Remnant Lipoprotein Cholesterol Levels Research Articles

The effects of endurance physical exercise with fat-free milk intake as a therapy for metabolic syndrome and/or sarcopenia

Background: Nutrition and exercise are important factors for addressing metabolic syndrome and sarcopenia as they are related to insulin secretion. Proteins, particularly branched-chain amino acids (BCAAs), have insulinotropic effects, while exercise reduces insulin secretion. It is thus important to investigate the effects of protein intake and exercise alone and in combination to determine suitable dietary and exercise therapies for treating metabolic syndrome and sarcopenia. Methods: Eight healthy young adult female volunteers participated in a crossover trial consisting of two 5-day experiments. Days 1 and 2 comprised a body-weight-maintained adjustment period during which the participants consumed control diets (energy, 2,010 kcal; protein, 51.9 g). Days 3 to 5 comprised the treatment period during which the participants consumed experimental diets (energy, 2,010 kcal; protein 82.3 g) containing 402 kcal of fat-free milk, and either performed only normal daily activities (non-Ex) or performed normal daily activities and exercised on a bicycle with an ergometer at a target intensity of about 50% of the maximal oxygen intake, expending 402 kcal of additional energy (Ex). Total urine samples were collected during the daytime (6:45 to 18:45) and nighttime (18:45 to 6:45 the next morning). Fasting blood samples were collected early in the morning before and after the treatment period. Results: Plasma valine, leucine, and BCAA levels were significantly elevated after both the non-Ex and Ex periods. Serum insulin levels were significantly elevated only after the non-Ex period. Urinary C-peptide immunoreactivity excretion levels increased significantly during the non-Ex period, but they decreased significantly during the Ex period. After the Ex period, the serum triglyceride and remnant lipoprotein-cholesterol (RLP-C) levels were significantly decreased. Homeostatic model assessment for insulin resistance (HOMA-IR) and atherosclerosis index (AI) values were slightly, yet significantly, increased after the non-Ex period, but were unchanged after the Ex period. The degree of change (Δ) in the RLP-C level significantly and positively correlated with the Δ HOMA-IR and Δ AI.

Abstract 17244: Association of Remnant Lipoprotein Cholesterol, Type 2 Diabetes Mellitus, and Major Adverse Cardiovascular Events: Insights From the UK Biobank

Background: Remnant lipoprotein-cholesterol (RLP-C) has emerged as a potential contributor to adverse cardiovascular events. While the association of low-density lipoprotein- cholesterol and atherosclerotic cardiovascular disease is well-established, the joint association of RLP-C and type 2 diabetes mellitus (T2DM) in driving major adverse cardiovascular events (MACE) remains less explored. Methods: We included a total of 118,004 participants from the UK Biobank with nuclear magnetic resonance-measured RLP-C. Participants were categorized into four groups based on their RLP-C levels and T2DM status: Group 1 (RLP-C below the median and no T2DM), Group 2 (RLP-C above the median and no T2DM), Group 3 (RLP-C below the median and T2DM), and Group 4 (RLP-C above the median and T2DM). Cox proportional hazards regression was employed to assess the association of these four categories with the time to incident MACE. The model was adjusted for age, sex, race, BMI, smoking, systolic blood pressure, anti-hypertensive and lipid-lowering therapy, and physical activity. Results: Our analysis revealed significant associations between RLP-C levels, T2DM, and the risk of MACE. Compared to the reference group (Group 1), Groups 2-4 had hazard ratio for the MACE outcome of 1.27 (95% CI: 1.18-1.37, p < .0001), 1.43 (95% CI: 1.29-1.59, p < .0001), and 2.04 (95% CI: 1.78-2.32, p < .0001), respectively (see Figure). Conclusion: This analysis from individuals in UK Biobank free from cardiovascular disease at baseline demonstrated a significant joint association between elevated RLP-C levels and T2DM, with the risk of major adverse cardiovascular events. Keywords: remnant lipoprotein cholesterol, type 2 diabetes mellitus, major adverse cardiovascular events, UK Biobank, nuclear magnetic resonance

Association between remnant lipoprotein cholesterol levels and risk of non-alcoholic fatty liver disease in non-obese populations: a Chinese longitudinal prospective cohort study

ObjectivesThe association between remnant lipoprotein cholesterol (RLP-C) levels and the incidence of non-alcoholic fatty liver disease (NAFLD) is unclear, especially in non-obese populations.SettingWe used data from a health assessment database....

Assessment of Remnant Lipoprotein Cholesterol and Oxidized Low density Lipoprotein Associated with Low-grade Inflammation in Coronary Heart Disease Subjects of Young South Indian Population.

