LDL Particles Research Articles

Lipoprotein particle alterations due to androgen therapy in individuals with dyskeratosis congenita.

SummaryBackgroundDyskeratosis congenita (DC) is a telomere biology disorder associated with high rates of bone marrow failure (BMF) and other medical complications. Oral androgens are successfully used to treat BMF in DC but often have significant side effects, including elevation of serum lipids. This study sought to determine the extent to which oral androgen therapy altered lipid and lipoprotein levels.MethodsNuclear magnetic resonance (NMR) was used to evaluate serum lipid profiles, and lipoprotein particle number and size in nine androgen-treated individuals with DC, 45 untreated individuals with DC, 72 unaffected relatives of DC patients, and 19 untreated individuals with a different inherited BMF syndrome, Fanconi anaemia (FA).FindingsAndrogen-treated individuals with DC had significantly decreased serum HDL cholesterol, HDL particle number and HDL particle size (p < 0·001, p < 0·001 and p < 0·001, respectively); significantly increased serum LDL cholesterol and LDL particle number (p < 0·001, p < 0·001, respectively), decreased apoA-I and increased apoB (p < 0⋅001, p < 0⋅05 respectively) when compared with untreated individuals with DC. There were no significant lipid profile differences between untreated DC and untreated FA participants; or between untreated DC participants and their unaffected relatives. Branched chain amino acids and lipoprotein insulin resistance were not significantly different with androgen treatment. GlycA, an inflammatory acute phase reactant, was significantly increased with androgen treatment (p < 0⋅001).InterpretationAndrogen treatment in DC creates an atherogenic lipoprotein profile, raising concern for the potential of elevated cardiovascular disease risk. Clinical guidelines for individuals on androgens for DC-related BMF should include cardiovascular disease monitoring. These findings could be relevant in individuals treated with androgen for other indications.FundingIntramural research programs of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and National Heart, Lung, and Blood Institute.

Glycoprotein Profile Measured by a 1H-Nuclear Magnetic Resonance Based on Approach in Patients with Diabetes: A New Robust Method to Assess Inflammation.

Patients with type 2 diabetes mellitus (T2DM) and atherogenic dyslipidemia (AD) are at higher risk of developing cardiovascular diseases (CVDs), so an interest in discovering inflammation biomarkers as indicators of processes related to CVD progression is increasing. This study aims (a) to characterize the plasma glycoprotein profile of a cohort of 504 participants, including patients with and without T2DM and/or AD and controls, and (b) to study the associations between the glycoprotein profile and other lipid and clinical variables in these populations. We characterized the plasma glycoprotein profiles by using 1H-NMR. We quantified the two peaks associated with the concentration of plasma glycoproteins (GlycA and GlycB) and their height/width ratios (H/W GlycA and H/W GlycB), as higher and narrower signals have been related to inflammation. We also quantified GlycF, the signal of which is proportional to the concentration of the acetyl groups of free N-acetylglucosamine, N-acetylgalactosamine, and N-acetylneuraminic in the samples. The lipoprotein profile was also determined (Liposcale®). Standard clinical and anthropometric measurements were taken. Multivariate classification models were developed to study the differences between the study groups. Reduced HDL-C levels, increased small dense LDL and HDL particles, and elevated TG levels were significantly associated with glycoprotein variables. Glycoprotein values in the diagnostic groups were significantly different from those in the CT groups. AD and DM conditions together contribute to a positive and significant synergetic effect on the GlycA area (<0.05) and the H/W ratios of GlycA (<0.01) and GlycB (<0.05). By adding the new glycoprotein variables to the traditionally used marker of inflammation C-reactive protein (CRP), the AUC increased sharply for classification models between the CT group and the rest (0.68 to 0.84), patients with and without dyslipidemia (0.54 to 0.86), and between patients with and without diabetes (0.55 to 0.75). 1H-NMR-derived glycoproteins can be used as possible markers of the degree of inflammation associated with T2DM and AD.

Concordance of apolipoprotein B concentration with the Friedewald, Martin-Hopkins, and Sampson formulas for calculating LDL cholesterol.

