Nonalcoholic Fatty Liver Disease is Associated With Coronary Artery Disease and Subclinical Atherosclerosis
2016; Future Medicine; Volume: 12; Issue: 4 Linguagem: Inglês
10.2217/fca-2016-0033
ISSN1744-8298
Autores Tópico(s)Liver Disease and Transplantation
ResumoFuture CardiologyVol. 12, No. 4 EditorialFree AccessNonalcoholic fatty liver disease is associated with coronary artery disease and subclinical atherosclerosisWilbert S AronowWilbert S Aronow*Author for correspondence: E-mail Address: wsaronow@aol.com Cardiology Division, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY, USAPublished Online:13 Jun 2016https://doi.org/10.2217/fca-2016-0033AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: atherosclerotic cardiovascular diseasebrachial-ankle pulse wave velocitycardioankle vascular indexcarotid intima-media thicknesscoronary artery calcificationcoronary artery diseasenonalcoholic fatty liver diseaseFirst draft submitted: 9 April 2016; Accepted for publication: 25 April 2016; Published online: 13 June 2016Nonalcoholic fatty liver disease (NAFLD) is fatty infiltration of the liver in absence of significant alcohol intake, steatogenic medication or hereditary disorders and is a common cause of chronic liver disease. NAFLD is a liver manifestation of the metabolic syndrome [1]. Insulin resistance and increased oxidative stress predispose to NAFLD, and risk factors for NAFLD include metabolic syndrome, diabetes, obesity, lack of physical activity, smoking and a high-fat diet. Cardiovascular disease is a major cause of mortality in patients with NAFLD.Among 612 patients undergoing coronary angiography, NALFD diagnosed by ultrasonography was present in 58% of patients [2]. Coronary artery disease (CAD) was diagnosed by coronary angiography in 84.6% of patients with NAFLD and in 64.1% of patients without NALFD (p < 0.001). Patients with NAFLD had a 2.32-times higher prevalence of CAD than those without NAFLD independent of demographic and metabolic factors [2]. At 5-year follow-up of 2103 patients with Type 2 diabetes, those with NAFLD developed an 84% higher incidence of cardiovascular disease (CAD, ischemic stroke or death from cardiovascular causes) than those without NAFLTD (p < 0.001) [3]. The increased development of cardiovascular disease in patients with NAFLTD was independent of cardiovascular risk factors [3].A prospective observational study included 1637 healthy Japanese men and women who were followed for 5 years [4]. Among 1221 persons available for analysis of outcomes, the incidence of atherosclerotic cardiovascular disease (CAD, ischemic stroke and cerebral hemorrhage) was higher in persons with NAFLD at baseline than those without NAFLD. Multivariate analyses demonstrated that NAFLD predicted cardiovascular disease independent of cardiovascular risk factors (odds ratio: 4.12; p = 0.004) [4]. Both NAFLD and the metabolic syndrome predicted cardiovascular disease, but only NAFLD showed a significant correlation with cardiovascular disease by multivariate analysis [4].Pisto et al. followed 988 persons from 1991–2009 [5]. During follow-up, 13.5% of patients with a nonfatty liver, 24.2% of patients with moderate liver fat content and 29.2% of patients with severe fatty liver content developed a cardiovascular event (p < 0.001). Severe hepatic fat content was predictive of future cardiovascular events when adjusted for age, gender and study group (hazard ratio: 1.92; p < 0.01). The risk for future cardiovascular events remained significant (hazard ratio: 1.74; p < 0.01) after additional adjustment for smoking, use of alcohol, serum LDL cholesterol, BMI and systolic blood pressure [5].The association of NAFLD with CAD was investigated in 273 Type 2 diabetic patients undergoing coronary computed tomography for chest pain [6]. After adjustment for age, gender, obesity, hypertension, smoking and serum LDL cholesterol, NAFLD was associated with significant CAD (odds ratio: 2.128; p = 0.04) [6].A prospective study of 80 patients with the metabolic syndrome undergoing coronary angiography investigated the association between NAFLD diagnosed by abdominal ultrasonography and the severity of CAD [7]. Coronary angiography showed