Bub Gil, Tateno Katsumi, Shrier Alvin, Glass Leon
Department of Physiology, McGill University, Montreal, Quebec, Canada.
J Cardiovasc Electrophysiol. 2003 Oct;14(10 Suppl):S229-36. doi: 10.1046/j.1540.8167.90315.x.
Complex cardiac arrhythmias often start and stop spontaneously. These poorly understood behaviors frequently are associated with pathologic modification of the structural heterogeneity and functional connectivity of the myocardium. To evaluate underlying mechanisms, we modify heterogeneity by varying the confluence of embryonic chick monolayer cultures that display complex bursting behaviors. A simple mathematical model was developed that reproduces the experimental behaviors and reveals possible generic mechanisms for bursting dynamics in heterogeneous excitable systems.
Wave propagation was mapped in embryonic chick myocytes monolayers using calcium-sensitive dyes. Monolayer confluence was varied by plating cultures with different cell densities and by varying times in culture. At high plating densities, waves propagate without breaks, whereas monolayers plated at low densities display spirals with frequent breaks and irregular activation fronts. Monolayers at intermediate densities display bursting rhythms in which there is paroxysmal starting and stopping of spiral waves of activity. Similar spatiotemporal patterns of activity were also observed as a function of the time in culture; irregular activity dominates the first 30 hours, followed by repetitive bursting dynamics until 54 hours, after which periodic target patterns or stable spirals prevail. In some quiescent cultures derived from older embryos, it was possible to trigger pacemaker activity following a single activation. We are able to reproduce all of these behaviors by introducing spatial heterogeneity and varying neighborhood size, equivalent to cell connectivity, in a spontaneous cellular automaton model containing a rate-dependent fatigue term.
We observe transitions from irregular propagating waves, to spiral waves that spontaneously start and stop, to target waves originating from localized pacemakers in cell culture and a simple theoretical model of heterogeneous excitable media. The results show how physiologic properties of spontaneous activity, heterogeneity, and fatigue can give rise to a wide range of different complex dynamic behaviors similar to clinically observed cardiac arrhythmias.
复杂心律失常常自发起始和终止。这些尚不清楚的行为通常与心肌结构异质性和功能连接性的病理改变有关。为评估潜在机制，我们通过改变表现出复杂爆发行为的胚胎鸡单层培养物的汇合度来改变异质性。建立了一个简单的数学模型，该模型重现了实验行为，并揭示了异质可兴奋系统中爆发动力学的可能通用机制。
使用钙敏染料绘制胚胎鸡心肌细胞单层中的波传播。通过接种不同细胞密度的培养物和改变培养时间来改变单层汇合度。在高接种密度下，波无间断地传播，而低密度接种的单层显示出频繁中断和不规则激活前沿的螺旋波。中等密度的单层表现出爆发节律，其中活动的螺旋波阵发性起始和终止。还观察到类似的时空活动模式随培养时间而变化；不规则活动在前30小时占主导，随后是重复的爆发动力学直至54小时，之后周期性靶波模式或稳定螺旋波占主导。在一些来自较老胚胎的静止培养物中，单次激活后有可能触发起搏器活动。我们能够通过在包含速率依赖性疲劳项的自发细胞自动机模型中引入空间异质性并改变邻域大小（等同于细胞连接性）来重现所有这些行为。
我们在细胞培养和异质可兴奋介质的简单理论模型中观察到从不规则传播波到自发起始和终止的螺旋波，再到源自局部起搏器的靶波的转变。结果表明自发活动、异质性和疲劳的生理特性如何能够产生与临床观察到的心律失常相似的广泛不同的复杂动态行为。