Coronary heart disease (CHD) is a major disease entity responsible for significant mortality and morbidity in the Indian population. The prevalence of CHD is increasing day by day in India. The hardening of arteries is linked to oxidative variations in low-density lipoproteins (LDLs). Modification of LDL to oxidized LDL (ox-LDL) is a crucial step in the oxidation hypothesis of atherogenesis. Oxidized LDL and remnant lipoprotein cholesterol (RLP-C) stimulate the immune and inflammatory reactions and promote atherosclerosis. Because of its lesser size along with high cholesterol content, and increased residence period in blood the remnant lipoproteins are highly atherogenic. Remnant lipoproteins transport more cholesterol to macrophages compared to LDL particles. Remnant lipoproteins enter into the arterial wall easily and are taken up directly by macrophages. This leads to the formation of foam cells, thus initiating the lipid-laden plaque. High sensitive C-reactive protein acts as a nonspecific inflammatory marker. Oxidized LDL along with RLP-C and high-sensitivity C-reactive protein (hs-CRP) play crucial role in progression of CHD. The aim of the study is to assess ox-LDL and RLP-C associated with hs-CRP as potential biomarkers in the development of CHD. This cross-sectional study was conducted in Sri Ramaswamy Memorial Medical College Hospital and Research Centre on subjects appearing for master health check-up and medicine. This cross-sectional study was conducted on 273 subjects who were age and sex match in the age group of ≤45 years. 91 Non-Diabetic subjects with CHD, 91 Diabetic subjects with CHD, and 91 normal healthy subjects were selected as control. After overnight fasting, body fluid samples were collected for analysis for lipid profile, ox-LDL, and hs-CRP. Oxidized LDL and hs-CRP were measured by enzyme-linked immunosorbent assay (ELISA) method and lipid profile was measured using Auto Analyser AU480. Statistical analysis was done using Student's t-test and Pearson's correlation analysis for the comparison between two groups. The mean level of ox-LDL, RLP-C, and hs-CRP was significantly elevated in CHD group. A significantly positive correlation was observed between plasma ox-LDL, RLP-C, and hs-CRP. These results suggest that the link between high ox-LDL, RLP-C, and hs-CRP levels might be interrelated to atherogenesis in subjects with CHD. In addition to conventional parameters, ox-LDL, RLP-C, and hs-CRP can prove to be a valuable tool in risk assessment of CHD. Journal of the Association of Physicians of India (2022): 10.5005/japi-11001-0009.

Remnant lipoprotein cholesterol is associated with incident new onset diabetes after transplantation (NODAT) in renal transplant recipients: results of the TransplantLines Biobank and cohort Studies

BackgroundNew onset diabetes after transplantation (NODAT) is a frequent and serious complication of renal transplantation resulting in worse graft and patient outcomes. The pathophysiology of NODAT is incompletely understood, and no prospective biomarkers have been established to predict NODAT risk in renal transplant recipients (RTR). The present work aimed to determine whether remnant lipoprotein (RLP) cholesterol could serve as such a biomarker that would also provide a novel target for therapeutic intervention.MethodsThis longitudinal cohort study included 480 RTR free of diabetes at baseline. 53 patients (11%) were diagnosed with NODAT during a median [interquartile range, IQR] follow-up of 5.2 [4.1–5.8] years. RLP cholesterol was calculated by subtracting HDL and LDL cholesterol from total cholesterol values (all directly measured).ResultsBaseline remnant cholesterol values were significantly higher in RTR who subsequently developed NODAT (0.9 [0.5–1.2] mmol/L vs. 0.6 [0.4–0.9] mmol/L, p = 0.001). Kaplan-Meier analysis showed that higher RLP cholesterol values were associated with an increased risk of incident NODAT (log rank test, p < 0.001). Cox regression demonstrated a significant longitudinal association between baseline RLP cholesterol levels and NODAT (HR, 2.27 [1.64–3.14] per 1 SD increase, p < 0.001) that remained after adjusting for plasma glucose and HbA1c (p = 0.002), HDL and LDL cholesterol (p = 0.008) and use of immunosuppressive medication (p < 0.001), among others. Adding baseline remnant cholesterol to the Framingham Diabetes Risk Score significantly improved NODAT prediction (change in C-statistic, p = 0.01).ConclusionsThis study demonstrates that baseline RLP cholesterol levels strongly associate with incident NODAT independent of several other recognized risk factors.

