High Thyroid-Stimulating Hormone Level is Associated with the Risk of Developing Atherosclerosis in Subclinical Hypothyroidism

Abstract

The aim of our study was to assess the potential role of thyroid-stimulating hormone (TSH) in the risk of developing atherosclerosis in subclinical hypothyroidism (SCH). A cohort of 240 SCH patients and 150 euthyroid volunteers were recruited for the study. SCH patients were stratified into 2 groups according to TSH levels (group A: TSH<10 mIU/l; group B: TSH>10 mIU/l). All subjects were examined for clinical and biochemical parameters. Visfatin, omentin-1, and circulating endothelial biomarkers were measured. Patients in group B received l-thyroxine replacement to achieve euthyroidism; after 6 months of euthyroidism all measurements were repeated. Patients with SCH had higher total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and C-reactive protein (CRP) levels and lower nitric oxide (NO) and omentin-1 levels compared to euthyroid subjects (all p<0.05). TC, LDL-C, and CRP decreased significantly, while NO and omentin-1 levels increased significantly after l-thyroxine replacement. Based on multivariate liner stepwise regression analysis, omentin-1 was independently correlated with BMI and TSH; NO was independently correlated with age, TSH, LDL-C, and omentin-1. High TSH level contributes to endothelial dysfunction in SCH, while TSH-induced decrease of omentin-1 provides a new link between SCH and atherogenic risk.

Key words

thyroid-stimulating hormone - adipokines - subclinical hypothyroidism

*

^* The first two authors contributed equally to this work.

