Non-alcoholic fatty liver disease as an independent factor of cardiometabolic risk of cardiovascular diseases

Non-alcoholic fatty liver disease (NAFLD) is a pressing public health problem affecting up to a third of the world's adult population. The main reasons for its high mortality rate are cardiovascular diseases. They are caused by subclinical atherosclerosis characteristic of NAFLD, venous thromboembolic complications, functional and structural myocardial disorders, calcification of heart valves, heart rhythm and conduction disturbances. At the same time, NAFLD can serve as an independent factor of the cardiometabolic risk of their development, which is associated with atherogenic dyslipidemia, as well as the release of numerous pro-inflammatory mediators both from the pathologically altered liver and as a result of systemic endotoxemia, which is the result of disturbance of the intestinal microbiota, accompanied by a decrease in intestinal microbial gene richness., a change in its composition and function, followed by bacterial translocation. Considering that most patients with NAFLD die from cardiovascular complications, it becomes obvious that exclusively “liver-oriented” principles of their treatment cannot be sufficient, but require a multidisciplinary team approach involving cardiologists, cardiac surgeons and doctors of other related specialties.

1. Ivashkin V.T., Mayevskaya M. V., Pavlov C. S., et al. Diagnostics and treatment of non-alcoholic fatty liver disease: clinical guidelines of the Russian Scientific Liver Society and the Russian gastroenterological association. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2016;26(2):24-42. (In Russ.) doi: 10.22416/1382-4376-2016-26-2-24-42.

2. Adams LA, Roberts SK, Strasser SI, et al. Nonalcoholic fatty liver disease burden: Australia, 2019-2030. J Gastroenterol Hepatol. 2020;35 (9):1628-35. doi: 10.1111/jgh.15009.

3. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015; 62 (Suppl 1): S47-64. doi: 10.1016/j.jhep.2014.12.012.

4. Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014;2(11):901-10. doi: 10.1016/S2213-8587(14)70032-4.

5. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37(4):917-23. doi: 10.1053/jhep.2003.50161.

6. Brunt EM, Kleiner DE, Wilson LA, et al. NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53(3):810-20. doi: 10.1002/hep.24127.

7. Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a populationbased study. Gut. 2010;59(10):1410-5. doi: 10.1136/gut.2010.213553.

8. Yamamura S, Eslam M, Kawaguchi T, et al. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int. 2020;40(12):3018-30. doi: 10.1111/liv.14675.

9. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415-45. doi: 10.1146/annurev-immunol-031210-101322.

10. Gehrke N, Schattenberg JM. Metabolic Inflammation-A Role for Hepatic Inflammatory Pathways as Drivers of Comorbidities in Nonalcoholic Fatty Liver Disease? Gastroenterology. 2020;158(7):1929-47. doi: 10.1053/j.gastro.2020.02.020.

11. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836-46. doi: 10.1002/hep.24001.

12. Calder PC. Fatty acids and inflammation: the cutting edge between food and pharma. Eur J Pharmacol. 2011;668 (Suppl 1):50-58. doi: 10.1016/j.ejphar.2011.05.085.

13. Fernandez-Real JM, Vayreda M, Richart C, et al. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab. 2001;86(3):1154-9. doi: 10.1210/jcem.86.3.7305.

14. Golabi P, Paik JM, Arshad T, et al. Mortality of NAFLD According to the Body Composition and Presence of Metabolic Abnormalities. Hepatol Commun. 2020;4(8):1136-48. doi: 10.1002/hep4.1534.

15. Katsiki N, Athyros VG, Mikhailidis DP. Abnormal Peri-Organ or Intra-organ Fat (APIFat) Deposition: An Underestimated Predictor of Vascular Risk? Curr Vasc Pharmacol. 2016; 14(5):432-41. doi: 10.2174/1570161114666160722112738.

16. Tilg H, Moschen AR, Szabo G. Interleukin-1 and in-flammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2016;64(3):955-65. doi: 10.1002/hep.28456.

17. Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11(2):183-90. doi: 10.1038/nm1166.

18. Kiechl S, Wittmann J, Giaccari A, et al. Blockade of receptor activator of nuclear factor-кВ (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat Med. 2013;19(3):358-63. doi: 10.1038/nm.3084.

19. Stienstra R, van Diepen JA, Tack CJ, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A. 2011;108(37):15324-9. doi: 10.1073/pnas.1100255108.

20. Wree A, McGeough MD, Pena CA, et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl). 2014;92(10):1069-82. doi: 10.1007/s00109-014-1170-1.

