Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts

Background-Vascular endothelial growth factor (VEGF) is a promising reagent for inducing myocardial angiogenesis. Skeletal myoblast transplantation ha s been shown to improve cardiac function in chronic heart failure models by regenerating muscle. We hypothesized that transplantation of VEGF-expressi ng myoblasts could effectively treat acute myocardial infarction by providi ng VEGF-induced cardioprotection through vasodilatation in the early phase, followed by angiogenesis effects in salvaging ischemic host myocardium com bined with the functional benefits of newly formed, skeletal myoblast-deriv ed muscle in the later phase. Methods and Results-Primary rat skeletal myoblasts were transfected with th e human VEGF(165) gene using hemagglutinating virus of Japan-liposome with > 95% transfection efficiency. Four million of these myoblasts (VEGF group) , control-transfected myoblasts (control group), or medium only (medium gro up) was injected into syngeneic rat hearts I hour after left coronary arter y occlusion. Myocardial VEGF-expression increased for 2 weeks in the VEGF g roup, resulting in enhanced angiogenesis without the formation of tumors. G rafted myoblasts had differentiated into multinucleated myotubes within hos t myocardium. Infarct size (33.3 +/- 1.4%, 38.1 +/- 1.4%, and 43.7 +/- 1.6% for VEGF, control, and medium groups, respectively; P=0.0005) was signific antly reduced with VEGF treatment, and cardiac function improved in the VEG F group (maximum dP/dt: 4072.0 +/- 93.6, 3772.5 +/- 101.1, and 3482.5 +/- 9 0.6 mm Hg/s in the 3 groups, respectively; P=0.0011; minimum dP/dt: -504.2 +/- 68.5, -2311.3 +/- 57.0, and -2124.0 +/- 57.9 mm Hg/s, respectively; P=0 .0008). Conclusions-This combined strategy of cell transplantation with gene therap y could be of importance for the treatment of acute myocardial infarction.