Agenda

Ventricular arrhythmias, including ventricular fibrillation, account for a significant proportion of sudden cardiac deaths. Although the Purkinje fibers are implicated in the development of these arrhythmias, the associated mechanisms remain poorly understood. This thesis investigates the contribution of the Purkinje fibers to ventricular arrhythmias by studying their electrophysiological and structural characteristics. The hypothesis is that abnormalities in the Purkinje network during embryonic development represent a major risk factor for mortality in congenital heart disease.
Two genetically modified mouse models were studied, one with a deletion of the Tbx5 gene, responsible for Holt-Oram syndrome, and the other with a deletion of the dystrophin gene, responsible for Duchenne muscular dystrophy (DMD). In humans, these two diseases are associated with ventricular arrhythmias. The results demonstrate that the loss of Tbx5 impairs the maturation of Purkinje fibers, reduces their communication with the myocardium, and creates a substrate that favors arrhythmias. In the DMD model, although Purkinje fibers do not degenerate, myocardial remodelling disrupts ventricular synchronization and promotes arrhythmogenesis.
In conclusion, this work shows that while Purkinje fibers do not initiate arrhythmias, they play a key role in the propagation of arrhythmias through defects in conduction and coupling with the myocardium. Thus, the Purkinje-muscle junction might be considered critical for the maintenance of arrhythmias. These findings offer valuable insights into potential therapeutic strategies targeting these critical areas in the treatment of ventricular arrhythmias.