Effects of Mechano-Electric Feedback on Scroll Wave Stability in Human Ventricular Fibrillation

Recruitment of stretch-activated channels, one of the mechanisms of mechano-electric feedback, has been shown to influence the stability of scroll waves, the waves that underlie reentrant arrhythmias. However, a comprehensive study to examine the effects of recruitment of stretch-activated channels with different reversal potentials and conductances on scroll wave stability has not been undertaken; the mechanisms by which stretch-activated channel opening alters scroll wave stability are also not well understood. The goals of this study were to test the hypothesis that recruitment of stretch-activated channels affects scroll wave stability differently depending on stretch-activated channel reversal potential and channel conductance, and to uncover the relevant mechanisms underlying the observed behaviors. We developed a strongly-coupled model of human ventricular electromechanics that incorporated human ventricular geometry and fiber and sheet orientation reconstructed from MR and diffusion tensor MR images. Since a wide variety of reversal potentials and channel conductances have been reported for stretch-activated channels, two reversal potentials, −60 mV and −10 mV, and a range of channel conductances (0 to 0.07 mS/µF) were implemented. Opening of stretch-activated channels with a reversal potential of −60 mV diminished scroll wave breakup for all values of conductances by flattening heterogeneously the action potential duration restitution curve. Opening of stretch-activated channels with a reversal potential of −10 mV inhibited partially scroll wave breakup at low conductance values (from 0.02 to 0.04 mS/µF) by flattening heterogeneously the conduction velocity restitution relation. For large conductance values (>0.05 mS/µF), recruitment of stretch-activated channels with a reversal potential of −10 mV did not reduce the likelihood of scroll wave breakup because Na channel inactivation in regions of large stretch led to conduction block, which counteracted the increased scroll wave stability due to an overall flatter conduction velocity restitution.

牵张激活通道（stretch-activated channels）的募集是机械电反馈（mechano-electric feedback）的核心机制之一，已有研究证实其可影响螺旋波（scroll waves）的稳定性——而螺旋波正是折返性心律失常（reentrant arrhythmias）的病理基础。然而，目前尚未有研究全面考察不同反转电位（reversal potential）与电导（conductances）的牵张激活通道募集对螺旋波稳定性的调控效应，且牵张激活通道开放改变螺旋波稳定性的具体分子与电生理机制也尚未被清晰阐明。本研究的核心目标在于验证如下假说：牵张激活通道的募集对螺旋波稳定性的影响存在差异，且该差异取决于通道的反转电位与电导参数，并进一步揭示对应实验现象背后的潜在机制。我们构建了强耦合的人类心室机电模型，该模型整合了从磁共振（MR）与弥散张量磁共振图像（diffusion tensor MR images）中重建得到的人类心室几何结构、心肌纤维走向与层片排列方向。鉴于已有文献报道了多种牵张激活通道的反转电位与电导取值范围，本研究选取了-60 mV与-10 mV两种典型反转电位，并设置了0至0.07 mS/µF的电导区间开展模拟实验。当牵张激活通道的反转电位为-60 mV时，其开放可通过异质性平坦化动作电位时程恢复曲线（action potential duration restitution curve），在所有电导取值下均能抑制螺旋波破裂。当牵张激活通道的反转电位为-10 mV时，其开放可在低电导区间（0.02至0.04 mS/µF）通过异质性平坦化传导速度恢复关系（conduction velocity restitution relation），部分抑制螺旋波破裂。而在高电导区间（>0.05 mS/µF），反转电位为-10 mV的牵张激活通道募集并不能降低螺旋波破裂的风险：这是因为大牵张区域内的钠通道失活（Na channel inactivation）会引发传导阻滞（conduction block），抵消了整体更平坦的传导速度恢复曲线所带来的螺旋波稳定性提升效应。