The association between nonalcoholic fatty liver disease (NAFLD) with cardiovascular and cerebrovascular outcomes, as well as their clinical impact, has yet to be established in the literature. This meta-analysis aims to evaluate the association between the NAFLD patients and the risk of atrial fibrillation (AF), heart failure (HF), stroke, cardiovascular mortality (CVM), and revascularization incidence. We performed a systematic literature search using PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until August 2022. A total of 12 cohort studies with 18,055,072 patients (2,938,753 NAFLD vs 15,116,319 non-NAFLD) were included in our analysis. The mean age of the NAFLD patients group and the non-NAFLD group was comparable (55.68 vs 55.87). The most common comorbidities among the NAFLD patients group included hypertension (38% vs 24%) and diabetes mellitus (14% vs 8%). The mean follow-up duration was 6.26 years. The likelihood of AF (risk ratio (RR), 1.42 (95% CI 1.19, 1.68), p < 0.001), HF (RR, 1.43(95% CI 1.03, 2.00), p < 0.001), stroke (RR, 1.26(95% CI 1.16, 1.36), p < 0.001), revascularization (RR, 4.06(95% CI 1.44, 11.46), p = 0.01), and CVM (RR, 3.10(95% CI 1.43, 6.73), p < 0.001) was significantly higher in the NAFLD patients group compared to that of the non-NAFLD group. However, all-cause mortality was comparable between both the groups of patients (RR, 1.30 (95% CI 0.63, 2.67), p = 0.48). In conclusion, the patients with NAFLD are at increased risk of AF, HF, and CVM.
ChalasaniNYounossiZLavineJE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology2012; 55(6): 2005–2023.
2.
YounossiZAnsteeQMMariettiM, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol2018; 15(1): 11–20.
3.
RiaziKAzhariHCharetteJH, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol2022; 7(9): 851–861.
4.
EstesCRazaviHLoombaR, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease: Estes et al. Hepatology2018; 67(1): 123–133.
5.
KimDKimWRKimHJ, et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology2013; 57(4): 1357–1365.
6.
WilliamsCDStengelJAsikeMI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology2011; 140(1): 124–131.
7.
RazaSRajakSAnjumB, et al. Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma. Hepatoma Res2019; 5: 42.
8.
WongRJAguilarMCheungR, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology2015; 148(3): 547–555.
9.
OngJPElarinyHCollantesR, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg2005; 15(3): 310–315.
10.
LonardoABellentaniSArgoCK, et al. Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups. Digest Liver Dis2015; 47(12): 997–1006.
11.
FrancqueSMVan der GraaffDKwantenWJ.Non-alcoholic fatty liver disease and cardiovascular risk: pathophysiological mechanisms and implications. J Hepatol2016; 65(2): 425–443. DOI: 10.1016/j.jhep.2016.04.005
12.
LeeSRHanKDChoiEK, et al. Nonalcoholic fatty liver disease and the risk of atrial fibrillation stratified by body mass index: a nationwide population-based study. Sci Rep2021; 11(1): 3737.
13.
TargherGByrneCDTilgH.NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut2020; 69(9): 1691–1705.
14.
LabenzCHuberYMichelM, et al. Impact of NAFLD on the incidence of cardiovascular diseases in a primary care population in Germany. Dig Dis Sci2020; 65(7): 2112–2119.
15.
XuJDaiLZhangY, et al. Severity of nonalcoholic fatty liver disease and risk of future ischemic stroke events. Stroke2021; 52(1): 103–110.
16.
LongMTYinXLarsonMG, et al. Relations of liver fat with prevalent and incident atrial fibrillation in the Framingham Heart Study. JAHA2017; 6(5): e005227.
17.
AlexanderMLoomisAKvan der LeiJ, et al. Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults. BMJ. Epub ahead of print 8 October 2019. DOI: 10.1136/bmj.l5367.
18.
JaiswalVIshakAPeng AngS, et al. Hypovitaminosis D and cardiovascular outcomes: a systematic review and meta-analysis. IJC Heart & Vasculat2022; 40: 101019.
19.
JaiswalVAngSPYaqoobS, et al. Cardioprotective effects of influenza vaccination among patients with established cardiovascular disease or at high cardiovascular risk: a systematic review and meta-analysis. Eur J Prev Cardiol. Epub ahead of print 20 July 2022. DOI: 10.1093/eurjpc/zwac152.
20.
JaiswalVKhanNJaiswalA, et al. Early surgery vs conservative management among asymptomatic aortic stenosis: a systematic review and meta-analysis. IJC Heart Vasculat2022; 43: 101125.