Associations between remnant lipoprotein cholesterol and central systolic blood pressure in a Chinese community-based population: a cross-sectional study

BackgroundThe lipid profile is reportedly related to peripheral blood pressure or pulse wave velocity. However, no studies have investigated the associations between lipid parameters, especially remnant lipoprotein cholesterol (RLP-C), and central systolic blood pressure (cSBP).MethodsThis study used baseline data of a community-based cohort in Beijing, China. Participants who had been treated with anti-hypertensive or lipid-lowering agents were excluded. RLP-C is equal to total cholesterol (TC) minus the sum of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). An Omron HEM-9000AI device was used to measure non-invasive cSBP. The associations between blood lipid profile and non-invasive cSBP were evaluated using multivariable regression models.ResultsThe 5173 included participants were 55.0 ± 8.5 years old; 35.7% (1845) of participants were men. Increased cSBP was significantly associated with increased TC, LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), triglyceride (TG), and RLP-C but with decreased HDL-C, even after adjusting for possible covariates. When simultaneously entering individual pairs of RLP-C and other blood lipid parameters into the multivariable regression model, RLP-C remained significantly associated with cSBP, even after adjusting for other lipids. Compared with participants who had RLP-C levels in the first quartile (Q1), cSBP for those with RLP-C in Q4 was increased to 4.57 (95% confidence interval [CI]: 3.08–6.06) mmHg after adjusting for LDL-C, 4.50 (95%CI: 2.98–6.02) mmHg after adjusting for TC, 3.91 (95%CI: 1.92–5.89) mmHg after adjusting for TG, 5.15 (95%CI: 3.67–6.63) mmHg after adjusting for HDL-C, and 4.10 (95%CI: 2.36–5.84) mmHg after adjusting for non-HDL-C.ConclusionsIncreased blood RLP-C level was significantly associated with higher cSBP in a Chinese population, independently of other lipids, which indicates its importance in individual cardiovascular risk assessment.

Simultaneous Evaluation of Postchallenge Glycemia and Lipidemia in Young Women

<i>Aim:</i> To determine the effects of simultaneously ingesting glucose and fat on postchallenge glycemia and lipidemia in 12 healthy young Japanese women. <i>Methods:</i> Three test trials were administered in a randomized crossover design: glucose (1 g/kg, G trial); fat cream (0.35 g/kg as fat; F trial); glucose + fat cream (GF trial). Blood samples were taken before and at 0.5, 1, 2, 4, and 6 h post-ingestion. <i>Results:</i> The GF trial's serum glucose peak value was lower than the G trial's, and its remnant lipoprotein-cholesterol (RLP-C) increase was less than the F trial's. The GF trial's apolipoprotein (Apo) B48 increase happened faster than the F trial's. The G and GF trials' insulinogenic index (I/G30) values were negatively correlated with the area under the curve (AUC) of glucose for 2 h. Fasting insulin level and HOMA-IR were positively (and QUICKI and I/G30 were negatively) correlated with the AUC of insulin for 2 h. The F and GF trials' fasting TG, RLP-C, ApoB48, and ApoC-III levels were positively correlated with the AUC of TG and RLP-C for 6 h. The fasting ApoB48 level predicted the AUC of ApoB48 for 6 h. <i>Conclusion:</i> The glucose peak was ameliorated by co-ingesting fat. I/G30 predicted an early postchallenge (0–2 h) glucose rise. The fasting insulin level, HOMA-IR, QUICKI, and I/G30 predicted an insulin rise. The RLP-C rise by fat ingestion was ameliorated by co-ingesting glucose. Fasting TG, RLP-C, ApoB48, and ApoC-III levels predicted postchallenge TG and RLP-C rises. The fasting ApoB48 level predicted postchallenge apoB48, i.e., a rise in intestinal lipoprotein.

Association between remnant lipoprotein cholesterol levels and non-alcoholic fatty liver disease in adolescents

Background & AimsRemnant lipoprotein cholesterol (RLP-C) is an atherogenic lipid profile associated with non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). With increased rates of CVD seen in adults with NAFLD, RLP-C has the potential to identify individuals with NAFLD who are at increased risk of CVD. This study examined in adolescents sex-different associations among RLP-C, NAFLD, and cardiometabolic risk factors, and whether RLP-C is associated with NAFLD beyond traditional cardiometabolic risk factors.MethodsAdolescents in the Raine Study had anthropometry, clinical, biochemistry and arterial stiffness measurements recorded at 17 years of age. Fatty liver, subcutaneous and visceral adipose thickness were assessed using abdominal ultrasound. Relationships among RLP-C, NAFLD, liver biochemistry, insulin resistance, adipokines, adiposity and arterial stiffness were assessed.ResultsNAFLD was diagnosed in 15.1% (19.6% females and 10.7% males) of adolescents. Increasing RLP-C levels were associated with increasing severity of hepatic steatosis and metabolic syndrome. Adolescents with NAFLD and serum RLP-C levels in the highest quartile compared with the lowest quartile, had higher serum leptin, homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein, low-density-lipoprotein cholesterol, triglycerides, BMI, subcutaneous and visceral adipose thickness, systolic blood pressure and arterial stiffness, but lower adiponectin and high-density-lipoprotein cholesterol. Using multivariable logistic regression, RLP-C in the lowest quartile compared with the highest quartile was associated with 85% lower odds of NAFLD in males and 55% in females, after adjusting for waist circumference, leptin, ALT, adiponectin and HOMA-IR.ConclusionsThere is an association between RLP-C and NAFLD beyond traditional risk factors of adiposity and insulin resistance in adolescents. Although raised serum RLP-C levels were associated with the severity of hepatic steatosis and markers of cardiometabolic risk, lower serum RLP-C might reflect reduced cardiovascular risk.Lay summaryRemnant lipoprotein cholesterol (RLP-C) is a part of the blood cholesterol that is linked with heart disease and non-alcoholic fatty liver disease (NAFLD) in adults. In the Raine Study, teenagers with high RLP-C levels had more severe fat accumulation in their liver. Thus, RLP-C might be the hidden link between NAFLD and future risk of heart disease.

