Current status and future prospects for cell transplantation to prevent congestive heart failure.
Current status and future prospects for cell transplantation to prevent congestive heart failure.
复制标题
DOI：
10.1053/j.semtcvs.2008.03.001
复制
发表时间：
2008-06
影响因子：
2.5
通讯作者：
P. Menasché
中科院分区：
文献类型：
--
作者：
P. Menasché
尽管大多数心脏细胞疗法试验都集中在急性心肌梗死患者身上，但也有人尝试“再生”慢性衰竭的心脏。这些研究需要使用骨骼肌成肌细胞和骨髓来源的细胞。在骨骼肌成肌细胞的情况下，随机安慰剂对照的成肌细胞自体移植治疗缺血性心肌病（MAGIC）试验未能显示成肌细胞注射增加射血分数超过对照组，但发现最高剂量的成肌细胞与安慰剂组相比具有显著的抗重塑作用，这提供了一个令人鼓舞的信号。在骨髓细胞的情况下，手术注射的单核细胞部分结合冠状动脉搭桥手术没有显示出实质性的好处，但积极的结果已报告与术中心外膜注射CD133（+）祖细胞。这些好坏参半的结果可能有三个原因。首先是细胞功能的显著异质性（特别是在骨髓的情况下），这将不可避免地转化为可变的临床结果。第二个原因是持续植入率低。第三种可能的解释是终点的选择和细胞作用的假定机制之间的不匹配。最初的假设是成体干细胞可以影响心肌组织再生，这导致通常将射血分数作为主要的替代终点。现在越来越多的人认识到，与胚胎干细胞相比，成体干细胞几乎没有再生能力，而且它们的假定有益作用更可能涉及旁分泌信号，在这种情况下，梗死面积、灌注或左心室容积可能是更合适的标志物。总之，这些观察结果为未来的研究提供了一个框架，其结果将被整合到第二代临床试验的方案设计中。
Although most cardiac cell therapy trials have focused on patients with acute myocardial infarction, attempts at "regenerating" chronically failing hearts have also been performed. These studies have entailed use of skeletal myoblasts and bone marrow-derived cells. In the case of skeletal myoblasts, the randomized placebo-controlled myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial has failed to show that myoblast injections increased ejection fraction beyond that seen in controls but the finding that the highest dose of myoblasts resulted in a significant antiremodeling effect compared with the placebo group provides an encouraging signal. In the case of bone marrow cells, surgical injections of the mononuclear fraction combined with coronary artery bypass surgery have not shown a substantial benefit but positive results have been reported with intraoperative epicardial injections of CD133(+) progenitors. There are three possible reasons for these mixed results. The first is the marked heterogeneity of cell functionality (particularly in the case of bone marrow), which would expectedly translate into variable clinical outcomes. The second reason is the low rate of sustained engraftment. The third possible explanation is a mismatch between the choice of end points and the presumed mechanism of action of the cells. The initial assumption that adult stem cells could effect myocardial tissue regeneration has led to usual focus on ejection fraction as the major surrogate endpoint. It is now increasingly recognized that adult stem cells, in contrast to their embryonic counterparts, have little if any regenerative capacity and that their presumed beneficial effects more likely involve paracrine signaling, in which case infarct size, perfusion, or left ventricular volumes might be more appropriate markers. Altogether, these observations provide a framework for future research, the results of which will then have to be integrated in the protocol design of second-generation clinical trials.