Dual regulation by subcellular calcium heterogeneity and heart rate variability on cardiac electromechanical dynamics.
Dual regulation by subcellular calcium heterogeneity and heart rate variability on cardiac electromechanical dynamics.
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DOI：
10.1063/5.0019313
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发表时间：
2020-09
期刊：
影响因子：
2.9
通讯作者：
Vrishti M. Phadumdeo;S. Weinberg
中科院分区：
文献类型：
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作者：
Vrishti M. Phadumdeo;S. Weinberg
心率在生理条件下不断变化，称为心率变异性 (HRV)，在临床研究中，低 HRV 与心律失常的较高风险相关。先前的研究表明，HRV 影响电活动的时间模式，特别是促心律失常交替的形成、动作电位持续时间 (APD) 的逐搏交替或细胞内钙 (Ca) 水平。我们之前表明，HRV 可能通过破坏同质心肌细胞中的 APD 和 Ca 交替而具有抗心律失常的作用。在这里，我们扩展了之前的工作，将亚细胞 Ca 处理的变化（也称为影响交替）纳入由扩散耦合 Ca 释放单元（CRU）组成的心肌细胞的非线性图模型中。每个 CRU 的 Ca 相关参数和初始条件各不相同，以模拟亚细胞 Ca 异质性，并且随机起搏序列再现 HRV。我们发现，亚细胞 Ca 异质性促进了空间不一致的亚细胞交替模式的形成，从而减少了低和中等 HRV 的全细胞 Ca 和 APD 交替，而高亚细胞 Ca 异质性和 HRV 均促进机电去同步。最后，我们发现对于低和中等 HRV，特定的亚细胞 Ca 相关参数和起搏序列都会影响机电动力学的测量，而对于高 HRV，这些测量主要取决于起搏序列。我们的结果表明，低水平的 HRV 往往会形成促心律失常的亚细胞不一致交替，而高 HRV 可能是抗心律失常的，因为亚细胞 Ca 异质性和 Ca 不稳定性导致的 APD 去同步的影响减轻。
Heart rate constantly varies under physiological conditions, termed heart rate variability (HRV), and in clinical studies, low HRV is associated with a greater risk of cardiac arrhythmias. Prior work has shown that HRV influences the temporal patterns of electrical activity, specifically the formation of pro-arrhythmic alternans, a beat-to-beat alternation in the action potential duration (APD), or intracellular calcium (Ca) levels. We previously showed that HRV may be anti-arrhythmic by disrupting APD and Ca alternations in a homogeneous cardiac myocyte. Here, we expand on our previous work, incorporating variation in subcellular Ca handling (also known to influence alternans) into a nonlinear map model of a cardiac myocyte composed of diffusively coupled Ca release units (CRUs). Ca-related parameters and initial conditions of each CRU are varied to mimic subcellular Ca heterogeneity, and a stochastic pacing sequence reproduces HRV. We find that subcellular Ca heterogeneity promotes the formation of spatially discordant subcellular alternans patterns, which decreases whole cell Ca and APD alternation for low and moderate HRV, while high subcellular Ca heterogeneity and HRV both promote electromechanical desynchronization. Finally, we find that for low and moderate HRV, both the specific subcellular Ca-related parameters and the pacing sequences influence measures of electromechanical dynamics, while for high HRV, these measures depend predominantly on the pacing sequence. Our results suggest that pro-arrhythmic subcellular discordant alternans tend to form for low levels of HRV, while high HRV may be anti-arrhythmic due to mitigated influence from subcellular Ca heterogeneity and desynchronization of APD from Ca instabilities.