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Background: Fibroblast growth factor 21 (FGF21) levels are often elevated in cardiovascular disease (CVD). However, no study has assessed its association with cardiovascular and all-cause mortality in a population free of clinically evident CVD., Methods: A total of 5543 Multi-Ethnic Study of Atherosclerosis (MESA) participants (mean age 62.7 years, 47.5 % male), free of clinically evident CVD at baseline, were studied. From baseline (2000-2002), 1606 deaths (including 387 CVD deaths) were observed over a median follow-up of 17.7 years. Multivariable Cox regression analysis was performed to assess the association of plasma FGF21 levels with mortality., Results: FGF21 levels at baseline were associated with all-cause mortality, even after adjustment for traditional risk factors, including demographic, socioeconomic and cardiovascular risk factors (adjusted hazard ratio 1.08 [95% confidence interval 1.01, 1.16] per 1 SD increase in ln-transformed levels; 1.27 for the highest vs, lowest quartile). Baseline FGF21 levels were significantly associated with both CVD and non-CVD mortality in unadjusted models. However, the association with non-CVD mortality, but not CVD mortality, remained statistically significant after adjusting for covariates. Similar results were obtained in FGF21 quartile analyses and also when using competing risk regression or matched case-control cohort in sensitivity analyses., Conclusions: In subjects without clinically-evident CVD at baseline, over 17.7 years follow-up there is a modest association of baseline FGF21 levels with all-cause mortality. The finding that this is driven primarily by a significant association with non-CVD mortality over almost two decades merits further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Machine learning has been shown to outperform traditional statistical methods for risk prediction model development. We aimed to develop machine learning-based risk prediction models for cardiovascular mortality and hospitalisation for ischemic heart disease (IHD) using self-reported questionnaire data., Methods: The 45 and Up Study was a retrospective population-based study in New South Wales, Australia (2005-2009). Self-reported healthcare survey data on 187,268 participants without a history of cardiovascular disease was linked to hospitalisation and mortality data. We compared different machine learning algorithms, including traditional classification methods (support vector machine (SVM), neural network, random forest and logistic regression) and survival methods (fast survival SVM, Cox regression and random survival forest)., Results: A total of 3687 participants experienced cardiovascular mortality and 12,841 participants had IHD-related hospitalisation over a median follow-up of 10.4 years and 11.6 years respectively. The best model for cardiovascular mortality was a Cox survival regression with L1 penalty at a re-sampled case/non-case ratio of 0.3 achieved by under-sampling of the non-cases. This model had the Uno's and Harrel's concordance indexes of 0.898 and 0.900 respectively. The best model for IHD hospitalisation was a Cox survival regression with L1 penalty at a re-sampled case/non-case ratio of 1.0 with Uno's and Harrel's concordance indexes of 0.711 and 0.718 respectively., Conclusion: Machine learning-based risk prediction models developed using self-reported questionnaire data had good prediction performance. These models may have the potential to be used in initial screening tests to identify high-risk individuals before undergoing costly investigation., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Elevated circulating levels of fibroblast growth factor 21 (FGF21) are associated with cardiovascular disease (CVD). Therefore, we investigated the relationship of plasma FGF21 with calcification at different vascular and valvular sites., Methods: A total of 5786 participants, free of clinically apparent CVD at baseline and with valid data on plasma FGF21 and calcification (Agatston score, volume and density) at coronary arteries, thoracic arteries, mitral and aortic valves, and aortic valve ring, were included in the analysis. Vascular calcification was measured at 2-3 follow-up visits., Results: At baseline, higher FGF21 levels were associated with prevalent descending thoracic aortic calcification (DTAC) (prevalence ratio = 1.06 [95% CI 1.01-1.11] per SD increase in log-transformed unit, P = 0.016). Among participants without prevalent calcification, higher FGF21 levels were associated with incident DTAC (relative risk [RR] = 1.13 [95% CI 1.04-1.22], P = 0.002). Among all participants, higher FGF21 levels were also associated with the progression of DTAC score and