Abstract 12837: Intercalated Disk Abnormalities, Conduction Slowing and Arrhythmogenesis in Desmoglein-2 Mutant Mice Prior to the Development of Cardiomyopathic Changes
Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibro-fatty replacement of the myocardium and life threatening arrhythmias. We investigated whether intercalated disk (ID) remodelling, as a consequence of desmosomal mutations, impacts on cardiac elecrophysiological properties before the onset of fibrosis and other cardiomyopathic changes.
Methods We studied transgenic mice with low cardiac over expression of N271S-dsg2 (Tg-NS/L, carrying the mouse homolog of the human ARVC mutation DSG2-N266S) at three different ages: <2 wks, 3-4 wks and > 6wks. Mice with cardiac over expression of wild-type dsg2 (Tg-WT) and wild-type mice served as controls. Surface ECGs were measured and electrical epicardial mapping was performed to determine ventricular conduction and arrhythmia susceptibility. The structure and molecular composition of the ID was assessed by electron microscopy (EM) and by immunofluorescence.
Results Cardiomyopathic changes were observed by EM in Tg-NS/L mice only from age >6 wks. Surface ECG demonstrated progressive QRS-prolongation and spontaneous occurrence of atrial and ventricular arrhythmias in Tg-NS/L only from age >6 wks. However, on epicardial mapping, ventricular activation time was prolonged in Tg-NS/L mice at 3-4 wks (mean±SEM 11.9±1.8 ms, n=5) compared to WT (7.6±0.6, n=4) and Tg-WT (7.4±0.5, n=5) (p<0.05). In addition in this same age group, ventricular arrhythmias were inducible in 3/5 Tg-NS/L mice, but not in controls. No such differences in activation time and arrhythmia inducibility were observed in 2 wks old mice. EM uncovered gap widening at desmosomes / adherens junctions, starting at 3-4 wks exclusively in Tg-NS/L mice. No changes in the gap junctions were seen. Immunofluorescence uncovered no differences in the level and localization of junctional proteins (incl. Cx43 and plakoglobin) between Tg-NS/L mice and controls.
Conclusions Dsg-2 mutant mice display conduction slowing and ventricular arrhythmias before development of cardiomyopathic changes. This coincided with the time-point at which gap-widening at desmosomes / adherens junctions was observed, suggesting that ID integrity is required for proper electrical conduction.
- © 2011 by American Heart Association, Inc.