Regulation of Cardiac Electrical Stability by Intra- and Extra-Cardiac Factors : Implications for Ventricular Arrhythmogenesis in the Chronic AV-block Dog Model

Ventricular arrhythmogenesis is an intriguingly complex and intricate phenomenon. Numerous conditions can predispose to ventricular arrhythmogenesis through various mechanisms. This thesis studied the regulation of cardiac electrical stability by several intra- and extracardiac factors, and related their effects to ventricular arrhythmogenesis. Coumel reduced the process of arrhythmogenesis to the unison of a trigger, substrate and modulator. In short, the trigger is the initial (local) derangement that sparks an arrhythmic episode. Such triggers develop from electrical instability at the level of the myocyte. The substrate is the tissue that enables the cardiac spread of aberrant electrical waves. Additionally, both trigger and substrate are under the influence of modulators, such as the autonomic nervous system. This thesis highlighted the role of several of such factors, including bradycardia, altered ventricular activation and the autonomic nervous system. First this thesis demonstrates that electrical parameters indicative of the trigger and substrate for arrhythmias can accurately reflect the anti-arrhythmic effects of drugs. Assessment of either electrical index in isolation of the other is insufficient to evaluate the electrical stability of the myocardium. Therefore, estimation of the arrhythmogenic conditions and risk should preferably depend on one or multiple parameters that reflect both trigger and substrate. Next, it confirmed the pro-arrhythmic effects of bradycardia and associated these effects with a primarily pro-arrhythmic effect on the substrate. With regard to the pro-arrhythmic effects of altered ventricular activation, it was shown that the severity of electromechanical dyssynchrony, induced by altered ventricular activation, correlated with the development of TdP-susceptibility in the chronic AV-block (CAVB) dog model. This is especially relevant to the clinical field of electrophysiology, as these results underscore the potentially pro-arrhythmic consequences of electromechanical dyssynchrony induced by improper pacing lead placement. Subsequently, the thesis studied the pro-arrhythmic character of the autonomic nervous system. First, it was shown that bilateral sympathetic denervation was a highly effective anti-arrhythmic strategy. Interestingly, pharmacological modulation of cardiac autonomic innervation lacked any anti-arrhythmic effects. The anti-arrhythmic efficacy of autonomic modulation in the CAVB dog model was explained through the process of neural remodeling, which is characterised by a progressive shift of autonomic tone towards sympathetic dominance. Subsequently, this thesis explored the transcriptomic heterogeneity of satellite glial cells in healthy murine stellate ganglia to study how these cells might modulate sympathetic activity and propagate autonomic imbalances. This study observed five subtypes of satellite glial cells and classified them based on different functional and/or developmental stages and showed that they employ several different singling pathways. As it became evident that the cardiac autonomic nervous system is a powerful modulator of ventricular arrhythmogenesis. the last chapter reviews the present state of well-established, novel and upcoming neuromodulatory therapies for cardiac arrhythmias. Hence, this thesis aimed to explore several intra- and extracardiac regulators of cardiac electrical stability. Understanding arrhythmogenesis and the factors that promote this process, can profoundly aid in identifying how these arrhythmic events could be suppressed or, even better, prevented