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(Circulation. 2006;114:I-174 – I-180.)
© 2006 American Heart Association, Inc.

Cell Transplantation and Tissue Engineering

Adenoviral Human BCL-2 Transgene Expression Attenuates Early Donor Cell Death After Cardiomyoblast Transplantation Into Ischemic Rat Hearts

Ingo Kutschka, MD; Theo Kofidis, MD; Ian Y. Chen, MSE; Georges von Degenfeld, MD, PhD; Monika Zwierzchoniewska, MD; Grant Hoyt, RA; Takayasu Arai, MD; Darren R. Lebl, MD; Stephen L. Hendry, MD; Ahmad Y. Sheikh, MD; David T. Cooke, MD; Andrew Connolly, MD; Helen M. Blau, PhD; Sanjiv S. Gambhir, MD, PhD; Robert C. Robbins, MD

From the Department of Cardiothoracic Surgery (I.K., T.K., M.Z., G.H., D.R.L., S.L.H., A.Y.S., D.T.C., R.C.R.), Molecular Imaging Program at Stanford, Departments of Radiology and Bioengineering, Bio-X Program (I.Y.C., S.S.G.), Department of Cardiovascular Medicine (T.A.), Baxter Laboratory in Genetic Pharmacology, Departments of Molecular Pharmacology and of Microbiology & Immunology (G.v.D., H.M.B.), Department of Pathology (A.C.), Stanford University, School of Medicine, Stanford, Calif.

Correspondence to Ingo Kutschka, Department of Thoracic and Cardiovascular Surgery, Städtisches Klinikum Braunschweig, Salzdahlumerstr. 90, 38126 Germany. E-mail: ingo.kutschka{at}t-online.de, i.kutschka@klinikum-braunschweig.de, and kutschka@stanford.edu

Background— Cell transplantation for myocardial repair is limited by early cell death. Gene therapy with human Bcl-2 (hBcl-2) has been shown to attenuate apoptosis in the experimental setting. Therefore, we studied the potential benefit of hBcl-2 transgene expression on the survival of cardiomyoblast grafts in ischemic rat hearts.

Methods and Results— H9c2 rat cardiomyoblasts were genetically modified to express both firefly luciferase and green fluorescent protein (mH9c2). The cells were then transduced with adenovirus carrying hBcl-2 (AdCMVhBcl-2/mH9c2). Lewis rats underwent ligation of the left anterior descending artery (LAD) to induce a sizable left ventricular (LV) infarct. Hearts were explanted and the infarcted region was restored using collagen matrix (CM) seeded with 1x10⁶ mH9c2 cells (n=9) or AdCMVhBcl-2/mH9c2 cells (n=9). Control animals received CM alone (n=6) or no infarct (n=6). Restored hearts were transplanted into the abdomen of syngeneic recipients in a "working heart" model. Cell survival was evaluated using optical bioluminescence imaging on days 1, 5, 8, 14, and 28 after surgery. The left heart function was assessed 4 weeks postoperatively using echocardiography and magnetic resonance imaging. During 4 weeks after surgery, the optical imaging signal for the AdCMVhBCL2/mH9c2 group was significantly (P<0.05) higher than that of the mH9c2-control group. Both grafts led to better fractional shortening (AdCMVhBcl-2/mH9c2: 0.21±0.03; mH9c2: 0.21±0.04; control: 0.15±0.03; P=0.04) and ejection fraction (AdCMVhBcl-2/mH9c2: 47.0±6.2; mH9c2: 48.7±6.1; control: 34.3±6.0; P=0.02) compared with controls. Importantly, no malignant cells were found in postmortem histology.

Conclusion— Transduction of mH9c2 cardiomyoblasts with AdCMVhBcl-2 increased graft survival in ischemic rat myocardium without causing malignancies. Both AdCMVhBcl-2/mH9c2 and mH9c2 grafts improved LV function.

Key Words: apoptosis • cells • gene therapy • grafting • myocardial infarction