21. Mridha AR, Wree A, Robertson AAB, et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol. 2017;66(5): 1037-46. doi: 10.1016/j.jhep.2017.01.022.

22. Baroja-Mazo A, Martm-Sanchez F, Gomez AI, et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol. 2014;15(8):738-48. doi: 10.1038/ni.2919.

23. Feve B, Bastard JP. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2009;5(6):305-11. doi: 10.1038/nrendo.2009.62.

24. Vandanmagsar B, Youm YH, Ravussin A, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011; 17(2):179-88. doi: 10.1038/nm.2279.

25. Nati M, Haddad D, Birkenfeld AL, et al. The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH). Rev Endocr Metab Disord. 2016;17(1):29-39. doi: 10.1007/s11154-016-9339-2.

26. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi: 10.1002/hep.28431.

27. Loomba R, Wong R, Fraysse J, et al. Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther. 2020;51(11):1149-59. doi: 10.1111/apt.15679.

28. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44(4):865-73. doi: 10.1002/hep.21327.

29. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51(2):595-602. doi: 10.1002/hep.23314.

30. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7(2):234-8. doi: 10.1016/j.cgh.2008.11.005.

31. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004.

32. Mellinger JL, Pencina KM, Massaro JM, et al. Hepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study. J Hepatol. 2015;63(2):470-6. doi: 10.1016/j.jhep.2015.02.045.

33. Targher G, Byrne CD, Lonardo A, et al. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol. 2016;65(3):589-600. doi: 10.1016/j.jhep.2016.05.013.

34. Parisinos CA, Hingorani AD. Is a fatty liver (always or ever) bad for the heart? Eur Heart J. 2018;39(5):394-6. doi: 10.1093/eurheartj/ehx718.

35. Henson JB, Simon TG, Kaplan A, et al. Advanced fibrosis is associated with incident cardiovascular disease in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Th er. 2020;51(7):728-36. doi: 10.1111/apt.15660.

36. Long MT, Zhang X, Xu H, et al. Hepatic Fibrosis Associates With Multiple Cardiometabolic Disease Risk Factors: The Framingham Heart Study. Hepatology. 2021;73(2): 548-59. doi: 10.1002/hep.31608.

37. Than NN, Newsome PN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis. 2015; 239(1):192-202. doi: 10.1016/j.atherosclerosis.2015.01.001.

38. Dusi V, Ghidoni A, Ravera A, et al. Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems. Mediators Inflamm. 2016; 2016: 5902947. doi: 10.1155/2016/5902947.

39. Duewell P, Kono H, Rayner K, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357-61. doi: 10.1038/nature08938.

40. Koeth RA, Lam-Galvez BR, Kirsop J, et al. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest. 2019;129(1):373-87. doi: 10.1172/JCI94601.

41. Wang Z, Bergeron N, Levison BS, et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur Heart J. 2019;40(7):583-94. doi: 10.1093/eurheartj/ehy799.

42. Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575-84. doi: 10.1056/NEJMoa1109400.

43. Qi J, You T, Li J, et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J Cell Mol Med. 2018;22(1):185-94. doi: 10.1111/jcmm.13307.

44. Roncal C, MarHnez-Aguilar E, Orbe J, et al. Trimethylamine-N-Oxide (TMAO) Predicts Cardiovascular Mortality in Peripheral Artery Disease. Sci Rep. 2019;9:15580. doi: 10.1038/s41598-019-52082-z.

45. Wu C, Xue F, Lian Y, et al. Relationship between elevated plasma trimethylamine N-oxide levels and increased stroke injury. Neurology. 2020;94(7):667-677. doi: 10.1212/WNL.0000000000008862.

46. Chen YM, Liu Y, Zhou RF, et al. Associations of gutflora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci Rep. 2016 ;6: 19076. doi: 10.1038/srep19076.

47. Zhu W, Gregory JC, Org E, et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016;165(1):111-24. doi: 10.1016/j.cell.2016.02.011.

48. Roberts AB, Gu X, Buffa JA, et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 2018; 24(9):1407-17. doi: 10.1038/s41591-018-0128-1.

49. Reiner MF, Muller D, Gobbato S, et al. Gut microbiotadependent trimethylamine-N-oxide (TMAO) shows a U-shaped association with mortality but not with recurrent venous thromboembolism. Thromb Res. 2019;174:40-7. doi: 10.1016/j.thromres.2018.12.011.

