Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.
Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.
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DOI：
10.1016/s0140-6736(12)60195-0
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发表时间：
2012-03-10
期刊：
影响因子：
168.9
通讯作者：
Marban, Eduardo
中科院分区：
文献类型：
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作者：
Makkar, Raj R.;Smith, Rachel R.;Cheng, Ke;Malliaras, Konstantinos;Thomson, Louise E. J.;Berman, Daniel;Czer, Lawrence S. C.;Marban, Linda;Mendizabal, Adam;Johnston, Peter V.;Russell, Stuart D.;Schuleri, Karl H.;Lardo, Albert C.;Gerstenblith, Gary;Marban, Eduardo
心肌球衍生细胞（CDCs）在临床前模型中可减少心肌梗死后的瘢痕形成，增加有活力的心肌，并提高心脏功能。我们旨在评估这种方法在心肌梗死后左心室功能障碍患者中的安全性。
在这项前瞻性、随机的“心肌球衍生自体干细胞逆转心室功能障碍”（CADUCEUS）试验中，我们在美国的两个医疗中心招募了心肌梗死后2 - 4周的患者（左心室射血分数为25% - 45%）。一个独立的数据协调中心以2∶1的比例将患者随机分配接受CDCs治疗或标准治疗。对于被分配接受CDCs治疗的患者，从心内膜心肌活检标本中培养的自体细胞在心肌梗死后1.5 - 3个月被注入梗死相关动脉。主要终点是6个月时因室性心动过速、心室颤动或突发意外死亡，或在细胞输注后发生心肌梗死、磁共振成像（MRI）显示新的心脏肿瘤形成，或发生主要不良心脏事件（MACE；死亡以及因心力衰竭或非致命性复发性心肌梗死住院的复合事件）的患者比例。我们还评估了6个月时MRI的初步疗效终点。数据分析人员对分组情况不知情。本研究在ClinicalTrials.gov注册，编号NCT00893360。
在2009年5月5日至2010年12月16日期间，我们随机分配了31名符合条件的参与者，其中25名纳入符合方案分析（17名在CDC组，8名在标准治疗组）。平均基线左心室射血分数（LVEF）为39%（标准差12），瘢痕占左心室质量的24%（10）。活检样本在36天（标准差6）内产生了规定的细胞剂量。在CDC输注后的24小时内未报告有并发症。到6个月时，两组均无患者死亡、发生心脏肿瘤或出现MACE。CDC组有4名患者（24%）发生严重不良事件，而对照组有1名（13%；p = 1.00）。与6个月时的对照组相比，接受CDCs治疗的患者的MRI分析显示瘢痕质量减少（p = 0.001），有活力的心脏质量增加（p = 0.01），局部收缩力增强（p = 0.02），以及局部收缩期室壁增厚（p = 0.015）。然而，到6个月时，两组之间舒张末期容积、收缩末期容积和LVEF的变化没有差异。
我们表明心肌梗死后冠状动脉内输注自体CDCs是安全的，这为将这种治疗扩展到2期研究提供了依据。我们所观察到的有活力心肌的空前增加与治疗性再生一致，值得进一步评估临床结果。
美国国家心肺血液研究所和西达赛奈理事会心脏干细胞中心
Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction. In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2–4 weeks after myocardial infarction (with left ventricular ejection fraction of 25–45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5–3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360. Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.