br Introduction Thyroid hormone TH is a critical regulator o

Introduction Thyroid hormone (TH) is a critical regulator of many physiological and developmental processes, following its activation from the stable prohormone (l-thyroxine, T4) to the short-lived active hormone, triiodothyronine (3,5,3′-triiodo-l-thyronine, T3) (Fig. 1). T3 induces amphibian metamorphosis by stimulating the remodeling of specific tissues and organs (Tata, 1993). In mammals, T3 is essential for development, with congenital hypothyroidism resulting in growth retardation, deafness, impaired neurogenesis, and congenital heart malformations (Legrand, 1986; Olivieri et al., 2002). THs also have important effects on oxygen consumption and metabolism. The actions of THs are mediated by the products of two TH receptor (TR) genes, the nuclear proteins, TRα and TRβ, which show differential patterns of expression in development and in adult tissues (Mai et al., 2004). Stimulation of these receptors results in the direct transcriptional activation of a wide range of genes (genomic effects). More recently, non-genomic effects of TH initiated at the cell surface, in the cytoplasm or in mitochondria have also been identified (Davis and Davis, 2002; Davis et al., 2011). Adding further complexity, TH signaling is highly regulated by the expression of cell and tissue-specific TH transporters that concentrate THs in target cells, by the relative expression and distribution of TR isoforms, by interaction of TRs with corepressors and coactivators, by cross-talk with several other signaling pathways, and by the sequence and location of the TH response element. Furthermore, TH signaling is tightly regulated by the activation and catabolism of THs by three selenoenzyme iodothyronine deiodinases: D1, D2 and D3—considerations that have been comprehensively reviewed elsewhere (Zoeller et al., 2007; Kress et al., 2009; Brent, 2012). T3 has profound effects on the buy d-amphetamine with chronic hyperthyroidism in adulthood resulting in a physiological-type of cardiac hypertrophy, characterized by a predominant increase in cardiomyocyte (CM) length rather than width, and by enhanced expression of α-MHC, as well as a marked reduction in systemic vascular resistance accompanied by increased cardiac contractility, systolic hypertension, and increased cardiac output. In contrast, prolonged hypothyroidism results in diastolic hypertension, reduced cardiac output and stroke volume, as well as cardiac dilatation and even overt heart failure. The effects of T3 on the heart are due to the transcriptional regulation of a number of contractile and calcium handling genes (Maillet et al., 2013). These effects have been most widely studied with respect to their role in postnatal heart development, and under the premise that CMs exit the cell cycle and become terminally differentiated soon after birth. Here, after a brief consideration of TH biology, we revisit the role of TH in postnatal heart development, given recent evidence indicating that the proliferative competence of CMs may be retained until well after the neonatal period, allowing murine CMs to undergo a proliferative burst during preadolescence in response to a T3 surge (Naqvi et al., 2014); that T3 can induce DNA synthesis in terminally differentiated adult CMs (Ledda-Columbano et al., 2006), and that remodeling post-myocardial infarction in mice is associated with local hypothyroidism of spared myocardium due to re-expression of D3, a thyroid-inactivating enzyme normally expressed only in the fetus (Janssen et al., 2013).
TH biology
Postnatal cardiac development In response to the rapid increase in body size, between birth and puberty, the murine heart increases in size almost 4-fold, with a commensurate increase in stroke volume (Naqvi et al., 2014). How are these profound changes in cardiovascular hemodynamics and morphology achieved?
TH and the heart: potential therapeutic implications TH replacement has been trialed in the operative setting in an attempt to minimize morbidity and to increase survival of children undergoing complex congenital heart disease surgery (Chowdhury et al., 2001). T3 therapy in these extremely sick patients is aimed at improving cardiac function and optimizing postoperative hemodynamics that may result from observed changes in TH metabolism, which decreases circulating T3 levels, as well as reducing TR-expression (particularly TRα) (Dillmann, 2010). TH levels also fall acutely in humans following myocardial infarction and replacement therapy with either T3 or the synthetic TH analog, 3,5-diiodothyroproprionic acid (DITPA), which exerts a positive inotropic effect without the potential adverse effects of iatrogenic hyperthyroidism (e.g., tachyarrhythmias, weight loss, anxiety), has been used to limit post-infarct patholological remodeling in preclinical studies (Zheng et al., 2004; Spooner et al., 1999; Mahaffey et al., 1995), as well as in clinical trials of patients with heart failure (Morkin et al., 2002; Goldman et al., 2009). Again in these studies, the rationale for using TH or analogs is largely to enhance cardiac contractility of the uninjured or failing myocardium in situations where TH metabolism is impaired and T3 levels are low (Gerdes and Iervasi, 2010). Where TH metabolism is unaltered, T3 would have to be given with caution as it could potentially deleteriously increase cardiac work and myocardial O2 consumption, although DITPA, with its lack of adverse cardiac effects, should be tolerated.