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

Abstract

BackgroundAttenuated 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 (Cav2.2‐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 ResultsLentiviral Cav2.2‐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 Cav2.2‐α shRNA decreased expression of Cav2.2‐α mRNA and protein in rat AVG neurons. Whole‐cell patch‐clamp data showed that Cav2.2‐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 Cav2.2‐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 Cav2.2‐α shRNA transfection compared with nontransfected sham rats and scrambled shRNA‐transfected rats. ConclusionsA decrease in N‐type Ca2+ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.

Keywords

• autonomic nervous system
• calcium channel
• ECG
• ganglia
• parasympathetic
• vagus nerve