ESPEYB21 3. Thyroid Defects in Thyroid Hormone Transport, Metabolism and Action (2 abstracts)
3.10. Resistance to thyroid hormone induced tachycardia in RTH[alpha] syndrome
Riccardo Dore , Laura Watson , Stefanie Hollidge , Christin Krause , Sarah Christine Sentis , Rebecca Oelkrug , Cathleen Geißler , Kornelia Johann , Mehdi Pedaran , Greta Lyons , Nuria Lopez-Alcantara , Julia Resch , Friedhelm Sayk , Karl Alexander Iwen , Andre Franke , Teide Jens Boysen , Jeffrey W Dalley , Kristina Lorenz , Carla Moran , Kirsten L Rennie , Anders Arner , Henriette Kirchner , Krishna Chatterjee & Jens Mittag
Nat Commun. 2023 Jun 7;14(1):3312. doi: 10.1038/s41467-023-38960-1. PMID: 37286550
Brief Summary: This study examined resistance to thyroid hormone (TH)-induced tachycardia in patients with Resistance to THα (RTHα). This rare condition is caused by mutations in the TH receptor alpha (TRα1), and leads to hypothyroidism in TRα1-expressing tissues, including the heart. While high doses of thyroxine (T4) are typically used to treat this condition, patients with RTHα do not exhibit the expected increase in heart rate despite overcoming tissue resistance to the hormone.
The authors used telemetry in a mouse model harboring the TRα1 mutation (TRα1+m), and found that the persistent bradycardia is due to an intrinsic cardiac defect rather than altered autonomic control. Although TH typically upregulates pacemaker channels (Hcn2 and Hcn4) involved in heart rate regulation, the study demonstrated that these channels are upregulated normally in RTHα patients and TRα1+m mice, but that the expression of other key ion channel genes, including potassium channel genes such as Kcnh2 as well as the calcium channel Ryr2, was irreversibly altered. Further investigation showed that fetal exposure to high levels of triiodothyronine (T3) via the mothers of TRα1+m animals restored altered expression and DNA methylation of ion channels, including Ryr2.
These findings suggest that the resistance to TH-induced tachycardia in RTHα syndrome results from altered expression of several key ion channel genes, probably caused by altered DNA methylation. These observations provide a mechanistic understanding for the lack of tachycardia in thyroxine-treated RTHα patients, and suggest that high dose hormone therapy of this disorder may be safer than previously thought.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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