\title{Genetic and Molecular Aspects of Thyrotoxic Cardiomyopathy}

\author{Darya Aleksandrovna Savitskaya$^{1}$ and Babenko Ayu$^{2}$ \\
$^{1}$Federal North-West Medical Research Centre, Russia \\
$^{2}$Almazov National Medical Research Centre, Russia}

\section{Introduction}

In this review we focused on the cardiomyopathy, which develops secondary to thyrotoxicosis. Whereas its secondary etiology, there is still evidence of heritable component. The investigation of molecular and genetic basis of thyrotoxic cardiomyopathy (TCMP) can improve treatment strategies and provide new potential drug targets for its therapy. Also increasing understanding of the pathophysiology of TCMP will improve risk prediction of severe cardiovascular complication in patients with thyrotoxicosis. One of the genetic basis research directions is the study of the single nucleotide polymorphisms (SNPs) of various genes, so-called genes of susceptibility or genes -- candidates. It is significant line of TCMP investigation because limited success in severe TCMP treatment is due to the less understanding of its molecular pathophysiology.

Recent studies have shown the associations of different TCMP components with SNPs in genes encoding proteins involved in thyroid hormone effects on tissues and arrhythmogenesis. Thyroid hormone effects on the heart are multiple and are largely mediated by triiodothyronine (T3) action through nuclear-based thyroid receptors \cite{1}. Type 2 deiodinase (D2) is assumed to play the key role in T3 tissue concentration changes, at least, in the tissues (such as myocardium, vessel wall) with high D2 gene expression. To date, there are a lot of data about association of SNPs in D2 gene with changes in D2 activity. One of them is Thr92Ala. Ala/Ala homozygous patients demonstrate lower D2 tissue activity compared to Ala/Thr heterozygous and Thr/Thr homozygous patients. Therefore, this polymorphism can decrease T3 effects in tissues with high D2 gene expression \cite{2,3}. In 2009, Grineva et al. \cite{4} reported that SNP Thr92Ala in type 2 D2 contributes to the severity of TCMP. According to this research of 145 patients with Graves’ disease Thr92Ala D2 polymorphism is associated with lower heart rate, left ventricular mass index (LVMI) and lower risk of concentric left ventricle hypertrophy (LVH) \cite{4}. Heart rate in Thr/Thr homozygous and heterozygous patients (99.8$\pm$3.01 and 96.7$\pm$2.80 beats/min, correspondingly) was significantly higher than in Ala/Ala homozygous ones (87.2$\pm$5.30 beats/min, p $<$ 0.01). Thr/Thr allele prevalence in patients LVH was almost twice as high as in patients without LVH (75\% compared to 49.5\%, p = 0.01). So, Ala/Ala homozygous patients have less severe TCMP.

Another gene, involved in thyroid hormones impact on the myocardium is KCNE1 gene, which encodes the minK peptide, associates with KCNQ1 in vitro to generate a potassium current closely resembling the slowly activating delayed rectifier (IKs) \cite{5}. The findings indicate that KCNE1 gene is $\alpha$-thyroid receptors targets and is regulated by thyroid status: a marked decrease in minK mRNA occurs in hyperthyroid mice’ hearts and hearts of T3-receptor knockout mice \cite{6}. Moreover, literature data show the strong association of the polymorphism Ser38Gly in KCNE1 gene and some cardiac diseases such as long QT syndrome and atrial fibrillation \cite{7}. All these finding make KCNE1 gene and its SNP Ser38Gly interesting to investigate in patients with TCMP. Data from the study of 165 patients with Graves’ disease have shown an interaction of this SNP with TCMP in patients aged 45 and older. In this age group atrial fibrillation (AF) was significantly more prevalent in GG genotype carriers: 35.3\% (GG) vs 13.9\% (AG+AA) (p = 0.037). Also, there was a significant difference in systolic blood pressure (SBP) by KCNE1 codon 38 genotypes. SBP were significantly higher in allele G homozygotes as compared to allele A carriers: 124.89$\pm$15.14mm Hg vs 131.35$\pm$15.32mm Hg (p = 0.012) \cite{8}.

Recently it was considered that $\beta$1-adrenergic receptor (ADRB1) gene is also candidate gene for TCMP prediction, because of it mediates sympathetic inotropic and chronotropic effects in the heart and is involved in arrhythmogenesis \cite{9,10,11}, because the density of $\beta$1-AR in myocardium during thyrotoxicosis is considerably increased and thyroid hormones are important elements of the regulation of $\beta$1-AR expression and \cite{12,13}. But several recent studies in TCMP genetics have concluded that frequent polymorphisms in $\beta$1-adrenergic receptor gene ($\beta$1-AR) Gly389Arg and Ser49Gly have no strong associations with myocardial remodeling (evaluated by echocardiography