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AIM: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, improves CVD risk by reducing the concentration of low-density lipoprotein-cholesterol (LDL-C). However, effects of PCK9 inhibitors on other aspects of diabetic dyslipidaemia, particularly in the postprandial situation, are less clear.MATERIAL AND METHODS: Twelve male patients with T2DM on an intensive insulin regimen completed a 6-week randomized, double-blind, placebo-controlled, proof-of-concept study. Participants received three biweekly dosages of subcutaneous alirocumab (150 mg) or placebo. Before and after the intervention, fasting and postprandial triglyceride (TG) plasma levels, apolipoprotein (apo) B48, lipoprotein composition isolated by ultracentrifugation, vascular function and markers of inflammation were evaluated.RESULTS: Alirocumab treatment reduced fasting plasma TG levels (between group median change -24.7%; P = 0.018) and fasting apoB48 serum levels (-35.9%; P = 0.039) compared with placebo. Alirocumab reduced the plasma TG area under the curve (AUC) (-26.4%; P = 0.006) and apoB48 AUC (-55.7%; P = 0.046), as well as plasma TG incremental AUC (-21.4%; P = 0.04) and apoB48 incremental AUC (-26.8%; P = 0.02). In addition, alirocumab reduced fasting and postprandial TG levels in very low-density lipoprotein (VLDL) and LDL. Alirocumab improved fasting pulse wave velocity, but no changes in postprandial markers of inflammation were observed.CONCLUSIONS: In addition to the well-known LDL-C-reducing effects, 6 weeks of alirocumab treatment lowered both fasting and postprandial plasma TG levels by reducing the TG levels in VLDL and LDL and the concentration of intestinal remnants.

Background Prevalence of cardiovascular disease risk factors and rates of atherosclerotic cardiovascular disease outcomes vary across racial/ethnic groups. This analysis examined the effects of evolocumab on LDL‐C (low‐density lipoprotein cholesterol) levels and LDL‐C goals achievement by race/ethnicity. Methods and Results Data from 15 phase 2 and 3 studies of treatment with evolocumab versus placebo or ezetimibe were pooled (n=7669). Results were analyzed by participant clinical characteristics and by self‐identified race/ethnicity. Key outcomes included percent change from baseline in LDL‐C, achievement of LDL‐C

Background Heterogeneity should be carefully addressed to facilitate establishment of effective population-level blood lipid management. The primary aim of the study was to investigate gender heterogeneity in prevalence of dyslipidemia, including trends with age and associated factors in middle age rural Chinese. Methods This is a cross-sectional study based on a baseline investigation of a population-based randomized controlled trial in rural China, involving 26,378 permanent residents of age 45–69. The age-specific prevalence of dyslipidemia was estimated for men and women, and the trends of prevalence with age were compared. Logistic regression was used to explore the factors associated with prevalent risk of dyslipidemia. Results The overall prevalence of dyslipidemia was significantly higher in females than in males for borderline high and above (BHA) total cholesterol (TC ≥ 200 mg/dL), BHA triglycerides (TG ≥ 150 mg/dL) and BHA low-density lipoprotein cholesterol (LDL-C ≥ 130 mg/dL), but was lower for low high-density lipoprotein cholesterol (HDL-C Conclusion Heterogeneity was found in comparing the prevalence of dyslipidemia in men and women, and gender heterogeneity was found in its trend with age and associated factors in middle aged rural Chinese. The effectiveness of population-level blood lipid management and CVD primary prevention programs in China is expected to be improved if gender heterogeneity is considered.

Aim: No meta-analysis has examined the effect of regular aquatic endurance exercise on lipid and lipoprotein levels. The purpose of the current work was to perform a meta-analysis to evaluate the effects of regular aquatic endurance exercise on lipid and lipoprotein levels. Methods: The inclusion criteria of the randomized controlled trials were healthy adults in an exercise group performing regular aquatic exercise and a control group not exercising, with a description of the serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, or triglyceride levels provided. The net change in the lipid and lipoprotein levels was calculated from each trial, and the changes in the lipid and lipoprotein levels were pooled using a random effects model. Results: The meta-analysis examined 10 trials involving aquatic endurance exercise and 327 subjects. The pooled net changes in HDL-C, LDL-C, and total cholesterol improved significantly (HDL-C, 4.6 mg/dL; LDL-C, −10.1 mg/dL; total cholesterol, −8.5 mg/dL). When trials were limited to those involving only women, the pooled net changes in HDL-C, LDL-C, and total cholesterol improved significantly. When trials were limited to those involving subjects with a mean age < 60 years, the pooled net changes in HDL-C, total cholesterol, and triglyceride improved significantly. When trials were limited to those with dyslipidemia, the pooled net changes in HDL-C, LDL-C, total cholesterol, and triglyceride improved significantly. Conclusions: Aquatic endurance exercise improved the lipid and lipoprotein levels and benefited women, middle-aged subjects, and patients with dyslipidemia in particular.

