New insights on the cardiac safety factor: Unraveling the relationship between conduction velocity and robustness of propagation
New insights on the cardiac safety factor: Unraveling the relationship between conduction velocity and robustness of propagation
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DOI：
10.1016/j.yjmcc.2019.01.010
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发表时间：
2019-03-01
影响因子：
5
通讯作者：
Vigmond, Edward J.
中科院分区：
文献类型：
--
作者：
Boyle, Patrick M.;Franceschi, William H.;Vigmond, Edward J.
心传导障碍与心律失常的发生有关。安全系数（SF）的概念已经被导出来描述传导的鲁棒性，但是这个度量的有用性受到一些限制。例如，由于难以测量必要的输入变量，SF计算只应用于合成数据。此外，SF缺乏定量验证；具体来说，除了传播失败（即传导阻滞）以SF < 1为特征外，特定SF值的实际意义尚不清楚。本研究旨在解决我们之前发表的SF配方的这些局限性，并探讨其与心脏组织相关电生理特性的关系。首先，在多电极阵列上培养HL-1心肌细胞单层，并使用细胞外电位记录估计繁殖的稳健性。单纯从实验数据重建的SF值大部分在1 ~ 5之间（高达89.1%的特征位点）。该范围与合成数据得出的值一致，证明该公式是合理的，其适用性不仅限于计算模型的分析。其次，对于在1、2和3维组织块中进行的模拟，我们计算了亚阈值和超阈值刺激下电流注射部位周围位置的真实SF值，发现它们与我们的SF公式估计的值相差< 10%。最后，我们检查了与心律失常发展相关条件下的SF动力学，以提供生理学上的见解。我们的分析表明，由细胞内兴奋性受损（例如，由于钠电流的功能丧失突变）引起的传导速度（θ）降低与传导强度降低（即SF降低）有关；然而，有趣的是，由组织尺度电导率调节引起的Theta变异性对SF没有影响。这些发现得到了第一原理相关关系的解析推导的支持。我们的结论是，我们的SF公式可以应用于实验和合成数据，它产生的值与传播所需的多余电荷呈线性变化。SF计算可以为理解心律失常的发生和持续提供有帮助的见解。
Cardiac conduction disturbances are linked with arrhythmia development. The concept of safety factor (SF) has been derived to describe the robustness of conduction, but the usefulness of this metric has been constrained by several limitations. For example, due to the difficulty of measuring the necessary input variables, SF calculations have only been applied to synthetic data. Moreover, quantitative validation of SF is lacking; specifically, the practical meaning of particular SF values is unclear, aside from the fact that propagation failure (i.e., conduction block) is characterized by SF < 1. This study aims to resolve these limitations for our previously published SF formulation and explore its relationship to relevant electrophysiological properties of cardiac tissue. First, HL-1 cardiomyocyte monolayers were grown on multi-electrode arrays and the robustness of propagation was estimated using extracellular potential recordings. SF values reconstructed purely from experimental data were largely between 1 and 5 (up to 89.1% of sites characterized). This range is consistent with values derived from synthetic data, proving that the formulation is sound and its applicability is not limited to analysis of computational models. Second, for simulations conducted in 1-, 2-, and 3-dimensional tissue blocks, we calculated true SF values at locations surrounding the site of current injection for sub- and supra-threshold stimuli and found that they differed from values estimated by our SF formulation by < 10%. Finally, we examined SF dynamics under conditions relevant to arrhythmia development in order to provide physiological insight. Our analysis shows that reduced conduction velocity (Theta) caused by impaired intrinsic cell-scale excitability (e.g., due to sodium current a loss-of-function mutation) is associated with less robust conduction (i.e., lower SF); however, intriguingly, Theta variability resulting from modulation of tissue scale conductivity has no effect on SF. These findings are supported by analytic derivation of the relevant relationships from first principles. We conclude that our SF formulation, which can be applied to both experimental and synthetic data, produces values that vary linearly with the excess charge needed for propagation. SF calculations can provide insights helpful in understanding the initiation and perpetuation of cardiac arrhythmia.