volume (RR = 1.07 [95% CI 1.03-1.12] and 1.08 [95% CI 1.03-1.12] respectively, both P < 0.01). No significant association of FGF21 was found for prevalence (prevalence ratio = 0.89-1.05), incidence (RR = 0.97-1.16) and progression of calcification (RR = 0.94-1.14) at the other sites., Conclusion: Higher FGF21 levels were associated with the presence, incidence and progression of DTAC. However, the magnitude of this association was similar to those of the non-significant associations of FGF21 levels with calcifications at other sites. Further research is needed to assess the potential of FGF21 as a biomarker for vascular calcification., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cholesterol in the circulation is mostly transported in an esterified form as a component of lipoproteins. The majority of these cholesteryl esters are produced in nascent, discoidal high density lipoproteins (HDLs) by the enzyme, lecithin:cholesterol acyltransferase (LCAT). Discoidal HDLs are discrete populations of particles that consist of a phospholipid bilayer, the hydrophobic acyl chains of which are shielded from the aqueous environment by apolipoproteins that also confer water solubility on the particles. The progressive LCAT-mediated accumulation of cholesteryl esters in discoidal HDLs generates the spherical HDLs that predominate in normal human plasma. Spherical HDLs contain a core of water insoluble, neutral lipids (cholesteryl esters and triglycerides) that is surrounded by a surface monolayer of phospholipids with which apolipoproteins associate. Although spherical HDLs all have the same basic structure, they are extremely diverse in size, composition, and function. This review is concerned with how the biogenesis of discoidal and spherical HDLs is regulated and the mechanistic basis of their size and compositional heterogeneity. Current understanding of the impact of this heterogeneity on the therapeutic potential of HDLs of varying size and composition is also addressed in the context of several disease states., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Relationships between dyslipidaemia and leukocyte counts have been investigated in several studies, demonstrating limited evidence of associations in humans. As such, studying a diverse range of cohorts will ensure evidence is robust. This study focused on investigating cross-sectional and longitudinal relationships in three large-scale cohorts., Methods: The cross-sectional analysis included a total of 27,566 participants with valid data on lipid measures and leukocyte counts from three study cohorts: National Health and Nutrition Survey (NHANES), Korean National Health and Nutrition Survey (KNHANES) and Treating to New Targets (TNT) trial. The longitudinal analysis included 9323 participants with valid data on lipid measures and leukocyte counts at baseline and one year with statin treatment. Associations between lipid levels and leukocyte counts were analysed by multivariable linear regression and adjusted for basic demographic and cardiovascular risk factors., Results: Cross-sectional data from NHANES demonstrated the association of lower high-density lipoprotein (HDL) cholesterol and higher triglycerides with higher leukocyte count (0.9% lower and 0.3% higher count per 10 mg/dL increase in HDL cholesterol and triglycerides respectively, both p  < 0.001). Similar trends were found in TNT trial (both p  < 0.001), but not in KNHANES. In the TNT trial, 10 mg/dL increase in triglycerides over one year was also associated with a 0.09 × 10 3 /μL increase in leukocyte count over the same period., Conclusions: The findings of this study are consistent with those of previous human studies, supporting weak yet noteworthy associations between dyslipidaemia and leukocytosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background and Aims: There is some evidence of a cross-sectional, and possibly causal, relationship of lipid levels with leukocyte counts in mice and humans. This study investigates the cross-sectional and longitudinal relationship of blood lipid and lipoprotein levels with leukocyte counts in the UK Biobank cohort., Methods: The primary cross-sectional analysis included 417,132 participants with valid data on lipid measures and leukocyte counts. A subgroup analysis was performed in 333,668 participants with valid data on lipoprotein(a). The longitudinal analysis included 9058 participants with valid baseline and follow-up data on lipid and lipoprotein levels and leukocyte counts. The association of lipid and lipoprotein levels with leukocyte counts was analysed by multivariable linear regression., Results: Several relationships were significant in both cross-sectional and longitudinal analysis. After adjustment for