IntroductionTwo new formulas, the Martin-Hopkins and the Sampson formula, were recently developed to overcome shortcomings of the Friedewald formula for calculating LDL-cholesterol. We aimed to compare the concordance of the two formulas with apolipoprotein B (apoB), a surrogate marker of the number of LDL particles.Materials and methodsIn a study of serum lipid data of 1179 patients who consulted the AZ St-Jan Hospital Bruges for cardiovascular risk assessment, the correlation and concordance of the Friedewald, Martin-Hopkins and Sampson formulas with apoB concentration, measured by immunonephelometry, were determined and compared.ResultsThe Martin-Hopkins formula showed significantly higher correlation coefficient than the Friedewald formula with apoB in the entire dataset and in patients with low LDL-cholesterol < 1.8 mmol/L. Both Martin-Hopkins and Sampson formulas yielded > 70% concordance of LDL-cholesterol with regard to treatment group classification based on population-equivalent thresholds of apoB in hypertriglyceridemic patients (2-4.5 mmol/L), with the highest concordance (75.6%) obtained using Martin-Hopkins formula vs. 60.5% with Friedewald formula.ConclusionThe Martin-Hopkins (and, to a lesser extent, Sampson) formula is more closely associated with the number of LDL particles than Friedewald formula. This, in combination with literature evidence of lesser accuracy of the Friedewald formula, is an argument to switch from Friedewald to a modified, improved formula.

Transcriptomic Profiles Reveal Downregulation of Low-Density Lipoprotein Particle Receptor Pathway Activity in Patients Surviving Severe COVID-19.

To assess the biology of the lethal endpoint in patients with SARS-CoV-2 infection, we compared the transcriptional response to the virus in patients who survived or died during severe COVID-19. We applied gene expression profiling to generate transcriptional signatures for peripheral blood mononuclear cells (PBMCs) from patients with SARS-CoV-2 infection at the time when they were placed in the Intensive Care Unit of the Pavlov First State Medical University of St. Petersburg (Russia). Three different bioinformatics approaches to RNA-seq analysis identified a downregulation of three common pathways in survivors compared with nonsurvivors among patients with severe COVID-19, namely, low-density lipoprotein (LDL) particle receptor activity (GO:0005041), important for maintaining cholesterol homeostasis, leukocyte differentiation (GO:0002521), and cargo receptor activity (GO:0038024). Specifically, PBMCs from surviving patients were characterized by reduced expression of PPARG, CD36, STAB1, ITGAV, and ANXA2. Taken together, our findings suggest that LDL particle receptor pathway activity in patients with COVID-19 infection is associated with poor disease prognosis.

The influence of menopause and cardiorespiratory fitness on lipoprotein particles in midlife women.

Lipoprotein particles may provide better information about cardiovascular risk than standard cholesterol measures for women. Whether lipoprotein subclasses change with menopausal stage is unclear. Given the high prevalence of low cardiorespiratory fitness in midlife women and benefit of cardiovascular disease risk, it is also important to understand the effect of fitness on lipoprotein profiles. This study evaluated the influence of menopausal status and fitness on lipoprotein particles in healthy midlife women. Lipoprotein particles were measured in high- (n = 25) and low- (n = 13) fit perimenopausal and late postmenopausal women, and in high-fit premenopausal (n = 10), perimenopausal (n = 12), and late postmenopausal women (n = 13). There were larger low-density lipoprotein particles (LDL-P; 21.7 ± 0.06 vs. 21.3 ± 0.1 nm, p = 0.002), more large LDL-P (623.1 ± 32.8 vs. 500.2 ± 52.6 nmol/L, p = 0.045), and fewer small LDL-P (145.5 ± 31.4 vs. 311.5 ± 44.7 nmol/L, p = 0.001) in the high-fit group vs. the low-fit group. High-density lipoprotein particles (HDL-P) were larger (10.1 ± 0.1 vs. 9.7 ± 0.1 nm, p = 0.002) in the high-fit group, with more large (14.8 ± 0.7 vs. 11.0 ± 0.9 μmol/L,p = 0.002), medium (12.9 ± 0.8 vs. 8.4 ± 0.9 μmol/L, p = 0.002) HDL-P, and fewer small HDL-P (10.2 ± 1.1 vs. 15.4 ± 1.6 μmol/L, p = 0.009) compared with the low-fit group. High-fit postmenopausal women had more large LDL-P (662.9 ± 47.5 nmol/L) compared with premenopausal women (479.1 ± 52.6 nmol/L, p = 0.035), and more HDL-P (40.2 ± 1.1 µmol/L) compared with premenopausal (34.9 ± 1.5 μmol/L, p = 0.023) and perimenopausal women (35.4 ± 1.3 μmol/L, p = 0.033). High fitness positively influences lipoprotein particles in healthy perimenopausal and late postmenopausal women. In healthy fit women, menopause may not have a large influence on lipoprotein particles. Novelty: In highly fit women, menopause may not have a negative influence on lipoprotein particle subclasses. High fitness is associated with a less atherogenic lipoprotein profile in perimenopausal and late postmenopausal women.

A Comprehensive Review of Hass Avocado Clinical Trials, Observational Studies, and Biological Mechanisms.

This first comprehensive review of fresh Hass avocados includes 19 clinical trials, five observational studies, and biological mechanisms. We identified four primary avocado health effects: (1) reducing cardiovascular disease risk in healthy overweight or obese adults with dyslipidemia by lowering non-HDL-C profiles, triglycerides, LDL oxidation, small atherogenic LDL particles and promoting postprandial vascular endothelial health for better peripheral blood flow; (2) lowering the risk of being overweight or obese, supporting weight loss, and reducing visceral fat tissue in overweight or obese women; (3) improving cognitive function in older normal-weight adults and in young to middle age overweight or obese adults especially in frontal cortex executive function; and (4) stimulating improved colonic microbiota health in overweight or obese adults by promoting healthier microflora and fecal metabolites. We also identified a unique combination of four Hass avocado nutritional features that appear to be primarily responsible for these health effects: (1) a 6 to 1 unsaturated (rich in oleic acid) to saturated fat ratio similar to olive oil; (2) a source of multifunctional prebiotic and viscous fiber; (3) a relatively low energy density of 1.6 kcal/g (79% of edible Hass avocado weight consists of water and fiber with a creamy, smooth texture); and (4) its oleic acid and water emulsion increases carotenoid absorption from low-fat fruits and vegetables (e.g., salsa or salad) when consumed with avocados. They are also a good source of micronutrients and polyphenols, and are very low in sodium and available carbohydrates supporting secondary health and wellness benefits. Hass avocado health effects are best demonstrated when consumed in a healthy dietary plan such as the Mediterranean diet. More extensive and longer clinical trials are needed to further enhance our understanding of the Hass avocado’s health effects.

Study on the correlation between subgroup of blood lipid with degree of coronary artery stenosis in patients with coronary atherosclerotic heart disease

Objective: To study the correlation between low-density lipoprotein particles (LDL-P) with other lipoprotein indexes. To explore the correlation between LDL-P and its subgroup particles(LDL1-P-LDL6-P) with the degree of coronary artery stenosis in patients with coronary atherosclerotic heart disease(CHD) combining with the result of coronary arteriography. To explore the value of lipoprotein subgroup granules in preventing the severity of coronary artery stenosis in CHD patients. Methods: Cross-sectional study. A total of 259 patients without lipid-lowering drugs for coronary angiography in the department of cardiology of TEDA International Cardiovascular Hospital during 3 months from August 2019 to December 2019 were collected, and 52 healthy subjects were recruited during the same period. The level of high sensitivity C-reactive protein (hs-CRP) and other biochemical indexes were detected by automatic biochemical analyzer. The level of LDL-P and other biochemical indexes were detected by nuclear magnetic resonance spectroscopy(NMRS). The relation between various biomarkers levels with coronary artery stenosis degree was analyzed. Analysis of variance and nonparametric tests were used to compare the differences of indexes among each group. Pearson correlation analysis was used to determine the correlation among the measured indexes. Logistic regression was used for multi-factor analysis, ROC curve was used to evaluate the diagnostic value of related indexes. Results: LDL-P was highly correlated with low-density lipoprotein cholesterol (LDL-C),apolipoprotein B (ApoB) and total cholesterol (TC) (r= 0.927, P<0.001; r=0.921, P<0.001; r=0.844, P<0.001). LDL-P, LDL4-P, LDL5-P and LDL6-P in patients with severe coronary stenosis were higher than those in patients with mild coronary stenosis(U=4 172.000, Z=4.256, P<0.001; t=2.573, P=0.011; U=3 995.000, Z=4.621, P<0.001;t=5.223, P<0.001), LDL-P and LDL6-P were higher than those of patients with moderate coronary stenosis (U=1 159.000, Z=2.294, P=0.022; t=2.075, P=0.041). High levels of hs-CRP, LDL5-P and LDL6-P were risk factors for the degree of coronary stenosis(OR=1.095, P=0.036;OR=1.015, P=0.046;OR=1.012, P=0.039). ROC analysis showed that the AUC of LDL-P, LDL5-P and LDL6-P on coronary stenosis was 0.67, 0.68 and 0.69, respectively. Hs-CRP combined with LDL5-P and LDL6-P had the greatest effect on the degree of coronary stenosis (AUC= 0.70). Conclusions: LDL-P is highly correlated with LDL-C. The levels of LDL-P and LDL6-P were significantly higher in patients with severe stenosis than in patients with mild and moderate stenosis. hs-CRP, LDL5-P and LDL6-P can be used as new risk factors for the degree of coronary stenosis and may be further used as risk predictors. The combined detection of hs-CRP, LDL5-P and LDL6-P is helpful for the diagnosis of the severity of coronary stenosis, and may further become risk predictors.

