Digestive Diseases and Sciences

, Volume 61, Issue 5, pp 1246–1267 | Cite as

Cardiovascular Disease and Myocardial Abnormalities in Nonalcoholic Fatty Liver Disease

  • Alessandro Mantovani
  • Stefano Ballestri
  • Amedeo Lonardo
  • Giovanni TargherEmail author


Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in many developed countries, affecting an estimated 30 % of the adult population. In this updated clinical review, we summarize the current knowledge regarding the strong association between NAFLD and the risk of coronary heart disease (CHD) and other functional, structural, and arrhythmic cardiac complications (e.g., left ventricular dysfunction, heart valve diseases and atrial fibrillation). We also briefly discuss the putative biological mechanisms linking NAFLD with these important extra-hepatic complications. To date, a large body of evidence has suggested that NAFLD is not simply a marker of CHD and other functional, structural, and arrhythmic cardiac complications, but also may play a part in the development and progression of these cardiac complications. The clinical implication of these findings is that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions aimed at decreasing the risk of CHD and other cardiac and arrhythmic complications.


Nonalcoholic fatty liver disease Cardiovascular disease Cardiac disease Cardiac arrhythmias Myocardial dysfunction Heart valve diseases 



G. T. is supported in part by grants from the University School of Medicine of Verona.

Compliance with ethical standards

Conflict of interest



  1. 1.
    Nascimbeni F, Pais R, Bellentani S, et al. From NAFLD in clinical practice to answers from guidelines. J Hepatol. 2013;59:859–871.PubMedCrossRefGoogle Scholar
  2. 2.
    Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013;10:330–344.PubMedCrossRefGoogle Scholar
  3. 3.
    Lonardo A, Bellentani S, Argo CK, et al. Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups. Dig Liver Dis. 2015;47:997–1006.PubMedCrossRefGoogle Scholar
  4. 4.
    Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62:S47–S64.PubMedCrossRefGoogle Scholar
  5. 5.
    Armstrong MJ, Adams LA, Canbay A, Syn WK. Extra-hepatic complications of nonalcoholic fatty liver disease. Hepatology. 2014;59:1174–1197.PubMedCrossRefGoogle Scholar
  6. 6.
    Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341–1350.PubMedCrossRefGoogle Scholar
  7. 7.
    Ballestri S, Lonardo A, Bonapace S, Byrne CD, Loria P, Targher G. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20:1724–1745.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Goland S, Shimoni S, Zornitzki T, et al. Cardiac abnormalities as a new manifestation of nonalcoholic fatty liver disease: echocardiographic and tissue Doppler imaging assessment. J Clin Gastroenterol. 2006;40:949–955.PubMedCrossRefGoogle Scholar
  9. 9.
    Fallo F, Dalla Pozza A, Sonino N, et al. Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension. Nutr Metab Cardiovasc Dis. 2009;19:646–653.PubMedCrossRefGoogle Scholar
  10. 10.
    Fotbolcu H, Yakar T, Duman D, et al. Impairment of the left ventricular systolic and diastolic function in patients with non-alcoholic fatty liver disease. Cardiol J. 2010;17:457–463.PubMedGoogle Scholar
  11. 11.
    Bonapace S, Perseghin G, Molon G, et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care. 2012;35:389–395.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Mantovani A, Zoppini G, Targher G, Golia G, Bonora E. Non-alcoholic fatty liver disease is independently associated with left ventricular hypertrophy in hypertensive type 2 diabetic individuals. J Endocrinol Invest. 2012;35:215–218.PubMedCrossRefGoogle Scholar
  13. 13.
    Hallsworth K, Hollingsworth KG, Thoma C, et al. Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease. J Hepatol. 2013;58:757–762.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim NH, Park J, Kim SH, et al. Non-alcoholic fatty liver disease, metabolic syndrome and subclinical cardiovascular changes in the general population. Heart. 2014;100:938–943.PubMedCrossRefGoogle Scholar
  15. 15.
    Karabay CY, Kocabay G, Kalayci A, et al. Impaired left ventricular mechanics in nonalcoholic fatty liver disease: a speckle-tracking echocardiography study. Eur J Gastroenterol Hepatol. 2014;26:325–331.PubMedCrossRefGoogle Scholar
  16. 16.
