Indian Pacing Electrophysiol. J. 2003;3(2):81
Atrial Remodeling: Evolving Concepts
Mauro Biffi, MD and Giuseppe
Boriani, MD
Institute of Cardiology,
University of Bologna, Italy.
Address for correspondence: Dr. Mauro Biffi, MD, Institute of
Cardiology, University of Bologna, Via Massarenti 9, 40138 Bologna,
Italy.
E-mail:
mbiffi@orsola-malpighi.med.unibo.it
The
term "Electrophysiological remodeling" defines the changes of atrial
electrophysiologic properties taking place in atrial myocites during
atrial fibrillation and/or following periods of sustained atrial
fibrillation (AF).
Early research was prompted by clinical observations: many patients
were seen to get through increasingly frequent and longer paroxisms of
AF to persistent AF, until chronic AF eventually ensued, without
significant changes of underlying heart disease.
Indeed, clinical electrophysiology investigations reported peculiar
differences between AF patients and patients without atrial
arrhythmias. It was felt that the electrophysiologic milieu was the
cause of AF 1,2, until a
change of perspective occurred in the early 90's, thanks to
experimental research.
In his pioneering work, Wijffels kept goats fibrillating by an
implanted device, while measuring atrial refractoriness and its rate
adaptation as
spontaneous restoration of sinus rhythm occurred. He found that, after
several self terminating short bouts of AF, the arrhythmia became
considerably longer until a duration of days or weeks was reached. The
electrophysiologic companionship of AF pattern transformation consisted
of significant shortening of atrial fibrillation cycle, which was
paralleled by shortening of atrial ERP and loss of ERP adaptation to
heart rate: either flat (no change with shortening cycle length) or
inverted (paradoxical shorter ERP at longer cycle length) ERP
relationships to cycle length were observed.
This findings had been already observed in AF patients1,2; the novelty was that AF itself
was the cause of these abnormal electrophysiologic properties, which
could
in turn promote further recurrences of AF, and arrhythmia persistence
in
some cases.
By the light of this observations, AF may be seen as self-maintaining
by creating a functional electrophysiologic substratum, despite the
coexistence of only minor structural heart disease or occasional
triggers. This principle has been summarised by Maurits Allessie in the
aphorism "AF begets AF".
Following this observations, several studies have addressed the issue
of the mechanisms by which atrial electrophysiologic remodeling occurs
in different settings: basic electrophysiology, experimental
electrophysiology,
and clinical electrophysiology. It is nowadays believed that, beyond
structural
heart disease, changes of the atrial electrophysiologic substratum are
responsible for AF recurrence and/or perpetuation.
The aim of this review will be to assess the extent at which atrial
remodeling occurs in the experimental animal and in humans, and its
relevance to
clinical practice.
Mechanisms of atrial remodeling
Reviewing literature, one has to consider carefully the investigational
setting of reported studies, for significant differences exist in
electrophysiologic properties and vulnerability to atrial arrhythmias
among species (small mammals atria hardly fibrillate, dogs and goats
only under pathologic conditions), so that concepts must lean on solid
evidence before moving from experimental to clinical electrophysiology,
and eventually to clinical practice.
On the other hand, the settings of experimental and basic
electrophysiology allow precisely controlled conditions, and a deeper
knowledge of the mechanisms, up to the ionic/genomic level.
It is well demonstrated that atrial remodeling is a time-dependent
process that develops as an adaptive regulation of cardiac myocites to
maintain cell homeostasis against external stressors 3.
The type and extent of remodeling depends on the strength and the
duration of exposure to the "stressor": adaptive responses may thus
occur at the ionic/genomic level (fully reversible) at short term, or
at the cellular level at mid (hibernation, usually reversible) and long
term (apoptosis and
fibrosis, irreversible).
The most common "stressors" of atrial myocites are: tachycardia (high
rate
of cell depolarisation), and volume/pressure overload (heart failure
syndrome).
The adaptive changes at the ionic level are quite different in the
tachycardia-dependent compared to the heart failure setting, as
demonstrated by basic electrophysiology, hence we need to focus on
different types of "ionic remodeling".
