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.
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.
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DOI：
10.1161/circresaha.114.303180
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发表时间：
2014-04-11
影响因子：
20.1
通讯作者：
Hare JM
中科院分区：
文献类型：
--
作者：
Karantalis V;DiFede DL;Gerstenblith G;Pham S;Symes J;Zambrano JP;Fishman J;Pattany P;McNiece I;Conte J;Schulman S;Wu K;Shah A;Breton E;Davis-Sproul J;Schwarz R;Feigenbaum G;Mushtaq M;Suncion VY;Lardo AC;Borrello I;Mendizabal A;Karas TZ;Byrnes J;Lowery M;Heldman AW;Hare JM
虽然越来越多的数据支持基于心肌细胞的治疗可有效改善接受 CABG 的慢性缺血性心肌病患者的左室功能，但细胞注射部位的潜在机制和影响仍存在争议。间充质干细胞 (MSC) 通过多种作用改善左室结构和功能，包括减少纤维化、新生血管生成和新生肌生成。检验以下假设：心肌内注射自体 MSC 后对心脏结构和功能的影响源于促恢复表型效应的一致性。六名患者因临床原因未接受旁路移植术，将自体 MSC 注射到运动不能/运动减退的心肌区域。 MRI 用于测量基线、3、6 和 18 个月时的疤痕、灌注、壁厚度和收缩力，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。 MRI 变量的综合评分用于评估不同区域抗纤维化效果、灌注和收缩的一致性。 18个月后，与基线相比，接受MSC的受试者表现出LVEF增加（+9.4±1.7%，p=0.0002）和疤痕质量减少（-47.5±8.1%；p<0.0001）。 MSC注射节段在疤痕大小、灌注和收缩改善方面具有一致的减少（一致评分：2.93±0.07），而血运重建（0.5±0.21）和未治疗节段（-0.07±0.34）表现出不一致的变化（与注射节段相比，p<0.0001）。将自体 MSC 心肌内注射到运动不能但未血运重建的节段可产生全面的区域功能恢复，从而推动整体左心室功能的改善。这些发现虽然由于缺乏安慰剂组而尚无定论，但具有重要的治疗和机制假设生成意义。
While accumulating data support the efficacy of intramyocardial cell-based therapy to improve 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. To test the hypothesis that the impact on cardiac structure and function following intramyocardial injections of autologous MSCs results from a concordance of pro-recovery phenotypic effects. 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, 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 LVEF (+9.4±1.7%, p=0.0002) and decreased scar mass (-47.5±8.1%; p<0.0001) compared to 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 non-treated segments (-0.07±0.34) demonstrated non-concordant changes (p<0.0001 vs. injected segments). Intramyocardial injection of autologous MSCs into akinetic yet non-revascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive due to lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications.