide, is
not included in the current guidelines for the management of patients
with AF.66 However, it may be considered as a therapeutic alterna-
tive for pharmacologic rhythm control, if the nonselective beta-
blocking effects are hemodynamically tolerated, and renal function
is adequate to avoid drug accumulation and toxicity.
The CTAF and SAFE-T studies demonstrated that sotalol is
inferior to amiodarone but more effective than placebo in maintain-
ing sinus rhythm; however, most participants in these studies had
normal LV function.103,109
The proarrhythmic potential of sotalol is similar to that of
dofetilide, warranting in-hospital initiation of the drug. The
SWORD study evaluated the effect of the D-isomer of sotalol in
patients with a history of myocardial infarction and a LVEF of
ⱕ40%. This study was prematurely terminated because of excess
mortality in the sotalol group.110
Class I Antiarrhythmic Drugs
The use of class I antiarrhythmic drugs (sodium channel
blockers, including flecainide) may be harmful and increase mortal-
ity in patients with structural heart disease.111,112 HF patients are
prone to suffer from the proarrhythmic and cardiodepressant adverse
effects of class I antiarrhythmic drugs.67 Accordingly, these drugs
should be avoided in HF patients.66,113
Catheter and Surgical Ablation of Atrial Fibrillation
Catheter Ablation of Atrial Fibrillation
Catheter ablation of AF was widely introduced into clinical
practice after the work of Haissaguerre et al showing that pulmonary
vein foci were common triggers for paroxysmal AF that could be
controlled by ablation that isolated the pulmonary veins.14,114 Ex-
tensive clinical experience, largely in patients without HF who are
referred for catheter ablation, has established that pulmonary vein
isolation is often effective for paroxysmal AF, but that important left
atrial substrate supporting persistent AF extends into the left atrium
such that wide area ablation of the antral regions of the pulmonary
veins is more effective in these patients (Fig. 2).115 Additional
ablation creating lines and targeting high frequency electrical activ-
ity continue to be evaluated in the hope of improving outcomes.
Recent publications report successful maintenance of sinus
rhythm in approximately 70% to 80% of patients, mostly without
antiarrhythmic drug therapy, but more than one procedure was
required in a significant number of patients.115,116 Two small
randomized trials of 70 and 112 patients found that catheter
ablation of AF was superior to treatment with antiarrhythmic
drugs in the maintenance of sinus rhythm, improvement of
exercise capacity and quality of life.117,118
However, these high success rates reported from patients with
predominantly no or minimal heart disease cannot be extrapolated to
patients with HF, and lower success rates may be expected for most

FIGURE 2. Catheter ablation of atrial fibrillation. Panel A, 3-dimensional reconstruction of the left atrium and the pulmonary
veins, posterior-anterior view. The isolation of the pulmonary veins was performed by antral circumferential linear ablation.
The blue shell represents the 3-dimensional reconstruction of the left atrium by intracardiac echocardiography and the map-
ping catheter; the yellow shell represents the registered 3-dimensional magnetic resonance image of the left atrium. The pul-
monary veins are depicted schematically as tubes as follows: dark red, left superior; light red, left middle; green, left inferior;
dark blue, right superior (2 branches); and, light blue, right inferior. The small right middle pulmonary vein is indicated by an
asterisk. Red dots represent ablation lesions. Three-dimensional reconstruction and image integration was performed using the
CARTOSOUND and the CARTOMERGE system (Biosense Webster, Diamond Bar, CA). Panel B, isolation of the pulmonary
veins, surface ECG and intracardiac readings. The pulmonary vein tachycardia does not affect the sinus rhythm of the atria
after electrical disconnection of the pulmonary veins from the left atrium. A deca-polar circumferential mapping catheter (L1,2
through L9,10) is positioned in a common ostium of the left pulmonary veins showing ongoing pulmonary vein tachycardia.
Surface ECG (leads I, II, III, V1, and V5), and intracardiac recordings from the left atrium (Abl), right atrium (RA1,2) and the
coronary sinus (CS1,2) demonstrate sinus rhythm. Panels A and B are from different patients.

42 | www.cardiologyinreview.com © 2009 Lippincott Williams & Wilkins

Cardiology in Review • Volume 18, Number 1, January/February 2010
TABLE 1. Catheter Ablation of Atrial Fibrillation in Patients With Left Ventricular Dysfunction and/or Heart Failure
No. Baseline Mean Follow-up
Study Patients NYHA Class (mo)
Hsu121 58 2.3 ⫾ 0.5 12
Chen120 94 Class II: 30% 14
Class III: 68%
Class IV: 2%
Tondo122 40 2.8 ⫾ 0.1 14
Gentlesk123 67 n/a 20
*Determined by transthoracic echocardiography.
