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Heart, Lung and Circulation (2017) xx, 1–8 REVIEW

1443-9506/04/$36.00
http://dx.doi.org/10.1016/j.hlc.2017.05.117

Atrial Fibrillation and Heart

Failure — Cause or Effect?
Sandeep Prabhu a,b,c, Aleksandr Voskoboinik a[23_TD$IF],b,c, David M. Kaye a,b,
Peter M. Kistler a,b,c*[24_TD$IF]
a
The Alfred Hospital, Melbourne, Victoria, Australia
[25_TD$IF]Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
b
c
University of Melbourne, Melbourne, Victoria, Australia

There are emerging epidemics of atrial fibrillation (AF) and heart failure in most developed countries, with a
significant health burden. Due to many shared pathophysiological mechanisms, which facilitate the main-
tenance of each condition, AF and heart failure co-exist in up to 30% of patients. In the circumstance where
known structural causes of heart failure (such as myocardial infarction) are absent, patients presenting with
both conditions present a unique challenge, particularly as the temporal relationship of each condition can
often remain elusive from the clinical history. The question of whether the AF is driving, or significantly
contributing to the left ventricular (LV) dysfunction, rather than merely a consequence of heart failure, has
become ever more pertinent, especially as catheter ablation now offers a significant advancement over
existing rhythm control strategies. This paper will review the inter-related physiological drivers of AF and
heart failure before considering the implications from the outcomes of recent clinical trials in patients with
AF and heart failure.
Keywords Atrial fibrillation  Heart failure  Cardiomyopathy  Myocardial fibrosis  Catheter ablation
 Pathophysiology

Age, the presence of NHYA class greater than II and a non-

Introduction ischaemic aetiology of heart failure were strong predictors
There are rising epidemics of [27_TD$IF]atrial fibrillation (AF) and heart for co-existence of AF [4]. Importantly, the co-existence of
failure in developed countries around the world, and both conditions confers increased mortality and morbidity
Australia is no exception [1]. The prevalence of AF in [5].
Australia in those older than 55 years is 5.4%, projecting to
6.4% by 2034, equating to more than 600,000 Australians.
Similarly, the health burden from heart failure continues to Physiological Interrelationship of
increase. It affects roughly 2% of the population, with a three-
fold higher incidence in the elderly [2]. Atrial fibrillation and
AF and Heart Failure
heart failure frequently coexist, given there are physiological Atrial fibrillation and heart failure are each associated with
mechanisms common to both. In the Framingham Heart physiological conditions that contribute to the initiation and
Study, over 38 years of follow-up, heart failure was the maintenance of the other. Atrial fibrillation precipitates left
strongest predictor of incident AF, conferring a six- to ventricular (LV) dysfunction via (1) the loss of atrial contrac-
eight-fold increase in the incidence of AF, with an attribut- tion, (2) the precipitating irregular ventricular rhythm and,
able risk of 10–12% [3]. Atrial fibrillation was present in 21% (3) rapid ventricular rates. Conversely, heart failure precip-
of a ‘‘real world” population of 3,513 heart failure patients. itates AF by contributing to atrial remodelling due to (1)

*Corresponding author.
© 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
Published by Elsevier B.V. All rights reserved.

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2 S. Prabhu et al.

Figure 1 The interplay of factors contributing to[21_TD$IF], and maintaining, atrial fibrillation and heart failure.

increased filling pressures, (2) alterations in calcium han- [9]. This highlights that rapid rates alone do not explain the
dling and (3) alterations to the electrical properties of the entirety of LV dysfunction precipitated by arrhythmia.
atrial tissue. As such, a circuitous ‘cause and effect’ or Indeed, 60 patients (20%) with normal LV function had
chicken and egg relationship underpins the complex interac- incessant or high burden tachycardia, at a higher average
tion between these two conditions. Figure 1 shows the inter- rate than those with reduced LV function [9]. As such, the
play of factors contributing to[28_TD$IF] and maintaining AF and heart term arrhythmia-mediated cardiomyopathy is more appro-
failure. priate than tachycardia-mediated cardiomyopathy.

