Associations between nonalcoholic fatty liver disease and subclinical atherosclerosis in middle-aged adults: the Coronary Artery Risk Development in Young Adults Study.
ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular mortality. Yet, whether or not NAFLD is independently related to atherosclerosis is unclear. In a population-based cross-sectional sample of middle-aged adults free from liver or heart disease, we tested the hypothesis that NAFLD is associated with subclinical atherosclerosis (coronary artery (CAC) and abdominal aortic calcification (AAC)) independent of obesity.Participants from the Coronary Artery Risk Development in Young Adults study with CT quantification of liver fat, CAC and AAC were included (n = 2424). NAFLD was defined as liver attenuation ?40 Hounsfield Units after exclusion of other causes of liver fat. CAC and AAC presence was defined as Agatston score >0.Mean participant age was 50.1 ± 3.6 years, (42.7% men, 50.0% black) and BMI was 30.6 ± 7.2 kg/m(2). The prevalence of NAFLD, CAC, and AAC was 9.6%, 27.1%, and 51.4%. NAFLD participants had increased prevalence of CAC (37.9% vs. 26.0%, p < 0.001) and AAC (65.1% vs. 49.9%, p < 0.001). NAFLD remained associated with CAC (OR, 1.33; 95% CI, 1.001-1.82) and AAC (OR, 1.74; 95% CI, 1.29-2.35) after adjustment for demographics and health behaviors. However, these associations were attenuated after additional adjustment for visceral adipose tissue (CAC OR, 1.05; 95% CI, 0.74-1.48, AAC OR = 1.20; 95% CI, 0.86-1.67). There was no interaction by race or sex.In contrast to prior research, these findings suggest that obesity attenuates the relationship between NAFLD and subclinical atherosclerosis. Further studies evaluating the role of NAFLD duration on atherosclerotic progression and cardiovascular events are needed.
Project description:Nonalcoholic fatty liver disease (NAFLD) is becoming common in the United States and throughout the world and can progress to cirrhosis, hepatocellular carcinoma, and death. There is a strong association between coronary artery disease and NAFLD due to common risk factors, such as metabolic syndrome, obesity, and diabetes mellitus. Subclinical atherosclerosis, defined as coronary artery calcification in asymptomatic patients, has been shown to have a higher incidence in patients with NAFLD. We performed a meta-analysis to examine the association of NAFLD with subclinical atherosclerosis measured by coronary artery calcium (CAC) scoring. Data were extracted from 12 studies selected using a predefined search strategy. NAFLD was diagnosed by abdominal ultrasound or computed tomography scans. The rate of coronary artery calcification was analyzed using random effects models, and publication bias was assessed using Egger's regression test. A total of 42,410 subjects were assessed, including 16,883 patients with NAFLD. Mean CAC score was significantly higher in subjects with NAFLD compared to those without NAFLD (odds ratio with random effects model, 1.64; 95% confidence inteval, 1.42-1.89). This association remained significant through subgroup analyses for studies with >1,000 subjects and a higher CAC score cutoff of >100. Higher aspartate aminotransferase levels were also associated with increased subclinical atherosclerosis (mean difference 1.77; 95% confidence interval, 1.19-2.34). Conclusion: There is an increased prevalence of subclinical atherosclerosis in patients with NAFLD, where subclinical atherosclerosis is defined using a "real world" clinical biomarker, namely the CAC score. Prospective studies are needed to establish a causative link between NAFLD and coronary artery disease. (Hepatology Communications 2018; 00:000-000).
Project description:<h4>Background</h4>Non-alcoholic fatty liver disease (NAFLD) is associated with high risk of cardiovascular disease. The prevalence is increasing to 45-65% in the general population with routine health check-up, and most subjects have the mild degree NAFLD in recent years. Moreover, there are no studies on the association between NAFLD severity and coronary atherosclerosis in the real-world setting by ultrasonography.<h4>Methods</h4>The aim of this study was to determine the relationship between the severity of NAFLD and subclinical coronary atherosclerosis. Overall, 817 subjects meet criteria for NAFLD were enrolled in the retrospective cohort study (155 subjects were excluded). The severity of NAFLD was divided into the normal, mild, moderate and severe degree based on the finding of abdominal ultrasonography. The assessment of coronary atherosclerosis was based on CAC scan/coronary CT angiography finding in terms of CAC score ≧ 100, CAC score ≧ 400, CAD-RADS ≧ 3 and presence of vulnerable plaque(s).<h4>Results</h4>A significant linear trend was observed between the severity of NAFLD and subclinical coronary atherosclerosis. Compared with the reference group (including normal, mild, and moderate NAFLD), severe degree NAFLD was the independently associated risk of subclinical coronary atherosclerosis in term of CAC score ≧ 100, CAC score ≧ 400, CAD-RADS ≧ 3 and presence of vulnerable plaque(s) based on binary logistic regression after adjustment for FRS score and body fat percentage.<h4>Conclusions</h4>Severe degree, but not mild to moderate, was associated with high risk of subclinical coronary atherosclerosis, independently of FRS score and body-fat percentage.
