Reduced N-Type Ca2+ channels in atrioventricular ganglion neurons are involved in ventricular arrhythmogenesis

Dongze Zhang, Huiyin Tu, Liang Cao, Hong Zheng, Robert Leo Muelleman, Michael Charles Wadman, Yulong Li

Research output: Contribution to journalArticle

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Abstract

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 a-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 Results--Lentiviral Cav2.2-α shRNA (2 lL, 29107 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 shRNAtransfected 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. Conclusions--A decrease in N-type Ca2+ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.

Original languageEnglish (US)
Article numbere007457
JournalJournal of the American Heart Association
Volume7
Issue number2
DOIs
StatePublished - Jan 1 2018

Fingerprint

Ganglia
Neurons
Small Interfering RNA
Transfection
Cardiac Arrhythmias
Myocardium
Heart Failure
Protein Array Analysis
Telemetry
Ventricular Premature Complexes
Electric Stimulation
Polymerase Chain Reaction
Messenger RNA
Mortality

Keywords

  • Autonomic nervous system
  • Calcium channel
  • ECG
  • Ganglia
  • Parasympathetic
  • Vagus nerve
  • Ventricular arrhythmia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Reduced N-Type Ca2+ channels in atrioventricular ganglion neurons are involved in ventricular arrhythmogenesis. / Zhang, Dongze; Tu, Huiyin; Cao, Liang; Zheng, Hong; Muelleman, Robert Leo; Wadman, Michael Charles; Li, Yulong.

In: Journal of the American Heart Association, Vol. 7, No. 2, e007457, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "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 a-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 Results--Lentiviral Cav2.2-α shRNA (2 lL, 29107 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 shRNAtransfected 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. Conclusions--A 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, Ventricular arrhythmia",
author = "Dongze Zhang and Huiyin Tu and Liang Cao and Hong Zheng and Muelleman, {Robert Leo} and Wadman, {Michael Charles} and Yulong Li",
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T1 - Reduced N-Type Ca2+ channels in atrioventricular ganglion neurons are involved in ventricular arrhythmogenesis

AU - Zhang, Dongze

AU - Tu, Huiyin

AU - Cao, Liang

AU - Zheng, Hong

AU - Muelleman, Robert Leo

AU - Wadman, Michael Charles

AU - Li, Yulong

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 a-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 Results--Lentiviral Cav2.2-α shRNA (2 lL, 29107 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 shRNAtransfected 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. Conclusions--A decrease in N-type Ca2+ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.

AB - 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 a-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 Results--Lentiviral Cav2.2-α shRNA (2 lL, 29107 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 shRNAtransfected 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. Conclusions--A decrease in N-type Ca2+ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.

KW - Autonomic nervous system

KW - Calcium channel

KW - ECG

KW - Ganglia

KW - Parasympathetic

KW - Vagus nerve

KW - Ventricular arrhythmia

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