50. Newton JL, Jones DE, Henderson E, et al. Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance. Gut. 2008;57(6):807-13. doi: 10.1136/gut.2007.139303.

51. Liu YC, Hung CS, Wu YW, et al. Influence of non-alcoholic fatty liver disease on autonomic changes evaluated by the time domain, frequency domain, and symbolic dynamics of heart rate variability. PLoS One. 2013;8(4): e61803. doi: 10.1371/journal.pone.0061803.

52. Ozveren O, Dogdu O, Sengul C, et al. Deterioration of heart rate recovery index in patients with non-alcoholic fatty liver disease (NAFLD). Med Sci Monit. 2014;20:1539-43. doi: 10.12659/MSM.890741.

53. Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut. 2020; 69(9):1691-705. doi: 10.1136/gutjnl-2020-320622.

54. Arslan U, Yenerçağ M. Relationship between non-alcoholic fatty liver disease and coronary heart disease. World J Clin Cases. 2020;8(20):4688-99. doi: 10.12998/wjcc.v8.i20.4688.

55. Baratta F, Pastori D, Angelico F, et al. Nonalcoholic Fatty Liver Disease and Fibrosis Associated With Increased Risk of Cardiovascular Events in a Prospective Study. Clin Gastroenterol Hepatol. 2020;18(10):2324-31. doi: 10.1016/j.cgh.2019.12.026.

56. Trovato GM. Non-alcoholic fatty liver disease and Atherosclerosis at a crossroad: The overlap of a theory of change and bioinformatics. World J Gastrointest Pathophysiol. 2020;11 (3):57-63. doi: 10.4291/wjgp.v11. i3.57.

57. Chen Y, Xu M, Wang T, et al. Advanced fibrosis associates with atherosclerosis in subjects with nonalcoholic fatty liver disease. Atherosclerosis. 2015;241(1):145-50. doi: 10.1016/j.atherosclerosis.2015.05.002.

58. VanWagner LB. New insights into NAFLD and subclinical coronary atherosclerosis. J Hepatol. 2018;68(5):890-2. doi: 10.1016/j.jhep.2018.01.023.

59. Villanova N, Moscatiello S, Ramilli S, et al. Marchesiniet G. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;42(2):473-80. doi: 10.1002/hep.20781.

60. Sookoian S, Gianotti TF, Rosselli MS, et al. Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis. 2011;218 (2):378-85. doi: 10.1016/j.atherosclerosis.2011.05.014.

61. Kaneto H, Katakami N, Matsuhisa M, et al. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm. 2010;2010:453892. doi: 10.1155/2010/453892.

62. Ando W, Yokomori H, Tsutsui N, et al. Serum matrix metalloproteinase-1 level represents disease activity as opposed to fibrosis in patients with histologically proven nonalcoholic steatohepatitis. Clin Mol Hepatol. 2018;24(1):61-76. doi: 10.3350/cmh.2017.0030.

63. Xu X, Lu L, Dong Q, et al. Research advances in the relationship between nonalcoholic fatty liver disease and atherosclerosis. Lipids Health Dis. 2015;14:158. doi: 10.1186/s12944-015-0141-z.

64. Thomsen C, Abdulla J. Characteristics of high-risk coronary plaques identified by computed tomographic angiography and associated prognosis: a systematic review and meta-analysis. Eur Heart J Cardiovasc Imaging. 2016;17(2):120-9. doi: 10.1093/ehjci/jev325.

65. Lee SB, Park GM, Lee JY, et al. Association between non-alcoholic fatty liver disease and subclinical coronary atherosclerosis: An observational cohort study. J Hepatol. 2018;68 (5):1018-24. doi: 10.1016/j.jhep.2017.12.012.

66. Silaghi CA, Silaghi H, Colosi HA, et al. Prevalence and predictors of non-alcoholic fatty liver disease as defined by the fatty liver index in a type 2 diabetes population. Clujul Med. 2016;89(1):82-8. doi: 10.15386/cjmed-544.

67. Patil R, Sood GK. Non-alcoholic fatty liver disease and cardiovascular risk. World J Gastrointest Pathophysiol. 2017;8(2):51-8. doi: 10.4291/wjgp.v8.i2.51.

68. Wong VW, Wong GL, Yip GW, et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut. 2011;60(12):1721-7. doi: 10.1136/gut.2011.242016.

