Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

Citation: Hajje G, Saliba Y, Itani T, Moubarak M, Aftimos G, et al. ( Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling Georges Hajje 0 Youakim Saliba 0 Tarek Itani 0 Majed Moubarak 0 Georges Aftimos 0 Nassim Fare` s 0 Sudhiranjan Gupta, Texas A& M University Health Science Center, United States of America 0 1 Laboratoire de Recherche en Physiologie et Physiopathologie, Faculte de Me decine, Po le Technologie Sante , Universite Saint Joseph, Beirut, Lebanon, 2 Institut National de Pathologie , Baabda , Lebanon The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-a), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-b1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. - Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This work was funded and supported by the Research Council of the Saint Joseph University - Faculty of Medicine. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. "GH and YS should be considered co-first authors on this work. It is estimated that more than 12% of the US population will develop a thyroid condition during their lifetime, and an estimated 20 million Americans have already some form of thyroid disease [1]. Besides, some of the most prominent and common symptoms of thyroid disease are those that result from the effects of thyroid hormone on the heart and cardiovascular system [2,3,4,5,6,7,8,9,10,11]. Both hyperthyroidism and hypothyroidism produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance [12,13,14,15,16,17]. Several important cardiac structural and functional proteins are transcriptionally regulated by thyroid hormones. The proteins that are positively regulated by thyroid hormones include sarcoplasmic reticulum calcium ATPase (SERCA2) that uptakes calcium into the sarcoplasmic reticulum during diastole [4,18], alpha myosin heavy chain (a-MHC) the fast myosin with higher ATPase activity as well as beta adrenergic receptors, sodium/potassium ATPase and voltage-gated potassium channels Kv1.5, Kv4.2 and Kv4.3 which together coordinate the electrochemical responses of the myocardium [3,6,17,19,20,21,22,23,24,25]; cardiac stress markers atrial and brain natriuretic peptides (ANP and BNP) are also regulated by thyroid hormones [19,20]. Other cardiac proteins are negatively regulated by thyroid hormones such as b-MHC the slow myosin, phospholamban the SERCA inhibitor and sodium/ calcium exchanger [5,19,20,26,27]. Thus, changes in the amounts of these proteins account for the altered cardiac diastolic and systolic function induced by thyroid disease. Non-genomic effects are also exerted by thyroid hormones on cardiac myocytes and ion transport [26,28]. In fact, triiodothyronine (T3) exerts effects on various sodium, potassium, and calcium channels in the heart, and thus changes in intracellular levels of calcium and potassium can increase inotropy and chronotropy [5,29,30]. Hypertrophied and, in particular, failing hearts are characterized by an accumulation of extracellular matrix elements and a corresponding increase in cardiac muscle stiffness [31,32,33,34, 35,36,37,38,39,40]. Fibronectin and collagen types I and III are the major components of the interstitial fibrillar network [41,42,43,44]; thus, it has been hypothesized that the up-regulation of fibroblasts genes encoding these components accounts, in part, for the increase in fibrosis observed during the transition to heart failure and contributes to the decline in contractile performance [31,45,46,47,48,49,50]. The elaboration of the extracellular matrix by fibroblasts is influenced by TGF-b1 and plays an important role in pressure-overload cardiac hypertrophy [51,52,53]. The cytokine TGF-b1 is expressed by and modulates myocytes, vascular cells and fibroblasts [54,55]; its expression rises in myocardium in experimental and human heart disease [55,56], and it promotes hypertrophy, fibrosis, apoptosis, and endothelial-mesenchymal transition [57,58,59,60]. Furthermore, a generalized increase in the level of contractile proteins, such as b-MHC and myofibroblast marker alpha smooth muscle actin (a-SMA), constitutes a marker of cardiac hypertrophy [61,62]. Shifts from the normally predominant aMHC toward b-MHC are often observed in cardiomyocytes from hypertrophied and failing hearts [63,64,65,66]. a-SMA is expressed in cardiomyocytes during early stages of heart development and in dedifferentiated cardiac fibroblasts and its reactivation is considered a potential marker of ventricular hypertrophy [67,68,69]. Finally, the BNP serum level is also considered to be one of several criteria indicating the initiation of a pathological response in hypertrophied failing hearts [70,71,72]. Cardiac and circulating pro-inflammatory markers such as CRP, interleukins and TNF-a have been also associated with cardiac disease [7 (...truncated)