Cholinergic control of cardiac electrical conduction and ventricular arrhythmia: endogenous or exogenous?

This commentary refers to ‘An endogenous cholinergic system controls electrical conduction in the heart’, by D. Xie et al., https://doi.org/10.1093/eurheartj/ehae699 and the discussion piece ‘The endogenous cholinergic system overwhelmingly predominates over the exogenous system in regulating ventricular bioelectrical homeostasis’, by D. Xie et al., https://doi.org/10.1093/eurheartj/ehaf012. Ventricular arrhythmia is the leading cause of death in patients with myocardial infarction. While numerous interventions are available to treat ventricular arrhythmias, effective management of lethal ventricular arrhythmias is still challenging in the clinic. The traditional concept suggests that cholinergic regulation of cardiac function is achieved through the parasympathetic nervous system. Parasympathetic activation induces acetylcholine (ACh) release from its nerve terminals, which subsequently activates muscarinic ACh receptors expressed in cardiomyocytes and further results in negative chronotropy, inotropy, dromotropy, and lusitropy.1 With great interest, I read the recent study from Xie D et al. who highlighted the significant contribution of the endogenous cholinergic system that is independent of exogenous parasympathetic innervation to control cardiac electrical conduction and ventricular arrhythmogenesis.2 However, several concerns raised below should be paid attention to strongly support the structural and functional presence of the endogenous cholinergic system in cardiomyocytes.