Background Dyslipidemia guidelines recommend non‐high‐density lipoprotein cholesterol (non‐ HDL ‐C) and apolipoprotein B (ApoB) as additional targets of therapy and consider lipoprotein(a) a significant cardiovascular risk marker. The current analysis evaluates the effects of evolocumab on these parameters in various patient populations over time. Methods and Results Data from 7690 patients, 4943 of whom received at least 1 dose of evolocumab, in 15 phase 2 and phase 3 studies with a duration ranging from 12 weeks to 5 years were pooled based on study length, patient population, and ezetimibe or placebo comparator groups. Patients could receive intensive statin therapy but not in the statin intolerance and monotherapy studies. The effects of evolocumab on percent change from baseline for non‐ HDL ‐C, ApoB, and lipoprotein(a) and achievement of treatment goals for non‐ HDL ‐C and ApoB were examined. Compared with placebo, evolocumab at both approved dosing regimens substantially reduced mean non‐ HDL ‐C (Q2W dose: −49% to −56%, monthly dose: −48% to −52%), mean ApoB (Q2W dose: −46% to −52%, monthly dose: −40% to −48%), and median lipoprotein(a) (Q2W dose: −22% to −38%, monthly dose: −20% to −33%) at 12 weeks. Effects on all 3 parameters persisted over 5 years. Lipid‐lowering effects were consistent among the patient populations examined (hypercholesterolemia/mixed dyslipidemia, statin intolerance, heterozygous familial hypercholesterolemia, and type 2 diabetes mellitus). Conclusions In this pooled analysis, evolocumab substantially reduced non‐ HDL ‐C, ApoB, and lipoprotein(a) compared with placebo. The effect was consistent and maintained in various patient populations over 5 years.

Background Limited data are available on the prospective relationship between beverage consumption and plasma lipid and lipoprotein concentrations. Two major sources of sugar in the US diet are sugar-sweetened beverages (SSBs) and 100% fruit juices. Low-calorie sweetened beverages are common replacements. Methods and Results Fasting plasma lipoprotein concentrations were measured in the FOS (Framingham Offspring Study) (1991-2014; N=3146) and Generation Three (2002-2001; N=3584) cohorts. Beverage intakes were estimated from food frequency questionnaires and grouped into 5 intake categories. Mixed-effect linear regression models were used to examine 4-year changes in lipoprotein measures, and Cox proportional hazard models were used to estimate hazard ratios for incident dyslipidemia, adjusting for potential confounding factors. We found that regular (1 serving per day) versus low (1 serving per month) SSB consumption was associated with a greater mean decrease in high-density lipoprotein cholesterol (β±standard error -1.6±0.4 mg/dL

Study Design Retrospective Cohort Objective This report identified the serum triglyceride (TG) concentrations in persons with spinal cord injury (SCI) and able-bodied (AB) individuals that the serum high-density lipoprotein cholesterol (HDL-C) equaled 40 mg/dl, a concentration below which is an independent risk factor for coronary artery disease. Methods Retrospective analysis was performed on 578 participants: 223 with SCI at or proximal to the 4th thoracic vertebrae (↑T4), 178 with SCI at or distal to the 5th thoracic vertebrae (↓T5), and 177 AB. Different statistical modeling approaches identified the intersecting serum TG concentration with a serum HDL-C concentration equal to 40 mg/dl. Participants were dichotomized into subgroups by TG concentration exceeding (Supra) or falling below (Sub) the intersecting value and the TG/HDL-C ratios were compared. Results Linear regression analysis revealed that the serum TG concentration that intersects with serum HDL-C concentration at 40 mg/dl was 121 mg/dl in SCI ↑T4 and 137 mg/dl in SCI ↓T5 group. A receiver operating characteristic curve identified the optimal TG concentration as 115 mg/dl in SCI ↑T4 and 137 mg/dl in SCI ↓T5 group with the latter concentration being similar to the AB group (e.g., 137 mg/dl). The TG/HDL-C ratios in the respective ↑T4, ↓T5, and AB Supra and Sub groups were similar within each group. Conclusions A lower TG concentration appears to be associated with dyslipidemia in persons with SCI than AB individuals. These findings should prompt clinicians to screen for and consider instituting lifestyle or pharmacological interventions at lower TG concentrations to reduce risk of CVD.

Background A higher circulating plasma ceramide ratio (C16:0/C24:0) is associated with an increased risk of heart failure, even after accounting for standard risk factors including lipid markers. However, the pathobiological mechanisms that underlie this association are incompletely understood. We tested the hypothesis that plasma ceramide ratio (C16:0/C24:0) is associated with adverse cardiac remodeling in the community. Methods and Results We evaluated 2652 Framingham Offspring Study participants (mean age, 66±9 years; 55% women) who attended their eighth examination cycle and underwent routine echocardiography and liquid chromatography–tandem mass spectrometry–based assays for circulating ceramide concentrations. We used multivariable linear regression models to relate C16:0/C24:0 (independent variable) to the following echocardiographic measures (dependent variables; separate models for each): left ventricular mass, left ventricular ejection fraction, left atrial emptying fraction, left atrial end‐systolic volume, E/e′ (a measure of left ventricular diastolic function), and left ventricular global circumferential and longitudinal strain by speckle‐tracking echocardiography. In multivariable‐adjusted analyses, higher C16:0/C24:0 per standard deviation increment was associated with lower left ventricular ejection fraction (0.991‐fold change in left ventricular ejection fraction; P =0.0004), worse global circumferential strain (β=0.34, P =0.004), higher left atrial end‐systolic volume (β=2.48, pP Conclusions Our cross‐sectional observations in a large community‐based sample are consistent with a potential detrimental impact of higher ceramide ratio (C16:0/24:0) on cardiac remodeling traits, which may partly explain the associations of these molecular species with clinical heart failure.

