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Background Chronic ischaemic heart failure (CIHF) remains an important health problem on the patient/family- and society level. In animal models, Wharton's jelly (umbilical cord matrix) multipotent stem cells (WJMSCs) effectively promote angiogenesis, can differentiate to cardiomyocytes, and drive functional myocardial regeneration. Effective uptake of regenerative cells in ischaemic-impaired tissue is fundamental for any therapeutic effect. Purpose To evaluate safety and myocardial uptake of WJMSCs transcoronary transfer in CIHF applied as a novel myocardial regeneration strategy employing allogenic yet hypo-immunogenic, off-the-shelf “unlimited” source of therapeutic cells (NCT03418233 pilot cohort). Material and methods In ten consecutive patients (age 62.6±2.5), with stable CIHF and no current need for revascularization (LVEF 29.3±3% by echo and 26.3±6% by SPECT; NT-proBNP 1746±329pg/mL; myocardial scar tissue 39.9±3.9% by SPECT) and patency of at least two major native coronary arteries or by-pass graft(s), the CardioCell Investigational Medical Product, based on 30x106 WJMSCs, was administered to viable yet hypokinetic segments using a novel algorithm including a dedicated catheter for transcoronary delivery of cellular therapies. The cells were labeled with 99mTc-extametazime to routinely evaluate their myocardial uptake magnitude. Results No symptoms or signs of novel myocardial ischaemia occurred with cell delivery and no patient showed any adverse periprocedural events. One hour after administration, myocardial WJMSCs uptake (SPECT) was 40.3±6%; see Fig for a typical raw data image. By 6 months there were no adverse events in the study cohort. Figure 1 Conclusions This work indicates safety and unprecedented high-grade myocardial uptake of WJMSCs in CIHF patients. Together with animal data, this provides basis for continued assessment of this strategy in an endpoint-powered randomized controlled clinical trial employing CardioCell as an “unlimited” off-the-shelf cellular therapy strategy. Acknowledgement/Funding K/ZDS/005644 and 265761 (National Centre for Research and Development STRATEGMED)

Introduction CIRCULATE-Acute Myocardial Infarction is a double-blind controlled trial randomizing (RCT) in 105 consecutive patients with their first, large AMI (cMRI-LVEF ≤45% and/or cMRI-infarct size ≥10% of LV) with successful infarct-related artery (IRA) primary percutaneous coronary intervention (pPCI) to transcoronary administration of Wharton's Jelly Mesenchymal Stem Cells (WJMSCs) vs. placebo (2:1). The pilot study cohort (PSC) preceded the RCT. Aim To evaluate WJMSCs long-term safety, and evolution of left-ventricular (LV) function in CIRCULATE-AMI PSC. Material and methods 30 000 000 WJMSCs (50% labelled with 99mTc-exametazime) were administered via IRA in a ten-patient PCS (age 32–65 years, peak hs-Troponin T 17.3±9.1ng/mL and peak CK-MB 533±89U/L, cMRI-LVEF 40.3±2.7% and infarct size 20.1±2.8%) at ≈5–7 days after AMI using a cell delivery-dedicated, coronary-non-occlusive method. Other treatments were per guidelines. WJMSCs showed an unprecedented high myocardial uptake (30.2±5.3%; 95% CI 26.9–33.5%), corresponding to ≈9×10 000 000 cells retention in the infarct zone – in absence of epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45±8 vs. 44±9, p=0.51) or any hs-Troponin T elevation. Five-year follow up included cardiac Magnetic Resonance Imaging (cMRI) (at baseline, 1 year and 3 years) and detailed echocardiography (echo) at baseline, 1 year, 3 years and 5 years. Results By 5 years, one patient died from a new, non-index territory AMI. There were no other cardiovascular events and MACCE that might be related to WJMSCs transplantation. On echo (Fig), there was an increase in left ventricular ejection fraction (LVEF) between WJMSCs administration point and 1 year (37.7±2.9% vs. 48.3±2.5%, p=0.002) that was sustained at 3 years (47.2±2.6%, p=0.005 vs. baseline) and at 5 years: (44.7±3.2%, p=0.039 vs. baseline). LVEF reached a peak at 1 year after the AMI and WJMSCs transfer (Fig). cMRI data (obtained up to 3 years; 1 year 41.9±2.6% vs. 51.0±3.3%, p<0.01; 3 years 52.2±4.0%, p<0.01 vs. baseline) were consistent with the echo LVEF assessment. Conclusions 5-year follow up in CIRCULATE-AMI PSC indicates that WJMSC transcoronary application is safe and may be associated with an LVEF improvement. The magnitude of LV increase appears to peak at 1 year, suggesting a potential role for repeated WJMSCs administration(s). Currently running double-blind RCT will provide placebo-controlled insights into the WJMSCs effect(s) on changes in LV function, remodelling, scar reduction and clinical outcomes. Echo-LVEF evolution Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STRATEGMED 265761 “CIRCULATE” National Centre for Research and Development/Poland/ZDS/00564 Jagiellonian University Medical College