Kanazawa Hideaki, Tseliou Eleni, Dawkins James F, De Couto Geoffrey, Gallet Romain, Malliaras Konstantinos, Yee Kristine, Kreke Michelle, Valle Ileana, Smith Rachel R, Middleton Ryan C, Ho Chak-Sum, Dharmakumar Rohan, Li Debiao, Makkar Raj R, Fukuda Keiichi, Marbán Linda, Marbán Eduardo
Cedars-Sinai Heart Institute, Los Angeles, CA Department of Cardiology, Keio University School of Medicine, Shinjuku Tokyo, Japan.
Cedars-Sinai Heart Institute, Los Angeles, CA.
J Am Heart Assoc. 2016 Feb 8;5(2):e002796. doi: 10.1161/JAHA.115.002796.
Infusion of allogeneic cardiosphere-derived cells (allo-CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long-term effects of allo-CDCs have not been assessed. We performed a placebo-controlled pivotal study for long-term evaluation, as well as shorter-term mechanistic studies.
Minipigs underwent 1.5-hour mid-left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo-CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC-treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo-CDC infusion. In addition, allo-CDCs improved regional function and decreased hypertrophy 2 months post-treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo-CDC-treated pigs at 2 months. Allo-CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short-term experiments designed to probe mechanism revealed antiapoptotic effects of allo-CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy.
Allo-CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits.
再灌注后输注同种异体心球衍生细胞（allo-CDCs）可在急性心肌梗死猪中引发心脏保护细胞后适应。然而，allo-CDCs的长期影响尚未得到评估。我们进行了一项安慰剂对照的关键研究以进行长期评估以及短期机制研究。
小型猪接受1.5小时左前降支中段球囊闭塞，随后进行再灌注，并在再灌注后30分钟随机接受冠状动脉内allo-CDCs或赋形剂。左心室造影（LVG）显示，接受CDC治疗的猪的射血分数（EF）得以保留，左心室重构减轻。在治疗后1小时和8周对猪进行心脏磁共振成像（MRI）和LVG以评估疗效。MRI显示allo-CDC输注后立即出现EF改善和左心室重构减轻。此外，allo-CDCs在治疗后2个月改善了局部功能并减轻了肥厚。组织学分析显示，在2个月时，接受allo-CDC治疗的猪梗死区的心肌挽救指数增加、血管生成增强、梗死面积/危险面积和瘢痕透壁性持续减小，以及胶原沉积减轻。allo-CDCs未引起淋巴细胞组织细胞浸润或全身体液记忆反应。旨在探究机制的短期实验显示，allo-CDCs对心肌细胞具有抗凋亡作用，并增加了细胞保护性巨噬细胞，但在细胞治疗后2小时总体炎症细胞浸润未增加。
再灌注后输注allo-CDCs是安全的，可改善心脏功能，并减小瘢痕大小和减轻重构。治疗后至少2个月这些有益作用持续存在。因此，细胞后适应不仅赋予急性心脏保护作用，还带来持久的结构和功能益处。
