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Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities

Trovato, Cristian and Passini, Elisa and Nagy, Norbert and Varró, András and Najah, Abi-Gerges and Severi, Stefano and Rodriguez, Blanca (2020) Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities. Journal of Molecular and Cellular Cardiology, 142. pp. 24-38. ISSN 0022-2828

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Abstract

Cardiac Purkinje cells (PCs) are implicated in lethal arrhythmias caused by cardiac diseases, mutations, and drug action. However, the pro-arrhythmic mechanisms in PCs are not entirely understood, particularly in humans, as most investigations are conducted in animals. The aims of this study are to present a novel human PCs elec- trophysiology biophysically-detailed computational model, and to disentangle ionic mechanisms of human Purkinje-related electrophysiology, pacemaker activity and arrhythmogenicity. The new Trovato2020 model incorporates detailed Purkinje-specific ionic currents and Ca2+ handling, and was developed, calibrated and validated using human experimental data acquired at multiple frequencies, both in control conditions and fol- lowing drug application. Multiscale investigations were performed in a Purkinje cell, in fibre and using an experimentally-calibrated population of PCs to evaluate biological variability. Simulations demonstrate the human Purkinje Trovato2020 model is the first one to yield: (i) all key AP features consistent with human Purkinje recordings; (ii) Automaticity with funny current up-regulation (iii) EADs at slow pacing and with 85% hERG block; (iv) DADs following fast pacing; (v) conduction velocity of 160 cm/s in a Purkinje fibre, as reported in human. The human in silico PCs population highlights that: (1) EADs are caused by ICaL reactivation in PCs with large inward currents; (2) DADs and triggered APs occur in PCs experiencing Ca2+ accumulation, at fast pacing, caused by large L-type calcium current and small Na+/Ca2+ exchanger. The novel human Purkinje model unlocks further investigations into the role of cardiac Purkinje in ventricular arrhythmias through computer modeling and multiscale simulations.

Item Type: Article
Subjects: R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában > R850-854 Experimental medicine / kisérleti orvostudomány
Depositing User: Dr. Norbert Nagy
Date Deposited: 28 Sep 2020 10:17
Last Modified: 03 Apr 2023 07:01
URI: http://real.mtak.hu/id/eprint/115032

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