Triglyceride-rich Lipoproteins Research Articles

Glycoprotein and Lipoprotein Profiles Assessed by 1H-NMR and Its Relation to Ascending Aortic Dilatation in Bicuspid Aortic Valve Disease

The bicuspid aortic valve (BAV) confers a high risk of ascending aorta dilatation (AAoD), although its progression seems highly variable. Furthermore, the implication of lipoprotein metabolism and inflammation in the mechanisms that underlie AAoD is not fully established. The aim of this study consisted of evaluating the impact of the lipoprotein and glycoprotein profiles in AAOD as well as its progression in BAV aortopathy. Using 1H-nuclear magnetic resonance (1H-NMR), we analyzed and compared the lipoprotein and glycoprotein profiles of plasma samples from 152 BAV patients with dilated and nondilated ascending aorta. Additionally, these profiles were also compared for 119 of these patients who were prospectively followed-up clinically and by echocardiography in the long-term (5 years). Ascending aorta dilation velocity (mm/year) was calculated for this analysis. Several parameters related to the lipoprotein profile including remnant cholesterol, small LDL and IDL-cholesterol were found to be significantly increased in the dilated group compared to those in the nondilated group. The glycoprotein A-nuclear magnetic resonance (NMR) signal, a novel inflammation biomarker, was also observed to be increased in the dilated group. After performing multivariate analysis, remnant cholesterol remained an independent variable related to AAoD. In the long-term follow-up, proatherogenic lipoprotein parameters were related to ascending aorta dilatation velocity ascending. After a lineal regression analysis, non-HDL particles remained as an independent predictor of ascending aorta dilation velocity. Patients with BAV and AAoD presented a more pro-atherogenic profile assessed by 1H-NMR, especially related to triglyceride-rich lipoproteins. This pro-atherogenic profile seems to contribute to the higher growth rate of ascending aorta diameter.

Human apoA-I[Lys107del] mutation affects lipid surface behavior of apoA-I and its ability to form large nascent HDL

Population studies have found that a natural human apoA-I variant, apoA-I[K107del], is strongly associated with low HDL-C but normal plasma apoA-I levels. We aimed to reveal properties of this variant that contribute to its unusual phenotype associated with atherosclerosis. Our oil-drop tensiometry studies revealed that compared to WT, recombinant apoA-I[K107del] adsorbed to surfaces of POPC-coated triolein drops at faster rates, remodeled the surfaces to a greater extent, and was ejected from the surfaces at higher surface pressures on compression of the lipid drops. These properties may drive increased binding of apoA-I[K107del] to and its better retention on large triglyceride-rich lipoproteins, thereby increasing the variant’s content on these lipoproteins. While K107del did not affect apoA-I capacity to promote ABCA1-mediated cholesterol efflux from J774 cells, it impaired the biogenesis of large nascent HDL particles resulting in the formation of predominantly smaller nascent HDL. Size-exclusion chromatography of spontaneously reconstituted 1,2-dimyristoylphosphatidylcholine-apoA-I complexes showed that apoA-I[K107del] had a hampered ability to form larger complexes but formed efficiently smaller-sized complexes. CD analysis revealed a reduced ability of apoA-I[K107del] to increase α-helical structure on binding to 1,2-dimyristoylphosphatidylcholine or in the presence of trifluoroethanol. This property may hinder the formation of large apoA-I[K107del]-containing discoidal and spherical HDL but not smaller HDL. Both factors, the increased content of apoA-I[K107del] on triglyceride-rich lipoproteins and the impaired ability of the variant to stabilize large HDL particles resulting in reduced lipid:protein ratios in HDL, may contribute to normal plasma apoA-I levels along with low HDL-C and increased risk for CVD.

Role of omega-3 fatty acids in the prevention and treatment of cardiovascular Diseases: A consensus statement from the Experts' Committee Of National Society Of Cardiometabolic Medicine.

Low-density lipoprotein cholesterol (LDL-C) has been considered as the primary target for the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, there are still residual cardiovascular risks in some patients even if LDL-C achieves the target level. Emerging evidence suggestes that elevated triglyceride (TG) level or triglyceride-rich lipoprotein (TRL) cholesterol (TRL-C) is one of the important components of the residual cardiovascular risks. Omega-3 fatty acids have been shown to be one of the effective drugs for reducing TG. However, its efficacy in reducing the risk of ASCVD is inconsistent in large randomized clinical trials. There is lack of consensus among Experts regarding the application of omega-3 fatty acids in cardiovascular diseases including heart failure, arrhythmia, cardiomyopathy, hypertension, and sudden death. Hence, the current consensus will comprehensively and scientifically present the detailed knowledge about the omega-3 fatty acids from a variety of aspects to provide a reference for its management of omega-3 fatty acids application in the Chinese population.