Advanced Quantitative Lipoprotein Characteristics Do Not Relate to Healthy Dietary Patterns in Adults from a Mediterranean Area.

We aimed to assess the potential relationship between dietary patterns (i.e., Mediterranean diet and healthy eating) and the advanced lipoprotein profile (ALP) in a representative cohort of the Mediterranean population. Thus, ALP data from 1142 participants, including 222 with type 1 (19.4%) and 252 type 2 diabetes (22.1%), and 668 subjects without diabetes were used to study cross-sectional associations between quantitative characteristics of lipoproteins and adherence to the Mediterranean diet. The alternate Mediterranean diet score (aMED) and the alternate healthy eating index (aHEI) were calculated. The ALP was determined by nuclear magnetic resonance (NMR) spectrometry. Bivariable and multivariable analyses were performed. Participants in the third tertile of the aMED showed higher levels of low-density lipoprotein triglycerides (LDL-TG) (mean (SD) 17.5 (5.0); p = 0.037), large high-density lipoprotein particles (HDL-P) (0.3 (0.1); p = 0.037), and medium low-density lipoprotein particles (LDL-P) (434.0 (143.0); p = 0.037). In comparison with participants in the second and first tertiles of the aHEI, participants in the third tertile had higher levels of LDL-TG (17.7 (5.0); p = 0.010), and large HDL-P (0.3 (0.1); p = 0.002), IDL-C (11.8 (5.0); p = 0.001), intermediate-density lipoprotein triglycerides (IDL-TG) (13.2 (4.2); p < 0.001), LDL-TG (17.7(5.0); p = 0.010), high-density lipoprotein triglycerides (HDL-TG) (14.5 (4.4); p = 0.029,) large HDL-P (0.3 (0.1); p = 0.002) and very–low-density lipoprotein particles (VLDL-P) size (42.1 (0.2); p = 0.011). The adjusted-multivariable analysis for potential confounding variables did not show any association between the lipoproteins and dietary patterns (i.e., aMED and aHEI). In conclusion, none of the quantitative characteristics of lipoproteins were concomitantly associated with the extent of adherence to the Mediterranean diet measured using the aMED or aHEI scores in the studied population. Our findings also revealed that people with the highest adherence were older, had a higher body mass index (BMI) and more frequently had dyslipidemia, hypertension, or diabetes than those with the lowest adherence to the Mediterranean diet (MDiet). Thus, further research may be needed to assess the potential role of the dietary pattern on the ALP.

The Reciprocal Relationship between LDL Metabolism and Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus and insulin resistance feature substantial modifications of the lipoprotein profile, including a higher proportion of smaller and denser low-density lipoprotein (LDL) particles. In addition, qualitative changes occur in the composition and structure of LDL, including changes in electrophoretic mobility, enrichment of LDL with triglycerides and ceramides, prolonged retention of modified LDL in plasma, increased uptake by macrophages, and the formation of foam cells. These modifications affect LDL functions and favor an increased risk of cardiovascular disease in diabetic individuals. In this review, we discuss the main findings regarding the structural and functional changes in LDL particles in diabetes pathophysiology and therapeutic strategies targeting LDL in patients with diabetes.

Thiosemicarbazone Copper Chelator BLT-1 Blocks Apicomplexan Parasite Replication by Selective Inhibition of Scavenger Receptor B Type 1 (SR-BI)

Coccidian parasites are obligate intracellular pathogens that affect humans and animals. Apicomplexans are defective in de novo synthesis of cholesterol, which is required for membrane biosynthesis and offspring formation. In consequence, cholesterol has to be scavenged from host cells. It is mainly taken up from extracellular sources via LDL particles; however, little is known on the role of HDL and its receptor SR-BI in this process. Here, we studied effects of the SR-BI-specific blocker BLT-1 on the development of different fast (Toxoplasma gondii, Neospora caninum, Besnoitia besnoiti) and slow (Eimeria bovis and Eimeria arloingi) replicating coccidian species. Overall, development of all these parasites was significantly inhibited by BLT-1 treatment indicating a common SR-BI-related key mechanism in the replication process. However, SR-BI gene transcription was not affected by T. gondii, N. caninum and B. besnoiti infections. Interestingly, BLT-1 treatment of infective stages reduced invasive capacities of all fast replicating parasites paralleled by a sustained increase in cytoplasmic Ca++ levels. Moreover, BLT1-mediated blockage of SR-BI led to enhanced host cell lipid droplet abundance and neutral lipid content, thereby confirming the importance of this receptor in general lipid metabolism. Finally, the current data suggest a conserved role of SR-BI for successful coccidian infections.

Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents.

Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.

Abstract 11174: Effect of APOCIII-L Rx on Lipoprotein Size and Particle Numbers Measured by NMR in Patients with Hypertriglyceridemia: Results of the AKCEA-APOCIII-L Rx Trial

Background: APOCIII-L Rx is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apoC-III and triglyceride-rich lipoproteins (TRLs). We examined the effect of APOCIII-L Rx on a variety of lipoprotein fractions measured by nuclear magnetic resonance (NMR) spectroscopy. Methods: The AKCEA-APOCIII-L Rx trial was a dose-ranging study in 114 patients with, or at risk for, ASCVD and fasting serum triglycerides 200-500 mg/dL. Patients (n=114) received AKCEA-APOCIII-L Rx (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. Comprehensive NMR LipoProfile ® analysis was performed by LipoScience/LabCorp in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months. Results: Results are reported as change from baseline to PAT for the 50 mg every 4 weeks dose versus placebo. APOCIII-L Rx resulted in a significant reduction in total TRL particle (TRLP) concentration by 51% (P&lt;0.0001) with largest reductions in large-size (by 68%, P&lt;0.0001) and medium-size (by 63%, P&lt;0.0001) TRLPs. Total LDL particle (LDLP) concentration was not changed, small LDLP numerically decreased by 39% (P= 0.0713) while medium LDLP increased by 187% (P=0.0119), accompanied by an increase in average LDL size by xx 2% (p=0.0039xx). Total HDL particle (HDLP) concentration increased by 15% (P=0.0006), represented primarily by an increase in small HDL subspecies (particle diameters &lt;8.3 mm) of 32% (P=0.0008). Lower cumulative doses of APOCIII-L Rx generally reflected a dose-dependent relationship in the above parameters. Conclusion: APOCIII-L Rx results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDLP. These findings suggest an improvement in overall atherogenic risk profile.

Abstract 9691: Lipoprotein Subclasses Are Associated With Hepatic Steatosis: Insights from the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) Clinical Trial

Introduction: Hepatic steatosis (HS) is associated with coronary artery disease (CAD) and cardiovascular (CV) events. Previously, we have demonstrated that granular measures of lipids (lipoprotein particle number/size) are associated with CAD and CV events and incremental to traditional lipid measures. Hypothesis: Granular measures of lipids are associated with HS detected by cardiac computed tomography (CT) and with HS detected by histopathology. Methods: We included 1524 subjects from the PROMISE trial. HS was defined as CT attenuation of the liver &lt;40HU or liver&lt;spleen HU on CT. Plasma lipoprotein particle parameters were measured by NMR. Principal components analysis was used for dimensionality reduction and logistic regression was used to test the association of lipoprotein factors and individual lipoproteins with HS cases and controls in uni/multivariable models. The association of lipoproteins with HS was validated in an independent cohort of 58 subjects (Laval U) with and without HS defined by histopathology on liver biopsy. Results: Subjects with HS (n=413) were slightly younger (59±8 vs 61±8 yrs) and more likely men (53 vs 44%) as compared to controls (n=1111). Three lipoprotein factors were associated with HS: LDL/LDL particle size (OR 1.36, 95%CI 1.21-1.53, p&lt;0.001); HDL/HDL size (OR 1.75, 95%CI, 1.53-2.02, p&lt;0.001), and TG-rich-lipoprotein particles (OR 0.74, 95% CI 0.65-0.84, p&lt;0.002). Individual lipoproteins heavily loaded in these factors were also significant in multivariable analysis (Figure). These lipoproteins were also associated with HS in the validation cohort: small LDL (OR 6.36, p&lt;0.05), large HDL (OR 0.29, p&lt;0.05), and large TG particles (OR 13.83, p&lt;0.05). Conclusions: We found association of small LDL, large HDL and large TG particles, previously associated with CV event risk, with HS phenotyped by CT and histopathology. These results suggest that use of lipoprotein subclasses may improve CV risk assessment in patients with HS.

