The relation between bradycardic dyssynchronous ventricular activation, remodeling and arrhythmogenesis

Sudden cardiac death (SCD) is a common cause of death and its incidence continues to rise. The occurrence of SCD is mainly due to development of malignant ventricular arrhythmias such as ventricular tachycardia or ventricular fibrillation. The underlying cause of SCD is almost always a complex remodeling of the heart. One of the most intriguing types of ventricular tachycardia is the Torsade de Pointes (TdP) arrhythmia. However, in humans it is difficult to study the different remodeling processes and the relation to the occurrence of TdP.

In this thesis, we used the chronic complete AV- block (CAVB) dog model to investigate several risk factors that may contribute to the risk of TdP. The model is typically characterized by its high incidence for TdP arrhythmias, which occurs after the induction of an artificially induced AV-block. As a result of AV-block, the heart rate drops acutely and the ventricles have to be activated from an idioventricular rhythm. These changes result in ventricular remodeling. Administration of dofetilide, a class III antiarrhythmic drug, causes TdP in about 75% of the anaesthetized dogs.

In the first part of this thesis, we demonstrated that this process of ventricular remodeling is the most important contributor for the occurrence of TdP. Dogs acutely tested after induction of AV-block were not susceptible for TdP arrhythmias, while after remodeling TdP inducibility was significantly increased. Also anesthesia significantly increased TdP susceptibility. On the other hand factors, like acute or chronic altered ventricular activation induced by pacing from the right ventricular apex, have no additional arrhythmic consequences. Interestingly, chronic pacing from the right ventricular apex induces regional ventricular adaptations, both mechanically and electrically. In a mapping study, we demonstrated that the regional electrical differences were required for the initiation of TdP. The first beat of the TdP arrhythmia always arises from the region with maximal heterogeneity of repolarization. Subsequently, we studied the effect of cardiac resynchronization therapy and demonstrated a more homogenous contraction of the ventricles and a decrease in TdP episodes. In the last part of the thesis we focused on several strategies that may play role in prevention of the occurrence of ventricular arrhythmias and SCD. In a large European clinical trial we demonstrated that a combination of clinical (left ventricular ejection fraction and secondary prophylactic indication) and electrophysiological parameters (electrophysiological study and T-wave alternans) was able to distinguish between an increased risk for mortality or appropriate ICD shock. Moreover, in a sub study we investigated a relatively new electrophysiological parameter: beat-to-beat variability of repolarization. Our results indicate that a higher beat-to-beat variability of repolarization is associated with an increased risk for appropriate ICD therapy. All together, our results indicate the potential of electrophysiological parameters in prediction of ventricular arrhythmias, which eventually could play a role patient tailored therapy.