当时钟敲响时：昼夜节律和心律失常之间的关系建模
When the clock strikes: Modeling the relation between circadian rhythms and cardiac arrhythmias
摘要：
最近观察到，心脏性猝死的发生与一天中的时间有密切的统计关系，即，心室纤维性颤动最有可能发生在上午12点到上午6点之间，下午6点到上午12点是下一个最有可能发生的时间段。因此，人们对了解心脏活动如何受到昼夜节律钟的影响产生了极大的兴趣，即，生理活动的时间振荡，周期接近24小时，与昼夜周期同步。尽管研究已经在细胞内水平确定了昼夜节律的遗传基础，但它们影响心脏病理的机制尚未完全了解。有证据表明，控制心肌细胞兴奋动力学的离子通道蛋白的电导特性的昼夜变化可能提供了关键的联系。在本文中，我们调查的昼夜节律之间的关系，表现在调制的离子通道特性和心律失常的易感性，通过使用一个数学模型，描述了在心室组织的电活动。我们发现，在通道电导的变化，导致在心脏细胞的动作电位的持续时间的极端值可能会导致异常高频折返活动或自发传导阻滞的兴奋波。这两种现象都增加了已知会引发潜在的危及生命的心律失常的波前的可能性。因此，破坏性的心脏兴奋动力学最有可能发生在昼夜循环的时间间隔中，在此期间，通道特性最接近这些极值，从而提供了昼夜节律和心脏病理之间的有趣关系。
英文摘要：
It has recently been observed that the occurrence of sudden cardiac death has a close statistical relationship with the time of day, viz., ventricular fibrillation is most likely to occur between 12 am-6 am, with 6 pm-12 am being the next most likely period. Consequently there has been significant interest in understanding how cardiac activity is influenced by the circadian clock, i.e., temporal oscillations in physiological activity with a period close to 24 hours and synchronized with the day-night cycle. Although studies have identified the genetic basis of circadian rhythms at the intracellular level, the mechanisms by which they influence cardiac pathologies are not yet fully understood. Evidence has suggested that diurnal variations in the conductance properties of ion channel proteins that govern the excitation dynamics of cardiac cells may provide the crucial link. In this paper, we investigate the relationship between the circadian rhythm as manifested in modulations of ion channel properties and the susceptibility to cardiac arrhythmias by using a mathematical model that describes electrical activity in ventricular tissue. We show that changes in the channel conductance that lead to extreme values for the duration of action potentials in cardiac cells can result either in abnormally high-frequency reentrant activity or spontaneous conduction block of excitation waves. Both phenomena increase the likelihood of wavebreaks that are known to initiate potentially life-threatening arrhythmias. Thus, disruptive cardiac excitation dynamics are most likely to occur in time-intervals of the day-night cycle during which the channel properties are closest to these extreme values, providing an intriguing relation between circadian rhythms and cardiac pathologies.
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