Thyroid hormones greatly impact energy homeostasis in the heart, and excess thyroid hormone leads to a hypermetabolic state. The thyroid gland produces two hormones, thyroxine (T4) and triiodothyronine (T3). The major form of thyroid hormone is thyroxine, which acts mostly as a prohormone. 1 The set point for thyroid hormone production and secretion by the thyroid gland is regulated by the hypothalamic thyrotropin-releasing hormone (TRH), which stimulates the production and secretion of thyroid stimulating hormone (TSH) that, in turn, controls thyroid hormone concentrations. Most of T4 is converted to biologically active T3 through the removal of an iodide by deiodinases. While there are three types of deiodinases, most of the circulating T3 is derived from Type 1; Type 1 activates thyroid hormone by converting T4 to active T3, and it deactivates thyroid hormone by converting T4 to inactive reverse T3 (rT3) or to T2.2 It is important to note that there is no significant intracellular deiodinase activity in cardiac cells; therefore, the heart relies mainly on the action of T3 since that is the hormone transported into the myocyte.3 Both T4 and T3 circulate in the blood almost entirely (> 95%) bound to thyroxine-binding globulin and a family of other hormone-binding proteins. The remaining unbound T3 is transported through a variety of membrane transport proteins and subsequently to the cell nucleus to regulate expression of selected genes. 4 Molecular Mechanisms of Thyroid Hormone ActionThe intracellular cardiac effects of thyroid hormone are exerted by two mechanisms: genomic and nongenomic. Several of the main effects are exerted through genomic actions, which consist of T3 linking to nuclear receptors that bind to thyroid-responsive elements (TREs) in the promoter of target genes. 5 There are several key myocyte-specific genes regulated by this mechanism (Table 1). 3 Binding of thyroid hormone to these TREs can either activate or repress gene expression, thereby regulating the expression of specific messenger RNA and translated proteins and producing different tissue-specific responses. Importantly, thyroid hormone-regulated genes are also involved in structural and regulatory proteins, and long-term exposure to high T3 levels can increase the synthesis of cardiac proteins, leading to cardiac hypertrophy and dysfunction. Extranuclear nongenomic activities provoke rapid changes in the cardiac myocyte plasma membrane and cytoplasmic organelles. These include changes in sodium, potassium, and calcium ion channels; changes in actin cytoskeleton polymerization; and changes to the intracellular signaling pathways in the heart and smooth muscle cells.Both genomic and nongenomic mechanisms act together to regulate cardiac function and cardiovascular hemodynamics.2 For example, they upregulate expression of the sarcoplasmic reticulum calcium-activated ATPase and downregulate phospholamban expression, thereby enhancing myocardial relaxation. They also increase expression of the more rapid contractile isoforms of the myo...

We have demonstrated that scar formation after myocardial infarction (MI) is associated with an endogenous pool of CD44posCD45neg multipotential mesenchymal stem cells (MSC). MSC differentiate into fibroblasts secreting collagen that forms a scar and mature into myofibroblasts that express alpha smooth muscle actin (α-SMA) that stabilizes the scar. In the aging mouse, cardiac repair after MI is associated with impaired differentiation of MSC; MSC derived from aged hearts form dysfunctional fibroblasts that deposit less collagen in response to transforming growth factor beta-1 (TGF-β1) and poorly mature into myofibroblasts. We found in vitro that the defect in myofibroblast maturation can be remedied by AICAR, which activates non-canonical TGF-β signaling through AMP-activated protein kinase (AMPK). In the present study, we injected aged mice with AICAR and subjected them to 1h occlusion of the left anterior descending artery (LAD) and then reperfusion for up to 30 days. AICAR-dependent AMPK signaling led to mobilization of an endogenous CD44posCD45neg MSC and its differentiation towards fibroblasts and myofibroblasts in the infarct. This was accompanied by enhanced collagen deposition and collagen fiber maturation in the scar. The AICAR-treated group has demonstrated reduced adverse remodeling as indicated by improved apical end diastolic dimension but no changes in ejection fraction and cardiac output were observed. We concluded that these data indicate the novel, previously not described role of AMPK in the post-MI scar formation. These findings can potentially lead to a new therapeutic strategy for prevention of adverse remodeling in the aging heart.

Impaired cardiac diastolic function occurs with aging in many species and may be difficult to measure noninvasively. In humans, left atrial (LA) volume is a robust measure of chronic diastolic function as the LA is exposed to increased left ventricular filling pressures. We hypothesized that LA volume would be a useful indicator of diastolic function in aging mice. Further, we asked whether pressures were propagated backwards affecting pulmonary arteries (PAs) and right ventricle (RV). We measured LA, PA, and RV infundibulum dimensions with echocardiography and used mouse-specific Doppler systems and pressure catheters for noninvasive and invasive measures. As C57BL/6 mice aged from 3 to 29-31 months, LA volume almost tripled. LA volume increases correlated with traditional diastolic function measures. Within groups of 14- and 31-month-old mice, LA volume correlated with diastolic function measured invasively. In serial studies, mice evaluated at 20 and 24 months showed monotonic increases in LA volume; other parameters changed less predictably. PA diameters, larger in 30-month-old mice than 6-month-old mice, correlated with LA volumes. Noninvasive LA volume and PA diameter assessments are useful and state independent measures of diastolic function in mice, correlating with other measures of diastolic dysfunction in aging. Furthermore, serial measurements over 4 months demonstrated consistent increases in LA volume suitable for longitudinal cardiac aging studies.