Tachycardia-dependent remodeling:
High atrial rate causes calcium overload. Chronic calcium overload may
cause ultrastructural changes that resemble myocardial ischemia or
hibernation, and may ultimately lead to irreversible cell damage. To
prevent dangerous calcium overload, atrial myocites decrease L-type
Ca++ current (ICa) at first by a short-term adaptation (functional
inactivation by voltage- and [Ca++] - dependent mechanisms), in the
long term by downregulation of ICa4,5,6,7. Decreased ICa shortens
action potential duration (refractoriness) and causes loss of action
potential adaptation to heart rate6,7:
these are the hallmark of tachycardia-dependent remodeling.
The process leading to ICa downregulation implies transcriptional
changes
at the genomic level, but the signal coupling calcium overload to
changes
in ion channel expression is unknown. It also remain to be understood
whether calcium overload is the only initiating signal in this setting.
The observations by Wijffels et al 8 in
the experimental animal are in full agreement with this model of atrial
remodeling. In patients with lone paroxysmal AF, Capucci et al 9 demonstrated a strict correlation of atrial
refractoriness to AF cycle, and observed progressive shortening of AF
cycle during long lasting AF, whereas AF cycle prolonged in
self-terminating AF episodes. Acute administration of class 1C drugs
was able to prolong AF cycle and terminate
long lasting AF episodes 10. These data
are
consistent with basic electrophysiology, and are clues that ionic
remodeling
occurs early during AF, and sets the background for AF recurrence.
In the clinical scenario, early AF recurrence after cardioversion of
chronic AF is the most threatened complication. In this setting a
typically tachycardia-dependent remodeling occurs: in a study of 101
patients 11 we identified loss of
atrial refractoriness adaptation to heart rate, short atrial
refractoriness and AF duration
as the only predictors of AF recurrence at logistic analysis.
In a series of 28 patients, Manios et al 12
similarly observed that failure of action potential adaptation to heart
rate was the only prognostic indicator for AF recurrence. Importantly,
they observed that the electrophysiological markers of
tachycardia-dependent
remodeling recover nearly 24 hours after AF cardioversion. This point
raises
an important question, that is, whether loss of refractoriness
adaptation
to heart rate is the cause of AF relapse (which could explain only AF
relapse
within 24-48 hours) or simply a "marker" of a pathologic atrium, which
has already undergone some degree of structural remodeling and thus is
prone to AF. Up to now, the question is unresolved.
Owing to this knowledge, a considerable amount of work has been done to
test the hypothesis that preventing calcium overload by Icablockers
would
prevent tachycardia-dependent remodeling also. Experimental studies
found
that pre-treatment with verapamil could attenuate 13
or prevent 14 rapid pacing-induced
shortening of atrial refractoriness at short term (< 24 hours of
rapid pacing), respectively in goats and dogs. Following these
observations, Daoud 15 reported that
pre-treatment with verapamil reduced short-duration (5.6 3.9 minutes)
AF-induced shortening of atrial refractoriness in humans. In the
clinical scenario, Tieleman et al 16
speculated that pre-treatment with verapamil or diltiazem was
responsible for reduced AF recurrence in the first month after
electrical cardioversion, due to attenuated or rapidly reversed
tachycardia-dependent
remodeling.
This hypothesis fits poorly with the electrophysiologic findings by
Manios12 who demonstrated that atrial
remodeling recovers spontaneously nearly 24 hours after cardioversion:
the role of verapamil is indeed unclear. Clinical studies have failed
to demonstrated any beneficial effect of verapamil in preventing AF
recurrence at long term; indeed, a small effect of verapamil
pre-treatment could reasonably be expected only in AF of short
duration, and does not affect the electrophysiologic changes occurring
with long-lasting AF 17.
Lee et al17 have performed a very
important
research in chronically instrumented dogs, in which electrophysiologic
data were studied at baseline and after creation of a
tachycardia-dependent
atrial remodeling, comparing a control group with a verapamil-treated
group.
Atrial refractoriness, dispersion of atrial refractoriness, rate
adaptation
of atrial refractoriness, atrial conduction velocity AF inducibility,
and
AF duration were evaluated respectively after 1 day, 1 week, and 6
weeks
of rapid atrial pacing. This study demonstrated that verapamil could
only
attenuate the refractoriness shortening after 1-day pacing, but could
not
prevent the electrophysiologic remodeling at long term (1 and 6 weeks).
