Reduced N‐Type Ca ²⁺ 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.

A brain within the heart: A review on the intracardiac nervous system

“…Moreover, some studies suggest that HF reduc es the cell excitability of the cardiac postganglionic parasympathetic neurons, while enhances cell excitability in cardiac postganglionic sympathetic neurons . These changes seem to be dependent on the modulation of N-type Ca2+ channel [78,79].…”

“…Therefore it is not surprising that most of these studies are performed using in vitro preparations of intracardiac neurons, what imposes several limitations to the interpretation of the respective findings. At this level the patch clamp technique has been widely used to understand the plasticity and function of intracardiac neurons [79,85], since it is the gold standard technique to analyze the electrical properties and functional connectivity of neurons. In addition the patch clamp technique offers the advantage to study simultaneously the function, organization and network of the ICNS.…”

Reduced Cell Excitability of Cardiac Postganglionic Parasympathetic Neurons Correlates With Myocardial Infarction-Induced Fatal Ventricular Arrhythmias in Type 2 Diabetes Mellitus

“…After the measurement of the inducibility of ventricular arrhythmia, vagal control of ventricular function was determined, as described previously (Zhang et al, 2017(Zhang et al, , 2018. Briefly, a Millar pressure transducer (SPR 524; size, 3.5-Fr; Millar Instruments, Houston, TX, United States) was slowly inserted into the right carotid artery and carefully advanced to the left ventricle for measurement of left ventricular systolic pressure (LVSP) and the maximum rate of increase of left ventricular pressure (LV dP/dt max ).…”

“…At the terminal experiment, the AVG located in a white epicardial adipose pad at the junction of inferior pulmonary veins and left atrium was exposed. AVG neurons were isolated by a 2step enzymatic digestion protocol, as described previously (Liu et al, 2012;Tu et al, 2014;Zhang et al, 2017Zhang et al, , 2018. Isolated AVG was placed in ice-cold modified Tyrode solution (mmol/L): 140 NaCl, 5 KCl, 10 HEPES, and 5 glucose.…”

“…Rat intracardiac ganglia are divided into the sinoatrial ganglion and atrioventricular ganglion (AVG) (Sampaio et al, 2003). Since the ventricle receives projection of nerve terminals from the AVG (Pardini et al, 1987), our previous study further demonstrated that reduced cell excitability of CPP neurons located in AVG could contribute to the withdrawal of ventricular vagal function and ventricular arrhythmogenesis (Zhang et al, 2018). More importantly, using the normal rats, our previous study also found that malignant ventricular arrhythmias mainly occur in the early and late stages after MI, whereas electrical remodeling of CPP neurons highly correlates with the occurrence of ventricular arrhythmias in the setting of an MIinduced chronic heart failure but not acute MI (Zhang et al, 2017).…”