G.V. NACCARELLI1, M.A. ALLESSIE2
Atrial Fibrillation Begets Atrial Fibrillation
Atrial fibrillation often progresses from its paroxysmal form to a more per- sistent and permanent form. The evolution of this disease over time can be partially explained by atrial remodelling, which may occur sooner rather than later depending on whether atrial fibrillation is allowed to continue, with progression of the structural heart disease. Three kinds of atrial remod- elling have been proposed: electrical, structural, and contractile [1, 2].
In the instrumented goat model, Wijffels et al. documented that ‘atrial fib- rillation begets atrial fibrillation’ [3]. In this model, there was evidence of electrical remodelling with shortening of the atrial refractory period com- pared to control within 24 h of atrial fibrillation. In addition, there was a loss of rate adaptation of atrial refractoriness manifested by short atrial effective refractory periods (AERPs) even at slower heart rates. The decrease in atrial refractory periods resulted in an increase in the rate of atrial fibril- lation, which therefore became more complex. Perpetuation of atrial fibrilla- tion resulted in even shorter atrial fibrillatory intervals.
Role of Calcium Currents in Atrial Electrical Remodelling
The cellular electrophysiological changes typical of rapid atrial pacing and atrial fibrillation are a decrease in action potential duration and a depression of the action potential plateau [4, 5]. It has been reported that L-type calcium current decreases within 24 h, consistent with the timing of the electrical
1Division of Cardiology, Penn State University College of Medicine, Hershey, PA, USA;
2Maastricht University, Maastricht, The Netherlands
remodelling noted above. Lai et al. [6] reported that mRNA of the L-type cal- cium channel and of calcium-ATPase was significantly (P < 0.05) down-reg- ulated in patients with atrial fibrillation of more than 3 months duration. It has also been documented that outward KACh currents increase.
Some of the biochemical mechanisms explaining tachycardia-induced changes on AERPs in humans have been described. Yu et al. [7] reported on 60 patients before and after induced atrial fibrillation. They documented that AERP was shortened by 30 ms after induced atrial fibrillation (P < 0.0001) and that shortening was attenuated by verapamil but unchanged by pro- cainamide, propafenone, propranolol, sotalol, or amiodarone. In addition, verapamil shortened the time course of post-atrial-fibrillation AERP changes from 6.1 to 3.1 min (P < 0.001). Wijfells et al. [8] documented that electrical remodelling was not mediated by changes in autonomic tone ischaemic stretch or levels of atrial natriuretic factor. In a human study by Daoud et al. [9], verapamil attenuated shortening of atrial refractory periods after atrial fibrillation; procainamide was ineffective in preventing this remodelling. Thus, the above cascade of electrical remodelling starts with a decreased L-type calcium current and a decrease in action potential duration followed by a decrease in the atrial fibrillation cycle length, which decreases wave length and circuit size. Further evidence that verapamil reduces tachy- cardia-induced remodelling of the atrium was reported by Tieleman et al.
[10]. They documented that electrical remodelling of the atrium during rapid atrial pacing was attenuated (P < 0.01) by verapamil with only a mini- mal decrease in the induction of atrial fibrillation by verapamil (34% vs con- trol 39%; P = 0.03). These data suggest that electrical remodelling is at least partially triggered by high calcium influx during rapid atrial pacing rates.
Electrical remodelling has important clinical significance. In the short- term (hours–days), it appears to be completely reversible and to play a role in the immediate (IRAF) and early (ERAF) recurrence of atrial fibrillation.
These changes also make atrial fibrillation more likely to be persistent and to reduce the likelihood that class III drugs will be effective. Several investiga- tors have shown that calcium channel blockade may minimise electrical remodelling and ERAF [11, 12]. Also, beta-blockers prevent ERAF but only in hypertensive patients with persistent atrial fibrillation, not in those with iso- lated atrial fibrillation [13].
If atrial fibrillation begets atrial fibrillation, the opposite may be true.
Several studies support the concept that sinus rhythm begets sinus rhythm.
Dell’Orfano et al. [14] reported that spontaneous conversion was highest in patients with the shortest episodes of atrial fibrillation. Dietrich et al. [15]
reported that the longer a patient remains in atrial fibrillation the harder it is to cardiovert and maintain sinus rhythm. Hobbs et al. [16] documented that the atrial fibrillation cycle length is shortest after prolonged atrial fibril-
lation and progressively prolongs after cardioversion, with prolonged peri- ods of sinus rhythm. Rapid conversions of atrial fibrillation by internal atrial defibrillators prolong the time to its next occurrence.
Structural and Contractile Remodelling of the Atria
During atrial fibrillation remodelling, there are different time domains [1, 2, 17]. In the short term, within seconds to minutes, metabolic changes, includ- ing ion concentration, pump activity, and phosphorylation, take place. The next step is an intermediate phase, lasting hours to days, that is characterised by altered gene expression and calcium down-regulation. Longer term effects, lasting weeks to months, include cellular changes, such as dedifferen- tiation and myolysis. Finally, there is a very long-term phase, involving the persistence of atrial fibrillation from months to years. In this phase, there is irreversible tissue damage, with histological changes showing fibrosis, fatty degeneration, and cell death.