• References

• 1 Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Int Med 2000; 132: 270-278
• 2 Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC. Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med 2006; 119: 541-551
• 3 Fietta P, Delsante G. Focus on adipokines. Theor Biol Forum 2013; 106: 103-129
• 4 Rodriguez-Rodriguez E, Perea JM, Lopez-Sobaler AM, Ortega RM. Obesity, insulin resistance and increase in adipokines levels: importance of the diet and physical activity. Nutr Hospital 2009; 24: 415-421
• 5 Northcott JM, Yeganeh A, Taylor CG, Zahradka P, Wigle JT. Adipokines and the cardiovascular system: mechanisms mediating health and disease. Canad J Physiol Pharmacol 2012; 90: 1029-1059
• 6 DeClercq V, Enns JE, Yeganeh A, Taylor CG, Zahradka P. Modulation of cardiovascular function by adipokines. Cardiovasc Hematol Disorders Drug Targets 2013; 13: 59-72
• 7 Mattu HS, Randeva HS. Role of adipokines in cardiovascular disease. J Endocrinol 2013; 216: T17-T36
• 8 Ntaios G, Gatselis NK, Makaritsis K, Dalekos GN. Adipokines as mediators of endothelial function and atherosclerosis. Atherosclerosis 2013; 227: 216-221
• 9 Sorisky A, Bell A, Gagnon A. TSH receptor in adipose cells. Horm Metab Res 2000; 32: 468-474
• 10 Gagnon A, Langille ML, Chaker S, Antunes TT, Durand J, Sorisky A. TSH signaling pathways that regulate MCP-1 in human differentiated adipocytes. Metabolism 2014; 63: 812-821
• 11 Antunes TT, Gagnon A, Bell A, Sorisky A. Thyroid-stimulating hormone stimulates interleukin-6 release from 3T3-L1 adipocytes through a cAMP-protein kinase A pathway. Obesity research 2005; 13: 2066-2071
• 12 Yang RZ, Lee MJ, Hu H, Pray J, Wu HB, Hansen BC, Shuldiner AR, Fried SK, McLenithan JC, Gong DW. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab 2006; 290: E1253-E1261
• 13 de Souza Batista CM, Yang RZ, Lee MJ, Glynn NM, Yu DZ, Pray J, Ndubuizu K, Patil S, Schwartz A, Kligman M, Fried SK, Gong DW, Shuldiner AR, Pollin TI, McLenithan JC. Omentin plasma levels and gene expression are decreased in obesity. Diabetes 2007; 56: 1655-1661
• 14 Tan BK, Adya R, Farhatullah S, Lewandowski KC, O’Hare P, Lehnert H, Randeva HS. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 2008; 57: 801-808
• 15 Yamawaki H, Kuramoto J, Kameshima S, Usui T, Okada M, Hara Y. Omentin, a novel adipocytokine inhibits TNF-induced vascular inflammation in human endothelial cells. Biochem Biophys Res Commun 2011; 408: 339-343
• 16 Bessa SS, Hamdy SM, El-Sheikh RG. Serum visfatin as a non-traditional biomarker of endothelial dysfunction in chronic kidney disease: an Egyptian study. Eur J Int Med 2010; 21: 530-535
• 17 Pepene CE. Evidence for visfatin as an independent predictor of endothelial dysfunction in polycystic ovary syndrome. Clin Endocrinol 2012; 76: 119-125
• 18 Moreno-Navarrete JM, Ortega F, Castro A, Sabater M, Ricart W, Fernandez-Real JM. Circulating omentin as a novel biomarker of endothelial dysfunction. Obesity (Silver Spring, Md) 2011; 19: 1552-1559
• 19 Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vascul Biol 2003; 23: 168-175
• 20 Donnini D, Ambesi-Impiombato FS, Curcio F. Thyrotropin stimulates production of procoagulant and vasodilative factors in human aortic endothelial cells. Thyroid 2003; 13: 517-521
• 21 Dardano A, Ghiadoni L, Plantinga Y, Caraccio N, Bemi A, Duranti E, Taddei S, Ferrannini E, Salvetti A, Monzani F. Recombinant human thyrotropin reduces endothelium-dependent vasodilation in patients monitored for differentiated thyroid carcinoma. J Clin Endocrinol Metab 2006; 91: 4175-4178
• 22 Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, Salvetti A, Ferrannini E, Monzani F. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 2003; 88: 3731-3737
• 23 Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, Csiba L, Desvarieux M, Ebrahim S, Hernandez Hernandez R, Jaff M, Kownator S, Naqvi T, Prati P, Rundek T, Sitzer M, Schminke U, Tardif JC, Taylor A, Vicaut E, Woo KS. Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3^rd, 4^th and 5^th watching the risk symposia, at the 13^th, 15^th and 20^th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovascul Dis (Basel, Switzerland) 2012; 34: 290-296
• 24 Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 2012; 22: 1200-1235
• 25 Turemen EE, Cetinarslan B, Sahin T, Canturk Z, Tarkun I. Endothelial dysfunction and low grade chronic inflammation in subclinical hypothyroidism due to autoimmune thyroiditis. Endocr J 2011; 58: 349-354
• 26 Ozcan O, Cakir E, Yaman H, Akgul EO, Erturk K, Beyhan Z, Bilgi C, Erbil MK. The effects of thyroxine replacement on the levels of serum asymmetric dimethylarginine (ADMA) and other biochemical cardiovascular risk markers in patients with subclinical hypothyroidism. Clin Endocrinol 2005; 63: 203-206
• 27 Balzan S, Del Carratore R, Nicolini G, Beffy P, Lubrano V, Forini F, Iervasi G. Proangiogenic effect of TSH in human microvascular endothelial cells through its membrane receptor. J Clin Endocrinol Metab 2012; 97: 1763-1770
• 28 Tian L, Zhang L, Liu J, Guo T, Gao C, Ni J. Effects of TSH on the function of human umbilical vein endothelial cells. J Mol Endocrinol 2014; 52: 215-222
• 29 Shibata R, Ouchi N, Kikuchi R, Takahashi R, Takeshita K, Kataoka Y, Ohashi K, Ikeda N, Kihara S, Murohara T. Circulating omentin is associated with coronary artery disease in men. Atherosclerosis 2011; 219: 811-814
• 30 Yoo HJ, Hwang SY, Hong HC, Choi HY, Yang SJ, Seo JA, Kim SG, Kim NH, Choi KM, Choi DS, Baik SH. Association of circulating omentin-1 level with arterial stiffness and carotid plaque in type 2 diabetes. Cardiovascul Diabetol 2011; 10: 103
• 31 Yamawaki H, Tsubaki N, Mukohda M, Okada M, Hara Y. Omentin, a novel adipokine, induces vasodilation in rat isolated blood vessels. Biochemical and biophysical research communications 2010; 393: 668-672
• 32 Zhang YJ, Zhao W, Zhu MY, Tang SS, Zhang H. Thyroid-stimulating hormone induces the secretion of tumor necrosis factor-alpha from 3T3-L1 adipocytes via a protein kinase A-dependent pathway. Exp Clin Endocrinol Diabetes 2013; 121: 488-493
• 33 Antunes TT, Gagnon A, Langille ML, Sorisky A. Thyroid-stimulating hormone induces interleukin-6 release from human adipocytes through activation of the nuclear factor-kappaB pathway. Endocrinology 2008; 149: 3062-3066
• 34 Santini F, Galli G, Maffei M, Fierabracci P, Pelosini C, Marsili A, Giannetti M, Castagna MG, Checchi S, Molinaro E, Piaggi P, Pacini F, Elisei R, Vitti P, Pinchera A. Acute exogenous TSH administration stimulates leptin secretion in vivo. Eur J Endocrinol 2010; 163: 63-67