KCNQ2 downregulation in left stellate ganglion neurons exacerbates malignant ventricular arrhythmias after myocardial infarction.

AIMS: Ventricular arrhythmias (VAs) are a leading cause of sudden cardiac death (SCD) following myocardial infarction (MI), with cardiac sympathetic hyperexcitability serving as a critical trigger. While β-blockers provide partial protection, residual arrhythmic risk persists. Neuronal M-channels (KCNQ2/3) function as critical "brakes" limiting sympathetic hyperexcitability, yet their role in post-MI ventricular arrhythmogenesis remains undefined. In this study, we investigated whether KCNQ2 downregulation in sympathetic ganglia contributes to heightened arrhythmic susceptibility following MI.

METHODS AND RESULTS: Male Sprague-Dawley rats (n = 104) were randomized into four groups: sham, MI, shCtrl+MI, and shKCNQ2 + MI. Adeno-associated viral vectors targeting KCNQ2 or scrambled controls were injected into the left stellate ganglion (LSG) 3 weeks before permanent left anterior descending coronary artery ligation. KCNQ2 expression was significantly reduced in LSG neurons following MI. Targeted KCNQ2 knockdown markedly exacerbated VAs burden during both acute (0-8 h) and chronic phases (4 weeks) post-MI, with increased ventricular fibrillation incidence (93% vs. 43% in shCtrl, P < 0.05). The basal firing activity of LSG neurons was significantly greater in shKCNQ2 + MI rats compared with shCtrl+MI rats. KCNQ2 deficiency exacerbated sympatho-vagal imbalance (elevated LF/HF ratio) and increased ventricular repolarization heterogeneity. Ex vivo studies confirmed enhanced arrhythmia inducibility and reduced ventricular fibrillation threshold in the KCNQ2 knockdown group.

CONCLUSION: Knockdown of KCNQ2 in LSG neurons exacerbates cardiac sympathetic discharge activity and heightens arrhythmic vulnerability post-MI; however, the absence of direct M-current measurements and gain-of-function validation limits causal conclusions.