Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities
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...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2020
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| _version_ | 1826305366066987008 |
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| author | Trovato, C Passini, E Nagy, N Varro, A Abi-Gerges, N Severi, S Rodriguez, B |
| author_facet | Trovato, C Passini, E Nagy, N Varro, A Abi-Gerges, N Severi, S Rodriguez, B |
| author_sort | Trovato, C |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:31:48Z |
| format | Journal article |
| id | oxford-uuid:f6385c51-add1-4cad-9060-6c3674e7ee23 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:31:48Z |
| publishDate | 2020 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:f6385c51-add1-4cad-9060-6c3674e7ee232022-03-27T12:33:39ZHuman Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalitiesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f6385c51-add1-4cad-9060-6c3674e7ee23EnglishSymplectic ElementsElsevier2020Trovato, CPassini, ENagy, NVarro, AAbi-Gerges, NSeveri, SRodriguez, BCardiac 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. |
| spellingShingle | Trovato, C Passini, E Nagy, N Varro, A Abi-Gerges, N Severi, S Rodriguez, B Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities |
| title | Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities |
| title_full | Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities |
| title_fullStr | Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities |
| title_full_unstemmed | Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities |
| title_short | Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities |
| title_sort | human purkinje in silico model enables mechanistic investigations into automaticity and pro arrhythmic abnormalities |
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