Project description:BACKGROUND:Biomarkers to predict the presence and severity of subclinical cardiovascular disease (CVD) in nonalcoholic fatty liver disease (NAFLD) are lacking. METHODS:3876 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), without known chronic liver disease underwent baseline non-contrast cardiac CT, with NAFLD defined by validated liver:spleen ratio (L:S)?<?1.0, and subclinical CVD defined by coronary artery calcium (CAC) score?>?0. Randomly-selected subgroups underwent detailed inflammatory marker testing, including LpPLA2 mass (N?=?2951), activity (N?=?3020), high-sensitivity C-reactive protein (hsCRP; N?=?3849), and interleukin-6 (IL-6; N?=?3764). Among those with NAFLD, we estimated the prevalence of CAC?>?0 and CAC?>?100 for each SD biomarker increase, using multivariable log-binomial regression models adjusted for cardiometabolic risk factors. RESULTS:Seventeen percent (N?=?668) of participants met the criteria for NAFLD. NAFLD participants were younger (mean age 61?±?10 vs. 63?±?10?years, p?<?.0001) but more likely to have an elevated BMI (mean 31.1?±?5.5 vs. 28.0?±?5.2?kg/m2, p?<?.0001), diabetes (22% vs. 11%, p?<?.0001), and increased inflammatory biomarkers, including LpPLA2 activity, hsCRP and IL-6 (all p?<?.0001). Among NAFLD participants, IL-6 was the only biomarker independently associated with prevalent CAC?>?0 (PR?=?1.06 [1.00-1.11]), or CAC?>?100 (PR?=?1.09 [1.02-1.17]). In contrast, circulating LpPLA2 mass/activity and hsCRP were not associated with either the prevalence or severity of subclinical CVD (all p?>?.05). CONCLUSION:In a large, multi-ethnic population with NAFLD, IL-6 is independently associated with the prevalence and severity of subclinical atherosclerosis. Further research into the longitudinal effects of NAFLD on progressive CVD will determine whether IL-6 is a marker or mediator of NAFLD-related atherosclerosis.
Project description:<h4>Background</h4>We sought to evaluate the association of metabolic syndrome (MetS) and computed tomography (CT)-derived cardiometabolic biomarkers (non-alcoholic fatty liver disease [NAFLD] and epicardial adipose tissue [EAT] measures) with long-term risk of major adverse cardiovascular events (MACE) in asymptomatic individuals.<h4>Methods</h4>This was a post-hoc analysis of the prospective EISNER (Early-Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) study of participants who underwent baseline coronary artery calcium (CAC) scoring CT and 14-year follow-up for MACE (myocardial infarction, late revascularization, or cardiac death). EAT volume (cm<sup>3</sup>) and attenuation (Hounsfield units [HU]) were quantified from CT using fully automated deep learning software (<?30 s per case). NAFLD was defined as liver-to-spleen attenuation ratio <?1.0 and/or average liver attenuation <?40 HU.<h4>Results</h4>In the final population of 2068 participants (59% males, 56?±?9 years), those with MetS (n?=?280;13.5%) had a greater prevalence of NAFLD (26.0% vs. 9.9%), higher EAT volume (114.1 cm<sup>3</sup> vs. 73.7 cm<sup>3</sup>), and lower EAT attenuation (-76.9 HU vs. -73.4 HU; all p?<?0.001) compared to those without MetS. At 14?±?3 years, MACE occurred in 223 (10.8%) participants. In multivariable Cox regression, MetS was associated with increased risk of MACE (HR 1.58 [95% CI 1.10-2.27], p?=?0.01) independently of CAC score; however, not after adjustment for EAT measures (p?=?0.27). In a separate Cox analysis, NAFLD predicted MACE (HR 1.78 [95% CI 1.21-2.61], p?=?0.003) independently of MetS, CAC score, and EAT measures. Addition of EAT volume to current risk assessment tools resulted in significant net reclassification improvement for MACE (22% over ASCVD risk score; 17% over ASCVD risk score plus CAC score).<h4>Conclusions</h4>MetS, NAFLD, and artificial intelligence-based EAT measures predict long-term MACE risk in asymptomatic individuals. Imaging biomarkers of cardiometabolic disease have the potential for integration into routine reporting of CAC scoring CT to enhance cardiovascular risk stratification. Trial registration NCT00927693.
