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]).

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; 1×106 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. 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.

[Long-term results of intracoronary transplantation of autologous bone marrow cells in dilated cardiomyopathy]. / Resultados a largo plazo del trasplante intracoronario de células mononucleares de médula ósea autólogas en pacientes con cardiopatía dilatada de diversa etiología.

BACKGROUND: Intracoronary delivery of autologous bone marrow mononuclear cells is an interesting therapeutic promise for patients with heart failure of different etiologies. AIM: To evaluate the long-term safety and efficacy of this therapy in patients with dilated cardiomyopathy of different etiologies under optimal medical treatment. PATIENTS AND METHODS: Prospective, open-label, controlled clinical trial. Of 23 consecutive patients, 12 were assigned to autologous bone marrow mononuclear cell intracoronary transplantation, receiving a mean dose of 8.19 ± 4.43 x 10(6) CD34+ cells. Mortality, cardiovascular readmissions and cancer incidence rate, changes in functional capacity, quality of life questionnaires and echocardiographic measures from baseline, were assessed at long-term follow-up (37.7 ± 9.7 months) in patients receiving or not the cells. RESULTS: No significant differences were observed in mortality, cardiovascular readmissions or cancer incidence rate amongst groups. An improvement in functional class and quality of life questionnaires in the transplanted group was observed (p < 0.01). The treated group showed a non-significant increase in left ventricular ejection fraction at long-term follow-up (from 26.75 ± 4.85% to 34.90 ± 8.57%, p = 0.059 compared to baseline). There were no changes in left ventricular volumes. We observed no improvement of these variables in the control group. CONCLUSIONS: Intracoronary transplantation of autologous bone marrow mononuclear cells is feasible and safe in patients with dilated cardiomyopathy of diverse etiologies. This therapy was associated to persistent improvements in functional class and quality of life. There was also a non-significant long-term improvement of left ventricular function.

Resultados a largo plazo del trasplante intracoronario de células mononucleares de médula ósea autólogas en pacientes con cardiopatía dilatada de diversa etiología / Long-term results of intracoronary transplantation of autologous bone marrow cells in dilated cardiomyopathy

Background: Intracoronary delivery of autologous bone marrow mononuclear cells is an interesting therapeutic promise for patients with heart failure of different etiologies. Aim: To evaluate the long-term safety and efficacy of this therapy in patients with dilated cardiomyopathy of different etiologies under optimal medical treatment. Patients and Methods: Prospective, open-label, controlled clinical trial. Of 23 consecutive patients, 12 were assigned to autologous bone marrow mononuclear cell intracoronary transplantation, receiving a mean dose of 8.19 ± 4.43 x 10(6) CD34+ cells. Mortality, cardiovascular readmissions and cancer incidence rate, changes in functional capacity, quality of life questionnaires and echocardiographic measures from baseline, were assessed at long-term follow-up (37.7 ± 9.7 months) in patients receiving or not the cells. Results: No significant differences were observed in mortality, cardiovascular readmissions or cancer incidence rate amongst groups. An improvement in functional class and quality of life questionnaires in the transplanted group was observed (p < 0.01). The treated group showed a non-significant increase in left ventricular ejection fraction at long-term follow-up (from 26.75 ± 4.85% to 34.90 ± 8.57%, p = 0.059 compared to baseline). There were no changes in left ventricular volumes. We observed no improvement of these variables in the control group. Conclusions: Intracoronary transplantation of autologous bone marrow mononuclear cells is feasible and safe in patients with dilated cardiomyopathy of diverse etiologies. This therapy was associated to persistent improvements in functional class and quality of life. There was also a non-significant long-term improvement of left ventricular function.

