Low-density Lipoprotein Particle Number Research Articles

Association of LDL-cholesterol subfractions with cardiovascular disorders: a systematic review

BackgroundCardiovascular disorders (CVDs) are the leading cause of death worldwide. This study aimed to evaluate the association between low-density lipoprotein (LDL) subfractions and cardiovascular disorders.MethodsTo ensure the rigor of the systematic review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. For this systematic review, a comprehensive search strategy was performed in important databases including PubMed, Scopus, Embase, International Statistical Institute (ISI) Web of Science, and google scholar from 2009 to February 2021. The following terms were used for systematic search: low-density lipoprotein, LDL, subfractions, subclasses, nuclear magnetic resonance, NMR, chromatography, high-pressure liquid, HPLC, cardiovascular disease, cerebrovascular, and peripheral vascular disease. Also, for evaluating the risk of bias, the Newcastle-Ottawa scale was employed.ResultsAt the end of the search process, 33 articles were included in this study. The results of most of the evaluated studies revealed that a higher LDL particle number was consistently associated with increased risk for cardiovascular disease, independent of other lipid measurements. Also, small dense LDL was associated with an increased risk of CVDs. There was no association between LDL subfraction and CVDs in a small number of studies.ConclusionsOverall, it seems that the evaluation of LDL subclasses can be used as a very suitable biomarker for the assessment and diagnosis of cardiovascular diseases. However, further studies are required to identify the mechanisms involved.

A pilot retrospective study of a physician-directed and genomics-based model for precision lifestyle medicine.

Precision lifestyle medicine is a relatively new field in primary care, based on the hypothesis that genetic predispositions influence an individual's response to specific interventions such as diet, exercise, and prescription medications. Despite the increase in commercially available genomic testing, few studies have investigated effects of a physician-directed program to optimize chronic disease using genomics-based precision medicine. We performed an pilot, observational cohort study to evaluate effects of the Wild Health program, a physician and health coach service offering genomics-based lifestyle and medical interventions, on biomarkers indicative of chronic disease. 871 patients underwent genomic testing, biomarker testing, and ongoing health coaching after initial medical consultation by a physician. Improvements in several clinically relevant out-of-range biomarkers at baseline were identified in a large proportion of patients treated through lifestyle intervention without the use of prescription medication. Notably, normalization of several biomarkers associated with chronic disease occurred in 47.5% (hemoglobin A1c [HbA1c]), 33.3% (low density lipoprotein particle number [LDL-P]), and 33.2% (C-reactive protein [CRP]). However, due to the inherent limitations of our observational study design and use of retrospective data, ongoing work will be crucial for continuing to shed light on the effectiveness of physician-led, genomics-based lifestyle coaching programs. Future studies would benefit from implementing a randomized controlled study design, tracking specific interventions, and evaluating physiological data, such as BMI.

Identification of a Gain-of-Function LIPC Variant as a Novel Cause of Familial Combined Hypocholesterolemia.

Background:Atherosclerotic cardiovascular disease is the main cause of mortality worldwide and is strongly influenced by circulating low-density lipoprotein (LDL) cholesterol levels. Only a few genes causally related to plasma LDL cholesterol levels have been identified so far, and only 1 gene, ANGPTL3, has been causally related to combined hypocholesterolemia. Here, our aim was to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in 4 generations of a French family.Methods:Using next-generation sequencing, we identified a novel dominant rare variant in the LIPC gene, encoding for hepatic lipase, which cosegregates with the phenotype. We characterized the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance–based lipoprotein profiling and lipidomics. To uncover the mechanisms underlying the combined hypocholesterolemia, we used protein homology modeling, measured triglyceride lipase and phospholipase activities in cell culture, and studied the phenotype of APOE*3.Leiden.CETP mice after LIPC-E97G overexpression.Results:Family members carrying the LIPC-E97G variant had very low circulating levels of LDL cholesterol and high-density lipoprotein cholesterol, LDL particle numbers, and phospholipids. The lysophospholipids/phospholipids ratio was increased in plasma of LIPC-E97G carriers, suggestive of an increased lipolytic activity on phospholipids. In vitro and in vivo studies confirmed that the LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase through modification of an evolutionarily conserved motif that determines substrate access to the hepatic lipase catalytic site. Mice overexpressing human LIPC-E97G recapitulated the combined hypocholesterolemic phenotype of the family and demonstrated that the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by different extrahepatic tissues but not the liver.Conclusions:We identified and characterized a novel rare variant in the LIPC gene in a family who presents with dominant familial combined hypocholesterolemia. This gain-of-function variant makes LIPC the second identified gene, after ANGPTL3, causally involved in familial combined hypocholesterolemia. Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism.

