Targeted M‐Channel Activation in the Left Stellate Ganglion Protects Against Ischemia‐Induced Ventricular Arrhythmias in Canines

Background Acute myocardial ischemia (AMI)‐triggered ventricular arrhythmias are closely linked to maladaptive sympathetic hyperactivity mediated via the left stellate ganglion (LSG). Although M‐type potassium channels regulate neuronal excitability and hold therapeutic potential for neurological disorders, their role in intrinsic LSG neurons during ischemia remains unexplored. We investigated whether pharmacological M‐channel activation in the LSG mitigates sympathetic overdrive and arrhythmogenesis in AMI. Methods and Results Twenty‐four beagles underwent LSG microinjection of either vehicle (n=12) or retigabine (M‐channel activator, 50 μM; n=12) 30 minutes before AMI induction. We assessed (1) neural parameters (LSG electrophysiology, plasma norepinephrine levels, and c‐fos+/tyrosine hydroxylase+ neuron expression); (2) cardiac electrophysiological parameters (beat‐to‐beat repolarization variability, spatial dispersion of effective refractory period and action potential duration, ventricular fibrillation threshold, and spontaneous ventricular arrhythmias incidence); and (3) autonomic and hemodynamic measures (heart rate variability and blood pressure). Retigabine pretreatment significantly suppressed ischemia‐induced LSG hyperactivity and reduced sympathetic activation markers compared with controls. Treated animals exhibited attenuated repolarization variability and reduced electrophysiological heterogeneity in ischemic myocardium. The retigabine group demonstrated a higher ventricular fibrillation threshold (26.67±2.61 versus 12.33±1.76 voltage (V), P =0.0008) and a lower incidence of ventricular arrhythmias during AMI, with only negligible effects on baseline cardiac repolarization duration or LSG function before ischemia induction. Conclusions Targeted activation of LSG M‐channels with retigabine stabilizes ischemia‐induced sympathetic hyperactivity, promotes cardiac autonomic balance, preserves repolarization homogeneity, and ultimately mitigates arrhythmic susceptibility. These findings highlight ganglionic M‐channel modulation as a translatable strategy to suppress neurogenic arrhythmogenesis in AMI.