Project description:BACKGROUND & AIMS:Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and is associated with development of metabolic disease including atherosclerotic cardiovascular disease (CVD). Our aim is to examine the association of hepatic steatosis with prevalent clinical and subclinical CVD outcomes in a large community-based sample, the Framingham Heart Study. METHODS:Hepatic steatosis was measured in 3529 participants using multidetector computed tomography scanning. Multivariable logistic regression was used to determine whether hepatic steatosis is associated with prevalent CVD adjusted for covariates. We also tested whether associations were independent of other metabolic diseases/traits. The primary clinical outcome was composite prevalent clinical CVD defined by prior non-fatal myocardial infarction, stroke, transient ischemic attack, heart failure, or peripheral arterial disease. Subclinical cardiovascular outcomes were coronary artery calcium (CAC) and abdominal artery calcium (AAC). RESULTS:3014 participants were included (50.5% women). There was a non-significant association of hepatic steatosis with clinical CVD (OR 1.14 [p=0.07]). Hepatic steatosis was associated with both CAC and AAC (OR 1.20 [p<0.001] and OR 1.16 [p<0.001], respectively). Associations persisted for CAC even when controlling for other risk factors/metabolic diseases, but for AAC, the associations became non-significant after adjustment for visceral adipose tissue. The association between hepatic steatosis and AAC was stronger in men than in women (p sex interaction=0.022). CONCLUSION:There was a significant association of hepatic steatosis with subclinical CVD outcomes independent of many metabolic diseases/traits with a trend towards association between hepatic steatosis and clinical CVD outcomes. The association with AAC was stronger in men than in women.
Project description:We reviewed published MESA (Multi-Ethnic Study of Atherosclerosis) study articles concerning peripheral arterial disease, subclavian stenosis (SS), abdominal aortic calcium (AAC), and thoracic artery calcium (TAC). Important findings include, compared to non-Hispanic whites, lower ankle-brachial index (ABI) and more SS in African Americans, and higher ABI and less SS in Hispanic and Chinese Americans. Abnormal ABI and brachial pressure differences were associated with other subclinical cardiovascular disease (CVD) measures. Both very high and low ABI independently predicted increased CVD events. Looking at aortic measures, TAC and AAC were significantly associated with other subclinical CVD measures. Comparisons of AAC with coronary artery calcium (CAC) showed that both were less common in ethnic minority groups. However, although CAC was much more common in men than in women in multivariable analysis, this was not true of AAC. Also, when AAC and CAC were adjusted for each other in multivariable analysis, there was a stronger association for AAC than for CAC with CVD and total mortality.
Project description:BACKGROUND:Atherosclerosis and its clinical sequelae represent the leading cause of mortality among patients with nonalcoholic fatty liver disease (NAFLD). While epidemiologic data support the hepatoprotective benefits of coffee in NAFLD, whether coffee improves NAFLD-associated CVD risk is unknown. METHODS:We examined 3710 ethnically-diverse participants from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, without history of known liver disease, and with available coffee data from a validated 120-item food frequency questionnaire. All participants underwent baseline non-contrast cardiac CT from which NAFLD was defined by liver:spleen ratio (L:S<1.0), and subclinical CVD was defined by coronary artery calcium (CAC)>0. Major CVD events were defined by the first occurrence of myocardial infarction, cardiac arrest, angina, stroke, or CVD death. We used log-binomial regression to calculate the adjusted prevalence ratio (PR) for CAC>0 by coffee intake and NAFLD status, and events were compared between groups using frequency of events within adjusted Cox proportional hazard regression models. RESULTS:Seventeen percent (N=637) of participants met criteria for NAFLD. NAFLD participants were more likely to have elevated BMI (mean 31.1±5.5kg/m2 vs. 28.0±5.2kg/m2, p<0.0001), and diabetes (22% vs. 11%, p<0.0001), but did not differ in daily coffee consumption (p=0.97). Among NAFLD participants, coffee consumption was not associated with prevalent, baseline CAC>0 (PR=1.02 [0.98-1.07]). Over 12.8years of follow-up, 93 NAFLD and 415 non-NAFLD participants experienced a CV event. However, coffee intake was not associated with incident CVD events, in either NAFLD (HR=1.05 [0.91-1.21]) or non-NAFLD participants (HR=1.03 [0.97-1.11]). CONCLUSION:In a large, population-based cohort, coffee consumption was not associated with the prevalence of subclinical CVD, nor did coffee impact the future risk of major CVD events, regardless of underlying NAFLD status.
