Cx43 CT domain influences infarct size and susceptibility to ventricular tachyarrhythmias in acute myocardial infarction.
OBJECTIVE
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.


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.


CONCLUSIONS
Loss of the regulatory domain of Cx43 leads to an increase in infarct size and increased susceptibility to arrhythmias following acute coronary occlusion.
Maass
Karen
K
SUNY Upstate Medical University, Syracuse, NY, USA.
Chase
Sharon E
SE
Lin
Xianming
X
Delmar
Mario
M
D000818:Animals; D018031:Connexin 43 / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D017629:Gap Junctions / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D012307:Risk Factors; D017180:Tachycardia, Ventricular / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology
D018031:Connexin 43