Johnston Peter V, Sasano Tetsuo, Mills Kevin, Evers Robert, Lee Shuo-Tsan, Smith Rachel Ruckdeschel, Lardo Albert C, Lai Shenghan, Steenbergen Charles, Gerstenblith Gary, Lange Richard, Marbán Eduardo
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md, USA.
Circulation. 2009 Sep 22;120(12):1075-83, 7 p following 1083. doi: 10.1161/CIRCULATIONAHA.108.816058. Epub 2009 Sep 8.
Cardiosphere-derived cells (CDCs) isolated from human endomyocardial biopsies reduce infarct size and improve cardiac function in mice. Safety and efficacy testing in large animals is necessary for clinical translation.
Mesenchymal stem cells, which resemble CDCs in size and thrombogenicity, have been associated with infarction after intracoronary infusion. To maximize CDC engraftment while avoiding infarction, we optimized the infusion protocol in 19 healthy pigs. A modified cocktail of CDCs in calcium-free PBS, 100 U/mL of heparin, and 250 microg/mL of nitroglycerin eliminated infusion-related infarction. Subsequent infusion experiments in 17 pigs with postinfarct left ventricular dysfunction showed CDC doses > or =10(7) but <2.5 x 10(7) result in new myocardial tissue formation without infarction. In a pivotal randomized study, 7 infarcted pigs received 300,000 CDCs/kg (approximately 10(7) total) and 7 received placebo (vehicle alone). Cardiac magnetic resonance imaging 8 weeks later showed CDC treatment decreased relative infarct size (19.2% to 14.2% of left ventricle infarcted, P=0.01), whereas placebo did not (17.7% to 15.3%, P=0.22). End-diastolic volume increased in placebo, but not in CDC-treated animals. Hemodynamically, the rate of pressure change (dP/dt) maximum and dP/dt minimum were significantly better with CDC infusion. There was no difference between groups in the ability to induce ventricular tachycardia, nor was there any tumor or ectopic tissue formation.
Intracoronary delivery of CDCs in a preclinical model of postinfarct left ventricular dysfunction results in formation of new cardiac tissue, reduces relative infarct size, attenuates adverse remodeling, and improves hemodynamics. The evidence of efficacy without obvious safety concerns at 8 weeks of follow-up motivates human studies in patients after myocardial infarction and in chronic ischemic cardiomyopathy.
从人的心内膜活检组织中分离出的心肌球衍生细胞（CDCs）可减小小鼠梗死面积并改善心脏功能。对于临床转化而言，在大型动物中进行安全性和有效性测试是必要的。
间充质干细胞在大小和血栓形成性方面与CDCs相似，冠状动脉内注入后曾被发现与梗死有关。为了在避免梗死的同时使CDCs最大程度地植入，我们在19只健康猪中优化了注入方案。一种改良的CDCs混合物，包含无钙PBS、100 U/mL肝素和250 μg/mL硝酸甘油，消除了与注入相关的梗死。随后在17只梗死后左心室功能障碍的猪身上进行的注入实验表明，CDC剂量≥10⁷但<2.5×10⁷可导致新的心肌组织形成而无梗死。在一项关键的随机研究中，7只梗死猪接受300,000个CDCs/kg（总计约10⁷），7只接受安慰剂（仅赋形剂）。8周后的心脏磁共振成像显示，CDC治疗使相对梗死面积减小（左心室梗死面积从19.2%降至14.2%，P = 0.01），而安慰剂组则未减小（从17.7%降至15.3%，P = 0.22）。舒张末期容积在安慰剂组增加，但在接受CDC治疗的动物中未增加。在血流动力学方面，CDC注入后压力变化率（dP/dt）最大值和dP/dt最小值明显更好。两组在诱发室性心动过速的能力上没有差异，也没有出现任何肿瘤或异位组织形成。
在梗死后左心室功能障碍的临床前模型中，冠状动脉内注入CDCs可导致新的心脏组织形成，减小相对梗死面积，减轻不良重塑，并改善血流动力学。在随访8周时无明显安全问题且有疗效证据，这促使开展针对心肌梗死后患者和慢性缺血性心肌病患者的人体研究。