demographic, socioeconomic and other confounding factors, a higher eosinophil count was associated with lower HDL cholesterol and apolipoprotein A-I concentration (p < 0.001). Higher triglycerides levels were associated with higher total leukocyte, basophil, eosinophil, monocyte and neutrophil counts (all p < 0.01). A higher lymphocyte count was associated with a higher apolipoprotein B level (p < 0.001). In the longitudinal analysis, lipoprotein(a) was inversely associated with basophil count in men but not women (p < 0.001)., Conclusions: Triglyceride levels demonstrate a robust positive association with total and differential leukocyte counts suggesting they may be directly involved in leukogenesis. However, unlike in murine models, the remainder of these relationships is modest, which suggests that cholesterol and lipoproteins are minimally involved in leukogenesis in humans., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed weight-loss procedures, but how severe obesity and RYGB affect circulating HDL-associated microRNAs (miRNAs) remains unclear. Here, we aim to investigate how HDL-associated miRNAs are regulated in severe obesity and how weight loss after RYGB surgery affects HDL-miRNAs. Plasma HDLs were isolated from patients with severe obesity (n = 53) before and 6 and 12 months after RYGB by immunoprecipitation using goat anti-human apoA-I microbeads. HDLs were also isolated from 18 healthy participants. miRNAs were extracted from isolated HDL and levels of miR-24, miR-126, miR-222, and miR-223 were determined by TaqMan miRNA assays. We found that HDL-associated miR-126, miR-222, and miR-223 levels, but not miR-24 levels, were significantly higher in patients with severe obesity when compared with healthy controls. There were significant increases in HDL-associated miR-24, miR-222, and miR-223 at 12 months after RYGB. Additionally, cholesterol efflux capacity and paraoxonase activity were increased and intercellular adhesion molecule-1 (ICAM-1) levels decreased. The increases in HDL-associated miR-24 and miR-223 were positively correlated with an increase in cholesterol efflux capacity (r = 0.326, P = 0.027 and r = 0.349, P = 0.017, respectively). An inverse correlation was observed between HDL-associated miR-223 and ICAM-1 at baseline. Together, these findings show that HDL-associated miRNAs are differentially regulated in healthy participants versus patients with severe obesity and are altered after RYGB. These findings provide insights into how miRNAs are regulated in obesity before and after weight reduction and may lead to the development of novel treatment strategies for obesity and related metabolic disorders., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and atherogenic lipoprotein abnormalities. Previous studies suggest an association of fibroblast growth factor 21 (FGF21) with NAFLD. Therefore, we assessed the association of circulating FGF21 levels with inflammatory markers, lipoprotein profile and NAFLD in the Multi-Ethnic Study of Atherosclerosis (MESA)., Methods: Among 6814 participants free of apparent cardiovascular disease at baseline (2000-2002), 3634 participants had valid data on variables of interest. After excluding participants with excessive alcohol consumption, 3446 participants were included in the analysis. NAFLD was defined using non-contrast cardiac computed tomography with a liver-to-spleen ratio (LSR) < 1 or liver attenuation <40 Hounsfield units (HU)., Results: The mean age of the participants was 63.5 years with 54% females, 36% Caucasian, 10% Chinese American, 31% African American and 23% Hispanic. 17% of the participants had NAFLD. After adjustment for demographic, socioeconomic and other confounders, a 1-SD increment in ln-transformed FGF21 level was associated with a 5.1% higher IL-6 level, a 0.31 nm larger very-low-density lipoprotein particle diameter, a 0.014 nm smaller high-density lipoprotein particle diameter, and a 5.25 nmol/L lower intermediate-density lipoprotein particle concentration (all p < 0.05). A 1-SD increment in ln-transformed FGF21 level was associated with LSR<1 and liver attenuation <40 HU (OR = 1.38 and 1.48; both p < 0.01), even after adjusting for the aforementioned inflammation and lipoprotein parameters., Conclusions: This study suggests an association between FGF21 and NAFLD, independent of inflammation and atherogenic lipoprotein abnormalities. Further studies are needed to assess FGF21 as a biomarker for future NAFLD risk., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Previous studies have demonstrated that elevated cholesterol results in increased white blood cell counts in mouse models. However, there is insufficient evidence to support this in humans., Objective: The objective of the study