Thyroid Hormone and Cardiac Disease: From Basic Concepts to Clinical Application

Nature's models of regeneration provide substantial evidence that a natural healing process may exist in the heart. Analogies existing between the damaged myocardium and the developing heart strongly indicate that regulatory factors which drive embryonic heart development may also control aspects of heart regeneration. In this context, thyroid hormone (TH) which is critical in heart maturation during development appears to have a reparative role in adult life. Thus, changes in TH -thyroid hormone receptor (TR) homeostasis are shown to govern the return of the damaged myocardium to the fetal phenotype. Accordingly, thyroid hormone treatment preferentially rebuilds the injured myocardium by reactivating developmental gene programming. Clinical data provide further support to this experimental evidence and changes in TH levels and in particular a reduction of biologically active triiodothyronine (T3) in plasma after myocardial infarction or during evolution of heart failure, are strongly correlated with patients morbidity and mortality. The potential of TH to regenerate a diseased heart has now been testing in patients with acute myocardial infarction in a phase II, randomized, double blind, placebo-controlled study (the THiRST study)

Cell-Type-Dependent Thyroid Hormone Effects on Glioma Tumor Cell Lines

Purpose. The present study investigated the potential effects of long-term T3 treatment on glioma tumor cell lines. Thyroid hormone action on cell growth, differentiation and survival during development may be of therapeutic relevance Methods and Results 1321N1 cell line, an astrocytoma grade II, and U87MG, a glioblastoma grade IV, were exposed for 2 and 4 days in medium deprived of T3 and in medium containing 1 nM T3. T3 promoted re-differentiation in both cell lines. However, T3 increased cell proliferation in 1321N1 (2 days) which declined thereafter (4 days) while in U87MG resulted in suppression of cell proliferation. At the molecular level, a 2.9 fold increase in the expression of TRα1 receptor was observed in U87MG versus 1321N1, P < 0.05. TRβ1 receptor was undetectable. These changes corresponded to a distinct pattern of T3-induced kinase signaling activation; T3 had no effect on ERK activation in both cell lines but significantly increased phospho-Akt levels in 1321N1. Conclusion. In conclusion, T3 can re-differentiate glioma tumor cells, whereas its effect on cell proliferation appears to be dependent on the type of tumor cell line with aggressive tumors being more sensitive to T3. TRα1 receptor may, at least in part, be implicated in this response

Protein kinase C and cardiac dysfunction: a review

Heart failure (HF) is a physiological state in which cardiac output is insufficient to meet the needs of the body. It is a clinical syndrome characterized by impaired ability of the left ventricle to either fill or eject blood efficiently. HF is a disease of multiple aetiologies leading to progressive cardiac dysfunction and it is the leading cause of deaths in both developed and developing countries. HF is responsible for about 73,000 deaths in the UK each year. In the USA, HF affects 5.8 million people and 550,000 new cases are diagnosed annually. Cardiac remodelling (CD), which plays an important role in pathogenesis of HF, is viewed as stress response to an index event such as myocardial ischaemia or imposition of mechanical load leading to a series of structural and functional changes in the viable myocardium. Protein kinase C (PKC) isozymes are a family of serine/threonine kinases. PKC is a central enzyme in the regulation of growth, hypertrophy, and mediators of signal transduction pathways. In response to circulating hormones, activation of PKC triggers a multitude of intracellular events influencing multiple physiological processes in the heart, including heart rate, contraction, and relaxation. Recent research implicates PKC activation in the pathophysiology of a number of cardiovascular disease states. Few reports are available that examine PKC in normal and diseased human hearts. This review describes the structure, functions, and distribution of PKCs in the healthy and diseased heart with emphasis on the human heart and, also importantly, their regulation in heart failure

Thyroid hormone receptor alpha 1 as a novel therapeutic target for tissue repair

Analogies between the damaged tissue and developing organ indicate that a regulatory network that drives embryonic organ development may control aspects of tissue repair. In this regard, there is a growing body of experimental and clinical evidence showing that TH may be critical for recovery after injury. Especially TR alpha 1 has been reported to play an essential role in cell proliferation and differentiation and thus in the process of repair/regeneration in the heart and other tissues. Patients after myocardial infarction, stroke or therapeutic interventions [such as PCI for coronary artery disease (CAD)] with lower TH levels appear to have increased morbidity and mortality. Accordingly, TH treatment in clinical settings of ischemia/reperfusion such as by-pass surgery seems to be cardioprotective against ischemic injury. Furthermore, TH therapy of donors is shown to result in organ preservation and increased numbers of donors and improved post-transplantation graft survival. TH and thyroid analogs may prove novel therapeutic agents for tissue repair

The Emerging Role of TR α

Thyroid hormone (TH) is critical for adapting living organisms to environmental stress. Plasma circulating tri-iodothyronine (T3) levels drop in most disease states and are associated with increased oxidative stress. In this context, T3 levels in plasma appear to be an independent determinant for the recovery of cardiac function after myocardial infarction in patients. Thyroid hormone receptor α1 (TRα1) seems to be crucial in this response; TRα1 accumulates to cell nucleus upon activation of stress induced growth kinase signaling. Furthermore, overexpression of nuclear TRα1 in cardiomyocytes can result in pathological or physiological growth (dual action) in absence or presence of its ligand, respectively. Accordingly, inactivation of TRα1 receptor prevents reactive hypertrophy after myocardial infarction and results in heart failure with increased phospholamban (PLB) expression and marked activation of p38MAPK. In line with this evidence, TH is shown to limit ischemia/reperfusion injury and convert pathologic to physiologic growth after myocardial infarction via TRα1 receptor. TRα1 receptor may prove to be a novel pharmacological target for cardiac repair/regeneration therapies

Echocardiographic Datasets Showing Development of Cardiac Remodelling in Rats at Different Time-points after Acute Myocardial Infarction

K E Y W O R D S: myocardial infarction heart failure cardiac remodelling echocardiography rat A B S T R A C T The simulation of the time course of development of heart failure after an acute myocardial infarction requires large, open-access datasets. In this report, we present large echocardiographic datasets of cardiac function in rats after myocardial infarction at two different time points (2 and 13 weeks). We present measurements that show the deterioration of global left ventricular (LV) function, regional function, development of LV dilation, reactive hypertrophy and changes in LV geometry. We present in addition measurements showing the degree of cardiac injury assessed by the area and weight of the scar tissue. These data represent the progressive nature of cardiac remodelling and could be used to build computational models to predict the development of heart function deterioration based on the extent of myocardial injury and the development of LV remodelling. Creative Commons BY-NC-SA 4.