Peris-Yagüe Víctor, Rubio Tony, Fakuade Funsho E, Voigt Niels, Luther Stefan, Majumder Rupamanjari
Biomedical Physics Group, Max Planck Institute for Dynamics and Self Organisation, Gottingen, Germany.
Centre de Formaćio Interdisciplinària Superior (CFIS), Universitat Politècnica de Catalunya, Barcelona, Spain.
Front Physiol. 2022 Mar 10;13:812535. doi: 10.3389/fphys.2022.812535. eCollection 2022.
State of the art mathematical models are currently used to bridge the gap between basic research conducted in the laboratory and preclinical research conducted on large animals, which ultimately paves the way for clinical translation. In this regard, there is a great need for models that can be used alongside experiments for in-depth investigation and validation. One such experimental model is the porcine atrium, which is commonly used to study the mechanisms of onset and control of atrial fibrillation in the context of its surgical management. However, a mathematical model of pig atria is lacking. In this paper, we present the first ionically detailed mathematical model of porcine atrial electrophysiology, at body temperature. The model includes 12 ionic currents, 4 of which were designed based on experimental patch-clamp data directly obtained from literature. The formulations for the other currents are adopted from the human atrial model, and modified for porcine specificity based on our measured restitution data for different action potential characteristics: resting membrane potential, action potential amplitude, maximum upstroke velocity and action potential duration and different levels of membrane voltage repolarization. The intracellular dynamics follows the Luo-Rudy formulation for guinea pig ventricular cardiomyocytes. The resulting model represents "normal" cells which are formulated as a system of ordinary differential equations. We extend our model to two dimensions to obtain plane wave propagation in tissue with a velocity of 0.58 m/s and a wavelength of 8 cm. The wavelength reduces to 5 cm when the tissue is paced at 200 ms. Using S1-S2 cross-field protocol, we demonstrate in an 11.26 cm square simulation domain, the ability to initiate single spiral waves (rotation period ≃ 180 ms) that remain stable for more than 40 s. The spiral tip exhibits hypermeander. In agreement with previous experimental results using pig atria, our model shows that early repolarization is primarily driven by a calcium-mediated chloride current, , which is completely inactivated at high pacing frequencies. This is a condition that occurs only in porcine atria. Furthermore, the model shows spatiotemporal chaos with reduced repolarization.
目前,先进的数学模型被用于弥合实验室基础研究与大型动物临床前研究之间的差距,这最终为临床转化铺平了道路。在这方面,非常需要能够与实验一起用于深入研究和验证的模型。一种这样的实验模型是猪心房,它通常用于在手术管理的背景下研究心房颤动的发作和控制机制。然而,缺乏猪心房的数学模型。在本文中,我们提出了第一个在体温下的猪心房电生理学离子详细数学模型。该模型包括12种离子电流,其中4种是基于直接从文献中获得的实验膜片钳数据设计的。其他电流的公式采用人类心房模型,并根据我们测量的不同动作电位特征(静息膜电位、动作电位幅度、最大上升速度和动作电位持续时间以及不同水平的膜电压复极化)的恢复数据对猪的特异性进行了修改。细胞内动力学遵循豚鼠心室心肌细胞的Luo-Rudy公式。由此产生的模型代表“正常”细胞,其被公式化为常微分方程组。我们将模型扩展到二维,以获得组织中平面波传播,速度为0.58米/秒,波长为8厘米。当组织以200毫秒起搏时,波长减小到5厘米。使用S1-S2跨场协议,我们在11.26平方厘米的模拟域中证明了启动单个螺旋波(旋转周期≃180毫秒)的能力,该螺旋波在40多秒内保持稳定。螺旋尖端表现出超曲折。与先前使用猪心房的实验结果一致,我们的模型表明早期复极化主要由钙介导的氯电流驱动,该电流在高起搏频率下完全失活。这是仅在猪心房中出现的一种情况。此外,该模型显示了复极化减少的时空混沌。