LAUSR

BACKGROUND Abnormal thyroid hormone (TH) metabolism is significantly associated with impaired left ventricular (LV) function and death. Although TH was traditionally thought to be produced exclusively by the thyroid gland, an increasing number of studies report TH production in other tissues. Based on these findings, we evaluated whether the genes required for TH biosynthesis are expressed in the human heart, and whether their expression is altered in patients with ischemic cardiomyopathy (ICM) and is related to epigenetic variations. METHODS Twenty-three LV tissue samples were obtained from ICM patients (n=13) undergoing heart transplantation and control donors (n=10) for RNA sequencing analysis. We increased the LV samples to 27 for the ELISA determination of total T4 and T3 tissue levels. For epigenomic studies, 850K Infinium MethylationEPIC BeadChip platform was performed. RESULTS Using RNA-sequencing, we displayed the expression levels of all components required for TH biosynthesis in human heart tissue. We observed significantly altered expression of genes encoding thyroperoxidase (TPO; -2.48-fold, P<0.05) and dual oxidase 2 (2.83-fold, P<0.05), the main enzymatic system of TH production, and significant relationships between their altered expression and LV remodeling parameters. In addition, epigenetic analysis revealed a differential methylation pattern in TPO, and triiodothyronine tissue levels were significantly decreased (P<0.01). CONCLUSIONS These results showed that the human heart expresses the TH biosynthesis machinery, being altered its main enzymatic system in patients with ICM. Given the relevance of TH in cardiac pathology, our results provide a foundation for new therapeutic approaches based on TPO for treating ICM.