Correlation of Ventricular Arrhythmogenesis with Neuronal Remodeling of Cardiac Postganglionic Parasympathetic Neurons in the Late Stage of Heart Failure after Myocardial Infarction

Abstract

Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with ventricular arrhythmogenesis in CHF rats.Methods and Results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-h continuous radiotelemetry ECG recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 3 and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of left ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3 or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF.Conclusion: Malignant ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of ventricular arrhythmias in the late stage of CHF.

Reduced N‐Type Ca 2+ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

“…Our recent study has demonstrated that the occurrence of lethal ventricular arrhythmias is accompanied by reduced N‐type Ca 2+ currents in AVG neurons and blunted ventricular vagal activity in coronary artery ligation‐induced CHF rats 26. In the present study, although in vivo transfection of Ca v 2.2‐α shRNA into AVG neurons significantly decreased expression and ion currents of N‐type Ca 2+ channels in ventricular vagal neurons and blunted ventricular vagal activity, it merely induced spontaneous PVCs but not lethal ventricular arrhythmias such as VT/VF in conscious rats.…”

“…The skin was first shaved and sterilized. After laparotomy was performed at the linea alba (abdomen), the radiotelemetry ECG transmitter 26 (TRM54PB, Millar Instruments, Houston, TX) was placed into the abdominal cavity and secured to the abdominal wall at the best position for battery recharging and signal communication. In accordance with the Millar User Manual for ECG recording, bipolar electrodes were tunneled subcutaneously.…”

“…Susceptibility to ventricular arrhythmias was measured as described previously. 26 On the day of the terminal experiment (1 day after radiotelemetry ECG recording), each rat was anesthetized (800 mg/kg urethane combined with 40 mg/kg a-chloralose, intraperitoneally). The animal's trachea was cannulated to facilitate mechanical respiration.…”

“…After the susceptibility to ventricular arrhythmias had been detected, the left femoral artery was cannulated with a polyethylene-50 catheter for measurement of blood pressure and heart rate. 26 A Millar pressure transducer (SPR 524; Millar Instruments, Houston, TX) was slowly inserted into the right carotid artery and carefully advanced to the left ventricle for measurement of left ventricular pressure and the maximum rate of left ventricular pressure rise. Hemodynamic data were recorded by powerLab 8/30 Data Acquisition System with LabChart 7 software (ADInstruments, Colorado Springs, CO).…”

Quantitative study of synaptic boutons on frog intracardiac neurons

“…Remodelling of neuronal function and altered synaptic plasticity have been implicated in myocardial infarction and in wide spectrum of neurological diseases [10]. In order to understand the role of the intracardiac nervous system, many studies have investigated the morphology, neurochemistry and function of intracardiac neurons and intracardiac nerves of various animal models [1][2][3]8].…”