Enhanced Late Sodium Current in Hypothyroid Animal Models: Implications for Cardiac Electrophysiology

Cardiac arrhythmias are a major cause of disability and sudden death worldwide, with thyroid diseases—particularly hypothyroidism—playing a significant role. Hypothyroidism alters cardiomyocyte morphology, excitation–contraction coupling, and the expression of key myocardial genes involved in calcium handling and ion channel function. To investigate the molecular mechanisms underlying hypothyroidism-induced arrhythmogenesis, focusing on late sodium current (I_Na,late), calcium/calmodulin-dependent protein kinase II (CaMKII) signaling, and oxidative stress from endothelial nitric oxide synthase (eNOS) uncoupling. Hypothyroidism was induced in Swiss mice via 0.1% (w/vol) methimazole in drinking water for 21 days. Electrocardiography (ECG), patch-clamp whole-cell voltage and current-clamp technique, arrhythmia susceptibility tests, reactive oxygen species (ROS) detection, and western blot analysis of ventricular cardiomyocytes were performed. Hypothyroidism altered potassium channel expression, decreased NCX current, and disrupted Ca²⁺ cycling. Mice exhibited stress-induced arrhythmias (dobutamine/caffeine challenge) associated with elevated cardiac ROS and eNOS uncoupling. ROS production and arrhythmia incidence were reduced by N-acetyl-L-cysteine, tetrahydrobiopterin, or the eNOS inhibitor L-NIO. Preliminary data indicate potential involvement of I_Na,late in arrhythmogenesis, and ranolazine treatment may mitigate this effect. Additionally, activated CaMKII emerged as a possible intracellular effector exacerbating calcium dysregulation in hypothyroidism. Hypothyroidism-induced arrhythmias may result from a synergistic interplay between altered ion channel activity, CaMKII-mediated calcium handling disruption, and oxidative stress driven by eNOS uncoupling.