Comparison of calculated remnant lipoprotein cholesterol levels with levels directly measured by nuclear magnetic resonance

BackgroundRemnant cholesterol (RC) can partly explain the residual risk in atherosclerotic cardiovascular disease (ASCVD). A consensus method of measuring RC levels has not been established yet. In clinical practice, RC levels are usually calculated from the standard lipid profile, which are not true RC. Nuclear magnetic resonance (NMR) can measure RC levels directly. This study aimed to characterize RC at fasting and non-fasting states in more details and establish the performance of calculated RC and NMR-measured RC.MethodsBlood samples at fasting state and at 2 h and 4 h postprandial states were collected in 98 subjects. Lipid parameters including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), subfractions 3, 4, and 5 of very low-density lipoprotein cholesterol (VLDL3-C, VLDL4-C, and VLDL5-C, respectively), and intermediate-density lipoprotein cholesterol (IDL-C) were measured by enzymatic method and NMR. RC levels calculated from the standard lipid profile or measured by NMR were referred here as RCe or RCn.ResultsThe RCe and RCn levels were different, but both of them increased after a meal (P < 0.05), especially at 4 h postprandial state. Low correlations were found between RCe and RCn in the 1st, 2nd, and 3rd quartiles of TG, but RCn showed great correlation with RCe in the highest quartile regardless of the fasting or non-fasting state (R = 0.611, 0.536, and 0.535 for 0 h, 2 h, and 4 h, respectively). However, across the 2nd and 3rd quartiles, RCe levels were nearly close to RCn levels. RCe levels tended to overestimate RCn levels in the 1st quartile of TGe levels with median differences of 0.23(− 0.13, 0.63) and underestimate RCn levels with median differences of − 0.23(− 0.33, 0.07) in the highest quartile of TGe levels.ConclusionsRC calculated from the standard lipid profile as TC minus LDL-C minus HDL-C is different from the NMR-measured RC. According to different TG levels, RC could overestimate or underestimate the actual RC level. Developing a consensus clinical method to measure RC levels is necessary, so that results from different studies and platforms can be more directly compared.Trial registrationChinese Clinical Trial Registry, ChiCTR1900020873. Registered in 21 January 2019 - Retrospectively registered.

Comparing remnant lipoprotein cholesterol measurement methods to evaluate efficacy of ezetimibe/statin vs statin therapy

Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies. To evaluate the effect of ezetimibe (Eze)+ statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods. This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80mg] vs Eze+statin [Eze 10mg+simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80mg] vs statin+Eze [atorvastatin 20/40mg+Eze 10mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies. Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r=0.29-0.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze+statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P<.01) with Eze+statins vs statins by VAP, calculated, and IM methods (between-treatment differences: -5.0 and -12.0, -2.0 and -5.4, and -1.5 and -12.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: -5.0 and -19.9 and -2.0 and -7.3) in second-line studies. Although the 3 methods showed little agreement, each supported Eze+statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements.

Comparing different assessments of remnant lipoprotein cholesterol: The very large database of lipids