was to investigate the relationship of plasma lipids with white blood cell counts (basophils, eosinophils, monocytes, neutrophils and lymphocytes) in the Multi-Ethnic Study of Atherosclerosis., Methods: The analysis included 2873 Multi-Ethnic Study of Atherosclerosis participants with a complete white blood count and differential analysis. The cross-sectional association of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels with different white blood cell counts was analyzed by multivariable linear regression., Results: After adjusting for sociodemographic and confounding factors including red blood cell counts, platelet counts, use of lipid-lowering medication, cardiovascular disease risk factors and other lipid measures, and multiple testing correction, a one-standard deviation increment in total cholesterol and low-density lipoprotein cholesterol was associated with 2.8% and 2.3% lower total white blood cell counts, 3.7% and 3.0% lower monocyte counts, and 3.4% and 2.7% lower neutrophil counts (all P < .01). The same increment in logarithm-transformed triglyceride levels was associated with 2.3% higher total white blood cell counts and 4.5% higher lymphocyte counts (both P < .001). Similar results were obtained after excluding participants taking lipid-lowering medication. A one-standard deviation increase in high-density lipoprotein cholesterol was associated with a 1.5% lower white blood cell count (P = .018) but was not significantly associated with changes in any individual cell type., Conclusion: While significant associations were observed between plasma lipid levels and white blood cell populations, the heterogeneous and modest nature of these relationships makes it hard to support the hypothesis that lipids are in the causal pathway for leukogenesis in humans., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Fibroblast growth factor 21 (FGF21) has been suggested as a novel biomarker for cardiovascular disease (CVD), especially in people with high CVD risk. However, it is not known whether FGF21 is a CVD biomarker in an initially healthy cohort. We therefore investigated the relationship of plasma FGF21 levels with measures of subclinical atherosclerosis and cardiovascular events in Multi-Ethnic Study of Atherosclerosis participants without known CVD at baseline., Methods: A total of 5788 participants had plasma FGF21 levels measured at the baseline exam (2000-2002). Carotid intima-media thickness (IMT), ankle-brachial index (ABI) and coronary artery calcification (CAC) were measured at baseline. Participants were followed up for incident CVD events over a median period of 14 years., Results: In cross-sectional analyses adjusting for socio-demographic variables, participants with higher FGF21 levels had higher carotid IMT, lower ABI, and higher prevalence of CAC (p < 0.001). However, these associations were not significant after simultaneously adjusting for demographic, socioeconomic and lifestyle factors, traditional CVD risk factors, and biomarkers of inflammation and hemostasis. Among 5768 patients with follow-up data, 820 developed incident CVD endpoints. Higher baseline FGF21 levels were not associated with the risk for incident CVD endpoints after adjusting for multiple confounding factors (odds ratio 1.03; 95% confidence interval, 0.94-1.12, per SD increase in ln-transformed FGF21 levels)., Conclusions: Although FGF21 has been suggested as a CVD biomarker for people with high CVD risk, our findings do not support a role of FGF21 as a CVD biomarker in those without a history of CVD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aims: Fibroblast 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)., Methods: 5783 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., Results: Elevated 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 < 0.001) or incident MetS (145.6 [84.9-240.8] vs 112.0 [57.0-194.5] pg/mL, p < 0.001), compared to those without. After adjusting for baseline demographic, socioeconomic and lifestyle factors, as well as cardiovascular risk factors and biomarkers, and compared to the lowest quartile, the highest FGF21 quartile was associated with prevalent MetS (odds ratio 2.80; 95% confidence interval, 2.30-3.40, p < 0.001). Among participants without MetS at baseline, the highest FGF21 quartile was associated with higher risk of incident MetS (hazards ratio 1.76; 95% confidence interval, 1.46-2.12, p < 0.001). Similar results were obtained when assessing ln-transformed FGF21 levels. Overall, no significant interaction was found with age, sex, and race/ethnicity for both prevalent and incident MetS., Conclusions: Higher FGF21 levels significantly predict the development of MetS in an ethnically diverse population followed long term. Further studies are needed to confirm the potential role of FGF21 as a biomarker for MetS., (Copyright © 2018. Published by Elsevier B.V.)

