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BackgroundElevated plasma lipoprotein (a) [Lp(a)] and coronary artery calcification (CAC) are established cardiovascular risk factors that correlate with each other. We hypothesized that other cardiovascular risk factors could affect their relationship.MethodsWe tested for interactions of 24 study variables related to dyslipidemia, diabetes, insulin resistance, hypertension, inflammation and coagulation with baseline Lp(a) on change in CAC volume and density over 9.5 years in 5975 Multi-Ethnic Study of Atherosclerosis (MESA) participants, free of apparent cardiovascular disease at baseline.ResultsElevated Lp(a) was associated with larger absolute increase in CAC volume (3.21 and 4.45 mm3/year higher for Lp(a) ≥30 versus

Previous small studies have reported an association between circulating fibroblast growth factor 21 (FGF21) levels and pericardial fat volume in post-menopausal women and high cardiovascular disease (CVD) risk patients. In this study, we investigated the relationship of FGF21 levels with pericardial fat volume in participants free of clinical CVD at baseline. We analysed data from 5765 men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) with both pericardial fat volume and plasma FGF21 levels measured at baseline. 4746 participants had pericardial fat volume measured in at least one follow-up exam. After adjusting for confounding factors, ln-transformed FGF21 levels were positively associated with pericardial fat volume at baseline (β = 0.055, p

BackgroundFibroblast growth factor 21 (FGF21) may play a role in the development of chronic kidney disease (CKD). We therefore investigated the relationship of plasma FGF21 levels with kidney function and albuminuria in the Multi-Ethnic Study of Atherosclerosis (MESA).MethodsThe analysis included 5724 MESA participants ages 45-84 years between 2000 and 2002, free of clinically apparent cardiovascular disease (CVD). Participants were followed up in person at four additional clinic visits over 10 years. Plasma FGF21 levels were measured at baseline examination by enzyme-linked immunosorbent assay. Kidney function was assessed by estimated glomerular filtration rate (eGFR). Outcomes were urinary albumin:creatinine ratio (UACR) progression, incident CKD by eGFR (reaching eGFR 5%/year).ResultsAt baseline, higher FGF21 levels, assessed as both continuous and categorical quartile variables, were significantly associated with lower eGFR and higher UACR, after adjusting for demographic, socioeconomic and other confounding factors [adjusted mean differences of -2.63 mL/min/1.73 m2 in eGFR and 0.134 in log normally transformed UACR (mg/g) for the highest FGF21 quartile compared with the lowest quartile, all P  0.05).ConclusionsOur study does not support a role of FGF21 as a biomarker for predicting kidney function decline or albuminuria in adults free of clinically apparent CVD at baseline.

BackgroundHigher plasma fibroblast growth factor 21 (FGF21) levels predict incident cardiovascular events in type 2 diabetes patients. However, whether FGF21 levels predict cardiovascular events in statin-treated patients in the general population is unknown. We investigated whether FGF21 levels predict major cardiovascular event (MCVE) in the Treating to New Targets (TNT) trial participants.MethodsAfter 8-week run-in on atorvastatin 10 mg/day, 10,001 patients with stable coronary disease in the TNT trial were randomized to 10 mg or 80 mg/day of atorvastatin for a median of 4.9 years. We analyzed data from 1996 patients with plasma FGF21 levels measured at randomization. Among them, 1835 patients had FGF21 measured one-year post-randomization.ResultsHigher ln-transformed FGF21 levels at randomization were associated with higher risk of incident MCVE (adjusted hazards ratio per SD increase = 1.18, P = 0.019). At 1-year post-randomization, FGF21 levels were lower in patients randomized to receive 80 mg versus 10 mg atorvastatin (186.9 versus 207.5 pg/mL respectively, P = 0.006). Higher ln-transformed FGF21 levels at 1-year post-randomization were also associated with higher subsequent risk of MCVEs (adjusted hazards ratio per SD increase = 1.24, P = 0.009). However, changes in FGF21 levels over 1-year were not related to subsequent MCVE risk. FGF21 levels had significant incremental value in net reclassification improvement in MCVE risk prediction.ConclusionsHigher plasma FGF21 levels are associated with higher CVD risk in statin-treated high-risk patients. Higher dose atorvastatin is associated with a reduction in FGF21 levels. FGF21 provides incremental value in CVD risk prediction in statin-treated patients.

