Widespread intracoronary allogeneic cardiosphere-derived cell therapy with and without cyclosporine in reperfused myocardial infarction.

Abstract

Allogeneic cardiosphere-derived cell (CDC) therapy has been demonstrated to improve myocardial function when administered to reperfused myocardial infarcts. We previously pretreated animals with low-dose cyclosporine immunosuppression to limit allogeneic CDC rejection, but whether it is necessary and, if so, can be initiated at the time of reperfusion remains uncertain. Closed-chest swine (n = 29 animals) were subjected to a 90-min left anterior descending (LAD) coronary artery occlusion. Using a three-way blinded design, we randomized two groups to receive global intracoronary infusions of 20 × 106 CDCs 30 min after reperfusion. A third control group was treated with saline. One CDC group received cyclosporine 10 min before reperfusion (2.5 mg/kg iv and 100 mg/day po), whereas the other groups received placebos. After 1 mo, neither chronic infarct size relative to area at risk (saline control, 46.2 ± 4.0%; CDCs, 46.4 ± 2.1%; and CDCs + cyclosporine, 49.2 ± 3.1%; P = 0.79) nor ejection fraction (saline control, 51 ± 2%; CDCs, 51 ± 2%; and CDC + cyclosporine, 48 ± 2%; P = 0.42) were different among treatment groups. Multiple histological measures of cellular remodeling, myocyte proliferation, and apoptosis were also not different among treatment groups. In contrast to previous studies, we were unable to reproduce the cardioprotective effects demonstrated by allogeneic CDCs without cyclosporine. Furthermore, initiation of intravenous cyclosporine at the time of reperfusion followed by oral therapy was not sufficient to elicit the functional improvement observed in studies where cyclosporine was started 72 h before CDC therapy. This suggests that oral cyclosporine pretreatment may be necessary to effect cardiac repair with allogeneic CDCs.NEW & NOTEWORTHY In a three-way blinded, randomized design, we determined whether allogeneic CDCs administered at reperfusion improved myocardial function and whether intravenous cyclosporine enhanced their efficacy. In contrast to prior studies using oral cyclosporine, CDCs with or without intravenous cyclosporine had no effect on function or infarct size. This indicates that CDCs may be most efficacious for treating chronic LV dysfunction where cyclosporine can be initiated at least 72 h before cell therapy.