17 While long-term adverse neurohormonal responses can be countered with �� blockers and ACE-inhibitors and the likelihood of recurrent ischemic events can be decreased with either aggressive secondary prevention,18 no therapy currently available can reduce the size of an established infarct. Cell therapy aims to alter this fixed trajectory for MI survivors: to intervene in the process of adverse LV remodeling, to reduce infarct size and to actually regenerate viable myocardial tissue in its place. The field to date has focused primarily on when to administer cells and what cells to administer, while relying on minimally-invasive delivery approaches (i.e., intracoronary infusion) that could also be readily and widely adopted by clinicians. More novel delivery approaches (i.e.

, transendocardial injection) have begun to establish a decent clinical safety profile,19 but seem to offer marginal added efficacy benefits. The result of all attempts to date has been partial restoration of cardiac structure and function. On the whole (in a meta-analysis considering 50 studies enrolling 2625 patients) autologous bone marrow cells, by far the cell type most extensively studied clinically, have led to a 4.0% increase in EF, an 8.9 mL reduction in ESV, a 5.2 mL reduction in EDV, and a 4.0% reduction in infarct size compared with control.20 These primary efficacy data can be termed marginally positive at best. Although one of the first and most positive studies21 is now reporting unanticipated benefits on long-term clinical endpoints (e.g.

, death, recurrent MI, HF development, revascularization),22 room for improvement undeniably still exists. Clinical Use of Cardiosphere-Derived Cells Cardiosphere-derived cells have yet undergone limited clinical use, but may have come the closest to achieving the goals of cell therapy, including viable tissue regeneration. The CADUCEUS (CArdiosphere-Derived AUtologous Stem CElls to Reverse VentricUlar DySfunction) trial demonstrated the safety and efficacy of autologous CDC administration via intracoronary infusion in patients with LV dysfunction post-MI.2 In the randomized, controlled, dose-escalating Phase I trial, autologous CDCs manufactured from endomyocardial biopsy specimens were infused into the infarct-related artery in 17 patients. Eight patients were followed as standard-of-care controls.

In > 12 months of follow-up, Batimastat safety endpoints were equivalent. Contrast-enhanced magnetic resonance imaging (MRI) revealed reductions of infarct size (scar mass normalized to total LV mass) in CDC-treated patients (-7.7 �� 4.8%), but not in controls (+0.3 �� 5.4%) over a period of 6 mo. The treatment effect in CDC patients nearly doubled at 12 mo (-12.3 �� 5.0%), amounting to a 46% relative reduction of infarct size (from a baseline of 24%), but remained unchanged in controls (-2.2 �� 7.1%). In comparison to the overall effect reported for bone marrow cells on infarct size,20 CDCs elicited much larger reductions.