{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T03:27:43Z","timestamp":1792553263884,"version":"4.5.0"},"reference-count":40,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T00:00:00Z","timestamp":1561939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T00:00:00Z","timestamp":1561939200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , and ionic currents were recorded from isolated ventricular myocytes\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                      to incorporate the experimentally observed changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Both primary and central hypothyroidism models increased the L-type Ca\n                      <jats:sup>2+<\/jats:sup>\n                      current (I\n                      <jats:sub>Ca-L<\/jats:sub>\n                      ) and decreased the ultra-rapid delayed rectifier K\n                      <jats:sup>+<\/jats:sup>\n                      current (I\n                      <jats:sub>Kur<\/jats:sub>\n                      ) 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\n                      <jats:sup>+<\/jats:sup>\n                      current (I\n                      <jats:sub>to<\/jats:sub>\n                      ) in cardiomyocytes from animals with primary but not central hypothyroidism.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      treatment with TSH for 24 hours enhanced isoproterenol-induced spontaneous activity in control ventricular cells and diminished I\n                      <jats:sub>to<\/jats:sub>\n                      density in cardiomyocytes from control and central but not primary hypothyroidism animals. In human myocytes, TSH decreased the expression of\n                      <jats:italic toggle=\"yes\">KCND3<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">KCNQ1<\/jats:italic>\n                      , I\n                      <jats:sub>to<\/jats:sub>\n                      , and the delayed rectifier K\n                      <jats:sup>+<\/jats:sup>\n                      current (I\n                      <jats:sub>Ks<\/jats:sub>\n                      ) encoding proteins in a protein kinase A\u2013dependent 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 \u03b2-adrenergic stimulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      The results suggest that suppression of repolarizing K\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2018.0709","type":"journal-article","created":{"date-parts":[[2019,5,14]],"date-time":"2019-05-14T06:55:34Z","timestamp":1557816934000},"page":"934-945","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":29,"title":["High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism"],"prefix":"10.1177","volume":"29","author":[{"given":"Julieta","family":"Fernandez-Ruocco","sequence":"first","affiliation":[{"name":"Instituto de Biof\u00edsica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janerio, Brazil."},{"name":"Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, Buenos Aires, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Gallego","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, Universidad del Pa\u00eds Vasco UPV\/EHU, Vitoria, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainhoa","family":"Rodriguez-de-Yurre","sequence":"additional","affiliation":[{"name":"Instituto de Biof\u00edsica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janerio, Brazil."},{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, Universidad del Pa\u00eds Vasco UPV\/EHU, Vitoria, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Zayas-Arrabal","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, Universidad del Pa\u00eds Vasco UPV\/EHU, Vitoria, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyre","family":"Echeazarra","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, Universidad del Pa\u00eds Vasco UPV\/EHU, Vitoria, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaia","family":"Alquiza","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, Universidad del Pa\u00eds Vasco UPV\/EHU, Vitoria, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Fern\u00e1ndez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, Universidad del Pa\u00eds Vasco UPV\/EHU, Vitoria, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan M.","family":"Rodriguez-Robledo","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, 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