Heart Rate Irregularity

AF-induced Heart Failure Apart from rapid ventricular rates, the irregularity of ven-
tricular rate itself can have adverse haemodynamic effects
The mechanisms behind heart failure precipitated by AF
resulting in LV dysfunction. Naito et al. explored the impact
have been explored in both animal models and extrapolated
of various pacing strategies upon cardiac output in a canine
from clinical experience.
model with iatrogenic atrioventricular (AV) block. They
found that, in both AV sequential pacing and in underlying
Tachycardia AF, irregular ventricular rhythm with the same average
Rapid ventricular rates have a well-described deleterious ventricular cycle length of 400 ms, resulted in a significant
impact upon LV systolic function in canine rapid-pacing 7–9% reduction in cardiac output [10]. Similarly, Clark et al.
models [6,7]. The physiological mechanisms implicated in examined the haemodynamic impact of regular and irregular
precipitating LV impairment include haemodynamic stress, ventricular pacing following atrioventricular node (AVN)
activation of neurohormonal systems, myocardial and car- ablation in 16 patients with high burden or chronic AF
diac exoskeleton remodelling and, if tachycardia continues, undergoing AVN ablation. At equivalent average ventricular
eventual induction of apoptosis, cell death and replacement cycle lengths (587 ms), cardiac output was notably dimin-
fibrosis [8]. Clinically, incessant or high burden rapid regular ished in patients paced irregularly compared with regular
tachycardias such as those seen in focal atrial tachycardia ventricular pacing (4.4 versus 5.2 L/min, p < 0.01). Right-
(FAT) are often accompanied by LV systolic dysfunction and left-sided filling pressures, as determined by right atrial
which is reversed following the restoration of sinus rhythm pressure and pulmonary capillary wedge pressure, were also
by catheter ablation [9]. Medi et al. demonstrated that LV significantly elevated during irregular pacing [11].
dysfunction was largely confined to those with incessant
atrial tachycardia with slower ventricular rates, speculating Loss of Atrial Systolic Function
that symptoms may be more subtle, as such patients present Pacing studies have utilised iatrogenic A-V dysynchrony to
later with heart failure rather than earlier with palpitations quantify the contribution of atrial systolic function to cardiac

