心肌细胞早后去极化节律产生的动力学机制研究

【作者】 张宁；

【导师】 古华光；

【作者基本信息】 陕西师范大学 ， 生理学， 2010， 硕士

【摘要】 心脏的搏动作为动物生命的基础,长期以来备受人们关注。而早后去极化(earlyafter-depolarizations, EAD)作为一种心律失常现象,严重威胁着人们的身体健康和生活质量。目前对早后去极化(EAD)形成机制的研究并不明确,一方面是由于心肌细胞离子通道种类繁多,动作电位的形成过程复杂；另一方面,是由于目前的大多数研究更多关注对生物学现象的描述,较少关注其产生的深层次机理。随着生命科学和非线性科学的进一步结合,非线性动力学的研究方法已经逐渐运用到了对心肌节律的研究中,并且成为了该领域的热点问题。新的研究视角为我们提供了一条进一步从理论层次认识心肌节律的途径。本研究利用非线性动力学方法对早后去极化(EAD)这一令人困扰的心律失常问题进行研究。在定性、定量刻画该现象的基础上,揭示了其产生的动力学机制。在本研究中,以培养的心肌细胞作为实验模型,通过心肌细胞电生理的方法,记录到了稳定的EAD样搏动节律。同时,在随机性异质ML电耦合网络模型上对心肌细胞的EAD节律进行了仿真和理论分析。主要结果有：1.在培养的心肌细胞团上,通过Fura-2/AM染色的方法观察细胞内Ca2+离子振荡节律,发现位于培养心肌细胞团不同位点的细胞可以表现出同步的EAD样放电节律。用膜片钳技术检测了该细胞团上其中一个单细胞的膜电位振荡,发现该细胞的膜电位也表现出EAD样的节律。EAD节律表现为心肌细胞膜电位在复极化未完成时,又一次发生异常的去极化,并且形成一次不成熟的动作电位。2.选用异质电耦合网络模拟心肌细胞团,网络的节点选用Morris-Lecar模型。在一定范围内随机选取单元振子参数,使得网络内的单元振子的参数配置不同,动力学行为也不同；参数选取在从周期1节律到去极化静息的Hopf分岔点附近,单元振子的行为要么为去极化静息,要么为周期1。在确定性网络,耦合强度增加会使得具有不同节律或电活动的细胞形成同步化周期1节律。考虑现实心肌细胞总是存在类似噪声的随机因素,选用引入了随机因素的网络进一步逼近实验中的心肌细胞团。在随机网络,耦合强度的增强可以提高心肌细胞网络节律的同步化水平,噪声的作用在很小程度上降低了节律的同步化程度,不会影响同步化现象,但是,噪声的作用使得同步化的周期1节律变为了同步化的EAD节律。由于Hopf分岔是从去极化静息到周期1的临界点。在噪声作用下,心肌细胞团(网络)会在去极化静息和周期1之间随机跃迁,这就是EAD节律的特征和动力学机制。上述结果表明,EAD节律是在Hopf分岔点附近的心肌细胞团或网络的同步化的随机振荡。而当振子的行为或参数远离Hopf分岔时,心肌细胞网络为同步化的周期1节律或静息。这说明异质的心肌细胞网络自身就具有产生多样同步节律的能力,包括所谓的“规则节律”(周期1节律)和“异常节律”(EAD节律)。各种不同节律的产生往往是系统参数的配置不同所引起的；而参数的变化可以引起各种节律之间的跃迁。这就为研究复杂的心肌节律的产生和跃迁提供了理论认识,并对由早后去极化(EAD)引起的心律失常的预防、诊断和治疗提供了新的思路。更多还原

【Abstract】 As the basis of normal life, the beating of heart has been paid much attention for a long time. A kind of arrhythmia, early after-depolarization (EAD), has been the serious threat to the people’s health and the quality of life. But the formation mechanism of EAD has not been clear. On the one hand, the cardiac ion channels, which participate in the cardiac action potential, are numerous and complex. On the other hand, most of the studies about currents are concentrated on the description of biological phenomena, while little studies on the deep formation mechanisms.Following the further combination between life science and nonlinear dynamics, the method of the nonlinear dynamics has gradually used to reveal the mechanism of cardiac rhythm, and has been a hotspot. The novel angle provides a new pathway to learn more information about the cardiac rhythm in the theoretical level. In this paper, the method of the nonlinear dynamics is employed to study EAD being as a boring arrhythmia. On the basis of qualitative and quantitative description of EAD, the dynamics and formation mechanisms of EAD are identified.In this study, the stable EAD rhythms are recorded in an experimental model--cultured cardiac myocytes by cardiac electrophysiology experiments. At the same time, the EAD rhythms are simulated and analyzed in the theoretical level by a mathematical network model, which is composed of heterogeneous units described by Morris-Lecar (ML) model with nearest-neighbor coupling method.The main results were as follows:1. Synchronized EAD rhythms of intracellular calcium concentration ([Ca2+]i) oscillation were discovered in different cells in cultured cardiac myocytes network, using Fura-2/AM staining method. EAD-like oscillation of membrane potential was recorded in a single cell located in the network, using patch clamp. The EAD was the abnormal depolarization generated during the repolarization, being as an immature action potential.2. A network composed of heterogeneous units described by Morris-Lecar (ML) model with nearest-neighbor and electronic coupling method was employed to simulate the cultured cardiac myocytes. To insure the different parameter configuration of the unit oscillation, the parameters of unit oscillators was chosen randomly in a region. The dynamics of unit oscillator are different correspondingly. When the parameters of unit oscillator are chosen near Hopf bifurcation point from period 1 rhythm to depolarized rest, the behaviors are either depolarized rest or period 1 rhythm. Synchronized period 1 rhythms are simulated in the deterministic network whose cells exhibit different rhythms when the coupling strength is increased. Considering the fact that the stochastic factors similar to noise is inevitable in the real cardiac cells, the network containing stochastic component are chosen to further simulate the cardiac cells in the experiment. The synchronous degree of rhythms of the cardiac cells is enhanced by increase of the coupling strength in the stochastic network. Under the influence of noise, the synchronous degree of rhythms is slightly decreased, and the synchronized phenomenon did not change, but the synchronized period 1 rhythm is changed into synchronized EAD rhythm.The Hopf bifurcation point is the critical point from depolarized rest to period 1 rhythm. Under the influence of noise, the behavior of the network is stochastic transition between the depolarized rest and period 1 rhythm. It is the characteristics and dynamics of the EAD rhythm.The above results indicate that EAD rhythm is the synchronized stochastic oscillation of cardiac myocytes or the network near a Hopf bifurcation point. When the behavior or parameters of the oscillator is far from the Hopf bifurcation, the synchronized network of cardiac myocytes is period 1 rhythm or rest. It shows that the heterogeneous network of cardiac myocytes has the capability to produce various synchronous rhythms by itself, including the "regular rhythm" (period 1 rhythm) and "abnormal rhythm" (EAD rhythm). The difference of the various rhythms is the parameters configuration of system, which can lead the system to transit between the different rhythms. The results provide novel understanding for the formation and transition of cardiac myocytes rhythm, and new way to prevent, diagnose and treat the arrhythmia induced by EAD.更多还原