†
After 1 procedure.
‡
Not significant.
§
Freedom or marked reduction in burden of atrial fibrillation.
LVEF indicates left ventricular ejection fraction; n/a, not assessed; NYHA, New York Heart Association.
therapies in this population. Indeed, left atrial scarring, decreased
LV function, persistent AF and advanced age have been shown to be
risk factors for procedural failure in catheter ablation
of AF.119,120
Nevertheless, the reversal of LV dysfunction, increase of
exercise capacity and improvement of the quality of life by catheter
ablation of AF was reported in several studies in patients with HF.
Patients often required more than 1 ablation, and the mean follow-up
time was less than 2 years in all series (Table 1).120 –123 Although
LVEF improved in these studies, this was determined by echocar-
diography, which is subject to measurement variability that may be
further aggravated by irregular heart rates of AF. Hsu et al reported
on catheter ablation for AF in a series of 58 patients with congestive
HF and impaired systolic function. During a mean follow-up of 1
year after the final procedure (50% of patients underwent a second
procedure), 78% of patients remained in sinus rhythm, and 69% off
antiarrhythmic drugs. The mean LVEF improved from 35% to 56%,
the LV dimensions decreased, and a better exercise capacity and
quality of life was reported. However, compared with a control
group without HF, the success rate in the HF group was slightly
lower.121 Similar results were obtained by Chen et al in an analysis
of 94 patients with impaired systolic function undergoing catheter
ablation for AF. After a mean follow-up of 14 months, 73% of
patients were free of AF, the LVEF increased nonsignificantly by
5%, and an improvement of the quality of life was reported.120 In 21
of the 25 patients with recurrent arrhythmia, a second successful
procedure was performed. Again, the success rate was slightly lower
than that of the control group with normal LV function.120 Further
reports by Tondo et al and Gentlesk et al corroborated these
findings.122,123
Although these data from highly experienced centers are
promising, a prognostic benefit of catheter ablation of AF over
state-of-the-art medical treatment has not been shown. The ongoing
CABANA trial addresses this question, but does not focus on HF
patients alone.124
Major complications of catheter ablation of AF, including
pericardial effusion and tamponade, cerebrovascular accident, pul-
monary vein stenosis, and vascular complications, occur in 4% to
6% of cases.125,126 Periprocedural mortality was 0.098% in a large
survey.127 Although a higher rate of complications would be ex-
pected in catheter ablation in HF populations, limited studies com-
paring the procedure in patients with and without LV dysfunction do
not show an excess in complications in HF patients.120 –122
According to current guidelines, catheter ablation for AF in
patients with HF and/or reduced EF is warranted in selected symp-
tomatic cases after failure of at least 1 antiarrhythmic drug.66,115
© 2009 Lippincott Williams & Wilkins
Atrial Fibrillation in Congestive Heart Failure
Success Change in Exercise Quality of
(%) LVEF (%)* Capacity Life
78 35356 Improved Improved
73† 36341‡ n/a Improved
87 33347 Improved Improved
86§ 42356 n/a n/a
Surgical Ablation of Atrial Fibrillation
The surgical maze procedure for AF was developed 2 decades
ago by Cox et al based on the concept of creating lines of incisions
that interrupted reentry wavefronts, allowing a path for normal sinus
propagation.128 –130 Maze procedures have been performed in man
since 1987, and the final iteration, the Cox maze III procedure–first
performed in 1988 –is regarded as the gold standard for the surgical
treatment of AF.115,129,131 The Cox maze III procedure has been
reported to confer long-term freedom of AF in over 95% of patients,
but the extent and rigor of long-term follow-up is not clear.131 AF
patients requiring other cardiac surgery may benefit from the addi-
tion of a maze procedure.132
Data in patients with reduced LV function are limited. Stulak
et al retrospectively analyzed 37 patients with a reduced LV function
(mean LVEF, 44%), who underwent a maze procedure for parox-
ysmal and chronic AF and flutter between 1993 and 2002. Within a
median follow-up of 48 months, the mean LVEF improved to 54%,
and atrial arrhythmias recurred in 4 patients. Improvement of the
functional capacity was observed in 56% of patients, and no patient
