Fractionation of electrograms is caused by colocalized conduction block and connexin disorganization in the absence of fibrosis as AF becomes persistent in the goat model
Introduction
Wijffels et al1 initially demonstrated in a landmark article that artificial maintenance of atrial fibrillation (AF) in the chronically instrumented goat model leads to a shortening of the atrial effective refractory period (AERP) associated with an increase in arrhythmia stability and inducibility. However, the time course of AERP shortening (48–72 hours) differs from the time course of progression to persistent AF (>7 days), suggesting that additional myocardial changes are responsible for the delayed increase in AF stability.2 In that these changes are not of the action potential or its causative ion channels, they are likely to be structural. The mechanism of myocardial remodeling leading to persistence of AF and its prevention and treatment are a major focus in this field.
Early studies highlighted the association between electrogram fractionation in the ventricles and slow conduction and its relevance to arrhythmogenesis.3, 4, 5 Later, mapping studies in human atria demonstrated greater electrogram fractionation during persistent AF6, 7 and, together with studies showing modest short-term results for catheter ablation of these complex fractionated atrial electrograms,8 supported the concept that areas of increased fractionation represent areas of slow atrial conduction that are critical to the maintenance of AF. Although a number of other causative mechanisms for atrial electrogram fractionation have since been described, including anchor points for reentry circuits, sites of high-frequency sources, and autonomic innervation,6, 7, 9, 10 the findings of histopathological and imaging studies of atrial fibrosis in patients with persistent AF11 have supported the widely held concept that fibrosis causes slow and discontinuous atrial conduction and is therefore responsible for the observed increased electrogram fractionation and arrhythmia stability.12
However, recent clinical studies have shown that areas of fractionation during AF and atrial fibrosis detected using gadolinium-enhanced magnetic resonance imaging (MRI) do not colocalize,7, 13 and hence not only do the relative roles of fractionation and fibrotic change, and their relationship, in AF stability and persistence remain unclear, but alternative contributory mechanisms of conduction slowing need be sought.
The aim of the study was to examine the hypothesis that electrogram fractionation with increasing persistence of AF results from localized conduction slowing and block in the absence of the need for fibrotic change, and resulting from changes in atrial connexin distribution.
Section snippets
Methods
Twelve adult female goats (mean weight 67 ± 8 kg) were used for the study. The experiments were conducted in accordance with a project license issued by the UK Home Office under the Animals (Scientific Procedures) Act 1986 and Directive 2010/63/EU of the European Parliament. The animals were allowed free access to food and water and were unrestrained in their pens throughout the experiment.
Results
All 12 goats successfully completed the protocol. Successive 1-month periods of AF resulted in a cumulative increase in AF stability (Figure 4), with no difference in the rate of decrease in AERP (time for AERP to decrease to half of nadir: first AF period 22.3 ± 4.9 hours, second AF period 16.6 ± 2.7 hours, and third AF period 18.7 ± 5.3 hours; P = .7) or the rate of decrease in AF cycle length. Ventricular cycle length during AF episodes remained constant (after 1 week 429 ± 39 ms, at the end
Discussion
The principal findings of this study are that increasing AF stability and the concurrent increase in the complexity of fibrillatory conduction are associated with an increase in atrial electrogram fractionation caused by colocalized areas of slow conduction and conduction block and an increase in the heterogeneity of Cx40 and lateralization of Cx43 in the absence of atrial fibrosis.
The functional association between the complexity of fibrillatory conduction and AF stability in the goat is in
Conclusion
Electrogram fractionation with increasing persistence of AF results from colocalization of atrial conduction block and slow conduction associated with changes in atrial connexin distribution in the absence of fibrotic change.
Acknowledgments
We thank Medtronic and Guidant for providing the pacemakers, leads and software. In addition we would like to acknowledge the ElectroCardioMaths Programme of the British Heart Foundation Centre at Imperial College and the NIHR Biomedical Research Centre Programme.
References (35)
The “second factor”: a first step toward diagnosing the substrate of atrial fibrillation?
J Am Coll Cardiol
(2009)- et al.
A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate
J Am Coll Cardiol
(2004) - et al.
Rotor meandering contributes to irregularity in electrograms during atrial fibrillation
Heart Rhythm
(2008) - et al.
Genesis of complex fractionated atrial electrograms in zones of slow conduction: a computer model of microfibrosis
Heart Rhythm
(2009) - et al.
Inverse relationship between fractionated electrograms and atrial fibrosis in persistent atrial fibrillation—a combined MRI and high density mapping
J Am Coll Cardiol
(2013) - et al.
Relationship between connexins and atrial activation during human atrial fibrillation
J Am Coll Cardiol
(2002) - et al.
Relative expression of immunolocalized connexins 40 and 43 correlates with human atrial conduction properties
J Am Coll Cardiol
(2002) - et al.
Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats
Circulation
(1995) - et al.
Extracardiac recordings of His-Purkinje activity during conduction disorders and junctional rhythms
Circulation
(1975) - et al.
Intraoperative electrophysiological mapping of the ventricles during sinus rhythm in patients with previous myocardial infarction: identification of the electrophysiological substrate of ventricular arrhythmias
Circulation
(1982)
Re-entrant ventricular arrhythmias in the late myocardial infarction period, 1: conduction characteristics in the infarction zone
Circulation
High-density mapping of atrial fibrillation in humans: relationship between high-frequency activation and electrogram fractionation
J Cardiovasc Electrophysiol
Functional nature of electrogram fractionation demonstrated by left atrial high-density mapping
Circ Arrhythm Electrophysiol
Configuration of unipolar atrial electrograms during electrically induced atrial fibrillation in humans
Circulation
Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation
Circulation
Repetitive 4-week periods of atrial electrical remodeling promote stability of atrial fibrillation: time course of a second factor involved in the self-perpetuation of atrial fibrillation
Circulation
Mapping of Electrically Induced Atrial Fibrillation in Humans [PhD thesis]
Cited by (0)
Dr Kirubakaran and Dr Chowdhury contributed equally as joint first authors, and Dr Garratt and Dr Peters contributed equally as joint last authors.
This work was supported and funded by the British Heart Foundation (grant nos. PG/03/135 and BHF RG/10/11/28457).