The association between fibroblast growth factor 21 (FGF21) and kidney function has been extensively studied in recent years in both animal and human studies. However, the exact functional role of FGF21 in the kidney remains unclear. Previous animal studies have shown that administration of FGF21 ameliorates kidney function, morphological glomerular abnormalities, dyslipidemia, hyperglycemia, insulin resistance, oxidative stress and obesity. In human studies, FGF21 levels negatively correlated with estimated glomerular filtration rate. FGF21 levels were elevated in patients with end-stage renal disease. The elevation of FGF21 levels in presence of kidney disease has also raised questions as to whether FGF21 is a potential biomarker for detecting a decline in renal function. In recent clinical trials, an FGF21 analogue reduced insulin levels and body weight, and ameliorated dyslipidemia in patients with type 2 diabetes mellitus and obesity, all of which are well-known risk factors for kidney disease. Thus, FGF21 may be a potential therapeutic target for the treatment of kidney disease, although adverse side effects should also be considered when administering FGF21 since FGF21 may affect bone development and reproduction. This review will assess current knowledge on the relationship between FGF21 and kidney function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Elevated 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., Methods: A 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., Results: Among 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 < 0.001). After adjusting for possible confounders, including demographic, socioeconomic and lifestyle factors, traditional CVD risk factors and circulating inflammatory markers, higher baseline FGF21 levels did not predict incident AF over the follow up period. There was no effect modification by sex or ethnicity., Conclusions: Baseline FGF21 levels were not associated with the development of AF in an ethnically diverse population followed long-term. Our findings do not support an important role of FGF21 in AF development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The metabolic properties of the endocrine fibroblast growth factor 21 (FGF21) have been extensively studied in the past decade. Previous studies have demonstrated the lipid-lowering, anti-inflammatory and anti-oxidant properties of FGF21. FGF21 is mainly secreted in the liver and adipose tissue in response to a range of physiological and pathological stimuli. In animal and in vitro studies, FGF21 has been shown to improve lipid profiles and inhibit key processes in the pathogenesis of atherosclerosis. It exerts its effects on the cardiovascular system via adiponectin dependent and independent mechanisms. However, the signalling pathways by which FGF21 exerts its effects on endothelial cells remains unknown and needs to be further investigated. The elevation of circulating FGF21 levels in cardiovascular disease has also raised questions as to whether FGF21 can be used as a biomarker to predict subclinical atherosclerosis and cardiovascular events. Recent findings from population studies must be validated in independent cohorts before FGF21 can be used as a biomarker in the clinical setting. The anti-atherosclerotic effects of FGF21 have been investigated in two recent clinical trials, where treatment with an FGF21 analog significantly improved the cardiometabolic profile in obese patients with type 2 diabetes. This review will evaluate recent advances that suggest there may be a role for FGF21 in atherosclerosis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Pericardial 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., Methods: We 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., Results: After 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). The association of pericardial fat volume with large VLDL-P concentration and HDL-P size, but not small HDL-P concentration, remained significant after further adjusting for each other as well as LDL cholesterol, HDL cholesterol, and triglycerides. The relationship of pericardial fat volume with incident CVD events, carotid IMT, and prevalence and severity of CAC did not differ by quartiles of large VLDL-P concentration, small HDL-P concentration, or HDL-P size (P for interaction>0.05)., Conclusion: Pericardial fat is associated with atherogenic lipoprotein abnormalities. However, its relationship with subclinical atherosclerosis and incident CVD events does not differ according to lipoprotein distribution., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Context: