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Background Cholesterol trafficked within plasma lipoproteins, in particular high-density lipoproteins (HDL), may represent an important source of cholesterol that is required for adrenal steroidogenesis. Based on a urinary gas chromatography method, compromised adrenal function has been suggested in men but not in women with (genetically determined) low plasma HDL-cholesterol (HDL-C). Objective The objective of the article was to examine the extent to which glucocorticoid production relates to HDL-C in a population-based cohort. Methods A total of 240 subjects (120 men and 120 women, aged 20–79 years) without relevant comorbidities were recruited from the general population. Glucocorticoid metabolites were measured by gas chromatography with tandem mass spectrometric detection in 24-hour urine collections to estimate total glucocorticoid production (TGP). Fasting plasma (apo)lipoproteins were assayed by routine methods. Results TGP was not decreased but tended to be increased in subjects with low HDL-C (NCEP-ATPIII criteria; P = .094). In univariate analysis, TPG was correlated inversely with HDL-C ( r = −0.353, P < .001) and apoA-I ( r = −0.263, P = .01). Multivariable linear regression analysis demonstrated that TGP was still inversely related to HDL-C (β = −0.145, P = .019) or alternatively to low HDL-C (β = −0.129, P = .013) taking age, sex, current smoking, and other metabolic syndrome components into account. Conclusion In this population-based study, urinary glucocorticoid metabolite excretion was inversely associated with HDL-C. We found no evidence for an attenuated adrenal function in men and women with low HDL-C. [ABSTRACT FROM AUTHOR]

Background High-density lipoproteins (HDLs) protect against the development of atherosclerotic cardiovascular disease. HDL function represents an emerging concept in cardiovascular research. Objective This study investigated the association between HDL functionality and acute myocardial infarction (MI) independent of HDL-cholesterol plasma levels. Methods Participants (non-ST-segment elevation MI, non-STEMI, n = 41; STEMI, n = 37; non-MI patients, n = 33) from a prospective follow-up study enrolling patients with acute chest pain were matched for age and plasma HDL cholesterol. The in vitro capacity of HDL to (1) mediate cholesterol efflux from macrophage foam cells, (2) prevent low-density lipoprotein oxidation, and (3) inhibit TNF-α-induced vascular adhesion molecule-1 expression in endothelial cells was determined. Results STEMI-HDL displayed reduced cholesterol efflux ( P < .001) and anti-inflammatory functionality ( P = .001), whereas the antioxidative properties were unaltered. Cholesterol efflux correlated with the anti-inflammatory HDL activity ( P < .001). Not C-reactive protein levels, a marker of systemic inflammation, but specifically plasma myeloperoxidase levels were independently associated with impaired HDL function (efflux: P = .022; anti-inflammation: P < .001). Subjects in the higher risk quartile of efflux (odds ratio [OR], 5.66; 95% confidence interval [CI], 1.26–25.00; P = .024) as well as anti-inflammatory functionality of HDL (OR, 5.53; 95% CI, 1.83–16.73; P = .002) had a higher OR for MI vs those in the three lower risk quartiles combined. Conclusion Independent of plasma HDL cholesterol levels, 2 of 3 antiatherogenic HDL functionalities tested were significantly impaired in STEMI patients, namely cholesterol efflux and anti-inflammatory properties. Increased myeloperoxidase levels might represent a major contributing mechanism for decreased HDL functionality in MI patients. [ABSTRACT FROM AUTHOR]

Background Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a cardiovascular risk marker, which is in part complexed to low-density lipoproteins, where it exerts pro-inflammatory properties. GlycA is a pro-inflammatory proton nuclear magnetic resonance spectroscopy biomarker whose signal originates from a subset of N -acetylglucosamine residues on the most abundant glycosylated acute-phase proteins. Objective We compared plasma GlycA and Lp-PLA 2 mass between subjects without type 2 diabetes mellitus (T2DM) or the metabolic syndrome (MetS) and subjects with T2DM and/or MetS. We also tested the relationship of GlycA with Lp-PLA 2 in each group. Methods Plasma GlycA, Lp-PLA 2 mass, high-sensitivity C-reactivity protein (hsCRP) and lipids were measured in 40 subjects with neither T2DM nor MetS (group 1) and in 58 subjects with T2DM and/or MetS (group 2). Results GlycA and hsCRP were higher ( P < .01 for each), whereas Lp-PLA 2 was lower in group 2 vs group 1 ( P < .001). GlycA was positively related to hsCRP in each group ( P < .001). In contrast, GlycA was correlated positively with Lp-PLA 2 in group 1 (r = 0.384, P = .015), but not in group 2 (r = 0.045; P = .74; interaction term for difference: P = .059). Although Lp-PLA 2 was correlated positively with non–high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in each group ( P ≤ .02), its inverse relationship with high-density lipoprotein cholesterol in group 1 (r = −0.381, P = .013) was absent in group 2 (r = −0.101, P = .42). Conclusions A pro-inflammatory glycoprotein biomarker, GlycA, is higher in subjects with either T2DM, MetS, or both. The normally present positive relationship of GlycA with Lp-PLA 2 is blunted in subjects with T2DM and/or MetS. [ABSTRACT FROM AUTHOR]