Type 2 Diabetes mellitus alters the cargo of (poly)phenol metabolome and the oxidative status in circulating lipoproteins

The incidence of diabetes on the worldwide population has tripled in the past 5 decades. While drug-based therapies are valuable strategies to treat and ease the socio-economic burden of diabetes, nutritional strategies offer valuable alternatives to prevent and manage diabetes onset and contribute to the sustainability of health budgets. Whilst, intervention studies have shown that (poly)phenol-rich diets improve fasting glucose levels and other blood parameters, very little is known about the distribution of ingested polyphenols in circulation and the impact of diabetes on its cargo.In this study we investigate the impact of type 2 diabetes on the cargo of plasma (poly)phenols. Our results show that phenolic compounds are heterogeneously distributed in circulation though mainly transported by lipoprotein populations. We also found that diabetes has a marked effect on the phenolic content transported by VLDL resulting in the decrease in the content of flavonoids and consequently a decrease in the antioxidant capacity. In addition to the reduced bioavailability of (poly)phenol metabolites and increase of oxidative status in LDL and HDL populations in diabetes, cell-based assays show that sub-micromolar amounts of microbial (poly)phenol metabolites are able to counteract the pro-inflammatory status in glucose-challenged endothelial cells.Our findings highlight the relevance of triglyceride-rich lipoproteins in the transport and delivery of bioactive plant-based compounds to the endothelium in T2DM supporting the adoption of nutritional guidelines as an alternative strategy to drug-based therapeutic approaches.

Prognostic Significance of Hypertriglyceridemia in Patients at High and Very High Cardiovascular Risk Depending on the Concentration of Highsensitivity C-reactive Protein.

It has been established that an increase in triglyceride-rich lipoprotein levels is associated with the development of systemic low-grade inflammation. Data on the prognostic role of hypertriglyceridemia (HTG) dependent on the state of low-grade inflammation are limited. The study's objective was to evaluate the predictive value of mild-to-moderate HTG (2.3- 11.2 mmol/L) regarding the development of cardiovascular events in patients at high and very high cardiovascular risk (CVR), depending on the high-sensitivity C-reactive protein (hsCRP) values. The study included 185 patients with high and very high CVR. The concentration of hsCRP in blood serum was measured using an enzyme-linked immunosorbent assay kit. The combined endpoint was cardiovascular death, nonfatal myocardial infarction or unstable angina (which required hospitalization), nonfatal stroke, and coronary revascularization. HTG was revealed in 17.3% of the patients. An increase in hsCRP ≥2.0 mg/L was observed in 51.9% of the patients. The event-free survival of patients with HTG was not statistically different from that in patients with TG <2.3 mmol/L (RR 1.61; 95% CI 0.86-3.00; p=0.133). In the subgroup of patients with hsCRP <2.0 mg/L, patients with HTG were not significantly different from patients without HTG. In the subgroup of patients with hsCRP≥2.0 mg/L, the presence of HTG was associated with a 4.63 times increase in the RR of adverse cardiovascular events (95% CI 1.35-15.8; p=0.015) after adjusting for potential confounders. In patients with high and very high CVR, an increase in TG ≥2.3 mmol/L was associated with the development of adverse cardiovascular events only in the subgroup of patients with an increase in hsCRP ≥2.0 mg/L. The presence of HTG was associated with a 4.63 times increase in RR of adverse cardiovascular events (95% CI 1.35-15.8; p=0.015).

