Large High-density Lipoprotein Particle Concentration Research Articles

Abstract P175: Combined Metabolic Health And Obesity Status Is Associated With Markers Of High-Density Lipoprotein Metabolism: Dallas Heart Study

Introduction: While high-density lipoprotein (HDL) cholesterol is a component of metabolic syndrome, an ASCVD risk factor, other markers of HDL metabolism better associate with ASCVD. However, it is unclear whether these markers better discriminate between metabolic health and obese groups. Hypothesis: We hypothesized that higher cholesterol efflux capacity (CEC) and a favorable HDL profile would be associated with metabolically healthy profiles within each weight category. Methods: Data from the second phase of the Dallas Heart Study were used to classify participants (n=2156) into four groups based on a harmonized definition of metabolic health and obesity status: Metabolically Healthy, Normal Weight (MHNW); Metabolically Unhealthy, Normal Weight (MUNW); Metabolically Healthy, Obese (MHO); Metabolically Unhealthy, Obese (MUO). MU was classified as having one or more of the following: elevated blood pressure (SBP/DBP ≥130/85 mmHg), fasting glucose (≥100 mg/dL), or fasting triglycerides (≥150 mg/dL); a history of CVD or diabetes; or any medications for these conditions. Obesity was defined as BMI ≥ 30kg/m 2 . CEC was measured using J774 macrophages, BODIPY- and radio-labeled cholesterol, and apoB-precipitated plasma. HDL particle (HDL-P) subfractions were quantified by NMR spectroscopy. Generalized linear models were used to compare paired means of CEC and HDL traits between groups controlling for age, sex, race, and smoking. Results: Small HDL-P concentration was higher in MU groups regardless of weight status. Total and medium HDL-P concentrations and radio-labeled CEC were higher in NW groups, regardless of metabolic health status. Mean HDL-P size and large HDL-P concentrations were different across all groups, with the rank order being MHNW, MUNW, MHO, MUO (Table 1). Conclusions: In conclusion, associations between HDL subfractions, CEC and metabolic/weight status are heterogeneous, highlighting the complexity of HDL physiology as it pertains to body weight and metabolic disease.

Physical Activity, Sedentary Leisure Time, Circulating Metabolic Markers, and Risk of Major Vascular Diseases.

Physical inactivity and sedentary behavior are associated with higher risk of cardiovascular disease (CVD). Little is known about the relevance of circulating metabolites for these associations. A nested case-control study within the prospective China Kadoorie Biobank included 3195 incident CVD cases (2057 occlusive CVD and 1138 intracerebral hemorrhage) and 1465 controls aged 30 to 79 years without prior CVD or statin use at baseline. Nuclear magnetic resonance spectroscopy was used to measure 225 metabolic markers and derived traits in baseline plasma samples. Linear regression was used to relate self-reported physical activity and sedentary leisure time to biomarkers, adjusting for potential confounders. These were contrasted with associations of biomarkers with occlusive CVD risk. Physical activity and sedentary leisure time were associated with >100 metabolic markers, with patterns of associations generally mirroring each other. Physical activity was inversely associated with very low and low-density and positively with large and very large HDL (high-density lipoprotein) particle concentrations. Physical activity was also inversely associated with alanine, glucose, lactate, acetoacetate, and the inflammatory marker glycoprotein acetyls. In general, associations of physical activity and sedentary leisure time with specific metabolic markers were directionally consistent with the associations of these metabolic markers with occlusive CVD risk. Overall, metabolic markers potentially explained ≈70% of the protective associations of physical activity and ≈50% of the positive associations of sedentary leisure time with occlusive CVD. Among Chinese adults, physical activity and sedentary behavior have opposing associations with a diverse range of circulating metabolites, which may partially explain their associations with CVD risk.

Associations of Aerobic Fitness and Maximal Muscular Strength With Metabolites in Young Men

