Riebel Leto Luana, Wang Zhinuo Jenny, Martinez-Navarro Hector, Trovato Cristian, Camps Julia, Berg Lucas Arantes, Zhou Xin, Doste Ruben, Sachetto Oliveira Rafael, Weber Dos Santos Rodrigo, Biasetti Jacopo, Rodriguez Blanca
Department of Computer Science, University of Oxford, Oxford, UK.
Systems Medicine, Clinical Pharmacology & Safety Science, R&D, AstraZeneca, Cambridge, UK.
Sci Rep. 2024 Sep 16;14(1):21584. doi: 10.1038/s41598-024-67951-5.
Human-based modelling and simulation offer an ideal testbed for novel medical therapies to guide experimental and clinical studies. Myocardial infarction (MI) is a common cause of heart failure and mortality, for which novel therapies are urgently needed. Although cell therapy offers promise, electrophysiological heterogeneity raises pro-arrhythmic safety concerns, where underlying complex spatio-temporal dynamics cannot be investigated experimentally. Here, after demonstrating credibility of the modelling and simulation framework, we investigate cell therapy in acute versus chronic MI and the role of cell heterogeneity, scar size and the Purkinje system. Simulations agreed with experimental and clinical recordings from ionic to ECG dynamics in acute and chronic infarction. Following cell delivery, spontaneous beats were facilitated by heterogeneity in cell populations, chronic MI due to tissue depolarisation and slow sinus rhythm. Subsequent re-entrant arrhythmias occurred, in some instances with Purkinje involvement and their susceptibility was enhanced by impaired Purkinje-myocardium coupling, large scars and acute infarction. We conclude that homogeneity in injected ventricular-like cell populations minimises their spontaneous beating, which is enhanced by chronic MI, whereas a healthy Purkinje-myocardium coupling is key to prevent subsequent re-entrant arrhythmias, particularly for large scars.
基于人体的建模与仿真为新型医学疗法提供了一个理想的试验平台，以指导实验和临床研究。心肌梗死（MI）是心力衰竭和死亡的常见原因，迫切需要新型疗法。尽管细胞疗法前景广阔，但电生理异质性引发了心律失常的安全性担忧，而潜在的复杂时空动态无法通过实验进行研究。在此，在证明建模与仿真框架的可信度之后，我们研究了急性与慢性心肌梗死中的细胞疗法以及细胞异质性、瘢痕大小和浦肯野系统的作用。模拟结果与急性和慢性梗死中从离子动力学到心电图动态的实验和临床记录一致。细胞递送后，细胞群体的异质性、组织去极化导致的慢性心肌梗死以及缓慢的窦性心律促进了自发搏动。随后发生了折返性心律失常，在某些情况下涉及浦肯野系统，并且浦肯野 - 心肌耦合受损、大瘢痕和急性梗死会增强其易感性。我们得出结论，注射的类心室细胞群体的同质性可将其自发搏动降至最低，慢性心肌梗死会增强这种自发搏动，而健康的浦肯野 - 心肌耦合是预防后续折返性心律失常的关键，尤其是对于大瘢痕而言。