Abstract 11456: Elevated Lipoprotein(a) is Associated with Statin Resistance

Introduction: LDL-C reduction by statins is the mainstay pharmacologic strategy for ASCVD risk reduction. Despite adherence, some patients fail to achieve LDL-C goals, a phenomenon known as statin resistance. Current LDL-C assays include cholesterol content on both lipoprotein(a) [Lp(a)] and LDL particles. Because statins do not lower Lp(a), Lp(a)-cholesterol may represent a statin insensitive pool within LDL-C. Hypothesis: Elevated Lp(a) contributes to statin resistance in patients treated with high-intensity statin therapy. Methods: A secondary analysis was performed on 2338 patients from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, randomized to receive atorvastatin 80mg or placebo; baseline and week 16 lipid parameters were analyzed. Results: In the atorvastatin group (n = 1092), mean (SD) baseline LDL-C, absolute LDL-C reduction, median percent LDL-C change from baseline (IQR), and Lp(a) were 123.8 (33.5) mg/dL, 52.2 (36.7) mg/dL, -47.6% (-59.1- -29.9%), and 10.6 (5.1-29.1) mg/dL, respectively. Median (IQR) baseline Lp(a) was higher [12.1 (5.9-38.1) vs 9.2 (4.4-22.4) mg/dL, p &lt; 0.001] in patients with attenuated percent LDL-C reduction compared to group median. The median percent LDL-C reduction on atorvastatin was 42.3% (24.3-52.5%) in patients with baseline Lp(a) between 50 - 99 mg/dL, and 32.6% (11.5-43.7%) with Lp(a) &gt; 100 mg/dL prevalent in ~10% of the population, both significantly attenuated compared to patients with Lp(a) &lt;30 mg/dL (50.4% [33.3-61.1%]), p &lt; 0.001. An LDL-C target of 70 mg/dL or less was achieved in 62.3% of patients with baseline Lp(a) &lt;30 mg/dL, compared to 55.2%, 43.3%, and 24.1% of those with Lp(a) 30 - 49 mg/dL, 50 - 99 mg/dL, and &gt; 100 mg/dL (p &lt; 0.001), respectively [Figure 1]. Conclusions: Elevated Lp(a) is associated with statin resistance and may identify patients who require additional or more potent lipid lowering therapies to achieve LDL-C goals.

Abstract 13992: Cardiovascular Disease Risk of Abnormal Glucose Tolerance Depends on Etiology: Insulin Resistance versus Beta-Cell Failure

Background: Cardiovascular disease (CVD) and abnormal glucose tolerance (Abnl-GT) are rapidly increasing in sub-Saharan Africa. Abnl-GT is a primary risk factor for CVD. Yet, different Abnl-GT etiologies, insulin resistance (IR) or β-cell failure, may have different CVD risk profiles. Therefore, in 493 African-born Blacks living in the United States [male: 64%, age: 38±10y (mean±SD)], we evaluated the CVD risk profile within each Abnl-GT etiology. Methods: OGTT were performed. Abnl-GT, a term combining diabetes and prediabetes, was defined as fasting plasma glucose (FPG)≥100 mg/dL and/or glucose at 2h≥140 mg/dL. IR was defined by the upper quartile of HOMA-IR (≥2.03). Abnl-GT-IR required both Abnl-GT and IR. Abnl-GT-β-cell failure was defined as Abnl-GT without IR. Fasting lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL) particle sizes, were measured. Dyslipidemia was defined as total cholesterol, TC&gt;200mg/dL, LDL&gt;130mg/dL, HDL&lt;35mg/dL and triglycerides, TG&gt;150mg/dL or any combination thereof. CVD risk was determined by the Pooled-Cohort Equation (PCE) [age, TC, HDL, SBP, diabetes, smoking status], as developed in the ARIC cohort. Results: Abnl-GT occurred in 37% (183/493) of participants, with Abnl-GT due to IR in 28% (69/183) and β-cell-failure in 62% (114/183). Neither systolic nor diastolic BP differed between the Abnl-GT groups (both P &gt;0.05). HDL, HDL-size and LDL-size were lower and TG higher in the IR group compared to the β-cell-failure group (all P &lt;0.01). The prevalence of dyslipidemia was higher in the IR than the β-cell-failure group at 49% (34/69) vs 28% (32/114) ( P &lt;0.05). The IR had a higher PCE score versus the β-cell failure group [26.5±2.7 vs 18.8.0±1.9 ( P =0.001)]. Conclusions: Although IR was a less common cause of Abnl-GT than β-cell failure, the IR group had a more adverse lipid profile and therefore a higher CVD risk compared to the β-cell failure group. Thus, the etiology of Abnl-GT should be taken into account when developing treatment strategies for patients at higher CVD risk.

