The endogenous cholinergic system overwhelmingly predominates over the exogenous system in regulating ventricular bioelectrical homeostasis

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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 ‘Cholinergic control of cardiac electrical conduction and ventricular arrhythmia: endogenous or exogenous?’, by D. Zhang, https://doi.org/10.1093/eurheartj/ehaf011. Recently, we discovered that ventricular cardiomyocytes possess a complete endogenous cholinergic system (ECS), which includes acetylcholine (ACh), ACh transmitter vesicles, ACh transporters, ACh metabolic enzymes and nicotinic ACh receptors (nAChRs). Our evidence indicates that these transmitter vesicles are primarily localized on the intracellular side of the cell membrane at both ends of ventricular cardiomyocytes, near gap junctions. This ECS regulates the conduction of ventricular electrical excitation, and its dysfunction is closely associated with ventricular arrhythmias. Notably, interventions targeting this system can effectively prevent and treat the onset and progression of ventricular arrhythmias.1 These findings underscore the essential role of the ECS in regulating ventricular electrical conduction and arrhythmogenesis. The heart is known to receive innervation from extrinsic cholinergic nerves. However, these nerves are predominantly localized in the sinoatrial node, atrioventricular node, atrial myocardium, and coronary arteries, with limited presence in the ventricular myocardium.2 Within the ventricles, extrinsic cholinergic nerves are sparsely distributed and primarily confined to the subendocardial layer.2 Additionally, evidence from the literature studies indicate that the electrophysiological impact of extrinsic cholinergic innervation on the ventricular myocardium is minimal.2,3 This limited influence stands in stark contrast to the pronounced electrophysiological effects of the ECS observed in our study, emphasizing its pivotal role in regulating ventricular electrical activity. Our research demonstrates that the ECS operates independently of extrinsic cholinergic innervation, supported by two lines of evidence: (1) at the cellular level, in the absence of extrinsic neural input, ACh puffs induce inward currents in ventricular cardiomyocytes, facilitating and even independently triggering electrical excitation. Interventions targeting key components of the ECS can modulate these inward currents and excitatory activity;1 (2) at the ex vivo heart level, when extrinsic neural input is severed, defects in nAChRs or interventions targeting key ECS components significantly impact the conduction of ventricular electrical excitation and the occurrence and progression of ventricular arrhythmias.1 Extrinsic cholinergic nerves have a negative influence on cardiac electrical conduction, whereas in our study, the ECS exerts positive effects.1,4 The observed positive effects are clearly attributed to the working mode of the ECS. Generally, the initiation and propagation of electrical excitation in cholinergic neurons are primarily mediated by nAChRs rather than muscarinic ACh receptors (mAChRs).5 Given that extrinsic cholinergic nerves primarily act through mAChRs,3 while the ECS exerts its effects via nAChRs,1 we infer that the ECS, rather than extrinsic cholinergic nerves, predominantly regulates ventricular electrical conduction. Extrinsic cholinergic nerves release ACh, which subsequently activates mAChRs on ventricular cardiomyocytes. This activation leads to cellular hyperpolarization by enhancing acetylcholine-activated inward rectifier K+ currents (IK,ACh) and suppression of various calcium-handling proteins, ultimately reducing electrical conduction velocity.2–4 The above describes the signalling pathway through which extrinsic cholinergic nerves regulate ventricular myocardial electrical activity. In our study, targeting key components of the ECS that are not directly associated with the extrinsic cholinergic nerve signalling pathway effectively modulate ventricular electrical conduction,1 further suggesting that the ECS critically controls ventricular electrical conduction and ventricular arrhythmias. Nothing to declare. Y.-H.C. is supported by the National Natural Science Foundation of China (82088101), the Key Research Center Construction Project of Shanghai (2022ZZ01008), and the Innovation Fund for Medical Sciences, Chinese Academy of Medical Sciences (2019-I2M-5-053).

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