Arrhythmia and sudden death associated with elevated cardiac chloride channel activity.

Abstract

The identification and analysis of several cationic ion channels and their associated genes have greatly improved our understanding of the molecular and cellular mechanisms of cardiac arrhythmia. Our objective in this study was to examine the involvement of anionic ion channels in cardiac arrhythmia. We used a transgenic mouse model to overexpress the human cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-regulated chloride channel. We used RNase protection and in situ hybridization assays to determine the level of CFTR expression, and radiotelemetry and in vivo electrophysiological study in combination with pharmacological intervention to analyse the cardiac function. Cardiac CFTR overexpression leads to stress-related sudden death in this model. In vivo intracardiac electrophysiological studies performed in anaesthetized mice showed no significant differences in baseline conduction parameters including atrial-His bundle (AH) or His bundle-ventricular (HV) conduction intervals, atrioventricular (AV) Wenckebach or 2:1 AV block cycle length and AV nodal functional refractory period. However, following isoproterenol administration, there was marked slowing of conduction parameters, including high-grade AV block in transgenic mice, with non-sustained ventricular tachycardia easily inducible using programmed stimulation or burst pacing. Our sudden death mouse model can be a valuable tool for investigation of the role of chloride channels in arrhythmogenesis and, potentially, for future evaluation of novel anti-arrhythmic therapeutic strategies and pharmacological agents.

• Authors: L Ye, W Zhu, P H Backx, M A Cortez, J Wu, Y-H Chow, C McKerlie, A Wang, L-C Tsui, G J Gross, J Hu
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 15 Issue 11 Pg. 2307-16 (Nov 2011) ISSN: 1582-4934 [Electronic] England
• PMID: 21155978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Chloride Channels
• Cystic Fibrosis Transmembrane Conductance Regulator
• Isoproterenol

Topics

• Animals
• Arrhythmias, Cardiac (chemically induced, metabolism)
• Atrioventricular Block (chemically induced)
• Atrioventricular Node (physiopathology)
• Bradycardia (chemically induced)
• Cardiac Pacing, Artificial
• Chloride Channels (metabolism)
• Cystic Fibrosis Transmembrane Conductance Regulator (biosynthesis, genetics, metabolism)
• Death, Sudden, Cardiac
• Heart
• Heart Conduction System (physiopathology)
• In Situ Hybridization
• Isoproterenol (administration & dosage, pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardium (metabolism)
• Tachycardia, Ventricular