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

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 (I) 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 Ca 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 Ca sparks and out-of-pace Ca waves. These changes were observed in a scenario of enhanced I. Interestingly, ranolazine, a clinically used blocker of I, restored the ECG alterations, reduced Ca 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 ventricular tachycardia, but pre-treatment with ranolazine prevented this.

Significance: We concluded that animals with hypothyroidism have increased susceptibility to developing arrhythmias and ranolazine, a clinically used blocker of I, is able to correct the arrhythmic phenotype.