Intracoronary Infusion of Skeletal Myoblasts Improves Cardiac Function in Doxorubicin-Induced Heart Failure

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Abstract
Skeletal myoblast transplantation is promising for the treatment of end-stage heart failure. Direct intramyocardial injection is useful for local cell delivery but may not be effective in global dissemination of cells into the heart, which would be advantageous in treating generalized cardiac dysfunction as in dilated cardiomyopathy. We hypothesized that intracoronary infusion of myoblasts would disseminate cells more effectively, leading to functional improvement in global heart failure. Heart failure was induced by the intraperitoneal administration of doxorubicin (total dose 15 mg/kg) in rat. One million primary skeletal myoblasts were then infused via the coronary arteries of an excised, failing doxorubicin-treated heart. After incubation under increased intracoronary pressure, the hearts were subsequently transplanted into syngeneic recipients. For the control group, doxorubicin-treated hearts were infused with medium only and transplanted. Four weeks after transplantation, Langendorff perfusion demonstrated that both maximum dP/dt (2797.6+/-103.3 versus 2326.9+/-133.1 mm Hg/s, P=0.01) and minimum dP/dt (-2067.4+/-88.1 versus -1718.8+/-91.3 mm Hg/s, P=0.02) were improved in myoblast-transplanted hearts compared with medium-infused hearts. This was associated with a sharper slope of the left ventricular developed pressure-volume curve and a reduced slope of the end-diastolic pressure-volume relation in the myoblast-transplanted hearts. Immunohistochemistry for skeletal myosin heavy chain showed that globally disseminated myoblasts had survived and differentiated into multinucleated myotubes that had aligned with the cardiac fiber axis within host myocardium. No significant myocardial infarction was observed. We demonstrated the feasibility and efficiency of skeletal myoblast transplantation via the intracoronary route as a promising strategy for improving cardiac function in global heart failure.

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