Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
J Am Heart Assoc. 2013 May 17;2(3):e000140. doi: 10.1161/JAHA.113.000140.
BACKGROUND: Intramyocardial injection of mesenchymal stem cells (MSCs) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic MSC therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy. METHODS AND RESULTS: Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (MI), and 3 months post-MI animals received either intramyocardial allogeneic MSC injection (200 mol/L cells; n=6) or left ventricle (LV) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the LV. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3-dimensional cardiac magnetic resonance imaging angiography-derived anatomy to accurately target infarct border zone injections. MSC-treated animals had a 19.62 ± 2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09 ± 2.31% from 3 to 6 months postinjection (P<0.0001). MSC-treated animals had unchanged end-diastolic volume (EDV; P=0.08) and end-systolic volume (ESV; P=0.28) from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002). In addition, MSC-treated animals had improved LV sphericity index. Percentage change in infarct size correlated with percentage change in EDV (r=0.68; P=0.01) and ESV (r=0.77; P=0.001). Ejection fraction increased from 29.69 ± 1.68% to 35.85 ± 2.74% at 3 months post-MSC injection and progressed to 39.02 ± 2.42% 6 months postinjection (P=0.0001), whereas controls had a persistently depressed ejection fraction during follow-up (P=0.33). CONCLUSION: Intramyocardial injection of allogeneic MSCs leads to a sustained and progressive reduction in infarct size, which in turn drives reverse remodeling and increases in ejection fraction. These findings support ongoing biological activity of cell therapy for substantial periods and suggest optimal end points for future clinical trials.
背景：在慢性缺血性心肌病的实验模型和人体中，心肌内注射间充质干细胞（MSCs）与逆重构相关。在此，我们通过检测同种异体 MSC 治疗是否通过持续和渐进性减少缺血性心肌病中的瘢痕大小来驱动心室重构，从而验证假说。
方法和结果：Gottingen 猪（n=12）进行了左前降支冠状动脉心肌梗死（MI），MI 后 3 个月，动物接受心肌内同种异体 MSC 注射（200 μmol/L 细胞；n=6）或左心室（LV）导管插入术而不注射（n=6）。通过连续心脏磁共振成像对猪进行 9 个月的随访，以评估 LV 的结构和功能变化。心肌内注射使用集成的成像平台进行，该平台结合了单极电压的电解剖映射和 3 维心脏磁共振成像血管造影衍生的解剖结构，以准确靶向梗死交界区注射。MSC 治疗组动物在注射后 3 个月时瘢痕大小减少 19.62±2.86%，从 3 个月到 6 个月时进一步减少 28.09±2.31%（P<0.0001）。MSC 治疗组动物在注射前至 6 个月时，舒张末期容积（EDV；P=0.08）和收缩末期容积（ESV；P=0.28）没有变化，而对照组在 EDV（P=0.0002）和 ESV（P=0.0002）均有进行性扩张。此外，MSC 治疗组动物的 LV 球形指数得到改善。梗死面积的百分比变化与 EDV（r=0.68；P=0.01）和 ESV（r=0.77；P=0.001）的百分比变化相关。射血分数从 MSC 注射后 3 个月的 29.69±1.68%增加到 35.85±2.74%，并在 6 个月后进一步增加到 39.02±2.42%（P=0.0001），而对照组在随访期间持续存在射血分数降低（P=0.33）。
结论：心肌内注射同种异体 MSCs 可导致梗死面积持续和渐进性减少，进而推动逆重构和射血分数增加。这些发现支持细胞治疗在相当长的时间内持续发挥生物学活性，并为未来临床试验提供了最佳终点。
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