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High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism

Background: Hypothyroidism, the most common endocrine disease, induces cardiac electrical remodeling that creates a substrate for ventricular arrhythmias. Recent studies report that high thyrotropin (TSH) levels are related to cardiac electrical abnormalities and increased mortality rates. The aim o...

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Autores principales: Fernandez-Ruocco, Julieta, Gallego, Monica, Rodriguez-de-Yurre, Ainhoa, Zayas-Arrabal, Julian, Echeazarra, Leyre, Alquiza, Amaia, Fernández-López, Victor, Rodriguez-Robledo, Juan M., Brito, Oscar, Schleier, Ygor, Sepulveda, Marisa, Oshiyama, Natalia F., Vila-Petroff, Martin, Bassani, Rosana A., Medei, Emiliano H., Casis, Oscar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc., publishers 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648210/
https://www.ncbi.nlm.nih.gov/pubmed/31084419
http://dx.doi.org/10.1089/thy.2018.0709
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author Fernandez-Ruocco, Julieta
Gallego, Monica
Rodriguez-de-Yurre, Ainhoa
Zayas-Arrabal, Julian
Echeazarra, Leyre
Alquiza, Amaia
Fernández-López, Victor
Rodriguez-Robledo, Juan M.
Brito, Oscar
Schleier, Ygor
Sepulveda, Marisa
Oshiyama, Natalia F.
Vila-Petroff, Martin
Bassani, Rosana A.
Medei, Emiliano H.
Casis, Oscar
author_facet Fernandez-Ruocco, Julieta
Gallego, Monica
Rodriguez-de-Yurre, Ainhoa
Zayas-Arrabal, Julian
Echeazarra, Leyre
Alquiza, Amaia
Fernández-López, Victor
Rodriguez-Robledo, Juan M.
Brito, Oscar
Schleier, Ygor
Sepulveda, Marisa
Oshiyama, Natalia F.
Vila-Petroff, Martin
Bassani, Rosana A.
Medei, Emiliano H.
Casis, Oscar
author_sort Fernandez-Ruocco, Julieta
collection PubMed
description Background: Hypothyroidism, the most common endocrine disease, induces cardiac electrical remodeling that creates a substrate for ventricular arrhythmias. Recent studies report that high thyrotropin (TSH) levels are related to cardiac electrical abnormalities and increased mortality rates. The aim of the present work was to investigate the direct effects of TSH on the heart and its possible causative role in the increased incidence of arrhythmia in hypothyroidism. Methods: A new rat model of central hypothyroidism (low TSH levels) was created and characterized together with the classical propylthiouracil-induced primary hypothyroidism model (high TSH levels). Electrocardiograms were recorded in vivo, and ionic currents were recorded from isolated ventricular myocytes in vitro by the patch-clamp technique. Protein and mRNA were measured by Western blot and quantitative reverse transcription polymerase chain reaction in rat and human cardiac myocytes. Adult human action potentials were simulated in silico to incorporate the experimentally observed changes. Results: Both primary and central hypothyroidism models increased the L-type Ca(2+) current (I(Ca-L)) and decreased the ultra-rapid delayed rectifier K(+) current (I(Kur)) densities. However, only primary but not central hypothyroidism showed electrocardiographic repolarization abnormalities and increased ventricular arrhythmia incidence during caffeine/dobutamine challenge. These changes were paralleled by a decrease in the density of the transient outward K(+) current (I(to)) in cardiomyocytes from animals with primary but not central hypothyroidism. In vitro treatment with TSH for 24 hours enhanced isoproterenol-induced spontaneous activity in control ventricular cells and diminished I(to) density in cardiomyocytes from control and central but not primary hypothyroidism animals. In human myocytes, TSH decreased the expression of KCND3 and KCNQ1, I(to), and the delayed rectifier K(+) current (I(Ks)) encoding proteins in a protein kinase A–dependent way. Transposing the changes produced by hypothyroidism and TSH to a computer model of human ventricular action potential resulted in enhanced occurrence of early afterdepolarizations and arrhythmia mostly in primary hypothyroidism, especially under β-adrenergic stimulation. Conclusions: The results suggest that suppression of repolarizing K(+) currents by TSH underlies most of the electrical remodeling observed in hypothyroidism. This work demonstrates that the activation of the TSH-receptor/protein kinase A pathway in the heart is responsible for the cardiac electrical remodeling and arrhythmia generation seen in hypothyroidism.