    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;62:773–783.PubMedCrossRefGoogle Scholar
  17. 17.
    Cassidy S, Hallsworth K, Thoma C, et al. Cardiac structure and function are altered in type 2 diabetes and non-alcoholic fatty liver disease and associate with glycemic control. Cardiovasc Diabetol. 2015;14:23.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Kocabay G, Karabay CY, Colak Y, et al. Left atrial deformation parameters in patients with non-alcoholic fatty liver disease: a 2D speckle tracking imaging study. Clin Sci (Lond). 2014;126:297–304.CrossRefGoogle Scholar
  19. 19.
    Granér 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. 2015;8:e001979.PubMedCrossRefGoogle Scholar
  20. 20.
    Mantovani A, Pernigo M, Bergamini C, et al. Nonalcoholic fatty liver disease is independently associated with early left ventricular diastolic dysfunction in patients with type 2 diabetes. PLoS One. 2015;10:e0135329.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Petta S, Argano C, Colomba D, et al. Epicardial fat, cardiac geometry and cardiac function in patients with non-alcoholic fatty liver disease: association with the severity of liver disease. J Hepatol. 2015;62:928–933.PubMedCrossRefGoogle Scholar
  22. 22.
    Sunbul M, Kivrak T, Durmus E, et al. Nonalcoholic steatohepatitis score is an independent predictor of right ventricular dysfunction in patients with nonalcoholic fatty liver disease. Cardiovasc Ther. 2015;33:294–299.PubMedCrossRefGoogle Scholar
  23. 23.
    Bonci E, Chiesa C, Versacci P, Anania C, Silvestri L, Pacifico L. Association of nonalcoholic fatty liver disease with subclinical cardiovascular changes: a systematic review and meta-analysis. Biomed Res Int. 2015;2015:213737.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Sert A, Aypar E, Pirgon O, Yilmaz H, Odabas D, Tolu I. Left ventricular function by echocardiography, tissue Doppler imaging, and carotid intima-media thickness in obese adolescents with nonalcoholic fatty liver disease. Am J Cardiol. 2013;112:436–443.PubMedCrossRefGoogle Scholar
  25. 25.
    Alp H, Karaarslan S, Eklioğlu BS, Atabek ME, Altın H, Baysal T. Association between nonalcoholic fatty liver disease and cardiovascular risk in obese children and adolescents. Can J Cardiol. 2013;29:1118–1125.PubMedCrossRefGoogle Scholar
  26. 26.
    Singh GK, Vitola BE, Holland MR, et al. Alterations in ventricular structure and function in obese adolescents with nonalcoholic fatty liver disease. J Pediatr. 2013;162:1160–1180.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Fintini D, Chinali M, Cafiero G, et al. Early left ventricular abnormality/dysfunction in obese children affected by NAFLD. Nutr Metab Cardiovasc Dis. 2014;24:72–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Pacifico L, Di Martino M, De Merulis A, et al. Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology. 2014;59:461–470.PubMedCrossRefGoogle Scholar
  29. 29.
    Dhingra R, Gona P, Wang TJ, Fox CS, D’Agostino RB, Vasan RS. Serum gamma-glutamyltransferase and risk of heart failure in the community. Arterioscler Thromb Vasc Biol. 2010;30:1855–1860.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Wannamethee SG, Whincup PH, Shaper AG, Lennon L, Sattar N. Gamma-glutamyltransferase, hepatic enzymes, and risk of incident heart failure in older men. Arterioscler Thromb Vasc Biol. 2012;32:830–835.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang Y, Tuomilehto J, Jousilahti P, et al. Serum gamma-glutamyltransferase and the risk of heart failure in men and women in Finland. Heart. 2013;99:163–167.PubMedCrossRefGoogle Scholar
  32. 32.
    Markus MR, Baumeister SE, Stritzke J, et al. Hepatic steatosis is associated with aortic valve sclerosis in the general population: the Study of Health in Pomerania (SHIP). Arterioscler Thromb Vasc Biol. 2013;33:1690–1695.PubMedCrossRefGoogle Scholar
  33. 33.
    Bonapace S, Valbusa F, Bertolini L, et al. Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus. PLoS One. 2014;9:e88371.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Mantovani A, Pernigo M, Bergamini C, et al. Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease. Metabolism. 2015;64:879–887.PubMedCrossRefGoogle Scholar
  35. 35.
