Thyroid hormone and cardiac disease: from basic concepts to clinical application

Abstract

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).

Figure 1

Schematic of the sequence of biological events occurring in response to environmental stimuli and lead to tissue restoration. In the case of intense and sustained stressful stimuli redifferentiation “deficit” occurs and results in a disease state (e.g., heart failure, cancer, etc.). Exogenous TH can enhance redifferentiation and restore damage.

Figure 2

Cardiac cells are de-differentiated upon exposure to progrowth stimuli such as phenylephrine (PE). This response is mediated via ERK/TRα1 and requires an intact mTOR signaling. Inhibition of mTOR signaling with rapamycin not only abolishes PE-induced nuclear TRα1 overexpression but results in marked TRα1 decrease with cell atrophy. De-differentiated cells retain the ability to re-differentiate when T3 is added to the medium. TRα1 by its dual action (liganded versus unliganded) seems to act as a regulator of the cell dedifferentiation/redifferentiation process.

Figure 3

Schematic of molecular, structural, and functional changes during post-ischaemic cardiac remodeling in untreated (a) and TH-treated hearts (b). TH shortly after myocardial infarction induces favorable changes in left ventricular chamber remodeling in a time-dependent manner; TH treatment accelerates the development of cardiac hypertrophy which normalizes wall tension and reshapes left ventricular chamber towards a more ellipsoidal shape at later stages [20].

Figure 4

Structural and phenotypic effects of T3 supplementation. After 10 days of culture, T3-supplemented myocardial fragments presented better preserved cardiomyocytes both at histological (a) and immunohistochemical examination (c). Weaker staining and progressive atrophy was observed in the corresponding untreated samples ((b) and (d), resp.). Myocardial sections were stained hematoxylin eosin (a), (b) for total protein content evaluation or immunostained for α-sarcomeric actinin (c), (d) for sarcomeric specif protein content. Images were acquired with a CCD camera and optical density was measured (scale bar = 50 μm). (e) Quantification of the histological results obtained from hematoxylin-eosin and α-sarcomeric-actinin staining of 10-day-old human myocardium in culture. P was determined using the two-tailed unpaired Student's t-test; data are expressed as mean ± SEM (experimental data derived from [28]).