Local lentiviral Connexin 43 (Cx43) transduction reduces incidence of post-infarct ventricular tachycardias (VT's) in mouse

Objectives: VT's are frequently observed after myocardial infarction and represent a potentially lethal complication. In the past we could demonstrate that VT incidence was significantly reduced after transplantation of electrically coupling cells expressing Cx43. Since long term most of intramyocardial transplanted cells die, in the present study resident cells within the scar were stably transfected with Cx43 by lentiviral gene transfer.

Methods: Cryolesions were generated in 35 CD1 wild type (WT) mice within the free left ventricular wall by use of a 3.5 mm copper probe. Three to four days postoperatively the chest was reopened and 5 µl of lentivirus solution were injected into the centre as well as the border zone of the lesion. While in treated animals (n = 20) CMV-Cx43-IRES-eGFP virus (1 × 10⁶-1 × 10⁷ infectious particles (IP/ml)) was used, control animals (n = 15) were injected with CMV-eGFP virus (1 × 10⁸-1 × 10⁹ IP/ml). In vivo electrophysiological investigation employing extrastimulus as well as burst stimulation protocols was performed two weeks after myocardial infarction. Thereafter animals were sacrificed and hearts harvested for further investigation.

Results: While in over 80% of control mice VT's were observed, a significant reduction of the VT incidence was seen after Cx43 treatment. Integration of the genome and expression of the encoded proteins within the lesion area was proven for both constructs by qPCR as well as western blot analysis. Furthermore eGFP expression within the myocardial lesion was shown by immunohistochemistry.

Conclusion: Post infarct VT incidence is significantly reduced after local lentiviral transfection of the lesioned myocardium. Compared to our previous cell transplantation data this treatment is immediately practicable, avoids cell rejection and provides permanent gene expression within the remaining scar tissue.