Mills William R, Mal Niladri, Kiedrowski Matthew J, Unger Ryan, Forudi Farhad, Popovic Zoran B, Penn Marc S, Laurita Kenneth R
The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109, USA.
J Mol Cell Cardiol. 2007 Feb;42(2):304-14. doi: 10.1016/j.yjmcc.2006.09.011. Epub 2006 Oct 27.
Clinical studies suggest increased arrhythmia risk associated with cell therapy for myocardial infarction (MI); however, the underlying mechanisms are poorly understood. We hypothesize that the degree of electrical viability in the infarct and border zone associated with skeletal myoblast (SKMB) or mesenchymal stem cell (MSC) therapy will determine arrhythmia vulnerability in the whole heart. Within 24 h of LAD ligation in rats, 2 million intramyocardially injected SKMB (n=6), intravenously infused MSC (n=7), or saline (n=7) was administered. One month after MI, cardiac function was determined and novel optical mapping techniques were used to assess electrical viability and arrhythmia inducibility. Shortening fraction was greater in rats receiving SKMB (17.8%+/-5.3%, p=0.05) or MSC (17.6%+/-3.0%, p<0.01) compared to MI alone (10.1%+/-2.2%). Arrhythmia inducibility score was significantly greater in SKMB (2.8+/-0.2) compared to MI (1.4+/-0.5, p=0.05). Inducibility score for MSC (0.6+/-0.4) was significantly lower than SKMB (p=0.01) and tended to be lower than MI. Optical mapping revealed that MSC therapy preserved electrical viability and impulse propagation in the border zone, but SKMB did not. In addition, injected SKMBs were localized to discrete cell clusters where connexin expression was absent. In contrast, infused MSCs engrafted in a more homogeneous pattern and expressed connexin proteins. Even though both MSC and SKMB therapy improved cardiac function following MI in rat, SKMB therapy significantly increased arrhythmia inducibility while MSC therapy tended to lower inducibility. In addition, only MSC therapy was associated with enhanced electrical viability, diffuse engraftment, and connexin expression, which may explain the differences in arrhythmia inducibility.
临床研究表明，心肌梗死（MI）细胞治疗与心律失常风险增加相关；然而，其潜在机制尚不清楚。我们假设，与骨骼肌成肌细胞（SKMB）或间充质干细胞（MSC）治疗相关的梗死区和边缘区的电活动程度将决定全心的心律失常易感性。在大鼠左前降支结扎后24小时内，心肌内注射200万个SKMB（n = 6）、静脉输注MSC（n = 7）或生理盐水（n = 7）。心肌梗死后1个月，测定心脏功能，并使用新型光学映射技术评估电活动和心律失常诱导性。与单纯心肌梗死组（10.1%±2.2%）相比，接受SKMB治疗的大鼠（17.8%±5.3%，p = 0.05）或MSC治疗的大鼠（17.6%±3.0%，p<0.01）的缩短分数更高。与心肌梗死组（1.4±0.5，p = 0.05）相比，SKMB组的心律失常诱导性评分显著更高（2.8±0.2）。MSC组的诱导性评分（0.6±0.4）显著低于SKMB组（p = 0.01），且有低于心肌梗死组的趋势。光学映射显示，MSC治疗可保留边缘区的电活动和冲动传导，但SKMB治疗则不能。此外，注射的SKMB定位于离散的细胞簇，这些细胞簇中缺乏连接蛋白表达。相比之下，输注的MSC以更均匀的模式植入并表达连接蛋白。尽管MSC和SKMB治疗均能改善大鼠心肌梗死后的心脏功能，但SKMB治疗显著增加心律失常诱导性，而MSC治疗则有降低诱导性的趋势。此外，只有MSC治疗与增强的电活动、弥漫性植入和连接蛋白表达相关，这可能解释了心律失常诱导性的差异。