Fibroblast growth factor 21 (FGF21) has been described to have beneficial effects on glucose and lipid metabolism, and FGF21 analogs are currently evaluated in phase 1 trials. However, the complete spectrum of effects and regulators of FGF21 is yet partly elucidated. Recent studies have shown that FGF21 plays a role in transmembrane cholesterol transport., Objective: We set out to examine the association between FGF21 and LDLR mediated transmembrane cholesterol transport, by comparing FGF21 levels in patients with genetically impaired LDLR function and unaffected relatives. Secondly, we explored whether the severity of the LDLR mutation was associated with FGF21 levels., Methods: We performed a cross-sectional study in carriers of an LDLR mutation and their unaffected relatives. Subjects were eligible if they participated in the Dutch national screening program for familial hypercholesterolemia (FH), were 18-55 years old, and were carrier of a pathogenic LDLR mutation with an untreated LDL-C level below the 75(th) or above the 90(th) percentile of the general population, or did not carry an FH mutation. The outcome measure was the level of FGF21, which was assessed using ELISA., Results: We included 224 carriers of an LDLR mutation and 148 unaffected relatives. FGF21 levels were lower in LDLR mutation carriers compared to unaffected relatives (median [interquartile range]: 96.92 [60.80-174.05] versus 136.98 [77.34-219.47] pg/mL, respectively; p = 0.08), but after adjusting for potential confounders, there was no association between LDLR mutations and FGF21 levels (p = 0.70). Neither, did we find a relationship between the severity of LDLR mutations and FGF21 levels (p = 0.51, after adjustment for potential confounders)., Conclusions: We showed that levels of FGF21 are not different in patients with and without LDLR mutations, which suggests that decreased LDLR expression does not have a negative effect on FGF21 levels. Given the potential beneficial effects of FGF21 analogs on lipids and lipoproteins in a phase 1 study, we deem this of great interest for future treatment options for FH patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Pericardial 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., Methods: We 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., Results: After 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)., Conclusion: Pericardial 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., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Insulin 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., Methods: We 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., Results: HOMA-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., Conclusions: Atherosclerotic 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., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Changes in relation to drug treatment to various control targets for diabetes were studied using the National Health and Nutrition Examination Survey, 1999-2010., Methods: Data on 3094 participants aged 20 years or older with diagnosed type II diabetes were analyzed. Use of medications for lowering glucose, blood pressure, and lipids in the past month was assessed by questionnaire. Data from two survey cycles were combined together to produce estimates for each 4-year period., Results: Usage of metformin increased from 34.8% to 53.8% and was the most prevalent medications during this period (P < .001), and half of subjects taking metformin could achieve glycated hemoglobin less than 7.0% in 2007-2010. Dipeptidyl peptidase-4 inhibitors were used by 7.4% of participants in 2007-2010. Usage of angiotensin receptor blockers and beta-blockers increased significantly from 7.4% to 21.4% and from 15.3% to 31.8%, respectively from 1999 to 2010 (P ≤ .001). A total of 64.7% of participants could attain blood pressure control by 2007-2010. Usage of statins doubled in 1999-2010 and 52.2% of subjects took statins by 2007-2010 (P < .001)., Conclusions: Metformin is the first-line drug for diabetes while dipeptidyl peptidase-4 inhibitors started to be used since 2007. Blood pressure control improved in 1999-2010 partly due to increased drug prescriptions. Although statins were widely used about half of the participants did not take them., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Arthritis is associated with cardiovascular diseases (CVDs). However, there are limited epidemiologic studies on arthritis in a national survey study. We therefore investigated the prevalence of self-reported arthritis and its association with CVDs., Methods: Data from 15,888 subjects aged 40 years or older in the United States National Health and Nutrition Examination Survey 1999 through 2008 were analyzed. CVD