Cardio protective effect of intermittent fasting on the lumen area ratio of the coronary artery in rats with a high-calorie diet

Atherosclerosis is a principal cause of coronary artery disease (CAD), one of the major causes of global premature mortality and morbidity. The glycolysis pathway will process excess carbohydrates in a high-calorie diet (HCD) into triglycerides, which, if accumulated, will cause an increase in the concentration of atherogenic triglyceride-rich lipoproteins. Therefore, intermittent fasting (IF) is a recommended lifestyle to prevent CAD through metabolic reprogramming pathways. This study was designed to evaluate the cardioprotective effect of eight weeks of IF 5:2 on the lumen area ratio of the coronary artery in rats with four weeks of HCD. A total of 24 Wistar male albino rats were divided into SD (standard diet), IF (IF 5:2), HCD (daily injection 0.013 g/gBW glucose), and IF-HCD (IF 5:2 and HCD). At the end of the experiment, all the rats were sacrificed. The coronary artery preparations were stained with H&amp;E stain, then evaluated with the OLYMPUS cellSens Standard to measure the arterial lumen area. The statistical analysis was done using Brown Forsythe test. In this study, no significant differences between all groups, and the effect of IF will only be seen if an HCD intervention has a significant effect. However, the IF group achieved the highest mean in the arterial lumen area ratio (SD=0.526±0.097; IF=0.631±0.021; HCD=0.611±0.064; IF-HCD=0.594±0.060). In conclusion, IF 5:2 may have a cardioprotective effect in healthy individuals, but the effect is unknown in individuals with HCD.

Dietary and Physiological Factors Affecting Lipid Metabolism and Cardiovascular Risk.

Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide. The risk of developing CVD is associated with an unhealthy lifestyle. A high level of low-density lipoprotein (LDL) cholesterol (LDL-C) is a primary risk factor for ASCVD. However, even if the LDL-C management target has been achieved, hypertriglyceridemia and a high level of total cholesterol minus high-density lipoprotein (HDL) cholesterol (non-HDL-C), which contains cholesterol concentrations of triglyceride-rich lipoproteins, are considered a significant residual risk factor for ASCVD and consequently the management of these conditions is important for controlling the residual risk for ASCVD.

The novel inflammatory biomarker GlycA and triglyceride-rich lipoproteins are associated with the presence of subclinical myocardial dysfunction in subjects with type 1 diabetes mellitus

BackgroundSubjects with Type 1 diabetes mellitus (T1DM) have an increased incidence of heart failure (HF). Several pathophysiological mechanisms have been involved in its development. The aim of this study was to analyze the potential contribution of the advanced lipoprotein profile and plasma glycosylation (GlycA) to the presence of subclinical myocardial dysfunction in subjects with T1DM.MethodsWe included subjects from a Danish cohort of T1DM subjects (Thousand & 1 study) with either diastolic and/or systolic subclinical myocardial dysfunction, and a control group without myocardial dysfunction, matched by age, sex and HbA1c. All underwent a transthoracic echocardiogram and an advanced lipoprotein profile obtained by using the NMR-based Liposcale® test. GlycA NMR signal was also analyzed. Systolic dysfunction was defined as left ventricular ejection fraction ≤ 45% and diastolic dysfunction was considered as E/e′≥12 or E/e′ 8–12 + volume of the left atrium > 34 ml/m2. To identify a metabolic profile associated with the presence of subclinical myocardial dysfunction, a multivariate supervised model of classification based on least squares regression (PLS-DA regression) was performed.ResultsOne-hundred forty-six subjects had diastolic dysfunction and 18 systolic dysfunction. Compared to the control group, patients with myocardial dysfunction had longer duration of diabetes (p = 0.005), and higher BMI (p = 0.013), serum NTproBNP concentration (p = 0.001), systolic blood pressure (p < 0.001), albuminuria (p < 0.001), and incidence of advanced retinopathy (p < 0.001). The supervised classification model identified a specific pattern associated with myocardial dysfunction, with a capacity to discriminate patients with myocardial dysfunction from controls. PLS-DA showed that triglyceride-rich lipoproteins (TGRLs), such as VLDL (total VLDL particles, large VLDL subclass and VLDL-TG content) and IDL (IDL cholesterol content), as well as the plasma concentration of GlycA, were associated with the presence of subclinical myocardial dysfunction.ConclusionProatherogenic TGRLs and the proinflammatory biomarker Glyc A are strongly associated to myocardial dysfunction in T1DM. These findings suggest a pivotal role of TGRLs and systemic inflammation in the development of subclinical myocardial dysfunction in T1DM.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk

BackgroundHigh triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator–activated receptor α modulator, reduces triglyceride levels and improves other lipid levels.MethodsIn a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes.ResultsAmong 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were −26.2% for triglycerides, −25.8% for very-low-density lipoprotein (VLDL) cholesterol, −25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), −27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease.ConclusionsAmong patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)