Background We asked whether, after excluding familial hypercholesterolemia, individuals with high low‐density lipoprotein cholesterol ( LDL ‐C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population‐based hyperlipidemias. Methods and Results We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (≥2 first‐degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias ( LDL ‐C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta‐analysis of the hyperlipidemic families and the population cohort (high LDL ‐C: hazard ratio, 1.74 [95% CI, 1.48–2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI, 1.09–1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid‐lowering medication. In lipidomic profiling, high LDL ‐C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P ‐value range 0.038–2.3×10 −56 ). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population ( LDL ‐C: r =0.80; triacylglycerides: r =0.96; no lipid species deviated between the cohorts). Conclusions Hyperlipidemias with family history conferred similar coronary artery disease risk as population‐based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL ‐C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population‐ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.

Background Although acute coronary syndromes (ACS) are a major cause of morbidity and mortality, relationships with biologically active lipid species potentially associated with plaque disruption/erosion in the context of their lipoprotein carriers are indeterminate. The aim was to characterize lipid species within lipoprotein particles which differentiate ACS from stable coronary artery disease. Methods and Results Venous blood was obtained from 130 individuals with de novo presentation of an ACS (n=47) or stable coronary artery disease (n=83) before coronary catheterization. Lipidomic measurements (533 lipid species; liquid chromatography electrospray ionization/tandem mass spectrometry) were performed on whole plasma as well as 2 lipoprotein subfractions: apolipoprotein A1 (apolipoprotein A, high‐density lipoprotein) and apolipoprotein B. Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high‐density lipoprotein (high‐density lipoprotein, 113 lipids; plasma, 73 lipids). Models including plasma lipid species alone improved discrimination between the stable and ACS groups by 0.16 (C‐statistic) compared with conventional risk factors. Models utilizing lipid species either in plasma or within lipoprotein fractions had a similar ability to discriminate groups, though the C‐statistic was highest for plasma lipid species (0.80; 95% CI, 0.75–0.86). Conclusions Multiple lysophospholipids, but not cholesterol, featured among the lipids which were present at low concentration within high‐density lipoprotein of those presenting with ACS. Lipidomics, when applied to either whole plasma or lipoprotein fractions, was superior to conventional risk factors in discriminating ACS from stable coronary artery disease. These associative mechanistic insights elucidate potential new preventive, prognostic, and therapeutic avenues for ACS which require investigation in prospective analyses.

Background Apolipoprotein B/apolipoprotein A‐I (apoB/apoA‐I) ratio and lipoprotein(a) (Lp[a]) are associated with aortic valve stenosis ( AVS ) disease progression. Clinical characteristics such as age, sex, and presence of concomitant coronary artery disease may strongly modify these associations; however, these effects have not been well defined in longitudinal studies. We set out to assess these associations between apoB/apoA‐I ratio, Lp(a), and AVS incidence in a large population study. Methods and Results We analyzed data from 17 745 participants (mean age, 59.2±9.1 years; men, 44.9%) in the EPIC ‐Norfolk (European Prospective Investigation Into Cancer in Norfolk Prospective Population Study) population study in whom apoB/apoA‐I and Lp(a) levels were measured. Participants were identified as having incident AVS if they were hospitalized or died with AVS as an underlying cause. After a median follow‐up of 19.8 years (17.9–21.0 years) there were 403 (2.2%) incident cases of AVS . The hazard ratio for AVS risk was 1.30 (95% CI , 1.19–1.41; P AVS incidence (hazard ratio, 1.06; 95% CI , 0.97–1.17 [ P =0.215]). Elevated Lp(a) (>50 mg/ dL ) remained an independent risk factor for AVS after adjustment for age, sex, low‐density lipoprotein cholesterol, and concomitant coronary artery disease (hazard ratio, 1.70; 95% CI , 1.33–2.19 [ P Conclusions In this population study, apoB/apoA‐I ratio was associated with risk of AVS incidence, especially in younger and female participants and those without concomitant coronary artery disease. Lp(a) was an independent risk factor for AVS incidence. Interventional trials are needed to investigate whether modulating apoB/apoA‐I or lowering Lp(a) can prevent or slow down AVS .

