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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 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 <70 mg/dL, and LDL-C reduction of ≥50% at 12 weeks and at 1 to 5 years. Across 12-week studies, mean percent change in LDL-C from baseline in evolocumab-treated participants was -52% to -59% for White and -46% to -67% for non-White participants, across clinical characteristics groups. LDL-C <70 mg/dL was achieved in 43% to 84% and 62% to 94% and LDL-C reduction of ≥50% in 63% to 78% and 58% to 86%, respectively. In 1- to 5-year studies, mean percent change in LDL-C was -46% to -52% for White and -49% to -55% for non-White participants. LDL-C <70 mg/dL was achieved in 53% to 84% and 66% to 77%, and LDL-C reduction of ≥50% in 53% to 67% and 58% to 68%, respectively. The treatment effect on mean percent change in LDL-C differed only in participants with type 2 diabetes mellitus, with a larger reduction in Asian participants. The qualitative interaction P values were nonsignificant, indicating consistent directionality of effect. Conclusions Similar reduction in LDL-C levels with evolocumab was observed across racial/ethnic groups in 12-week and 1- to 5-year studies. Among those with diabetes mellitus, Asian participants had greater LDL-C reduction.

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 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, p<0.0001), and lower left atrial emptying fraction (0.99-fold change; P <0.0001). The C16:0/C24:0 ratio was not associated with either E/e' or global longitudinal strain, and the association with higher left ventricular mass was rendered statistically nonsignificant upon correction for multiple comparisons. 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 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<0.001) per SD increase in apoB/apoA-I. Adjusting for age, sex, and coronary artery disease, there was no significant association between apoB/apoA-I and 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<0.001]). 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 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: 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 <0.0001) in the fully adjusted model. The adjusted mean difference in the HDL-C decreased rate was 0.010 (95% confidence interval, 0.008, 0.012) mmol/L per year for tea consumers versus nonconsumers (never or less than once/month group). Interactions between tea consumption and age, sex, lifestyle scores, and metabolic syndrome (all P -interaction <0.0001) were identified. The associations between greater tea consumption and slower decrease in 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 <0.0001)., 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: ChiCTR-TNRC-11001489., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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-CECs 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-CECs were apolipoprotein AI ( R 2 =0.35, P <0.0001) and high-density lipoprotein cholesterol ( R 2 =0.21, P <0.0001) for J774-HDL-CECs and HepG2-HDL-CECs, respectively. Baseline and longitudinal changes in HDL-CECs were associated with several lipoprotein size and concentration indices, although high-density lipoprotein cholesterol was the best predictor of longitudinal changes in J774-HDL-CECs ( 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., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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 <0.05). The 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., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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 (<130 mg/dL) 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 (NCT00239681). 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 <0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (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: NCT00239681., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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 GENdEr 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<0.001). Lp(a) was strongly associated with LDL-C (adjusted β 0.17; P<0.001). Individuals with high Lp(a) were more likely to have 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., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

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<0.01). Almond consumption also reduced abdominal fat (-0.07±0.03 kg; 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: NCT01101230., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)