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

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 electrophysiology 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 following 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.

SUBMITTER: Trovato C

PROVIDER: S-EPMC7294239 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Trovato Cristian C Passini Elisa E Nagy Norbert N Varró András A Abi-Gerges Najah N Severi Stefano S Rodriguez Blanca B

Journal of molecular and cellular cardiology 20200403

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 electrophysiology biophysically-detailed computational model, and to disentangle ionic mechanisms of human Purkinje-related electrophysiology, pacemaker activity and arrhythm ...[more]

PMID: 32251669

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

Publications

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

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