Background Our objective was to identify the determinants of high‐density lipoprotein cholesterol efflux capacity ( HDL ‐ CEC ) changes in patients with coronary artery disease who participated in a lifestyle modification program aimed at increasing physical activity levels and improving diet quality. Methods and Results A total of 86 men with coronary artery disease aged between 35 and 80 years participated in a 1‐year lifestyle modification program that aimed to achieve a minimum of 150 minutes of aerobic physical activity weekly and improve diet quality. HDL ‐ CEC s were measured before and after the 1‐year intervention using 3 H‐cholesterol–labeled J774 and HepG2 cells. Visceral, subcutaneous, and cardiac adipose tissue levels were assessed before and after the intervention using magnetic resonance imaging. Lipoprotein particle size and concentrations were measured by proton nuclear magnetic resonance spectroscopy and a complete lipoprotein‐lipid profile was obtained. At baseline, the best correlate of HDL ‐ CEC s were apolipoprotein AI ( R 2 =0.35, P R 2 =0.21, P HDL ‐ CEC s and HepG2‐ HDL ‐ CEC s, respectively. Baseline and longitudinal changes in HDL ‐ CEC s were associated with several lipoprotein size and concentration indices, although high‐density lipoprotein cholesterol was the best predictor of longitudinal changes in J774‐ HDL ‐ CEC s ( R 2 =0.18, P =0.002) and apolipoprotein AI was found to be the best predictor of longitudinal changes in HepG2 cholesterol efflux capacities ( R 2 =0.21, P =0.002). Conclusions Results of this study suggest that increases in high‐density lipoprotein cholesterol and apolipoprotein AI levels typically observed in patients with coronary artery disease undergoing healthy lifestyle modification therapy may be indicative of higher plasma concentrations of functional high‐density lipoprotein particles.

Background The relation between tea consumption and age‐related changes in high‐density lipoprotein cholesterol ( HDL ‐C) concentrations remains unclear, and longitudinal human data are limited. The aim of current study was to examine the relation between tea intake and longitudinal change in HDL ‐C concentrations. Methods and Results Baseline (2006) tea consumption was assessed via a questionnaire, and plasma HDL ‐C concentrations were measured in 2006, 2008, 2010, and 2012 among 80 182 individuals (49±12 years of age) who did not have cardiovascular diseases or cancer, or did not use cholesterol‐lowering agents both at baseline (2006) and during the follow‐up period (2006–2012). The associations between baseline tea consumption and rate of change in HDL ‐C concentrations were examined using generalized estimating equation models. Tea consumption was inversely associated with a decreased rate of HDL ‐C concentrations ( P ‐trend P ‐interaction HDL ‐C concentrations were more pronounced in men, individuals aged 60 or older, individuals with a lower lifestyle score, and individuals with metabolic syndrome (all P ‐trend Conclusions Tea consumption was associated with slower age‐related decreases in HDL ‐C concentrations during 6 years of follow‐up. Clinical Trial Registration URL : www.chictr.org . Unique identifier: Chi CTR ‐ TNRC ‐11001489.

Background Consumption of almonds or dark chocolate and cocoa has favorable effects on markers of coronary heart disease; however, the combined effects have not been evaluated in a well‐controlled feeding study. The aim of this study was to examine the individual and combined effects of consumption of dark chocolate and cocoa and almonds on markers of coronary heart disease risk. Methods and Results A randomized controlled, 4‐period, crossover, feeding trial was conducted in overweight and obese individuals aged 30 to 70 years. Forty‐eight participants were randomized, and 31 participants completed the entire study. Each diet period was 4 weeks long, followed by a 2‐week compliance break. Participants consumed each of 4 isocaloric, weight maintenance diets: (1) no treatment foods (average American diet), (2) 42.5 g/d of almonds (almond diet [ALD]), (3) 18 g/d of cocoa powder and 43 g/d of dark chocolate (chocolate diet [ CHOC ]), or (4) all 3 foods ( CHOC + ALD ). Compared with the average American diet, total cholesterol, non–high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol after the ALD were lower by 4%, 5%, and 7%, respectively ( P CHOC + ALD decreased apolipoprotein B by 5% compared with the average American diet. For low‐density lipoprotein subclasses, compared with the average American diet, the ALD showed a greater reduction in large buoyant low‐density lipoprotein particles (−5.7±2.3 versus −0.3±2.3 mg/dL; P =0.04), whereas the CHOC + ALD had a greater decrease in small dense low‐density lipoprotein particles (−12.0±2.8 versus −5.3±2.8 mg/dL; P =0.04). There were no significant differences between diets for measures of vascular health and oxidative stress. Conclusions Our results demonstrate that consumption of almonds alone or combined with dark chocolate under controlled‐feeding conditions improves lipid profiles. Incorporating almonds, dark chocolate, and cocoa into a typical American diet without exceeding energy needs may reduce the risk of coronary heart disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01882881.

Background Levels of LDL (low‐density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid‐related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations. Methods and Results We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low‐density lipoprotein) particle subclasses in 11 984 JUPITER trial participants ( NCT 00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95% CI ] per SD increment) among placebo‐allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non–high‐density lipoprotein cholesterol, and triglycerides, but not LDL‐c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On‐statin levels of the smallest VLDL particle subclass were associated with a 68% per‐ SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk—this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C‐index 0.780 versus 0.712; P CATHGEN ), similar patterns of lipoprotein‐related risk were observed. Conclusions Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00239681.

The effect of severity of liver cirrhosis, an alcoholic and non-alcoholic genesis, on the results of serum lipids and lipoproteins was evaluated. Serum cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-Ch), and low-density lipoprotein cholesterol (LDL-Ch) were measured in the sera of 59 patients suffering from alcoholic cirrhosis and 34 patients with non-alcoholic cirrhosis. The level of serum triglycerides depends on the severity of liver damage in alcoholic liver cirrhosis, being the highest in Child-Pugh score B. The severity of liver damage significantly affects the HDL-Ch and LDL-Ch levels in cirrhosis of non-alcoholic origin, reaching the highest value for LDL-Ch and the lowest for HDL-Ch in score C. It should not be generalized that the levels of lipids and lipoproteins in liver cirrhosis progressively diminished with the deterioration of liver function. The serum HDL-Ch and LDL-Ch may be considered as markers of severity of liver damage in non-alcoholic cirrhosis, but the triglycerides only in disease of alcoholic origin.

