Numerical Simulation of Cardiac Electrophysiology

描述（由申请人提供）：心脏组织的电刺激对于心脏起搏和除颤至关重要。然而，对电场如何作用于心脏组织的基本机制知之甚少。本提案的目的是研究心脏电刺激过程中的兴奋和折返诱导机制。有7个具体目标，每个目标都作为一个假设陈述。1)插入电极在强电击期间影响组织的电行为。插入电极阵列通常用于记录细胞外电位。每个插入电极代表电阻不均匀性，其在除颤电击期间可能使组织变形。因此，插入电极可以提供用于远场刺激的机制。2)心外膜电极会影响强电击期间组织的电行为。远离电极，电流根据它们各自的电导率分布在细胞内和细胞外空间之间。然而，在心外膜电极附近，电流离开细胞内空间以利用低电阻细胞外路径（高电导率电极材料），从而使组织去极化。组织超极化，其中电流重新进入组织并重新分布回到细胞内空间。3)光学映射记录代表跨膜电位在深度上的平均值的信号，其影响模拟与实验的比较。4)组织表面的虚拟电极诱导折返。通过灌注组织的浴中的电极的弱S1刺激诱导向外传播的波前。如果随后通过相同电极施加强阳极S2刺激，则其使组织表面超极化，但使表面下方的区域去极化。这些相邻的去极化和超极化区域可能导致组织表面下方具有涡丝的中断激发和折返。5)S3刺激通过终止折返而发挥保护作用。S2-S3间期决定了折返是继续还是终止于S2和S3波阵面的碰撞。6)快速起搏诱导四叶折返。一般而言，单极起搏不能诱导折返，因为传播失败没有首选方向。然而，不相等的各向异性比提供了这样一个优选的方向，从而促进了再入。因此，短阵快速起搏应诱导四叶折返而无需强电击。7)通过虚拟阳极的快速传播导致更高级别的脆弱性。如果冲击太强，则不会诱发再入。更强的刺激在虚拟阳极处产生更强的超极化。破裂波前快速传播通过该非常易兴奋的组织，然后在虚拟阳极的边缘处失效，在该边缘处波前遇到不应组织。基于bidomain模型的计算机模拟将被用来实现这些具体目标，并测试这些假设。每个假设都是由实验数据激发的，理论模拟的目标是解释这些数据。

DESCRIPTION (provided by applicant): Electrical stimulation of cardiac tissue is crucial for pacing and defibrillation of the heart. Yet, the fundamental mechanisms governing how electric fields polarize cardiac tissue are poorly understood. The goal of this proposal is to study the mechanism of excitation and reentry induction during electrical stimulation of the heart. There are 7 specific aims, each stated as a hypothesis. 1) Plunge electrodes influence the electrical behavior of the tissue during a strong shock. Arrays of plunge electrodes are often used to record the extracellular potential. Each plunge electrode represents a resistive inhomogeneity which may polarize the tissue during a defibrillation shock. Thus, plunge electrodes may provide a mechanism for far-field stimulation. 2) Epicardial electrodes influence the electrical behavior of the tissue during a strong shock. Far from an electrode, current distributes between the intra- and extracellular spaces according to their respective conductivities. However, near an epicardial electrode, current leaves the intracellular space to take advantage of the low resistance extracellular path (the high conductivity electrode material), thereby depolarizing the tissue. The tissue hyperpolarizes where current reenters the tissue and redistributes back into the intracellular space. 3) Optical mapping records signals representing the transmembrane potential averaged over depth, which affects the comparison of simulations with experiments. 4) Virtual electrodes at the tissue surface induce reentry. A weak S1 stimulus through an electrode in a bath perfusing the tissue induces an outwardly propagating wave front. If a strong anodal S2 stimulus is then applied through the same electrode, it hyperpolarizes the tissue surface but depolarizes regions below the surface. These adjacent de- and hyperpolarized regions may lead to break excitation and reentry having vortex filaments below the tissue surface. 5) An S3 stimulus exerts a protective effect by terminating reentry. The S2-S3 interval determines if reentry continues or terminates by the collision of the S2 and S3 wave fronts. 6) Rapid pacing induces quatrefoil reentry. In general, unipolar pacing cannot induce reentry because there is no preferred direction for propagation failure. However, unequal anisotropy ratios provides such a prefered direction, facilitating reentry. Burst pacing should therefore induce quatrefoil reentry without strong shocks. 7) Rapid propagation through virtual anodes results in an upper level of vulnerability. Reentry is not induced if a shock is too strong. Stronger stimuli produce stronger hyperpolarization at virtual anodes. Break wave fronts propagate rapidly through this very excitable tissue, and then fail at the edge of the virtual anode, where the wave front meets refractory tissue. Computer simulations based on the bidomain model will be used to achieve these specific aims and to test these hypotheses. Each hypothesis is motivated by experimental data, and the goal of the theoretical simulations is to interpret these data.