Background and aimsFibroblast growth factor 21 (FGF21) plays an important role in glucose and lipid metabolism. We have investigated the relationship of plasma FGF21 levels with both prevalent and incident metabolic syndrome (MetS) in participants from the Multi-Ethnic Study of Atherosclerosis (MESA).Methods5783 participants from four major ethnic groups (non-Hispanic white, African American, Hispanic American, and Chinese American) were included in the cross-sectional analysis. Longitudinal analysis involved 3479 participants without MetS at baseline, of whom 1100 participants developed incident MetS over 9.2 years.ResultsElevated FGF21 levels were found in participants with prevalent MetS (median [interquartile range] = 189.4 [114.4-302.1] vs. 123.7 [65.9-210.3] pg/mL, p

Studies on the relationship of cholesterol concentrations and lipid-lowering medications with dementia risk have yielded inconsistent findings. Therefore, we investigated the association of lipid concentrations and lipid-lowering medications with cognitive function in the Multi-Ethnic Study of Atherosclerosis across 3 different cognitive domains assessed by means of the Cognitive Abilities Screening Instrument (CASI; version 2), the Digit Symbol Coding (DSC) Test, and the Digit Span (DS) Test in 2010-2012. After adjustment for sociodemographic and confounding factors, including concentrations of other lipids and use of lipid-lowering medication, higher total cholesterol, low-density lipoprotein cholesterol, and non-high-density-lipoprotein cholesterol concentrations were modestly associated with higher DS Test scores. None of the lipid parameters were associated with CASI or DSC Test scores. Similarly, changes in lipid concentrations were not associated with any cognitive function test score. Using treatment effects model analysis and after adjusting for confounding factors, including lipid concentrations, the use of any lipid-lowering medication, especially statins, was associated with higher scores on the CASI and backward DS tests but not on the DSC and forward DS tests. Our study does not support a robust association between lipid concentrations and cognitive function or between the use of lipid-lowering medication, especially statins, and worse cognitive function.

Background and aimsElevated circulating levels of fibroblast growth factor 21 (FGF21) are associated with multiple cardiovascular disease (CVD) risk factors and incident events. Previous small cross-sectional studies, mainly in Chinese populations, have suggested FGF21 may play a role in the development of atrial fibrillation (AF). We therefore investigated the relationship of FGF21 levels with incident AF in participants free of clinically apparent CVD at baseline in a large, multi-ethnic cohort.MethodsA total of 5729 participants of four major ethnic groups (Caucasian, African American, Hispanic American, and Chinese American) from the Multi-Ethnic Study of Atherosclerosis (MESA), who were free of AF and had plasma FGF21 levels measured by ELISA at the baseline exam, were included in the analysis. Participants were followed up for incident AF over a median period of 12.9 years. Cox proportional hazards regression analysis was used.ResultsAmong the 5729 participants, 778 participants developed incident AF. Participants with incident AF had significantly higher baseline FGF21 levels than those without incident AF (median = 166.0 and 142.8 pg/mL, p

It is not known whether the concentration of high-density lipoprotein (HDL) cholesterol is related to renal function in statin-treated patients. We therefore investigated whether HDL cholesterol levels predicted renal function in atorvastatin-treated patients in the TNT (Treating to New Targets) trial. A total of 9542 participants were included in this analysis. Renal function was assessed by estimated glomerular filtration rate (eGFR). HDL cholesterol levels at month 3 were used as this is the time point at which on-treatment HDL cholesterol levels became stable. Among 6319 participants with a normal eGFR (≥60 mL/min per 1.73 m2) at baseline, higher HDL cholesterol levels at month 3 were significantly associated with lower risk of decline in eGFR (ie, having eGFR

ObjectivePericardial fat and lipoprotein abnormalities contribute to increased risk of cardiovascular disease (CVD). We investigated the relationship between pericardial fat volume and lipoprotein distribution, and whether the association of pericardial fat volume with subclinical atherosclerosis and incident CVD events differs according to lipoprotein distribution.MethodsWe analyzed data from 5407 participants from the Multi-Ethnic Study of Atherosclerosis who had measurements of pericardial fat volume, lipoprotein distribution, carotid intima-media thickness (IMT), and coronary artery calcium (CAC). All participants were free of clinically apparent CVD at baseline. Incident CVD was defined as any adjudicated CVD event.ResultsAfter adjusting for demographic factors, traditional risk factors, and biomarkers of inflammation and hemostasis, a larger pericardial fat volume was associated with higher large VLDL particle (VLDL-P) concentration and small HDL particle (HDL-P) concentration, and smaller HDL-P size (regression coefficients = 0.585 nmol/L, 0.366 μmol/L, and -0.025 nm per SD increase in pericardial fat volume respectively, all P 0.05).ConclusionPericardial fat is associated with atherogenic lipoprotein abnormalities. However, its relationship with subclinical atherosclerosis and incident CVD events does not differ according to lipoprotein distribution.