El trasplante intracoronario de células mononucleares de médula ósea se asocia a mejoría la función ventricular izquierda, en pacientes con cardiopatía dilatada de diferente etiología: Proyecto INNOVA Chile N°205-4350 / Autologous bone marrow cell transplantation improves ejection fraction in patients with dilated cardiomyopathy of diverse etiologies: Proyecto innova chile n° 205-4350

Introducción: Estudios recientes indican que el trasplante intracoronario de células mononucleares de médula ósea (BMCs) autólogas, mejoran la fracción de eyección (FEVI) y otros marcadores clínicos en pacientes con insuficiencia cardíaca (IC). Objetivo: Evaluar la seguridad y eficacia de la administración intracoronaria de BMCs autólogas, en pacientes con insuficiencia cardíaca (IC) en fase dilatada, de diferente etiología y en óptimas condiciones de tratamiento médico. Método: De 23 pacientes consecutivos que cumplieron con los criterios de inclusión, 12 fueron asignados a trasplante intracoronario de BMCs autólogas, recibiendo una dosis media de 8.19+/-4.43 x 10(6) células CD34+ (Grupo trasplantado). Los pacientes restantes sólo recibieron terapia estándar (Grupo control). Todos los pacientes fueron evaluados mediante Electrocardiograma, Ecocardiografía, Holter ECG, RMN Cardíaca, Test de esfuerzo, Potenciales Ventriculares Tardíos, Variabilidad de Frecuencia Cardíaca y evaluación clínica a los 0, 3, 6 y 12 meses. La capacidad funcional (CF) fue evaluada clínicamente y por cuestionarios de calidad de vida. Elanálisis estadístico fue realizado mediante Test Anova, y test de Bonferroni. Resultados: El grupo trasplantado presentó un aumento significativo de la FEVI a los 6 meses (26.75+/-4.85 vs 37.82+/-6.97 por ciento, p=0.001) mejoría que se mantuvo a los 12 meses (26.75+/-4.85 vs 37.27+/-7.51 por ciento, p=0.002). Hubo una mejora significativa de la CF en el grupo trasplantado a los 6 y 12 meses (p<0.001). No hubo cambios significativos en los volúmenes de ventrículo izquierdo, así como en las restantes variables estudiadas. En el grupo control no observamos cambios de estas variables. No hubo complicaciones en relación al trasplante de BMCs. Conclusión: En pacientes con IC severa y baja FEVI, el trasplante intracoronario de células BMCs au-tólogas, se asoció a una mejoría significativa de la FEVI y la CF, a los 6 y 12 meses. Adicionalmente, no observamos ...

Background: Recent studies indicate that intra-coronary delivery of autologous bone marrow mono-nuclear cells (BMCs) improves the ejection fraction (LVEF) and other clinical markers in patients with heart failure (HF). Aim: To evaluate the safety and efficacy of intraco-ronary delivery of autologous BMCs in patients with HF in dilated phase under optimal medical treatment. Method: Of 23 consecutive patients who met the inclusion criteria, 12 were assigned to autologous BMCs intracoronary transplantation, receiving a mean dose of 8.19+/-4.43 x 106 CD34+ cells (BMCs group). The remaining patients received only standard therapy (control group). All patients were evaluated by Electrocardiogram, Echocardiography, Holter Monitoring, Cardiac Magnetic Resonance Imaging, Stress Testing, Ventricular Late potetials, Heart Rate Variability, and regular clinical examination at baseline and at follow-up (3, 6 and 12 months). Repeated measures ANOVA and Bonferroni testing were used for statistic analysis. Results: The BMCs group presented a significant increase in EF at sixth months (26.75+/-4.85 vs. 37.82+/-6.97 per cent, p=0.001) and 12 months post-transplant (26.75+/-4.85 vs. 37.27+/-7.51 per cent, p=0.002). There was a significant improvement in functional (NYHA) in the transplanted group at 6 and 12 months (p<0.001). There were no significant changes concerning left ventricular volumes, heart rate variability and exercise stress testing. We observed no improvement of these variables in the control group. There were no complications related to the BMCs transplant. Conclusions: Intracoronary infusion of auto-logous BMCs, in addition to standard therapy, was associated with significant improvement of left ventricular function at 12 months in patients with HF. We observed no complications relative to the procedure.