Drug and device testing in a preclinical model sensitive to cardiac arrhythmias

Abstract

Sudden cardiac death is still the leading cause of mortality worldwide and in 50-70% of the cases related to ventricular tachyarrhythmia. The process of initiation and perpetuation of ventricular arrhythmias is complex and coincides with (a combination of) diverse substrates, triggers, and underlying electrophysiological mechanisms.

In the research field of cardiac electrophysiology, arrhythmia management is still improving and focusses on evaluating proarrhythmic responses of new developed compounds, the discovery of new pharmacological targets, and improvement of antiarrhythmic strategies. The focus on alternatives for animal use in science is expanding tremendously, though it faces challenges in approaching the physiological state of a living organism and thereby being of translational significance. A preclinical model standardized for electrophysiological research, best resembling human electrophysiology, hemodynamics, pharmacodynamics etc., is of crucial value in examining pro- and antiarrhythmic drug and device responses. The canine heart shares a moderate resemblance in cardiac electrophysiology with that of the human, and is recommended as appropriate research model in electrophysiology studies as incorporated in the ICH S7B guidelines. The dog with complete AV block induced by radiofrequency ablation of the His bundle has been standardized over the last three decades with a strong focus on pro- and antiarrhythmic properties in pharmacological research. Under anesthesia, a combination of the preceding components of bradycardia-induced remodeling makes the AV block heart susceptible for Torsade de Pointes (TdP) arrhythmias.

The studies incorporated in this thesis concentrate on two parts for targeting ventricular arrhythmias. 1) Drug testing: with a focus on targeting the second main repolarizing current IKs and the establishment of underlying proarrhythmic triggers for ventricular arrhythmias, and 2) Device testing: by preparing the AV block dog model in terms of exercise and respiratory behavior for testing a new pacing strategy.

Here, we gained new insights into the development of cardiac arrhythmias under proarrhythmic conditions. Furthermore, the studies in the second part of the thesis contributed to the development of a biofeedback pacing device with the ability to adapt to changes in physiological variables using input from sensors. The final version of this device will be beneficial for patients with heart failure and its cardiorespiratory comorbidities.