Download Arrhythmia induced cardiomyopathy secondary to atrial fibrillation

Arrhythmia induced cardiomyopathy secondary to atrial fibrillation:
an easy condition to recognise and treat?
Nathan Denham; ST5 Cardiology, Countess of Chester Hospital NHS Foundation Trust
Email: [email protected]
What is arrhythmia induced cardiomyopathy?
Arrhythmia induced cardiomyopathy is a condition characterised by either a
tachyarrhythmia (also known as a tachycardia induced cardiomyopathy or
tachycardiomyopathy) or frequent ventricular ectopy (also known as ectopy induced
cardiomyopathy) that results in left ventricular dysfunction and heart failure. In addition,
the dysfunction is partially or completely reversible once control of the tachyarrhythmia or
frequent ectopy is achieved1.
Key features of an arrhythmia that will result in arrhythmia induced cardiomyopathy (AIC)
are: rapid ventricular rates, an irregular rhythm, and asynchronous myocardial contraction,
however not all need to be present to result in AIC1-3. The length of time spent in and
persistence of the arrhythmia are also important, but have yet to be clearly defined beyond
work in animal models. With that in mind, the resistance of the arrhythmia to treatment
and the presence (or lack of) symptoms act as risk factors to develop AIC.
Atrial fibrillation (AF) is the commonest cause of AIC and is reported to be present in 10-50%
of patients with heart failure4. 25-50% of patients with left ventricular dysfunction and AF
demonstrate some degree of AIC, however AIC frequently co-exists with other aetiologies of
heart failure5. There is therefore a pure AIC where the arrhythmia is the only cause of heart
failure and an impure one where an arrhythmia worsens and / or exacerbates heart failure
of another aetiology6.
What is the pathophysiology of AIC?
Animal models have proved useful in understanding AIC using frequent and rapid pacing of
the right ventricle, which causes a dilated cardiomyopathy and is reversible once pacing is
terminated2. The studies have not been able however to clearly define the relative
contributions of rate, irregularity and ventricular dyssynchrony in causing heart failure.
The proposed pathophysiological cascade has been well described elsewhere 5. In summary,
an arrhythmia in a predisposed individual (of which age, pre-existing myocardial dysfunction
and co-morbidity are important) results in energy depletion, ischaemia and oxidative stress
at a cellular level. This leads to myocyte dysfunction, neurohormonal activation and
abnormal calcium handling, which in the longer term results in the structural and functional
changes seen in AIC. Where the dividing line between reversible and irreversible LV
dysfunction occurs is unclear, but appears to be time dependent, necessitating earlier
diagnosis and intervention.
How do I recognise the patient with AIC?
We are frequently faced with patients in clinical practice who have the combination of AF
and heart failure, however teasing out which came first (the old chicken or the egg
question) is not easy. A high index of suspicion is therefore required for AIC, particularly
given the reversibility of the condition.
Useful recommendations for identifying responders include: onset of AF before or at the
same time as heart failure, a normal ECG other than the presence of AF, no other cause of
heart failure likely (exclusion of ischaemic heart disease, valve disease and alcohol induced
cardiomyopathy), and the absence of late gadolium enhancement on cardiac MRI5,7.
In practice, an additional pointer is either: a trial of restoring sinus rhythm with direct
current cardioversion (DCCV) or rate control of the AF; and monitoring the response of the
left ventricle with serial imaging, with recovery expected within 3-6 months if sinus rhythm
or good rate control is maintained8.
How do I manage AIC secondary to AF?
Guideline directed medical therapy of both AF and heart failure with a reduced ejection
fraction (HFREF) remains the standard of care with rate control recommended as first line
therapy9,10. Evidence from the RACE II trial11 showed no benefit from a lenient versus a strict
rate control regime however the study recruited patients with reasonable rate control at
baseline (mean 96 beats per minute in both groups) which therefore is unlikely to have
included a significant number of those with a tachycardia-induced cardiomyopathy.
Given at present we do not fully understand the rate threshold for developing AIC, we
equally have no clear target rate to aim for in affected patients. There is also evidence that
treatment of rate alone is insufficient to treat AIC, most likely due to the ongoing irregularity
of the ventricular response12. Rate control may therefore not be the most appropriate first
line therapy in all comers with AIC secondary to AF, particularly in individuals reliant on
atrial contraction for ventricular filling (e.g. hypertrophic cardiomyopathy or heart failure
with a preserved ejection fraction); and in those who show no improvement despite good
rate control that subsequently benefit from a trial of sinus rhythm.
Rhythm control is theoretically preferable in the management of AIC due to targeting both
the rate and irregularity of AF. Results from initial randomised control trials (RCT) however
were unable to confirm this in practice. The rhythm control versus rate control trial for AF
and heart failure (AFCHF)13 is the largest RCT to date, and showed no difference in the
primary endpoint (cardiovascular death) or secondary endpoints (all cause mortality, stroke
or worsening heart failure). Rhythm control included a combination of anti-arrhythmic drugs
(AAD) and DCCV. One possible reason why no difference was seen is that entry was not
limited to specific aetiologies of LV dysfunction, therefore the majority had a low probability
of having AIC and the potential for reversibility. Another reason is the requirement for long
term AAD therapy and their unwanted effects offset any benefit gained from rhythm
control.
