Numerical Simulation of Cardiac Electrophysiology

描述(申请人提供)：电刺激心脏组织是心脏起搏和除颤的关键。然而，人们对电场如何极化心脏组织的基本机制知之甚少。这项建议的目的是研究心脏电刺激过程中的兴奋和再入诱导机制。有7个具体的目标，每个目标都是作为一个假设陈述的。1)在强烈电击中，插入电极会影响组织的电行为。通常使用插入电极阵列来记录细胞外电位。每个插入电极代表一种可能在除颤电击期间使组织极化的阻性不均匀。因此，插入电极可以提供一种用于远场刺激的机制。2)心外膜电极影响组织在强烈电击时的电行为。在远离电极的地方，电流根据各自的电导率在细胞内和细胞外空间之间分配。然而，在心外膜电极附近，电流离开细胞内空间以利用低阻的细胞外路径(高电导率电极材料)，从而使组织去极化。在电流重新进入组织并重新分布到细胞内空间的地方，组织超极化。3)光学标测记录了代表平均跨膜电位的信号，这影响了模拟与实验的比较。4)组织表面的虚拟电极诱导再入。微弱的S1刺激通过浴缸中的电极灌流组织，会产生向外传播的波前。如果通过同一电极施加强阳极S2刺激，它会使组织表面超极化，但会使表面以下区域去极化。这些相邻的去极化和超极化区域可能导致在组织表面以下具有涡旋细丝的破裂激发和再入。5)S3刺激通过终止再入起到保护作用。S2-S3间隔确定再入是通过S2和S3波前的碰撞继续还是终止。6)快速起搏可诱发四叶折返。一般来说，单极起搏不会导致再入，因为传播失败没有首选方向。然而，不同的各向异性比提供了这样一个更好的方向，有利于再入。因此，突发起搏应该会在没有强烈冲击的情况下导致四翼重返大气层。7)通过虚拟阳极的快速传播会导致较高级别的漏洞。如果激波太强，就不会引起再入。更强的刺激在虚拟阳极处产生更强的超极化。破裂波前迅速传播通过这个非常容易兴奋的组织，然后在虚拟阳极的边缘失效，在那里波前与难治组织相遇。基于比多曼模型的计算机模拟将被用来实现这些特定的目标并检验这些假设。每个假设都是由实验数据驱动的，而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.