RESUMEN
This study aims to investigate the cardiac electrical remodeling associated with intoxication by methylmercury (MeHg). We evaluated the chronic effects of MeHg on in vivo electrocardiograms and on ex vivo action potentials and depolarizing (ICa-L) and repolarizing (Ito) currents. The acute effect of MeHg was evaluated on HEK293 cells expressing human ERG, Kv4.3 and KCNQ1/KCNE1 channels. Chronic MeHg treatment increased QTc and Tpeak-Tend interval duration, prolonged action potential duration and decreased amplitude of Ito and ICa-L. In addition, heterologously expressed IhKv4.3, IhERG or IhKCNQ1/KCNE1 decreased after acute exposure to MeHg at subnanomolar range. The introduction of the in vitro effects of MeHg in a computer model of human ventricular action potentials triggered early afterdepolarizations and arrhythmia. In conclusion, cardiac electrical remodeling induced by MeHg poisoning is related to the reduction of Ito and ICa-L. The acute effect of MeHg on hKv4.3; hERG and hKCNQ1/KCNE1 currents and their transposition to in silico models show an association between MeHg intoxication and acquired Long QT Syndrome in humans. MeHg can exert its high toxicity either after chronic or acute exposure to concentrations as low as picomolar.
Asunto(s)
Arritmias Cardíacas/mortalidad , Arritmias Cardíacas/fisiopatología , Remodelación Atrial/fisiología , Fenómenos Electrofisiológicos/fisiología , Compuestos de Metilmercurio/envenenamiento , Potenciales de Acción , Animales , Canales de Calcio/metabolismo , Simulación por Computador , Susceptibilidad a Enfermedades , Células HEK293 , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Modelos Cardiovasculares , Canales de Potasio/metabolismo , Ratas Wistar , Pérdida de PesoRESUMEN
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 (ICa-L) and decreased the ultra-rapid delayed rectifier K+ current (IKur) 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 (Ito) 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 Ito density in cardiomyocytes from control and central but not primary hypothyroidism animals. In human myocytes, TSH decreased the expression of KCND3 and KCNQ1, Ito, and the delayed rectifier K+ current (IKs) 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 ß-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.
Asunto(s)
Arritmias Cardíacas/metabolismo , Remodelación Atrial/fisiología , Hipotiroidismo/metabolismo , Miocitos Cardíacos/metabolismo , Tirotropina/metabolismo , Potenciales de Acción , Animales , Antitiroideos/toxicidad , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Bexaroteno/toxicidad , Calcio/metabolismo , Simulación por Computador , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Electrocardiografía , Humanos , Hipotiroidismo/complicaciones , Hipotiroidismo/fisiopatología , Isoproterenol/farmacología , Canal de Potasio KCNQ1/efectos de los fármacos , Canal de Potasio KCNQ1/genética , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Miocitos Cardíacos/efectos de los fármacos , Técnicas de Placa-Clamp , Propiltiouracilo/toxicidad , ARN Mensajero/metabolismo , Ratas , Canales de Potasio Shal/efectos de los fármacos , Canales de Potasio Shal/genética , Tirotropina/farmacologíaRESUMEN
Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1ß in DM mice. IL-1ß causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1ß-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1ß axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1ß as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.
Asunto(s)
Diabetes Mellitus Experimental/inmunología , Interleucina-1beta/inmunología , Macrófagos/inmunología , Miocitos Cardíacos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Taquicardia Ventricular/inmunología , Receptor Toll-Like 2/inmunología , Potenciales de Acción , Animales , Antirreumáticos/farmacología , Arritmias Cardíacas/etiología , Arritmias Cardíacas/inmunología , Arritmias Cardíacas/metabolismo , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Caspasa 1/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Inflamasomas/antagonistas & inhibidores , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Ratones , Ratones Transgénicos , Contracción Miocárdica , Miocitos Cardíacos/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Potasio/metabolismo , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/inmunología , Taquicardia Ventricular/etiología , Taquicardia Ventricular/metabolismo , Receptor Toll-Like 2/genéticaRESUMEN
Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll-like receptors (TLRs) seem to be involved in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardiac electrical remodeling and arrhythmias, and the signaling pathway involved in these effects. Membrane potential was recorded in Wistar rat ventricle. Ca(2+) transients, as well as the L-type Ca(2+) current (ICaL) and the transient outward K(+) current (Ito), were recorded in isolated myocytes after 24 h exposure to the TLR4 agonist, lipopolysaccharide (LPS, 1 µg/ml). TLR4 stimulation in vitro promoted a cardiac electrical remodeling that leads to action potential prolongation associated with arrhythmic events, such as delayed afterdepolarization and triggered activity. After 24 h LPS incubation, Ito amplitude, as well as Kv4.3 and KChIP2 mRNA levels were reduced. The Ito decrease by LPS was prevented by inhibition of interferon regulatory factor 3 (IRF3), but not by inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4) or nuclear factor kappa B (NF-κB). Extrasystolic activity was present in 25% of the cells, but apart from that, Ca(2+) transients and ICaL were not affected by LPS; however, Na(+)/Ca(2+) exchanger (NCX) activity was apparently increased. We conclude that TLR4 activation decreased Ito, which increased AP duration via a MyD88-independent, IRF3-dependent pathway. The longer action potential, associated with enhanced Ca(2+) efflux via NCX, could explain the presence of arrhythmias in the LPS group.