Background Current recommendations for lipoprotein(a) (Lp[a]) focus on the control of other risk factors, including lowering low‐density lipoprotein cholesterol ( LDL ‐C), with little evidence to support this approach. Identifying interactions between Lp(a) and other risk factors could identify individuals at increased risk for Lp(a)‐mediated disease. Methods and Results We used a case‐only study design and included 939 participants (median age=49 years, interquartile range 46–53, women=33.1%) from the GENdE r and Sex determInantS of cardiovascular disease: from bench to beyond‐Premature Acute Coronary Syndrome ( GENESIS ‐ PRAXY ) study, a multicenter prospective cohort study of premature acute coronary syndrome. There was a higher prevalence of elevated Lp(a) levels (>50 mg/dL; 80th percentile) in PRAXY participants as compared to the general population (31% versus 20%; P LDL ‐C (adjusted β 0.17; P LDL ‐C >2.5 mmol/L, indicating a synergistic interaction (adjusted odds ratio 1.51; 95% CI 1.08–2.09; P =0.015). The interaction with high Lp(a) was stronger at increasing LDL ‐C levels ( LDL ‐C >3.5, adjusted odds ratio 1.87; LDL ‐C >4.5, adjusted odds ratio 2.72). In a polytomous logistic model comparing mutually exclusive LDL ‐C categories, the interaction with high Lp(a) became attenuated at LDL ‐C ≤3.5 mmol/L (odds ratio 1.16; 95% CI 0.80–1.68, P =0.447). Other risk factors were not associated with high Lp(a). Conclusions In young acute coronary syndrome patients, high Lp(a) is more prevalent than in the general population and is strongly associated with high LDL ‐C, suggesting that Lp(a) confers greater risk for acute coronary syndrome when LDL ‐C is elevated. Individuals with high Lp(a) and LDL ‐C >3.5 mmol/L may warrant aggressive LDL ‐C lowering.

Type 1 diabetes (T1DM) is associated with increased risk of macrovascular complications. We examined longitudinal associations of serum conventional lipids and nuclear magnetic resonance (NMR)-determined lipoprotein subclasses with carotid intima-media thickness (IMT) in adults with T1DM (n=455) enrolled in the Diabetes Control and Complications Trial (DCCT). Data on serum lipids and lipoproteins were collected at DCCT baseline (1983–89) and were correlated with common and internal carotid IMT determined by ultrasonography during the observational follow-up of the DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, at EDIC ‘Year 1’ (199–1996) and EDIC ‘Year 6’ (1998–2000). This article contains data on the associations of DCCT baseline lipoprotein profiles (NMR-based VLDL & chylomicrons, IDL/LDL and HDL subclasses and ‘conventional’ total, LDL-, HDL-, non-HDL-cholesterol and triglycerides) with carotid IMT at EDIC Years 1 and 6, stratified by gender. The data are supplemental to our original research article describing detailed associations of DCCT baseline lipids and lipoprotein profiles with EDIC Year 12 carotid IMT (Basu et al. in press) [1]. Keywords: Lipids and lipoproteins, Carotid intima-media thickness, Type 1 diabetes

Acyl-CoA:cholesterol acyltransferase 2 (ACAT2) generates cholesterol esters (CE) for packaging into newly synthesized lipoproteins and thus is a major determinant of blood cholesterol levels. ACAT2 is expressed exclusively in the small intestine and liver, but the relative contributions of ACAT2 expression in these tissues to systemic cholesterol metabolism is unknown. We investigated whether CE derived from the intestine or liver would differentially affect hepatic and plasma cholesterol homeostasis. We generated liver-specific (ACAT2(L-/L-)) and intestine-specific (ACAT2(SI-/SI-)) ACAT2 knockout mice and studied dietary cholesterol-induced hepatic lipid accumulation and hypercholesterolemia. ACAT2(SI-/SI-) mice, in contrast to ACAT2(L-/L-) mice, had blunted cholesterol absorption. However, specific deletion of ACAT2 in the intestine generated essentially a phenocopy of the conditional knockout of ACAT2 in the liver, with reduced levels of plasma very low-density lipoprotein and hepatic CE, yet hepatic-free cholesterol does not build up after high cholesterol intake. ACAT2(L-/L-) and ACAT2(SI-/SI-) mice were equally protected from diet-induced hepatic CE accumulation and hypercholesterolemia. These results suggest that inhibition of intestinal or hepatic ACAT2 improves atherogenic hyperlipidemia and limits hepatic CE accumulation in mice and that depletion of intestinal ACAT2 is sufficient for most of the beneficial effects on cholesterol metabolism. Inhibitors of ACAT2 targeting either tissue likely would be beneficial for atheroprotection.