Early metabolomic, lipid and lipoprotein changes in response to medical and surgical therapeutic approaches to obesity

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to explore the early metabolomic changes in response to GLP-1RA (liraglutide) therapy vs. placebo and in comparison to bariatric surgery. MethodsThree clinical studies were conducted: a bariatric surgery cohort study of participants with morbid obesity who underwent either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) studied over four and twelve weeks, and two randomized placebo-controlled, crossover double blind studies of liraglutide vs. placebo administration in participants with type 2 diabetes (T2D) and participants with obesity studied for three and five weeks, respectively. Nuclear magnetic resonance spectroscopy-derived metabolomic data were assessed in all eligible participants who completed all the scheduled in-clinic visits. The primary outcome of the study was to explore the changes of the metabolome among participants with obesity with and without T2D receiving the GLP-1RA liraglutide vs. placebo and participants with obesity undergoing bariatric surgery during the three to five-week study period. In addition, we assessed the bariatric surgery effects longitudinally over the twelve weeks of the study and the differences between the bariatric surgery subgroups on the metabolome. The trials are registered with ClinicalTrials.gov, numbers NCT03851874, NCT01562678 and NCT02944500. ResultsBariatric surgery had a more pronounced effect on weight and body mass index reduction (−14.19 ± 5.27 kg and − 5.19 ± 5.27, respectively, p < 0.001 for both) and resulted in more pronounced metabolomic and lipidomic changes compared to liraglutide therapy at four weeks postoperatively. Significant changes were observed in lipoprotein parameters, inflammatory markers, ketone bodies, citrate, and branched-chain amino acids after the first three to five weeks of intervention. After adjusting for the amount of weight loss, a significant difference among the study groups remained only for acetoacetate, β-hydroxybutyrate, and citrate (p < 0.05 after FDR correction). Glucose levels were significantly reduced in all intervention groups but mainly in the T2D group receiving GLP-1RA treatment. After adjusting for weight loss, only glucose levels remained significant (p = 0.001 after FDR correction), mainly due to the glucose change in the T2D group receiving GLP-1RA. Similar results with those observed at four weeks were observed in the surgical group when delta changes at twelve weeks were assessed. Comparing the two types of bariatric surgery, an intervention effect was more pronounced in the RYGB subgroup regarding total triglycerides, triglyceride-rich lipoprotein size, and trimethylamine-N-oxide (p for intervention: 0.031, 0.028, 0.036, respectively). However, after applying FDR correction, these changes deemed to be only suggestive; only time effects remained significant with no significant changes persisting in relation to the types of bariatric surgery. ConclusionsThe results of this study suggest that the early metabolomic, lipid and lipoprotein changes observed between liraglutide treatment and bariatric surgery are similar and result largely from the changes in patients' body weight. Specific changes observed in the short-term post-surgical period between bariatric vs. nonsurgical treated participants, i.e., acetoacetate, β-hydroxybutyrate, and citrate changes, may reflect changes in patient diets and calorie intake indicating potential calorie and diet-driven metabolomics/lipidomic effects in the short-term postoperatively. Significant differences observed between SG and RYGB need to be confirmed and extended by future studies.

ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis.

Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) or remnants are important risk factors for the development of atherosclerotic cardiovascular disease (ASCVD). The ongoing challenge of not being able to achieve recommended LDL-C targets despite maximally tolerated lipid-lowering therapy (LLT) has led to the development of novel therapeutic agents including angiopoietin-like 3 (ANGPTL3) inhibitors. ANGPTL3 is a glycoprotein produced by the liver that inhibits lipoprotein lipase and endothelial lipase. Data from genetic and clinical studies have shown that a lower ANGPTL3 level is associated with lower plasma LDL-C, triglyceride (TG), and other lipoproteins. Pharmacological inactivation of ANGPTL3 with the monoclonal antibody, evinacumab, results in a 50% reduction in LDL-C, even in patients with homozygous familial hypercholesterolemia (HoFH). The safe and effective targeted delivery of nucleic acid-based therapies will shape the future of the lipid arena. ANGPTL3 is a novel target in lipoprotein metabolism, targeting not only LDL-C via an LDL-receptor (LDLR) independent mechanism but also TRLs and carries a significant promise for further ASCVD risk reduction.

