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Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophy...

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Autores principales: Zhang, Yingnan, Zhang, Kelly, Prakosa, Adityo, James, Cynthia, Zimmerman, Stefan L, Carrick, Richard, Sung, Eric, Gasperetti, Alessio, Tichnell, Crystal, Murray, Brittney, Calkins, Hugh, Trayanova, Natalia A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584370/
https://www.ncbi.nlm.nih.gov/pubmed/37851708
http://dx.doi.org/10.7554/eLife.88865
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author Zhang, Yingnan
Zhang, Kelly
Prakosa, Adityo
James, Cynthia
Zimmerman, Stefan L
Carrick, Richard
Sung, Eric
Gasperetti, Alessio
Tichnell, Crystal
Murray, Brittney
Calkins, Hugh
Trayanova, Natalia A
author_facet Zhang, Yingnan
Zhang, Kelly
Prakosa, Adityo
James, Cynthia
Zimmerman, Stefan L
Carrick, Richard
Sung, Eric
Gasperetti, Alessio
Tichnell, Crystal
Murray, Brittney
Calkins, Hugh
Trayanova, Natalia A
author_sort Zhang, Yingnan
collection PubMed
description Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophysiological (EP) remodeling. Here, we developed a novel genotype-specific heart digital twin (Geno-DT) approach to investigate the role of pathophysiological remodeling in sustaining VT reentrant circuits and to predict the VT circuits in ARVC patients of different genotypes. This approach integrates the patient’s disease-induced structural remodeling reconstructed from contrast-enhanced magnetic-resonance imaging and genotype-specific cellular EP properties. In our retrospective study of 16 ARVC patients with two genotypes: plakophilin-2 (PKP2, n = 8) and gene-elusive (GE, n = 8), we found that Geno-DT accurately and non-invasively predicted the VT circuit locations for both genotypes (with 100%, 94%, 96% sensitivity, specificity, and accuracy for GE patient group, and 86%, 90%, 89% sensitivity, specificity, and accuracy for PKP2 patient group), when compared to VT circuit locations identified during clinical EP studies. Moreover, our results revealed that the underlying VT mechanisms differ among ARVC genotypes. We determined that in GE patients, fibrotic remodeling is the primary contributor to VT circuits, while in PKP2 patients, slowed conduction velocity and altered restitution properties of cardiac tissue, in addition to the structural substrate, are directly responsible for the formation of VT circuits. Our novel Geno-DT approach has the potential to augment therapeutic precision in the clinical setting and lead to more personalized treatment strategies in ARVC.
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spelling pubmed-105843702023-10-19 Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins Zhang, Yingnan Zhang, Kelly Prakosa, Adityo James, Cynthia Zimmerman, Stefan L Carrick, Richard Sung, Eric Gasperetti, Alessio Tichnell, Crystal Murray, Brittney Calkins, Hugh Trayanova, Natalia A eLife Computational and Systems Biology Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophysiological (EP) remodeling. Here, we developed a novel genotype-specific heart digital twin (Geno-DT) approach to investigate the role of pathophysiological remodeling in sustaining VT reentrant circuits and to predict the VT circuits in ARVC patients of different genotypes. This approach integrates the patient’s disease-induced structural remodeling reconstructed from contrast-enhanced magnetic-resonance imaging and genotype-specific cellular EP properties. In our retrospective study of 16 ARVC patients with two genotypes: plakophilin-2 (PKP2, n = 8) and gene-elusive (GE, n = 8), we found that Geno-DT accurately and non-invasively predicted the VT circuit locations for both genotypes (with 100%, 94%, 96% sensitivity, specificity, and accuracy for GE patient group, and 86%, 90%, 89% sensitivity, specificity, and accuracy for PKP2 patient group), when compared to VT circuit locations identified during clinical EP studies. Moreover, our results revealed that the underlying VT mechanisms differ among ARVC genotypes. We determined that in GE patients, fibrotic remodeling is the primary contributor to VT circuits, while in PKP2 patients, slowed conduction velocity and altered restitution properties of cardiac tissue, in addition to the structural substrate, are directly responsible for the formation of VT circuits. Our novel Geno-DT approach has the potential to augment therapeutic precision in the clinical setting and lead to more personalized treatment strategies in ARVC. eLife Sciences Publications, Ltd 2023-10-18 /pmc/articles/PMC10584370/ /pubmed/37851708 http://dx.doi.org/10.7554/eLife.88865 Text en © 2023, Zhang et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Zhang, Yingnan
Zhang, Kelly
Prakosa, Adityo
James, Cynthia
Zimmerman, Stefan L
Carrick, Richard
Sung, Eric
Gasperetti, Alessio
Tichnell, Crystal
Murray, Brittney
Calkins, Hugh
Trayanova, Natalia A
Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins
title Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins
title_full Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins
title_fullStr Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins
title_full_unstemmed Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins
title_short Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins
title_sort predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584370/
https://www.ncbi.nlm.nih.gov/pubmed/37851708
http://dx.doi.org/10.7554/eLife.88865
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