ObjectivePericardial fat may increase the risk of cardiovascular disease (CVD) by increasing circulating levels of inflammation and hemostasis biomarkers. We investigated the associations of pericardial fat with inflammation and hemostasis biomarkers, as well as incident CVD events, and whether there are any ethnic differences in these associations.MethodsWe analyzed results from 6415 participants from the Multi-Ethnic Study of Atherosclerosis who had measurements of pericardial fat volume and circulating levels of C-reactive protein (CRP), fibrinogen, interleukin (IL)-6, factor VIII, D-dimer and plasmin-antiplasmin complex (PAP), and had a mean follow-up period of 9.5 years. Incident CVD event was defined as any adjudicated CVD event.ResultsAfter adjusting for confounding factors, pericardial fat volume was positively associated with natural log (ln) of IL-6 levels, but inversely associated with ln D-dimer and ln PAP levels (β = 0.067, -0.032, and -0.105 respectively, all P < 0.05). Although a larger pericardial fat volume was associated with a higher risk of incident CVD, the association was attenuated to borderline significance after adjusting for traditional cardiovascular risk factors (P = 0.050). There was a borderline significant ethnicity interaction (P = 0.080), whereby the association between pericardial fat volume and incident CVD was significant in Hispanic Americans, even after further adjusting for biomarkers of inflammation and hemostasis (hazard ratio = 1.31 per SD increase, 95% confidence interval 1.09-1.57, P = 0.004).ConclusionPericardial fat was associated with several inflammation and hemostasis biomarkers. The association of pericardial fat with incident CVD events was independent of these biomarkers only among Hispanic Americans.

ObjectiveInsulin resistance may be related to vascular calcification as both are associated with abdominal obesity. We investigated the association of insulin resistance with abdominal aortic calcium (AAC), coronary artery calcium (CAC) and thoracic aortic calcium (TAC), and whether it differs according to different levels of subcutaneous fat area (SFA) and visceral fat area (VFA) in a cross-sectional study design.MethodsWe investigated 1632 participants without diabetes from the Multi-Ethnic Study of Atherosclerosis with valid data on homeostasis model assessment index (HOMA-IR), AAC, CAC, and TAC. Adipocytokines, SFA, and VFA were also determined.ResultsHOMA-IR was associated with the presence of CAC, but not AAC and TAC, and the association remained significant after adjusting for traditional risk factors, adipocytokines, abdominal muscle mass, SFA, and VFA (prevalence ratio = 1.04 per one interquartile range [IQR] increase, P = 0.01). As the strength of the association of HOMA-IR with vascular calcification may differ by abdominal fat composition, subgroup analysis was performed among participants with different tertiles of SFA and VFA. Significant interactions between HOMA-IR with SFA and VFA separately were observed for the presence of TAC, but not AAC and CAC, even after adjusting for confounding factors. The association of HOMA-IR with TAC tended to be stronger in participants with more SFA and VFA.ConclusionsAtherosclerotic calcification, especially in the coronary arteries, is related to insulin resistance. Further studies are needed to delineate the mechanisms by which visceral obesity can lead to vascular calcification.

Features of the metabolic syndrome are independent risk factors for new-onset diabetes mellitus (NODM) related to statin therapy. Obesity is the predominant underlying risk factor for the metabolic syndrome and diabetes mellitus. This study investigated whether change in body weight may predict NODM in statin-treated patients. A total of 7,595 patients without prevalent diabetes mellitus at baseline from the Treating to New Targets (TNT) study were included in this analysis. They were randomized to atorvastatin 10 or 80 mg/day and monitored for a median of 4.9 years. NODM developed in 659 patients (8.1% in the 10-mg group and 9.2% in the 80-mg group). There was a significant increase in body weight (0.9 kg, p

ObjectiveDue to its anti-oxidant and anti-inflammatory properties, bilirubin has been associated with reduced cardiovascular risk. A recent study demonstrated an L-shaped association of pre-treatment total bilirubin levels with total mortality in a statin-treated cohort. We therefore investigated the association of total bilirubin levels with total mortality in a nationally representative sample of older adults from the general population.MethodsA total of 4,303 participants aged ≥ 60 years from the United States National Health and Nutrition Examination Survey 1999-2004 with mortality data followed up through December 31, 2006 were included in this analysis, with a mean follow-up period of 4.5 years.ResultsParticipants with total bilirubin levels of 0.1-0.4 mg/dl had the highest mortality rate (19.8%). Compared with participants with total bilirubin levels of 0.5-0.7 mg/dl and in a multivariable regression model, a lower total bilirubin level of 0.1-0.4 mg/dl was associated with higher risk of total mortality (hazard ratios, 1.36; 95% confidence interval, 1.07-1.72; P = 0.012), while higher levels (≥ 0.8 mg/dl) also tended to be associated with higher risk of total mortality, but this did not reach statistical significance (hazard ratios, 1.24; 95% confidence interval, 0.98-1.56; P = 0.072).ConclusionIn this nationally representative sample of older adults, the association of total bilirubin levels with total mortality was the highest among those with a level between 0.1 and 0.4 mg/dl. Further studies are needed to investigate whether higher total bilirubin levels could be associated with a higher mortality risk, compared to a level of 0.5-0.7 mg/dl.