Functional modeling of genetic disease in the zebrafish

Sudden cardiac death due to ventricular arrhythmias accounts for up to 50% of total mortality in patients with structural heart disease. Nonetheless, the Implantable Cardioverter-Defibrillator (ICD) can improve survival in these patients. However, it has become clear that the current selection criterion for ICD implantation lacks sensitivity and specificity in identifying the patient at highest risk of these lethal ventricular arrhythmias. Therefore, other, more accurate risk predictors are needed to improve patient selection for ICD therapy. n this thesis, parameters of contractile (Part I), electrical (Part II) and neural remodeling (Part III) are evaluated in relation to susceptibility of ventricular arrhythmias in order to find new markers of increased arrhythmic risk. To do so, patient cohorts and an arrhythmogenic animal model, i.e. the chronic atrioventricular block (CAVB) dog, were used.

In part 1 of this thesis we have shown that three in vivo contractile parameters, i.e. the force-frequency relationship (FFR), mechanical restitution (MR) and post-extrasystolic potentiation (PESP) are altered in CAVB dogs that are inducible to multiple episodes of Torsade de Pointes arrhythmias, a specific ventricular arrhythmia that can result in sudden cardiac death. Therefore, these markers may eventually be used to identify patients at risk for triggered ventricular arrhythmias.

In part 2 we studied parameters that reflect changes in electrophysiology. One important parameter is short-term variability of repolarization (STV), which reflects the instability of the electrical impulse between consecutive beats. We have shown that STV displays a specific circadian pattern in highly arrhythmic patients, with two prominent peaks during the day, which were not present in patients without arrhythmic episodes. Furthermore, we have shown that STV of the intracardiac electrogram recorded via the ICD-lead increases abruptly a couple of minutes prior to the occurrence of ventricular arrhythmias. Furthermore, we developed an automatic STV measurement that can be implemented into an ICD. With this technique, the ICD would be able to monitor continuously for imminent arrhythmias and initiate preventive treatment when an upcoming arrhythmic episode is sensed.

In the final part of this thesis we have shown that low frequency oscillations of action potential duration are augmented in CAVB-dogs that are inducible to TdP arrrythmias. These oscillations are caused by the effects of the autonomic nervous system on the heart, which have been shown to be of importance for the initiation and perpetuation of arrhythmias.