Reduced N-Type Ca²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis.

BACKGROUND:Attenuated cardiac vagal activity is associated with ventricular arrhythmogenesis and related mortality in patients with chronic heart failure. Our recent study has shown that expression of N-type Ca²⁺ channel α-subunits (Ca_v2.2-α) and N-type Ca²⁺ currents are reduced in intracardiac ganglion neurons from rats with chronic heart failure. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium receives projection of neuronal terminals only from the AVG. In this study we tested whether a decrease in N-type Ca²⁺ channels in AVG neurons contributes to ventricular arrhythmogenesis. METHODS AND RESULTS:Lentiviral Ca_v2.2-α shRNA (2 μL, 2×10⁷ pfu/mL) or scrambled shRNA was in vivo transfected into rat AVG neurons. Nontransfected sham rats served as controls. Using real-time single-cell polymerase chain reaction and reverse-phase protein array, we found that in vivo transfection of Ca_v2.2-α shRNA decreased expression of Ca_v2.2-α mRNA and protein in rat AVG neurons. Whole-cell patch-clamp data showed that Ca_v2.2-α shRNA reduced N-type Ca²⁺ currents and cell excitability in AVG neurons. The data from telemetry electrocardiographic recording demonstrated that 83% (5 out of 6) of conscious rats with Ca_v2.2-α shRNA transfection had premature ventricular contractions (P<0.05 versus 0% of nontransfected sham rats or scrambled shRNA-transfected rats). Additionally, an index of susceptibility to ventricular arrhythmias, inducibility of ventricular arrhythmias evoked by programmed electrical stimulation, was higher in rats with Ca_v2.2-α shRNA transfection compared with nontransfected sham rats and scrambled shRNA-transfected rats. CONCLUSIONS:A decrease in N-type Ca²⁺ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.

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