Abstract 10979: Liver-Humanized Mice Provide a New Platform to Study Human Cardiometabolic Diseases

Introduction: Conventional mouse models do not fully recapitulate human cardiometabolic diseases (CMD), e.g. , atherosclerosis and nonalcoholic steatohepatitis (NASH), due to species differences in metabolism. Liver-humanized mice (LHM), i.e. , mice repopulated with human hepatocytes, have been shown to be an improved translatable model to study human hepatic and lipoprotein metabolism. Hypothesis: As dietary challenge is often used to induce CMD in animal models, we sought to characterize lipoprotein and lipid metabolism in LHM challenged by different diets. Methods: Immune-deficient FRGN mice receiving hepatocytes from different human donors (LHM) or NOD mouse (liver-murinized mice, LMM) were fed a high-fat/high-sucrose diet (HFHSD) for 8 weeks or a high-fat/high-fructose/high-cholesterol diet (NASH-diet) for 8, 12, 16 or 20 weeks. Plasma lipids and lipoproteins were quantified after size-exclusion chromatography separation or by routine clinical assays. Cholesterol in the descending aorta was analyzed by GC-MS. Histologic analysis of hearts or livers was done using hematoxylin/eosin or Oil Red O staining, and anti-mouse CD68-antibody was used to detect murine macrophages. Results: Compared with LMM, LHM fed either HFHSD or NASH-diet accumulated plasma cholesterol and triglycerides within LDL and triglyceride-rich particles (VLDL and remnants). However, only the NASH-diet induced a notable hyperlipidemia and a substantial increase in cholesteryl esters within the aorta. NASH-diet also determined a clear accumulation of neutral lipids and CD68-positive cells in the aortic valves of LHM. Similarly, hepatocyte ballooning, liver steatosis and fibrosis were also induced by the NASH-diet. All these pathologic changes occurred during diet challenge at different time points. Conclusions: LHM developed severe hyperlipidemia, atherosclerosis and NASH when fed a NASH-diet, but not on HFHSD. The high quantity of cholesterol in the NASH-diet likely compensates for the high utilization of cholesterol of LHM due to their known increase in bile acid synthesis, prompting dyslipidemia and CMD. LHM fed a NASH-diet is an improved model for human CMD and for the development of therapeutic strategies rapidly translatable to the human condition.

Altered vitamin K biodistribution and metabolism in experimental and human chronic kidney disease

Chronic kidney disease (CKD) is accompanied with extensive cardiovascular calcification, in part correlating with functional vitamin K deficiency. Here, we sought to determine causes for vitamin K deficiency beyond reduced dietary intake. Initially, vitamin K uptake and distribution into circulating lipoproteins after a single administration of vitamin K1 plus K2 (menaquinone 4 and menaquinone 7, respectively) was determined in patients on dialysis therapy and healthy individuals. The patients incorporated very little menaquinone 7 but more menaquinone 4 into high density lipoprotein (HDL) and low-density lipoprotein particles than did healthy individuals. In contrast to healthy persons, HDL particles from the patients could not be spiked with menaquinone 7 invitro and HDL uptake was diminished in osteoblasts. A reduced carboxylation activity (low vitamin K activity) of uremic HDL particles spiked with menaquinone 7 vs. that of controls was confirmed in a bioassay using human primary vascular smooth muscle cells. Kidney menaquinone 4 tissue levels were reduced in 5/6-nephrectomized versus sham-operated C57BL/6 mice after four weeks of a vitamin K rich diet. From the analyzed enzymes involved in vitamin K metabolism, kidney HMG-CoA reductase protein was reduced in both rats and patients with CKD. In a trial on the efficacy and safety of atorvastatin in 1051 patients with type 2 diabetes receiving dialysis therapy, no pronounced vitamin K deficiency was noted. However, the highest levels of PIVKA-II (biomarker of subclinical vitamin K deficiency) were noted when a statin was combined with a proton pump inhibitor. Thus, profound disturbances in lipoprotein mediated vitamin K transport and metabolism in uremia suggest that menaquinone 7 supplementation to patients on dialysis therapy has reduced efficacy.