69. Friedrich-Rust M, Schoelzel F, Maier S, et al. Severity of coronary artery disease is associated with non-alcoholic fatty liver dis-ease: A single-blinded prospective mono-center study. PLoS One. 2017;1210):0186720. doi: 10.1371/journal.pone.0186720.

70. Boddi M, Tarquini R, Chiostri M, et al. Nonalcoholic fatty liver in nondiabetic patients with acute coronary syndromes. Eur J Clin Invest. 2013;43(5):429-38. doi: 10.1111/eci.12065.

71. Keskin M, Hayiroglu Mi, Uzun AO, et al. Effect of Nonalcoholic Fatty Liver Disease on In-Hospital and Long-Term Outcomes in Patients With ST-Segment Elevation Myocardial Infarction. Am J Cardiol. 2017;120(10):1720-6. doi: 10.1016/j.amjcard.2017.07.107.

72. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49(4):608-12. doi: 10.1016/j.jhep.2008.06.018.

73. Arslan U, Kocaoglu I, Balci M, et al. The association between impaired collateral circulation and non-alcoholic fatty liver in patients with severe coronary artery disease. J Cardiol. 2012;60(3):210-4. doi: 10.1016/j.jjcc.2012.05.003.

74. Ghoneim S, Dhorepatil A, Shah AR, et al. Non-alcoholic steatohepatitis and the risk of myocardial infarction: A population-based national study. World J Hepatol. 2020;12(7):378-88. doi: 10.4254/wjh.v12.i7.378.

75. Sinn DH, Kang D, Chang Y, et al. Non-alcoholic fatty liver disease and the incidence of myocardial infarction: A cohort study. J Gastroenterol Hepatol. 2020;35(5):833-9. doi: 10.1111/jgh.14856.

76. Anstee QM, Mantovani A, Tilg H, et al. Risk of cardiomyopathy and cardiac arrhythmias in patients with nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2018;15(7):425-39. doi: 10.1038/s41575-018-0010-0.

77. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363(14):1341-50. doi: 10.1056/NEJMra0912063.

78. Luo B, Li B, Wang W, et al. NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS One. 2014;9(8): e104771. doi: 10.1371/journal.pone.0104771.

79. Perseghin G, Lattuada G, De Cobelli F, et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology. 2008; 47(1):51-8. doi: 10.1002/hep.21983.

80. Rijzewijk LJ, Jonker JT, van der Meer RW, et al. Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J Am Coll Cardiol. 2010;56(3):225-33. doi: 10.1016/j.jacc.2010.02.049.

81. Lautamaki R, Borra R, Iozzo P, et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2006;291(2):282-90. doi: 10.1152/ajpendo.00604.2005.

82. VanWagner LB, Wilcox JE, Colangelo LA, et al. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study. Hepatology. 2015;62(3):773-83. doi: 10.1002/hep.27869.

83. Graner M, Nyman K, Siren R, et al. Ectopic fat depots and left ventricular function in nondiabetic men with nonalcoholic fatty liver disease. Circ Cardiovasc Imaging. 2014;8 (1):001979. doi: 10.1161/CIRCIMAGING.114.001979.

84. Widya RL, de Mutsert R, den Heijer M, et al. Association between Hepatic Triglyceride Content and Left Ventricular Diastolic Function in a Population-based Cohort: The Netherlands Epidemiology of Obesity Study. Radiology. 2016;279(2):443-50. doi: 10.1148/radiol.2015150035.

85. Jung JY, Park SK, Ryoo JH, et al. Effect of non-alcoholic fatty liver disease on left ventricular diastolic function and geometry in the Korean general population. Hepatol Res. 2017;47 (6):522-32. doi: 10.1111/hepr.12770.

86. Lee YH, Kim KJ, Yoo ME, et al. Association of non-alcoholic steatohepatitis with subclinical myocardial dysfunction in non-cirrhotic patients. J Hepatol. 2018;68(4):764-72. doi: 10.1016/j.jhep.2017.11.023.

87. Bonci E, Chiesa C, Versacci P, et al. Association of Nonalcoholic Fatty Liver Disease with Subclinical Cardiovascular Changes: A Systematic Review and Meta-Analysis. Biomed Res Int. 2015;2015:213737. doi: 10.1155/2015/213737.

88. Simon TG, Bamira DG, Chung RT, et al. Nonalcoholic Steatohepatitis is Associated with Cardiac Remodeling and Dysfunction. Obesity. 2017;25 (8):1313-6. doi: 10.1002/oby.21879.