    Otto CM, Prendergast B. Aortic-valve stenosis—from patients at risk to severe valve obstruction. N Engl J Med. 2014;371:744–756.PubMedCrossRefGoogle Scholar
  36. 36.
    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;35:1781–1786.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Völzke H, Haring R, Lorbeer R, et al. Heart valve sclerosis predicts all-cause and cardiovascular mortality. Atherosclerosis. 2010;209:606–610.PubMedCrossRefGoogle Scholar
  38. 38.
    Fox CS, Vasan RS, Parise H, et al. Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study. Circulation. 2003;107:1492–1496.PubMedCrossRefGoogle Scholar
  39. 39.
    Rahman F, Kwan GF, Benjamin EJ. Global epidemiology of atrial fibrillation. Nat Rev Cardiol. 2014;11:639–654.PubMedCrossRefGoogle Scholar
  40. 40.
    Diabetes mellitus; auricular fibrillation; arteriosclerosis obliterans of the legs; gangrene of the 1st and 2d toes of the right foot; fatty degeneration of the liver. Arq Bras Med. 1952; 42:212–216.Google Scholar
  41. 41.
    Sinner MF, Wang N, Fox CS, et al. Relation of circulating liver transaminase concentrations to risk of new-onset atrial fibrillation. Am J Cardiol. 2013;111:219–224.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Alonso A, Misialek JR, Amiin MA, et al. Circulating levels of liver enzymes and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities cohort. Heart. 2014;100:1511–1516.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Targher G, Mantovani A, Pichiri I, et al. Non-alcoholic fatty liver disease is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes. Clin Sci (Lond). 2013;125:301–309.CrossRefGoogle Scholar
  44. 44.
    Targher G, Valbusa F, Bonapace S, et al. Non-alcoholic fatty liver disease is associated with an increased incidence of atrial fibrillation in patients with type 2 diabetes. PLoS One. 2013;8:e57183.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Käräjämäki A, Pätsi OP, Savolainen M, Kesäniemi YA, Huikuri HV, Ukkola O. Non-alcoholic fatty liver disease as a predictor of atrial fibrillation in middle-aged population (OPERA study). PLoS One. 2015;10:e0142937.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Ozveren O, Izgi C, Eroglu E, et al. Doppler tissue evaluation of atrial conduction properties in patients with non-alcoholic fatty liver disease. Ultrason Imaging. Epub. 07/08/2015.Google Scholar
  47. 47.
    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;47:362–367.PubMedCrossRefGoogle Scholar
  48. 48.
    Okin PM, Devereux RB, Lee ET, Galloway JM, Howard BV. Electrocardiographic repolarization complexity and abnormality predict all-cause and cardiovascular mortality in diabetes: the Strong Heart study. Diabetes. 2004;53:434–440.PubMedCrossRefGoogle Scholar
  49. 49.
    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;24:663–669.PubMedCrossRefGoogle Scholar
  50. 50.
    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:e001820.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Hu YF, Chen YJ, Lin YJ, Chen SA. Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol. 2015;12:230–243.PubMedCrossRefGoogle Scholar
  52. 52.
    Hamirani YS, Pandey S, Rivera JJ, et al. Markers of inflammation and coronary artery calcification: a systematic review. Atherosclerosis. 2008;201:1–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Sung KC, Wild SH, Kwag HJ, Byrne CD. Fatty liver, insulin resistance, and features of metabolic syndrome: relationships with coronary artery calcium in 10,153 people. Diabetes Care. 2012;35:2359–2364.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kim D, Choi SY, Park EH, et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology. 2012;56:605–613.PubMedCrossRefGoogle Scholar
  55. 55.
    Lee MK, Park HJ, Jeon WS, et al. Higher association of coronary artery calcification with non-alcoholic fatty liver disease than with abdominal obesity in middle-aged Korean men: the Kangbuk Samsung Health Study. Cardiovasc Diabetol. 2015;14:88–95.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Liu J, Musani SK, Bidulescu A, et al. Fatty liver, abdominal adipose tissue and atherosclerotic calcification in African Americans: the Jackson Heart Study. Atherosclerosis. 2012;224:521–525.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Chhabra R, O’Keefe JH, Patil H, et al. Association of coronary artery calcification with hepatic steatosis in asymptomatic individuals. Mayo Clin Proc. 2013;88:1259–1265.PubMedCrossRefGoogle Scholar
  58. 58.
