自体间充质干细胞应用于接受冠状动脉搭桥术的患者时，可在局部功能、组织灌注和纤维化负担方面产生一致的改善：心脏手术患者间充质干细胞治疗的前瞻性随机研究（PROMETHEUS）试验。
Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial.
作者信息
Karantalis Vasileios, DiFede Darcy L, Gerstenblith Gary, Pham Si, Symes James, Zambrano Juan Pablo, Fishman Joel, Pattany Pradip, McNiece Ian, Conte John, Schulman Steven, Wu Katherine, Shah Ashish, Breton Elayne, Davis-Sproul Janice, Schwarz Richard, Feigenbaum Gary, Mushtaq Muzammil, Suncion Viky Y, Lardo Albert C, Borrello Ivan, Mendizabal Adam, Karas Tomer Z, Byrnes John, Lowery Maureen, Heldman Alan W, Hare Joshua M
机构信息
From the University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL (V.K., D.L.D., R.S., M.M., V.Y.S., A.W.L., J.M.H.); Johns Hopkins University, Cardiovascular Division, Baltimore, MD (G.G., S.S., E.B., J.D.-S., A.C.L.); University of Maryland, Cardiothoracic Surgery, Baltimore, MD (S.P., J.C.); Veterans Affairs Healthcare System, Cardiothoracic Surgery, Miami, FL (J.S., T.Z.K.); Jackson Health System, Cardiology, Miami, FL (J.P.Z.); University of Miami Miller School of Medicine, Radiology, Miami, FL (J.F., P.P.); University of Texas MD Anderson, Stem Cell Transplantation, Houston, TX (I.M.N.), Johns Hopkins University, Heart and Vascular Institute, Baltimore, MD (K.W.), Johns Hopkins University, Comprehensive Transplant Center (A.S.); University of Southern California, Internal Medicine, Los Angeles, CA (G.F.); Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (I.B.); EMMES Corporation, Rockville, MD (A.M.), University of Miami Miller School of Medicine, Hematology/Oncology, Miami, FL (J.B.); and University of Miami Miller School of Medicine, Cardiology, Miami, FL (T.Z.K., M.L.).
出版信息
Circ Res. 2014 Apr 11;114(8):1302-10. doi: 10.1161/CIRCRESAHA.114.303180. Epub 2014 Feb 24.
RATIONALE
Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis.
OBJECTIVE
To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects.
METHODS AND RESULTS
Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4 ± 1.7%, P=0.0002) and decreased scar mass (-47.5 ± 8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93 ± 0.07), whereas revascularized (0.5 ± 0.21) and nontreated segments (-0.07 ± 0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments).
CONCLUSIONS
Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications.
CLINICAL TRIAL REGISTRATION URL
http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.
理论依据
尽管越来越多的数据支持在接受冠状动脉旁路移植术（CABG）的慢性缺血性心肌病患者中，心肌内细胞治疗可改善左心室（LV）功能，但其潜在机制以及细胞注射部位的影响仍存在争议。间充质干细胞（MSC）通过多种作用改善左心室结构和功能，包括减少纤维化、新生血管形成和新肌生成。
目的
检验以下假设，即心肌内注射自体MSC后对心脏结构和功能的影响源于促进恢复的表型效应的一致性。
方法与结果
6例患者因临床原因将自体MSC注射到未接受旁路移植的运动减弱/运动低下心肌区域。在基线、3个月、6个月和18个月时，使用磁共振成像（MRI）测量瘢痕、灌注、壁厚和收缩力，并比较单独接受MSC注射、单独接受血运重建或两者均未接受的区域的结构和功能恢复情况。使用MRI变量的综合评分来评估不同区域抗纤维化作用、灌注和收缩的一致性。18个月后，与基线相比，接受MSC治疗的受试者左心室射血分数增加（+9.4±1.7%，P=0.0002），瘢痕质量减少（-47.5±8.1%；P<0.0001）。注射MSC的节段瘢痕大小、灌注和收缩改善具有一致性（一致性评分：2.93±0.07），而接受血运重建的节段（一致性评分：0.5±0.21）和未治疗的节段（一致性评分：-0.07±0.34）则表现出不一致的变化（与注射节段相比，P<0.0001）。
结论
将自体MSC心肌内注射到运动减弱但未进行血运重建的节段可产生全面的区域功能恢复，进而促进整体左心室功能改善。尽管由于缺乏安慰剂组，这些发现尚无定论，但具有重要的治疗意义并能生成机制假说。
临床试验注册网址
http://clinicaltrials.gov/show/NCT00587990。唯一标识符：NCT00587990。
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