Cardiac contractility, electrophysiology and energy metabolism are markedly dependent on the level of circulating thyroid hormone. Some of the effects are secondary to changes in heart rate and systemic blood pressure, but most genes involved in the effects on cardiac function are transcriptionally regulated by T3. Knock-out models in which expression of the various T3-receptors (TR) was manipulated indicate a principal role of TRα, although signalling through TRβ is possible. Cardiac conversion of T4 to T3 is minimal, at least in rodents, and the level of plasma T3 is the determining factor under normal conditions. Impaired T3-signalling may in part explain the critical changes in cardiac gene expression that are seen in pathological hypertrophy of the heart following chronic hemodynamic overload or following myocardial infarction (MI). Reduced expression of TRs was indeed found in some rodent models of heart failure and normalizing TR expression through viral transfection improved contractile function. However, other studies reported increased expression of TRs at later stages of remodeling. Several studies now report the re-expression of cardiac deiodinase type 3 (D3) in pathological hypertrophy. D3 inactivates T3 and T4 and is mainly expressed in tissues during development. The stimulation of D3 activity in pathological hypertrophy is associated with severe impairment of cardiac T3 signaling. Hypoxia-induced signaling appears to drive D3 expression, which is also seen in other metabolically stressed cell types. Impairment of T3 signaling will reduce energy turnover and the induction of D3 may be seen as an adaptive response. However, in the heart it will also aggravate the changes in gene expression that contribute to contractile dysfunction in pathological remodeling.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology