Are epicardial adipose tissue and transforming growth factor beta1 risk factors of atrial fibrillation in patients with metabolic syndrome?

Objective. To determine the relationship between the thickness of epicardial adipose tissue (EAT) and the serum concentration of transforming growth factor beta1 (TGF-beta1) with the severity of left atrial myocardial fibrosis in patients with metabolic syndrome (MS) and to define the role of these factors in atrial fibrillation (AF) development.

Design and methods. The study included 258 patients: patients with MS without AF (n = 57), patients with MS and AF (n = 83), patients with AF without MS (n = 36), and otherwise healthy subjects without cardiovascular disease and metabolic disorders (n = 82). Serum level of TGF-beta1 was assessed by ELISA. Epicardial adipose tissue thickness (EAT) was measured by ultrasound on the Vivid 7 apparatus (General Electric, USA). To assess fibrosis we constructed anatomical and amplitude maps of the left atrium (LA) using the non-fluoroscopic electro-anatomical mapping system CARTO3 (Biosense Webster, USA)

Results. EAT in patients with MS and AF is higher than in patients with MS without AF (4,7 ± 1,9 and 4,2 ± 1,6 mm, respectively, p = 0,023), higher than in patients with AF without MS (4,7 ± 1,9 and 4,3 ± 1,7 mm, p = 0,01) and significantly higher than in healthy subjects (4,7 ± 1,9 and 2,3 ± 0,9 mm, respectively, p < 0,001). The EAT positively correlated with the percentage of fibrosis of LA estimated by the mapping method (r = 0,549, p < 0,0001). The serum concentration of TGF-beta1 in patients with AF and MS was 6700,2 [2588,4, 17500,3] pg/ml. It was 4,7 times higher than in healthy subjects (p < 0,0001), 2,6 times higher than in patients with MS without AF and higher than in patients with AF without MS. Positive correlations were found between TGF-beta1 and LA volume (r = 0,203, p = 0,03). Binomial regression analysis showed that the probability of AF presence in patients with MS was higher when traditional predictors of this arrhythmia were present — the volume of the LA (odds ratio (OR) = 1,092, 95% confidence interval (CI) 1,026–1,162, p = 0,005), systolic blood pressure (OR = 1,093, 95% CI 1,021–1,169, p = 0,01), as well as EAT (OR = 2,21, 95% CI 1,111–4,386, p = 0,024) and TGF-beta1 (OR = 1,01, 95% CI 1,006–1,015, p = 0,002).

Conclusions. Thickness of epicardial adipose tissue and transforming growth factor beta1 are associated with AF also in MS. Probably, epicardial fat and transforming growth factor beta1 stimulate atrial myocardial fibrosis which is the risk factor of AF. 

1. Yoshida T, Fujii T, Uchino S, Takinami M. Epidemiology, prevention, and treatment of new-onset atrial fibrillation in critically ill: a systematic review. JIntensive Care. 2015;3(11):1–11. doi:10.1186/s40560-015-0085-4

2. Norberg J, Bäckström S, Jansson JH, Johansson L. Estimating the prevalence of atrial fibrillation in a general population using validated electronic health data. Clin Epidemiol. 2015; 3: (19) 1–11. doi:10.2147/CLEP.S53420

3. Chen LY, Sotoodehnia N, Buzkova P, Lopez FL, Yee LM, Heckbert SR et al. Atrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study. JAMAIntern Med. 2013;173 (1):29–35. doi:10.1001/2013.jamainternmed.744

4. Chamberlain AM, Agarwal SK, Ambrose M, Folsom AR, Soliman EZ, Alonso A. Metabolic syndrome and incidence of atrial fibrillation among blacks and whites in the Atherosclerosis Risk in Communities Study. Am Heart J. 2010;159(5):159–164. doi:10.1016/j.ahj.2010.02.005

5. Mohanty S, Mohanty P, Di Biase L, Bai R, Pump A, Santangeli P et al. Impact of metabolic syndrome on procedural outcomes in patients with atrial fibrillation undergoing catheter ablation. J Am Coll Cardiol. 2012;59(14):1295–301. doi:10.1016/j. jacc.2011.11.051

