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Big Ducks in the Heart: Canard Analysis Can Explain Large Early Afterdepolarizations in Cardiomyocytes
SIAM Journal on Applied Dynamical Systems ( IF 1.7 ) Pub Date : 2020-07-22 , DOI: 10.1137/19m1300777
Joshua Kimrey , Theodore Vo , Richard Bertram

SIAM Journal on Applied Dynamical Systems, Volume 19, Issue 3, Page 1701-1735, January 2020.
Early afterdepolarizations (EADs) are pathological voltage fluctuations that can occur in cardiac cells and are a potent source of potentially fatal arrhythmias. Recent works examining the mechanisms underlying EADs in minimal computational cardiac models have revealed that voltage-driven EADs are canard-induced mixed-mode oscillations whose properties are mediated by the rate at which these cells are paced. In this work, we analyze the mechanisms for the pacing-induced generation of different EAD behaviors in a reduced four-dimensional Luo--Rudy I model using slow-fast analysis. While previous explanations for EADs in this model have required manipulation of the underlying multitimescale structure, our approach does not and we find that the canard mechanism persists in generating EADs in this context. We also find that the canard mechanism gives a more complete explanation for the onset and properties of the EADs induced (e.g., EAD amplitude and number). In addition, we also find that the canards play an essential role in producing a richer set of behaviors than were seen in other minimal models, some of which have also been observed in experiments. These behaviors include pacing-induced termination of EADs, the periodic alternation of cardiac action potentials with and without EADs, as well as bistability between standard and EAD-containing action potentials at a fixed pacing rate. Finally, we show that this bistability can lead to hysteretic transitions between standard and arrhythmogenic action potentials under sufficiently slow oscillations in the pacing rate.


中文翻译:

心脏中的大鸭子:Canard分析可以解释心肌细胞的早期大去极化

SIAM应用动力系统杂志,第19卷第3期,第1701-1735页,2020年1月。
早期除极后(EAD)是可能在心脏细胞中发生的病理性电压波动,并且是潜在致命性心律失常的有效来源。最近的研究在最小的心脏计算模型中研究了EAD的基本机制,发现电压驱动的EAD是Canard诱导的混合模式振荡,其特性由这些细胞的起搏速率介导。在这项工作中,我们使用慢速快速分析方法分析了简化的四维Luo-Rudy I模型中起搏诱导不同EAD行为生成的机制。尽管以前在此模型中对EAD的解释要求对基本的多时标结构进行操作,但我们的方法却不需要,并且我们发现canard机制在这种情况下仍然可以生成EAD。我们还发现canard机制对诱导的EAD的发作和性质(例如EAD振幅和数量)给出了更完整的解释。此外,我们还发现,与其他最小模型相比,卡纳德人的行为在产生更丰富的行为方面起着至关重要的作用,其中一些也已在实验中观察到。这些行为包括起搏诱导的EAD终止,有和没有EAD时心脏动作电位的周期性变化,以及在固定起搏速率下标准动作电位和含EAD动作电位之间的双稳态。最后,我们表明,在起搏速度足够慢的振荡下,这种双稳态可以导致标准电位和心律失常作用电位之间的滞后转变。,EAD振幅和数量)。此外,我们还发现,与其他最小模型相比,卡纳德人的行为在产生更丰富的行为方面起着至关重要的作用,其中一些也已在实验中观察到。这些行为包括起搏诱导的EAD终止,有和没有EAD时心脏动作电位的周期性变化,以及在固定起搏速率下标准动作电位和含EAD动作电位之间的双稳态。最后,我们表明,在起搏速率足够缓慢的振荡下,这种双稳态可以导致标准电位和心律失常作用电位之间的滞后转变。,EAD振幅和数量)。此外,我们还发现,与其他最小模型相比,卡纳德人的行为在产生更丰富的行为方面起着至关重要的作用,其中一些也已在实验中观察到。这些行为包括起搏诱导的EAD终止,有和没有EAD时心脏动作电位的周期性变化,以及在固定起搏速率下标准动作电位和含EAD动作电位之间的双稳态。最后,我们表明,在起搏速度足够慢的振荡下,这种双稳态可以导致标准电位和心律失常作用电位之间的滞后转变。实验中也观察到了其中一些。这些行为包括起搏诱导的EAD终止,有和没有EAD时心脏动作电位的周期性变化,以及在固定起搏速率下标准动作电位和含EAD动作电位之间的双稳态。最后,我们表明,在起搏速度足够慢的振荡下,这种双稳态可以导致标准电位和心律失常作用电位之间的滞后转变。实验中也观察到了其中一些。这些行为包括起搏诱导的EAD终止,有和没有EAD时心脏动作电位的周期性变化,以及在固定起搏速率下标准动作电位和含EAD动作电位之间的双稳态。最后,我们表明,在起搏速度足够慢的振荡下,这种双稳态可以导致标准电位和心律失常作用电位之间的滞后转变。
更新日期:2020-07-23
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