Direct effects
	Thyroid hormone action mediated by nuclear receptors: Direct effects of T3 on cardiac function are mediated by binding of T3 to its nuclear receptor sites (6). In 1986, it was demonstrated that the cellular homologue of the erb-A oncogene binds T3 with high affinity and limited capacity and has binding characteristics identical to the nuclear T3 receptor (7,8). Subsequently, additional (a and b) forms of T3 receptors have been identified which differ in the predominance with which they are present in specific tissues. The sequence of events leading to nuclear T3 effects can be briefly described in the following manner. T3 enters the cell and part of this entry may be mediated through a stereospecific transport mechanism. T3 then crosses the nuclear membrane to enter the nucleus. A nuclear T3 complex binds to specific T3 regulatory elements (TRE), stretches of 10-20 nucleotides which are localised in the vicinity of the transcriptional start site of T3-responsive genes. Binding of the T3 nuclear receptor complex to the TRE leads to the formation of an active transcription complex. Enhanced transcription of T3-reponsive genes ensues, increased amounts of mRNA are produced, and translated into specific proteins. T3-induced increases in specific mRNA can be mediated by post- transcriptional alterations (5). Thyroid hormone-induced changes in specific cardiac proteins: H leads to cardiac hypertrophy resulting in a 30-50% increase in heart weight. T3 induced hypertrophy is completely reversible with restoration of the euthyroid status. The cardiac hypertrophy is mediated by a T3-induced increase in total protein synthesis which is accompanied by an increased amount of total and specific mRNA being present in the H heart in comparison to the eu- or hypothyroid (hypo) heart. Furthermore, the T3-induced increase in the velocity of contraction of the heart can in part be explained by alterations in myosin isoenzyme predominance (9). The myosin holoenzyme consists of two myosin heavy chains (MHC) and four light chains. Myosin V1 which predominates in the normal heart consists of two MHC a whereas V3 contains two MHC b and V2 is a heterodimer of MHC a and b. Myosin ATPase activity of V1 is markedly higher than that of V3. Changes in myosin isoenzyme predominance in animal hearts are regulated by T3-induced alterations in the expression of the gene coding for MHC a and MHC b (12). T3 administration stimulates the expression of MHC a gene but decreases the expression of MHC b gene. In the hypo heart, V3 predominates and myosin with low ATPase activity participates in the contractile process (10,11). This leads to the decreased velocity of contraction of the hypo papillary muscle. In contrast in H hearts, myosin is exclusively composed of V1 leading to a fast turnover of the globular head of myosin moving along the thin filament. The marked T3-induced changes in myosin isoenzyme predominance, resulting from a direct effect of T3 on the heart mediated through nuclear T3 receptor sites, occur in small animals and cannot be documented to the same extent in the human heart. However, in a reported hypo patient with severe biventricular failure, in which the left ventricular ejection fraction increased from 14 to 44% after 9 months of T4 therapy, mRNA was extracted from pre- and posttreatment endomyocardial biopsy specimens, and mRNA species expressed by putatively T3- responsive myocardial genes were amplified by PCR. The steady state concentration of MHC increased 11-fold, with a minimal reduction in the b-MHC level, suggesting that T3-regulated expression of the MHC isoenzyme genes may play a role in T3 modulation of human myocardial contractility (13). The H heart relaxes with a higher speed (lusitropic activity). The influence on diastolic relaxation is primarily mediated by T3 induced increases of the transcription of the sarcoplasmic reticulum (SR) CA2+ATPase gene, an ion pump which actively removes calcium from the cytoplasm during diastole (14,15). Lowering of the cytosolic calcium concentration during diastole leads to the relaxation of cardiac muscle. T3 administration to hypo rats markedly and rapidly increases the mRNA level for the slow isoform of CA2+ATPase in the heart (16). The T3 mediated specific alterations in the level of the mRNA coding for the CA2+ATPase result in increased pump units. Extra nuclear effects: Limited evidence has accumulated for T3 influence on the transport of sugars and amino acids across plasma membranes (17). Direct, nuclear receptor-independent, action of T3 on the activity of the sarcolemnal Ca++ATPase has been shown (18). T3 also stimulates both the Ca++ATPase activity as well as the calcium movement across the membrane, due to changes in calcium channels (19-21). Furthermore, marked T3-induced increase in the activity of the cardiac Na+/K+ATPase has been demonstrated (22). This enzyme is located in the cardiac cell membrane and extrudes Na+ from the anterior of the cell in exchange for extracellular K+. Overall, T3 markedly stimulates enzymes involved in Ca++ and ion flux (23,24). These enzymes significantly contribute to ATP breakdown in the cell and to the stimulatory effect of T3 on oxygen consumption. Studies in which the use of the chemical energy stored in ATP was measured in heart muscles from animals of different thyroid status have indicated that in H hearts, a larger fraction goes to heat production whereas in euthyroid animals more is spent for useful contractile energy. This inefficient use of chemical energy may explain the well established finding that H of long duration and great severity leads in the end to cardiac failure (5).