Abstract

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. Although bone marrow-derived mesenchymal stem cells have been previously assessed for their therapeutic potential in individuals with heart failure and reduced ejection fraction, no clinical trial has evaluated intravenous infusion of UC-MSCs in these patients. Evaluate the safety and efficacy of the intravenous infusion of UC-MSC in patients with chronic stable heart failure and reduced ejection fraction. Patients with heart failure and reduced ejection fraction under optimal medical treatment were randomized to intravenous infusion of allogenic UC-MSCs (Cellistem, Cells for Cells S.A., Santiago, Chile; 1×106 cells/kg) or placebo (n=15 per group). UC-MSCs in vitro, compared with bone marrow-derived mesenchymal stem cells, displayed a 55-fold increase in the expression of hepatocyte growth factor, 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 MRI (P=0.025 versus baseline). Echocardiographic left ventricular ejection fraction change from baseline to month 12 differed significantly between groups (+7.07±6.22% versus +1.85±5.60%; P=0.028). In addition, at all follow-up time points, UC-MSC-treated patients displayed improvements of New York Heart Association functional class (P=0.0167 versus baseline) and Minnesota Living with Heart Failure Questionnaire (P<0.05 versus baseline). At study completion, groups did not differ in mortality, heart failure admissions, arrhythmias, or incident malignancy. Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment. Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with UC-MSCs. URL: https://www.clinicaltrials.gov/ct2/show/NCT01739777. Unique identifier: NCT01739777.

Highlights

  • Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with Umbilical cord–derived mesenchymal stem cells (UC-mesenchymal stem cells (MSC))

  • Bone marrow–derived mesenchymal stem cell cardiac magnetic resonance heart failure heart failure with reduced ejection fraction left ventricular end-diastolic volume left ventricular ejection fraction left ventricular end-systolic volume Minnesota Living with Heart Failure Questionnaire mesenchymal stem cells New York Heart Association umbilical cord–derived mesenchymal stem cell

  • All patients were assessed at baseline and at the pre-established follow-up points of 3, 6, and 12 months. These evaluations consisted of a clinical assessment for adverse events and New York Heart Association (NYHA) functional classification; Minnesota Living with Heart Failure Questionnaire (MLHFQ) and Kansas City Cardiomyopathy Questionnaire; laboratory testing including complete blood count, liver and renal function tests, brain natriuretic peptide, and high sensitivity C-reactive protein; resting ECG, signal averaged ECG, 24-hour ECG Holter monitoring; transthoracic echocardiography, cardiac magnetic resonance (CMR), and cardiopulmonary exercise test

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Summary

Methods

Study Design and Patient PopulationThe RIMECARD trial (Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy) was a phase 1/2, randomized, double-blind, placebo-controlled clinical1194 Circulation Research October 27, 2017 trial. The RIMECARD trial (Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy) was a phase 1/2, randomized, double-blind, placebo-controlled clinical. 1194 Circulation Research October 27, 2017 trial. The study was conducted at Clínica Santa Maria and Clínica Dávila, Chile. Participants were referred from these private healthcare centers or public hospitals and randomized between December 2012 and June 2014. The experimental design was approved by the ethics committee at both participant health centers and the Chilean Metropolitan Health Service. All patients agreed to participate and signed an informed consent approved by the institutional review board.

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