We determined relationships of the anti-oxidative enzyme, paraoxonase-1 (PON-1), with high density lipoprotein (HDL) subfractions, and tested whether these relationships are stronger than those with HDL cholesterol and apolipoprotein A-I (apoA-I) in subjects with and without type 2 diabetes mellitus (T2DM). Design and methods Serum PON-1 (arylesterase activity) and HDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 67 T2DM patients and in 56 non-diabetic subjects. Results PON-1 activity, HDL cholesterol and apoA-I were decreased in T2DM (all p<0.05). The HDL particle concentration was unaltered, but large HDL particles, medium HDL particles and HDL particle size were decreased, whereas small HDL particles were increased in T2DM (all p<0.05). PON-1 was more closely related to HDL cholesterol than to apoA-I (p=0.001). In turn, the positive relationship of PON-1 with the HDL particle concentration and with large HDL particles was stronger than that with HDL cholesterol (both p<0.01). The inverse relationship of PON-1 with T2DM was only modestly attenuated by HDL cholesterol or HDL particle characteristics. Conclusions PON-1 activity is more closely related to the HDL particle concentration or large HDL particles than to HDL cholesterol. Impaired PON-1 activity in T2DM is not to a considerable extent explained by altered HDL subfraction levels. [ABSTRACT FROM AUTHOR]

Abstract: Background: Intrinsic functional properties of high density lipoproteins (HDL) are considered to be physiologically important for atheroprotection. We compared the HDL anti-inflammatory capacity between patients with acute myocardial infarction (MI) and patients with non-cardiac chest pain, and prospectively determined the association of new major adverse cardiovascular events (MACE) with this metric of HDL function. Methods: A prospective study was carried out in 93 patients referred for acute chest pain (65 patients with acute MI). The HDL anti-inflammatory capacity was determined as the ability to suppress tumor necrosis factor-α-induced vascular cell adhesion molecule-1 mRNA expression in endothelial cells in vitro. Results: Acute MI at admission was associated with impaired HDL anti-inflammatory capacity (p =0.001), even after adjustment for HDL cholesterol and apolipoprotein A-I (p =0.003). Twenty nine MACE were ascertained during a median follow-up of 1210 (910–1679) days. New MACE was associated with impaired HDL anti-inflammatory capacity (hazard ratio: 1.80 (1.17–2.77) per SD change, p =0.007) in age, sex, HDL cholesterol and apolipoprotein-AI adjusted analysis. Conclusions: The ability of HDL to attenuate endothelial inflammation is impaired in acute MI, and this metric of HDL function may serve as a predictor of new MACE, even independent of HDL cholesterol and apolipoprotein A-I. [Copyright &y& Elsevier]

Abstract: Background: High density lipoproteins (HDL) contain paraoxonase-1 (PON-1), which has strong anti-oxidative properties. Apolipoprotein E (apoE) may enhance PON-1 activity in vitro, but the extent to which PON-1 activity is determined by circulating apoE levels is unknown. Here we determined relationships of serum PON-1 activity with apoE in subjects without and with metabolic syndrome (MetS). Methods: We measured PON-1 activity (arylesterase activity), plasma apoE and serum amyloid A (SAA) in 93 subjects without and in 75 subjects with MetS (25 and 54 subjects with Type 2 diabetes mellitus (T2DM), respectively; p < 0.001). Results: PON-1 activity was lower in MetS (p < 0.005) coinciding lower HDL cholesterol, apoA-I (p < 0.001)) and SAA levels (p < 0.01), whereas apoE was increased in relation to higher triglycerides (p < 0.01). In subjects without MetS, PON-1 activity was correlated positively with apoE (r = 0.376, p < 0.001), but this relationship was absent in MetS subjects (r = 0.085, p = 0.47). Multiple linear regression analysis showed that the relationship of PON-1 activity with apoE was different in subjects with MetS compared to subjects without MetS (β = −0.270, p = 0.014 for the interaction between apoE and MetS), independently from age, sex, T2DM, use of glucose lowering drugs, anti-hypertensives and the inverse relation with SAA levels (p = 0.008). Of the individual MetS components, apoE only interacted with low HDL-C on PON-1 activity (β = −0.175, p = 0.074). The relationship of apoE with PON-1 activity was neither modified by T2DM (p = 0.49), nor by SAA (p = 0.79). Conclusion: Higher apoE levels may confer higher PON-1 activity. The relationship of PON-I activity with total plasma apoE is apparently abrogated in MetS. [Copyright &y& Elsevier]

Background: The preference of the apolipoprotein (apo) B/apoA-I ratio over the total cholesterol/HDL cholesterol (TC/HDL-C) ratio in cardiovascular risk prediction is disputed. Cholesteryl ester transfer protein (CETP) is instrumental in lipoprotein remodelling and affects the cholesterol content in pro- and antiatherogenic lipoproteins relative to their major apolipoproteins. We tested the influence of common CETP variations on the strength of associations of a first major adverse cardiovascular event (MACE) with the apoB/apoA-I ratio compared with the TC/HDL-C ratio. Methods: A prospective case-cohort study was performed (PREVEND cohort; no previous cardiovascular disease and no use of lipid-lowering drugs initially). Fasting serum TC/HDL-C, apoB/apoA-I, triglycerides, and common CETP variations (TaqIB [rs708272] and -629C>A [rs1800775] polymorphisms) were measured at baseline. The composite end point was incident MACE. Results: A total of 532 of 6780 subjects experienced a first MACE during 10.8 years follow-up. The age- and sex-adjusted hazard ratio was 1.31 (95 % confidence interval 1.23–1.41) for the apoB/apoA-I ratio and 1.22 (95% confidence interval 1.26–1.39) for the TC/HDL-C ratio (both P < .001). These relationships were essentially similar within each TaqIB and -629C>A CETP genotype group. No interactions of the apoB/apoA-I ratio and the TC/HDL-C ratio with the TaqIB and the -629C>A CETP variations on incident MACE were observed (P > .20 for all). Conclusion: The relationship of first MACE with the TC/HDL-C and the apoB/apoA-I ratio is not to an important extent dependent on common CETP variations. CETP variations are unlikely to affect the strength of the relationship of first MACE with the apoB/apoA-I ratio compared with the TC/HDL-C ratio. [ABSTRACT FROM AUTHOR]