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins.

The copper metabolism MURR1 domains/coiled-coil domain containing 22/coiled-coil domain containing 93 (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear. We here investigated the contribution of retriever to hepatocytic lipoprotein receptor recycling and plasma lipids regulation. Using somatic CRISPR/Cas9 gene editing, we generated liver-specific VPS35L or VPS26C-deficient mice. We determined total and surface levels of LDLR and LRP1 and plasma lipids. In addition, we studied the protein levels and composition of CCC and retriever. Hepatocyte VPS35L deficiency reduced VPS26C levels but had minimal impact on CCC composition. VPS35L deletion decreased hepatocytic surface expression of LDLR and LRP1, accompanied by a 21% increase in plasma cholesterol levels. Hepatic VPS26C ablation affected neither levels of VPS35L and CCC subunits, nor plasma lipid concentrations. However, VPS26C deficiency increased hepatic LDLR protein levels by 2-fold, probably compensating for reduced LRP1 functioning, as we showed in VPS26C-deficient hepatoma cells. Upon PCSK9 (proprotein convertase subtilisin/kexin type 9)-mediated LDLR elimination, VPS26C ablation delayed postprandial triglyceride clearance and increased plasma triglyceride levels by 26%. Our study suggests that VPS35L is shared between retriever and CCC to facilitate LDLR and LRP1 transport from endosomes to the cell surface. Conversely, retriever subunit VPS26C selectively transports LRP1, but not LDLR, and thereby may control hepatic uptake of postprandial triglyceride-rich lipoprotein remnants.

Abstract 14379: The Association of Triglyceride-Rich Lipoproteins With Cognitive Function: ELSA-Brazil (the Brazilian Longitudinal Study of Adult Health)

Background: Plasma triglyceride levels correspond to the sum of the triglyceride (TG) content in triglyceride-rich lipoproteins (TRL) and their remnants. Experimental studies have shown TRL adverse effects in the brain, but there is limited data about their role in cognitive function. We investigated the cross-sectional association of TG and TRL-cholesterol with domain-specific cognitive tests. Methods: A total of 4,443 participants (51±9 years, 54,2% women) without previous cerebrovascular disease and not on lipid-lowering drugs were evaluated using the delayed word recall test, the category fluency test and the trail making test. TRL were measured by the Vertical Auto Profile (VAP) test, an ultracentrifugation method, and TG by the conventional method. Then, we constructed multiple linear regression models to analyze these associations. Results: The mean TRL level was 32.1±12.2 mg/dl, and the median (IQR) TG was 109 (79-153) mg/dl. There was a negative association between TRL and global cognitive z-score after adjustment for age, sex, ethnicity, education, smoking status, physical activity, alcohol use, depression, systolic blood pressure, diabetes, thyrotropic hormone, LDL, HDL, TG and waist circumference (p=0.009), due to the inverse association with trail making test (p=0.009). We found no association between TG with any cognition tests after adjustment. Conclusion: TRL levels measured by VAP are independently associated with the global cognitive and executive function. TG was not associated with cognitive performance.

Abstract 12864: Nuclear Magnetic Resonance Lipoprotein Particle Subclasses Associate With Chronic Inflammatory Related Diseases Differently Than Cardiovascular Diseases: The Multi-Ethnic Study of Atherosclerosis

Introduction: Chronic inflammatory related disease (ChrIRD) is a novel outcome capturing non-cancer, non-cardiovascular clinical events driven by subclinical inflammation. Derangements in triglyceride-rich, low-density, and high-density lipoprotein particle (TRLp, LDLp, HDLp) subclass concentrations known to associate with inflammation and future cardiovascular disease have not been extensively evaluated in ChrIRD. Hypothesis: Lipoprotein particle subclasses may predict future ChrIRD in a similar direction and magnitude as with CVD. Methods: We measured 17 lipoprotein subclass particle concentrations by NMR spectroscopy in the Multi-Ethnic Study of Atherosclerosis (MESA). MESA is a US cohort including 6,759 White (38.6%), Chinese (11.9%), Black (27.6%), and Hispanic (22%) men and women initially aged 45-84 years and free of CVD. Participants were contacted at least annually to ascertain clinical events. Incident CVD (MI, Stroke, PAD, CV Death) and ChrIRD death/hospitalization risk per-quartile of lipoprotein marker levels were evaluated using disease-specific multivariable Cox regression models adjusted for traditional risk factors. Results: Disparate risk associations with ChrIRD and CVD were observed (Figure). Elevated small HDLp, total LDLp, and small TRLp, and were inversely associated with ChrIRD events. Additionally, larger TRLp size was associated higher ChrIRD risk. Metrics of HDL, LDL, and TRL associations with incident CVD as expected. In contrast, Very large TRLp was inverse with both clinical outcomes (HR [95% CI] CVD: 0.83 [0.75-0.96] ptrend=0.09, ChrIRD: 0.85 [0.69-0.99], ptrend =0.02). Conclusions: TRL, LDL, and HDL particles differentially associate with CVD and ChrIRD. Established predictors of CVD, including total TRL and LDL particles, small LDL, and large /medium TRL, may be inert or even protective in development of ChrIRD events due to distinct pathophysiologic contributions that warrant further investigation.