More recently, a number of smaller studies have been published which have shown benefit
from restoration of sinus rhythm through a rhythm control strategy with an improvement in
left ventricular ejection fraction (LVEF)14-19, however it should be noted not all have
reported positive results20.
This has led to the publication of a number of meta-analyses21-23 which have reported a
significant improvement in LVEF in patients who undergo catheter ablation of AF who have
symptomatic heart failure and a reduced LVEF at baseline.
An important observation from the larger of the two meta-analyses22 is that the time to
ablation from first episode of AF and diagnosis of heart failure both result in a statistically
lower recurrence rates, suggesting timing of rhythm control in AIC is important to prevent
irreversible LV remodelling. An alternative explanation is that AIC is more likely when there
is a clear deterioration in LVEF within a short time from AF onset compared with those with
longstanding AF, who are less likely to have AIC and therefore least likely to benefit from an
invasive approach. Catheter ablation does not result in rhythm control in all-comers
however, with only around 60% remaining in sinus rhythm at the end of the follow up
period (mean follow up just under 2 years). The success of a single procedure is also low
with freedom from atrial arrhythmia after a single ablation achieved in around 40%, with
the majority going on to need 2 or more procedures to maintain sinus rhythm. The need for
repeat procedure is more frequent compared to those without LV dysfunction 23, however
those with the worst LVEF have the most to gain by restoration of sinus rhythm potentially
offsetting the risk of multiple procedures24. When rhythm control is achieved, a number of
the individual trials consistently report improvements in NYHA functional class, six minute
walk distance (6MWD) and Minnesota living with heart failure questionnaire (MLWHFQ)
scores which is supported by the meta-analysis21. Whether this was maintained beyond the
short follow up period of, on average, 2 years is unclear, and data on harder endpoints,
specifically mortality, is currently lacking.
Not all who entered these trials did receive an improvement in LVEF however. Whether this
reflects an inability to correctly recognise AIC or an inability to intervene before irreversible
remodelling had occurred is unclear. Another possibility is that AIC is being overdiagnosed
and is not as important a clinical entity in the real world as work in animal models suggests,
particularly compared to a tachycardia-induced cardiomyopathy alone. There was variation
in the entry populations with regard with paroxysmal versus persistent AF, and adequacy of
rate control prior to undergoing an ablation making direct comparisons difficult with respect
how much benefit is achieved by restoring sinus rhythm over better rate control.
Improvement in LVEF after ablation has also been shown in those who fail to achieve sinus
rhythm when a trial of AAD (amiodarone) and DCCV is given first. Bortone et al7 reported an
improvement in LVEF was achieved after at least 3 months of sinus rhythm after ablation
however entry into the trial was stringent selecting those where an AIC was highly likely to
be the cause of HFREF. This again suggests the ability to suspect and correctly recognise AIC
is essential if patients are to benefit from an invasive approach. The study however was
non-randomised, and may simply reflect improved medical care in the ablation group with a
natural improvement in LVEF often seen in non-ischaemic cardiomyopathy on guidelinedirected medical therapy rather than benefits from ablation itself
Catheter ablation has also been shown to be superior to atrioventricular node ablation and
cardiac resynchronisation pacing for improvement in LVEF, 6MWD and MLWHFQ scores in
those with drug resistant AF and symptomatic HFREF12. It does therefore hint that in
selected groups, rhythm control may be superior to rate control, but the numbers in this
trial were low (around forty in each arm) so it would need to be replicated in larger trials
before any firm recommendations could be made.
Finally, catheter ablation is also superior to amiodarone in the treatment of AF in patients
with symptomatic heart failure. The AATAC-AF trial25 has shown statistically significant
benefits from ablation in: freedom from atrial arrhythmia, improvement in LVEF, 6MWD,
MLWHFQ scores, rehospitalisation and all cause mortality. Not only does this suggest
catheter ablation should be the first line rhythm control intervention in heart failure, but
also why rhythm versus rate control trials using AAD such as AFCHF13 should be reassessed
in the ablation era. The CASTLE AF study26 looking at the effects of morbidity and mortality
from catheter ablation versus medical therapy of AF in LV dysfunction is expected to answer
this important question with results expected after 2019.
Until further large scale randomised control trials provide greater insight into the
management of AIC with particular reference to hard endpoints of morbidity and mortality,
current guideline-directed therapy of good rate control remains the key aim in everyday
practice.
Conclusions
In summary, AIC is an important cause of heart failure, not just by itself but also in
combination with other aetiologies leading to a worsening of symptoms and LVEF. AF is the
commonest arrhythmia responsible for AIC, with growing evidence that rhythm control
should be the first line therapy (particularly with catheter ablation) over rate control as
recommended in current guidelines. The real difficulty however arises in clinical practice in
separating out those with a true AIC, and concomitant AF and HFREF. Recognising the
possibility of AIC should alert the clinician to trialling rhythm control therapy first (e.g.
amiodarone and DCCV) and assessing response, with a view to a more invasive strategy
afterwards. This is particularly important as the benefits of rhythm control seem to be time
dependent before irreversible LV remodelling occurs. Despite the poor success rate from a
single ablation, the clinician should not be dissuaded from repeat attempts as patients with
AIC potentially have the most to gain due to reversibility of LV dysfunction. Whether this
selective rhythm control strategy will result in improvements in morbidity and mortality
remain to be seen.
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