Thyroid Hormones-An Underestimated Player in Dilated Cardiomyopathy?

Abstract

Dilated cardiomyopathy (DCM) is the most prevalent cardiomyopathy, typified by left ventricular dilation and systolic dysfunction. Many patients with DCM have altered thyroid status, especially lower levels of free triiodothyronine (T3) and elevated levels of thyroid-stimulating hormone. Moreover, growing evidence indicates that even subtle changes in thyroid status (especially low T3) are linked with a worse long-term prognosis and a higher risk of mortality. Notably, recent discoveries have shown that not only local myocardial thyroid hormones (THs) bioavailability could be diminished due to impaired expression of the activating deiodinase, but virtually all genes involved in TH biosynthesis are also expressed in the myocardium of DCM patients. Importantly, some studies have suggested beneficial effects of TH therapy in patients suffering from DCM. Our aim was to discuss new insights into the association between TH status and prognosis in DCM, abnormal expression of genes involved in the myocardial synthesis of TH in DCM, and the potential for TH use in the future treatment of DCM.

Keywords: dilated cardiomyopathy; prognosis; thyroid hormones; thyroid status; treatment.

Figure 2

Local effects of type 2 (D2) and type 3 (D3) deiodinases in the normal heart and in DCM: (a) The physiological role of deiodinases in the human heart. In the healthy heart, D2 activates T4 to the bioactive hormone T3. D3 expression is undetectable in the healthy heart, except for embryonic development; (b) Deiodinase function in cardiomyocytes in a rodent model of DCM by Wassner et al. [22]. In this model inactivating D3 is overexpressed, which leads to local hypothyroidism by inactivating T3 to T2; (c) Deiodinase function in a rodent model of DCM by Wang et al. [23]. In this model activating D2 is overexpressed, which leads to local hyperthyroidism by activating T4 to T3; (d) Deiodinase function in the human cardiomyocytes in DCM and altered genes involved in TH biosynthesis in patients with DCM according to Gil-Cayuela et al. [25]. In DCM the activity of both D2 and D3 is reduced. Additionally, DCM subjects have increased T4 and decreased T3 levels in the myocardium compared to the control group. Notably, in DCM the myocardial expression of 2 of ll genes involved in TH biosynthesis, i.e., dual oxidase-2 and thyroperoxidase, is upregulated and downregulated, respectively, which may also contribute to a net effect of DCM on cardiac TH levels. T4—thyroxine, T3—triiodothyronine, rT3—reverse T3, T2—3,3-diiodothyronine, D2—type 2 deiodinase, D3—type 3 deiodinase, TH—thyroid hormones, DCM—dilated cardiomyopathy.

Figure 1

Effects of TH on the cardiovascular system at the cellular level and at organ level: (a) Cellular genomic mechanisms include T3 binding to thyroid hormone receptor (THR) in the nucleus of cardiomyocytes, which regulates transcription of various genes by binding to thyroid hormone response elements (TREs). Nongenomic cellular pathways involve modulation of ion channels in the cell membrane of cardiomyocytes, Na⁺/K⁺-ATPase, Na⁺/Ca²⁺ exchanger, MAP kinase, PI3-kinase, and AKT-dependent signaling pathways, mitochondriogenesis and endothelial NO generation; (b) TH modulate cardiac inotropy, lusitropy and chronotropy, systemic vascular resistance and preload with a consequent increase in cardiac output. TH—thyroid hormones, T3—triiodothyronine, THR—thyroid hormone receptor, TREs—thyroid hormone response elements, SERCA—sarcoplasmic reticulum calcium-activated ATPase, MAP kinase—mitogen-activated protein kinase, PI3-kinase—phosphatidylinositol 3-kinase, AKT—protein kinase B, NO—nitric oxide, EPO—erythropoietin, LV—left ventricular.

Figure 1

Effects of TH on the cardiovascular system at the cellular level and at organ level: (a) Cellular genomic mechanisms include T3 binding to thyroid hormone receptor (THR) in the nucleus of cardiomyocytes, which regulates transcription of various genes by binding to thyroid hormone response elements (TREs). Nongenomic cellular pathways involve modulation of ion channels in the cell membrane of cardiomyocytes, Na⁺/K⁺-ATPase, Na⁺/Ca²⁺ exchanger, MAP kinase, PI3-kinase, and AKT-dependent signaling pathways, mitochondriogenesis and endothelial NO generation; (b) TH modulate cardiac inotropy, lusitropy and chronotropy, systemic vascular resistance and preload with a consequent increase in cardiac output. TH—thyroid hormones, T3—triiodothyronine, THR—thyroid hormone receptor, TREs—thyroid hormone response elements, SERCA—sarcoplasmic reticulum calcium-activated ATPase, MAP kinase—mitogen-activated protein kinase, PI3-kinase—phosphatidylinositol 3-kinase, AKT—protein kinase B, NO—nitric oxide, EPO—erythropoietin, LV—left ventricular.