89. Garbuzenko D. V. Multiorganic hemodynamic disorders in hepatic cirrhosis. Ther arkh. 2007;79(2):73-7 (In Russ.)

90. O'Neal WT, Efird JT, Nazarian S, et al. Mitral annular calcification and incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis. Europace. 2015;17(3):358-63. doi: 10.1093/europace/euu265.

91. Rossi A, Targher G, Zoppini G, et al. Aortic and mitral annular calcifications are predictive of all-cause and cardiovascular mortality in patients with type 2 diabetes. Diabetes Care. 2012;35(8):1781-6. doi: 10.2337/dc12-0134.

92. Mantovani A, Pernigo M, Bergamini C, et al. Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease. Metabolism. 2015;64(8):879-87. doi: 10.1016/j.metabol.2015.04.003.

93. Monnerat G, Alarcon ML, Vasconcellos LR, et al. Macrophage-dependent IL-1e production induces cardiac arrhythmias in diabetic mice. Nat Commun. 2016;7:13344. doi: 10.1038/ncomms13344.

94. Aschar-Sobbi R, Izaddoustdar F, Korogyi AS, et al. Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFa. Nat Commun. 2015;6:6018. doi: 10.1038/ncomms7018.

95. Fu XX, Zhao N, Dong Q, et al. Interleukin-17A contributes to the development of post-operative atrial fibrillation by regulating inflammation and fibrosis in rats with sterile pericarditis. Int J Mol Med. 2015;36(1):83-92. doi: 10.3892/ijmm.2015.2204.

96. Lip GY, Tse HF, Lane DA. Atrial fibrillation. Lancet. 2012;379(9816):648-61. doi: 10.1016/S0140-6736(11)61514-6.

97. Mantovani A, Dauriz M, Sandri D, et al. Association between non-alcoholic fatty liver disease and risk of atrial fibrillation in adult individuals: An updated meta-analysis. Liver Int. 2019;39(4):758-69. doi: 10.1111/liv.14044.

98. Cai X, Zheng S, Liu Y, et al. Nonalcoholic fatty liver disease is associated with increased risk of atrial fibrillation. Liver Int. 2020;40(7):1594-600. doi: 10.1111/liv.14461.

99. Haghbin H, Gangwani MK, Ravi SJK, et al. Nonalcoholic fatty liver disease and atrial fibrillation: possible pathophysiological links and therapeutic interventions. Ann Gastroenterol. 2020;33(6):603-14. doi: 10.20524/aog.2020.0550.

100. Straus SM, Kors JA, De Bruin ML, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47(2):362-7. doi: 10.1016/j.jacc.2005.08.067.

101. Targher G, Valbusa F, Bonapace S, et al. Association of nonalcoholic fatty liver disease with QTc interval in patients with type 2 diabetes. Nutr Metab Cardiovasc Dis. 2014;24(6): 663-9. doi: 10.1016/j.numecd.2014.01.005.

102. Hung CS, Tseng PH, Tu CH, et al. Nonalcoholic Fatty Liver Disease Is Associated With QT Prolongation in the General Population. J Am Heart Assoc. 2015;4(7): e001820. doi: 10.1161/JAHA.115.001820.

103. Mantovani A, Rigamonti A, Bonapace S, et al. Nonalcoholic Fatty Liver Disease Is Associated With Ventricular Arrhythmias in Patients With Type 2 Diabetes Referred for Clinically Indicated 24-Hour Holter Monitoring. Diabetes Care. 2016;39(8):1416-23. doi: 10.2337/dc16-0091.

104. Kwok CS, Rashid M, Beynon R, et al. Prolonged PR interval, first-degree heart block and adverse cardiovascular outcomes: a systematic review and meta-analysis. Heart. 2016; 102(9):672-80. doi: 10.1136/heartjnl-2015-308956.

105. Wijarnpreecha K, Panjawatanan P, Kroner PT, et al Association between cardiac conduction defect and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Ann Gastroenterol. 2020;33(6):661-6. doi: 10.20524/aog.2020.0535.

106. Mangi MA, Minhas AM, Rehman H, et al. Association of Non-alcoholic Fatty Liver Disease with Conduction Defects on Electrocardiogram. Cureus. 2017;9(3): e1107. doi: 10.7759/cureus.1107.

107. Mantovani A, Rigolon R, Pichiri I, et al. Nonalcoholic fatty liver disease is associated with an increased risk of heart block in hospitalized patients with type 2 diabetes mellitus. PLoS One. 2017;12(10): e0185459. doi: 10.1371/journal.pone.0185459.