Background –Autonomic cardiac innervation plays a crucial role in modulating ventricular electrophysiology and arrhythmogenesis. We have shown that intrinsic cardiac neurons (ICN) modulate ventricular susceptibility to arrhythmias via epicardial nerves extending from the atria to the ventricles. Underlying mechanisms, especially of the modulation of the left ventricular (LV) action potential (AP), remain unclear. The aim of this study is a more detailed characterization of the functional role of ICNs for LV electrophysiological properties and arrhythmogenesis by epicardial optical mapping.

Methods – All experiments were performed in 12-16 week old C57Bl/6J mice (n=24), 12 hearts underwent partial atrial denervation (PAD) achieved by carefully dissection of atrial fat pads. In ex vivo retrograde perfused hearts we combined an endocardial electrophysiology catheter-based technique to assess ventricular arrhythmia (VA) susceptibility by standardized stimulation protocols and simultaneously epicardial optical mapping of a fast-responding potentiometric dye (Rh237) to assess AP characteristics of the LV anterior wall. Optical mapping data was analyzed using the open-source software ElectroMap. VA susceptibility was quantified by an established scoring system.

Results – Epicardial optical mapping of the anterior left ventricular wall showed a shortened AP duration (APD) at 90 % repolarization (APD₉₀₎ in PAD hearts independent of the pacing cycle length (CL) (APD90 at CL 100 ms: Control: 58.85±2.79 ms, PAD: 55.51±2.27 ms, P=0.0036; Figure 1A/B). The number of induced VAs, VA susceptibility as well as the inducibility of ventricular tachycardias (VT) were increased in the PAD group (number of induced VAs: Control: n=4.17±1.8, PAD: n=6.13±1.36, P=0.0012; VA susceptibility: Control: 8.08±4.03, PAD: 20.0±7.41, P=0.0012; VT inducibility: Control: 25.0 %, PAD: 87.5 %, P=0.0198; Figure 1C).

_{Conclusions – Our findings show that ICNs directly affect LV repolarization characteristics modulating ventricular arrhythmogenicity. They indicate that PAD increases VA susceptibility by APD shortening, which facilitate reentry. Further investigation will be necessary to better understand the molecular mechanisms of ICN–mediated modulation of LV AP.}

Figure 1: (A) Representative traces of murine action potentials in a control heart (black) and after partial atrial denervation (PAD, blue). (B) Left ventricular action potential duration at 90 % repolarization (APD₉₀) was shortened after PAD independent from pacing cycle length (CL). (C) Inducibility of ventricular arrhythmias (VA) was elevated in PAD hearts.