    Oni ET, Agatston AS, Blaha MJ, et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis. 2013;230:258–267.PubMedCrossRefGoogle Scholar
  59. 59.
    Lautamäki 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:E282–E290.PubMedCrossRefGoogle Scholar
  60. 60.
    Yilmaz Y, Kurt R, Yonal O, et al. Coronary flow reserve is impaired in patients with nonalcoholic fatty liver disease: association with liver fibrosis. Atherosclerosis. 2010;211:182–186.PubMedCrossRefGoogle Scholar
  61. 61.
    Nakamori S, Onishi K, Nakajima H, et al. Impaired myocardial perfusion reserve in patients with fatty liver disease assessed by quantitative myocardial perfusion magnetic resonance imaging. Circ J. 2012;76:2234–2240.PubMedCrossRefGoogle Scholar
  62. 62.
    Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30:1212–1218.PubMedCrossRefGoogle Scholar
  63. 63.
    Targher G, Bertolini L, Padovani R, et al. Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes. J Hepatol. 2010;53:713–718.PubMedCrossRefGoogle Scholar
  64. 64.
    Lin YC, Lo HM, Chen JD. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol. 2005;11:4838–4842.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Mellinger JL, Pencina KM, Massaro JM, et al. Hepatic steatosis and cardiovascular disease outcomes: an analysis of the Framingham Heart Study. J Hepatol. 2015;63:470–476.PubMedCrossRefGoogle Scholar
  66. 66.
    Chan WK, Tan AT, Vethakkan SR, Tah PC, Vijayananthan A, Goh KL. Ultrasonography-diagnosed non-alcoholic fatty liver disease is not associated with prevalent ischemic heart disease among diabetics in a multiracial Asian hospital clinic population. Clin Res Hepatol Gastroenterol. 2014;38:284–291.PubMedCrossRefGoogle Scholar
  67. 67.
    Arslan U, Türkoğlu S, Balcioğlu S, Tavil Y, Karakan T, Cengel A. Association between nonalcoholic fatty liver disease and coronary artery disease. Coron Artery Dis. 2007;18:433–436.PubMedCrossRefGoogle Scholar
  68. 68.
    Açikel M, Sunay S, Koplay M, Gündoğdu F, Karakelleoğlu S. Evaluation of ultrasonographic fatty liver and severity of coronary atherosclerosis, and obesity in patients undergoing coronary angiography. Anadolu Kardiyol Derg. 2009;9:273–279.PubMedGoogle Scholar
  69. 69.
    Wong VW, Wong GL, Yip GW, et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut. 2011;60:1721–1727.PubMedCrossRefGoogle Scholar
  70. 70.
    Choi DH, Lee SJ, Kang CD, et al. Nonalcoholic fatty liver disease is associated with coronary artery disease in Koreans. World J Gastroenterol. 2013;19:6453–6457.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Idilman IS, Akata D, Hazirolan T, et al. Nonalcoholic fatty liver disease is associated with significant coronary artery disease in type 2 diabetic patients: a computed tomography angiography study. J Diabetes. 2015;7:279–286.PubMedCrossRefGoogle Scholar
  72. 72.
    Ampuero J, Gallego-Durán R, Romero-Gómez M. Association of NAFLD with subclinical atherosclerosis and coronary–artery disease: meta-analysis. Rev Esp Enferm Dig. 2015;107:10–16.PubMedGoogle Scholar
  73. 73.
    Ballestri S, Romagnoli D, Nascimbeni F, Francica G, Lonardo A. Role of ultrasound in the diagnosis and treatment of nonalcoholic fatty liver disease and its complications. Expert Rev Gastroenterol Hepatol. 2015;9:603–627.PubMedCrossRefGoogle Scholar
  74. 74.
    Boddi M, Tarquini R, Chiostri M, et al. Nonalcoholic fatty liver in nondiabetic patients with acute coronary syndromes. Eur J Clin Invest. 2013;43:429–438.PubMedCrossRefGoogle Scholar
  75. 75.
    Inci MF, Özkan F, Ark B, et al. Sonographic evaluation for predicting the presence and severity of coronary artery disease. Ultrasound Q. 2013;29:125–130.PubMedCrossRefGoogle Scholar
  76. 76.
