The main actions of thyroid hormone are induced through binding of the bioactive hormone T3 to nuclear thyroid hormone receptors (TRs).1 There are two receptor types, encoded by the genes THRA and THRB, with differing tissue expressions. TRα1 is primarily expressed in the heart, bone, gastrointestinal tract, skeletal muscle, and brain. TRβ1 is abundantly expressed and is the predominant form in the liver and kidneys, whereas TRβ2 has a more limited expression, including the hypothalamus and pituitary gland.

We have documented reduced survival and increased cardiovascular morbidity in a cohort of patients with RTHβ for the first time. These outcomes might be driven by lifelong cardiac exposure to thyroid hormone excess; and effective therapies, targeting hormone resistant pathways, could potentially curtail this risk.

There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20–40th percentiles of FT4 and the 60–80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years.