had a deterioration of the functional status. Three patients required
the implantation of a permanent pacemaker, and there was no
perioperative mortality.133
Perioperative risks have to be considered when contemplating
a surgical approach. Khargi et al reviewed 48 studies on surgical
treatment of AF, including the classic cut-and-sew Cox maze III
procedure and the use of alternative sources of energy. Most of the
procedures were combined with valve or bypass procedures. The
postoperative 30-day mortality was 2% to 4%, the need for
the placement of a pacemaker was 5% to 6%, and major complica-
tions (bleeding, need for placement of an intra-aortic balloon pump,
or cerebral vascular accident) occurred in 8% of patients.134
Minimally invasive surgical techniques are advancing. Bilat-
eral video-assisted thoracoscopic pulmonary vein isolation using a
bipolar radiofrequency clamp on the beating heart–with or without
additional linear ablation, ablation of ganglionated plexi and/or
exclusion of the left atrial appendage–is feasible; and overall success
rates of 74% to 91% at 3 to 6 months post procedure are repor-
ted.135–137 Published series are small, and specific complications
seem to be infrequent, comprising pericarditis, pleural effusion,
pneumo- and hemothorax, and diaphragmatic paralysis.135–137 In
one series of 74 patients, 1 patient died early in the experience due
to tearing of the base of the left atrial appendage.137 A randomized
study comparing the thoracoscopic approach with radiofrequency
catheter ablation of AF regarding efficacy and safety is currently
recruiting participants.138
www.cardiologyinreview.com | 43
Seiler and Stevenson Cardiology in Review • Volume 18, Number 1, January/February 2010
Surgical ablation for AF may be considered as a concomitant
procedure in patients undergoing cardiac surgery for other reasons
such as mitral valve surgery. It may be considered in patients who
failed one or multiple catheter ablation procedures, are not candi-
dates for catheter ablation, or prefer a surgical approach.66
Rate Control or Rhythm Control?
Several randomized trials (PIAF, AFFIRM, RACE, STAF,
HOT CAFE, AF-CHF and CAFÉ-II) compared rate control and
rhythm control, both strategies predominantly performed with phar-
macologic therapy. A survival benefit has not been demonstrated for
one strategy over the other.139 –145
The AF-CHF and CAFÉ-II studies investigated rate control
versus rhythm control in HF patients. In AF-CHF, a total of 1376
patients with a LVEF ⱕ35% and HF NYHA II to IV symptoms, or
asymptomatic HF with a LVEF ⱕ25%, and at least one episode of
AF within 6 months before enrollment were included. The mean
follow-up period was 37 months. The primary end point of cardio-
vascular mortality was not different between the rate and rhythm
control groups. Furthermore, there was no difference in the second-
ary outcomes of all-cause mortality, stroke, worsening HF, and the
combination of cardiovascular death, stroke and worsening HF.144
The much smaller CAFÉ-II study enrolled 61 patients with symp-
tomatic HF and systolic dysfunction. Symptoms and functional
outcomes of a rhythm control versus a rate control strategy were
analyzed after 1-year of follow-up. One patient died in each study
arm. Patients in the rhythm control group had a greater improvement
in LV function and a better quality of life, but there was no
difference in the NYHA class and the 6-minute-walk distance
between groups.145
Consistent findings of studies comparing a rhythm or rate
control strategy are a higher rate of hospitalization and more adverse
drug events in the rhythm control groups, without consistent benefit
in quality of life or exercise capacity (Table 2).139 –145
In the AFFIRM study, the presence of sinus rhythm was an
independent predictor of survival, but antiarrhythmic drug use was
associated with an increased mortality risk. This finding suggests
that the beneficial antiarrhythmic effects of the currently available
antiarrhythmic drugs were offset by their adverse effects.146
In the absence of data clearly favoring one strategy over the
other, it is reasonable to individualize therapy, considering the
benefits and risks of each strategy. Our practice is to consider
patients for rhythm control at a first episode of persistent AF, for
symptomatic paroxysmal AF, and when adequate rate control is
difficult to achieve. Otherwise a rate control strategy is pursued.113
Catheter ablation is reserved for patients with symptomatic AF who
fail pharmacologic therapy.
