Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
The EMMES Corporation, Rockville, MD, USA.
Lancet. 2012 Mar 10;379(9819):895-904. doi: 10.1016/S0140-6736(12)60195-0. Epub 2012 Feb 14.
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.
心肌梗死后，心脏球源性细胞（CDCs）可减少瘢痕形成，增加存活心肌，改善心功能。本研究旨在评估此类方法对心肌梗死后左心室功能障碍患者的安全性。
在美国的两家医疗中心，在心肌梗死后 2-4 周（左心室射血分数 25-45%）的患者中，我们开展了前瞻性、随机、对照的 CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction（CADUCEUS）试验。由独立的数据协调中心以 2:1 的比例将患者随机分配至接受 CDC 或标准治疗。对于接受 CDC 的患者，将从心内膜活检标本中生长的自体细胞在心肌梗死后 1.5-3 个月内输注至梗死相关动脉。主要终点是 6 个月时因室性心动过速、心室颤动或突然不明原因死亡，或细胞输注后心肌梗死、MRI 上新的心脏肿瘤形成或主要不良心脏事件（MACE；死亡和因心力衰竭或非致命性复发性心肌梗死而住院的复合终点）而导致的患者比例。我们还在 6 个月时通过 MRI 评估了初步疗效终点。数据分析人员对分组情况设盲。本研究在 ClinicalTrials.gov 注册，编号为 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 名合格患者，其中 25 名患者纳入意向治疗分析（CDC 组 17 名，标准治疗组 8 名）。平均基线左心室射血分数（LVEF）为 39%（SD 12），瘢痕占左心室质量的 24%（10）。活检样本在 36 天内（SD 6）产生了规定的细胞剂量。CDC 输注后 24 小时内未报告任何并发症。在 6 个月时，两组均无患者死亡、发生心脏肿瘤或 MACE。CDC 组有 4 名（24%）患者发生严重不良事件，对照组有 1 名（13%）（p=1·00）。与对照组相比，接受 CDC 治疗的患者在 6 个月时 MRI 分析显示瘢痕质量减少（p=0·001），存活心肌质量增加（p=0·01），局部收缩力增强（p=0·02），局部收缩期壁增厚（p=0·015）。然而，两组在 6 个月时的舒张末期容积、收缩末期容积和 LVEF 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，这为该疗法扩展至 2 期研究提供了依据。我们观察到的存活心肌的显著增加，这与治疗再生一致，值得进一步评估临床结局。
美国国家心肺血液研究所和西达赛奈董事会心脏干细胞中心。
