Cardiac dysfunction caused by myocardium-specific expression of a mutant thyroid hormone receptor

Thyroid hormone deficiency has profound effects on the cardiovascular syste m, resulting in decreased cardiac contractility, adrenergic responsiveness, and vascular volume and increased peripheral vascular resistance. To deter mine the importance of direct cardiac effects in the genesis of hypothyroid cardiac dysfunction, the cardiac myocyte was specifically targeted with a mutant thyroid hormone receptor (TR)-beta (Delta 337T-TR-beta(1)) driven by the alpha-myosin heavy chain (alpha-MHC) gene promoter. As a control in th ese experiments, a wild-type (Wt) TR-beta(1) was also targeted to the heart by using the same promoter. Transgenic mice expressing the mutant TR displ ayed an mRNA expression pattern consistent with cardiac hypothyroidism, eve n though their peripheral thyroid hormone levels were normal. When these an imals were rendered hypothyroid or thyrotoxic, mRNA expression of MHC isofo rms remained unchanged in the hearts of the Delta 337T transgenic animals, in contrast to Wt controls or transgenic animals expressing Wt TR-beta(1), which exhibited the expected changes in steady-state MHC mRNA levels. Studi es in Langendorff heart preparations from mutant TR-beta(1) transgenic anim als revealed evidence of heart failure with a significant reduction in +dP/ dT, -dP/dT, and force-frequency responses compared with values in Wt contro ls and transgenic mice overexpressing the Wt TR-beta(1). In contrast, in vi vo measures of cardiac performance were similar between Wt and mutant anima ls, indicating that the diminished performance of the mutant transgenic hea rt in vitro was compensated for by other mechanisms in vivo. This is the fi rst demonstration indicating that isolated cardiac hypothyroidism causes ca rdiac dysfunction in the absence of changes in the adrenergic or peripheral vascular system.