Structural changes from remodelling show left atrial appendage enlarge- ment, reduced atrial contractility, decreasing cardiac output, and an increased propensity for clot formation. Whether histological changes occur due to cardiomyocyte degeneration depends on the duration of the remodel- ling. Using atrial pressure volume-loop studies, Schotten et al. [18] reported that there is atrial stunning and contractile remodelling even 48 h after atri- al fibrillation. Although the refractory period is shortened during this phase, once conversion of atrial fibrillation occurs, not only do the atrial refractory periods return to normal but the atrial work index and contractile function also return. Thus, with dilatation of the atrium, sinus rhythm also reverts to atrial fibrillation, and once sinus rhythm returns the atrium shrinks back to a more normal size. This has been documented in multiple studies, while left atrial volume increases have been shown in echo studies [19]. In addition, the return to improved left atrial function after cardioversion of persistent atrial fibrillation has been documented in echo Doppler studies [20]. Left atrial emptying, after DC cardioversion of atrial fibrillation, takes up to 3 weeks to return to normal baseline due to atrial stunning. AVE0118 has been documented to enhance atrial contractility in the isolated right atrium in atrial fibrillation patients [21]. This positive chronotropic effect may be an added benefit of such drugs.
As noted above, heart failure provokes dilatation and left atrial volume increases over time. In turn, dilatation can provoke stretched-induced arrhythmias [22, 23]. Regional stretch for even 30 min can alter stretch-acti- vated channels. This may also augment the synthesis of angiotensin II, which induces myocy te hypertrophy, increases L-type calcium current, and
decreases Ito. In addition to increased atrial size, increases in atrial pressure load can alter the electrophysiologic properties of the atrium through stretch receptors purportedly located in the sarcolemmal membrane. Acute and chronic atrial dilatation diminishes resting-membrane potential and action- potential amplitude, thereby decreasing conduction velocity and increasing the heterogeneity of atrial repolarisation. Although atrial stretch may increase calcium influx through stretch-activated and L-type calcium chan- nels in the short-term, long-standing atrial fibrillation leads to decreased inward L-type calcium currents by as much as 60–70%, accelerating repolari- sation and thereby shortening the atrial action potential duration and effec- tive refractory period. Atrial fibrillation can also stimulate transient calcium flux by substantial increases in the sodium–calcium exchanger, which is thought to be responsible for delayed after-depolarisations and triggered activity.
Several investigators [24–26] have documented histological remodelling of the atrium by 4 months of atrial fibrillation, as evidenced by myolysis, enlarged atrial cells, glycogen accumulation, and a reduction in connexin 40 expression. The development of small islands without connexin make atrial fibrillation more complex; and in the presence of fibrosis and conduction abnormalities atrial fibrillation can persist through micro-reentrant mecha- nisms. This structural remodelling appears to be a slow process, often taking as long as 2–3 months.
Does Blockade of the Angiotensin System Have Benefit?
Li et al. [27] have shown that fibrosis may be minimised by the addition of the ACE inhibitor enalapril. Other studies [28, 29] have demonstrated that ACE inhibitors and angiotensin receptor blockers can reverse some of the anatomic remodelling that occurs with atrial fibrillation. In addition, data from TRACE and SOLVD suggest that ACE inhibitors and angiotensin recep- tor blockers prevent atrial fibrillation [30, 31]. Madrid et al. [32] prospective- ly documented that patients with persistent atrial fibrillation treated with amiodarone plus irbesartan had a lower recurrence rate of atrial fibrillation post-conversion compared to patients receiving amiodarone alone. Murray et al. [33], based on an AFFIRM sub-study, documented that the benefits of ACE inhibition and angiotensin receptor blockers in preventing atrial fibril- lation appear to be limited to patients with congestive heart failure and left ventricular dysfunction. Whether the benefit of angiotensin II blockade is secondary to decreasing atrial stretch, minimising and reversing atrial fibro- sis, and other structural changes, or occurs through some direct antagonistic effect on the angiotensin system is not clear.
Can Atrial Selective Potassium Channel Blockade Attenuate Atrial Remodelling?
As noted above, classic class III agents that block the IKrchannel seem to be ineffective once the atrium has remodelled. Newer drugs targeting the IKur
and the IKACh channel, which are not expressed in the ventricle, appear to have different results [34]. Thus, the efficacy of drugs like D-sotalol in block- ing IKr decreased as a result of electrical remodelling during 48 h of atrial fibrillation, whereas newer antiarrhythmic drugs, such as AVE0118, which blocks IKur, Ito, and IKACh, do not lose efficacy by electrical remodelling [35].
AVE0118 significantly increased AERP in the remodelled compared to the normal atrium [35]. Hopefully, this unique electrophysiological action will lead to better efficacy for termination and prevention of atrial remodelling in patients with persistent atrial fibrillation. These newer drugs, due to their relative atrial selectivity, may also minimise problems with ventricular proarrhythmias, such as torsades de pointes [34].
Can Catheter Ablation Reverse Atrial Remodelling?
Whether histological changes can be reversed in advance stages of atrial fib- rillation is controversial. An encouraging report showed that following pul- monary vein isolation procedures in congestive heart failure, that left ven- tricular ejection fraction, fractional shortening improved, with a decrease in left ventricular dimensions in addition to an improvement in exercise capac- ity and quality of life [36].
Conclusions
The progression of atrial fibrillation may be explained by the above- described effects of atrial remodelling. Maintaining sinus rhythms in atrial fibrillation by whatever means may slow the progression of remodelling and give patients benefit until safer antiarrhythmic drugs and ablation proce- dures are developed.
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