Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation.
Skeletal myoblasts are an attractive cell type for transplantation because they are autologous and resistant to ischemia. However, clinical trials of myoblast transplantation in heart failure have been plagued by ventricular tachyarrhythmias and sudden cardiac death. The pathogenesis of these arrhythmias is poorly understood, but may be related to the fact that skeletal muscle cells, unlike heart cells, are electrically isolated by the absence of gap junctions. Using a novel in vitro model of myoblast transplantation in cardiomyocyte monolayers, we investigated the mechanisms of transplant-associated arrhythmias. Cocultures of human skeletal myoblasts and rat cardiomyocytes resulted in reentrant arrhythmias (spiral waves) that reproduce the features of ventricular tachycardia seen in patients receiving myoblast transplants. These arrhythmias could be terminated by nitrendipine, an l-type calcium channel blocker, but not by the Na channel blocker lidocaine. Genetic modification of myoblasts to express the gap junction protein connexin43 decreased arrhythmogenicity in cocultures, suggesting a specific means for increasing the safety (and perhaps the efficacy) of myoblast transplantation in patients.
Institute of Molecular Cardiobiology, Johns Hopkins University, Carnegie 568, 600 N Wolfe St, Baltimore, MD 21205, USA.
M Roselle
MR
Abraham
Charles A
CA
Henrikson
Leslie
L
Tung
Marvin G
MG
Chang
Miguel
M
Aon
Tian
T
Xue
Ronald A
RA
Li
Brian
B
O' Rourke
Eduardo
E
Marbán
D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D018920:Coculture Techniques; D018031:Connexin 43 / Q000235:genetics* / Q000502:physiology; D015316:Genetic Therapy; D006367:HeLa Cells; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000196:embryology*; D032446:Myoblasts / Q000502:physiology / Q000637:transplantation*
D018031:Connexin 43