    Akabame S, Hamaguchi M, Tomiyasu K, et al. Evaluation of vulnerable coronary plaques and non-alcoholic fatty liver disease (NAFLD) by 64-detector multislice computed tomography (MSCT). Circ J. 2008;72:618–625.PubMedCrossRefGoogle Scholar
  77. 77.
    Puchner SB, Lu MT, Mayrhofer T, et al. High-risk coronary plaque at coronary CT angiography is associated with nonalcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial. Radiology. 2015;274:693–701.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Osawa K, Miyoshi T, Yamauchi K, et al. Nonalcoholic hepatic steatosis is a strong predictor of high-risk coronary-artery plaques as determined by multidetector CT. PLoS One. 2015;10:e0131138.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Emre A, Terzi S, Celiker E, et al. Impact of nonalcoholic fatty liver disease on myocardial perfusion in nondiabetic patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Am J Cardiol. 2015;116:1810–1814.PubMedCrossRefGoogle Scholar
  80. 80.
    Shi KQ, Wu FL, Liu WY, et al. Non-alcoholic fatty liver disease and risk of in-stent restenosis after bare metal stenting in native coronary arteries. Mol Biol Rep. 2014;41:4713–4720.PubMedCrossRefGoogle Scholar
  81. 81.
    Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–649.PubMedCrossRefGoogle Scholar
  82. 82.
    Targher G, Byrne CD. Circulating markers of liver function and cardiovascular disease risk. Arterioscler Thromb Vasc Biol. 2015;35:2290–2296.PubMedCrossRefGoogle Scholar
  83. 83.
    Schindhelm RK, Dekker JM, Nijpels G, et al. Alanine aminotransferases predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis. 2007;191:391–396.PubMedCrossRefGoogle Scholar
  84. 84.
    Jepsen P, Vilstrup H, Mellemkjaer L, et al. Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study. Hepatogastroenterology. 2003;50:2101–2104.PubMedGoogle Scholar
  85. 85.
    Targher G, Bertolini L, Rodella S, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007;30:2119–2121.PubMedCrossRefGoogle Scholar
  86. 86.
    Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. 2007;13:1579–1584.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Haring R, Wallaschofski H, Nauck M, Dörr M, Baumeister SE, Völzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyltranspeptidase levels. Hepatology. 2009;50:1403–1411.PubMedCrossRefGoogle Scholar
  88. 88.
    Lazo M, Hernaez R, Bonekamp S, et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ. 2011;343:d6891.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol. 2012;10:646–650.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhou YJ, Li YY, Nie YQ, Huang CM, Cao CY. Natural course of nonalcoholic fatty liver disease in southern China: a prospective cohort study. J Dig Dis. 2012;13:153–160.PubMedCrossRefGoogle Scholar
  91. 91.
    Treeprasertsuk S, Leverage S, Adams LA, Lindor KD. St Sauver J, Angulo P. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int. 2012;32:945–950.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Younossi ZM, Otgonsuren M, Venkatesan C, Mishra A. In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not. Metabolism. 2013;62:352–360.PubMedCrossRefGoogle Scholar
  93. 93.
    Kim D, Kim WR, Kim HJ, Therneau TM. Association between non-invasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013;57:1357–1365.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Pisto P, Santaniemi M, Bloigu R, et al. Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study. BMJ Open. 2014;4:e004973.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Pickhardt PJ, Hahn L, Muñoz del Rio A, et al. Natural history of hepatic steatosis: observed outcomes for subsequent liver and cardiovascular complications. Am J Roentgenol. 2014;202:752–758.CrossRefGoogle Scholar
  96. 96.
    Wong VW, Wong GL, Yeung JC, et al. Long-term clinical outcomes after fatty liver screening in patients undergoing coronary angiogram: a prospective cohort study. Hepatology. 2015. doi: 10.1002/hep.28253.Google Scholar
  97. 97.
    Moon SH, Hong SP, Cho YS, et al. Hepatic FDG uptake is associated with future cardiovascular events in asymptomatic individuals with non-alcoholic fatty liver disease. J Nucl Cardiol. Epub. 10/28/2015.Google Scholar
  98. 98.
