PCI后干细胞治疗不能改善预后

美国心脏协会(AHA)年会上公布的TIME研究6个月随访结果显示，在ST段抬高型心肌梗死(STEMI)后接受经皮冠脉介入(PCI)治疗的患者中，对梗死区输注骨髓单核细胞(BMC)不能改善左室功能。该研究同时在线发表于《美国医学会杂志》(JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726])。

Jay H. Traverse博士

这项双盲研究由明尼阿波利斯雅培西北医院心脏研究所的Jay H. Traverse博士及其同事开展，共纳入132例符合以下标准的高危患者：3年内曾发生STEMI，左室射血分数(LVEF)≤45%，计划进行PCI和支架置入。患者随机分组，一组在PCI后第3天接受干细胞治疗，另一组在PCI后第7天接受干细胞治疗。手术当天进行骨髓穿刺，分离和贮存BMC。少数患者被排除出研究或退出研究，剩下120例患者接受第2次随机分组，一组接受自体BMC输注(79例)，另一组接受安慰剂输注(41例)。

研究的主要终点是PCI后6个月时MRI扫描所见的总体和局部左室功能的变化情况。结果显示，PCI后3天接受干细胞治疗者的这些预后与PCI后7天接受干细胞治疗者无显著差异。各组在次要终点(如梗死体积缩小情况和心室容积变化情况)方面的差异也不显著。

然而，接受活性BMC输注者的所有预后也与接受安慰剂输注者无显著差异。这可能表明在PCI后立即输注BMI不能改善左室功能。

不过，BMI未能改善左室功能的原因可能也在于，在该人群中使用的BMC产品可能存在表型和功能性方面的问题。另外，从更年轻且更健康的供体获得的同种异体BMC可能具有更好的再生能力。

尽管这些患者具有高度风险，但在随访期间较少发生临床事件。1例患者在干细胞治疗前死于蛛网膜下腔出血。11例患者需再次血运重建，6例使用置入式心脏复律除颤器。在各组中，这些不良事件的发生率无显著差异。

研究者表示，虽然6个月的随访结果显示，PCI后3天或7天输注BMC在改善左室功能恢复、改善左室容积和降低梗死面积方面的效果均不优于安慰剂，但通过更长期的随访和采用新的复合终点来评估，或许仍可发现这种细胞在急性心肌梗死后所起的作用。

该研究获美国国立心肺血液研究所资助。Traverse博士声明无经济利益冲突，但其同事与多家药企存在多种联系。

随刊述评：研究结果难以解读

洛杉矶西达斯-西奈心脏研究所的Eduardo Marban博士和Konstantinos Malliaras博士表示，这项研究目的明确、设计严谨且执行严格，但结果难以解读。这既可能是因为这种治疗对该患者人群无效，也可能是因为该研究使用的细胞产品存在一些不足(JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.64751])。

Marban博士是心脏干细胞治疗开发公司Capricor的创立者，他和Malliaras博士与该公司存在利益联系。

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By: MARY ANN MOON, Cardiology News Digital Network

Intracoronary delivery of bone marrow mononuclear cells to the infarct zone of patients who have undergone percutaneous coronary intervention following an ST-segment elevation myocardial infarction did not improve left ventricular function at 6 months in the TIME trial.

The trial was designed to examine the difference in effect of infusing the bone marrow mononuclear cells (BMCs) into the infarct-related artery at 7 days after PCI and at 3 days, Dr. Jay H. Traverse reported at the annual scientific sessions of the American Heart Association.

Unfortunately, neither of these approaches were any better than placebo infusion at improving the recovery of left ventricular function, improving left ventricular volume, or reducing infarct size at 6 months’ follow-up in this double-blind Timing in Myocardial Infarction Evaluation (TIME) clinical trial, said Dr. Traverse, of the Minneapolis Heart Institute at Abbott Northwestern Hospital.

"However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI [acute myocardial infarction]," Dr. Traverse and his associates said in an article published online simultaneously with his presentation (JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726]).

Recent research indicates that the timing of BMC infusion after PCI due to ST-segment elevation myocardial infarction (STEMI) might be critical. In the days following STEMI, there are significant temporal changes in the release of cytokines and growth factors "that may support stem-cell homing and angiogenesis, leading to improved cell survival and engraftment," they noted.

"Conversely, reactive oxygen species and inflammatory cytokines ... released by [damaged] myocardium and circulating inflammatory cells may adversely affect the bone marrow and stem cell function and/or survival." This could in turn impair the quality and potency of BMCs harvested from the patient.

The results of one large study indicated that stem cells harvested 5-7 days after an acute MI performed better than those harvested earlier, but "this important variable has never been evaluated in a prospective trial that randomly selects the day of cell delivery," the researchers said.

The TIME trial was designed to do so.

A total of 132 high-risk patients were enrolled during a 3-year period after they had experienced STEMI, shown a left ventricular ejection fraction (LVEF) of 45% or less, and were slated for PCI with stenting. These subjects were randomly assigned to have stem cell therapy on either day 3 or day 7 after PCI; they underwent bone marrow aspiration on the day of the procedure, and their BMCs were isolated and stored.

After some of these patients were excluded or withdrawn from the study, the remaining 120 patients underwent a second randomization to receive either the autologous BMCs (79 patients) or placebo infusions (41 patients).

The primary end points of TIME were changes in global and regional left ventricular function on MRI scanning at 6 months post PCI. There were no significant differences in these outcomes between subjects who received stem-cell therapy 3 days after PCI and those who received it 7 days after PCI, the investigators reported.

There also were no significant differences among the study groups in secondary outcomes such as reduction in infarct volume or change in ventricular volumes.

However, there also were no significant differences in any outcomes between subjects who received active BMCs and those who received placebo infusions. This may indicate that, contrary to previous findings, BMCs do not improve left ventricular function when administered in the immediate post-STEMI setting.

But it also is possible that "the phenotype and functionality of the BMC product in this population may be an issue," and that allogeneic BMCs procured from younger, healthier donors may have a better regenerative capacity, Dr. Traverse and his colleagues said.

It was encouraging that despite their high risk, these study subjects had few clinical events during follow-up. One death occurred (due to subarachnoid hemorrhage) before stem-cell therapy was administered. Eleven patients required repeat revascularization, and 6 received implantable cardioverter-defibrillators (ICDs). There were no significant differences among the study groups in the rates of these adverse events.

This study was funded by the National Heart, Lung, and Blood Institute. Dr. Traverse reported no financial conflicts of interest, but his associates reported numerous ties to industry sources.