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

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 × 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.