Abstract: Although there is great interest in the notion that dysfunctional transformation of high-density lipoprotein (HDL) facilitates development of atherosclerosis and cardiovascular disease (CVD), few studies in human populations directly address this issue. As apolipoprotein E (apoE) is a constituent of HDL thought to be important for HDL antiatherogenic function, we sought to assess the role of apoE in CVD risk in subjects likely to display dysfunctional transformation of HDL. Association of apoE levels with incident CVD risk was investigated using Cox multivariable proportional hazards modeling. Analyses were performed in subgroups of women and men likely to display dysfunctional transformation of HDL deriving from previous subgroup identification based upon defining characteristics of concurrently high levels of HDL cholesterol and systemic inflammation as reflected by high C-reactive protein levels. Results revealed apoE levels (dichotomized as highest quartile vs combined 3 lowest quartiles) as predicting subgroup risk in women (hazard ratio, 4.52; 95% confidence interval, 1.07-19.12; P = .040) but not in men. Further sex differences were manifested in terms of the relationship of apoE levels with age. Analysis revealed positive correlation of apoE levels with age in women (r = 0.47, P < .0001) but not in men (r = 0.04, P = .43). Apolipoprotein E levels predict incident CVD risk in women with high levels of HDL cholesterol and C-reactive protein but not in men. Future studies should be oriented toward investigations of apoE as related to multiplicity of HDL functionality and toward assessment of potential roles for apoE in dysfunctional transformation of HDL. [Copyright &y& Elsevier]

Abstract: Background: High density lipoproteins (HDLs) have been implicated in glucose homeostasis. Among subjects with normal fasting glucose (NFG), impaired fasting glucose (IFG) and Type 2 diabetes mellitus (T2DM) we tested whether pancreatic β-cell function relates to HDL functionality, as determined by HDL anti-oxidative capacity and cellular cholesterol efflux to plasma. Subjects and methods: HDL anti-oxidative capacity (inhibition of LDL oxidation in vitro), cellular cholesterol efflux (the ability of plasma to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single human donor), glucose and insulin were determined in fasting plasma samples from 37 subjects with NFG, 36 with IFG and 22 with T2DM (no glucose lowering drug or insulin treatment; HbA1c 6.0±1.0%). Homeostasis model assessment was used to estimate pancreatic β-cell function (HOMA-β) and insulin resistance (HOMAir). Results: HOMA-β was lowest, whereas HOMAir was highest in T2DM (P <0.01 and P <0.001 vs. NFG). HDL anti-oxidative capacity and cellular cholesterol efflux did not differ significantly according to glucose tolerance category. In univariate analysis and after controlling for HOMAir both HDL anti-oxidative capacity (P <0.05) and cellular cholesterol efflux (P <0.01) were positively correlated with HOMA-β in T2DM, but not in NFG and IFG. In age-, sex- and HOMAir-adjusted analyses, T2DM status interacted positively with HDL anti-oxidative capacity (P =0.001) and cellular cholesterol efflux (P =0.042) on HOMA-β. HbA1c interacted similarly with HDL functionality measures on HOMA-β. Conclusions: Pancreatic β-cell function relates to pathophysiologically relevant measures of HDL function in T2DM, but not in NFG and IFG. Better HDL functionality may contribute to maintenance of β-cell function in subjects with well-controlled T2DM. [Copyright &y& Elsevier]

Abstract: The cholesterol esterifying enzyme, lecithin:cholesterol acyltransferase (LCAT), is crucial in high density lipoprotein (HDL) metabolism. The role of LCAT activity on incident cardiovascular disease (CVD) is unknown. We determined the association of incident CVD with plasma LCAT activity, and evaluated whether LCAT may modify the cardioprotective effect of higher HDL cholesterol. In a community-based prospective nested case-control study (PREVEND cohort), an exogenous substrate assay was used to measure plasma LCAT activity in 116 men who developed CVD (cases) and in 111 male controls. Plasma LCAT activity was 5% higher in cases (P =0.027) in association with higher total cholesterol, non-HDL cholesterol and triglycerides. Age-adjusted incident CVD was increased with higher LCAT activity (continuous variable: hazard ratio (HR) 1.23; 95% CI 1.01–1.49, P =0.037; upper quartile vs. lowest 3 quartiles: HR 1.60; 95% CI 1.07–2.39, P =0.021). This relationship was not significant after adjustment for lipids. Compared to subjects with HDL cholesterol above the median and lower LCAT activity (lowest 3 quartiles) the age-adjusted cardiovascular risk was elevated in subjects with similarly higher HDL cholesterol and higher LCAT activity (HR 2.38; 95% CI 1.27–4.49, P =0.007), lower HDL cholesterol and lower LCAT activity (HR 2.58; 95% CI 1.64–4.49, P <0.001) and lower HDL cholesterol and higher LCAT activity (HR 2.76; 95% CI 1.58–4.83, P <0.001). These HRs were unchanged after non-HDL cholesterol and triglyceride adjustment. In conclusion, high plasma LCAT activity does not predict reduced CVD risk, and may attenuate cardioprotection associated with higher HDL cholesterol. [Copyright &y& Elsevier]