Clinical Relevance of Nuclear Magnetic Resonance LipoProfile

Identifying risk factors for cardiovascular diseases in patients is key to reducing their resulting morbidity and mortality. Currently, risk factors are assessed using parameters that include and emphasize the role of the level of cholesterol carried by lipoproteins. Most providers focus on targeting cholesterol levels in patient management. However, recent research shows that lipoprotein particle number is more predictive of cardiovascular risk than cholesterol levels. The Nuclear Magnetic Resonance (NMR) LipoProfile test assesses the number of lipoprotein particles, sizes of lipoproteins, levels of cholesterol, and patient risk categories. Furthermore, it enables the identification of patients with underestimated cardiovascular risks—those with a discordant high number of low-density lipoprotein (LDL) particles (LDL-P) despite low cholesterol levels. While the NMR LipoProfile test requires a higher cost and longer waiting time for results in comparison to the lipid panel test, its advantages cannot be ignored. This review article focuses on exploring the routine use of NMR LipoProfile in clinical practice.

Metabolic Properties of Lowdensity Lipoprotein (LDL) Triglycerides in Patients with Type 2 Diabetes, Comparison with Small Dense LDL-Cholesterol.

Aims: Abnormal compositional changes in low-density lipoprotein (LDL) particles, such as triglyceride (TG) enrichment and size reduction, are common in patients with diabetes. Several cohort studies have demonstrated that LDL-TG and sdLDL-cholesterol (C) are sensitive biomarkers for predicting atherosclerotic cardiovascular diseases beyond LDL-C. Although sdLDL has been extensively studied, little is known about the properties of LDL-TG. We investigated similarities or differences between LDL-TG and sdLDL-C. Methods: Fasting plasma was obtained from 1,085 patients with type 2 diabetes who were enrolled in the diabetes regional cohort study (ViNA Cohort). LDL-TG and sdLDL-C concentrations were measured using a homogeneous assay established by us. In a subset of subjects, LDL-TG and sdLDL-C levels were measured postprandially or after treatment with lipid-lowering drugs. Results: In a quartile analysis, higher LDL-TG quartiles were associated with higher frequency of female and fibrate users, whereas sdLDL-C quartiles were associated with frequency of men, drinking, and metabolic syndrome-related measurements. Higher quartiles of LDL-TG/LDL-C were associated with smoking, drinking, fibrate users, and statin users. LDL-TG was significantly correlated with TG, LDL-C, sdLDL-C, and apolipoprotein (apo) B, with apoB being the primary determinant. LDL-TG correlated to high sensitive C-reactive protein (CRP) independently of other lipids. Mean LDL-TG did not change with fasting/non-fasting. Statin treatment reduced LDL-TG, whereas fibrates increased it, but these drugs reduced sdLDL-C equally. Conclusions: LDL-TG levels were more tightly regulated by the number of LDL particles than plasma TG levels were. SdLDL-C was closely associated with metabolic syndrome-related factors, whereas LDL-TG was associated with low-grade systemic inflammation.

Administration of eicosapentaenoic acid may alter lipoprotein particle heterogeneity in statin-treated patients with stable coronary artery disease: A pilot 6-month randomized study

BackgroundWe hypothesized that the addition of eicosapentaenoic acid (EPA) to ongoing statin therapy could change the particle heterogeneity of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles, even in stable coronary artery disease (CAD) patients. MethodsWe assigned CAD patients already receiving statin therapy to one of two groups: an EPA group (1800 mg/day; n = 30) and a control group (n = 30). A gel permeation high-performance liquid chromatography method was used to measure the particle concentration and number of lipoprotein subclasses. ResultsIn the EPA group, significant decreases of both the concentration and number of medium LDL (p = 0.0002 and 0.0001), small LDL (p = 0.0004 and 0.0005) and very small LDL (p = 0.0005 and 0.002) particles were observed. Conversely, the concentration and number of large HDL particles increased significantly (p = 0.024 and 0.048). The concentration of very large HDL particles also increased significantly (p = 0.028). Furthermore, significant correlations between the variables that showed significant changes in the LDL and HDL particle subclasses, and the EPA/arachidonic acid (AA) ratio were found. No other significant associations of lipoprotein particle heterogeneity with the serum EPA/AA ratio were noted in either the control group or the EPA group. Interestingly, univariate and multivariate regression analyses revealed that increased serum lecithin–cholesterol acyltransferase activity, a key enzyme of HDL cholesterol efflux, was a predictor for increased above-mentioned HDL particles subclasses. ConclusionsAdministration of EPA might alter both LDL and HDL particle heterogeneity, causing decreased concentration and number of smaller LDL particles and increased concentration and number of larger HDL particles. Furthermore, addition of EPA to ongoing statin therapy appears to be capable of increasing the EPA/AA ratio, which might have an anti-atherosclerotic effect on lipoprotein particle heterogeneity, even in stable CAD patients with well-controlled serum lipid levels. Clinical Trial RegistrationUMIN (http://www.umin.ac.jp/) Study ID: UMIN000010452.

Maternal hypercholesterolemia programs dyslipidemia in adult male mouse progeny.

As a collection of metabolic abnormalities including inflammation, insulin resistance, hypertension, hormone imbalance, and dyslipidemia, maternal obesity has been well-documented to program disease risk in adult offspring. Although hypercholesterolemia is strongly associated with obesity, less work has examined the programming influence of maternal hypercholesterolemia (MHC) independent of maternal obesity or high-fat feeding. This study was conducted to characterize how MHC per se impacts lipid metabolism in offspring. Female (n = 6/group) C57BL/6J mice were randomly assigned to: (1.) a standard chow diet (Control, CON) or (2.) the CON diet supplemented with exogenous cholesterol (CH) (0.15%, w/w) throughout mating and the gestation and lactation periods. At weaning (postnatal day (PND) 21) and adulthood (PND 84), male offspring were characterized for blood lipid and lipoprotein profile and hepatic lipid endpoints, namely cholesterol and triglyceride (TG) accumulation, fatty acid profile, TG production, and mRNA expression of lipid-regulatory genes. Both newly weaned and adult offspring from CH mothers demonstrated increased very low-density lipoprotein (VLDL) particle number and size and hepatic TG and n-6 polyunsaturated fatty acid accumulation. Further, adult CH offspring exhibited reduced fatty acid synthase (Fasn) and increased diglyceride acyltransferase (Dgat1) mRNA expression. These programming effects appear to be independent of changes in hepatic TG production and postprandial lipid clearance. Study results suggest that MHC, independent of obesity or high-fat feeding, can induce early changes to serum VLDL distribution and hepatic lipid profile that persist into adulthood.

