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Re‐expression of REST Promotes Ventricular Arrhythmogenesis via Repressing N‐type Calcium Channel in Ventricular Vagal Neurons in Chronic Heart Failure

Ventricular arrhythmia is a common complication in chronic heart failure (CHF) and accounts for nearly 50–60% of mortality in patients with CHF. Decrease in cardiac vagal activity is considered to be an important trigger for ventricular arrhythmogenesis in CHF. Our previous study has demonstrated that expression of N‐type calcium channel α‐subunits (Cav2.2‐α) and N‐type Ca2+ currents were reduced in atrioventricular ganglion (AVG) neurons in CHF rats. We have also demonstrated that reduced expression of Cav2.2‐α in AVG neurons contributes to ventricular arrhythmogenesis. The repressor element 1‐silencing transcription factor (REST) is a key to block Cav2.2‐α expression. Normally REST is not expressed in neuronal cells. Here, we test the hypothesis that re‐expression of REST inhibits N‐type Ca2+ channel function in AVG neurons and further trigger ventricular arrhythmogenesis in coronary arterial ligation‐induced CHF rat. Using reverse‐phase protein array, we found that there was no expression of REST in the AVG from sham rats, while REST expression was significantly increased in the AVG from CHF rats. In vivo transfection of lentiviral REST shRNA (2 μl, 1×107 TU/ml) into the AVG markedly reduced REST expression in the AVG from CHF rats. REST shRNA also increased Cav2.2‐α expression in AVG neurons from CHF rats. The results from whole‐cell patch clamp recording showed that REST shRNA increased N‐type Ca2+ currents in AVG neurons from CHF rats (19.47±1.13 pA/pF in REST shRNA transfected CHF rats vs. 11.37±1.65 pA/pF in non‐transfected CHF rats). The data obtained from radiotelemetry ECG recording in conscious rat demonstrated that transfection of REST shRNA into AVG neurons reduced the cumulative duration of ventricular tachycardia/fibrillation in CHF rats (2.64 ±2.05 sec/hour in REST shRNA transfected CHF rats vs. 10.03±3.43 sec/hour in non‐transfected CHF rats). We conclude that re‐expression of REST decreases Cav2.2‐α expression and N‐type Ca2+ currents in AVG neurons and subsequently triggers ventricular arrhythmogenesis in the CHF state.