Furthermore, verapamil did not affect atrial inducibility, and
increased
the duration of induced AF. Consistent with this finding is the
observation
of increased fragmented activity in paroxysmal AF patients treated by
verapamil,
as reported by Kumagay 18, which would
favour AF persistence. In his study, Lee 17
reported a significant depression of atrial conduction velocity after 6
weeks rapid pacing: this abnormality had no evidence of recovery during
two days of follow-up after pacing had been stopped. A similar finding
had been previously reported in 2 studies 19,20 of chronic paced dogs, and were related to
structural abnormalities occurring along time 21.
All these data make the point
that verapamil use is of little value when high atrial rates persist
longer
than 24 hours, and thus give an explanation to the results observed in
clinical practice.
While demonstrating ICa reduction by downregulation of L-type Ca++
channels, Yue et al 6 observed an
unchanged inward T-type Ca++ current (ICaT ) even after several weeks
of rapid atrial pacing, who could thus represent a continuous "spill"
of calcium into atrial cells undergoing high frequency depolarisations.
This prompted Fareh et al 22 to
investigate the effect of mibefradil, a pure T-type Ca++ blocker, in a
chronic rapid-pacing dog model to prevent the development of an
electrophysiologic substrate for AF. After 1 week of rapid pacing,
mibefradil-treated dogs did not differ from control dogs (no rapid
pacing) in any electrophysiologic parameter, except for a slightly
increased heterogeneity of atrial refractoriness, whereas
placebo-treated dogs had developed all the characteristic abnormalities
of tachycardia-dependent remodeling (easy AF inducibility included). A
potential direct electrophysiologic effect of mibefradil was also
excluded in this study, thus supporting the evidence that prevention of
tachycardia-induced remodeling as the only
protective effect of mibefradil. Indeed, the AF-promoting effects of
rapid pacing were negatively correlated to mibefradil plasma
concentrations, showing
a dose-dependent protection against atrial remodeling.
In a similar study on dogs, Fareh et al 23
also demonstrated that prevention of tachycardia-dependent remodeling
is possible with the T-type Ca++ channel blocker mibefradil, but not
with
L-type Ca++ channel blockers.
There is considerable evidence that, in tachycardia-dependent
remodeling, calcium overload plays an important role either at short or
at long term
if high atrial rates persist. In the clinical setting, small benefits
may
be observed at short term by verapamil, whereas T-type Ca++ channel
blockers
seem promising to prevent long term remodeling during persistent AF.
These data support the concept that new therapies should target the
development of the substrate for AF, as opposed to "traditional"
antiarrhythmic therapy which aims to modify the product of the
arrhythmic substrate.
Heart failure-dependent remodeling: Heart
failure (HF) is the most important clinical syndrome associated to AF 24. Heart failure causes important ionic
remodeling either at the atrial or at the ventricular level by powerful
neurohormonal changes. The study of atrial remodeling in HF is very
difficult in humans because of the structural changes caused by
underlying myocardial pathology, and because of the confounding effect
of drugs acting on the neurohormonal milieu and of antiarrhythmic
agents. For this reason most of available data rely upon basic and
experimental research, most often on ventricular myocites.
Heavy alterations in calcium handling are prominent in ventricular
myocites: the sarcoplasmic carrier of Ca++ is downregulated in failing
myocites 25, leading to increased
cytosolic [Ca++] as a maladaptive attempt to maintain contractility.
Sodium-calcium exchanger current (NCX) is instead upregulated in HF,
acting to compensate the impaired Ca++ removal due to the sarcoplasmic
carrier 26,27,28,
to protect contractile function and cellular Ca++ homeostasis. NCX
exchanges one Ca++ for three Na+ , thus carrying a net current in the
direction of Na+ transport. The net current carried by NCX may cause
delayed afterdepolarisation (DAD) in certain
electrophysiologic situations, which proved to be arrhythmogenic in HF 29.
Danshi li et al. 30 created a canine
model
of rapid ventricular pacing-induced HF, and observed for the first time
in atrial myocites a decrease in ICa, in Na+ current (Ito), in slow
rectifying
K+ current (Iks), and an increase in NCX. Heart failure decreased both
Iks and ICa 30%, whereas atrial tachycardia decreases ICa 70% without
affecting Ik 6. The electrophysiologic
manifestations were
an unchanged action potential duration (APD) at slow heart rates
compared to control dogs, whereas an increase of APD at faster high
rates was observed.
