Central Hypothyroidism Impairs Heart Rate Stability and Prevents Thyroid Hormone Induced Cardiac Hypertrophy and Pyrexia.

Tachycardia, cardiac hypertrophy and elevated body temperature are major signs of systemic hyperthyroidism, which are considered to reflect the excessive thyroid hormone (TH) action in the respective peripheral tissues. However, recent observations indicate that the central actions of TH also contribute substantially to cardiovascular regulation and thermogenesis.Here, we dissect the individual contributions of peripheral TH action versus the central contribution in body temperature regulation and cardiovascular functions by taking advantage of mice lacking the TH transporters MCT8 and OATP1C1 (M/O dko), which exhibit elevated serum T3 levels while their brain is in a profoundly hypothyroid state. We compared these animals to wildtype mice that were treated orally with T3 to achieve similarly elevated serum T3 levels, but do not exhibit central hypothyroidism. For the studies we used radiotelemetry, infrared thermography, gene expression profiling, Western blot, and ELISA assays.Our analyses revealed mild hyperthermia and cardiac hypertrophy in T3-treated wildtype mice but not in M/O dko animals, suggesting that central actions of TH are required for these hyperthyroid phenotypes. Although the average heart rate was unaffected in either model, the M/O dko exhibited an altered heart rate frequency distribution with tachycardic bursts in active periods and bradycardic episodes during resting time, demonstrating that the stabilization of heart rate by the autonomic nervous system can be impaired in these centrally hypothyroid animals.Our studies unravel distinct phenotypical traits of hyperthyroidism that depend on an intact central nervous system, and provide valuable insight into the cardiovascular pathology of the Allan-Herndon-Dudley Syndrome, a condition caused by the lack of MCT8 in humans.