Intracoronary infusion of skeletal myoblasts improves cardiac function in doxorubicin-induced heart failure

Background-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 ce lls into the heart, which would be advantageous in treating generalized car diac dysfunction as in dilated cardiomyopathy. We hypothesized that intraco ronary infusion of myoblasts would disseminate cells more effectively, lead ing to functional improvement in global heart failure. Methods and Results-Heart failure was induced by the intraperitoneal admini stration of doxorubicin (total dose 15 mg/kg) in rat. One million primary s keletal myoblasts were then infused via the coronary arteries of an excised , failing doxorubicin-treated heart. After incubation under increased intra coronary 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, Lange ndorff perfusion demonstrated that both maximum dP/dt (2797.6 +/- 103.3 ver sus 2326.9 +/- 133.1 mmHg/s, P=0.01) and minimum dP/dt (-2067.4 +/- 88.1 ve rsus -1718.8 +/- 91.3 mmHg/s, P=0.02) were improved in myoblast-transplante d hearts compared with medium-infused hearts. This was associated with a sh arper slope of the left ventricular developed pressure-volume curve and a r educed slope of the end-diastolic pressure-volume relation in the myoblast- transplanted hearts. Immunohistochemistry for skeletal myosin heavy chain s howed that globally disseminated myoblasts had survived and differentiated into multinucleated myotubes that had aligned with the cardiac fiber axis w ithin host myocardium. No significant myocardial infarction was observed. Conclusions-We demonstrated the feasibility and efficiency of skeletal myob last transplantation via the intracoronary route as a promising strategy fo r improving cardiac function in global heart failure.