Association of serum 25-Hydroxy Vitamin D level with lipid, lipoprotein, and apolipoprotein level

ABSTRACT Introduction 25-Hydroxy vitamin D (Vit D3) deficiency was found to be associated with vascular dysfunction, arterial stiffening, extent of coronary artery disease and cardiovascular mortality. Previous studies showed positive correlation between serum Vit D3 and HDL-C and negative correlation between Vit D3 and LDL-C. The aim of this study is to investigate more details about the possible association of serum Vit D3 level with lipid, lipoprotein and apolipoprotein level. Methods Totally 101 patients were included in this study and Vit D3, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), High-density lipoprotein cholesterol (HDL-C), total triglyceride (TG), non-high-density lipoprotein cholesterol (Non-HDL-C), low-density lipoprotein particle (LDL-P), small dense low-density lipoprotein particle (sLDL-P), small dense low-density lipoprotein cholesterol (sdLDL-C), High-density lipoprotein cholesterol particles (HDL-P), High-density lipoprotein 2-cholesterol (HDL2-C), Apolipoprotein B(ApoB), Apolipoprotein A1 (Apo A1) and Apolipoprotein B/Apolipoprotein A1 ratio (ApoB/A ratio) were tested. Results Our results show that patients with Vit D3 deficiency (Vit D3 < 30 ng/ml) have significantly higher level of LDL-C, TG, Non-HDL-C, LDL-P, sLDL-P, sdLDL-C, ApoB and ApoB/A ratio compare with patients have normal Vit D3 level (Vit D3 > 30 ng/ml). Patients with normal Vit D3 level have significantly higher level of HDL-C and HDL2-C. Correlation study shows that Vit D3 level is negative correlated with TC, LDL-C, TG, Non-HDL-C, LDL-P, sLDL-P, sdLDL-C, ApoB and ApoB/A ratio and positive correlated with HDL2-C level. Conclusion Our results show that Vit D3 deficiency links to an increased risk for dyslipidemia and that may be the reason that patients with vitamin D deficiency tend to have higher risk of coronary artery disease.

Mendelian Randomization Identifies the Potential Causal Impact of Dietary Patterns on Circulating Blood Metabolites.

Nutrition plays an important role in the development and progress of several health conditions, but the exact mechanism is often still unclear. Blood metabolites are likely candidates to be mediating these relationships, as their levels are strongly dependent on the frequency of consumption of several foods/drinks. Understanding the causal effect of food on metabolites is thus of extreme importance. To establish these effects, we utilized two-sample Mendelian randomization using the genetic variants associated with dietary traits as instrumental variables. The estimates of single-nucleotide polymorphisms’ effects on exposures were obtained from a recent genome-wide association study (GWAS) of 25 individual and 15 principal-component dietary traits, whereas the ones for outcomes were obtained from a GWAS of 123 blood metabolites measured by nuclear magnetic resonance spectroscopy. We identified 413 potentially causal links between food and metabolites, replicating previous findings, such as the association between increased oily fish consumption and higher DHA, and highlighting several novel associations. Most of the associations were related to very-low-density, intermediate-density (IDL), and low-density lipoproteins (LDL). For example, we found that constituents of IDL particles and large LDL particles were raised by coffee and alcohol while lowered by an overall healthier diet and fruit consumption. Our findings provide a strong base of evidence for planning future RCTs aimed at understanding the role of diet in determining blood metabolite levels.

Incorporation of biochemical parameters and diagnostic algorithms in the laboratory computer system for the early detection of lipid abnormalities from the lipid units

IntroductionThe combination of biochemical markers, together with the design and implementation of diagnostic algorithms in laboratory computer systems could become very powerful tools in the stratification of cardiovascular risk. ObjectivesTo implement new biochemical markers and diagnostic algorithms not yet available, in order to provide an estimation of cardiovascular risk and the diagnostic orientation of lipid alterations. Material and methodsStudy of the implementation of Apolipoprotein B and Lipoprotein (a), as well as the inclusion of different diagnostic algorithms. This was carried out jointly by the different Lipid Units of the Spanish Society of Atherosclerosis, Hospital Virgen Macarena in Seville, Hospital Juan Ramon Jiménez, Hospital Infanta Elena, and Hospital de Rio Tinto during 2018 and 2019. ResultsThe four diagnostic algorithms entered into the Laboratory Information System (LIS), showed a total of 9985 patients with c-LDL >200 mg/dL. The diagnostic algorithm was extended to include Apo B, with 8182 determinations showing an Apolipoprotein B > 100 mg/dL). A total of 747 lipoprotein (a) were determined, of which 30.65% were >50 mg/dL. More than two-thirds (71.80%) showed results compatible with small and dense LDL particles. ConclusionsThe implementation of new analytical parameters and algorithms in Primary Care laboratory results can identify a considerable number of patients with different alterations in lipid metabolism. This, together with the classic risk factors, could contribute to a correct risk stratification in preventing the progression of CVD.