New Strategies
New Antiarrhythmic Drug: Dronedarone
The investigational drug dronedarone is a noniodinated ana-
logue of amiodarone with a similar electrophysiologic profile.147 It
is significantly more effective than placebo in maintaining sinus
rhythm and reducing the ventricular rate during recurrence of ar-
rhythmia, without evidence to this point of pulmonary or thyroid
toxicity.148 The DIONYSOS study compared the efficacy and safety
of dronedarone to that of amiodarone in patients with AF, in whom
cardioversion and antiarrhythmic treatment is indicated.149 Prelim-
inary analysis showed the superiority of amiodarone for preventing
the primary end point of recurrence of AF or premature study drug
discontinuation for intolerance or lack of efficacy, but also a trend
toward more adverse events in the amiodarone group.150
The ATHENA study examined the effect of dronedarone
compared with placebo on mortality or hospitalization for cardio-
44 | www.cardiologyinreview.com
vascular events in patients with AF. Eighty-one percent of patients
were at least 65 years of age, 21% had a history of congestive HF,
and 12% of participants had a LVEF ⬍45%. Dronedarone reduced
the primary outcome of the combination of death and hospitalization
for cardiovascular events by 24%, and there was a trend toward a
lower all cause mortality in the dronedarone group.151 However, the
ANDROMEDA trial–analyzing similar endpoints in patients with
HF and systolic dysfunction–was prematurely terminated for safety
reasons because of excess early mortality due to worsening HF.152
It is believed that the adverse outcome of the ANDROMEDA study
is due to an inappropriate discontinuation of angiotensin converting
enzyme inhibitor therapy that may have been prompted by an
increase in serum creatinine.148,151–153 In healthy subjects, drone-
darone reduces the creatinine clearance by 17.7% by partial inhibi-
tion of the renal tubular organic cation transporter, but without a
reduction in renal plasma flow or glomerular filtration rate.154
Atrium-Selective Drugs
Drugs that have little or no effect on ventricular myocardium
are of particular interest for avoiding ventricular proarrhythmia.
Vernakalant is an investigational agent that prolongs atrial
repolarization, mainly targeting the atrium-selective Kv1.5 channels
carrying the IKur current; but other ion channels including Ito and INa
are blocked as well.153 A phase IIb study of the oral formulation of
vernakalant has been completed.155 Patients receiving a dose of 500
mg vernakalant twice daily had significantly less recurrence of AF
after cardioversion.156 In a phase III study, the intravenous formu-
lation of Vernakalant demonstrated a rapid conversion of AF of
short duration and was well tolerated.157 The intravenous formula-
tion of vernakalant is currently under evaluation for FDA approval,
which has not yet been granted.158
Ranolazine is an antianginal drug which blocks multiple ionic
currents including late INa, IKr, IKs and others.153,159 It is atrial-
selective in producing use-dependent block of sodium channels,
leading to suppression of AF.160 In the MERLIN-TIMI 36 study
which randomized patients with acute coronary syndrome to rano-
lazine or placebo in addition to standard medication, the ranolazine
group showed a trend toward less new-onset AF.161 Further studies
are necessary to evaluate the potential role of ranolazine in the
treatment of AF.
Ablation Strategies
A number of technical advances can be anticipated that seek
to improve the efficacy and safety of catheter ablation. These include
multielectrode catheters that can simultaneously ablate from multi-
ple sites,162 and balloon catheters that can be deployed in the antral
regions of the pulmonary veins for ablation by ultrasound, freezing,
or heating.163–166
New Strategies for Preventing Thromboembolism–
Appendage Occlusion Devices
More than 90% of left atrial thrombi in nonrheumatic AF
form in the left atrial appendage.167 Percutaneous occlusion of the
appendage offers a potential alternative to long-term anticoagulation
that is under study.66 Several catheter-deployed devices have been
studied. The PLAATO device (ev3, Plymouth, MN) was first im-
planted in 2001, but the system was withdrawn in 2006.168,169 Meier
et al reported in 2003 the use of an Amplatzer Septal Occluder
(AGA Medical Corporation, Golden Valley, MN) for the occlusion
of the left atrial appendage,170 but periprocedural and late emboli-
zations of the device have been reported.169,170 A third device, the
Watchman device (Atritech, Plymouth, MN), consisting of a nitinol
cage with a polytetrafluoroethylene membrane on the surface and
fixation barbs,171 was evaluated in the PROTECT AF multicenter
© 2009 Lippincott Williams & Wilkins
