PDF(Pubmed)
Abstract：
Calcium (Ca2+) sparks are the elementary events of excitation-contraction coupling, yet they are not explicitly represented in human ventricular myocyte models. A stochastic ventricular cardiomyocyte human model that adapts to intracellular Ca2+ ([Ca2+]i) dynamics, spark regulation, and frequency-dependent changes in the form of locally controlled Ca2+ release was developed. The 20,000 CRUs in this model are composed of 9 individual LCCs and 49 RyRs that function as couplons. The simulated action potential duration at 1 Hz steady-state pacing is ~0.280 s similar to human ventricular cell recordings. Rate-dependence experiments reveal that APD shortening mechanisms are largely contributed by the L-type calcium channel inactivation, RyR open fraction, and [Ca2+]myo concentrations. The dynamic slow-rapid-slow pacing protocol shows that RyR open probability during high pacing frequency (2.5 Hz) switches to an adapted \"nonconducting\" form of Ca2+-dependent transition state. The predicted force was also observed to be increased in high pacing, but the SR Ca2+ fractional release was lower due to the smaller difference between diastolic and systolic [Ca2+]SR. Restitution analysis through the S1S2 protocol and increased LCC Ca2+-dependent activation rate show that the duration of LCC opening helps modulate its effects on the APD restitution at different diastolic intervals. Ultimately, a longer duration of calcium sparks was observed in relation to the SR Ca2+ loading at high pacing rates. Overall, this study demonstrates the spontaneous Ca2+ release events and ion channel responses throughout various stimuli.
摘要：
钙（Ca2）火花是激发-收缩耦合的基本事件，然而，它们在人类心室肌细胞模型中没有明确的表现。适应细胞内Ca2+([Ca2+]i)动力学的随机心室心肌细胞人模型,火花调节,并开发了局部控制的Ca2释放形式的频率依赖性变化。该模型中的20,000个CRU由9个单独的LCC和49个RyR组成，用作偶联子。1Hz稳态起搏时的模拟动作电位持续时间约为0.280s，与人心室细胞记录相似。速率依赖性实验表明，APD缩短机制在很大程度上是由L型钙通道失活造成的，RyR开放部分,和[Ca2+]myo浓度。动态慢速-快速-慢速起搏方案表明，在高起搏频率（2.5Hz）期间，RyR开放概率转换为适应的“非传导”形式的Ca2依赖性过渡状态。在高起搏中也观察到预测力增加，但是由于舒张压和收缩压[Ca2]SR之间的差异较小，SRCa2释放分数较低。通过S1S2方案的恢复分析和LCCCa2依赖性激活率的增加表明，LCC开放的持续时间有助于调节其在不同舒张间隔下对APD恢复的影响。最终,在高起搏速率下，观察到与SRCa2负荷有关的钙火花持续时间更长。总的来说,这项研究证明了在各种刺激中自发的Ca2释放事件和离子通道反应。