6. Nalliah CJ, Sanders P, Kottkamp H, Kalman JM. The role of obesity in atrial fibrillation. Eur Heart J. 2016;37(20):1565–1572. doi:10.1093/eurheartj/ehv486

7. Lavie CJ, Pandey A, Lau DH, Alpert MA, Sanders P. Obesity and atrial fibrillation prevalence, pathogenesis, and prognosis. Effects of weight loss and exercise. J Am Coll Cardiol. 2017;70 (16):2022–2035. doi:10.1016/j.jacc.2017.09.002

8. Haemers P, Hamdi H, Guedj K, Suffee N, Farahmand P, Popovic N et al. Atrial fibrillation is associated with the fibrotic remodeling of adipose tissue in the subepicardium of human and sheep atria. Eur Heart J. 2017;38(1):53–61. doi:10.1093/eurheartj/ehv625

9. Aune D, Sen A, Schlesinger S, Norat T, Janszky I, Romundstad P. Body mass index, abdominal fatness, fat mass and risk of atrial fibrillation: a systemic review and dose-response metaanalysis of prospective studies. Eur J

10. Epidemiol. 2017;32(3):181–192. doi:10.1093/eurheartj/ ehv625 Ионин В. А., Листопад О.В., Нифонтов С. Е., Баранова Е. И., Соболева А. В., Шляхто Е. В. Роль галектина 3 и эпикардиального жира в развитии фибрилляции предсердий при метаболическом синдроме. Ученые записки СанктПетербургского государственного медицинского университета имени академика И.П. Павлова. 2015;22(1):43–46. doi:10.24884/1607-4181-2015-22-1-43-46 [Ionin VA, Listopad OV, Nifontov SE, Baranova EI, Soboleva AV, Shlyakhto EV. Role of galectin 3 and epicardial fat thickness in the development of atrial fibrillation in patients with metabolic syndrome. The Scientific Notes of the I.P. Pavlov St. Petersburg State Medical University. 2015;22(1):43–46. doi:10.24884/1607-4181-2015-22-1-43-46 In Russian].

11. Antonopoulos AS, Antoniades C. The role of epicardial adipose tissue in cardiac biology: classic concepts and emerging roles. J Physiol. 2017;595(12):3907–3917. doi:10.1113/JP273049

12. Hatem SN, Redheuil A, Gandjbakhch E. Cardiac adipose tissue and atrial fibrillation: the perils of adiposity. Cardiovasc Res. 2016;109(4):502–509. doi:10.1093/cvr/cvw001

13. Tsai CT, Chiang FT, Tseng CD, Hwang JJ, Kuo KT, Wu CK, et al. Increased expression of mineralocorticoid receptor in human atrial fibrillation and a cellular model of atrial fibrillation. J Am Coll Cardiol. 2010;55(8):758–770. doi:10.1016/j.jacc.2009.09.045

14. Cao H, Zhou Q, Lan R, Roe OD, Chen X, Chen Y et al. A functional polymorphism C 509Tin TGFβ-1 promoter contributes to susceptibility and prognosis of lone atrial fibrillation in Chinese population. PLoS One. 2014;9(11):e112912. doi:10.1371/journal.pone.0112912

15. Li J, Yang Y, Ng CY, Zhang Z, Liu T, Li G.Association of plasma transforming growth factor-β1 levels and the risk of atrial fibrillation: a meta-analysis. PLoS One. 2016;11(5):e0155275. doi:10.1371/journal.pone.0155275

16. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab. 2003;88(11):5163–5168. doi:10.1210/jc.2003-030698

17. Заславская Е.Л., Морозов А.Н., Ионин В.А., Ма И, Нифонтов С.Е., Баранова Е.И. и др. Роль трансформирующего фактора роста бета1 и галектина 3 в формировании фиброза левого предсердия у пациентов с пароксизмальной формой фибрилляции предсердий и метаболическим синдромом. Российский кардиологический журнал. 2018;154(2):60–66. doi:10.15829/1560-4071-2018-2-60-66 [Zaslavskaya EL, Morozov AN, Ionin VA, Ma I, Nifontov SЕ, Baranova ЕI et al. The role of transforming growth factor beta 1 and galectin 3 in formation of the left atrium fibrosisin patients with paroxysmal atrial fibrillation and metabolic. Russian Journal of Cardiology. 2018;(2):60–66. doi:10. 15829/1560-4071-2018-2-60-66 In Russian].

18. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC et al. AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology. J Am Coll Cardiol. 2014;64(21):e1–76. doi:10.1016/j. jacc.2014.03.022

19. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation. 1994;89(2):724–730. doi:10.1161/01.CIR.89.2.724

20. Stritzke J, Markus MR, Duderstadt S, Lieb W, Luchner A, Döring A et al. The aging process of the heart. Obesity is the main risk factor for left atrial enlargement during aging. The MONICA/KORA (monitoring of trends and determinations in cardiovascular disease/cooperative research in the region of Augsburg) study. J Am Coll Cardiol. 2009;54(21):1982–1989. doi:10.1161/01.CIR.89.2.724

21. Alpert MA, Omran J, Bostick PB. Effects of obesity on cardiovascular hemodynamics, cardiac morphology, and ventricular function. Curr Obes Rep. 2016;5(4):424–434. doi:10.1007/s13679-016-0235-6

22. Venteclef N, Guglielmi V, Balse E, Gaborit B, Cotillard A, Atassi F et al. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J. 2015;36(13):795–805. doi:10.1093/eurheartj/eht099

23. Gaeta M, Bandera F, Tassinari F, Capasso L, Cargnelutti M, Pelissero G et al. Is epicardial fat depot associated with atrial fibrillation? A systematic review and meta-analysis. Europace. 2017;19(5):747–752. doi:10.1093/europace/euw398

24. Salazar J, Luzardo E, Mejías JC, Rojas J, Ferreira A, Rivas-Ríos JR et al. Epicardial fat: physiological, pathological, and therapeutic implications. Cardiol Res Pract. 2016; article ID:1291537;1–15. doi:10.1155/2016/1291537

25. Протасов К.В., Доржиева В.З., Батунова Е.В.. Биомаркеры почечной функции и системного фиброза у больных фибрилляцией предсердий. Забайкальский мед. вестн. 2017;2:20– 27. [Protasov KV, Dorzhieva VZ, Batunova EV. Biomarkers of renal function and fibrosis in patients with atrial fibrillation. Transbaikalian Medical Bulletin. 2017(2)20–27. In Russian].

26. Abed HS, Samuel CS, Lau DH Kelly DJ, Royce SG, Alasady M et al. Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. Heart Rhythm. 2013;10(1):90–100. doi:10.1016/jhrthm.2012.08.043

27. Rahmutula DI, Marcus GM, Wilson EE, Ding CH, Xiao Y, Paquet AC et al. Molecular basis of selective atrial fibrosis due to overexpression of transforming growth factor-β1. Cardiovasc Res. 2013;99(4):769–779. doi:10.1093/cvr/cvt074

28. Khan, R. Sheppard R. Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology. 2006;118(1):10–24. doi:10.1016/j.jacc.2015.06.1313

29. Biernacka A, Dobaczewski M, Frangogiannis NG. TGFβ-1 signaling in fibrosis. Growth Factors. 2011;29(5):196–202 doi:10.1016/j.bbadis.2009.06.004

30. Wang Y, HouX, Li Y.Association between transforming growth factor 1 polymorphisms and atrial fibrillation in essential hypertensive subjects. J Biomed Science. 2010;17(23):1–5. doi:10.1186/1423- 0127-17-23

31. Wang Q, Xi W, Yin L Wang J, Shen H, Gao Y et al. Human epicardial adipose tissue cTGF expression is an independent risk factor for atrial fibrillation and highly associated with atrial fibrosis. Scientific Reports. 2018;8(1):3585. doi:10.1038/s41598-018-21911-y