Abstract 15399: Proteomic Landscape of Plasma Lipoprotein Responses to Regular Exercise

Introduction: Lipoproteins are among the strongest predictors of CVD and are altered through regular exercise. However, the molecular changes underlying the potential benefits of exercise on plasma lipoproteins are unclear. Methods: Proteins (n=4979) were quantified from the plasma of 647 Black and White adults (56% women, mean age = 34.9 yrs) before and after 20-weeks of endurance exercise training using SomaScan. All subjects had complete data for 7 lipoprotein traits that improved with training: HDL-C, TG, large TG rich lipoprotein particles (LTRLP), small LDL particles (SLDLP), large HDL particles (LHDLP), TRLP size, and LDLP size. Fully adjusted linear mixed models were used to test the association of 1) baseline proteins with baseline lipoproteins and 2) delta proteins with delta lipoproteins (delta = post training - baseline value). Significance was determined as FDR&lt;0.05. Results: We identified numerous proteins associated with baseline levels of at least one of the seven lipoprotein traits (range: 48-1099) and whose changes in response to regular exercise were associated with concomitant changes in lipoproteins (range: 4-95) ( Table 1 ). Substantial overlap was found between proteins associated with lipoproteins across timepoints, with 16 proteins associated with 4 or more lipoprotein traits at both timepoints. Plasma abundance of 12/16 proteins significantly changed with training (FDR &lt;0.05). Additionally, for these proteins plasma abundance changed in concordance with the beneficial direction of the associated lipoprotein trait (e.g., proteins associated with atheroprotective lipoprotein traits increased with training and proteins associated with atherogenic traits decreased). Conclusions: Beneficial alterations to plasma lipoproteins with regular exercise are reflected in changes to the plasma proteome. Proteins identified here may represent novel markers of the benefits of regular exercise and of systemic lipoprotein metabolism.

Abstract 15518: The Effects of High Glucose and Lipoprotein Lipase on Macrophage Regulatory Function

Introduction: Atherosclerosis has an established inflammatory, macrophage(MФ)-mediated component which can be exacerbated by uncontrolled diabetes. However, there are also protective, regulatory MФ processes that can help quell atherosclerosis. Lipoprotein Lipase (LPL) on the MФ surface hydrolyzes circulating triglyceride-rich lipoproteins into glycerol and free fatty acids to provide a non-glucose energy source. Hypothesis: We hypothesized that regulatory MФs have high LPL activity, which could promote fatty acid metabolism to drive inflammation-resolving functions, and that this LPL activity is inhibited by ambient glucose. Methods and Results: MФs were cultured and differentiated from bone marrow harvested from wild-type mice aged 9-16 weeks. Two weeks after harvest, these MФs were polarized with (1) interferon-γ and lipopolysaccharide to stimulate classically-activated, inflammatory MФs or (2) interleukin-4 to stimulate alternatively-activated, regulatory MФs. The resulting phenotypes were validated by canonical transcript markers (Tnfa/Nos2 for inflammatory MФs and Ym1/Arg1 for regulatory MФs) and cell surface markers (CD86 and CD206, respectively). Using a triglyceride analog that fluoresces when cleaved by LPL, we found that regulatory MФs have far greater LPL activity than inflammatory macrophages at baseline (33 ± 2 vs 1 ± 0.2 a.u., p &lt; 0.001, n=8). By varying glucose concentration during the polarization, this effect was most pronounced at normal, physiological concentrations of glucose (5 mM, ~90 mg/dL) and blunted at a high-glucose concentration that can be found in uncontrolled diabetes (25 mM). We also report on lipoxygenase expression and specialized pro-resolving mediator production as effector functions downstream of LPL activity in regulatory MФs. Conclusions: Taken together, our findings support a model in which regulatory MФs are programmed to utilize LPL to drive the inflammation-resolving phenotype and that this process works best at low, physiologic glucose concentrations. Future translational work will investigate whether a lack of LPL-mediated regulatory MФ function is a reason why patients with uncontrolled diabetes have higher atherosclerotic burden and plaque instability.

