Experimental hypothyroidism induces cardiac arrhythmias and ranolazine reverts and prevents the phenotype

Autor(es)

Souza, Diego Santos ; Marques, Leisiane Pereira ; Costa, Alexandre Dantas ; Cruz, Jader Santos ; Rhana, Paula ; Santos-Miranda, Artur ; Joviano-Santos, Julliane Vasconcelos ; Durco, Aimee Obolari ; Lins Vasconcelos, Carla Maria ; Roman-Campos, Danilo

• Tipo de documento: Artigo Científico
• Fonte: Life Sciences; v. 308, p. 13-pg., 2022-09-13.

Resumo

Aims: Hypothyroidism is associated with an increased risk of cardiovascular disease and enhanced susceptibility to arrhythmias. In our investigation, we evaluated the potential involvement of late sodium current (INa,late) in cardiac arrhythmias in an experimental murine model of hypothyroidism.Main methods: Male Swiss mice were treated with methimazole (0.1 % w/vol, during 21 days) to induce experimental hypothyroidism before ECG, action potential (AP) and intracellular Ca2+ dynamics were evaluated. Susceptibility to arrhythmia was measured in vitro and in vivo.Key findings: The results revealed that hypothyroid animals presented ECG alterations (e.g. increased QTc) with the presence of spontaneous sustained ventricular tachycardia. These changes were associated with depolarized resting membrane potential in isolated cardiomyocytes and increased AP duration and dispersion at 90 % of the repolarization. Aberrant AP waveforms were related to increased Ca2+ sparks and out-of-pace Ca2+ waves. These changes were observed in a scenario of enhanced INa,late. Interestingly, ranolazine, a clinically used blocker of INa, late, restored the ECG alterations, reduced Ca2+ sparks and aberrant waves, decreased the in vitro events and the severity of arrhythmias observed in isolated cardiomyocytes from hypothyroid animals. Using the in vivo dobutamine + caffeine protocol, animals with hypothyroidism developed catecholaminergic bidirectional ven-tricular tachycardia, but pre-treatment with ranolazine prevented this.Significance: We concluded that animals with hypothyroidism have increased susceptibility to developing ar-rhythmias and ranolazine, a clinically used blocker of INa,late, is able to correct the arrhythmic phenotype. (AU)

• Processo FAPESP: 20/14635-1 - Modelagem de doenças monogênicas para estudos fisiopatológicos e testes farmacológicos utilizando células especializadas derivadas de iPSCs
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