Spiral waves and reentry dynamics in an in vitro model of the healed infarct border zone.
Spiral waves and reentry dynamics in an in vitro model of the healed infarct border zone.
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DOI：
10.1161/circresaha.108.176248
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发表时间：
2009-11-20
影响因子：
20.1
通讯作者：
Abraham MR
中科院分区：
文献类型：
--
作者：
Chang MG;Zhang Y;Chang CY;Xu L;Emokpae R;Tung L;Marbán E;Abraham MR
心肌梗死（MI）后出现的大多数室性心动过速（VT）的基础是折返。标测研究表明，大多数室性心动过速发生在心肌梗死后晚期，起源于梗死边缘区（IBZ）。在IBZ愈合的体外模型中研究折返动力学和单个离子通道在折返中的作用。我们设计了体外模型的愈合IBZ共培养骨骼肌管（SkM）与新生大鼠心室肌细胞（NRVMs），并进行光学映射在高的时间和空间分辨率。在培养中，NRVM成熟形成横纹肌细胞，电解偶联的SkM模拟在愈合的IBZ中观察到的纤维化。高分辨率映射显示，SkMs产生局部传导速度（CV）减慢，增加CV的离散度和方向依赖性的激活延迟，而不影响心肌细胞的兴奋性。在共培养物中，快速起搏容易诱导折返;利多卡因（一种Na+通道阻滞剂）治疗显著降低折返率和CV，增加折返路径长度并终止30%的折返性心律失常（n=18）。与此相反，尼群地平，L-型钙通道（LTCC）阻滞剂终止100%的折返发作，同时增加折返周期长度和路径长度和降低折返CV（n=16）。K+通道阻滞剂增加折返APD，但很少终止折返（n=12）。共培养再现了愈合的IBZ的几个建筑和EP特征。再入终止LTCC，但不是Na+通道阻滞剂表明一个更大的Ca 2+依赖性的传播。这些结果可能有助于解释纯Na+通道阻滞剂在预防和终止MI后晚期临床VT方面的低疗效。
Reentry underlies most ventricular tachycardias (VT) seen post-myocardial infarction (MI). Mapping studies reveal that the majority of VTs late post-MI arise from the infarct border-zone (IBZ). To investigate reentry dynamics and the role of individual ion channels on reentry in in vitro models of the healed IBZ. We designed in vitro models of the healed IBZ by co-culturing skeletal myotubes (SkM) with neonatal rat ventricular myocytes (NRVMs) and performed optical mapping at high temporal and spatial resolution. In culture, NRVMs mature to form striated myocytes and electrically uncoupled SkMs simulate fibrosis seen in the healed IBZ. High resolution mapping revealed that SkMs produced localized slowing of conduction velocity (CV), increased dispersion of CV and directional-dependence of activation delay without affecting myocyte excitability. Reentry was easily induced by rapid pacing in co-cultures; treatment with lidocaine, a Na+ channel blocker, significantly decreased reentry rate and CV, increased reentry pathlength and terminated 30% of reentrant arrhythmias (n=18). In contrast, nitrendipine, an L-type Ca2+ channel (LTCC) blocker terminated 100% of reentry episodes while increasing reentry cycle length and pathlength and decreasing reentry CV (n=16). K+ channel blockers increased reentry APD, but infrequently terminated reentry (n=12). Co-cultures reproduce several architectural and EP features of the healed IBZ. Reentry termination by LTCC, but not Na+ channel blockers suggests a greater Ca2+-dependence of propagation. These results may help explain the low efficacy of pure Na+ channel blockers in preventing and terminating clinical VTs late after MI.