Acute myocardial infarction reparation/regeneration strategy using Wharton’s jelly multipotent stem cells as an ‘unlimited’ therapeutic agent: 3-year outcomes in a pilot cohort of the CIRCULATE-AMI trial

Introduction: CIRCULATE-AMI (NCT03404063), a cardiac magnetic resonance imaging (cMRI) infarct size-reduction-powered double-blind randomized controlled trial (RCT) of standardized Wharton jelly multipotent stem cells (WJMSCs, CardioCell Investigational Medical Product) vs. placebo (2 : 1) transcoronary transfer on acute myocardial infarction (AMI) day similar to 5-7, is preceded by safety and feasibility evaluation in a pilot study cohort (CIRCULATE-AMI PSC). Aim: To evaluate WJMSC transplantation safety and evolution of left ventricular (LV) remodeling in CIRCULATE-AMI PSC. Material and methods: In 10 consecutive patients (32-65 years, peak CK-MB 533 +/- 89 U/l, cMRI-LVEF 40.3 +/- 2.7%, cMRI-infarct size 20.1 +/- 2.8%), 30 x 10(6) WJMSCs were administered using a novel cell delivery-dedicated, coronary-non-occlusive method (CIRCULATE catheter). Other treatment was guideline-based. Results: WJMSC transfer was safe and occurred in the absence of coronary (TIMI-3 in all) or myocardial (corrected TIMI frame count (cTFC) 45 +/- 8 vs. 44 +/- 9, p = 0.51) flow deterioration or troponin elevation. By 3 years, 1 patient died from a new, non-index territory AMI; there were no other major adverse cardiovascular and cerebrovascular events (MACCE) and no adverse events that might be related to WJMSCs. cMRI infarct size was reduced from 33.2 +/- 7.6 g to 25.5 +/- 6.4 g at 1 year and 23.1 +/- 5.6 g at 3 years (p = 0.03 vs. baseline). cMRI, SPECT, and echo showed a consistent, statistically significant increase in LVEF at 6-12 months (41.9 +/- 2.6% vs. 51.0 +/- 3.3%, 36.0 +/- 3.9% vs. 44.9 +/- 5.0%, and 38.4 +/- 2.5% vs. 48.0 +/- 2.1% respectively, p < 0.01 for all); the effect was sustained at 3 years. Conclusions: CIRCULATE-AMI PSC data suggest that WJMSC transcoronary application similar to 5-7 days after large AMI in humans is feasible and safe and it may be associated with a durable LVEF improvement. CIRCULATE-AMI RCT will quantify the magnitude of LV adverse remodeling attenuation with CardioCell/placebo administration.