Thus, a peculiar type of remodeling with an attenuated rate-adaptation
of atrial refractoriness and long APD at high rates is observed in
experimental HF. This is quite different from atrial
tachycardia-dependent remodeling, which shows decreased APD at any
cycle length and flat or reversed adaptation of refractoriness to heart
rate.
The mechanisms of AF onset in the setting of HF must be very different.
Structural changes (interstitial fibrosis) related to underlying
disease
cause conduction abnormalities that predispose to reentrant
arrhythmias,
increased NCX may promote DADs by transient inward depolarising
current,
which may be enhanced by high cathecolamine levels and by decreased
Iks.
It seems then likely that AF may be initiated by triggered activity, in
the HF setting.
If a different sort of atrial remodeling occurs in HF, peculiar
interventions for targeting this arrhythmogenic substrate should be
sought.
Danshi Li and co-workers 31 performed an
elegant investigation on 15 dogs with HF induced by rapid ventricular
pacing compared to 10 dogs without HF subjected to rapid atrial pacing
(RAP), evaluating the effect of dofetilide on vulnerability to AF. It
was observed that dofetilide,
a pure Ikr blocker, was extremely effective in terminating AF and in
preventing AF reinduction in dogs with HF-dependent AF. On the
contrary, dofetilide was completely ineffective in dogs with atrial
tachycardia-dependent AF. The electrophysiologic findings were
striking: atrial refractoriness was shorter and showed less rate
adaptation in RAP vs HF dogs; dofetilide increased refractoriness
significantly and to a greater extent in HF dogs, whereas it had
nonsignificant effects in RAP dogs.
This finding was related to the increased dependency of atrial
refractoriness on Ikr in HF dogs, due to downregulation of Iks
occurring in HF dogs.
Significant clinical results were indeed observed by Torp-Pedersen et
al 32 investigating dofetilide effects
in advanced
HF patients (class III-IV): a significant proportion of AF patient
converted to sinus rhythm by dofetilide, and dofetilide patients had a
significantly higher proportion of sinus rhythm persistence during
clinical follow up compared to control patients.
Nonetheless, AF incidence increases with the severity and the duration
of HF despite therapeutic interventions.
Shinigawa et al33 studied the
electrophysiologic
remodeling occurring during atrial tachycardia in a canine model when
HF was superimposed, and also after reversal of HF was allowed to take
place. They observed that the electrophysiologic changes related to
atrial
tachycardia were completely attenuated by HF, and that reversal of HF
led
to normalisation of both ventricular and atrial volume and
contractility,
with recovery of atrial electrophysiologic abnormalities. However,
extensive
interstitial fibrosis had developed compared to a group of control
dogs,
and this invariably caused local conduction slowing and heterogeneity
of
conduction velocity. This changes were irreversible.
Interestingly, in the same experimental canine model of HF, Danshi Li
et
al 34 reported that angiotensin II
causes
structural atrial remodeling inducing collagen synthesis by
fibroblasts,
and that enalapril interferes with signal transduction at the cellular
level, thereby reducing the amount of interstitial fibrosis by 30%
compared
to control dogs or to hydralazine-treated dogs.
These two studies carry the important notion of targeting the
development
of the arrhythmogenic substrate understanding the pathophysiologic
mechanisms of the disease or of the clinical syndrome.
It is interesting to note that, either in atrial tachycardia-dependent
or in HF-dependent remodeling, both reversible and irreversible changes
occur. In either situation, the abnormalities due to ionic remodeling
(APD, refractoriness and its adaptation to heart rate) appear to be
reversible
when the "stressor" is removed, but in the same time structural changes
at the cellular level have occurred, which are irreversible. This
"structural
remodeling" adds slowing and heterogeneity of conduction velocity to
the
abnormalities of refractoriness in both situations, and may explain the
reduced efficacy of medical interventions in patients with persistent
or
permanent AF.
Experimental research has clearly demonstrated that
"electrophysiologically" different arrhythmias share a common
electrocardiographic picture of atrial fibrillation, and that the
underlying differences imply peculiar therapeutic interventions.
All these investigations have brought in the clinical arena a new way
of thinking antiarrhythmic therapy: development of new drugs should be
guided
by the principle of targeting the specific ionic currents depending on
the pathophysiologic mechanisms of the arrhythmia, to achieve the
optimal
ratio between efficacy and safety. Also, the concept of preventing
structural
remodeling of atrial myocites should be investigated and promptly
brought
into clinical practice.
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