Abstract 11601: Association Between Remnant Cholesterol and Coronary Plaque Features: The Miami Heart Study at Baptist Health South Florida

Introduction: Remnant particles, the product of partial metabolism of triglyceride-rich lipoproteins, have been associated with atherosclerotic cardiovascular diseases (ASCVD), independent of low-density lipoprotein cholesterol (LDL-C). This study aims to further examine the role of remnant cholesterol (RC) in atherogenesis by assessing its association with plaque characteristics. Methods: After excluding individuals on statin therapy (n=527), we included 1,832 statin-naïve participants from the Miami Heart Study, a prospective cohort of clinical ASCVD-free individuals in Miami (2015-2018) evaluated using coronary computed tomography angiography (CTA). RC was estimated as non-high density lipoprotein cholesterol minus LDL-C. Multivariable logistic regression models were used to estimate the association between low/high RC/LDL-C groups (defined by &lt; or ≥ medians) and plaque features. Results: Mean age of participants was 52.5±6.7 years, 54% women, 49.5% Hispanic. Median LDL-C and RC were 129.1 and 21.6 mg/dL, respectively. For each SD increase in RC levels, the odds of having non-calcified coronary plaque increased (OR 1.19 [95% CI 1.07-1.33]) and so did the segmental involvement score (OR 1.05 [95% CI 1.01-1.09]) independent of traditional risk factors including LDL-C. The prevalence of coronary plaque features per RC/LDL-C group are shown in Table. Among those with low LDL-C, having high RC conferred a significantly higher risk of non-calcified plaque (OR 1.61 [95% CI 1.11-2.32]) compared to having low RC, although associations were not statistically significant with other plaque features (Table). Conclusions: In asymptomatic individuals with low LDL-C, elevated RC was independently associated with non-calcified plaque.

Abstract 14556: Deep Phenotyping APOC3 Knockouts in a Population With High Consanguinity

Apolipoprotein C-III (APOC3) plays an integral role in the regulation of triglyceride-rich lipoproteins, by inhibiting the clearance of triglycerides carried by VLDL and chylomicron remnants in the blood. Prior work has shown that heterozygous loss of function (LOF) carriers of APOC3 have lower triglyceride levels and a lower risk of coronary artery disease (CAD). The quantitative impact of disease risk remains unknown in complete knockouts (KOs). Additionally, the effects and safety implications of complete APOC3 LOF have not been characterized. APOC3 inhibition is an active therapeutic strategy to lower CAD risk; hence these questions have therapeutic relevance. Among 37,244 unrelated sequenced individuals, including 19,681 cases of myocardial infarction (MI), in the Pakistan Genomic Resource - a biobank with high levels of consanguinity - we identified 207 heterozygous LOF carriers and 14 KOs. As expected, the KOs had undetectable APOC3 levels. We also observed a decrease in plasma triglycerides (P = 9E-85), VLDL-C levels (P = 2E-73), APOE levels (P = 5.4E-9) and an increase in HDL-C levels (P = 1E-34) and APOA1 levels (P = 6E-5) consistent with a gene-dosage effect. We observed a significant decrease in the risk of MI among heterozygous carriers (P = 0.01); however, we did not observe any protection from MI risk in complete KOs. Conversely, we observed a non-significant increase in the risk of MI in complete KOs compared to non-carriers; of the 14 knockouts identified, 9 were found to have MI. The loss of protection against MI could not be explained by the genetic background or by the increase in levels of homozygosity of the KOs. By recalling complete KOs and their family members, we were able to identify and phenotype an additional 33 complete KOs and 152 heterozygotes and assess other safety concerns related to complete APOC3 inhibition (i.e., glucose intolerance, fat content in the liver, etc.). In conclusion, by leveraging a highly consanguineous cohort, we have identified and phenotyped APOC3 KOs that have, hitherto, not been identified elsewhere. We did not observe APOC3 LOF to confer protection in complete KOs and observed other biomarker and phenotypic associations; these findings should inform existing therapeutic programs targeting APOC3.