Remnant lipoprotein cholesterol (RLP-C) is a risk factor for atherosclerotic cardiovascular disease, but there is no standard method for measurement. Some studies have used very low-density lipoprotein cholesterol estimated by the Friedewald equation to approximate RLP-C using a basic lipid panel, whereas others have attempted to measure RLP-C with ultracentrifugation. The aim of the study was to compare RLP-C levels estimated from basic lipid parameters to those measured by ultracentrifugation. We analyzed 1,350,908 individuals from the Very Large Database of Lipids, comparing one estimate of RLP-C using basic lipid parameters (RLP-Cestimated=non-high-density lipoprotein cholesterol - Friedewald-estimated low-density lipoprotein cholesterol for triglycerides <355mg/dL [4mmol/L], or non-high-density lipoprotein - directly measured low-density lipoprotein for triglycerides ≥355mg/dL) to levels measured by vertical auto profile ultracentrifugation (RLP-Cmeasured=dense subfraction of very low-density lipoprotein cholesterol+intermediate-density lipoprotein cholesterol). We calculated correlations between RLP-Cestimated and RLP-Cmeasured along with median within-subject differences between RLP-Cestimated and RLP-Cmeasured across quintiles of RLP-Cestimated. We also assessed correlations with RLP-C estimated from basic lipid parameters using a novel method of calculating low-density lipoprotein cholesterol with a patient-specific conversion factor (RLP-Cestimated-N). Our cohort was 48% male, and median (interquartile range) age was 59 (49-69) years. Median (interquartile range) RLP-Cestimated and RLP-Cmeasured were 23 (16.4-33.2) and 24 (19-32) mg/dL, respectively. The correlation between RLP-Cestimated and RLP-Cmeasured was 0.76. Based on the specified definition of RLP-Cestimated, the correlation between RLP-Cestimated and triglyceride/5 for triglyceride<355mg/dL was exactly 1.0. RLP-Cestimated was lower than RLP-Cmeasured in the firstandsecond quintiles of RLP-Cestimated but greater in the highest quintile. The correlations with RLP-Cestimated-N were 0.98 and 0.81 for RLP-Cestimated and RLP-Cmeasured, respectively. A previously used estimate of RLP-C using basic lipid parameters correlates weakly with remnants measured by ultracentrifugation. Our findings emphasize the need to standardize definitions and measurements of RLP-C.

Remnant Lipoprotein Cholesterol Independently Associates With In-Stent Restenosis After Drug-Eluting Stenting for Coronary Artery Disease

This study evaluated the prognostic value of remnant lipoprotein cholesterol (RLP-C) as a predictor of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation in patients with coronary artery disease (CAD). Consecutive patients with CAD (n = 612) who underwent both successful coronary DES implantation and follow-up angiography ranging from 6 to 24 months were enrolled. The independent predictors of ISR were explored by multivariate logistic regression analysis; 95 (15.52%) patients were identified to have ISR. Multivariate logistic regression analysis showed that RLP-C concentration (odds ratio [OR]: 4.245, 95% confidence interval [CI]: 2.493-7.229), age (OR: 1.026, 95% CI: 1.002-1.051), diabetes mellitus (DM; OR: 1.811, 95% CI: 1.134-2.892), and lesion length (OR: 1.013, 95% CI: 1.002-1.024) were associated with ISR. Via subgroup analysis, we found that RLP-C was independently associated with ISR in both CAD with DM (OR: 4.154, 95% CI: 1.895-9.104) and CAD without DM (OR: 4.455, 95% CI: 2.097-9.464) groups. In the analysis of the receiver operating characteristics curve, RLP-C level >0.515 mmol/L exhibited 77.9% sensitivity and 56.5% specificity (area under the curve: 0.705, 95% CI: 0.648-0.762) in predicting ISR. In conclusion, RLP-C is independently associated with the development of ISR in patients with CAD after DES implantation.

Remnant Lipoprotein Cholesterol and Cardiovascular and Cerebrovascular Events in Patients with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is characterized by an atherogenic dyslipidaemia and an increased cardiovascular risk. Remnant lipoprotein cholesterol (RLP-C) is emerging as a novel cardiovascular risk factor, but its predictive value in patients with NAFLD is unknown. We investigated factors affecting RLP-C levels, and the association with major adverse cardiovascular and cerebrovascular events (MACCE) in NAFLD. A prospective observational cohort study was carried out including 798 unselected patients with cardio-metabolic diseases screened by ultrasound for the presence of NAFLD. Fasting RLP-C (mg/dL) was calculated as total cholesterol—(HDL (high-density lipoprotein) + LDL (low-density-lipoprotein)). Primary endpoint of the follow-up study was a combined endpoint of MACCE. Patients with NAFLD (79.2%) had higher median fasting RLP-C in comparison to those without (27.0 vs. 20.0 mg/dL, respectively p < 0.001). Metabolic syndrome, NAFLD, age above median, and female sex were independently associated to fasting RLP-C above the median. In patients with NAFLD, values of RLP-C were associated with liver disease severity, as shown by the increasing value of RLP-C across tertiles of aspartate aminotransferase (AST) (p = 0.002) and gamma-glutamyl transpeptidase (GGT) (p < 0.001). Furthermore, levels of RLP-C and Hamaguchi score, were significantly correlated (r = 0.193, p < 0.001). During a median follow-up of 32 months (interquartile range: 14.2–51.7, 1700 person-years), 41 MACCE (2.41%/year) were registered in 596 NAFLD patients. The rate of events was higher in NAFLD patients with RLP-C above the median compared to those below (log-rank test p = 0.040). Age (hazard ratio (HR) 1.039, 95% confidence interval (CI), 1.005–1.074, p = 0.024), previous cardiovascular events (HR 2.210, 95% CI, 1.052–4.643, p = 0.036), female sex (HR 0.454, 95% CI, 0.208–0.989, p = 0.047) and RLP-C above the median (HR 2.202, 95% CI, 1.132–4.285, p = 0.020) were associated with MACCE. In conclusion, we found that NAFLD was independently associated with higher circulating RLP-C, and that high RLP-C levels were predictive of MACCE in patients with NAFLD.