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 HLC 2387 No. of Pages 8

Atrial Fibrillation and Heart Failure 3

output. Benchimol et al. performed a haemodynamic analy- pro-fibrotic [21], and pro-inflammatory pathways [22], pro-
sis of 18 patients with compete heart block under varying moting electrical and structural remodelling [22].
strategies of AV sequential pacing and varying ventricular
rates. They found that atrial systole significantly contributed Neurohormonal Activation
to cardiac output at all ventricular rates, but most obviously Left ventricular dysfunction is associated with the activation
at rates 50–80 beats per minute [12]. Mukharji et al. quantified of several neuro-hormonal pathways implicated in atrial
atrial contribution to systolic function in 20 patients both remodelling. The most important of which is activation of
with and without underlying LV systolic dysfunction. Atrial the renin angiotensin system, which in turn activates a myr-
contribution to cardiac output was estimated at 20%, irre- iad of pathways including: mitogen-activated protein kinase
spective of the presence of underlying LV dysfunction [13]. (MAPK) [23], the Janus kinase (JAK)/signal transducers and
activators of transcription (STAT) [24], transforming growth
Genetic Factors factor b1 (TGF-b1) [25], angiotensin II activated platelet-
Nonetheless, the incomplete penetrance of AF phenotypes to derived growth factor A (PDGF-A) [26], Rac1 and nuclear
precipitating LV dysfunction in all patients, highlights the factor-kappa B (NF-kB) [27]. Additionally, angiotensin II can
likely role of other contributing factors in those patients activate these signalling pathways both indirectly and
susceptible to LV dysfunction. A myriad of genetic mutations directly via activation of angiotensin II type 1 (AT-1) recep-
implicated in non-ischaemic cardiomyopathy may play a role tors [28]. This promotes myocyte hypertrophy, apoptosis,
in determining susceptibility to LV dysfunction. These may collagen deposition and interstitial remodelling, all which
include those encoding molecules involved in contractile contribute to structural remodelling of the atria and the
function, cellular integrity and/or cytoskeletal structure development of AF. To some extent, natriuretic peptides
[14]. In the setting of atrial arrhythmia with rapid rates, those such as atrial natriuretic peptide (ANP) and B-type natri-
patients with a tachycardia-mediated cardiomyopathy had a uretic peptide (BNP) exert a counter-regulatory effect, oppos-
higher frequency of the angiotensin converting enzyme ing the activity of angiotensin II [29,30]. The overall
(ACE) gene polymorphism compared with both patients progression of remodelling may depend upon the interplay
with tachycardia and normal left ventricular ejection fraction of these opposing processes.
(LVEF), and healthy controls (p < 0.035 and p < 0.009,
respectively) [15]. The genomic determinants of arrhyth- Abnormal Calcium Handling
mia-mediated cardiomyopathy remain to be fully elucidated. In addition to neurohormonal pathways promoting atrial
remodelling in the setting of heart failure, disordered cal-
cium handling contributes to a propensity to AF. In an ovine
Occurrence of AF in Pre-existing model of heart failure, Clarke et al. determined that a reduc-
tion in L-type calcium current (ICa–L) in atrial myocytes
Heart Failure resulted in increased intra-cellular calcium, predisposing
Electrical and Structural Remodelling in to early and late after-depolarisations, promoting the auto-
matic atrial activity identified as triggers for AF [31]. Ling
Heart Failure
et al. demonstrated that irregular ventricular rhythms in the
Systolic LV dysfunction is associated with atrial structural setting of heart failure, were associated with reduced expres-
and electrical changes which initiate and sustain AF. Sanders sion of sarcoplasmic reticulum calcium channels, compared
et al. characterised the atrial electrophysiological properties with patients with regular pacing, and in sinus rhythm [32].
in patients with heart failure (n = 21) compared with age-
matched controls with no heart failure (n = 21), in the absence
of documented AF. Heart failure was associated with an Adrenergic Stimulation
increase in atrial effective refractory period (ERP), regional The autonomic nervous system plays an important role in
conduction slowing, increased fractionation and increased heart failure. Chronically reduced cardiac output leads to
areas of low voltage and scar [16]. These features are hall- sustained adrenergic overactivity and an increase in circu-
marks of atrial remodelling underlying even modest burdens lating noradrenaline and adrenaline [33]. In addition to sig-
of AF [17]. This study clearly demonstrated the capacity of nificant derangements to ventricular adrenergic regulatory
heart failure to precipitate a physiological environment processes [34], increased adrenergic stimulation has been
favourable to AF. shown to increase the inducibility of AF in a dose-dependent
manner. The mechanisms in which autonomic inputs pro-
Mechanisms of Heart Failure mote atrial arrhythmia have been well documented.
Precipitating AF b-adrenergic stimulation results in a protein kinase A medi-
The hallmark of LV dysfunction (both systolic and diastolic) ated cascade of phosphorylation of a range of intracellular
is an elevated LV end diastolic pressure leading to increased proteins involved in calcium handling, including ryanodine
left atrial (LA_ filling pressures[29_TD$IF]) [18]. Elevated atrial pressure receptor 2(RyR2), SERCA2a and Ica-L promoting condi-
increases atrial wall stress with consequent effects upon the tions favourable for delayed after depolarisations. Direct
renin angiotensin system [19], calcium handling [20], effects upon Inward Rectifier (IK1) and Pacemaker (If)

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4 S. Prabhu et al.