Objectives High density lipoprotein (HDL)-associated paraoxonase-1 (PON-1) exerts anti-oxidative properties, whereas phospholipid transfer protein (PLTP) is able to convert mature HDL into larger and smaller HDL particles. Here we tested associations of PON-1 with PLTP in type 2 diabetes mellitus (T2DM), a condition characterized by lower PON-1 activity and higher PLTP activity. Design and methods Serum PON-1 (arylesterase activity), plasma PLTP activity (liposome-vesicle HDL system), and (apo)lipoproteins were measured in 81 T2DM subjects (mean age 59 ± 9 years; 31 women; no insulin treatment). In 48 participants, HDL subfractions were measured by nuclear magnetic resonance spectroscopy. Results In univariate correlation analysis, PON-1 activity was positively related to PLTP activity (r = 0.348, p = 0.001). PLTP activity was positively related to blood pressure, body mass index and triglycerides, whereas PON-1 activity was positively to HDL cholesterol and apoA-I ( p < 0.05 to < 0.01 for each). Both PLTP activity and PON-I activity were positively related to large HDL particles (r = 0.379, p = 0.008 and r = 0.411, p = 0.004, respectively). In multivariable linear regression analysis, PON-1 activity was associated with PLTP activity independent of clinical covariates and HDL cholesterol or apoA-I (β = 0.340, p = 0.001 and β = 0.320, p = 0.003, respectively). The association of PON-1 activity with PLTP activity was lost in analysis which included large HDL particles (large HDL: β = 0.411, p = 0.004). Conclusions PON-1 activity is positively related to PLTP activity in T2DM, raising the possibility that PLTP could act to maintain PON-1. This association may in part be attributable to a common relationship of PON-1 and PLTP with large HDL particles. [ABSTRACT FROM AUTHOR]

Cholesterol Efflux Capacity (CEC) is considered to be a key atheroprotective property of high-density lipoproteins (HDL). However, the role of HDL-CEC in atherosclerosis and cardiovascular (CV) risk is still controversial, and data in individuals with diabetes are limited. In this study, we have investigated the relationship of CEC and other HDL characteristics with clinical and subclinical atherosclerosis in subjects with elevated cardiovascular diseases (CVD) risk and Type 2 Diabetes Mellitus (T2DM). Using multiple linear regression analyses, we determined the relationship of HDL-CEC with carotid intima-media thickness (cIMT, Z-Score), an endothelial dysfunction (EnD) Score (Z-Score), prevalent CVD (n = 150 cases) and history of CV events (CVE, n = 85 cases) in an observational cohort (CODAM, n = 574, 59.6 ± 0.3 yr, 61.3% men, 24.4% T2DM). Stratified analyses were performed to determine if the associations differed between individuals with normal glucose metabolism (NGM) and those with disturbed glucose metabolism. HDL-CEC was not associated with either marker of atherosclerosis (cIMT, EnD Score) nor with CVD or CVE. In contrast, other HDL characteristics that is, HDL-Cholesterol (HDL-C, Z-Score), apolipoprotein A-I (apoA-I, Z-Score), HDL size (Z-Score) and HDL particle number (HDL-P, Z-Score) were inversely and significantly associated with the EnD Score (s −0.226 to −0.097, P <.05) and CVE (ORs 0.61 to 0.68, P <.05). In stratified analyses, HDL size and HDL-P were significantly associated with the EnD Score in individuals with NGM (P interaction.039 and.005, respectively), but not in those with (pre)diabetes. HDL-C and apoA-I were inversely associated with prevalent CVD in individuals with (pre)diabetes (P interaction =.074 and.034, respectively), but not in those with NGM. HDL-CEC is not associated with clinical or subclinical atherosclerosis, neither in the whole population nor in individuals with (pre)diabetes, while other HDL characteristics show atheroprotective associations. The atheroprotective associations of HDL-size and HDL-P are lost in (pre)diabetes, while higher concentrations of HDL-C and apoA-I are associated with a lower prevalence of CVD in (pre)diabetes. • HDL-CEC is not associated with subclinical or clinical atherosclerosis • HDL-C, apoA-I, HDL size, and HDL-P show atheroprotective associations • Atheroprotective associations of HDL-size and HDL-P are lost with (pre)diabetes [ABSTRACT FROM AUTHOR]

Objectives Low-normal thyroid function within the euthyroid range may influence plasma lipoprotein levels. Associations between variation in thyroid function and pre-β-high density lipoproteins (pre-β-HDL), i.e. lipid-poor or lipid free HDL particles that act as initial acceptor of cell-derived cholesterol, are unknown. We determined relationships of plasma pre-β-HDL with thyroid function in euthyroid subjects with and without type 2 diabetes mellitus (T2DM). Design and Subjects TSH, free T4, plasma (apo)lipoproteins, pre-β-HDL, pre-β-HDL formation (pre-β-HDL generation during incubation with lecithin:cholesterol acyltransferase being inhibited) and phospholipid transfer protein (PLTP) activity were measured in fasting plasma from 72 T2DM and 82 non-diabetic subjects. Results TSH was similar and free T4 was slightly higher ( P < 0.05) in T2DM vs. non-diabetic subjects. HDL cholesterol and apoA-I were lower, whereas pre-β-HDL (expressed as % of apoA-I), triglycerides and PLTP activity were higher in T2DM ( P < 0.05 to P < 0.001). In T2DM, pre-β-HDL formation (in apoA-I concentration and in % of apoA-I) was positively related to free T4, PLTP activity, total cholesterol and triglycerides ( P < 0.05 for each). Multivariable linear regression analyses, adjusted for age, sex, PLTP activity, total cholesterol and triglycerides, demonstrated that pre-β-HDL formation was positively related to free T4 (in apoA-I concentration: β = 0.278, P = 0.014; in % of apoA-I: β = 0.343, P = 0.003) in T2DM, but not in non-diabetic subjects (both P > 0.30; interaction terms: both P < 0.05). Conclusions Variations in thyroid function within the euthyroid range may influence the metabolism of pre-β-HDL in T2DM. [ABSTRACT FROM AUTHOR]