Hashimoto Thyroiditis and Dyslipidemia in Childhood: A Review

Hashimoto autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in the pediatric population. Development of AIT is mediated mainly by cellular immune response directed toward thyroid autoantigens, leading to inflammation and impaired function of thyroid gland. Both thyroid dysfunction and inflammation affect the metabolism of plasma lipoproteins. The alterations in lipid profile worsen with the advancement of hypothyroidism, ranging from discrete changes in euthyroid AIT patients, to atherogenic dyslipidemia in the overt hypothyroidism. In this review, characteristics of dyslipidemia in pediatric AIT patients, and the consequences in respect to the risk for cardiovascular disease (CVD) development are discussed. Additionally, benefit of L-thyroxine treatment on serum lipid profile in pediatric AIT patients is addressed. Finally, potential usefulness of novel lipid biomarkers, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), non-cholesterol sterols, low-density lipoprotein particle size and number, and high-density lipoprotein structure and functionality in AIT patients is also covered. Further longitudinal studies are needed in order to elucidate the long-term cardiovascular outcomes of dyslipidemia in pediatric patients with Hashimoto AIT.

Distinct Influence of Omega-3 Fatty Acids on the Plasma Metabolome of Healthy Older Adults.

Omega-3 polyunsaturated fatty acids (n3-PUFA) are well recognized for their potent triglyceride-lowering effects, but the potential influence of these bioactive lipids on other biological processes, particularly in the context of healthy aging, remains unknown. With the goal of gaining new insight into some less well-characterized biological effects of n3-PUFAs in healthy older adults, we performed metabolomics of fasting peripheral blood plasma collected from 12 young adults and 12 older adults before and after an open-label intervention of n3-PUFA (3.9 g/day, 2.7 g eicosapentaenoic [EPA], 1.2 g docosahexaenoic [DHA]). Proton nuclear magnetic resonance (1H-NMR) based lipoprotein subclass analysis revealed the expected reduction in total triglyceride (TG), but also demonstrated that n3-PUFA supplementation reduced very low-density lipoprotein (VLDL) particle number, modestly increased high-density lipoprotein (HDL) cholesterol, and shifted the composition of HDL subclasses. Further metabolite profiling by 1H-NMR and mass spectrometry revealed pronounced changes in phospholipids, cholesterol esters, diglycerides, and triglycerides following n3-PUFA supplementation. Furthermore, significant changes in hydroxyproline, kynurenine, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) following n3-PUFA supplementation provide further insight into some less well-recognized biological effects of n3-PUFA supplementation, including possible effects on protein metabolism, the kynurenine pathway, and glucose metabolism.

One-Year Changes in Cardiovascular Risk Markers in Police Officers

PURPOSE: The present study retrospectively examined one-year changes in certain traditional and non-traditional cardiovascular disease (CVD) risk markers in police officers (n = 84). Subjects were full time police officers employed by a moderate-to-large municipality. METHODS: As a part of their annual physical exam, police officers underwent evaluation of several CVD risk markers including body weight, a graded exercise test (GXT; Bruce protocol), pushups completed in 1 minute, situps completed in 1 minute, handgrip strength, body composition (through DEXA), and fasting bloodwork. Maximal oxygen uptake (VO2max) was estimated using the Foster equation. Resting systolic blood pressure (RSBP) and resting diastolic blood pressure (RDBP) were measured before the start of the GXT protocol. Blood analysis was performed by a College of American Pathologists-accredited laboratory. All blood samples were analyzed for total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol (HDL-C), low-density lipoprotein (LDL) cholesterol (LDL-C), glucose (GLU), LDL particle number (LDLnum), LDL size (LDLsz), small LDL particle number (sLDLnum), HDL particle number (HDLnum), and HDL size (HDLsz). All data were analyzed using paired t-tests (p < 0.05). RESULTS: With respect to the fitness testing variables measured, significant increases were noted in pushups performed (4 pushups) and handgrip strength (4.45 kg) while RDBP was significantly reduced (4 mm/Hg). Within the traditional fasting blood panel, GLU was significantly increased (5.5 mg/dL) while LDL-C was significantly reduced (8.4 mg/dL). Non-traditional CVD risk markers were also significantly altered. Increases were noted in LDLnum (309 nmol/L), sLDLnum (347 nmol/L), and HDLnum (6.6 umol/L) while reductions in LDLsz (0.53 nm) and HDLsz (0.5 nm) researched statistical significance. CONCLUSIONS: While beneficial changes were noted in several traditional CVD risk markers, unfavorable alterations occurred in the majority of the non-traditional CVD risk markers measured. In addition, these findings support the need for required health and fitness programs for law enforcement personnel.