channels increase focal firing, whilst modulation of action particularly in patients with heart failure [44], with an accept-
potential duration (APD) via enhanced ICa-L (adrenergic) or able risk profile, albeit with a lower procedural efficacy
IKAch (cholinergic) can promote phase 2 and phase 3 early compared with patients without heart failure [45].
after-depolarisations. The net effect is the promotion of con-
ditions favourable to rapid firing and focal activity. In addi-
tion, b stimulation, via calcium activation of calmodulin and Predictors of LVEF Recovery Post-[31_TD$IF]
calcinuerin, also activates transcription processes implicated
in driving ultra-structural changes. Lastly, the effect of IKAch
Catheter Ablation
activity on APD abbreviation is [30_TD$IF]thought to occur with signif- Inferences may be cautiously drawn from limited clinical
icant regional variation, promoting conditions favourable for trials exploring the use of catheter ablation to improve LV
functional re-entry and pro-arrhythmia [35]. However, when function for patients with co-existing AF and heart failure.
AF and heart failure co-exist, patients may paradoxically Prospective randomised studies have generally included
develop a marked attenuation of sympathetic activity, patients with a variety of aetiologies for heart failure and
impairing the ability to respond to acute haemodynamic both paroxysmal and persistent AF. The patients most likely
stresses. Thus, a complex interplay between AF and heart to benefit from restoration of sinus rhythm with catheter
failure characterises the adrenergic response [36]. ablation include: (1) no alternate explanation for cardiomy-
opathy; (2) the absence of myocardial fibrosis; (3) patients co-
Functional Mitral Regurgitation diagnosed with AF and heart failure; and, (4) high AF
Additionally, functional mitral regurgitation (FMR), which burden.
often accompanies ventricular remodelling in the setting of
systolic heart failure, also contributes to the development of Heart Failure Aetiology
AF. In 894 patients with previous AMI and FMR, a dose- Whilst the occurrence of AF in previously known heart
dependent relationship between FMR severity and both the failure obviously presents little challenge in determining
presence of AF and new onset AF was reported [37]. Atrial cause and effect, the temporal sequence of events from the
fibrillation itself may contribute to functional mitral regurgi- clinical history may not always be clear. Several early clinical
tation resulting in further atrial remodelling, over and above trials have demonstrated that the restoration of sinus rhythm
the contribution of LV dysfunction [38]. with successful catheter ablation improved LVEF irrespec-
tive of heart failure aetiology [7,46–48]. However, these trials
were complicated by non-standardised definitions of heart
Clinical Trials of AF Ablation in failure aetiology, such as the failure to distinguish between a
causative diagnosis (for example, myocardial infarction) and
Heart Failure concurrent diagnosis (for example, non-occlusive, or non-
The clinical experience of managing patients with co-existing contributory coronary disease). Gentlesk et al[32_TD$IF]., in a retrospec-
AF and heart failure can provide important insights into the tive analysis, reported the outcomes of patients (n = 50) with
extent to which AF is contributing or indeed responsible for so-called unexplained cardiomyopathy with LV function
heart failure in this patient population. In particular, the normalised in 72% post ablation [48]. A meta-analysis sug-
restoration of sinus rhythm may result in a significant gested that pre-existing structural heart disease, such as prior
improvement in ventricular function highlighting the role myocardial infarction, predicted reduced procedural efficacy
of arrhythmias in unexplained or deteriorating cardiomyop- [43], and poor recovery of systolic function [49]. In a retro-
athy. Table 1 summarises these trials of AF ablation in spective analysis of 101 patients with persistent AF and heart
patients with heart failure, and the LV function outcomes. failure (LVEF <45%), those patients (n = 77) with no known
aetiology for the LV dysfunction (idiopathic cardiomyopa-
thy) had a 14% absolute improvement in LV function post-
Rhythm Control in Heart Failure ablation (p<0.001), with 38% of these patients normalising
LVEF (>55%) at follow-up [49]. To date, there have been no
A large multi-centre randomised study did not support a prospective randomised trials evaluating the role of catheter
strategy of pharmacological rhythm control compared with ablation in patients with persistent AF and an otherwise
rate control in patients with AF and heart failure with the unexplained cardiomyopathy.
primary endpoints of mortality and worsening heart failure
[39,40]. On subgroup analysis, the benefits of sinus rhythm Myocardial Fibrosis
were potentially negated by the poor efficacy and significant Ling et al. reported the outcomes of patients with persistent
toxicities of pharmacotherapy for rhythm control, namely AF, idiopathic cardiomyopathy (LVEF <50%) and the
amiodarone. Further analyses demonstrated that the group absence of late gadolinium enhancement (LGE) on MRI
who maintained sinus rhythm were symptomatically better imaging undergoing catheter ablation [50]. They hypothes-
[41], and received a mortality benefit, including death from ised that the absence of LGE was indicative of an arrhythmia-
pump failure [42]. In recent times, catheter ablation has mediated cardiomyopathy, whereas its presence signified an
established itself as superior to medical therapy [43], established cardiomyopathy in which AF was less likely to be

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Table 1 Clinical trials of AF ablation in patients with heart failure an outcome upon LV function.