• The Diabetes Risk Index (DRI) predicts the incidence of type 2 diabetes. • DRI is a multimarker that integrates data from BCAA and lipoprotein subspecies. • High DRI is associated with a high risk of incident Hypertension. • DRI associates with future hypertension even in low-risk individuals. The present study aims to evaluate the performance of the Diabetes Risk Index (DRI), a metabolomic index based on lipoprotein particles and branched chain amino acids, on the incidence of newly developed hypertension in a large community dwelling cohort. The DRI was calculated by combining 6 lipoprotein parameters [sizes of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), concentrations of large VLDL, small LDL, and large HDL particles], and the concentrations of valine and leucine. DRI scores were estimated in 4169 participants from the PREVEND prospective cohort. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident hypertension. During a median follow-up of 8.6 years, 924 new hypertension cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI and incident hypertension with a hazard ratio (HR) per 1 SD increase of 1.45 (95% CI 1.36,1.54; p < 0.001). After additional adjustment for traditional risk factors, the HR remained significant (HR adj 1.21, 95% CI 1.10, 1.33, p <0.001). Likewise, subjects in the top quartile of DRI presented with a higher risk of hypertension (HR adj 1.64, 95% CI 1.28, 2.10, p <0.001). Furthermore, the net reclassification improvement assessment improved after the addition of DRI to a traditional risk model (p <0.001), allowing proper reclassification of 34% of the participants. Higher DRI scores were associated with an increased risk of incident hypertension. Such association was independent of traditional clinical risk factors for hypertension. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population.Methods: HDL anti-inflammatory capacity was determined as its ability to suppress TNFα (tumor necrosis factor α)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNFα effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls.Results: HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; P<0.001) and was inversely associated with incident CVD in a fully adjusted model (odds ratio [OR] per 1 SD, 0.74 [CI, 0.61-0.90]; P=0.002). Furthermore, this association was approximately similar with all individual components of the cardiovascular disease end point. The HDL anti-inflammatory was not correlated with cholesterol efflux capacity (r=-0.02; P>0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; P=0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; P<0.001). Adding HDL anti-inflammatory capacity improved risk prediction by the Framingham risk score, with a model likelihood-ratio statistic increase from 10.50 to 20.40 (P=0.002).Conclusions: The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction. [ABSTRACT FROM AUTHOR]

Background: High-density lipoprotein (HDL) cholesterol concentration (HDL-C) is an established atheroprotective marker, in particular for coronary artery disease; however, HDL particle concentration (HDL-P) may better predict risk. The associations of HDL-C and HDL-P with ischemic stroke and myocardial infarction (MI) among women and Blacks have not been well studied. We hypothesized that HDL-P would consistently be associated with MI and stroke among women and Blacks compared with HDL-C.Methods: We analyzed individual-level participant data in a pooled cohort of 4 large population studies without baseline atherosclerotic cardiovascular disease: DHS (Dallas Heart Study; n=2535), ARIC (Atherosclerosis Risk in Communities; n=1595), MESA (Multi-Ethnic Study of Atherosclerosis; n=6632), and PREVEND (Prevention of Renal and Vascular Endstage Disease; n=5022). HDL markers were analyzed in adjusted Cox proportional hazard models for MI and ischemic stroke.Results: In the overall population (n=15 784), HDL-P was inversely associated with the combined outcome of MI and ischemic stroke, adjusted for cardiometabolic risk factors (hazard ratio [HR] for quartile 4 [Q4] versus quartile 1 [Q1], 0.64 [95% CI, 0.52-0.78]), as was HDL-C (HR for Q4 versus Q1, 0.76 [95% CI, 0.61-0.94]). Adjustment for HDL-C did not attenuate the inverse relationship between HDL-P and atherosclerotic cardiovascular disease, whereas adjustment for HDL-P attenuated all associations between HDL-C and events. HDL-P was inversely associated with the individual end points of MI and ischemic stroke in the overall population, including in women. HDL-P was inversely associated with MI among White participants but not among Black participants (HR for Q4 versus Q1 for Whites, 0.49 [95% CI, 0.35-0.69]; for Blacks, 1.22 [95% CI, 0.76-1.98]; Pinteraction=0.001). Similarly, HDL-C was inversely associated with MI among White participants (HR for Q4 versus Q1, 0.53 [95% CI, 0.36-0.78]) but had a weak direct association with MI among Black participants (HR for Q4 versus Q1, 1.75 [95% CI, 1.08-2.83]; Pinteraction<0.0001).Conclusions: Compared with HDL-C, HDL-P was consistently associated with MI and ischemic stroke in the overall population. Differential associations of both HDL-C and HDL-P for MI by Black ethnicity suggest that atherosclerotic cardiovascular disease risk may differ by vascular domain and ethnicity. Future studies should examine individual outcomes separately. [ABSTRACT FROM AUTHOR]