was defined as a self-reported history of heart attack, congestive heart failure, coronary heart disease, angina, or stroke., Results: The overall prevalence of self-reported arthritis in subjects aged 40 years or older increased from 33.5% in 1999 through 2000 to 37.0% in 2007 through 2008 (P for trend = 0.017). Among subjects with arthritis in 1999 through 2008, 35.3% had osteoarthritis (OA), 17.9% had rheumatoid arthritis (RA), and 10.2% had other types of arthritis, but 36.6% were unaware of their type of arthritis. Compared with subjects without OA, subjects with OA had higher odds for CVDs (odds ratio [OR], 1.53; P < .001), especially angina (OR, 2.18: P < .001). Compared with subjects without RA, subjects with RA had higher odds for CVDs (adjusted OR, 2.39; P < .001), especially congestive heart failure (OR, 3.59; P < .001)., Conclusions: Both RA and OA are strongly associated with CVDs in the general population. Further studies are needed to investigate their causal relationship., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: A low circulating level of bilirubin is associated with increased cardiovascular risk. As statins can stimulate heme oxygenase-1 (HO-1), which increases bilirubin production, we investigated whether statins in routine use increase total bilirubin levels in subjects at high cardiovascular risk., Methods: Data from 3290 subjects with self-reported history of hypercholesterolemia, diabetes, or cardiovascular diseases in the United States National Health and Nutrition Examination Survey (NHANES) 1999-2008 were analyzed., Results: Subjects taking statins (n = 1156) had lower total bilirubin levels than those not taking any lipid-lowering medication (n = 2134) after adjusting for age, sex, race/ethnicity, and survey period (adjusted mean = 0.699 vs 0.729 mg/dl respectively, P=0.001). The association remained significant after adjusting for more covariates (P = 0.002), but was attenuated after further adjusting for glycosylated hemoglobin, insulin resistance index, and low-density lipoprotein (LDL) cholesterol (P = 0.043). The use of lovastatin, rosuvastatin, and cerivastatin was associated with lower total bilirubin levels in the full adjustment model (P < 0.05)., Conclusion: The use of statins was associated unexpectedly with lower total bilirubin levels. This could be explained at least partly by the effect of statins on glycemia and LDL cholesterol. Our results do not suggest that the anti-oxidant and anti-inflammatory effects of statins are due to HO-1 induction and increased serum bilirubin levels., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Plasma activities of alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyl transferase (GGT) are often increased in cardiometabolic diseases. We investigated if hypertension is associated with increased activities of these plasma markers., Methods: We included 235 hypertensive and 708 normotensive subjects (mean age 47.3±9.6 and 58.0±10.2 years respectively) from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS-2) in 2000-2004 who had drank <1/week. In the follow-up study in 2005-2008 (CRISPS-3), 126 out of the 708 subjects had developed hypertension., Results: Raised plasma ALT (OR=1.22 per SD of log-transformed level, P=0.045) and GGT (OR=1.38 per SD of log-transformed level, P=0.001) levels were associated with hypertension at baseline in CRISPS-2 after adjusting for covariates. Among subjects not on anti-hypertensive medications, plasma ALP, ALT and GGT were related to blood pressure (P<0.01). In subjects normotensive at CRISPS-2, plasma GGT, but not ALP, ALT and AST, was an independent predictor of new-onset hypertension at CRISPS-3 (OR=1.38 per SD of log-transformed level, P=0.020 and OR=2.68 for 3rd tertile vs. 1st tertile, P=0.004) after adjusting for covariates., Conclusions: Among the 4 plasma markers, increased GGT activity is the strongest predictor for existing and new-onset hypertension in Hong Kong Chinese., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Adrenomedullin, a vasodilatory peptide, facilitates the differentiation of pre-adipocytes, and affects lipolysis and glucose uptake. We investigated the association of common single nucleotide polymorphisms (SNPs) in the gene encoding adrenomedullin (ADM) with dysglycemia in the Hong Kong Chinese population., Methods: Four SNPs were genotyped in 1391 subjects without dysglycemia at baseline from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, which had a median follow-up time of 6.4 years. Dysglycemia included impaired fasting glucose, impaired glucose tolerance, and diabetes according to the WHO 1998 criteria. At follow-up, 382 subjects had developed dysglycemia., Results: In stepwise logistic regression, the SNP