    Targher G, Byrne CD. Nonalcoholic fatty liver disease, cardiovascular outcomes and mortality in patients undergoing a coronary angiogram. Hepatology. 2015. doi: 10.1002/hep.28306.PubMedGoogle Scholar
  99. 99.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419.PubMedCrossRefGoogle Scholar
  100. 100.
    Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–755.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Adams L, Lymp JF, St Sauver J, et al. The natural history of non-alcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121.PubMedCrossRefGoogle Scholar
  102. 102.
    Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873.PubMedCrossRefGoogle Scholar
  103. 103.
    Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–238.PubMedCrossRefGoogle Scholar
  104. 104.
    Söderberg C, Stål P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602.PubMedCrossRefGoogle Scholar
  105. 105.
    Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–1554.PubMedCrossRefGoogle Scholar
  106. 106.
    Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–397.PubMedCrossRefGoogle Scholar
  107. 107.
    Lonardo A, Ballestri S, Targher G, Loria P. Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol. 2015;9:629–650.PubMedCrossRefGoogle Scholar
  108. 108.
    Byrne CD, Targher G. Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease. Arterioscler Thromb Vasc Biol. 2014;34:1155–1161.PubMedCrossRefGoogle Scholar
  109. 109.
    Targher G, Byrne CD. Diagnosis and management of nonalcoholic fatty liver disease and its hemostatic/thrombotic and vascular complications. Semin Thromb Hemost. 2013;39:214–228.PubMedCrossRefGoogle Scholar
  110. 110.
    Loria P, Carulli L, Bertolotti M, Lonardo A. Endocrine and liver interaction: the role of endocrine pathways in NASH. Nat Rev Gastroenterol Hepatol. 2009;6:236–247.PubMedCrossRefGoogle Scholar
  111. 111.
    Dongiovanni P, Donati B, Fares R, et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol. 2013;19:6969–6978.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Pirola CJ, Sookoian S. The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for non-alcoholic fatty liver: a meta-analysis. Hepatology. 2015;62:1742–1756.PubMedCrossRefGoogle Scholar
  113. 113.
    Silaghi CA, Silaghi H, Crăciun AE, et al. Age, abdominal obesity, and glycated hemoglobin are associated with carotid atherosclerosis in type 2 diabetes patients with nonalcoholic fatty liver disease. Med Ultrason. 2015;17:300–307.PubMedGoogle Scholar
  114. 114.
    Hong HC, Hwang SY, Ryu JY, et al. The synergistic impact of non-alcoholic fatty liver disease and metabolic syndrome on subclinical atherosclerosis. Clin Endocrinol (Oxf). 2015. doi: 10.1111/cen.12940.Google Scholar
  115. 115.
    Ito M, Adachi-Akahane S. Inter-organ communication in the regulation of lipid metabolism: focusing on the network between the liver, intestine, and heart. J Pharmacol Sci. 2013;123:312–317.PubMedCrossRefGoogle Scholar
  116. 116.
    Kelly CR, Kahn S, Kashyap P, et al. Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook. Gastroenterology. 2015;149:223–237.PubMedCrossRefGoogle Scholar
  117. 117.
    Tilg H, Moschen AR. Microbiota and diabetes: an evolving relationship. Gut. 2014;63:1513–1521.PubMedCrossRefGoogle Scholar
  118. 118.
    Sweeney TE, Morton JM. The human gut microbiome: a review of the effect of obesity and surgically induced weight loss. JAMA Surg. 2013;148:563–569.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. 2011;121:2126–2132.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Le Roy T, Llopis M, Lepage P, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62:1787–1794.PubMedCrossRefGoogle Scholar
  121. 121.
    Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology. 2011;140:976–986.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Jiang C, Xie C, Li F, et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest. 2015;125:386–402.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Wieland A, Frank DN, Harnke B, Bambha K. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2015;42:1051–1063.PubMedCrossRefGoogle Scholar
  124. 124.
    Gregory JC, Buffa JA, Org E, et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J Biol Chem. 2015;290:5647–5660.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Cannon JA, McMurray JJ. Gut feelings about heart failure. J Am Coll Cardiol. 2014;64:1915–1916.PubMedCrossRefGoogle Scholar
  126. 126.
    Serino M, Blasco-Baque V, Nicolas S, Burcelin R. Far from the eyes, close to the heart: dysbiosis of gut microbiota and cardiovascular consequences. Curr Cardiol Rep. 2014;16:540–547.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014;124:4204–4211.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Caldwell SH, Swerdlow RH, Khan EM, et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. 1999;31:430–434.PubMedCrossRefGoogle Scholar
  129. 129.
