Abstract
BackgroundThere is mounting interest in using c-kit positive human cardiac stem cells (c-kitpos hCSCs) to repair infarcted myocardium in patients with ischemic cardiomyopathy. A recent phase I clinical trial (SCIPIO) has shown that intracoronary infusion of 1 million hCSCs is safe. Higher doses of CSCs may provide superior reparative ability; however, it is unknown if doses >1 million cells are safe. To address this issue, we examined the effects of 20 million hCSCs in pigs.MethodsRight atrial appendage samples were obtained from patients undergoing cardiac surgery. The tissue was processed by an established protocol with eventual immunomagnetic sorting to obtain in vitro expanded hCSCs. A cumulative dose of 20 million cells was given intracoronarily to pigs without stop flow. Safety was assessed by measurement of serial biomarkers (cardiac: troponin I and CK-MB, renal: creatinine and BUN, and hepatic: AST, ALT, and alkaline phosphatase) and echocardiography pre- and post-infusion. hCSC retention 30 days after infusion was quantified by PCR for human genomic DNA. All personnel were blinded as to group assignment.ResultsCompared with vehicle-treated controls (n=5), pigs that received 20 million hCSCs (n=9) showed no significant change in cardiac function or end organ damage (assessed by organ specific biomarkers) that could be attributed to hCSCs (P>0.05 in all cases). No hCSCs could be detected in left ventricular samples 30 days after infusion.ConclusionsIntracoronary infusion of 20 million c-kit positive hCSCs in pigs (equivalent to ~40 million hCSCs in humans) does not cause acute cardiac injury, impairment of cardiac function, or liver and renal injury. These results have immediate translational value and lay the groundwork for using doses of CSCs >1 million in future clinical trials. Further studies are needed to ascertain whether administration of >1 million hCSCs is associated with greater efficacy in patients with ischemic cardiomyopathy.
Highlights
C-kitpos cardiac stem cells (CSCs) are one of a number of stem/progenitor cells described in the mammalian heart and one of the two types ever used clinically for cardiac regeneration [1,2]
No hCSCs could be detected in left ventricular samples 30 days after infusion
Further studies are needed to ascertain whether administration of >1 million hCSCs is associated with greater efficacy in patients with ischemic cardiomyopathy
Summary
C-kitpos cardiac stem cells (CSCs) are one of a number of stem/progenitor cells described in the mammalian heart and one of the two types ever used clinically for cardiac regeneration [1,2]. We recently reported the results of the first in-human clinical trial of autologous c-kitpos CSCs in patients with ischemic cardiomyopathy [2] In this phase I trial, designed to evaluate the safety and feasibility of intracoronary administration of c-kitpos CSCs, 1 million cells were injected in the infarct-related artery using the stop-flow technique. The administration of c-kitpos CSCs was shown to be safe and there were encouraging results related to efficacy, with a significant improvement in left ventricular (LV) ejection fraction in the hCSC treated group [2] These encouraging findings have sparked growing interest in utilizing c-kitpos CSCs in additional trials with escalating doses >1 million cells, in light of reports of dose-dependent responses with stem cells[3].
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