Effect of skeletal muscle Na(+) channel delivered via a cell platform on cardiac conduction and arrhythmia induction.
BACKGROUND
In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle Na(+) channel (SkM1) to epicardial border zones normalizes conduction and reduces induction of ventricular tachycardia/ventricular fibrillation. We now studied the impact of canine mesenchymal stem cells (cMSCs) in delivering SkM1.


RESULTS
cMSCs were isolated and transfected with SkM1. Coculture experiments showed cMSC/SkM1 but not cMSC alone and maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC, and cMSC/SkM1. In vivo epicardial border zones electrograms were broad and fragmented in sham, narrower in cMSCs, and narrow and unfragmented in cMSC/SkM1 (P<0.05). During programmed electrical stimulation of epicardial border zones, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P<0.05). Programmed electrical stimulation-induced ventricular tachycardia/ventricular fibrillation was equivalent in all groups (P>0.05).


CONCLUSIONS
cMSCs provide efficient delivery of SkM1 current. The interventions performed (cMSCs or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy.
Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, NY 10032, USA.
Gerard J J
GJ
Boink
Jia
J
Lu
Helen E
HE
Driessen
Lian
L
Duan
Eugene A
EA
Sosunov
Evgeny P
EP
Anyukhovsky
Iryna N
IN
Shlapakova
David H
DH
Lau
Tove S
TS
Rosen
Peter
P
Danilo
Zhiheng
Z
Jia
Nazira
N
Ozgen
Yevgeniy
Y
Bobkov
Yuanjian
Y
Guo
Peter R
PR
Brink
Yelena
Y
Kryukova
Richard B
RB
Robinson
Emilia
E
Entcheva
Ira S
IS
Cohen
Michael R
MR
Rosen
D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004285:Dogs; D022062:Electrophysiologic Techniques, Cardiac; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D014162:Transfection; D014693:Ventricular Fibrillation / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C466180:Scn4a protein, rat; C568322:Scn5a protein, rat; D015222:Sodium Channels; D012964:Sodium