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Widespread Intracoronary Allogeneic Cardiosphere-Derived Cell Therapy With and Without Cyclosporine in Reperfused Myocardial Infarction.

BACKGROUND
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.


METHODS AND RESULTS
Closed-chest swine (n=29) were subjected to a 90-minute LAD occlusion. Using a three-way blinded design, we randomized two groups to receive global intracoronary infusions of 20x106 CDCs 30-minutes after reperfusion. A third control group was treated with saline. One CDC group received cyclosporine 10-minutes prior to reperfusion (2.5 mg/kg i.v. and 100 mg p.o./day) while the other groups received placebos. After 1-month, neither chronic infarct size relative to area at risk (Saline control: 46.2±4.0%, CDCs: 46.4±2.1%, CDCs+Cyclosporine: 49.2±3.1%, p=0.79) nor ejection fraction (Saline control: 51±2%, CDCs:51±2%, 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.


CONCLUSIONS
In contrast to previous studies, we were unable to reproduce the cardioprotective effects demonstrated by allogeneic CDCs without cyclosporine. Furthermore, initiation of i.v. 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 hours before CDC therapy. This suggests that oral cyclosporine pretreatment may be necessary to effect cardiac repair with allogeneic CDCs.