Endocrine Abstracts

Objectives: Thyroid hormones (TH) affect cardiovascular functions via direct actions on the heart and via indirect actions on central nervous system. Mutations in TH receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart.

Methods: The current experiments aimed at investigating the role of peripheral and central TRα1-signalling by further phenotyping TRα1 mutant mice (harboring R384C mutant TRα1) and making use of several techniques including radiotelemetry, electrocardiogram, transcriptomic, DNA methylation as well as in vivo pharmacology.

Results: In long-term radiotelemetry, TRα1 mutant mice showed bradycardia, broader heart rate (HR) distribution and blunted response to pharmacological denervation as compared to wildtypes at 22°C, suggesting a poor autonomic control of HR. While HR distribution and autonomic control of HR ameliorated at 30°C, the bradycardic state persisted. Interestingly, a 12-day oral T3 treatment, which reactivates the mutant TRα₁ function, did not induce tachycardia - a key feature in hyperthyroid wildtypes. Microarray analysis in hearts showed decreased levels of Hcn2 and Hcn4 in TRα₁ mutant mice, which were reversed by T3 treatment. However, the expression of several calcium and potassium channels, responsible for the repolarization of cardiomyocytes, were irreversibly decreased and not restored by T3 treatment in adulthood, clearly pointing towards developmental defects and possibly accounting for the T3-resistant bradycardia observed in TRα₁ mutant mice. In fact, exposure of TRα₁ mutant mice to higher maternal TH concentrations in utero restored the expression of some of these genes, via the normalization of several differentially methylated CpG sites in cardiac DNA of TRα₁ mutant adult mice. Moreover, electrocardiogram recordings in untreated TRα₁ mutant mice revealed longer PQ and QT intervals, whereas T3-induced tachycardia in wildtypes was fully abolished by peripheral injection of 4-aminopyridine, a potassium channels blocker, together indicating atrial and ventricular abnormalities such as long QT syndrome, often observed in hypothyroid patients.

Conclusions: Our findings highlight that developmental actions of TRα1 can lead to a T3 resistant heart and demonstrate that the TH-mediated induction of Hcn2 and Hcn4 is not sufficient for tachycardia development.