    Caldwell SH, de Freitas LA, Park SH, et al. Intra-mitochondrial crystalline inclusions in nonalcoholic steatohepatitis. Hepatology. 2009;49:1888–1895.PubMedCrossRefGoogle Scholar
  130. 130.
    Dominic EA, Ramezani A, Anker SD, Verma M, Mehta N, Rao M. Mitochondrial cytopathies and cardiovascular disease. Heart. 2014;100:611–618.PubMedCrossRefGoogle Scholar
  131. 131.
    Heusch G, Libby P, Gersh B, et al. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet. 2014;383:1933–1943.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest. 2006;116:1813–1822.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Lonardo A, Loria P, Argo C, Caldwell S. Perspectives on cellular dysfunction in nonalcoholic steatohepatitis: a case of ‘multiorganelle failure’? Proceedings of a virtual workshop on nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5:135–139.PubMedCrossRefGoogle Scholar
  134. 134.
    Caldwell S. NASH (nonalcoholic steatohepatitis): a case of multiorganelle failure. Free Radic Biol Med. 2014;75:S6.PubMedCrossRefGoogle Scholar
  135. 135.
    Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res. 2008;102:488–496.PubMedCrossRefGoogle Scholar
  136. 136.
    Lonardo A, Lombardini S, Scaglioni F, et al. Fatty liver, carotid disease and gallstones: a study of age-related associations. World J Gastroenterol. 2006;12:5826–5833.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Singh S, Allen AM, Wang Z, et al. Fibrosis progression in nonalcoholic fatty liver vs. non-alcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13:643–654.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Adams LA. NAFLD. Accurate quantification of hepatic fat—is it important? Nat Rev Gastroenterol Hepatol. 2015;12:126–127.PubMedCrossRefGoogle Scholar
  139. 139.
    Pastori D, Polimeni L, Baratta F, Pani A, Del Ben M, Angelico F. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis. 2015;47:4–11.PubMedCrossRefGoogle Scholar
  140. 140.
    Trebicka J, Schierwagen R. Statins, Rho GTPases and KLF2: new mechanistic insight into liver fibrosis and portal hypertension. Gut. 2015;64:1349–1350.PubMedCrossRefGoogle Scholar
  141. 141.
    Lonardo A, Loria P. Potential for statins in the chemoprevention and management of hepatocellular carcinoma. J Gastroenterol Hepatol. 2012;27:1654–1664.PubMedCrossRefGoogle Scholar
  142. 142.
    Lonardo A, Loria P. If steatosis is the atherosclerosis of the liver, are statins the “aspirin” for steatosis? Dig Liver Dis. 2012;44:451–452.PubMedCrossRefGoogle Scholar
  143. 143.
    Dongiovanni P, Petta S, Mannisto V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015;63:705–712.PubMedCrossRefGoogle Scholar
  144. 144.
    Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143:1158–1172.PubMedCrossRefGoogle Scholar
  145. 145.
    Hendrikx T, Walenbergh SM, Hofker MH, Shiri-Sverdlov R. Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non-alcoholic steatohepatitis. Obes Rev. 2014;15:424–433.PubMedCrossRefGoogle Scholar
  146. 146.
    Mahajan R, Lau DH, Brooks AG, et al. Electrophysiological, electro-anatomical, and structural remodeling of the atria as consequences of sustained obesity. J Am Coll Cardiol. 2015;66:1–11.PubMedCrossRefGoogle Scholar
  147. 147.
    Al Chekakie MO, Welles CC, Metoyer R, et al. Pericardial fat is independently associated with human atrial fibrillation. J Am Coll Cardiol. 2010;56:784–788.PubMedCrossRefGoogle Scholar
  148. 148.
    Ding J, Hsu FC, Harris TB, et al. The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr. 2009;90:499–504.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Jeong JW, Jeong MH, Yun KH, et al. Echocardiographic epicardial fat thickness and coronary artery disease. Circ J. 2007;71:536–539.PubMedCrossRefGoogle Scholar
  150. 150.
    Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation. 2003;108:2460–2466.PubMedCrossRefGoogle Scholar
  151. 151.