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spelling pubmed-66482102019-07-23 High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism Fernandez-Ruocco, Julieta Gallego, Monica Rodriguez-de-Yurre, Ainhoa Zayas-Arrabal, Julian Echeazarra, Leyre Alquiza, Amaia Fernández-López, Victor Rodriguez-Robledo, Juan M. Brito, Oscar Schleier, Ygor Sepulveda, Marisa Oshiyama, Natalia F. Vila-Petroff, Martin Bassani, Rosana A. Medei, Emiliano H. Casis, Oscar Thyroid Thyroid Dysfunction: Hypothyroidism, Thyrotoxicosis, and Thyroid Function Tests Background: Hypothyroidism, the most common endocrine disease, induces cardiac electrical remodeling that creates a substrate for ventricular arrhythmias. Recent studies report that high thyrotropin (TSH) levels are related to cardiac electrical abnormalities and increased mortality rates. The aim of the present work was to investigate the direct effects of TSH on the heart and its possible causative role in the increased incidence of arrhythmia in hypothyroidism. Methods: A new rat model of central hypothyroidism (low TSH levels) was created and characterized together with the classical propylthiouracil-induced primary hypothyroidism model (high TSH levels). Electrocardiograms were recorded in vivo, and ionic currents were recorded from isolated ventricular myocytes in vitro by the patch-clamp technique. Protein and mRNA were measured by Western blot and quantitative reverse transcription polymerase chain reaction in rat and human cardiac myocytes. Adult human action potentials were simulated in silico to incorporate the experimentally observed changes. Results: Both primary and central hypothyroidism models increased the L-type Ca(2+) current (I(Ca-L)) and decreased the ultra-rapid delayed rectifier K(+) current (I(Kur)) densities. However, only primary but not central hypothyroidism showed electrocardiographic repolarization abnormalities and increased ventricular arrhythmia incidence during caffeine/dobutamine challenge. These changes were paralleled by a decrease in the density of the transient outward K(+) current (I(to)) in cardiomyocytes from animals with primary but not central hypothyroidism. In vitro treatment with TSH for 24 hours enhanced isoproterenol-induced spontaneous activity in control ventricular cells and diminished I(to) density in cardiomyocytes from control and central but not primary hypothyroidism animals. In human myocytes, TSH decreased the expression of KCND3 and KCNQ1, I(to), and the delayed rectifier K(+) current (I(Ks)) encoding proteins in a protein kinase A–dependent way. Transposing the changes produced by hypothyroidism and TSH to a computer model of human ventricular action potential resulted in enhanced occurrence of early afterdepolarizations and arrhythmia mostly in primary hypothyroidism, especially under β-adrenergic stimulation. Conclusions: The results suggest that suppression of repolarizing K(+) currents by TSH underlies most of the electrical remodeling observed in hypothyroidism. This work demonstrates that the activation of the TSH-receptor/protein kinase A pathway in the heart is responsible for the cardiac electrical remodeling and arrhythmia generation seen in hypothyroidism. Mary Ann Liebert, Inc., publishers 2019-07-01 2019-07-17 /pmc/articles/PMC6648210/ /pubmed/31084419 http://dx.doi.org/10.1089/thy.2018.0709 Text en © Julieta Fernandez-Ruocco et al. 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Thyroid Dysfunction: Hypothyroidism, Thyrotoxicosis, and Thyroid Function Tests
Fernandez-Ruocco, Julieta
Gallego, Monica
Rodriguez-de-Yurre, Ainhoa
Zayas-Arrabal, Julian
Echeazarra, Leyre
Alquiza, Amaia
Fernández-López, Victor
Rodriguez-Robledo, Juan M.
Brito, Oscar
Schleier, Ygor
Sepulveda, Marisa
Oshiyama, Natalia F.
Vila-Petroff, Martin
Bassani, Rosana A.
Medei, Emiliano H.
Casis, Oscar
High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism
title High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism
title_full High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism
title_fullStr High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism
title_full_unstemmed High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism
title_short High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism
title_sort high thyrotropin is critical for cardiac electrical remodeling and arrhythmia vulnerability in hypothyroidism
topic Thyroid Dysfunction: Hypothyroidism, Thyrotoxicosis, and Thyroid Function Tests
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648210/
https://www.ncbi.nlm.nih.gov/pubmed/31084419
http://dx.doi.org/10.1089/thy.2018.0709
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