Cardiac cell therapy: overexpression of connexin43 in skeletal myoblasts and prevention of ventricular arrhythmias.
Cell-based therapies have great potential for the treatment of cardiovascular diseases. Recently, using a transgenic mouse model Roell et al. reported that cardiac engraftment of connexin43 (Cx43)-overexpressing myoblasts in vivo prevents post-infarct arrhythmia, a common cause of death in patients following heart attack. We carried out a similar study but in a clinically relevant context via transplantation of autologous connexin43-overexpressing myoblasts in infarcted rats. Seven days after coronary ligation, rats were randomized into three groups: a control group injected with myoblasts, a null group injected with myoblasts transduced with an empty lentivirus vector (null) and a Cx43 group injected with myoblasts transduced with a lentivirus vector encoding connexin43. In contrast to Roell's report, arrhythmia occurrence was not statistically different between groups (58%, 64% and 48% for the control (n= 12), null (n= 14) and Cx43 (n= 23) groups, respectively, P= 0.92). Using ex vivo intramural monophasic action potential recordings synchronous electrical activity was observed between connexin43-overexpressing myoblasts and host cardiomyocytes, whereas such synchrony did not occur in the null-transduced group. This suggests that ex vivo connexin43 gene transfer and expression in myoblasts improved intercellular electrical coupling between myoblasts and cardiomyocytes. However, in our model such electrical coupling was not sufficient to decrease arrhythmia induction. Therefore, we would suggest a note of caution on the use of combined Cx43 gene and cell therapy to prevent post-infarct arrhythmias in heart failure patients.
INSERM, l'institut du thorax, Nantes, France.
Sarah
S
Fernandes
Harold V M
HV
van Rijen
Virginie
V
Forest
Stéphane
S
Evain
Anne-Laure
AL
Leblond
Jean
J
Mérot
Flavien
F
Charpentier
Jacques M T
JM
de Bakker
Patricia
P
Lemarchand
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology*; D018031:Connexin 43 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism*; D008297:Male; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D018031:Connexin 43