71 Infarct healing and arrhythmias affected by gap junction remodelling in Cx43-deficient mice

Abstract

Changes in gap junctions have been implicated in anatomic substrates of ventricular tachycardia (VT) in patients with healed myocardial infarcts (MI) but the exact role of altered cell-cell coupling has been difficuk to define. To determine the potential value of mouse models to identify gene products critical in arrhythmogenesis following MI, we ligated the coronary artery in mice (C57BL/6J) heterozygous for a connexin43 (Cx43) null allele (Cx43+/-) (n=30) and wildtype mice (Cx43+/+) (n=23) and characterized ventricular remodeling by histology. Spontaneous arrhythmias were observed for 1 week then hearts were analyzed with extrastimulus protocol for inducing ventricular tachycardia. In histology we determined whether diminished coupling affects infarct healing and post-MI remodeling. Ventricular sections were examined histologically 1 and 10 weeks after infarction. Specific morphological features were evaluated including whether infarcts were transmural or non-transmural, and the presence or absence of ventricular aneurysmal dilatation, patchy interstitial fibrosis at infarct border zones, and surviving subendocardial myocytes. A layer of surviving subendocardial myocytes was seen more frequently in hearts in which VT could be induced but the occurrence of this feature was similar in Cx43+/- and +/+ hearts. The other features of post-infarct remodeling pertinent to development of arrhythmias and contractile dysfunction in hearts with healed infarcts were also observed with equal frequency in Cx43 +/- and +/+ hearts. Thus, reduced basal coupling does not by itself significantly alter infarct healing or post-MI remodeling. Infarct healing in mice closely resembles human ischemic heart disease.