Abstract 11882: Reduced N-type Calcium Channels in Ventricular Vagal Neurons and Ventricular Arrhythmogenesis
Attenuated cardiac vagal activity is linked to ventricular arrhythmogenesis, and is associated with mortality in patients with chronic heart failure (CHF). However, the sites and mechanisms responsible for decreased cardiac vagal activity are still poorly understood. Our previous studies showed that expression of N-type Ca++ channel α-subunits (Cav2.2-α) and N-type Ca++ currents were reduced in intracardiac ganglion neurons from coronary artery ligation-induced CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium only receives projection of neuronal terminals from the AVG. Here, we tested the hypothesis that reducing N-type Ca++ channels in AVG neurons contributes to ventricular arrhythmogenesis. Lentiviral Cav2.2-α shRNA (2 μl, 1x106 pfu/ml) or scrambled shRNA was in-vivo transfected into rat AVG neurons. Non-transfected sham rats served as control. Using real-time single-cell PCR 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. The results from whole-cell patch clamp recording showed that Cav2.2-α shRNA reduced N-type Ca++ currents and cell excitability in AVG neurons. The data obtained from telemetry ECG recording demonstrated that 83% (5 out of 6) of conscious rats with Cav2.2-α shRNA transfection had premature ventricular contraction (p<0.05 vs. 0% of non-transfected sham rats or scrambled shRNA transfected rats). Additionally, an index of susceptibility to ventricular arrhythmias, inducibility of ventricular arrhythmias evoked by programmed electrical stimulation is higher in rats with Cav2.2-α shRNA transfection (1.8 ± 0.3 ventricular arrhythmia score), compared to non-transfected sham rats and scrambled shRNA transfected rats (0 ventricular arrhythmia score, p<0.05 vs. these two groups). From these results, we conclude that reduced N-type Ca++ channels in AVG neurons cause vagal neuronal dysfunction, which is a trigger to initiate ventricular arrhythmias. These results suggest that reduced N-type Ca++ channels in AVG neurons might be involved in ventricular arrhythmogenesis and sudden cardiac death in the CHF state.
Author Disclosures: D. Zhang: None. H. Tu: None. H. Zheng: None. R.L. Muelleman: None. Y. Li: None.
- © 2016 by American Heart Association, Inc.