Dyslipidemia in nonalcoholic fatty liver disease.

To summarize recent findings regarding the characterization of lipoprotein disturbances in nonalcoholic fatty liver disease (NAFLD) and their relationship with cardiovascular disease (CVD) and make recommendations for the management of this situation. Advanced lipoprotein profile (using NMR spectroscopy) has shown profound lipoprotein derangements which are overlooked with conventional analyses: increased number and size of very low-density lipoproteins particles, increased number of low-density lipoprotein particles (especially small sized), smaller high-density lipoprotein particles, and an increase in the triglyceride content of all these lipoproteins. Other changes such as impaired functionality of high-density lipoprotein particles have also been observed. Beyond low-density lipoprotein-related parameters, the importance of triglyceride-rich lipoproteins in the pathogenesis of atherosclerosis has recently gained interest. Several studies suggest that these lipoproteins may have an independent role in CVD in NAFLD populations. Although outcome studies with lipid-lowering drugs in NAFLD are lacking, treatment with both statins, and especially, triglyceride-lowering drugs could be promising for these populations at high residual cardiovascular risk. In addition to being the main determinant of dyslipidemia, disturbances in triglyceride-rich lipoproteins are thought to be the key factor of increased CVD risk in NAFLD. Treatments specifically aimed at modifying these derangements warrant further study in this high-risk population.

Non-Traditional Cardiovascular Risk Markers in the Era of Established Major Risk Factors and Multiple Guidelines.

The non-traditional cardiovascular (CV) risk factors that appear to be of most clinical interest include: apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-sensitivity C-Reactive protein (hsCRP), homocysteine, interleukin 1 (IL1), lipoprotein (a) [Lp(a)], the density of low-density lipoprotein (LDL) particles, the LDL particle number, tissue/tumor necrosis factor-α (TNF-α) and uric acid. These non-traditional risk factors may be of value in adding further confirmation and attention to suspected significant CV risk. They can also provide a better understanding of current concepts of atherogenesis (e.g. various potential mechanisms associated with inflammation) as an etiology and in guiding current plus future therapies. In the mid-20th century, atherosclerosis and CV disease were considered mechanistic occurrences with essentially no attention to possible metabolic and molecular etiologies. Therefore, the only treatments then centered around mainly surgical procedures to try to improve blood flow, first with peripheral arterial disease (PAD) and later coronary artery disease (CAD). Now, failure to treat CV risk factors, especially where there is good evidence-based medicine, as in the case of statins for high CV risk patients, is considered medical negligence. Nevertheless, many problems remain to be solved regarding atherosclerosis prevention and treatment.

Safety and efficacy of ETC-1002 in hypercholesterolaemic patients: a meta-analysis of randomised controlled trials.

Due to the myopathic adverse events of statins, safer alternatives are being studied. Bempedoic acid (ETC-1002) is a novel low-density lipoprotein cholesterol (LDL-C)-lowering agent, currently under trial in hypercholesterolaemic patients. To investigate the tolerability and efficacy of ETC-1002 in hypercholesterolaemic patients through a systematic review of published randomised controlled trials (RCTs). Five databases were searched for RCTs that investigated the safety and efficacy of ETC-1002 in hypercholesterol-aemic patients. The retrieved search results were screened, and then data were extracted and analysed (as mean difference [MD] or odds ratio [OR]) using the RevMan software. Five RCTs (625 hypercholesterolaemic patients) were identified. ETC-1002 was superior to placebo in terms of percent-age changes from baseline in serum levels of LDL-C (MD -26.58, 95% confidence interval [CI] -35.50 to -17.66, p < 0.0001), non-high-density lipoprotein cholesterol (MD -21.54, 95% CI -28.48 to -14.6, p < 0.00001), and apolipoprotein-B (MD -15.97, 95% CI -19.36 to -12.57, p < 0.0001). When compared to ezetimibe, ETC-1002 was superior in reducing LDL-C (-30.1 ± 1.3 vs. -21.1 ± 1.3). Regarding safety, ETC-1002 did not increase the risk of all adverse events (OR 0.58, 95% CI 0.37-0.91, p = 0.02) and arthralgia (OR 0.32, 95% CI 0.13-0.81, p = 0.02) compared to placebo. All other adverse events including myalgia, headache, and urinary tract infections were similar between ETC-1002 and placebo groups. The evidence certainty in the assessed outcomes was moderate to high except for lipoprotein(a), free fatty acids, and very low-density lipoprotein particle number (very low certainty). ETC-1002 is a safe and effective lipid-lowering agent and may be a suitable alternative in statin-intolerant pa-tients. Well-designed studies are needed to explore the long-term safety and efficacy of ETC-1002 in these patients.

