Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Maass K

PROVIDER: S-EPMC2777952 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background The study sought to assess the prognostic impact of acute myocardial infarction ( AMI ) with and without ST -segment-elevation myocardial infarction ( STEMI and NSTEMI ) in patients with ventricular tachyarrhythmias and sudden cardiac arrest ( SCA ) on admission. Methods and Results A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia ( VT ), fibrillation ( VF ), and sudden cardiac arrest ( SCA ) on admission from 2002 to 2016. AMI versus non- AMI and STEMI versus NSTEMI were compared applying multivariable Cox regression models and propensity-score matching for evaluation of the primary prognostic end point defined as long-term all-cause mortality at 2.5 years. Secondary end points were 30 days all-cause mortality, cardiac death at 24 hours, in hospital death, and recurrent percutaneous coronary intervention (re- PCI ) at 2.5 years. In 2813 unmatched high-risk patients with ventricular tachyarrhythmias and SCA , AMI was present in 29% (10% STEMI , 19% NSTEMI ) with higher rates of VF (54% versus 31%) and SCA (35% versus 26%), whereas VT rates were higher in non- AMI (56% versus 30%) ( P < 0.05). AMI -related VT ≥48 hours was associated with higher mortality (log rank P = 0.001). Multivariable Cox regression models revealed non- AMI (hazard ratio = 1.458; P = 0.001) and NSTEMI (hazard ratio = 1.460; P = 0.036) associated with increasing long-term all-cause mortality at 2.5 years, which was also proven after propensity-score matching (non- AMI versus AMI : 55% versus 43%, log rank P = 0.001, hazard ratio = 1.349; NSTEMI versus STEMI : 45% versus 34%, log rank P = 0.047, hazard ratio = 1.372). Secondary end points including 30 days and in-hospital mortality, as well as re- PCI were higher in non- AMI patients. Conclusions In high-risk patients presenting with ventricular tachyarrhythmias and SCA , non- AMI revealed higher mortality than AMI , respectively NSTEMI than STEMI , alongside AMI -related VT ≥48 hours.