Study Design No. Patients HF type AF type (HF LVEF Outcome Other outcomes
group) (ablation arm)

Hsu, 2004, NEJM Prospective, single 116 consecutive LVEF < 45% Persistent (91%) LVEF improved +21  13%, Reduced LVED diam
centre patients for ablation p < 0.001
Non-randomised. 58 with CCF Dilated CM (55%) Paroxysmal (9%) Reduced LA size
Ablation in HF vs
Ablation in normal LV
12 month F/U 58 with no CCF Ischaemic CM (21%) Improved QOL
Valvular disease (16%) Improved exercise capacity
Congential CM (3%)
Hypertrophic CM
(7%)
Chen, 2004, JACC Prospective, single 377 consecutive LVEF  40% Persistent (57%) Non-significant LVEF Improved QOL
centre non-randomised patients for ablation improvement (+5%, p = 0.1)
6 months F/U 94 with HF Dilated or ischaemic Paroxysmal (43%)
or valvular (91%)
283 with normal LV
Gentlesk, 2007, JCE Prospective, single 366 consecutive LVEF  50% Persistent (30%) Mean LVEF improved (+12%, Reduced LVED and LVES
centre. patients for ablation p < 0.001) dimensions
20  9 month F/U 67 with HF Dilated CM (73%) Paroxysmal (70%) Reduced atrial size
299 with normal LV Ischaemic CM (18%)
Valvular CM (9%)
Structural heart disease 50 patients with HF LVEF  50% Unspecified Mean LVEF improved Not specified
(ischaemic and valvular) (+15%, p < 0.001)
excluded.
Dilated CM (100%) 72% normalisation
[2_TD$IF]MacDonald, Prospective, multicentre, 41 patients with HF LVEF < 35% Persistent (100%) No change in MRI measured No change in BNP,
2011, Heart randomised. LVEF. Improvement in GBPS 6MWT distance or QOL.
LVEF (+8.2 vs +1.4%,
p = 0.032)
12 month F/U Dilated CM (22%)
Ischaemic (49%)
Other (29%)

5
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Table 1. (continued).

Study Design No. Patients HF type AF type (HF LVEF Outcome Other outcomes
group) (ablation arm)
Jones, 2013, JACC Prospective, multi- 52 patients LVEF  35% Persistent (100%) Non-significant LVEF Improved VO2max
centre, randomised trial improvement (+5.6%, p = 0.06)
12 month F/U 26 rate control Dilated CM (73%) Improved QOL
26 AF ablation Ischaemic CM (27%) Reduced BNP
Ling, 2013, Prospective, single 16 patients with HF LVEF < 50% Persistent (75%) LVEF improved Reduced LVESV
Heart Rhythm centre referred for ablation (+20  10%, p < 0.001)
6 months Dilated CM (100%) Paroxysmal (25%) Reduced LA volume
All LGE negative
Hunter, 2014, Prospective, single 50 patients LVEF < 50% Persistent (100%) LVEF improved Improved VO2max
Circ AE centre, randomised trial (+8.1  5.1%, p < 0.001)
6 month F/U 24 rate control Dilated CM (31%) Reduced BNP
26 AF ablation Hypertension (31%) Improved QOL
Ischaemic CM (23%)
Other (16%)
Anselmino, 2014, Meta-analysis, 26 1838 patients with HF LVEF < 50% Paroxysmal (45%) LVEF improved (+13%, Reduced NT-pro-BNP
Circ AE studies (various) p < 0.001)
23  11 months F/U Persistent (55%) % patients LVEF <35% Increased recurrence
(25% vs 10%)
Prabhu, 2016, JCE Retrospective, multi- 101 patients with HF LVEF  45% Persistent (78%) IDCM: LVEF improved IDCM:
centre analysis referred for ablation (+14%, p < 0.001)
3 years Dilated CM (76%) Paroxysmal (22%) Known HD: No signif. Improved AF control
Change LVEF (+3%, p = 0.25)
Ischaemic CM (16%) Improved NYHA status
Valvular CM (4%) Improved
Hypertrophic CM Less mortality
(4%)
KHD:
Improved NYHA

S. Prabhu et al.
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Atrial Fibrillation and Heart Failure 7

responsible for LV impairment. Patients without LGE under-

going AF ablation showed an average improvement of 20%
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Please cite this article in press as: Prabhu S, et al. Atrial Fibrillation and Heart Failure — Cause or Effect? Heart, Lung and
Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.05.117