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.