Redução da expressão de conexina 43 provoca arritmias atriais em ratos com hipotireoidismo experimental

Abstract

Hypothyroidism is a disorder characterized by decreased production or action of thyroid hormones – triiodothyronine (T3) and thyroxine (T4) – which participate in metabolic processes in various tissues. This condition may be a risk factor for some cardiovascular diseases, including atrial arrhythmias. The objective of this study was to investigate electrophysiological and morphological changes in the right and left atria of rats with experimental hypothyroidism. Male Wistar rats (6-9 months, 150-250 g) were used, divided into control and hypothyroid groups. Hypothyroidism was induced with 0.02% methimazole in drinking water for 28 days. After induction, in vivo ECG measurements were performed in both groups, and the atria were removed for analysis of arrhythmia susceptibility and contractile characterization in isolated organ baths, histological examination, and assessment of connexin 43 expression. In vivo ECG showed a reduction in heart rate (307.98 ± 21.06 vs. 263.71 ± 29.38 bpm; p = 0.0043), prolongation of P wave duration (20.52 ± 2.91 vs. 33.93 ± 9.44 ms; p = 0.0046), and PR interval (50.82 ± 4.01 vs. 56.89 ± 6.15 ms; p = 0.0377) in the hypothyroid group. In isolated right atrium, using the burst pacing protocol, a greater predisposition to arrhythmias and electrical instability was observed, evidenced by a higher number of episodes (0.5 ± 0.55 vs. 2.83 ± 2.14; p = 0.027) and increased duration of these events (1.80 ± 2.26 vs. 26.31 ± 16.20 s; p = 0.004). Atrial contractility functional assessment revealed prolonged systolic duration (0.175 ± 0.036 vs. 0.314 ± 0.107 s; p = 0.023) in the hypothyroid group, with no significant changes in contractile amplitude (0.373 ± 0.045 vs. 0.318 ± 0.096 N). There was no difference in caffeine induced Ca2+ overshoot (0.031 ± 0.010 vs. 0.036 ± 0.020 gf) nor in the inotropic effect induced by isoproterenol (198.4 ± 74.8% vs. 220.7 ± 64.9%), suggesting that the slowing of systole and electrical instability could be associated with morphological changes. Histological analysis of atrial tissue revealed structural remodeling in the experimental group, with increased extracellular matrix spacing, which may contribute to the slowing of electrical conduction. Hypothyroidism also reduced connexin 43 expression (0.348 ± 0.047 vs. 0.850 ± 0.119 a.u.; p < 0.0001) in the atria of these animals. The combination of observed histological alterations and reduced connexin 43 expression may create a highly vulnerable substrate for the development of atrial fibrillation, one of the most prevalent arrhythmias in thyroid dysfunctions. Thus, hypothyroidism significantly affects the electrical stability and dromotropic function of atrial tissue, increasing susceptibility to arrhythmias, particularly atrial fibrillation. Structural remodeling, cellular uncoupling, and reduced connexin expression were observed, suggesting that the interaction between electrical and structural mechanisms plays a central role in the predisposition to atrial arrhythmias. Therefore, early interventions are needed to prevent cardiovascular complications in patients with hypothyroidism.