Cardiac conduction disturbances and differential effects on atrial and ventricular electrophysiological properties in desmin deficient mice
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Desmin mutations in humans cause desmin-related cardiomyopathy, resulting in heart failure, atrial and ventricular arrhythmias, and sudden cardiac death. The intermediate filament desmin is strongly expressed in striated muscle cells and in Purkinje fibers of the ventricular conduction system. The aim of the present study was to characterize electrophysiological cardiac properties in a desmin-deficient mouse model.
The impact of desmin deficiency on cardiac electrophysiological characteristics was examined in the present study. In vivo electrophysiological studies were carried out in 29 adult desmin deficient (Des−/−) and 19 wild-type (Des+/+) mice. Additionally, epicardial activation mapping was performed in Langendorff-perfused hearts.
Intracardiac electrograms showed no significant differences in AV, AH, and HV intervals. Functional testing revealed equal AV-nodal refractory periods, sinus-node recovery times, and Wenckebach points. However, compared to the wild-type situation, Des−/− mice were found to have a significantly reduced atrial (23.6 ± 10.3 ms vs. 31.8 ± 12.5 ms; p = 0.045), but prolonged ventricular refractory period (33.0 ± 8.7 ms vs. 26.7 ± 6.5 ms; p = 0.009). The probability of induction of atrial fibrillation was significantly higher in Des−/− mice (Des−/−: 38% vs. Des+/+: 27%; p = 0.0255), while ventricular tachycardias significantly were reduced (Des−/−: 7% vs. Des+/+: 21%; p < 0.0001). Epicardial activation mapping showed slowing of conduction in the ventricles of Des−/− mice.
Des−/− mice exhibit reduced atrial but prolonged ventricular refractory periods and ventricular conduction slowing, accompanied by enhanced inducibility of atrial fibrillation and diminished susceptibility to ventricular arrhythmias. Desmin deficiency does not result in electrophysiological changes present in human desminopathies, suggesting that functional alterations rather than loss of desmin cause the cardiac alterations in these patients.
KeywordsDesmin Desmin-related cardiomyopathies Arrhythmias Conduction Desmin knockout mouse Desminopathy Myofibrillar myopathy Connexin
This work was supported by institutional grants from the University of Bonn (BONFOR O-109.0008 and O-109.0024 awarded to J.W.S.) and by the German Research Foundation (DFG) (SCHR 562/4-1, 4-2 awarded to R.S.). R.S. and C.S.C. are members of the German network on muscular dystrophies (MD-NET2, Project 7) funded by the German ministry of education and research (BMBF) and of the multi-location DFG research group FOR1228. Thanks to H.J.M. van Rijen and C. de Bakker for their technical assistance regarding with the epicardial mapping system. Thanks to D. Axt for technical assistance and H. Begerau for programming and designing the software for the analysis of the epicardial activation maps. There are no financial disclosures or conflicts of interest existing for any of the authors.