21.
JaiswalVPeng AngSHanifM, et al. The racial disparity among post transcatheter aortic valve replacement outcomes: a meta-analysis. IJC Heart Vasculat2023; 44: 101170.
DerSimonianRLairdN.Meta-analysis in clinical trials. Contr Clin Trials1986; 7(3): 177–188.
24.
HigginsJPTThompsonSG.Quantifying heterogeneity in a meta-analysis. Statist Med2002; 21(11): 1539–1558.
25.
SterneJACSuttonAJIoannidisJPA, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ2011; 343(jul22 1): d4002–d4002.
26.
AllenAMTherneauTMMaraKC, et al. Women with nonalcoholic fatty liver disease lose protection against cardiovascular disease: a longitudinal cohort study. Am J Gastroenterol2019; 114(11): 1764–1771.
27.
BarattaFPastoriDAngelicoF, et al. Nonalcoholic fatty liver disease and fibrosis associated with increased risk of cardiovascular events in a prospective study. Clin Gastroenterol Hepatol2020; 18(10): 2324–2331.e4.
28.
IchikawaKMiyoshiTOsawaK, et al. Prognostic value of non-alcoholic fatty liver disease for predicting cardiovascular events in patients with diabetes mellitus with suspected coronary artery disease: a prospective cohort study. Cardiovasc Diabetol2021; 20(1): 8.
29.
VanWagnerLBWilcoxJENingH, et al. Longitudinal association of non-alcoholic fatty liver disease with changes in myocardial structure and function: the CARDIA study. JAHA2020; 9(4): e014279.
30.
KäräjämäkiAJPätsiOPSavolainenM, et al. Non-alcoholic fatty liver disease as a predictor of atrial fibrillation in middle-aged population (OPERA Study). PLoS One2015; 10(11): e0142937.
31.
MaWWuWWenW, et al. Association of NAFLD with cardiovascular disease and all-cause mortality: a large-scale prospective cohort study based on UK Biobank. Ther Adv Chron Dis2022; 13: 204062232211224.
32.
ZebILiDBudoffMJ, et al. Nonalcoholic fatty liver disease and incident cardiac events. J Am Coll Cardiol2016; 67(16): 1965–1966.
33.
HuangDQEl-SeragHBLoombaR.Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol2021; 18(4): 223–238.
34.
AkterS.Non-alcoholic fatty liver disease and steatohepatitis: risk factors and pathophysiology. Middle East J Dig Dis2022; 14(2): 167–181.
35.
ParkHELeeHChoiSY, et al. The risk of atrial fibrillation in patients with non-alcoholic fatty liver disease and a high hepatic fibrosis index. Sci Rep2020; 10(1): 5023.
36.
ChoiJLeeSRChoiEK, et al. Non-alcoholic fatty liver disease and the risk of incident atrial fibrillation in young adults: a nationwide population-based cohort study. Front Cardiovasc Med2022; 9: 832023.
37.
BotsMLSalonenJTElwoodPC, et al. Glutamyltransferase and risk of stroke: the EUROSTROKE project. J Epidemiol Community Health2002; 56(suppl. 1): i25–i29.
38.
MantovaniAPetraccaGCsermelyA, et al. Non-alcoholic fatty liver disease and risk of new-onset heart failure: an updated meta-analysis of about 11 million individuals. Gut. Epub ahead of print 25 July 2022. DOI: 10.1136/gutjnl-2022-327672.
39.
OstovanehMRAmbale-VenkateshBFujiT, et al. Association of liver fibrosis with cardiovascular diseases in the general population: the multi-ethnic study of atherosclerosis (MESA). Circ: Cardiovasc Imag2018; 11(3): e007241.
40.
GongHLiuXChengF.Relationship between non-alcoholic fatty liver disease and cardiac arrhythmia: a systematic review and meta-analysis. J Int Med Res2021; 49(9): 030006052110470.
41.
ParkJKimGKimH, et al. The association of hepatic steatosis and fibrosis with heart failure and mortality. Cardiovasc Diabetol2021; 20(1): 197.
42.
ShangYNasrPWidmanL, et al. Risk of cardiovascular disease and loss in life expectancy in NAFLD. Hepatology. Epub ahead of print 23 April 2022. DOI:10.1002/hep.32519.
43.
CiardulloSBianconiECannistraciR, et al. Peripheral artery disease and all-cause and cardiovascular mortality in patients with NAFLD. J Endocrinol Invest2022; 45(8): 1547–1553.
44.