Relationship of lipoprotein-associated apolipoprotein C-III with lipid variables and coronary artery disease risk: The EPIC-Norfolk prospective population study

Plasma apolipoprotein C-III (apoC-III) levels are associated with coronary artery disease (CAD) risk. To assess whether lipoprotein-associated apoC-III levels predict risk of CAD events. apoC-III associated with apoB, apoAI, and Lp(a) (apoCIII-apoB, apoCIII-apoAI, and apoCIII-Lp(a), respectively) were measured using high-throughput chemiluminescent enzyme-linked immunoassays in 2711 subjects (1879 controls and 832 cases with CAD) in the European Prospective Investigation into Cancer and Nutrition-Norfolk prospective population study with 7.4years of follow-up. These measures were correlated with a variety of lipid measurements and the presence of CAD. The indices of "total apoCIII-apoB" and "total apoCIII-apoAI" were derived by multiplying plasma apoB and apoAI, respectively. apoCIII-apoB (P=.001), apoCIII-Lp(a) (P<.001), apoCIII-apoAI (P=.005) were higher in cases vs controls; tended to correlate positively with body mass index, hsCRP, apoC-III, low-density lipoprotein (LDL) cholesterol, triglycerides, remnant cholesterol, very low density lipoprotein, LDL and high-density lipoprotein particle number and very low density lipoprotein size; but negatively with LDL and high-density lipoprotein particle size (P<.001 for all). apoCIII-apoB, apoCIII-apoAI, apoCIII-Lp(a), total apoCIII-Lp(a), and total apoCIII-apoB were predictors of CAD after adjustment of age, sex, body mass index, smoking, diabetes, hypertensive and lipid-lowering drug use, but they lost their significance after further adjustment of lipid and lipoprotein variables. This study suggests that enzyme-linked immunoassay-measured lipoprotein-associated apoC-III markers reflect atherogenic lipid particles but do not independently predict risk of CAD events.

CVD Risk Stratification in the PCSK9 Era: Is There a Role for LDL Subfractions?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce the risk of cardiovascular events and all-cause mortality in patients at high risk of cardiovascular disease (CVD). Due to high costs and unknown long-term adverse effects, critical evaluation of patients considered for PCSK9 inhibitors is important. It has been proposed that measuring low-density lipoprotein (LDL) subfractions, or LDL particle numbers (LDL-P), could be of value in CVD risk assessment and may identify patients at high risk of CVD. This review evaluates the evidence for the use of LDL subfractions, or LDL-P, when assessing CVD risk in patients for whom PCSK9 inhibitors are considered as a lipid-lowering therapy. Numerous methods for measuring LDL subfractions and LDL-P are available, but several factors limit their availability. A lack of standardization makes comparison between the different methods challenging. Longitudinal population-based studies have found an independent association between different LDL subfractions, LDL-P, and an increased risk of cardiovascular events, but definitive evidence that these measurements add predictive value to the standard risk markers is lacking. No studies have proven that these measurements improve clinical outcomes. PCSK9 inhibitors seem to be effective at lowering all LDL subfractions and LDL-P, but any evidence that measuring LDL subfractions and LDL-P yield clinically useful information is lacking. Such analyses are currently not recommended when considering whether to initiate PCKS9 inhibitors in patients at risk of CVD.

