Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue.
Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue.
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DOI：
10.1016/j.bpj.2017.03.006
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发表时间：
2017-05
影响因子：
3.4
通讯作者：
Christopher Y. Ko;Michael Liu;Z. Song;Z. Qu;J. Weiss
中科院分区：
文献类型：
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作者：
Christopher Y. Ko;Michael Liu;Z. Song;Z. Qu;J. Weiss
心肌细胞的自发钙(Ca)波是触发心律失常的延迟后除极(DAD)的基础。这些亚细胞/细胞事件如何克服心脏组织中的源-宿因素，以产生足够幅度的DAD来触发动作电位，目前尚不完全清楚。在这里，我们使用实验和计算相结合的建模方法，定量评估了亚细胞尺度(钙波起始点的数量)、细胞尺度(肌浆网钙负荷)和组织尺度(心肌细胞群体中钙释放的同步性)因素如何决定心肌组织的DAD特征。用高钙(2.7mmoL/L)和异丙肾上腺素(0.25mmoL/L)刺激兔膜片钳心肌细胞，诱发舒张期钙波和阈值下DADS。结果表明，高钙(2.7mmoL/L)和异丙肾上腺素(0.25mmoL/L)可诱发舒张期钙波和阈值下DAD。随着起搏次数从1次增加到5次，肌浆网钙含量(用咖啡因脉冲评估)增加，钙波起始点数目增加，整合的钙瞬变和DADS的持续时间变大和变短，至钙波开始的潜伏期缩短，方差减小。在计算机分析中，结合了这些实验测量的心室组织计算机模型显示，虽然所有这些因素都促进了较大的DAD产生触发活动的可能性更高，但潜伏期的变化和SR钙负荷的影响最大。因此，将定量的实验数据结合到组织水平的模拟中发现，细胞内钙的增加主要通过增加邻近心肌细胞内钙波的同步性(减小的潜伏期方差)和肌浆网钙负荷来促进组织中DAD介导的触发活动，而每个心肌细胞的钙波起始部位的数量并不重要。
Spontaneous calcium (Ca) waves in cardiac myocytes underlie delayed afterdepolarizations (DADs) that trigger cardiac arrhythmias. How these subcellular/cellular events overcome source-sink factors in cardiac tissue to generate DADs of sufficient amplitude to trigger action potentials is not fully understood. Here, we evaluate quantitatively how factors at the subcellular scale (number of Ca wave initiation sites), cellular scale (sarcoplasmic reticulum (SR) Ca load), and tissue scale (synchrony of Ca release in populations of myocytes) determine DAD features in cardiac tissue using a combined experimental and computational modeling approach. Isolated patch-clamped rabbit ventricular myocytes loaded with Fluo-4 to image intracellular Ca were rapidly paced during exposure to elevated extracellular Ca (2.7 mmol/L) and isoproterenol (0.25μmol/L) to induce diastolic Ca waves and subthreshold DADs. As the number of paced beats increased from 1 to 5, SR Ca content (assessed with caffeine pulses) increased, the number of Ca wave initiation sites increased, integrated Ca transients and DADs became larger and shorter in duration, and the latency period to the onset of Ca waves shortened with reduced variance. In silico analysis using a computer model of ventricular tissue incorporating these experimental measurements revealed that whereas all of these factors promoted larger DADs with higher probability of generating triggered activity, the latency period variance and SR Ca load had the greatest influences. Therefore, incorporating quantitative experimental data into tissue level simulations reveals that increased intracellular Ca promotes DAD-mediated triggered activity in tissue predominantly by increasing both the synchrony (decreasing latency variance) of Ca waves in nearby myocytes and SR Ca load, whereas the number of Ca wave initiation sites per myocyte is less important.