An open-labeled randomized trial with parallel groups was carried out to study the effects of Dif1stat (Monascus purpureus-Linear aliphatic alcohols-Niacin) in the treatment of primary moderate hypercholesterolemia. The trial lasted 8 months. The patients, males and females, were assigned to two groups: A (#130), treated with diet, and B (#110) submitted to diet + Dif1stat. After 4 months, group A did not show significant changes in Total cholesterol (TC), LDL-cholesterol (LDLC), HDL-cholesterol (HDLC) or non-HDL-cholesterol (non-HDLC). The same group, showed a reduction in TC (-22%), LDLC (-30%) and non-HDLC (-27%) after 8 months (Por = 0.001). After 4 months, TC (-21.3%), LDLC (-29%), and non-HDLC (-26%) were significantly lowered in group B (Por = 0.001). In group B, TC, LDLC and non-HDLC showed a further reduction after 8 months: -29.4, -38 and -37%, respectively (Por = 0.001). Even triglycerides (TG) decreased significantly (-33%) (Por = 0.001). After 8 months, group B showed a significant reduction of TG (-33%) (Por = 0.001), when compared to group A. Some safety parameters were significantly reduced in both groups: AST and gamma-GT in group A after 4 and 8 months, as well as ALT, AST and gamma-GT in group B after 8 months (Por = 0.001). Dif1stat, given with a suitable diet, was well tolerated in the long-term and induced an anti-atherogenic plasma lipid and lipoprotein profile, in patients with moderate hypercholesterolemia.

Background In patients with discordance between low‐density lipoprotein ( LDL ) cholesterol and LDL particle ( LDL ‐P) concentrations, cardiovascular risk more closely correlates with LDL −P. Methods and Results We investigated the effect of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentration and size in hypercholesterolemic patients, using nuclear magnetic resonance spectroscopy. Plasma samples were collected from patients receiving alirocumab 150 mg every 2 weeks (n=26) or placebo (n=31) during a phase II , double‐blind, placebo‐controlled trial in patients ( LDL cholesterol ≥100 mg/ dL ) on a stable atorvastatin dose. In this post hoc analysis, percentage change in concentrations of LDL −P, very‐low‐density lipoprotein particles, and high‐density lipoprotein particles from baseline to week 12 was determined by nuclear magnetic resonance. Alirocumab significantly reduced mean concentrations of total LDL ‐P (−63.3% versus −1.0% with placebo) and large (−71.3% versus −21.8%) and small (−54.0% versus +17.8%) LDL ‐P subfractions and total very‐low‐density lipoprotein particle concentrations (−36.4% versus +33.4%; all P P LDL ‐P size remained relatively unchanged in both groups; however, very‐low‐density and high‐density lipoprotein particle sizes increased to a significantly greater extent with alirocumab. Conclusions Alirocumab significantly reduced LDL ‐C and LDL ‐P concentrations in hypercholesterolemic patients receiving stable atorvastatin therapy. These findings may be of particular relevance to patients with discordant LDL ‐C and LDL ‐P concentrations. Clinical Trial Registration URL : https://clinicaltrials.gov . Unique identifier: NCT01288443.

Background Evidence consistently shows that almond consumption beneficially affects lipids and lipoproteins. Almonds, however, have not been evaluated in a controlled‐feeding setting using a diet design with only a single, calorie‐matched food substitution to assess their specific effects on cardiometabolic risk factors. Methods and Results In a randomized, 2‐period (6 week/period), crossover, controlled‐feeding study of 48 individuals with elevated LDL ‐C (149±3 mg/dL), a cholesterol‐lowering diet with almonds (1.5 oz. of almonds/day) was compared to an identical diet with an isocaloric muffin substitution (no almonds/day). Differences in the nutrient profiles of the control (58% CHO , 15% PRO , 26% total fat) and almond (51% CHO , 16% PRO , 32% total fat) diets were due to nutrients inherent to each snack; diets did not differ in saturated fat or cholesterol. The almond diet, compared with the control diet, decreased non‐ HDL ‐C (−6.9±2.4 mg/dL; P =0.01) and LDL ‐C (−5.3±1.9 mg/dL; P =0.01); furthermore, the control diet decreased HDL ‐C (−1.7±0.6 mg/dL; P P =0.02) and leg fat (−0.12±0.05 kg; P =0.02), despite no differences in total body weight. Conclusions Almonds reduced non‐ HDL ‐C, LDL ‐C, and central adiposity, important risk factors for cardiometabolic dysfunction, while maintaining HDL ‐C concentrations. Therefore, daily consumption of almonds (1.5 oz.), substituted for a high‐carbohydrate snack, may be a simple dietary strategy to prevent the onset of cardiometabolic diseases in healthy individuals. Clinical Trial Registration URL : www.clinicaltrials.gov ; Unique Identifier: NCT 01101230.

Background— Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. Methods and Results— Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1 , MIR33B/SREBF1 , and TNIP1 were identified. CpG cg06500161, located in ABCG1 , was associated in opposite directions with both high-density lipoprotein cholesterol (β coefficient=−0.049; P =8.26E-17) and triglyceride levels (β=0.070; P =1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06–1.25). Conclusions— Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.