    Mazurek T, Kiliszek M, Kobylecka M, et al. Relation of pro-inflammatory activity of epicardial adipose tissue to the occurrence of atrial fibrillation. Am J Cardiol. 2014;113:1505–1508.PubMedCrossRefGoogle Scholar
  152. 152.
    Eveborn GW, Schirmer H, Lunde P, Heggelund G, Hansen JB, Rasmussen K. Assessment of risk factors for developing incident aortic stenosis: the Tromsø Study. Eur J Epidemiol. 2014;29:567–575.PubMedCrossRefGoogle Scholar
  153. 153.
    Owens DS, Katz R, Johnson E, et al. Interaction of age with lipoproteins as predictors of aortic valve calcification in the multi-ethnic study of atherosclerosis. Arch Intern Med. 2008;168:1200–1207.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Chan KL, Dumesnil JG, Tam J, Ni A, Teo K. Effect of rosuvastatin on C-reactive protein and progression of aortic stenosis. Am Heart J. 2011;161:1133–1139.PubMedCrossRefGoogle Scholar
  155. 155.
    Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–1356.PubMedCrossRefGoogle Scholar
  156. 156.
    Wu SJ, Zou H, Zhu GQ, et al. Increased levels of systolic blood pressure within the normal range are associated with significantly elevated risks of nonalcoholic fatty liver disease. Medicine (Baltimore). 2015;94:e842.CrossRefGoogle Scholar
  157. 157.
    Chung GE, Kim D, Kwark MS, et al. Visceral adipose tissue area as an independent risk factor for elevated liver enzyme in nonalcoholic fatty liver disease. Medicine (Baltimore). 2015;94:e573.CrossRefGoogle Scholar
  158. 158.
    Ix JH, Chertow GM, Shlipak MG, Brandenburg VM, Ketteler M, Whooley MA. Association of fetuin-A with mitral annular calcification and aortic stenosis among persons with coronary heart disease: data from the Heart and Soul Study. Circulation. 2007;115:2533–2539.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Sato M, Kamada Y, Takeda Y, et al. Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects. Liver Int. 2015;35:925–935.PubMedCrossRefGoogle Scholar
  160. 160.
    Chatterjee S, Bavishi C, Sardar P, et al. Meta-analysis of left ventricular hypertrophy and sustained arrhythmias. Am J Cardiol. 2014;114:1049–1052.PubMedCrossRefGoogle Scholar
  161. 161.
    Sesti G, Sciacqua A, Fiorentino TV, Perticone M, Succurro E, Perticone F. Association between noninvasive fibrosis markers and cardio-vascular organ damage among adults with hepatic steatosis. PLoS One. 2014;9:e104941.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Sun W, Zhang D, Sun J, et al. Association between non-alcoholic fatty liver disease and autonomic dysfunction in a Chinese population. QJM. 2015;108:617–624.PubMedCrossRefGoogle Scholar
  163. 163.
    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:e61803.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Pimenta NM, Santa-Clara H, Cortez-Pinto H, et al. Body composition and body fat distribution are related to cardiac autonomic control in non-alcoholic fatty liver disease patients. Eur J Clin Nutr. 2014;68:241–246.PubMedCrossRefGoogle Scholar
  165. 165.
    Jakovljevic DG, Hallsworth K, Zalewski P, et al. Resistance exercise improves autonomic regulation at rest and haemodynamic response to exercise in non-alcoholic fatty liver disease. Clin Sci (Lond). 2013;125:143–149.CrossRefGoogle Scholar
  166. 166.
    Lonardo A, Sookoian S, Pirola CJ, Targher G. Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism. 2015. doi: 10.1016/j.metabol.2015.09.017.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Alessandro Mantovani
    • 1
  • Stefano Ballestri
    • 2
  • Amedeo Lonardo
    • 3
  • Giovanni Targher
    • 1
    Email author
  1. 1.Division of Endocrinology, Diabetes and Metabolism, Department of MedicineUniversity and Azienda Ospedaliera Universitaria IntegrataVeronaItaly
  2. 2.Division of Internal Medicine, Pavullo HospitalAzienda USL of ModenaPavulloItaly
  3. 3.Outpatient Liver Clinic and Division of Internal Medicine, Department of Biomedical, Metabolic and Neural Sciences, NOCSAE, Baggiovara, Azienda USLUniversity of Modena and Reggio EmiliaModenaItaly

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