Circulating Oxidized Low-Density Lipoprotein Levels Independently Predict 10-Year Progression of Subclinical Carotid Atherosclerosis: A Community-Based Cohort Study.

Aims: To investigate the association between circulating oxidized low-density lipoprotein (ox-LDL) levels and progression of subclinical atherosclerosis and to examine whether this link is independent of other low-density lipoprotein (LDL)-related parameters.Methods: Totally, 804 subjects who were free of cardiovascular disease at baseline completed risk factor surveys and carotid ultrasound measurements in 2002 and 2012. Modified Poisson regression was performed to examine the association between baseline serum ox-LDL levels and the 10-year risk of progression of carotid atherosclerosis which was defined as the development of at least one new plaque in a previously plaque-free carotid segment at re-examination.Results: The mean age of the subjects was 58.6 ± 7.7 years at baseline and 43.3% were men. A total of 504 (62.7%) subjects had carotid plaque progression at re-examination. Subjects in the intermediate and highest tertiles of ox-LDL had a significantly higher adjusted risk of atherosclerosis progression than those in the lowest tertile [relative risk (95% confidence interval) 1.17 (1.01–1.34) for the intermediate tertile and 1.23 (1.07–1.42) for the highest tertile]. This association was independent of baseline levels of LDL-C, total LDL particle number, and small LDL particle number.Conclusion: This study demonstrates that serum ox-LDL levels predict 10-year progression of subclinical atherosclerosis. Moreover, this effect is independent of the cholesterol content, the number, and the size of LDL particles.

P1504Discordant low-density lipoprotein particle number versus low-density lipoprotein cholesterol is associated with increased C-reactive protein and poorer outcomes

P1504Discordant low-density lipoprotein particle number versus low-density lipoprotein cholesterol is associated with increased C-reactive protein and poorer outcomes

Residual atherosclerotic cardiovascular disease risk in statin-treated adults: The Multi-Ethnic Study of Atherosclerosis

Residual atherosclerotic cardiovascular disease (ASCVD) risk in statin-treated US adults without known ASCVD is not well described. To quantitate residual ASCVD risk and its predictors in statin-treated adults. We studied 1014 statin-treated adults (53.3% female, mean 66.0years) free of clinical ASCVD in the Multi-Ethnic Study of Atherosclerosis. We examined ASCVD event rates by National Lipid Association risk groups over 11-year follow-up and the relation of standard risk factors, biomarkers, and subclinical atherosclerosis measures with residual ASCVD event risk. Overall, 5.3% of participants were at low, 12.2% at moderate, 60.3% at high, and 22.2% at very high baseline risk. Despite statin therapy, age- and race-standardized ASCVD rates per 1000 person-years for men and women were both 4.9 for low/moderate risk, 19.1 and 14.2 for high risk, and 35.6 and 26.7 for very high risk, respectively. Specific independent predictors of residual risk included current smoking, family history, diabetes, high-sensitivity C-reactive protein, low-density lipoprotein particle number, carotid intimal medial thickness, and especially coronary artery calcium score. Those on moderate- or high-intensity statins at baseline (compared with low intensity) had 39% lower risks and those who increased statin intensity 62% lower ASCVD event risks (P<.01). Residual risk of ASCVD remains high despite statin treatment and is predicted by specific risk factors and subclinical atherosclerosis. These findings may be helpful for identifying those at highest risk needing more aggressive treatment.

Apolipoprotein C-III Levels and Incident Coronary Artery Disease Risk: The EPIC-Norfolk Prospective Population Study.

