Thyroid hormone resistance in the heart: Role of the thyroid hormone receptor β isoform

Several cardiac genes possess thyroid hormone (TH) response elements regulated by TH receptors. Mutation in TR-β gene causes the human syndrome of resistance to TH, which is characterized by elevated serum concentration of T₄ and T₃ and variable degrees of insensitivity to TH. It is unclear, however, whether a mutant TR-β could function as a dominant negative in the heart when expressed from the endogenous locus. A well-described resistance to TH (Δ337T) was either introduced into germline of mice (KI-mut) or expressed as a transgene in the heart using a cardiac-specific promoter (KS-mut). Mice were studied at baseline, after 5-propyl-2-thiouracil (PTU) or after PTU and T₃ treatment (PTU + T₃). PTU + T₃ treatment significantly increased left ventricular mass in all groups compared with baseline measurements, although the increase in left ventricular mass was significantly less in KI-mut animals. Baseline heart rates (HRs) were similar in wild-type (WT) and KI-mut but were lower in KS-mut animals. After TH deprivation (PTU), HR decreased in WT and KI-mut animals; similarly, HR increased in WT and KI-mut after PTU + T ₃. In contrast, HR in KS-mut animals did not change after either treatment. Except for cardiac hypertrophy, the presence of a germline TR-β mutation had surprisingly little effect on cardiac function.