• TG/HDL-C ratio and LP-IR score (NMR) are lipid-based measures of insulin resistance. • We determined associations of HOMA-IR and these lipid measures with atherosclerosis. • All measures were independently associated with carotid intima media thickness; n = 170. • All measures were independently associated with incident CVD; n = 505/6232, FU 8.2 yr. • HOMA-IR was not superior to these lipid measures, obviating insulin measurement. The triglyceride/HDL cholesterol (TG/HDL-C) ratio and the Lipoprotein Insulin Resistance (LP-IR) score are lipid markers of insulin resistance. Their associations with carotid intima media thickness (cIMT; subclinical atherosclerosis) and incident cardiovascular disease (CVD) have not been thoroughly investigated. In a cross-sectional cohort (89 subjects without type 2 diabetes (T2D) and 81 subjects with T2D we determined cIMT (ultrasound), homeostasis model assessment of insulin resistance (HOMA-IR) and the TG/HDL-C ratio. The LP-IR score, based on 6 lipoprotein characteristics determined by nuclear magnetic resonance spectroscopy, was measured in 123 participants. A prospective study was carried out among 6232 participants (Prevention of REnal and Vascular ENd-stage Disease study). Cross-sectionally, the adjusted associations of HOMA-IR, the TG/HDL-C ratio and the LP-IR score with cIMT were approximately similar (standardized β = 0.34 (95 % CI 0.19–0.48), 0.24 (95 % CI 0.09–039) and 0.41 (95 % CI 0.23––0.59), respectively). Prospectively, 507 new cases of CVD were observed after a median follow-up of 8.2 (interquartile range 7.5–8.8) years. HOMA-IR, the TG/HDL-C ratio and LP-IR were each associated with incident CVD independent of potential confounders (HR 1.12, 95 % CI 1.02–1.24;1.22, 95 % CI 1.11–1.35 and 1.15. 95 % CI 1.01–1.31, respectively). The association of the TG/HDL-C ratio with incident CVD was somewhat stronger than that of HOMA-IR. Lipoprotein-based markers of insulin resistance are at least as strongly associated with subclinical atherosclerosis and clinical atherosclerosis development as HOMA-IR, obviating the need to measure insulin to determine the impact of insulin resistance. For practical purposes, the easily obtainable TG/HDL-C ratio may suffice. [ABSTRACT FROM AUTHOR]

Objective Familial dysbetalipoproteinemia (FD) or Type III hyperlipoproteinemia is closely associated with the ε2ε2 genotype of the common APOE polymorphism although not all ε2 homozygotes develop FD indicating that additional factors play a role including insulin resistance (IR). The current study was undertaken to explore relationships and influences among factors, especially IR, that might elucidate FD progression pathways. Methods Bayesian network (BN) modeling, a probabilistic graphical exploratory data analysis tool that portrays relationships and influences among variables as simple diagrams, was applied to 52 e2e2 subjects. An algorithm based on apolipoprotein and lipid values identified 24 subjects having FD. BN modeling parameters included plasma apoE, HDL cholesterol (HDL–C), apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), apoA-I/HDL-C ratio, apoA-II/HDL-C ratio, insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Results Modeling resulted in twenty network graphs. Each graph revealed apoE and the apoA-II/HDL-C ratio as sole determinants of FD prevalence. BN results did not demonstrate a direct role for insulin and HOMA-IR. However, multiple graphs in the set did reveal indirect influence of IR on FD prevalence as conveyed through the apoA-II/HDL-C ratio; while all remaining graphs in the set demonstrated the apoA-II/HDL-C ratio as directly influencing insulin levels and HOMA-IR. For apoE, the other determinant of FD prevalence, results revealed no relationship with IR parameters. Conclusions In so far as insulin levels and HOMA-IR are associated with IR in e2e2 subjects, IR may act indirectly in FD progression via the apoA-II/HDL-C ratio; and/or the apoA-II/HDL-C ratio acts directly to promote IR. [ABSTRACT FROM AUTHOR]

Objective Familial dysbetalipoproteinemia (FD) or Type III hyperlipoproteinemia is a mixed hyperlipidemia closely associated with the ε2ε2 genotype of the common APOE polymorphism although not all homozygotes progress to FD. Unlike the polymorphism, few studies explore effects of apolipoprotein E (apoE) blood levels on FD development. Likewise, despite the known apoE2 lipoprotein binding preference for high-density lipoprotein (HDL); little work exists exploring HDL in FD. Accordingly, this study was undertaken to investigate potential roles in FD development for apoE and HDL. Additionally, insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were investigated in view of reports linking insulin resistance to FD. Methods APOE genotyping and levels of apoE, apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), insulin, HOMA-IR, lipids, and NMR lipoprotein analysis were determined in a cohort of healthy individuals ( N = 7169). A lipid-based algorithm identified FD in 24 of 52 e2e2 subjects. Logistic regression modeling assessed associations of FD development with measured variables. Results Univariate models revealed associations with FD significant and positive for apoE, apoA-II/apoA-I, apoA-I/HDL-C, apoA-II/HDL-C, and HOMA-IR. For HDL-C, association was significant but inverse. Results of multivariable models containing apoE with single parameters added revealed statistical significance only for the apoA-II/HDL-C ratio (OR 10.52, 95%CI 1.17–94.79, p = 0.036) concurrent with significance for apoE (OR 2.21, 95%CI 1.06–4.65, p = 0.035). Interaction was not demonstrated ( p = 0.36). NMR results revealed for FD versus nonFD subjects generally higher levels of VLDL and small HDL and for IDL few differences. Conclusion High apoE and high apoA-II/HDL-C independently associate with FD development in ε2ε2 individuals. [ABSTRACT FROM AUTHOR]

