Circulation Research. 2005
Published online before print June 23, 2005, doi: 10.1161/01.RES.0000174794.22491.a0
Published online before print June 23, 2005, doi: 10.1161/01.RES.0000174794.22491.a0
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Submitted on December 29, 2004
Revised on June 10, 2005
Accepted on June 13, 2005
Antiarrhythmic Engineering of Skeletal Myoblasts for Cardiac Transplantation
M. Roselle Abraham ;
From the Institute of Molecular Cardiobiology (M.R.A., C.A.H., M.A., T.X., R.A.L., B.O’R., E.M.), and the Department of Biomedical Engineering (L.T., M.G.C.), Johns Hopkins University, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: marban{at}jhmi.edu.
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.
Key words: arrhythmia • electrophysiology • gene therapy • optical mapping
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