Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial)

Rationale: Umbilical cord-derived mesenchymal stem cells (UC-MSC) are easily accessible and expanded in vitro, possess distinct properties, and improve myocardial remodeling and function in experimental models of cardiovascular disease. While bone marrow-derived mesenchymal stem cells (BM-MSCs) have been previously assessed for their therapeutic potential in individuals with heart failure and reduced ejection fraction (HFrEF), no clinical trial has evaluated UC-MSCs in these patients. Objective: Evaluate the safety and efficacy of the infusion of UC-MSC in patients with chronic stable HFrEF. Methods and Results: HFrEF patients under optimal medical treatment were randomized to intravenous infusion of allogenic UC-MSCs (Cellistem, Cells for Cells S.A., Santiago, Chile) (1x10 6 cells/Kg) or placebo (n=15 per group). UC-MSCs in vitro , compared to BM-MSCs, displayed a 55-fold increase in the expression of Hepatocyte Growth Factor (HGF), known to be involved in myogenesis, cell migration and immunoregulation. UC-MSC treated patients presented no adverse events related to the cell infusion and none of the patients tested at 0, 15 and 90 days presented alloantibodies to the UC-MSCs (n=7). Only the UC-MSC treated group exhibited significant improvements in left ventricular ejection fraction at 3, 6 and 12 months of follow-up assessed both through transthoracic echocardiography (p=0.0167 versus baseline) and cardiac magnetic resonance imaging (p=0.025 versus baseline). Echocardiographic LVEF change from baseline to month 12 differed significantly between groups (+7.07±6.22% vs +1.85±5.60, p=0.028). In addition, at all follow-up time points, UC-MSCs treated patients displayed improvements of NYHA functional class (p=0.0167 versus baseline) and MLHFQ (p<0.05 versus baseline). At study completion, groups did not differ in mortality, heart failure admissions, arrhythmias or incident malignancy. Conclusions: Intravenous infusion of UC-MSC was safe in this group of patients with stable HFrEF under optimal medical treatment. Improvements in left ventricular function, functional status and quality of life were observed in patients treated with UC-MSCs. Trial registration number : NCT01739777. Registry URL: https://clinicaltrials.gov/ct2/show/NCT01739777.