A MATHEMATICAL MODEL OF ARRHYTHMOGENESIS IN VENTRICULAR CARDIOMYOPATHIES DUE TO GAP JUNCTION RESTRUCTURING
Genetic defects in cell-cell adhesion sites have been associated with arrhythmogenic ventricular cardiomyopathies (AVCs) and are known to compromise cell-cell coupling. Clinical observations from AVC patients have revealed fibrofatty replacement of healthy heart tissue, which provides an anatomical substrate for arrhythmia, progressive cardiac failure, and sudden death. On the other hand, the absence of fibrofatty tissue in the heart of young patients and in some AVC variants suggests that the observed severe arrhythmias might also occur due to restructuring of gap junctions (GJs) in an environment of degraded mechanical coupling between cardiomyocytes. In this study we develop a mathematical model to investigate the effect of GJ restructuring on arrhythmogenesis in AVCs. We consider a paced ventricular cellpair and simulate the effect of GJ restructuring by randomly fluctuating the electrical coupling conductance. The emergence of marked arrhythmic episodes is promptly noticed. By further decreasing the fluctuation range with time, propagation fails and action potential generation ceases even before the termination of the stimulus signal. Results from the model simulations are consistent with clinical observations, suggesting an alternative mechanism for the generation of lethal ventricular arrhythmias in AVCs.