ABSTRACT
MECHANISMS OF THYROID HORMONE ACTION Through the action of the hypothalamic releasing hormone (TRH), thyrotropin or thyroidstimulating hormone (TSH) is released from the anterior pituitary and stimulates the release of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland. T3 is the more active cellular form of thyroid hormone and has both genomic and nongenomic actions to influence cardiac function by effects on stimulation of transcriptional processes and cellular
membrane activity. The genomic actions of T3 are mediated predominately by binding of T3 to nuclear receptors of the same super family as those for steroid hormones. This mechanism has been reviewed (1). In brief, T4 and T3 rapidly cross membranes because of their lipophilic nature and possibly through specific transport proteins located in the cell membrane of cardiac myocytes. Thyroid hormone enters the nucleus and binds with high affinity to thyroid hormone receptors. These are activated either as a homodimer or bind a second hormone receptor and become activated as a heterodimer (2,3). These in turn bind to the DNA of target genes’ thyroid response elements in various configurations leading to either stimulation or inhibition of gene activity and transcriptional activity (4-7). The multiple hemodynamic changes reported in hyperthyroidism may be explained by the transcriptional changes of several genes. Thyroid hormone-responsive target genes include both regulatory and structural genes. These include transcriptional modulation of myosin heavy chain alpha, myosin heavy chain beta, making up the thick filament of cardiac myocytes, sarcoplasmic reticulum calcium-ATPase, Na,K-ATPase, phospholamban, voltagegated potassium channels, adenylyl cyclase types V and VI, and the Na, Ca exchanger (8-14). The activation of the myosin heavy chain alpha gene results in an increase in muscle fiber velocity and theoretically in increased myocardial contractility. The dominant component in human myofibril proteins is myosin heavy chain beta, which is repressed (7,8) making the exact contribution of these structural proteins to human cardiovascular manifestations of thyroid disease less certain. Another indirect genomic action of thyroid hormone is the alteration in function of the sarcoplasmic reticulum, including sarcoplasmic reticulum calcium-ATPase and phospholamban. In hyperthyroid heart disease, the release of calcium and subsequent reuptake by the sarcoplasmic reticulum, which determines systolic contractile function as well as diastolic relaxation, is altered. This process favors an increase in myocardial contractility (inotropy) and an improvement in diastolic relaxation. Upregulation of sarcoplasmic reticulum calcium-ATPase and changes in the phosphorylation of phospholamban can increase contractility as well as diastolic relaxation and may account for the hemodynamic changes in thyroid disease (10-12).
