© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
The ‘Second Factor’ of tachycardia-induced atrial remodeling
Dept. of Cardiology, Thoraxcenter, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, Netherlands
* Corresponding author. Tel.: +31-50-361-2355; fax: +31-50-361-4391
Received 6 March 2000; accepted 13 March 2000
See article by Van der Velden et al. [6] (pages 476–486) in this issue.
During recent years, atrial fibrillation (AF) research has received increasing attention. One of the explanations for this may be the ageing of the population with an increase in the prevalence of AF. Another important reason surely is the discovery of AF-induced atrial electrical remodeling as originally described by Wijffels et al. [1] in their masterpiece article ‘AF begets AF’. In this article the authors described the effects of automatic repetitive re-induction of AF by a ‘fibrillation-pacemaker’ on atrial electrophysiology in previously healthy, chronically instrumented goats. At the start of the protocol the induced episodes of AF typically lasted just a few seconds after which a new episode had to be induced automatically by the pacemaker. However, with an increased duration of the stimulation protocol, the induced episodes prolonged until eventually AF did not convert spontaneously anymore. They suggested that this was due to the progressive shortening of the atrial effective refractory period. Since the atrial conduction velocity over Bachmann's bundle did not change, the calculated wavelength decreased, which explained the increased propensity of the atria to fibrillate. Importantly, they described that this process of atrial electrical remodeling was reversible within 1 week after restoration of sinus rhythm, which offered a lot of potential for future improvement of anti-arrhythmic therapy in AF. As a result, many studies on the process of atrial electrical remodeling have been performed, investigating the cause of shortening of the refractory period [2], or evaluation of the existence of electrical remodeling and its reversibility in humans with AF [3–5].
However, close examination of the relationship between the shortening of the atrial refractory period and the prolongation of the induced episodes of AF in the experiments by Wijffels el al. [1] revealed that the time courses of both processes were fairly different. Whereas after 2 days the atrial refractory period did not shorten any further, AF only became persistent after 1–2 weeks. Wijffels et al. therefore discussed that other factors might have been important for the induction of persistent AF, such as conduction slowing, structural changes with local conduction block or atrial dilatation [1].
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1 Conduction slowing and stabilisation of AF |
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 Top 1 Conduction slowing and... 2 Structural remodeling and...3 ConclusionReferences |
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The study by Van der Velden and colleagues [6] in this issue of Cardiovascular Research is a direct follow-up of the original study by Wijffels et al. [1]. Using a simplified fibrillation pacemaker in chronically instrumented goats, they investigated the effects of various durations of automatic repetitive induction of AF on the expression and distribution of the gap junction proteins connexin 40 (CX40) and connexin 43 (CX43) in the atrial tissue of goats. They described that with an increased duration of pacing, the expression of CX40 decreased significantly, and the protein became more heterogeneously distributed. The expression of CX 43 did not change. Both the CX40/43 immunofluorescence signal and the CX40/43 protein ratios decreased with an increased duration of the stimulation protocol. By contrast, the mRNA levels of CX40 and CX43 remained unchanged, suggesting that the changes occurred at a post-translational level, such as proteolysis. Furthermore, in the present study the heterogeneity of CX40 distribution correlated with the stabilization of AF [6]. As CX 40 is known to influence the conduction properties of atrial tissue and the vulnerability for atrial arrhythmias [7], it is logical that the authors concluded that ‘the time course of the changes in distribution and content of CX40 gap junctional remodeling might be involved in the pathogenesis of sustained AF’ [6]. In other words, the authors suggest that after completion of the early changes in the atrial refractory period, attenuated gap junctional remodeling with conduction slowing might be a second factor in the tachycardia-induced increase in the stability of AF.
However, in contrast to this hypothesis, previous studies which were performed in a comparable animal model [1,8,9] could not determine any changes in conduction velocity. Although Konings et al. [9], using epicardial mapping, did find a decrease in conduction velocity during chronic AF as compared to acute AF, they stated that this conduction slowing was solely due to the increased frequency of activation during chronic AF and that the atria were ‘still capable of conducting at normal speed’ [9]. On the other hand, profound changes in activation patterns during AF were described, from the more organized type I AF in the acute experiments, to the fractionated and disorganized type III AF in the goats with chronic AF, which could occur due to local conduction slowing or block [9]. Therefore Van der Velden et al. [6] suggest that the change in expression and distribution of CX40 results in microscopic changes in conduction properties with the generation of small areas of conduction block and dispersion of conduction, which will stabilise AF. Taken together, the above data support the notion that conduction through the atria may be slowed while the intrinsic conduction velocity is normal, i.e. the path length may have increased to such an extent that even with a normal wavelength AF is deemed to stabilise.
