Sensibilidade β-adrenérgica e variabilidade alterada da frequência cardíaca no hipotireoidismo: uma abordagem mecanicista

Abstract

Hypothyroidism is one of the most prevalent endocrine disorders worldwide, affecting more than 10% of adults, and is associated with structural and functional alterations of the cardiovascular system. Although its chronotropic and hemodynamic effects are well described, the mechanisms integrating autonomic modulation and β-adrenergic sensitivity in the genesis of cardiac electrical alterations are poorly understood. This study aimed to investigate changes in cardiac electrical function resulting from autonomic modulation associated with hypothyroidism in a murine model. Methods: Male Swiss mice were used (n = 6–7 per group; 5–6 weeks old; 25–30 g). Hypothyroidism was induced with methimazole (0.1% in drinking water) for 21 days, while the control group received water only. Cardiac function was assessed by in vivo electrocardiography on days 0, 11, and 21, determining heart rate, electrical conduction, and heart rate variability in the time and frequency domains. β-adrenergic sensitivity was analyzed through intraperitoneal administration of isoproterenol, dobutamine, and salbutamol, with electrocardiographic monitoring before and 3 minutes after administration. Adenylyl cyclase activity was assessed in isolated hearts perfused using a Langendorff system, before and after stimulation with forskolin. The expression of β₁ and β₂ receptors, protein kinase A (PKA), and phospholamban (PLB) was determined by Western blot. Results: Hypothyroid animals showed a significant reduction in heart rate, prolongation of the PR interval, and an increase in corrected QT. Heart rate variability revealed an increase in the Very Low Frequency (VLF) component, an increase in the Root mean square of successive differences (RMSSD), and a reduction in the Standard deviation of NN intervals (SDNN), characterizing autonomic imbalance with vagal predominance and decreased overall adaptability. Hypothyroid hearts showed a significant reduction in β₁-receptor expression and PKA substrate phosphorylation, as well as an increase in β₂-receptor expression. These results indicate that hypothyroidism reduces canonical β₁-adrenergic/PKA signaling while increasing β₂-adrenergic receptor expression. The chronotropic response to isoproterenol and dobutamine was attenuated, accompanied by reduced PKA substrate phosphorylation, indicating decreased cardiac β₁-adrenergic responsiveness. In contrast, the response to salbutamol was increased, with no changes in PKA substrate phosphorylation or PLB expression/phosphorylation, suggesting that β₁-adrenergic signaling is selectively impaired in hypothyroidism, with a possible reorganization toward the β₂-adrenergic signaling pathway. Forskolin stimulation restored the heart rate response without altering the p-PLB/PLB ratio, which remained unchanged, indicating preservation of the intracellular steps downstream of β-adrenergic receptor activation. Conclusion: Hypothyroidism induces marked remodeling of cardiac adrenergic signaling, with a greater contribution of alternative pathways associated with the β₂ adrenergic receptor. These findings demonstrate that thyroid hormone deficiency leads to reorganization of cardiac adrenergic signaling, contributing to bradycardia, reduced chronotropic adaptability, and decreased complexity of autonomic control in hypothyroidism.