rs11042725 was a significant independent predictor of the development of dysglycemia (OR=1.31, P=0.012), together with baseline age (P<0.001), plasma triglycerides (P<0.001), body mass index (P=0.004), 2-h glucose after oral glucose tolerance test (P<0.001), homeostasis model assessment of insulin resistance index (P=0.045), and follow-up duration (P=0.009). The association was more significant in women (P=0.002) and in subjects without regular exercise (P=0.001)., Conclusions: Our study suggests a potential role of genetic variants in the ADM gene in the development of dysglycemia in our local Chinese population., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: We examined the use of lipid lowering medications and control of dyslipidemia among US adults in 1999-2006., Methods: Data were extracted from the National Health and Nutrition Examination Survey 1999-2006., Results: The mean low-density lipoprotein-cholesterol (LDL-C) level significantly decreased from 3.25+/-0.03 mmol/L in 1999-2002 to 3.02+/-0.02 mmol/L in 2003-2006 in men, and from 3.11+/-0.03 to 2.98+/-0.03 mmol/L in women (p<0.001). Statins and fibrates were the most commonly used medications. Among those diagnosed with hypercholesterolemia, the proportion on treatment increased from 32.4% to 38.9% (p=0.001) in the 8-year period. The proportion of participants with a history of diabetes treated with a statin increased from 20.9+/-2.2% in 1999-2002 to 37.6+/-2.5% in 2003-2006 (p<0.001). However, only 39.9% of people with diabetes and 45.4% of people with ischemic heart disease (IHD) achieved LDL-C target levels., Conclusions: Between 1999 and 2006, LDL-C level decreased in US adults and use of lipid lowering medications increased. More effort is still needed to detect and treat dyslipidemia in the community, particularly in people at high cardiovascular risk., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Alkaline phosphatase (ALP) is elevated in peripheral arterial disease (PAD). We therefore examined the relationship of PAD with ALP and other liver enzymes in the United States National Health and Nutrition Examination Survey 1999-2004., Methods: The analysis included 5995 men and non-pregnant women aged >or=40 years with no missing data in variables of interest. PAD was defined as ankle-brachial blood pressure index (ABI) <0.90 in either leg., Results: Serum alkaline phosphatase (ALP) level was associated significantly with lower ABI after adjustment for confounding factors (p=0.019). No significant association of ABI with other liver enzymes was found. Serum ALP level increased with increasing age, body mass index, C-reactive protein, monocyte count, serum uric acid, lead, cadmium, and prevalence of hypercholesterolemia, diabetes, smoking, non-alcohol drinking, and cardiovascular diseases after adjusting for age, sex, race/ethnicity, and survey years (p<0.02). The highest quartile of serum ALP was associated with an odds ratio of 1.89 (95% confidence interval [CI]: 1.25-2.85) for PAD after adjustment for confounding factors (p for trend=0.023). In subjects with normal kidney function (glomerular filtration rate >90 ml/min/1.73 m(2)), the odds ratio increased to 4.22 (95% CI 1.45-12.35) (p=0.010)., Conclusion: Elevated serum ALP is correlated with PAD, independent of other traditional cardiovascular risk factors.

Purpose: This study aimed to examine the trends in prevalence, treatment, and control of diagnosed diabetes in United States adults 20 years of age or older., Methods: Data from the National Health and Nutrition Examination Survey 1999-2004 were used. Glycemic, blood pressure, and total cholesterol target levels were defined as having glycosylated hemoglobin <7.0%, blood pressure <130/80 mm Hg, and total cholesterol <200 mg/dL, respectively., Results: The prevalence of diagnosed diabetes was 7.8% in 2003-2004 and increased significantly in people aged 40-59 years, women, non-Hispanic whites, and obese people in the period 1999-2004. Although there was no significant change in the pattern of antidiabetic treatment, the age-adjusted percentage of people with diagnosed diabetes achieving glycemic and blood pressure target levels increased from 35.8% to 57.1% (p = 0.002) and from 35.7% to 48.3% (p = 0.04), respectively. However, there were only insignificant increases in percentages of those persons achieving total cholesterol target level (from 48.8% to 50.4%) and those achieving all 3 target levels (from 7.5% to 13.2%)., Conclusions: In 1999-2004, the prevalence of diagnosed diabetes increased significantly in some subgroups of the population. However, the increases in percentages of people with diabetes achieving glycemic and blood pressure targets are encouraging, although there is room for improvement.