Thyroid hormone receptor signaling in normal and failing heart

Although it is well-accepted that alterations in thyroid function occur in patients with heart failure, this was ascribed previously to euthyroid-sick syndrome rather than real hypothyroidism. This has been called into question by a series of reports that implicate a primary change in the myocardial response to thyroid hormone as being responsible, at least in part, for the changes in myocardial form and function seen in the failing heart. Based on our findings that myocardial thyroid hormone receptor (TR) isoform expression is altered in patients with heart failure, our group has focused on the possibility that these changes in TR expression are responsible for certain aspects of the failure phenotype. In this regard TR isoforms were found to have differential effects on the cardiac myocyte phenotype. Specifically, TRα is linked to cardiac myocyte growth that is dependent upon the p38MAPK family. In contrast, TRβ has little effect on cardiac myocyte growth, limits p38 activation, and stimulates a number of the known thyroid-responsive cardiac myocyte genes. We conclude from these investigations that changes in the expression of TR isoforms play a direct role in myocardial growth and gene expression in heart failure. Furthermore, manipulation of the TH:TR axis in an isoform-specific manner may represent a new therapeutic approach to congestive heart failure (CHF) and may complement treatment profiles already in use for this syndrome.