involvement of more vessels (2.5 ± 0.9 vs 1.0 ± 1.0; p < 0.001) and more severe CAD diagnosed by Gensini scores (p < 0.001) among patients who had NAFLD. Multivariate regression analysis showed that NAFLD was the only independent factor affecting the CAD severity score [7].Another study investigated a cross-sectional analysis of 355 patients undergoing coronary angiography and abominal ultrasonography for NAFLD [8]. Multivariate analysis showed that NAFLD was independently associated with the prevalence of CAD (odds ratio: 2.58; p < 0.01) and also independently with severity of CAD measured by the Gensini score (odds ratio: 2.02; p < 0.05) [8].Sun et al. performed abdominal computed tomography to detect NAFLD in 542 patients before undergoing coronary angiography for suspected CAD [9]. Logistic regression analysis showed that NAFLD independently increased the risk of CAD seen on coronary angiography (odds ratio: 7.585; p < 0.001). NAFLD was significantly more prevalent in patients as the severity of CAD increased [9]. These investigators concluded that patients with NAFLD should be closely followed for not only presence of CAD, but also for its severity [9].Coronary collateral development has been shown to improve survival in patients with CAD. The metabolic syndrome and associated insulin resistance has been shown to be associated with poor coronary collateral development. A study investigated 151 nondiabetic patients with stable angina pectoris who had more than 95% stenosis in at least one major coronary artery [10]. Abdominal ultrasonography performed after coronary angiography demonstrated that NAFLD was present in 65% of study patients and was more prevalent in patients with poor collateral development (82.9% in NAFLD patients vs 49.4% in non-NAFLD patients, p < 0.001). The mean Rentrop collateral score was significantly lower in patients with NAFLD than in patients without NAFLD (p < 0.001). NAFLD was significantly related to poor circulation (odds ratio: 6.20; 95% CI: 2.61–14.75) after logistic regression analysis was performed using factors associated with poor collateral development [10].Many studies have shown an association between NAFLD and subclinical atherosclerosis. Most of these studies prove that this association is independent of metabolic syndrome and cardiovascular risk factors.Coronary artery calcification (CAC) is a surrogate marker for atherosclerotic burden and an independent marker of CAD risk. Data were analyzed from 10,153 individuals who received an ultrasound of the abdomen for assessment of fatty liver and a cardiac computerized tomography computed CAC score [11]. Fatty liver was associated with a CAC score >0 independent of metabolic syndrome, coronary risk factors and previous cardiovascular disease (odds ratio: 1.21; p = 0.04) [11]. The CARDIA study included 2424 patients, mean age 50 years, which used computed tomography to quantify liver fat, CAC and abdominal aortic calcification [12]. Patients with NAFLD had increased prevalence of CAC (37.9 vs 26.0%; p < 0.001) and abdominal aortic calcification (65.1 vs 49.9%; p <0.001). This association of NAFLD with CAC and abdominal aortic calcification persisted after adjustment for demographics and health behaviors [12].A study involved a cross-sectional analysis of 3796 persons in the MESA study who had computed tomography imaging [13]. This study showed that NAFLD is associated with increased inflammation measured by high sensitivity C-reactive protein ≥2 mg/l (odds ratio: 1.47; 95% CI: 1.20–1.79) and CAC greater than 0 (odds ratio: 1.37; 95% CI: 1.11–1.68) independent of coronary risk factors, obesity, and metabolic syndrome [13]. There was a graded association among NAFLD, obesity and metabolic syndrome with inflammation and CAC [13].Measurement of carotid intima-media thickness (CIMT) using ultrasound is a marker of subclinical atherosclerosis. CIMT is a strong predictor of future vascular events and better predicts the risk of stroke compared with myocardial infarction. A cross-sectional study showed that subjects with NAFLD had higher average and maximum CIMT than controls [14]. NAFLD was an independent predictor of having high average CIMT (odds ratio: 4.8; 