Deglurkar Indu, Mal Niladri, Mills William R, Popovic Zoran B, McCarthy Patrick, Blackstone Eugene H, Laurita Kenneth R, Penn Marc S
Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Hum Gene Ther. 2006 Nov;17(11):1144-51. doi: 10.1089/hum.2006.17.1144.
Cell-based gene therapy to alter the myocardial tissue microenvironment has been shown to improve mechanical cardiac function, but little is known regarding its effects on arrhythmogenic risk. Clinical studies with skeletal myoblasts (SKMBs) have suggested a potential increase in arrhythmogenic risk. Therefore, we studied the functional mechanical and electrical effects of transient reestablishment of stem cell homing via transplantation of stromal-cell derived factor-1 (SDF-1)-expressing SKMBs. Eight weeks after anterior myocardial infarction, rats received in five divided doses into the periinfarct zone 1 million SKMBs transfected with AdSDF-1 (n=15) or AdGFP (n=8). Echocardiography was used to quantify changes in cardiac function, and optical mapping was used to determine the arrhythmogenic risk. Eight weeks after cell therapy, we observed a 54% (p=0.004) increase in shortening fraction in AdSDF-1:SKMB-treated rats, but only an 18.8% increase (p=not significant) with GFP:SKMB. SDF-1-treated hearts exhibited an increase in vascular density compared with control SKMBs (34.9+/-7.1 vs. 20.7+/-5.6 vessels/mm2; p<0.01). Optical mapping performed 8 weeks after cell therapy revealed that all animals that received SKMBs regardless of viral transfection had inducible ventricular tachycardia (VT) whereas only 50% of saline-treated animals had inducible VT (p<0.05). Transient reestablishment of stem cell homing via transplantation of modified SKMBs is sufficient to improve cardiac function. However, despite improved mechanical function, the risk of ventricular tachycardia increased. We propose that future studies on functional effects of cell-based gene therapies should address both mechanical and electrical consequences.
基于细胞的基因疗法可改变心肌组织微环境，已被证明能改善心脏机械功能，但对其致心律失常风险的影响却知之甚少。对骨骼肌成肌细胞（SKMBs）的临床研究表明，致心律失常风险可能会增加。因此，我们研究了通过移植表达基质细胞衍生因子-1（SDF-1）的SKMBs来短暂重建干细胞归巢的功能、机械和电效应。在急性心肌梗死后8周，将大鼠分为5组，向梗死周边区域注射100万个用AdSDF-1转染的SKMBs（n = 15）或AdGFP（n = 8）。使用超声心动图来量化心脏功能的变化，并用光学标测来确定致心律失常风险。细胞治疗8周后，我们观察到AdSDF-1:SKMB治疗的大鼠缩短分数增加了54%（p = 0.004），而GFP:SKMB治疗的大鼠仅增加了18.8%（p无统计学意义）。与对照SKMBs相比，SDF-1治疗的心脏血管密度增加（34.9±7.1对20.7±5.6条血管/mm2；p<0.01）。细胞治疗8周后进行的光学标测显示，所有接受SKMBs的动物，无论病毒转染情况如何，均可诱发出室性心动过速（VT），而仅50%的生理盐水治疗动物可诱发出VT（p<0.05）。通过移植改良的SKMBs短暂重建干细胞归巢足以改善心脏功能。然而，尽管机械功能有所改善，但室性心动过速的风险增加了。我们建议，未来关于基于细胞的基因治疗功能效应的研究应同时关注机械和电方面的后果。