 TABLE 2. Randomized Controlled Studies Comparing Rhythm Control and Rate Control
Baseline Characteristics Comparison of Outcomes
No. NYHA NYHA Exercise Rate of Adverse Drug

© 2009 Lippincott Williams & Wilkins

Study Patients Class LV Function Mortality Class Tolerance LV Function Quality of Life Hospitalization Effects
PIAF139 252 Class IV n/a n/a n/a Rhythm control n/a No difference Rate control Rate control
excluded better better better
AFFIRM140 4060 n/a EF: 55% ⫾ 14% No difference n/a n/a n/a No difference Rate control Rate control
better better
RACE141 522 Class I: 49%/ FS: 30% ⫾ 10%/ No difference† n/a n/a n/a n/a n/a Rate control
51%* 30% ⫾ 10%* better
Class II:
48%/46%*
Class III: 3%/
3%*
STAF142 200 Class ⱖII: 55.5% EF ⬍45%: No difference‡ No difference n/a No difference n/a Rate control n/a
13.5% better
HOT CAFÉ143 205 Class I: FS: 33% ⫾ 7%/ No difference No difference Rhythm control Rhythm control n/a Rate control n/a
Cardiology in Review • Volume 18, Number 1, January/February 2010

48%/29%* 30% ⫾ 7%* better better better

Class II:
48%/57%*
Class III:
5%/14%*
AF-CHF144 1376 Class III/IV: 31% EF: 27% ⫾ 6% No difference n/a n/a n/a n/a Rate control n/a
better
CAFÉ-II145 61 Class II: 80% At least n/a No No difference Rhythm control Rhythm control n/a n/a
Class III: 20% moderate difference better better
systolic
impairment:
57%
*Rate/rhythm control group.
†
Death from cardiovascular causes.
‡
Combined endpoint of death, cardiopulmonary resuscitation, cerebrovascular event and systemic embolism.
EF indicates ejection fraction; FS, fractional shortening; LV, left ventricular; n/a, no data or no analysis; NYHA, New York Heart Association.

www.cardiologyinreview.com | 45
Atrial Fibrillation in Congestive Heart Failure
Seiler and Stevenson Cardiology in Review • Volume 18, Number 1, January/February 2010
study.172 The preliminary results presented in March 2009 at the
American College of Cardiology Scientific Sessions reported that
the device was not inferior to warfarin for the primary efficacy end
point–stroke, cardiovascular and unexplained mortality and systemic
embolization. However, procedural complications, mostly pericar-
dial effusions, occurred in 7.2% of patients.173
PREVENTION OF ATRIAL FIBRILLATION IN HEART
FAILURE
The relation of atrial fibrosis and electrical remodeling to AF
suggest strategies for prevention. A number of retrospective analyses
and meta-analyses suggest some strategies for prevention, but prospec-
tive data are largely lacking, such that specific recommendations are not
yet adequately supported.66 Angiotensin converting enzyme inhibitors
or angiotensin receptor blockers, beta blockers, and in patients with
coronary disease, statins are part of the standard pharmacologic therapy
for HF.67,174 Angiotensin converting enzyme inhibitors and angiotensin
receptor blockers were found to reduce the occurrence of AF assessed
in a meta-analysis including 11 studies with over 56,000 patients. The
benefit was greatest in HF patients with a 44% relative risk reduc-
tion.175 In a meta-analysis of 7 studies including almost 12,000 patients,
beta blockers reduced the relative risk of AF in HF patients by 27%.176
Furthermore, the use of statins was associated with a decreased risk of
incidence or recurrence of AF in a meta-analysis of 6 studies with over
3500 patients, but none of the included studies was dedicated to HF
patients.177 A multicenter registry of more than 25,000 patients with
LV dysfunction showed that lipid lowering therapy which consisted
mostly of statins was associated with a reduced prevalence of AF
(odds ratio 0.69).178
There is controversy as to whether cardiac resynchronization
therapy prevents AF. A small nonrandomized study by Fung et al
showed an almost 4-fold lower incidence of AF with cardiac
resynchronization therapy.179 However, a posthoc analysis of the
larger CARE-HF study did not support a reduction in AF.98
CONCLUSIONS
AF and HF are common, interrelated, and aggravate each
other. Although there is evidence that sinus rhythm is associated
with better survival, data demonstrating a survival benefit of the
clinical strategy of rhythm control to maintain sinus rhythm over
a rate control strategy are still lacking. Hence, therapy has to be
individualized in these complex patients, based on symptoms,
benefits and risks of therapies. A number of advances in phar-
macologic therapy, catheter and surgical ablation, and methods to
prevent atrial thrombi are emerging. Those that demonstrate
initial safety and efficacy will require study in large randomized
trials to define benefit on survival, as well as quality of life
measures, and HF. There is evidence to support the feasibility of
preventative pharmacologic measures which require further
study.
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