95% CI: 1.8–12.8) and high maximum CIMT (odds ratio: 5.4; 95% CI: 2.0–14.4) after adjusting for obesity, metabolic syndrome, insulin resistance and lipid parameters [14].A large cross-sectional study of 8632 persons revealed a significantly higher CIMT (p < 0.0001) and brachial-ankle pulse wave velocity (ba PWV) (p < 0.0001) in persons with NAFLD compared with those without NAFLD [15]. Logistic regression analysis showed that NAFLD conferred a 35% increased odds ratio of elevated CIMT and a 30% increased odds ratio of ba PWV independent of coronary risk factors and the metabolic syndrome [15].A meta-analysis of ten studies including 1947 patients showed that pathological CIMT was present in 35.1% of NAFLD patients compared with 21.8% of patients without NAFLD (p < 0.0001) [16]. A meta-analysis of four studies including 1198 patients showed that CAD diagnosed by coronary angiography was present in 80.4% of patients with NAFLD versus 60.7% of patients without NAFLD (p < 0.001) [16].Another measure of arterial stiffness is ba PWV. A prospective study of 728 men and 497 women free of hypertension and diabetes investigated progression of arterial stiffening by measuring ba PWV [17]. At 5-year follow-up, multiple regression analysis revealed that NAFLD is an independent and significant predictor for progression of ba PWV (p <0.001) in men and in women after adjustment for cardiovascular risk factors [17].The cardioankle vascular index (CAVI) indicates stiffness of the entire arterial segment from aorta to the ankle. A study of 443 patients undergoing CAVI, carotid ultrasonography and coronary angiography showed by multiple logistic analyses that high CAVI indicates progression of CAD and carotid arteriosclerosis [18]. CAVI also predicts stroke [18,19]. In a cross-sectional analysis of 2954 subjects, NAFLD was associated with a 42% increase in risk of arterial stiffness [20]. The risk of arterial stiffness increased with severity of NAFLD. The association was statistically significant after adjustment for other risk factors including BMI, waist circumference, smoking status, diabetes and hypertension [20].Even though strong epidemiological evidence is available linking NAFLD with atherosclerotic vascular disease and subclinical atherosclerosis, our knowledge of the biochemical pathways contributing to this association is incomplete. More studies are needed to understand the underlying biochemical pathways and markers responsible for the above clinical findings, which could lead to development of needed therapeutic interventions.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Milić S, Lulić D, Štimac D. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations. World J. Gastroenterol. 20(28), 9330–9337 (2014).Medline, Google Scholar2 Wong VW, Wong GL, Yip GW et al. 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Medicine (Baltimore) 94(12), e654 (2015).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByCardiovascular comorbidity in non-alcoholic fatty liver disease30 October 2020 | Experimental and Clinical Gastroenterology, No. 10PERIODONTAL STATUS IN PATIENTS WITH DISEASES OF HEPATOBILIARY SYSTEM, BURDENED WITH TOBACCO AND DRUG ADDICTION1 January 2020 | Wiadomości Lekarskie, Vol. 73, No. 3Effects of Chronic Whey Protein Supplementation on Atherosclerosis in ApoE−/− MiceJournal of Nutritional Science and Vitaminology, Vol. 64, No. 2Association between non‐alcoholic fatty liver disease and peripheral artery disease in patients with type 2 diabetes9 October 2017 | Internal Medicine Journal, Vol. 47, No. 10Arterial Stiffness and Nonalcoholic Fatty Liver Disease: Which is the Chicken and Which is the Egg?The Open Hypertension Journal, Vol. 9, No. 1 Vol. 12, No. 4 Follow us on social media for the latest updates Metrics History Published online 13 June 2016 Published in print July 2016 Information© Future Medicine LtdKeywordsatherosclerotic cardiovascular diseasebrachial-ankle pulse wave velocitycardioankle vascular indexcarotid intima-media thicknesscoronary artery calcificationcoronary artery diseasenonalcoholic fatty liver diseaseFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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