Background and aims High-density lipoprotein cholesterol (HDL-C), an established risk marker for atherosclerotic cardiovascular disease (CVD), has been shown to be inversely and independently associated with incident hypertension. Paraoxonase-1 (PON-1) is an HDL-bound esterase enzyme associated with CVD, but its relationship with incident hypertension has not been previously investigated. We aimed at evaluating the prospective association between PON-1 and hypertension risk. Methods PON-1 arylesterase activity was measured in serum at baseline in 3988 participants without pre-existing hypertension in the Prevention of Renal and Vascular End-stage Disease (PREVEND) prospective population-based study. During a median follow-up of 10.7 years, 1206 participants developed hypertension. Results In age- and sex-adjusted analysis, the hazard ratio (95% CI) for incident hypertension per 1 standard deviation increase in PON-1 was 1.01 (0.96–1.07; p = 0.656), which remained non-significant after adjustment for several established hypertension risk factors and other potential confounders (0.99, 0.93 to 1.05; p = 0.764). The association was also non-existent on further adjustment for HDL-C (1.00 (0.94–1.06; p = 0.936)) and did not importantly vary across several clinical subgroups. In analyses in the same set of participants, HDL-C was continuously inversely and independently associated with hypertension risk; the association persisted after further adjustment for PON-1 activity and was not modified by PON-1 activity. Conclusions In this Caucasian cohort of men and women, HDL-C, but not its anti-oxidant constituent - PON-1, is inversely, continuously and independently associated with future risk of hypertension. The association is independent of and not modified by PON-1. [ABSTRACT FROM AUTHOR]

Background Protection of low-density lipoproteins (LDL) against oxidative modification is a key anti-atherosclerotic property of high-density lipoproteins (HDL). This study evaluated the predictive value of the HDL antioxidative function for cardiovascular mortality, all-cause mortality and chronic graft failure in renal transplant recipients (RTR). Methods The capacity of HDL to inhibit native LDL oxidation was determined in vitro in a prospective cohort of renal transplant recipients (RTR, n = 495, median follow-up 7.0 years). Results The HDL antioxidative functionality was significantly higher in patients experiencing graft failure (57.4 ± 9.7%) than in those without (54.2 ± 11.3%; P = 0.039), while there were no differences for cardiovascular and all-cause mortality. Specifically glomerular filtration rate ( P = 0.001) and C-reactive protein levels ( P = 0.006) associated independently with antioxidative functionality in multivariate linear regression analyses. Cox regression analysis demonstrated a significant relationship between antioxidative functionality of HDL and graft failure in age-adjusted analyses, but significance was lost following adjustment for baseline kidney function and inflammatory load. No significant association was found between HDL antioxidative functionality and cardiovascular and all-cause mortality. Conclusion This study demonstrates that the antioxidative function of HDL (i) does not predict cardiovascular or all-cause mortality in RTR, but (ii) conceivably contributes to the development of graft failure, however, not independent of baseline kidney function and inflammatory load. [ABSTRACT FROM AUTHOR]

Background Paraoxonase-1 (PON-1) has been suggested to be associated with cardiovascular disease (CVD) risk, however, aspects of the association, such as shape and independence from conventional risk factors are still uncertain. We aimed to assess the association of PON-1 with CVD risk and determine its potential utility for CVD risk prediction. Methods PON-1 was measured as its arylesterase activity at baseline in the PREVEND prospective study of 6902 participants. Results During a mean follow-up of 9.3 years, 730 CVD events were recorded. Serum PON-1 was weakly correlated with several cardiovascular risk markers including high-density lipoprotein cholesterol (HDL-C) (r = 0.18; P < 0.001) and was approximately log-linearly associated with CVD risk. In analyses adjusted for conventional risk factors, the hazard ratio (95% CI) for CVD per 1 standard deviation (SD) increase in log e PON-1 was 0.92 (0.85–0.99; P = 0.020), which remained persistent after additional adjustment for potential confounders 0.93 (0.86–0.99; P = 0.037). The association was attenuated on further adjustment for HDL-C 0.95 (0.88–1.02; P = 0.153). In a meta-analysis of 6 population-based prospective studies involving 15 064 participants and 2958 incident CVD outcomes, the pooled multivariable adjusted (including HDL-C) relative risk (95% CI) for CVD was 0.95 (0.90–1.02; P = 0.138) per 1 SD increase in PON-1 values. Adding PON-1 to a CVD risk prediction model containing conventional risk factors did not improve the C-index or net reclassification. Conclusions There is an approximately log-linear inverse association between PON-1 activity and CVD risk, which is partly dependent on HDL-C levels. In addition, serum PON-1 activity provides no significant improvement in CVD risk assessment beyond conventional CVD risk factors. [ABSTRACT FROM AUTHOR]