Apolipoprotein C-III (apoC-III) is a key regulator of triglyceride metabolism. Elevated triglyceride-rich lipoproteins and apoC-III levels are causally linked to coronary artery disease (CAD) risk. The mechanism(s) through which apoC-III increases CAD risk remains largely unknown. The aim was to confirm the association between apoC-III plasma levels and CAD risk and to explore which lipoprotein subfractions contribute to this relationship between apoC-III and CAD risk. Plasma apoC-III levels were measured in baseline samples from a nested case-control study in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. The study comprised 2711 apparently healthy study participants, of whom 832 subsequently developed CAD. We studied the association of baseline apoC-III levels with incident CAD risk, lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy and inflammatory biomarkers. ApoC-III levels were significantly associated with CAD risk (odds ratio, 1.91; 95% confidence interval, 1.48-2.48 for highest compared with lowest quintile), retaining significance after adjustment for traditional CAD risk factors (odds ratio, 1.47; 95% confidence interval, 1.11-1.94). ApoC-III levels were positively correlated with triglyceride levels, (r=0.39), particle numbers of very-low-density lipoprotein (r=0.25), intermediate-density lipoprotein (r=0.23), small dense low-density lipoprotein (r=0.26), and high-sensitivity C-reactive protein (r=0.15), whereas an inverse correlation was observed with large low-density lipoprotein particle number (r=-0.11), P<0.001 for each. Mediation analysis indicated that the association between apoC-III and CAD risk could be explained by triglyceride elevation (triglyceride, very-low-density lipoprotein, and intermediate-density lipoprotein particles), small low-density lipoprotein particle size, and high-sensitivity C-reactive protein. ApoC-III levels are significantly associated with incident CAD risk. Elevated levels of remnant lipoproteins, small dense low-density lipoprotein, and low-grade inflammation may explain this association.

Abstract WP219: The Relationship of Low-Density Lipoprotein (LDL) Particle Number (LDL-P) and LDL Particle Size and Incident Stroke Events: The Multi-Ethnic Study of Atherosclerosis

Background &amp; Objectives: The role of lipid and lipoprotein biomarkers in risk prediction of ischemic heart disease is well established, but their value as independent predictors for ischemic stroke is less certain. Certain LDL subclasses based on particle sizes are associated with atherosclerotic risk. However, there is little information available on the relation of LDL particle number (LDL-P, nmol/L), LDL particle size (nm) with stroke. We evaluated associations between LDL-P and LDL particle size with the risk of ischemic stroke (IS) and transient ischemic attack (TIA). Methods: We studied US adults aged of 45-84 years not on lipid-lowering medications enrolled in the Multi-Ethnic Study of Atherosclerosis between 2000 and 2002 with follow-up through December 2011. We evaluated associations of LDL-P (total LDL-P, large LDL-P and small LDL-P) and LDL particle size measured by NMR with, (1) composite of incident IS and TIA, and (2) IS alone. Standardized hazard ratios (HRs) were adjusted for age, sex, race (model 1), plus diabetes, hypertension medication, systolic and diastolic blood pressure, family history, smoking, HDL (model 2), and plus LDL concentration (model 3). Results: We identified 129 subjects with incident IS, 61 with TIA and 5,328 without any type of stroke during follow-up; mean ages were 67.4, 66.7 and 61.2 years, respectively (p&lt;0.0001). White ethnicity was 37.2%, 42.6% and 37.6%), respectively. For the composite outcome of IS and TIA, while small LDL-P (HR 1.20, 95%CI 1.04 to 1.39) was predictive in model 1, this was attenuated after additional adjustment in models 2 and 3. For the outcome of IS alone, total LDL-P (HR 1.25, 95% CI 1.06 to 1.48) and small LDL-P (HR 1.34, 95% CI 1.13 to 1.60) were associated with incident IS in model 1, but there was no significant association of large LDL-P or LDL size with IS. Only small LDL-P remained predictive of IS in model 2 (HR 1.32, 95% CI 1.05 to 1.65) and in model 3 (HR 1.31, 95% CI 1.03 to 1.67). Conclusions: Increased small LDL-P, not particle size, is most closely associated with incident IS and could be useful in risk stratification beyond standard risk factors and lipid measures.