Abstract 422: Association of Remnant Lipoprotein Cholesterol and Levels of Glucose and Insulin: the Very Large Database of Lipids

Background: A defining feature of diabetic dyslipidemia is elevation of triglyceride-rich lipoproteins, particularly remnant lipoprotein cholesterol (RLP-C). Lowering these lipoproteins may reduce risk of atherosclerotic cardiovascular disease in diabetic patients, though the relationship between RLP-C and hyperglycemia as well as hyperinsulinemia remains inadequately characterized. The purpose of this study was to determine the association of RLP-C with serum glucose and insulin across a broad range of insulin resistance. Methods: We used a sample of individuals from the Very Large Database of Lipids with measured fasting serum glucose and insulin levels, as well as lipoprotein cholesterol levels measured by the Vertical Auto Profile test (Atherotech, Birmingham, AL). RLP-C was defined as the sum of VLDL 3 -C + IDL-C. The study population was divided into deciles of HOMA-IR, calculated as [Insulin х Glucose/405]. We performed multivariable linear regression models to determine associations of RLP-C with insulin and glucose after adjusting for age, sex, real LDL-C, triglycerides, AST, BUN and creatinine. Covariates not normally distributed were log-transformed. Analysis was performed in overall population and across HOMA-IR deciles. Results: We included a total of 146,826 individuals (43.6% male, mean age 54.9 ± 15.9 years). Median values were: insulin, 9 uU/mL; glucose, 95 mg/dL; RLP-C, 26 mg/dL. The models in our Table explained 60% of variance in RLP-C. Overall, insulin (β=-1.85, p&lt;0.001) and glucose (β=-0.84, p&lt;0.001) had significant negative associations with RLP-C. However, levels of RLP-C were significantly associated with insulin but not glucose across most HOMA-IR deciles (Table). Conclusion: RLP-C is significantly associated with levels of serum insulin but not with glucose across a spectrum of insulin resistance. Further characterization of the relationship between RLP-C and serum insulin is needed to help guide future therapies for patients with diabetes.

Relationship between lipoprotein subfraction cholesterol and residual risk for cardiovascular outcomes: A post hoc analysis of the AIM-HIGH trial

The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial failed to demonstrate incremental clinical benefit of extended-release niacin (ERN) in 3414 statin-treated patients with established cardiovascular (CV) disease who had low baseline levels of high-density lipoprotein cholesterol (HDL-C) as compared to placebo. A previous secondary analysis suggested that ERN provided outcome benefits in ERN-treated patients with high triglycerides (TGs; >200mg/dL) and very low HDL-C (<32mg/dL) at baseline. The current analysis sought to ascertain how changes in TG-enriched lipoproteins and HDL subfractions impact residual risk in the comparator treatment arms. We evaluated the relationship between niacin treatment, lipoproteins and their subfractions, and CV outcomes in a non-prespecified, post hoc analysis of the AIM-HIGH trial. Lipoprotein subfraction analysis was performed with zonal ultracentrifugation in 2457 AIM-HIGH participants at baseline and 1year of treatment. Hazard ratios were estimated using Cox proportional hazards models for relationships between lipoproteins and the composite primary endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Analyses were performed for the entire cohort and in participants with TGs > 200mg/dL and HDL-C < 32mg/dL. Apoprotein B-containing lipoproteins and their subfractions decreased significantly in both treatment arms but decreased more with ERN treatment. HDL-C and its subfractions increased significantly in both treatment groups, but more so in patients treated with ERN. For the entire study population, neither apoB- nor apoA1-containing lipoprotein subfractions predicted risk at baseline or at 1year of follow-up. In the high TG and low HDL-C subgroup treated with placebo, changes at 1year in HDL2-C, total cholesterol/HDL2-C, and non-HDL-C/HDL2-C may be associated with increased CV events, whereas in the ERN treatment arm, changes at 1year in very low-density lipoprotein cholesterol and very low-density lipoprotein subfractions, total remnant lipoproteins, and various risk ratios may be associated with increased CV events, while HDL2-C may be associated with reduced risk. We provide hypothesis-generating findings that ERN may confer benefit in patients with coronary heart disease who have high TGs and low HDL by reducing serum levels of remnant lipoprotein cholesterol and increasing HDL2-C.

Effect of Combination Therapy of Ezetimibe and Atorvastatin on Remnant Lipoprotein Versus Double Atorvastatin Dose in Egyptian Diabetic Patients.