ZhuWDengCJXuanLP, et al. Peripheral artery disease and risk of fibrosis deterioration in nonalcoholic fatty liver disease: a prospective investigation. Biomed Environ Sci2020; 33(4): 217–226.
45.
Mahfood HaddadTHamdehSKanmanthareddyA, et al. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: a systematic review and meta-analysis. Diabet Metabol Syndr Clin Res Rev2017; 11: S209–S216.
46.
KhalidYSDasuNRSugaH, et al. Increased cardiovascular events and mortality in females with NAFLD: a meta-analysis. Am J Cardiovasc Dis2020; 10(3): 258–271.
47.
FuCENgCHYongJN, et al. A meta-analysis on associated risk of mortality in nonalcoholic fatty liver disease. Endocrine Prac2023; 29(1): 33–39.
48.
LiuYZhongGCTanHY, et al. Nonalcoholic fatty liver disease and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis. Sci Rep2019; 9(1): 11124.
49.
BisacciaGRicciFMelchiorreE, et al. Cardiovascular morbidity and mortality related to non-alcoholic fatty liver disease: a systematic review and meta-analysis of prospective studies. Eur Heart J2021; 42(suppl. 1): ehab724.2462.
50.
HaJYimSYKaragozianR.Mortality and liver-related events in lean versus non-lean nonalcoholic fatty liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. Epub ahead of print 26 November 2022. DOI: 10.1016/j.cgh.2022.11.019.
51.
SaokaewSKanchanasurakitSThawichaiK, et al. Association of non-alcoholic fatty liver disease and all-cause mortality in hospitalized cardiovascular disease patients: a systematic review and meta-analysis. Medicine2021; 100(5): e24557.
52.
LiuH.Nonalcoholic fatty liver disease and cardiovascular disease. WJG2014; 20(26): 8407.
53.
AneniECOniETMartinSS, et al. Blood pressure is associated with the presence and severity of nonalcoholic fatty liver disease across the spectrum of cardiometabolic risk. J Hyperten2015; 33(6): 1207–1214.
54.
GeislerCERenquistBJ.Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones. J Endocrinol2017; 234(1): R1–R21.
55.
JungHNJungCH.The role of anti-inflammatory adipokines in cardiometabolic disorders: moving beyond adiponectin. Int J Mol Sci2021; 22(24): 13529.
56.
MonneratGAlarcónMLVasconcellosLR, et al. Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice. Nat Commun2016; 7(1): 13344.
57.
SarduCSantamariaMFunaroS, et al. Cardiac electrophysiological alterations and clinical response in cardiac resynchronization therapy with a defibrillator treated patients affected by metabolic syndrome. Medicine2017; 96(14): e6558.
58.
KimHWLeeDHLeeSA, et al. A relationship between serum potassium concentration and insulin resistance in patients with type 2 diabetes mellitus. Int Urol Nephrol2015; 47(6): 991–999.
59.
Nasiri-AnsariNAndroutsakosTFlessaCM, et al. Endothelial cell dysfunction and nonalcoholic fatty liver disease (NAFLD): a concise review. Cells2022; 11(16): 2511.
60.
KwakMSKimD.Non-alcoholic fatty liver disease and lifestyle modifications, focusing on physical activity. Korean J Intern Med2018; 33(1): 64–74.
61.
ArnettDKBlumenthalRSAlbertMA, et al. 2019ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines. Circulation2019; 140(11): e563–e595.
62.
LuoFDasAChenJ, et al. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol2019; 18(1): 54.
63.
NelsonRH.Hyperlipidemia as a risk factor for cardiovascular disease. Prim Care Clin Off Pract2013; 40(1): 195–211.
64.
DeGomaEMKnowlesJWAngeliF, et al. The evolution and refinement of traditional risk factors for cardiovascular disease. Cardiol Rev2012; 20(3): 118–129.
65.
IoannouGNWeissNSBoykoEJ, et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology2006; 43(5): 1145–1151.
66.
MossmannMWainsteinMVMarianiS, et al. Increased serum IL-6 is predictive of long-term cardiovascular events in high-risk patients submitted to coronary angiography: an observational study. Diabetol Metab Syndr2022; 14(1): 125.
67.
Fontes-CalTCMMattosRTMedeirosNI, et al. Crosstalk between plasma cytokines, inflammation, and liver damage as a new strategy to monitoring NAFLD progression. Front Immunol2021; 12: 708959.
68.
FerranniniGRosenthalNHansenMK, et al. Liver function markers predict cardiovascular and renal outcomes in the CANVAS Program. Cardiovasc Diabetol2022; 21(1): 127.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
