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Myocardium of patients with dilated cardiomyopathy presents altered expression of genes involved in thyroid hormone biosynthesis.

ABSTRACT: The association between dilated cardiomyopathy (DCM) and low thyroid hormone (TH) levels has been previously described. In these patients abnormal thyroid function is significantly related to impaired left ventricular (LV) function and increased risk of death. Although TH was originally thought to be produced exclusively by the thyroid gland, we recently reported TH biosynthesis in the human ischemic heart.Based on these findings, we evaluated whether the genes required for TH production are also altered in patients with DCM.Twenty-three LV tissue samples were obtained from patients with DCM (n = 13) undergoing heart transplantation and control donors (n = 10), and used for RNA sequencing analysis. The number of LV DCM samples was increased to 23 to determine total T4 and T3 tissue levels by ELISA.We found that all components of TH biosynthesis are expressed in human dilated heart tissue. Expression of genes encoding thyroperoxidase (-2.57-fold, P < 0.05) and dual oxidase 2 (2.64-fold, P < 0.01), the main enzymatic system of TH production, was significantly altered in patients with DCM and significantly associated with LV remodeling parameters. Thyroxine (T4) cardiac tissue levels were significantly increased (P < 0.01), whilst triiodothyronine (T3) levels were significantly diminished (P < 0.05) in the patients.Expression of TH biosynthesis machinery in the heart and total tissue levels of T4 and T3, are altered in patients with DCM. Given the relevance of TH in cardiac pathology, our results provide a basis for new gene-based therapeutic strategies for treating DCM.

SUBMITTER: Gil-Cayuela C

PROVIDER: S-EPMC5761948 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Myocardium of patients with dilated cardiomyopathy presents altered expression of genes involved in thyroid hormone biosynthesis.

Gil-Cayuela Carolina C Ortega Ana A Tarazón Estefanía E Martínez-Dolz Luis L Cinca Juan J González-Juanatey José Ramón JR Lago Francisca F Roselló-Lletí Esther E Rivera Miguel M Portolés Manuel M

PloS one 20180110 1

<h4>Background</h4>The association between dilated cardiomyopathy (DCM) and low thyroid hormone (TH) levels has been previously described. In these patients abnormal thyroid function is significantly related to impaired left ventricular (LV) function and increased risk of death. Although TH was originally thought to be produced exclusively by the thyroid gland, we recently reported TH biosynthesis in the human ischemic heart.<h4>Objectives</h4>Based on these findings, we evaluated whether the ge ...[more]

PMID: 29320567

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Project description:BackgroundEach of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.MethodsAn international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.ResultsFifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.ConclusionsIn the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

Project description:Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20-48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant.

Dataset Information

Myocardium of patients with dilated cardiomyopathy presents altered expression of genes involved in thyroid hormone biosynthesis.

Publications

Myocardium of patients with dilated cardiomyopathy presents altered expression of genes involved in thyroid hormone biosynthesis.

Similar Datasets

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