ObjectivesThe aim of this study was to determine the associations between statin use and major adverse cardiovascular andcerebrovascular events (MACCE) and amputation-free survival in critical limb ischemia (CLI) patients.BackgroundCLI is an advanced form of peripheral arterial disease associated with nonhealing arterial ulcers and high rates ofMACCE and major amputation. Although statin medications are recommended for secondary prevention in peripheral arterial disease, their effectiveness in CLI is uncertain.MethodsWe reviewed 380 CLI patients who underwent diagnostic angiography or therapeutic endovascular intervention from2006 through 2012. Propensity scores and inverse probability of treatment weighting were used to adjust forbaseline differences between patients taking and not taking statins.ResultsStatins were prescribed for 246 (65%) patients. The mean serum low-density lipoprotein (LDL) level was lower inpatients prescribed statins (75 ± 28 mg/dl vs. 96 ± 40 mg/dl, p< 0.001). Patients prescribed statins had more baseline comorbidities including diabetes, coronary artery disease, and hypertension, as well as more extensive lower extremity disease (all p values130 mg/dl had increased HRs of MACCE andmortality compared with patients with lower levels of LDL.ConclusionsStatins are associated with lower rates of mortality and MACCE and increased amputation-free survival in CLI patients.

Fasting samples of 1329 apparently healthy vegetarian Gujarati population were tested for total cholesterol, triglycerides and three major fractions of lipoproteins, i.e. high density lipoproteins, low density lipoproteins and very low density lipoproteins. All the values showed marked increase with the age. Except for serum triglycerides, values differ in males and females in the age group of above 45 years. Compared to Northern Indian population low density lipoprotein and high density lipoprotein values were higher, but values of triglycerides and very low density lipoproteins were lower. There is no significant difference in total cholesterol values. Compared to Southern Indian population low density lipoprotein and very low density lipoprotein values were higher but values of triglycerides, total cholesterol and high density lipoprotein were lower. All serum lipid values were significantly lower than the Westem population. The range of values for both the sexes is presented for different age groups.

An experimental model of hypercholesterolemic rabbits suitable for studying the hypocholesterolemic effect of compounds was developed. Rabbits were made hypercholesterolemic by oral administration of cholesterol (100mg/kg body weight/day) suspended in groud nut oil by gastric intubation (Ryle's tube). Cholesterol can be given to rabbits from 10 days to 6 months depending on the degree of hypercholesterolemia required and duration of study of hypocholesterolemic effect. In one month cholesterol feeding experiment, the serum cholesterol level in normal controls (not given cholesterol) was 67±11.3 mg/dl and in cholesterol fed animals 191.3±70.6 mg/dl. In 2 months experiment, besides hypercholesterolemia, abnormal serum lipid profile and increase in lipid content in liver, heart and aorta were also seen. To such animals when water and methanol extracts of garlic were given along with cholesterol, there was significant decrease in serum cholesterol level. The advantage of this method over the method in which cholesterol is mixed with diet to induce hypercholesterolemia is that exactly same and calculated amount of cholesterol can be given for each animal. This minimises the variations in serum cholesterol levels in different animals.

[Background]: The genetic determinism of blood lipid concentrations, the main risk factor for atherosclerosis, is practically unknown in species other than human and mouse. Even in model organisms, little is known about how the genetic determinants of lipid traits are modulated by age-specific factors. To gain new insights into this issue, we have carried out a genome-wide association study (GWAS) for cholesterol (CHOL), triglyceride (TRIG) and low (LDL) and high (HDL) density lipoprotein concentrations measured in Duroc pigs at two time points (45 and 190 days)., [Results]: Analysis of data with mixed-model methods (EMMAX, GEMMA, GenABEL) and PLINK showed a low positional concordance between trait-associated regions (TARs) for serum lipids at 45 and 190 days. Besides, the proportion of phenotypic variance explained by SNPs at these two time points was also substantially different. The four analyses consistently detected two regions on SSC3 (124 Mb, CHOL and LDL at 190 days) and SSC6 (135 Mb, CHOL and TRIG at 190 days) with highly significant effects on the porcine blood lipid profile. Moreover, we have found that SNP variation within SSC3, SSC6, SSC10, SSC13 and SSC16 TARs is associated with the expression of several genes mapping to other chromosomes and related to lipid metabolism., [Conclusions]: Our data demonstrate that the effects of genomic determinants influencing lipid concentrations in pigs, as well as the amount of phenotypic variance they explain, are influenced by age-related factors., This work has been funded by grants AGL2007-66707-C02 and AGL2010-22208-C02 (Ministerio de Ciencia e Innovación) and CSD 2007-00036 (Ministerio de Ciencia e Innovación, Consolider Ingenio 2010 Program).

