心力衰竭患者静脉输注脐带间充质干细胞的安全性和有效性：一项1/2期随机对照试验（RIMECARD试验[静脉输注脐带间充质干细胞治疗心脏病的随机临床试验]）
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]).
作者信息
Bartolucci Jorge, Verdugo Fernando J, González Paz L, Larrea Ricardo E, Abarzua Ema, Goset Carlos, Rojo Pamela, Palma Ivan, Lamich Ruben, Pedreros Pablo A, Valdivia Gloria, Lopez Valentina M, Nazzal Carolina, Alcayaga-Miranda Francisca, Cuenca Jimena, Brobeck Matthew J, Patel Amit N, Figueroa Fernando E, Khoury Maroun
机构信息
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.).
出版信息
Circ Res. 2017 Oct 27;121(10):1192-1204. doi: 10.1161/CIRCRESAHA.117.310712. Epub 2017 Sep 26.
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 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 (=0.0167 versus baseline) and cardiac MRI (=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%; =0.028). In addition, at all follow-up time points, UC-MSC-treated patients displayed improvements of New York Heart Association functional class (=0.0167 versus baseline) and Minnesota Living with Heart Failure Questionnaire (<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.
原理
脐带间充质干细胞（UC-MSC）易于获取且能在体外扩增，具有独特特性，并能改善心血管疾病实验模型中的心肌重塑和功能。尽管此前已评估过骨髓间充质干细胞对射血分数降低的心力衰竭患者的治疗潜力，但尚无临床试验评估过对这些患者静脉输注UC-MSC的效果。
目的
评估对慢性稳定型心力衰竭且射血分数降低的患者静脉输注UC-MSC的安全性和疗效。
方法与结果
接受最佳药物治疗的射血分数降低的心力衰竭患者被随机分为接受异体UC-MSC静脉输注组（Cellistem，Cells for Cells S.A.，智利圣地亚哥；1×10个细胞/千克）或安慰剂组（每组15例）。与骨髓间充质干细胞相比，UC-MSC在体外肝细胞生长因子的表达增加了55倍，已知该因子参与肌生成、细胞迁移和免疫调节。接受UC-MSC治疗的患者未出现与细胞输注相关的不良事件，在0、15和90天检测时，没有患者出现针对UC-MSC的同种抗体（n = 7）。仅接受UC-MSC治疗的组在随访3、6和12个月时，经胸超声心动图评估（与基线相比P = 0.0167）和心脏磁共振成像评估（与基线相比P = 0.025）的左心室射血分数均有显著改善。两组从基线到第12个月的超声心动图左心室射血分数变化有显著差异（+7.07±6.22% 对 +1.85±5.60%；P = 0.028）。此外，在所有随访时间点，接受UC-MSC治疗的患者纽约心脏协会心功能分级均有改善（与基线相比P = 0.0167），明尼苏达心力衰竭生活问卷评分也有改善（与基线相比P<0.05）。在研究结束时，两组在死亡率、心力衰竭住院率、心律失常或新发恶性肿瘤方面无差异。
结论
对这组接受最佳药物治疗的稳定型心力衰竭且射血分数降低的患者静脉输注UC-MSC是安全的。接受UC-MSC治疗的患者左心室功能、功能状态和生活质量均有改善。
临床试验注册
网址：https://www.clinicaltrials.gov/ct2/show/NCT01739777。唯一标识符：NCT01739777。
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