Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure

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Abstract

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Abstract

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. 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.

Objective:

Evaluate the safety and efficacy of the intravenous infusion of UC-MSC in patients with chronic stable heart failure and reduced ejection fraction.

Methods and Results:

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; 1×10 ⁶ 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.

Conclusions:

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.

Clinical Trial Registration:

URL: https://www.clinicaltrials.gov/ct2/show/NCT01739777. Unique identifier: NCT01739777

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Most cited references 36

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Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.

Joshua Hare, Joel Fishman, Gary Gerstenblith … (2012)

Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. clinicaltrials.gov Identifier: NCT01087996.

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A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

Joshua Hare, Jay Traverse, Timothy D Henry … (2009)

Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

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Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography.

Victor Mor-Avi, Roberto Lang, Luigi Badano … (2011)

Echocardiographic imaging is ideally suited for the evaluation of cardiac mechanics because of its intrinsically dynamic nature. Because for decades, echocardiography has been the only imaging modality that allows dynamic imaging of the heart, it is only natural that new, increasingly automated techniques for sophisticated analysis of cardiac mechanics have been driven by researchers and manufacturers of ultrasound imaging equipment.Several such technique shave emerged over the past decades to address the issue of reader's experience and inter measurement variability in interpretation.Some were widely embraced by echocardiographers around the world and became part of the clinical routine,whereas others remained limited to research and exploration of new clinical applications.Two such techniques have dominated the research arena of echocardiography: (1) Doppler based tissue velocity measurements,frequently referred to as tissue Doppler or myocardial Doppler, and (2) speckle tracking on the basis of displacement measurements.Both types of measurements lend themselves to the derivation of multiple parameters of myocardial function. The goal of this document is to focus on the currently available techniques that allow quantitative assessment of myocardial function via image-based analysis of local myocardial dynamics, including Doppler tissue imaging and speckle-tracking echocardiography, as well as integrated backscatter analysis. This document describes the current and potential clinical applications of these techniques and their strengths and weaknesses,briefly surveys a selection of the relevant published literature while highlighting normal and abnormal findings in the context of different cardiovascular pathologies, and summarizes the unresolved issues, future research priorities, and recommended indications for clinical use.

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Author and article information

Journal

Journal ID (nlm-ta): Circ Res

Journal ID (iso-abbrev): Circ. Res

Journal ID (publisher-id): RES

Title: Circulation Research

Publisher: Lippincott Williams & Wilkins

ISSN (Print): 0009-7330

ISSN (Electronic): 1524-4571

Publication date (Print): 27 October 2017

Publication date (Electronic): 26 October 2017

Volume: 121

Issue: 10

Pages: 1192-1204

Affiliations

From the Laboratory of Nano-Regenerative Medicine (J.B., P.L.G., F.A.-M., J.C., F.E.F., M.K.) and Department of Internal Medicine (F.J.V., R.E.L., F.E.F.), Faculty of Medicine, Universidad de los Andes, Santiago, Chile; Department of Cardiology, Clínica Santa Maria, Santiago, Chile (J.B., E.A., C.G., R.L., P.A.P., G.V.); Program for Translational Research in Cell Therapy, Clínica Universidad de los Andes, Santiago, Chile (J.B., F.J.V., F.E.F., M.K.); Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile (P.L.G., F.A., J.C., F.E.F., M.K.); Department of Cardiology, Clínica Davila, Santiago, Chile (R.E.L., P.R., I.P.); Cells for Cells, Santiago, Chile (V.M.L., M.K.); Public Health School, Faculty of Medicine, Universidad de Chile, Santiago, Chile (C.N.); Division of Physical Medicine Rehabilitation, University of Utah, Salt Lake City (M.J.B.); and Department of Surgery, University of Miami School of Medicine, FL (A.N.P.).

Author notes

Correspondence to Fernando E. Figueroa, MD, Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, San Carlos de Apoquindo 2500, Las Condes, Santiago, Chile. E-mail ffigueroa@ 123456uandes.cl

Article

Accession ID: 00019

DOI: 10.1161/CIRCRESAHA.117.310712

PMC ID: 6372053

PubMed ID: 28974553

SO-VID: c80be10c-baac-46af-bb59-ee68d760dc7a

License:

Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

History

Date received : 31 January 2017

Date revision received : 14 August 2017

Date accepted : 24 August 2017

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Keywords: cardiomyopathies,clinical trial,heart failure,mesenchymal stromal cells,umbilical cord

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Keywords: cardiomyopathies, clinical trial, heart failure, mesenchymal stromal cells, umbilical cord

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 [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy])

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Abstract

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Conclusions:

Clinical Trial Registration:

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Most cited references 36

Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.

A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography.

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