Project description:Nonalcoholic fatty liver disease (NAFLD) is related to risk factors of coronary artery disease, such as dyslipidemia, diabetes, and metabolic syndrome, which are closely linked with visceral adiposity. The aim of this study was to investigate whether NAFLD was associated with coronary artery calcification (CAC), which is used as a surrogate marker for coronary atherosclerosis independent of computed tomography (CT)-measured visceral adiposity. Out of 5,648 subjects who visited one of our health screening centers between 2003 and 2008, we enrolled 4,023 subjects (mean age, 56.9 ± 9.4 years; 60.7% males) without known liver disease or a history of ischemic heart disease. CAC score was evaluated using the Agatston method. On univariate analysis, the presence of CAC (score >0) was significantly associated with age, sex, body mass index, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein cholesterol, triglycerides, and increased risk of diabetes, hypertension, smoking, and NAFLD. Increasing CAC scores (0, <10, 10-100, ? 100) were associated with higher prevalence of NAFLD (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.61-2.10; P<0.001). Multivariable ordinal regression analysis was adjusted for traditional risk factors, and CT-measured visceral adipose tissue area in a subgroup of subjects showed that the increased CAC scores were significantly associated with the presence of NAFLD (OR, 1.28, 95% CI, 1.04-1.59; P = 0.023) independent of visceral adiposity.Patients with NAFLD are at increased risk for coronary atherosclerosis independent of classical coronary risk factors, including visceral adiposity. These data suggest that NAFLD might be an independent risk factor for coronary artery disease.
Project description:Abdominal aortic calcification (AAC) is a measure of subclinical cardiovascular disease (CVD). Data are limited regarding its relation to other measures of atherosclerosis.Among 1812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic) within the population-based Multiethnic Study of Atherosclerosis, we examined the cross-sectional relation of AAC with coronary artery calcium (CAC), ankle brachial index (ABI), and carotid intimal medial thickness (CIMT), as well as multiple measures of subclinical CVD.AAC prevalence ranged from 34% in those aged 45-54 to 94% in those aged 75-84 (p < 0.0001), was highest in Caucasians (79%) and lowest in blacks (62%) (p < 0.0001). CAC prevalence, mean maximum CIMT ? 1mm, and ABI < 0.9 was greater in those with vs. without AAC: CAC 60% vs. 16%, CIMT 38% vs. 7%, and ABI 5% vs. 1% for women and CAC 80% vs. 37%, CIMT 43% vs. 16%, and ABI 4% vs. 2% for men (p < 0.01 for all except p < 0.05 for ABI in men). The substantially greater prevalence for CAC in men compared to women all ages is not seen for AAC. By age 65, 97% of men and 91% of women have AAC, CAC, increased CIMT, and/or low ABI. The presence of multi-site atherosclerosis (? 3 of the above) ranged from 20% in women to 30% in men (p < 0.001), was highest in Caucasians (28%) and lowest in Chinese (16%) and ranged from 5% in those aged 45-54 to 53% in those aged 75-84 (p < 0.01 to p < 0.001). Finally, increased AAC was associated with 2-3-old relative risks for the presence of increased CIMT, low ABI, or CAC.AAC is associated with an increased likelihood of other vascular atherosclerosis. Its additive prognostic value to these other measures is of further interest.
Project description:This study investigated the associations of non-alcoholic fatty liver disease (NAFLD) and abdominal aortic calcification (AAC) volume and density, and whether these relationships vary by race/ethnicity and/or sex, information that are limited in current literature.We studied 1004 adults from the Multi-Ethnic Study of Atherosclerosis to assess the relationship between NAFLD (liver-to-spleen ratio <1) and the following measures of AAC: presence (volume score >0, using Poisson regression); change in volume score (increasing vs. no change, using Poisson regression); and morphology (volume and density score, where volume score >0, using linear regression); and interaction by race/ethnicity and sex.Among Blacks, those with NAFLD had greater prevalence for AAC compared to Whites regardless of sex (Prevalence Ratio [PR] = 1.41, CI = 1.15-1.74, p-interaction = 0.02). Concurrent interaction by race/ethnicity and sex was found comparing Chinese and Blacks to Whites (p-interaction = 0.017 and 0.042, respectively) in the association between NAFLD and the prevalence of increasing AAC. Among women, this relationship was inverse among Chinese (PR = 0.59, CI = 0.28-1.27), and positive among Whites (PR = 1.34, CI = 1.02-1.76). This finding was reversed evaluating the men counterpart. Black men also had a positive association (PR = 1.86, CI = 1.29-2.70), which differed from the inverse relationship among White men, and was greater compared to Black women (PR = 1.45, CI = 1.09-1.94). NAFLD was unrelated to AAC morphology.NAFLD was related to the presence of AAC, however, limited to Blacks. Significant concurrent interaction by race/ethnicity (Chinese and Blacks vs. Whites) and sex was found in the relationship between NAFLD and increasing AAC. These findings suggest disparities in the pathophysiologic pathways in which atherosclerosis develops.