Numerical models based on a minimal set of sarcolemmal electrogenic proteins and an intracellular Ca(2+) clock generate robust, flexible, and energy-efficient cardiac pacemaking.
Numerical models based on a minimal set of sarcolemmal electrogenic proteins and an intracellular Ca(2+) clock generate robust, flexible, and energy-efficient cardiac pacemaking.
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DOI：
10.1016/j.yjmcc.2013.03.004
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发表时间：
2013-06
影响因子：
5
通讯作者：
Lakatta EG
中科院分区：
文献类型：
--
作者：
Maltsev VA;Lakatta EG
最近的证据支持这样的观点，即心脏起搏细胞的稳健的并且重要的是灵活的自动性由膜离子电流（“M-时钟”）和基于肌浆网（SR）的Ca 2+振荡器（“Ca 2+时钟”）的耦合系统赋予，该耦合系统产生自发的舒张Ca 2+释放。本研究确定了人类生物起搏器的数值模型，其特征是由最小的一组产电蛋白和Ca 2+时钟产生的强大而灵活的自动性。根据奥卡姆剃刀原理（简约性原理），从Maltsev-Lakatta起搏细胞模型中排除分子来源未知的M-时钟成分，得到13种仅含4或5个成分的不同模型类型，并通过参数敏感性分析进行探索。对SR Ca 2+泵送（即Ca 2+时钟性能）和离子电流电导的扩展范围进行采样，得到各种各样的参数组合，即特定模型集。我们测试了每组模拟人类心率自主调节的能力（最小心率为50至70 bpm;最大心率为140至210 bpm），以响应胆碱能和β-肾上腺素能受体的刺激。我们发现，只有那些包括Ca 2+时钟的模型（包括最小的4参数模型“ICaL+IKr+INCX+ Ca 2+时钟”）才能够再现自主调节的全范围。如果或ICaT的纳入降低了灵活性，但增加了模型的稳健性（在测试期间，相对较多的数据集没有失败）。由具有明确分子身份的组分组成的新模型（即缺乏IbNa和Ist）描绘了更现实的起搏：预计较小的Na+流入将需要更少的能量用于Na+挤出。新的大型数据库的简化耦合时钟的数值模型可能作为一个有用的工具，设计的生物起搏器。它还将提供一个概念基础的鲁棒性，灵活性和能源效率的起搏器的基础上现实的组成部分的一般理论。
Recent evidence supports the idea that robust and, importantly, FLEXIBLE automaticity of cardiac pacemaker cells is conferred by a coupled system of membrane ion currents (an “M-clock”) and a sarcoplasmic reticulum (SR)-based Ca2+ oscillator (“Ca2+clock”) that generates spontaneous diastolic Ca2+ releases. This study identified numerical models of a human biological pacemaker that features robust and flexible automaticity generated by a minimal set of electrogenic proteins and a Ca2+clock. Following the Occam’s razor principle (principle of parsimony), M-clock components of unknown molecular origin were excluded from Maltsev-Lakatta pacemaker cell model and thirteen different model types of only 4 or 5 components were derived and explored by a parametric sensitivity analysis. The extended ranges of SR Ca2+ pumping (i.e. Ca2+clock performance) and conductance of ion currents were sampled, yielding a large variety of parameter combination, i.e. specific model sets. We tested each set’s ability to simulate autonomic modulation of human heart rate (minimum rate of 50 to 70 bpm; maximum rate of 140 to 210 bpm) in response to stimulation of cholinergic and β-adrenergic receptors. We found that only those models that include a Ca2+clock (including the minimal 4-parameter model “ICaL+IKr+INCX+Ca2+clock”) were able to reproduce the full range of autonomic modulation. Inclusion of If or ICaT decreased the flexibility, but increased the robustness of the models (a relatively larger number of sets did not fail during testing). The new models comprised of components with clear molecular identity (i.e. lacking IbNa & Ist) portray a more realistic pacemaking: A smaller Na+ influx is expected to demand less energy for Na+ extrusion. The new large database of the reduced coupled-clock numerical models may serve as a useful tool for the design of biological pacemakers. It will also provide a conceptual basis for a general theory of robust, flexible, and energy-efficient pacemaking based on realistic components.