Abstract: Background: Plasma cholesteryl ester transfer (CET), reflecting endogenous transfer of cholesteryl esters from HDL to very low and low density lipoproteins, is elevated in Type 2 diabetes mellitus (T2DM), and may predict (subclinical) cardiovascular disease. Low normal thyroid function may adversely affect lipoprotein metabolism and atherosclerosis development. We tested whether plasma CET is related to thyroid function in euthyroid T2DM and non-diabetic subjects. Subjects and methods: Plasma CET was measured in 74 T2DM and 82 non-diabetic subjects with thyroid-stimulating hormone (TSH) and free thyroxine levels within the reference range. Results: Plasma CET was 20% higher in T2DM (P = 0.003) coinciding higher cholesteryl ester transfer protein (CETP) mass (P = 0.009) and triglycerides (P = 0.02). In univariate analysis, plasma CET was correlated positively with TSH in T2DM only (r = 0.330, P = 0.004). Multiple linear regression analysis revealed a positive interaction between the presence of T2DM and TSH on plasma CET after controlling for age, sex, body mass index, non-HDL cholesterol, triglycerides and CETP mass (β = 0.167, P = 0.030). The relationship of plasma CET with TSH was also positively modified by plasma glucose and HbA1c (interaction terms: β = 0.119, P = 0.036, β = 0.170, P = 0.001, respectively). Additionally, plasma triglycerides interacted positively with TSH on plasma CET in T2DM (β = 0.198, P = 0.011). Conclusions: Low normal thyroid function, as inferred from higher TSH, confers increased plasma CET in the context of chronic hyperglycemia. Effects of thyroid function on plasma CET may be particularly relevant in hypertriglyceridemic T2DM. Low normal thyroid function could influence atherosclerosis susceptibility in T2DM by affecting the plasma cholesteryl ester transfer process. [Copyright &y& Elsevier]

Abstract: Background: Lipid-poor or lipid-free high density lipoprotein (HDL) particles, designated pre ß-HDL, stimulate removal of cell-derived cholesterol to the extracellular compartment, which is an initial step in the reverse cholesterol transport pathway. Pre ß-HDL levels may be elevated in subjects with established cardiovascular disease. We determined the relationship of carotid intima media thickness (IMT), a marker of subclinical atherosclerosis, with pre ß-HDL in subjects without clinically manifest cardiovascular disease. Methods: IMT and plasma pre ß-HDL, assayed by crossed immuno-electrophoresis, were determined in 70 non-diabetic subjects (aged 56±9years; non-smokers only; 27 women). Results: IMT was correlated positively with pre ß-HDL, both expressed as plasma apolipoprotein (apo) A-I concentration (r=0.271, p =0.023) and as% of apo A-I (r =0.341, p =0.004). In contrast, IMT was correlated inversely with HDL cholesterol (r =−0.253, p =0.035). IMT was also related positively to pre ß-HDL after adjustment for age, sex, systolic blood pressure (in apoA-I concentration, ß =0.203, p =0.043; in% of plasma apoA-I, ß =0.235, p =0.023). IMT remained associated with pre ß-HDL after additional adjustment for either body mass index, plasma glucose, cholesterol, triglycerides, HDL cholesterol, apoA-I and apoB. Conclusion: Subclinical atherosclerosis may relate to higher plasma pre ß-HDL independently of apoA-I and HDL cholesterol levels. [Copyright &y& Elsevier]

Abstract: Objective: High density lipoprotein (HDL) particles protect apolipoprotein B-containing lipoproteins from oxidative modification. An impaired anti-oxidative functionality of HDL in type 2 diabetes mellitus (T2DM) may contribute to enhanced formation of oxidative stress products, such as Advanced Glycation Endproducts (AGEs). We tested whether in T2DM the HDL anti-oxidative capacity is related to the accumulation of AGEs in the skin. Methods: Skin autofluorescence (AF), a non-invasive read-out for AGEs, and HDL anti-oxidative capacity, i.e. the ability of HDL to protect against LDL oxidation in vitro, were assessed in 67 non-smoking T2DM patients without complications (median age: 60 (53–65), 60% males, 6.5 (5.2–8.5) years of diabetes duration). Results: In univariate analysis, skin AF correlated inversely with HDL anti-oxidative capacity (r =−0.305, P <0.02), but not with HDL cholesterol or apolipoprotein A-I. HDL anti-oxidative capacity correlated inversely with glucose, HbA1c, triglycerides, and insulin resistance (homeostasis model assessment) (P <0.05 to P ≤0.001). Multiple linear regression showed that skin AF remained inversely related to HDL anti-oxidative capacity (partial r =−0.314, P =0.015) taking account of age, plasma glucose, non-HDL cholesterol, triglycerides, HOMAir, and CRP. Conclusion: These findings suggest that skin AF is inversely related to the HDL anti-oxidative capacity rather than to the HDL cholesterol concentration in T2DM. Impaired anti-oxidative functionality of HDL could contribute to tissue accumulation of AGEs. [Copyright &y& Elsevier]

Abstract: Objective: The relationship of cardiovascular disease (CVD) with plasma cholesteryl ester transfer protein (CETP) levels is controversial. We determined whether plasma cholesteryl ester transfer (CET), reflecting CETP-mediated transfer of cholesteryl esters from endogenous HDL towards apolipoprotein B-lipoproteins, predicts incident CVD. Methods: A prospective nested case–control study was carried out in 114 men who developed CVD and 105 controls. Participants did not use lipid lowering drugs at baseline. Plasma CET was assayed using an isotope method. Results: Plasma CET was 19% higher (P =0.030), whereas CETP mass was unaltered (P =0.30) in cases vs. controls. Plasma CET predicted CVD (age-adjusted hazard ratio (HR): 1.20 (95% CI 1.02–1.46, P =0.028), but incident CVD was unrelated to CETP mass (HR: 0.88 (95% CI 0.73–1.07), P =0.20). Plasma CET still predicted CVD after additional adjustment for total cholesterol/HDL cholesterol, triglycerides and non-lipid risk markers (HR: 1.22 (95% CI 1.02–1.46, P =0.031). Conclusion: Plasma CET rather than CETP mass may be a determinant of cardiovascular risk. [Copyright &y& Elsevier]