Connexin-43 remodeling drives atrial arrhythmias in hypothyroidism: ranolazine as a potential therapeutic strategy

Hypothyroidism is associated with cardiovascular complications, including supraventricular arrhythmias. Thus, this study investigated functional and morphological alterations in the atrial of hypothyroid rats and evaluated the effects of acute ranolazine treatment on arrhythmia susceptibility. Hypothyroidism was induced in Wistar rats with methimazole (0.02 % in drinking water) for 28 days. The experimental approach included in vivo electrocardiography (ECG), ex vivo assessment of atrial contractility and arrhythmia induction by burst pacing, histological analyses, PCR, and immunofluorescence. Hypothyroid rats exhibited reduced heart rate, prolonged P-wave duration, and increased PR interval, indicating impaired atrial function. Ex vivo atrial preparations also showed increased susceptibility to arrhythmias, characterized by a higher number and longer duration of arrhythmic episodes following burst pacing. Acute ex vivo administration of the antiarrhythmic drug ranolazine significantly reduced arrhythmias susceptibility. Histological analysis revealed myocardial disorganization, and increased vacuolization in hypothyroid rat atria. In addition, Cx43 expression was markedly reduced, potentially contributing to impaired intercellular electrical coupling and increased arrhythmogenic susceptibility. Overall, these findings demonstrate that hypothyroidism induces significant electrophysiological, structural and contractile atrial remodeling, resulting in increased susceptibility to atrial arrhythmia. These findings highlight the importance of thyroid hormone signaling in maintaining atrial electrical stability and suggest that targeting electrical instability with ranolazine may have therapeutic potential in hypothyroid cardiac remodeling.