Correlation of Triglyceride-Rich Lipoprotein Cholesterol and Diabetes Mellitus in Stroke Patients.

Previous studies have revealed that triglyceride-rich lipoprotein cholesterol (TRL-c) is closely related to diabetes mellitus (DM) in hypertensive patients. However, this relationship in stroke patients has not been reported. The aims of this study are to investigate the relationship between TRL-c and diabetes in adult Chinese stroke. Patients with stroke treated in the Department of Neurology of the Second Affiliated Hospital of Nanchang University from January 2019 to January 2021 were selected. TRL-c was calculated from total cholesterol minus (high-density and low-density lipoprotein). DM was diagnosed based on previous medical history (diagnosed by secondary hospitals or above) and/or current use of hypoglycemic drugs and/or intravenous blood glucose measurement (fasting blood glucose ≥7.0 mmol/L or nonfasting blood glucose > 11.1 mmol/L). The relationship between the TRL-c and DM was determined using multivariate logistic regression, smoothing curve fitting (penalized spline method), and subgroup analysis. A total of 890 patients with stroke (age, 66.1 ± 11.8 years) were enrolled, including 329 females. Multivariate logistic regression analysis demonstrated that TRL-c had a positive association with DM (OR 1.88; 95% CI: 1.22 to 2.89). Strong linear associations of TRL-c with DM were confirmed by restricted cubic spline analysis. And the association between TRL-c and DM was consistent in the different subgroups. Positive associations were found between TRL-c and DM in patients with stroke.

Sugar-Sweetened Beverage Consumption and Plasma Lipoprotein Cholesterol, Apolipoprotein, and Lipoprotein Particle Size Concentrations in US Adults

Prospective cohort studies have found a relation between sugar-sweetened beverage (SSB) consumption (sodas and fruit drinks) and dyslipidemia. There is limited evidence linking SSB consumption to emerging features of dyslipidemia, which can be characterized by variation in lipoprotein particle size, remnant-like particle (RLP), and apolipoprotein concentrations. To examine the association between SSB consumption and plasma lipoprotein cholesterol, apolipoprotein, and lipoprotein particle size concentrations among US adults. We examined participants from the Framingham Offspring Study (FOS; 1987-1995, n = 3047) and the Women's Health Study (1992, n = 26,218). Concentrations of plasma LDL cholesterol, apolipoprotein B (apoB), HDL cholesterol, apolipoprotein A1 (apoA1), triglyceride (TG), and non-HDL cholesterol, as well as total cholesterol:HDL cholesterol ratio and apoB:apoA1 ratio, were quantified in both cohorts; concentrations of apolipoprotein E, apolipoprotein C3, RLP-TG, and RLP cholesterol (RLP-C) were measured in the FOS only. Lipoprotein particle sizes were calculated from nuclear magnetic resonance signals for lipoprotein particle subclass concentrations (TG-rich lipoprotein particles [TRL-Ps]: very large, large, medium, small, and very small; LDL particles [LDL-Ps]: large, medium, and small; HDL particles [HDL-Ps]: large, medium, and small). SSB consumption was estimated from food frequency questionnaire data. We examined the associations between SSB consumption and all lipoprotein and apoprotein measures in linear regression models, adjusting for confounding factors such as lifestyle, diet, and traditional lipoprotein risk factors. SSB consumption was positively associated with LDL cholesterol, apoB, TG, RLP-TG, RLP-C, and non-HDL cholesterol concentrations and total cholesterol:HDL cholesterol and apoB:apoA1 ratios; and negatively associated with HDL cholesterol and apoA1 concentrations (P-trend range: <0.0001 to 0.008). After adjustment for traditional lipoprotein risk factors, SSB consumers had smaller LDL-P and HDL-P sizes; lower concentrations of large LDL-Ps and medium HDL-Ps; and higher concentrations of small LDL-Ps, small HDL-Ps, and large TRL-Ps (P-trend range: <0.0001 to 0.001). Higher SSB consumption was associated with multiple emerging features of dyslipidemia that have been linked to higher cardiometabolic risk in US adults.