Apart form the above, true conduction slowing may also be important with respect to stabilisation of AF. Gaspo et al. [10,11] showed that after 1 week of rapid atrial pacing in dogs the sodium-current and the conduction velocity decreased, which coincided with the development of chronic AF.
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2 Structural remodeling and the vulnerability for AF |
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Top1 Conduction slowing and...2 Structural remodeling and...3 ConclusionReferences |
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The other important finding of the study by Van der Velden et al. [6], being the correlation between the degree of myolysis and the stability of AF, is discussed less extensively and not mentioned in their conclusion. This is presumably due to the fact that it is hard to imagine how the contractile apparatus of the myocardial cell interferes with its electrophysiologic properties, resulting in the stabilisation of AF. Nevertheless, this finding deserves more emphasis because clinical studies have shown a clear correlation between the success of anti-arrhythmic therapy and atrial contractility, as determined with echocardiographic-doppler recordings. Decreased left atrial appendage emptying velocities during AF [12,13] were associated with an increased tendency of the arrhythmia to recur after a successful cardioversion. In case the decreased contractility is the clinical representative of the myolysis described in the present study by Van der Velden et al., their finding is in agreement with these clinical studies.
However, this does not explain why myolysis is correlated with the induction of stable AF. The significant correlation between myolysis and gap junction remodeling indicate that both processes occur simultaneously. This should make us realize that both myolysis and gap-junctional remodeling are just 2 out of the many structural changes which occur during ongoing AF. Because all of these changes move into the same direction with an increased duration of the stimulation protocol, all parameters will correlate to some extent with the stabilisation of AF. Therefore, one should be cautious to draw firm conclusions from the present study on the etiology of the stabilisation of AF during atrial remodeling. On the other hand, the present study gives further support to the theory that loss of atrial contractility, due to myolysis, could be used as a marker of atrial remodeling and predict arrhythmia prognosis. In this way transthoracic and transesophageal echocardiograpy could be used as non-invasive tools to study atrial remodeling.
Although not studied in the present study by Van der Velden et al., atrial dilatation is another example of structural remodeling which has been shown to correlate with the stabilisation of AF. In the study by Morillo and colleagues [14], which was performed at the same time as the study by Wijffels et al. [1], 6 weeks of rapid atrial pacing in chronically instrumented dogs increased the vulnerability for AF. Shortening of the atrial refractory periods and atrial dilatation were common findings in all dogs. Furthermore, an increase of the atrial area >40% was strongly related to the occurrence of stable AF during rapid atrial pacing [14]. Also from clinical studies it is clear that AF induces atrial dilatation [15]. On the other hand, atrial fibrillation is more difficult to treat in patients with enlarged atria [16]. However, the exact time course of atrial dilatation in relation to stabilisation of AF is not clear. Whether atrial dilatation follows the same time course as the described myolysis and gap junctional remodeling remains to be investigated. Which of these structural changes finally will prove to be ‘the second factor in atrial remodeling’ is hard to predict. A safer statement will be that after atrial electrical remodeling has increased the vulnerability for AF, secondary structural changes are important for the final stabilisation of AF, leading to persistent AF.
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3 Conclusion |
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Top1 Conduction slowing and...2 Structural remodeling and...3 ConclusionReferences |
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The study by Van der Velden et al. [6] in this issue of Cardiovascular Research further clarifies the pathophysiology of tachycardia-induced atrial remodeling. It shows that next to shortening of the atrial refractory periods, gap-junctional remodeling and myolysis correlate with the stabilisation of AF. Whether this is a causal relation, or due to co-existent changes such as atrial dilatation remains to be investigated.
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References |
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Top1 Conduction slowing and...2 Structural remodeling and...3 ConclusionReferences |
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