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Sodium Current Reduction Unmasks a Structure-Dependent Substrate for Arrhythmogenesis in the Normal Ventricles

BACKGROUND: Organ-scale arrhythmogenic consequences of source-sink mismatch caused by impaired excitability remain unknown, hindering the understanding of pathophysiology in disease states like Brugada syndrome and ischemia. OBJECTIVE: We sought to determine whether sodium current (I(Na)) reduction...

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Autores principales: Boyle, Patrick M., Park, Carolyn J., Arevalo, Hermenegild J., Vigmond, Edward J., Trayanova, Natalia A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904970/
https://www.ncbi.nlm.nih.gov/pubmed/24489810
http://dx.doi.org/10.1371/journal.pone.0086947
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author Boyle, Patrick M.
Park, Carolyn J.
Arevalo, Hermenegild J.
Vigmond, Edward J.
Trayanova, Natalia A.
author_facet Boyle, Patrick M.
Park, Carolyn J.
Arevalo, Hermenegild J.
Vigmond, Edward J.
Trayanova, Natalia A.
author_sort Boyle, Patrick M.
collection PubMed
description BACKGROUND: Organ-scale arrhythmogenic consequences of source-sink mismatch caused by impaired excitability remain unknown, hindering the understanding of pathophysiology in disease states like Brugada syndrome and ischemia. OBJECTIVE: We sought to determine whether sodium current (I(Na)) reduction in the structurally normal heart unmasks a regionally heterogeneous substrate for the induction of sustained arrhythmia by premature ventricular contractions (PVCs). METHODS: We conducted simulations in rabbit ventricular computer models with 930 unique combinations of PVC location (10 sites) and coupling interval (250–400 ms), I(Na) reduction (30 or 40% of normal levels), and post-PVC sinus rhythm (arrested or persistent). Geometric characteristics and source-sink mismatch were quantitatively analyzed by calculating ventricular wall thickness and a newly formulated 3D safety factor (SF), respectively. RESULTS: Reducing I(Na) to 30% of its normal level created a substrate for sustained arrhythmia induction by establishing large regions of critical source-sink mismatch (SF<1) for ectopic wavefronts propagating from thin to thick tissue. In the same simulations but with 40% of normal I(Na), PVCs did not induce reentry because the volume of tissue with SF<1 was >95% smaller. Likewise, when post-PVC sinus activations were persistent instead of arrested, no ectopic excitations initiated sustained reentry because sinus activation breakthroughs engulfed the excitable gap. CONCLUSION: Our new SF formulation can quantify ectopic wavefront propagation robustness in geometrically complex 3D tissue with impaired excitability. This novel methodology was applied to show that I(Na) reduction precipitates source-sink mismatch, creating a potent substrate for sustained arrhythmia induction by PVCs originating near regions of ventricular wall expansion, such as the RV outflow tract.
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spelling pubmed-39049702014-01-31 Sodium Current Reduction Unmasks a Structure-Dependent Substrate for Arrhythmogenesis in the Normal Ventricles Boyle, Patrick M. Park, Carolyn J. Arevalo, Hermenegild J. Vigmond, Edward J. Trayanova, Natalia A. PLoS One Research Article BACKGROUND: Organ-scale arrhythmogenic consequences of source-sink mismatch caused by impaired excitability remain unknown, hindering the understanding of pathophysiology in disease states like Brugada syndrome and ischemia. OBJECTIVE: We sought to determine whether sodium current (I(Na)) reduction in the structurally normal heart unmasks a regionally heterogeneous substrate for the induction of sustained arrhythmia by premature ventricular contractions (PVCs). METHODS: We conducted simulations in rabbit ventricular computer models with 930 unique combinations of PVC location (10 sites) and coupling interval (250–400 ms), I(Na) reduction (30 or 40% of normal levels), and post-PVC sinus rhythm (arrested or persistent). Geometric characteristics and source-sink mismatch were quantitatively analyzed by calculating ventricular wall thickness and a newly formulated 3D safety factor (SF), respectively. RESULTS: Reducing I(Na) to 30% of its normal level created a substrate for sustained arrhythmia induction by establishing large regions of critical source-sink mismatch (SF<1) for ectopic wavefronts propagating from thin to thick tissue. In the same simulations but with 40% of normal I(Na), PVCs did not induce reentry because the volume of tissue with SF<1 was >95% smaller. Likewise, when post-PVC sinus activations were persistent instead of arrested, no ectopic excitations initiated sustained reentry because sinus activation breakthroughs engulfed the excitable gap. CONCLUSION: Our new SF formulation can quantify ectopic wavefront propagation robustness in geometrically complex 3D tissue with impaired excitability. This novel methodology was applied to show that I(Na) reduction precipitates source-sink mismatch, creating a potent substrate for sustained arrhythmia induction by PVCs originating near regions of ventricular wall expansion, such as the RV outflow tract. Public Library of Science 2014-01-28 /pmc/articles/PMC3904970/ /pubmed/24489810 http://dx.doi.org/10.1371/journal.pone.0086947 Text en © 2014 Boyle et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Boyle, Patrick M.
Park, Carolyn J.
Arevalo, Hermenegild J.
Vigmond, Edward J.
Trayanova, Natalia A.
Sodium Current Reduction Unmasks a Structure-Dependent Substrate for Arrhythmogenesis in the Normal Ventricles
title Sodium Current Reduction Unmasks a Structure-Dependent Substrate for Arrhythmogenesis in the Normal Ventricles
title_full Sodium Current Reduction Unmasks a Structure-Dependent Substrate for Arrhythmogenesis in the Normal Ventricles
title_fullStr Sodium Current Reduction Unmasks a Structure-Dependent Substrate for Arrhythmogenesis in the Normal Ventricles
title_full_unstemmed Sodium Current Reduction Unmasks a Structure-Dependent Substrate for Arrhythmogenesis in the Normal Ventricles
title_short Sodium Current Reduction Unmasks a Structure-Dependent Substrate for Arrhythmogenesis in the Normal Ventricles
title_sort sodium current reduction unmasks a structure-dependent substrate for arrhythmogenesis in the normal ventricles
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904970/
https://www.ncbi.nlm.nih.gov/pubmed/24489810
http://dx.doi.org/10.1371/journal.pone.0086947
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