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

ABSTRACT: 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 Ca²⁺ 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 ?-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.

SUBMITTER: Fernandez-Ruocco J

PROVIDER: S-EPMC6648210 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Fernandez-Ruocco Julieta J Gallego Monica M Rodriguez-de-Yurre Ainhoa A Zayas-Arrabal Julian J Echeazarra Leyre L Alquiza Amaia A Fernández-López Victor V Rodriguez-Robledo Juan M JM Brito Oscar O Schleier Ygor Y Sepulveda Marisa M Oshiyama Natalia F NF Vila-Petroff Martin M Bassani Rosana A RA Medei Emiliano H EH Casis Oscar O

Thyroid : official journal of the American Thyroid Association 20190613 7

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:</i ...[more]

PMID: 31084419

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Project description:BackgroundUsing engineered nanomaterial-based toners, laser printers generate aerosols with alarming levels of nanoparticles that bear high bioactivity and potential health risks. Yet, the cardiac impacts of printer-emitted particles (PEPs) are unknown. Inhalation of particulate matter (PM) promotes cardiovascular morbidity and mortality, and ultra-fine particulates (<?0.1??m aerodynamic diameter) may bear toxicity unique from larger particles. Toxicological studies suggest that PM impairs left ventricular (LV) performance; however, such investigations have heretofore required animal restraint, anesthesia, or ex vivo preparations that can confound physiologic endpoints and/or prohibit LV mechanical assessments during exposure. To assess the acute and chronic effects of PEPs on cardiac physiology, male Sprague Dawley rats were exposed to PEPs (21?days, 5?h/day) while monitoring LV pressure (LVP) and electrocardiogram (ECG) via conscious telemetry, analyzing LVP and heart rate variability (HRV) in four-day increments from exposure days 1 to 21, as well as ECG and baroreflex sensitivity. At 2, 35, and 70?days after PEPs exposure ceased, rats received stress tests.ResultsOn day 21 of exposure, PEPs significantly (P <?0.05 vs. Air) increased LV end systolic pressure (LVESP, +?18?mmHg) and rate-pressure-product (+?19%), and decreased HRV indicating sympathetic dominance (root means squared of successive differences [RMSSD], -?21%). Overall, PEPs decreased LV ejection time (-?9%), relaxation time (-?3%), tau (-?5%), RMSSD (-?21%), and P-wave duration (-?9%). PEPs increased QTc interval (+?5%) and low:high frequency HRV (+?24%; all P <?0.05 vs. Air), while tending to decrease baroreflex sensitivity and contractility index (-?15% and?-?3%, P <?0.10 vs. Air). Relative to Air, at both 2 and 35?days after PEPs, ventricular arrhythmias increased, and at 70?days post-exposure LVESP increased. PEPs impaired ventricular repolarization at 2 and 35?days post-exposure, but only during stress tests. At 72?days post-exposure, PEPs increased urinary dopamine 5-fold and protein expression of ventricular repolarizing channels, Kv1.5, Kv4.2, and Kv7.1, by 50%.ConclusionsOur findings suggest exposure to PEPs increases cardiovascular risk by augmenting sympathetic influence, impairing ventricular performance and repolarization, and inducing hypertension and arrhythmia. PEPs may present significant health risks through adverse cardiovascular effects, especially in occupational settings, among susceptible individuals, and with long-term exposure.

Dataset Information

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

Publications

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

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