Background Previous research has suggested that vitamin D and sunlight are related to cardiovascular outcomes, but associations between sunlight and risk factors have not been investigated. We examined whether increased sunlight exposure was related to improved cardiovascular risk factor status. Methods Residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine previous-year sunlight radiation exposure for 17,773 black and white participants aged 45+ from the US. Exploratory and confirmatory analyses were performed by randomly dividing the sample into halves. Logistic regression models were used to examine relationships with cardiovascular risk factors. Results The lowest, compared to the highest quartile of insolation exposure was associated with lower high-density lipoprotein levels in adjusted exploratory (−2.7 mg/dL [95% confidence interval: −4.2, −1.2]) and confirmatory (−1.5 mg/dL [95% confidence interval: −3.0, −0.1]) models. The lowest, compared to the highest quartile of insolation exposure was associated with higher systolic blood pressure levels in unadjusted exploratory and confirmatory, as well as the adjusted exploratory model (2.3 mmHg [95% confidence interval: 0.8, 3.8]), but not the adjusted confirmatory model (1.6 mg/dL [95% confidence interval: −0.5, 3.7]). Conclusions The results of this study suggest that lower long-term sunlight exposure has an association with lower high-density lipoprotein levels. However, all associations were weak, thus it is not known if insolation may affect cardiovascular outcomes through these risk factors.

Lipoprotein Lp(a) excess has been identified as a powerful predictor of premature atherosclerotic vascular diseases. To evaluate this in a North-Indian population, 130 CAD patients and 130 controls were analyzed. The size of the apo(a) phenotypic isoforms was inversely proportional to Lp(a) concentrations. The mean concentration of Lp(a) in the CAD patients was 42±34 mg/dl whereas in the normal subjects it was much lower, 27±27 mg/dl. 157 subjects out of the total 260 subjects showed plasma levels of >20mg/dl. The frequency of high Lp(a) levels was much higher in patients(73%) than controls (43%). These data suggest (1) that there is heterogeneity of the Lp(a) polymorphism, (2) Higher Lp(a) levels were found in patients than in the controls, (3) Patients showed 1.5 fold increase in Lp(a) levels as compared to the controls. We conclude that low molecular weight apo(a) isoforms are significantly associated with increased risk of CAD in the North-Indian population.

Lysophosphatidic acid (LPA) is a simple phospholipid derived from cell membranes that has extracellular signaling properties mediated by at least five G protein-coupled receptors referred to as LPA(1)-LPA(5). In the nervous system, receptor-mediated LPA signaling has been demonstrated to influence a range of cellular processes; however, an unaddressed aspect of LPA signaling is its potential to produce specific secondary effects, whereby LPA receptor-expressing cells exposed to, or "primed," by LPA may then act on other cells via distinct, yet LPA-initiated, mechanisms. In the present study, we examined cerebral cortical astrocytes as possible indirect mediators of the effects of LPA on developing cortical neurons. Cultured astrocytes express at least four LPA receptor subtypes, known as LPA(1)-LPA(4). Cerebral cortical astrocytes primed by LPA exposure were found to increase neuronal differentiation of cortical progenitor cells. Treatment of unprimed astrocyte-progenitor cocultures with conditioned medium derived from LPA-primed astrocytes yielded similar results, suggesting the involvement of an astrocyte-derived soluble factor induced by LPA. At least two LPA receptor subtypes are involved in LPA priming, since the priming effect was lost in astrocytes derived from LPA receptor double-null mice (LPA(1)((-/-))/LPA(2)((-/-))). Moreover, the loss of LPA-dependent differentiation in receptor double-null astrocytes could be rescued by retrovirally transduced expression of a single deleted receptor. These data demonstrate that receptor-mediated LPA signaling in astrocytes can induce LPA-dependent, indirect effects on neuronal differentiation.

Yunsuk Koh,1 Heidi Bidstrup,2 David L Nichols2 1Department of Health, Human Performance, and Recreation, Baylor University, Waco, TX, USA; 2Department of Kinesiology, Texas Woman's University, Denton, TX, USA Abstract: The current study examined the effects of niacin and a single bout of aerobic exercise on plasma glucose, insulin, and C-peptide in sedentary, nondiabetic postmenopausal women. As a crossover design, 17 participants underwent four different trials: rest during the no-niacin condition (R), exercise during the no-niacin condition (E), rest during the with-niacin condition (RN), and exercise during the with-niacin condition (EN). All participants took 1,000 mg/day of extended-release niacin for 4 weeks during the with-niacin conditions (RN and EN). The exercise treatment consisted of a single bout of treadmill walking at 60% heart rate reserve until 400 kcal were expended. Blood samples were collected at 24 hours after each trial and analyzed for changes in plasma glucose, insulin, and C-peptide. A two by two analysis of variance was used to examine the changes in dependent variables, and the Bonferroni adjustment was employed as the post hoc test. The level of statistical significance was set at P

Background Persons with spinal cord injury (SCI) often have low levels of physical activity, which predispose to increased adiposity and decreased high density lipoprotein cholesterol (HDL-C) concentrations, and, generally, normal low density lipoprotein cholesterol (LDL-C) concentrations. In spite of the mixed lipoprotein profile, the SCI population has been reported to have an elevated risk of cardiovascular-related morbidity and mortality. Nuclear magnetic resonance spectroscopy may permit a more precise quantification of lipoprotein particle (P) species, enabling a more accurate inference of risk for cardiovascular disease (CVD) in the SCI population. Methods Fasting blood samples were obtained on 83 persons with chronic SCI and 62 able-bodied (AB) subjects. Fasting plasma insulin (FPI), triglycerides (TG), and P number and size of VLDL (very low density lipoprotein), LDL, and HDL subclasses were determined. AB and SCI subjects were stratified based on HDL-C (i.e., Low