Cardiovascular Research Advance Access first published online on July 20, 2009
This version [Corrected Proof] published online on August 21, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp250
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Cx43 CT domain influences infarct size and susceptibility to ventricular tachyarrhythmias in acute myocardial infarction
1 SUNY Upstate Medical University, Syracuse, NY, USA
2 NYU School of Medicine, New York, NY, USA
3 Center for Arrhythmia Research, University of Michigan, 5025 Venture Drive, Ann Arbor, MI 48108, USA
* Corresponding author. Tel: +1 734 998 7500/7512; fax: +1 734 998 7711. E-mail address: mdelmar{at}umich.edu
Aims: Hearts of mice expressing K258stop in place of connexin43 (Cx43) protein were subjected to acute myocardial infarction in order to assess the importance of Cx43 regulation on infarct size and arrhythmia susceptibility. This mutation K258stop prevents chemical regulation of Cx43 channels, including by low intracellular pH.
Methods and results: Langendorff-perfused hearts of mice harbouring one Cx43 knockout (KO) allele and one K258stop or Cx43 allele (K258stop/KO; Cx43/KO as control) were subjected to 1 h of ischaemia and 4 h of reperfusion by reversibly occluding the left anterior descending (LAD) coronary artery. Inducibility of ventricular tachyarrhythmias (VTs) was tested by applying an endocardial burst-pacing protocol during LAD occlusion. Separately, time course and the extent of acidification-induced closure of gap junction channels were tested by dual-voltage clamp. Infarct volume (as per cent of area at risk) was significantly larger in K258stop/KO hearts compared with Cx43/KO controls (42.2 ± 3 vs. 30.4 ± 1.7%, P = 0.004, n = 8 each). During LAD occlusion, K258stop/KO hearts had a higher incidence of pacing-induced VT and a higher frequency of occurrence of spontaneous premature ventricular beats. The occurrence of ventricular arrhythmias was also significantly larger in the K258stop/KO hearts during reperfusion. In separate experiments, we demonstrated reduced sensitivity to acidification-induced uncoupling in cell pairs obtained from K258stop/KO hearts.
Conclusion: Loss of the regulatory domain of Cx43 leads to an increase in infarct size and increased susceptibility to arrhythmias following acute coronary occlusion.
KEYWORDS Gap junctions; Cx43; Genetic models of arrhythmia; Transgenic mouse models; Ventricular arrhythmia
Time for primary review: 34 days
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Cardiovasc Res 2009 84: 337-338.
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  Y. Wang and Y. Cheng The tail of Cx43: its crucial protective role in acute myocardial infarction Cardiovasc Res, December 1, 2009; 84(3): 337 - 338. [Full Text] [PDF]
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