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J Thorac Cardiovasc Surg 2006;132:918-924
© 2006 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Grafted skeletal myoblast sheets attenuate myocardial remodeling in pacing-induced canine heart failure model

Hiroki Hata, MDa, Goro Matsumiya, MD, PhDa, Shigeru Miyagawa, MD, PhDa, Haruhiko Kondoh, MD, PhDa, Naomasa Kawaguchi, MD, PhDb, Nariaki Matsuura, MD, PhDb, Tatsuya Shimizu, MD, PhDc, Teruo Okano, PhDc, Hikaru Matsuda, MD, PhDa, Yoshiki Sawa, MD, PhDa,*

a Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
b Department of Molecular Pathology, School of Allied Health Science, Osaka University Graduate School of Medicine, Osaka, Japan
c Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.

Received for publication October 23, 2005; revisions received December 19, 2005; accepted for publication January 10, 2006.

* Address for reprints: Yoshiki Sawa, MD, PhD, Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine (E1), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. (Email: sawa{at}surg1.med.osaka-u.ac.jp).

Objective: To overcome problems related to the intramyocardial injection of cells, including cell loss and a limited graft area, we developed a cell delivery system that uses tissue-engineered myoblast grafts grown as sheets. Here, we assessed the feasibility and efficacy of our method in a canine dilated cardiomyopathy model.

Methods: Skeletal myoblasts were incubated on temperature-responsive culture dishes, and the sheets of cells were detached by decreasing the temperature. Twelve dogs were given continuous ventricular pacing at 230 beats/min for 4 weeks; then the myoblast sheets (n = 5) were grafted onto the left ventricular wall or a sham operation was performed (n = 7). The number of cells was adjusted to 1.5~2.5 x 106 cells per graft, and each dog received approximately 20 grafts.

Results: The cell sheets were easily grafted onto a large area of the left ventricular surface, and there were no serious sequelae. Four weeks after graft implantation, echocardiography demonstrated that the left ventricular ejection fraction (graft, 26.0% ± 5.6%; control, 19.5% ± 6.8%; P < .05) and fractional shortening (graft, 17.9% ± 3.6%; control, 7.8% ± 2.1%; P < .05) were significantly ameliorated with reduced left ventricular dilatation (graft, 7.3 ± 1.3 cm2; control, 10.2 ± 0.4 cm2; P < .05) and increased wall thickness (graft, 5.6 ± 0.7 mm; control, 4.4 ± 0.6 mm; P < .05). Histologic evidence indicated the grafted myoblasts had survived, accompanied by a significant reduction in fibrosis and apoptosis, and a significant increase in proliferation.

Conclusions: Grafting of skeletal myoblast sheets attenuated cardiac remodeling and improved cardiac performance. This novel method was feasible and effective in a large animal model, suggesting an innovative and promising strategy for treating patients with end-stage dilated cardiomyopathy.

Abbreviations and Acronyms CK = color kinesis; DCM = dilated cardiomyopathy; FS = fractional shortening; LV = left ventricular; LVAWTh = left ventricular anterior wall thickness; LVEF = left ventricular ejection fraction; LVESA = end-systolic LV area; PCNA = proliferating cell nuclear antigen; TUNEL = terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling




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