A high level of remnant lipoprotein cholesterol (RLP-C) is a predominant feature in diabetic patients with atherosclerosis. This study aimed to investigate the effect of ezetimibe added to statin therapy compared to doubling standard statin dose. Sixty-five eligible patients were recruited then prospectively randomized to receive ezetimibe 10 mg/day plus their 40 mg daily atorvastatin dose (group 1) or atorvastatin 80 mg/day (group 2) for 3 months. Efficacy was evaluated using plasma levels of RLP-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL), percentage of brachial artery flow-mediated dilation, and lipid profile. Forty patients completed the study and provided efficacy data. Group 1 showed more reduction in RLP-C (45.7% vs 31.7%, P = .02), apolipoprotein B (28.5% vs 9.5%, P = .01), total cholesterol (34.7% vs 24.6%, P = .003), triglycerides (49% vs 24.4%, P = .000), non-HDL (49.3% vs 33%, P = .002), and low-density lipoprotein cholesterol (49.6% vs 35.2%, P = .02) compared to group 2. Group 1 showed a greater increase in HDL (66% vs 35%, P = .002); and flow-mediated dilation (30% vs 17%, P = .01) compared to group 2. It is concluded that adding ezetimibe 10 mg to atorvastatin 40 mg may be a better choice than doubling atorvastatin dose in improving RLPs, endothelial function, and lipid profile in diabetic cardiovascular patients who could not achieve their therapeutic treatment goals with the standard atorvastatin dose.

Abstract 405: Utility of Very Low-density Lipoprotein Cholesterol to Total Triglyceride Ratio (VLDL-C/TG) and Non-VLDL TG to Quantify Remnant Lipoprotein Cholesterol (RLP-C): The Very Large Database of Lipids Study 7C

Background: RLP-C is comprised of atherogenic triglyceride- (TG-) rich lipoproteins, commonly defined as the sum of intermediate-density lipoprotein cholesterol (IDL-C) and very low-density lipoprotein cholesterol remnants (VLDL 3 -C). In clinical practice, the VLDL-C/TG ratio is used to diagnose type III dyslipidemia, a primary lipoprotein disorder characterized by high levels of RLP-C. Methods: Serum lipids of 556,307 U.S. adults with TG ≥130 mg/dL were analyzed by ultracentrifugation (VAP, Atherotech, Birmingham, AL). We estimated TG content in VLDL (VLDL-TG) as the product of VLDL-C and validated variable TG/VLDL-C factors. Non-VLDL-TG was then calculated as total TG minus VLDL-TG, for which negative values represented the presence of RLP-C. We examined the relationship of non-VLDL-TG to 1000 quantiles of VLDL-C/TG ratio. We defined a VLDL-C/TG ratio cutpoint for presence of RLP-C based on the quantile at which median non-VLDL-TG≤0. Results: We found median non-VLDL-TG≤0 at VLDL-C/TG = 0.18 (Figure) . There were 174,907 adults who did not meet diagnostic criteria for type III dyslipidemia (VLDL-C/TG 0.18 to &lt;0.30), whose levels of RLP-C and non-VLDL-TG levels were 37 (31-46) and -20 (-40 to -8) mg/dL, respectively. A total of 1,550 adults met classical diagnostic criteria for type III dyslipidemia (VLDL-C/TG ≥0.3), whose plasma levels of RLP-C and non-VLDL-TG levels were 80 (67-101) and -187 (-290 to -129) mg/dL, respectively. Conclusion: A threshold of VLDL-C/TG ≥0.18 correlates with the accumulation of RLP-C in plasma. If validated in future studies, these findings will improve identification of individuals who are at greater risk for atherosclerotic disease.

Remnant Lipoprotein Cholesterol and Mortality After Acute Myocardial Infarction: Further Evidence for a Hypercholesterolemia Paradox From the TRIUMPH Registry.

Remnants are partially hydrolyzed, triglyceride-rich lipoproteins that, like other apolipoprotein B-containing lipoproteins, are atherogenic. Prior observational studies suggest paradoxically better outcomes in hypercholesterolemic patients who sustain an acute myocardial infarction (AMI), one of several known recurrent risk paradoxes. To date, the association of directly measured remnant lipoprotein cholesterol (RLP-C) with survival after an AMI has not been examined. Higher RLP-C levels may be paradoxically associated with lower mortality. We examined 2465 AMI survivors in a prospective, 24-center US study of AMI outcomes. Lipoprotein cholesterol subfractions were directly measured by ultracentrifugation. RLP-C was defined as intermediate-density lipoprotein cholesterol (IDL-C) + very-low-density lipoprotein cholesterol subfraction 3 (VLDL3 -C). Given a linear relationship between RLP-C and mortality, we examined RLP-C by tertiles and continuously. Cox regression hazard ratios (HRs) were adjusted for the Global Registry of Acute Coronary Events (GRACE) score and 23 other covariates. Participants were age 58 ± 12 years (mean ± SD), and 68% were men. After 2 years of follow-up, 226 (9%) participants died. The mortality proportion was 12.4% in the lowest tertile of RLP-C (0-15 mg/dL), 8.5% in the middle tertile (16-23 mg/dL), and 6.8% in the highest tertile (24-120 mg/dL; P < 0.001). A 1-SD increase in RLP-C (11 mg/dL) predicted a 24% lower adjusted risk of 2-year mortality (HR: 0.76, 95% confidence interval [CI]: 0.64-0.91). Similar results were found for a 1-SD increase in IDL-C (HR per 8 mg/dL: 0.80, 95% CI: 0.67-0.96), VLDL3 -C (HR per 4 mg/dL: 0.74, 95% CI: 0.61-0.89), and very-low-density lipoprotein cholesterol (VLDL-C; HR per 8 mg/dL: 0.69, 95% CI: 0.55-0.85). Higher RLP-C levels were associated with lower mortality 2 years after AMI despite rigorous adjustment for known confounders. Unknown protective factors or a lead-time bias likely explains the paradox.

