Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy.
Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy.
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DOI：
10.1371/journal.pone.0113805
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Marbán E
中科院分区：
文献类型：
--
作者：
Yee K;Malliaras K;Kanazawa H;Tseliou E;Cheng K;Luthringer DJ;Ho CS;Takayama K;Minamino N;Dawkins JF;Chowdhury S;Duong DT;Seinfeld J;Middleton RC;Dharmakumar R;Li D;Marbán L;Makkar RR;Marbán E
心外膜注射心脏来源的细胞产品是安全和有效的心肌梗死后（MI），但临床上可翻译的transendocardial注射从来没有被评估。我们试图评估经皮经血管内注射心脏来源的细胞在猪慢性缺血性心肌病中的可行性、安全性和有效性。我们共研究了89头小型猪; 63头完成了指定的方案。在NOGA引导的经内皮素注射后，我们定量了MI后小型猪（n = 22）中逐渐增加剂量的同种异体心脏球或心脏球衍生细胞的植入。 接下来，在梗塞的小型猪（n = 16）中进行经内皮素注射更好的移植产品的剂量范围、盲法、随机化、安慰剂对照（“剂量优化”）研究。 最后，在一项设盲、随机、安慰剂对照（“关键”）研究（n = 22）中测试了上级产品和剂量（1.5亿个心脏微球）。 对比度增强心脏MRI显示，所有剂量的cardiosphere均保留了收缩功能并减弱了重塑。最大可行剂量（1.5亿个细胞）在减少瘢痕大小、增加存活心肌和改善射血分数方面最有效。在关键性研究中，注射后8周，组织病理学显示，与对照组相比，给药小型猪中无过度炎症，也无肌细胞肥大。随着时间的推移，没有产生同种异体反应性供体特异性抗体。MRI显示，与安慰剂组相比，治疗组瘢痕大小减小，存活质量增加，心脏扩张减弱，对射血分数无影响。在猪慢性缺血性心肌病中，同种异体心脏微球的剂量优化注射是安全的，可减小瘢痕大小，增加存活心肌，并减弱心脏扩张。瘢痕大小的减少，反映了存活心肌的增加，与治疗性再生一致。
Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy. We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled (“dose optimization”) study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled (“pivotal”) study (n = 22). Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo. Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration.
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