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

Abstract

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 ~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 × 10 6 WJMSCs were administered using a novel cell delivery-dedicated, coronary-non-occlusive method (CIRCU-LATE 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, one 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 ~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.

Multi-modality imaging in the CIRCULATE-AMI pilot study cohort: a framework for an imaging-based randomized controlled trial of Wharton jelly mesenchymal stem cell use to stimulate myocardial repair/regeneration

“…In our recent pilot study, transcoronary administration of 30 × 10 6 standardized, multipotent Wharton jelly mesenchymal stem cells (WJMSC) 5 to 7 days after AMI was safe [ 5 ], and it was associated with minimal left ventricular remodelling and improved haemodynamics throughout 3 years of follow-up [ 8 ], providing the basis for a larger-scale clinical trial. Here, we present multi-modality imaging in the CIRCULATE-AMI pilot study cohort as a framework for an imaging endpoint-powered, randomized controlled trial of WJMSC use to stimulate myocardial repair/regeneration.…”