Lipid phenotypes at the extremes of high-density lipoprotein cholesterol: The very large database of lipids-9

Low serum levels of high-density lipoprotein cholesterol (HDL-C) are an important risk factor for atherosclerotic disease. To date, therapeutically raising HDL-C has not been shown to impact risk for cardiovascular events. We aim to characterize lipid parameters at the extremes of HDL-C. We examined cholesterol profiles from 1,350,908 US adults and children from the Very Large Database of Lipids who were clinically referred for advanced lipoprotein testing from 2009 to 2011. We categorized patients into HDL-C percentile categories (<0.1th, 0.1th-<1st, 1st-5th, 25th-75th, 95th-99th, >99th-99.9th, and >99.9th). Within these groups, we examined HDL-C subclasses, low-density lipoprotein cholesterol (LDL-C), LDL and very-low density lipoprotein densities, non-HDL-C, triglycerides (TG), very-low density lipoprotein cholesterol, and remnant lipoprotein cholesterol (RLP-C), as well as prevalence of Fredrickson-Levy dyslipidemias. Extremely low HDL-C percentiles were associated with increased LDL density, TG, and especially RLP-C. Very high HDL-C levels (≥ 92 mg/dL) showed increasing HDL2-C/HDL3-C ratio and very low levels of RLP-C and triglyceride-rich lipoproteins. Type IV dyslipidemia had the highest prevalence among classical dyslipidemia and was the most frequent at extremely low HDL-C percentiles. These findings demonstrate a high prevalence of elevated triglyceride-rich lipoprotein levels and increased LDL density in patients with extremely low HDL-C levels. The relative contributions of these various changes in lipid profiles of patients with low HDL-C to cardiovascular risk need to be further scrutinized to more fully establish if low HDL-C is truly an independent risk factor for coronary heart disease or simply reflects detrimental shifts in the levels of atherogenic lipoproteins.

Polymorphisms in LPL, CETP, and HL protect HIV-infected patients from atherogenic dyslipidemia in an allele-dose-dependent manner.

IntroductionHIV-infected patients treated with Highly Active Antiretroviral Therapy (HAART) may be predisposed to hypertriglyceridemia, which gives rise to a highly atherogenic lipid profile known as atherogenic dyslipidemia (AD). We propose that genetic variability leaves some HIV-infected patients more predisposed to AD than others [1, 2].MethodsThis was a cross-sectional, observational study conducted in 468 antiretroviral-treated HIV-infected patients attending at the outpatient clinic of a tertiary hospital over a 6-month period, who were classified as normolipidemic (n=173) or presenting with AD (triglycerides: 1.7 mmol/L and HDLc < 1.02 [men] or 1.28 mmol/L [women]) (n=148). Polymorphisms were identified in the APOA5, APOC3, LPL, CETP, HL, MTP, APOE, LRP5 and VLDLR genes.ResultsAtherogenic dyslipidemia was detected in 31% of patients, most of whom were men (77%). This group was also older and had higher levels of remnant lipoprotein cholesterol (RLPc) than normolipidemic patients. The polymorphisms rs328 in LPL, rs708272 in CETP and rs1800588 in HL were 10–40% significantly more frequent in normolipidemic patients. At least 1 of these polymorphisms was detected in 90% of normolipidemic patients; in AD patients, the percentage decreased to 75% (p=0.003). This effect was dependent on both the allele and the dose of HAART and independent of the regimen administered. The protective combination showed a trend towards higher HDLc (1.13 [0.40] vs 1.24 [0.23] mmol/L), lower triglycerides (2.23 [2.34] vs 1.89 [1.24] mmol/L) and lower RLPc (16.41 [11.42] vs 12.99 [11.69] mmol/L).ConclusionsPolymorphisms in LPL, CETP and HL protect HIV-infected patients from developing AD in a dose-dependent manner [3].