Idiopathic Atrial Fibrillation: Which Electrophysiological Substrate?
R.N.W. HAUER
Introduction
Atrial fibrillation (AF) frequently occurs in the setting of structural heart disease. Fibrosis and dilatation of the atria related to hypertension, car- diomyopathy, valvular heart disease, and other causes of haemodynamic overload are important contributors to the development of AF. However, AF may also occur in apparently structurally normal hearts. Several studies have shown shortening of atrial refractoriness after long-lasting periods of atrial tachyarrhythmias, also known as electrical remodelling [1–7]. At a later stage, this electrical remodelling is followed by structural remodelling, which includes dedifferentiation of atrial cardiomyocytes [4]. Thus, this form of structural disease is due to long-lasting AF itself. In contrast, the development of AF in the very early stages cannot be explained by a sub- strate due to remodelling. In these early stages, triggers, very often single or multiple premature complexes originating from the pulmonary veins [8], are important. Multiple premature complexes may occur as short-lasting atrial tachycardia episodes with a high rate and the appearance of AF in the sur- face electrocardiogram. However, after termination of the firing of the focus, the tachyarrhythmia is interrupted as well. In this situation isolation of the trigger is a logical therapeutic approach and indeed is often very successful.
In addition, an initiating electrophysiologic substrate in the atrium may enhance susceptibility to the occurrence of long-lasting AF episodes. In the presence of such a substrate, the above-mentioned trigger is still necessary for the onset of the AF episode. However, after termination of the focal trig- ger activity, the tachyarrhythmia will continue and contribute to a more sus-
Department of Cardiology, Heart Lung Center Utrecht, University Medical Center, Utrecht, The Netherlands
tained pattern. In previous studies we found that patients with rare episodes of idiopathic AF (AF in the absence of structural heart disease) had enhanced spatial dispersion of refractoriness unrelated to electrical remod- elling [9, 10]. This initiating electrophysiologic substrate will favour reen- trant mechanisms because of unidirectional block and activation delays at multiple sites. This is supported by the facilitation of AF induction by pro- grammed electrical stimulation.
Human and animal studies have demonstrated that the gap-junction pro- tein connexin40 (Cx40) is expressed mainly in the atrium and conduction system. Lack of Cx40 has been reported to result in increased atrial vulnera- bility and propensity to arrhythmias in the mouse [11]. In addition, it has been described that changes in the expression levels and distribution pattern of Cx40 may act as a substrate promoting AF susceptibility [12]. A previous study found that a linked polymorphism at nucleotides –44(G?A) and +71(A?G) in regulatory regions of the Cx40 gene, combined with a mutation in the cardiac sodium channel gene SCN5A, was associated with familial atrial standstill [13]. The described polymorphism in the Cx40 gene occurs in about 7% of the general population. In a recent study, we found that this rare, linked Cx40 polymorphism is related to enhanced spatial dispersion of refractoriness and susceptibility to reentry and AF [14].
Methods
Thirty patients with Wolff-Parkinson-White syndrome were studied. Of these, 14 had prior documented sporadic episodes of AF (AF group) and 16 had no evidence of AF (control group). The mean number of AF episodes in the AF group was 1 (range 1–5), medium duration 1 h (range 15 min to 3 h). The mean asymptomatic interval prior to the electrophysiologic study was 148 days. Electrocardiographic telemetric monitoring was carried out for at least 24 h immediately before the electrophysiologic study. None of the patients had AF episodes during the telemetric observation period.
Structural heart disease and conditions with potential effect on haemody- namic or electrophysiologic functions were carefully excluded. None of the patients were on antiarrhythmic drugs.
During the electrophysiologic study, a decapolar catheter was positioned at the right atrial free wall and a quadripolar catheter was placed in the right atrial appendage. Twelve unipolar electrograms were recorded. AF was induced with a progressively aggressive stimulation protocol. Fibrillation intervals were measured at all recording sites. The mean of all fibrillatory
58 R.N.W. Hauer
intervals at a single site was used as an index for the local refractory period.
The averages and SD for these indices were calculated. Spatial dispersion of refractoriness was determined by calculating the coefficient of dispersion (CD), defined as the standard deviation of all local mean fibrillatory inter- vals expressed as a percentage of the overall mean fibrillatory interval. Based on the previous study [9], a CD value of 3.0 or less was considered normal.
Cx40 polymorphisms were detected by direct DNA sequencing [13].
Results
In the control group, AF was induced by burst pacing in the large majority of patients, whereas in the AF group burst pacing was required in only one out of 14 patients. Most patients were inducible to AF with only a single extra stimulus in the AF group. Mean CD in control group was 1.59 ± 0.18 and in the AF group 5.96 ± 0.70. In the AF group, 13 out of 14 patients had enhanced CD (> 3.0), whereas in the control group all patients had a normal CD. This difference was significant (P < 0.001). Since mean fibrillatory intervals were not different in the two groups, the occurrence of remodelling was very unlikely.
Through molecular genetic analyses, three groups could be distinguished:
(1) –44AA/+71GG, (2) –44GG/+71AA, and (3) the heterozygous group –44GA/+71GA. AF was induced more easily with a single extra stimulus in patients with the –44AA genotype (the rare genotype) than in those with the –44GG genotype (86% vs 29%, P = 0.042). Carriers of the –44AA genotype had a significantly higher CD than those with the –44GG genotype (6.37 1.21 vs 2.38 ± 0.39, P = 0.018). Heterozygotes had intermediate values.
Conclusions
Both triggers and an atrial electrophysiologic substrate contribute to the development of AF episodes. In the absence of structural heart disease, AF itself promotes a substrate due to electrical remodeling by shortening of refractoriness. However, before this remodeling susceptibility to AF is due to an initiating substrate. This substrate facilitates reentrant mechanisms and appeared to be due to enhanced spatial dispersion of refractoriness. The ini- tiating substrate is associated with a minor form of Cx40 polymorphism in selected patients. Further studies are needed to confirm this relationship in other patient categories and to assess causation.
59 Idiopathic Atrial Fibrillation: Which Electrophysiological Substrate?
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