High physical fitness is associated with a reduction in risk of cardiovascular diseases and death, but the underlying mechanisms are insufficiently understood. To determine how aerobic fitness and muscular strength are associated with serum metabolome measures. This cross-sectional study included Finnish men receiving military refresher training from May 5, 2015, to November 28, 2015, representing partly overlapping groups of individuals with the lowest vs highest aerobic fitness and the lowest vs highest muscular strength. Data analyses were conducted from January 1, 2018, to May 31, 2019. The associations of aerobic fitness (determined with maximum oxygen consumption in milliliters per minute per kilogram, measured with maximal cycle ergometer test) and muscular strength (determined with a maximal strength test for lower extremities in kilograms) with 66 metabolome measures from fasting serum samples (nuclear magnetic resonance-based metabolomics) were analyzed. Participants included 580 Finnish men (mean [SD] age, 26.1 [6.5] years). Including overlap between groups, there were 196 men in the lowest aerobic fitness group and 197 men in the highest aerobic fitness group as well as 196 men in the lowest muscular strength group and 197 men in the highest muscular strength group. Of 66 studied metabolome measures, 48 differed between high vs low aerobic fitness groups, including small very low-density lipoprotein (standardized median difference, -0.67; 95% CI, -0.83 to -0.49), large high-density lipoprotein (standardized median difference, 0.89; 95% CI, 0.69-1.15), total triglyceride levels (standardized median difference, -0.52; 95% CI, -0.65 to -0.34), isoleucine (standardized median difference, -0.37; 95% CI, -0.55 to -0.16), leucine (standardized median difference, -0.55; 95% CI, -0.72 to -0.34), phenylalanine (standardized median difference, -0.54; 95% CI, -0.71 to -0.32), glycerol (standardized median difference, -0.64; 95% CI, -0.81 to -0.48), and glycoprotein (standardized median difference, -0.78; 95% CI, -0.95 to -0.62) concentration, a high unsaturation degree of fatty acids (standardized median difference, 0.59; 95% CI, 0.42-0.81), and apolipoprotein B to apolipoprotein A1 ratio (standardized median difference, -0.88; 95% CI, -1.08 to -0.67). Adding aerobic fitness into the regression model after age, education, smoking, use of alcohol, and dietary factors accounted for more than an additional 5% of variation for 25 metabolome measures (R2 range, 5.01%-15.90% by measure). With these 2 criteria, maximal muscular strength was not associated with any metabolome measures. Aerobic fitness was associated with high large high-density lipoprotein particle concentration (R2, 14.97%; 95% CI, 10.65%-20.85%), low apolipoprotein B to apolipoprotein A1 ratio (R2, 14.49%; 95% CI, 10.58%-19.51%), and low glycoprotein concentration (R2, 15.90%; 95% CI, 11.22%-21.51%). Aerobic fitness was also associated with low very low-density lipoprotein, triglyceride, isoleucine, leucine, phenylalanine, glycerol, and glycoprotein concentrations and with a high unsaturation degree of fatty acids. Adjusting for recent physical activity influenced the results minimally. Adjusting for body fat percentage showed that some of the associations were mechanistically associated with body fat percentage. This study provides data on the association of high aerobic fitness with underlying oxidative lipid metabolism associated with a reduction in cardiometabolic risk. High maximal muscular strength is not similarly associated with these benefits.

High-Density Lipoprotein Particles, Cell-Cholesterol Efflux, and Coronary Heart Disease Risk.

Objective- The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to preβ-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal preβ-1-HDL. Approach and Results- HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative-stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor preβ-1 particles ( R2=0.535) and between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (α-1+α-2) HDL particles ( R2=0.712). Cases had significantly higher (87%) preβ-1 concentrations than controls, but the functionality of their preβ-1 particles (preβ-1 concentration normalized ABCA1-dependent efflux capacity) was significantly lower (-31%). Cases had significantly lower (-12%) mean concentration of large HDL particles, but the functionality of their particles (α-1+α-2 concentration normalized SR-BI-dependent efflux capacity) was significantly higher (22%) compared with that of controls. HDL antioxidative capacity was significantly lower (-16%) in cases than in controls. There were no significant correlations between either preβ-1 functionality or large HDL particle functionality with HDL antioxidative capacity or the concentrations of inflammatory- and oxidative-stress markers. Conclusions- HDL cell-cholesterol efflux capacity is significantly influenced by both the concentration and the functionality of specific HDL particles participating in cell-cholesterol efflux. Coronary heart disease patients have higher than normal preβ-1 concentrations with decreased functionality and lower than normal large HDL particle concentrations with enhanced functionality.

Retraction: The improvement of large High-Density Lipoprotein (HDL) particle levels, and presumably HDL metabolism, depend on effects of low-carbohydrate diet and weight loss.

[This retracts the article DOI: 10.17179/excli2015-642.].

The improvement of large High-Density Lipoprotein (HDL) particle levels, and presumably HDL metabolism, depend on effects of low-carbohydrate diet and weight loss

Depressed levels of atheroprotective large HDL particles are common in obesity and cardiovascular disease (CVD). Increases in large HDL particles are favourably associated with reduced CVD event risk and coronary plaque burden. The objective of the study is to compare the effectiveness of low-carbohydrate diets and weight loss for increasing blood levels of large HDL particles at 1 year. This study was performed by screening for body mass index (BMI) and metabolic syndrome in 160 consecutive subjects referred to our out-patient Metabolic Unit in South Italy. We administered dietary advice to four small groups rather than individually. A single team comprised of a dietitian and physician administered diet-specific advice to each group. Large HDL particles at baseline and 1 year were measured using two-dimensional gel electrophoresis. Dietary intake was assessed via 3-day diet records. Although 1-year weight loss did not differ between diet groups (mean 4.4 %), increases in large HDL particles paralleled the degree of carbohydrate restriction across the four diets (p<0.001 for trend). Regression analysis indicated that magnitude of carbohydrate restriction (percentage of calories as carbohydrate at 1 year) and weight loss were each independent predictors of 1-year increases in large HDL concentration. Changes in HDL cholesterol concentration were modestly correlated with changes in large HDL particle concentration (r=0.47, p=.001). In conclusion, reduction of excess dietary carbohydrate and body weight improved large HDL levels. Comparison trials with cardiovascular outcomes are needed to more fully evaluate these findings.

Sex differences in the associations of visceral adiposity, homeostatic model assessment of insulin resistance, and body mass index with lipoprotein subclass analysis in obese adolescents

The relationship of lipoprotein particle subclasses to visceral adipose tissue area (VAT-area) in obese children has not been examined previously. The study aims were to compare the relationships of VAT-area, homeostatic model assessment of insulin resistance (HOMA-IR), and body mass index (BMI) with lipids and lipoprotein subclasses in obese adolescents and to determine whether these relationships vary by sex. This cross-sectional study of obese adolescents (BMI ≥ 95th percentile), aged 12 to 18 years, measured VAT-area by dual-energy X-ray absorptiometry, BMI, fasting lipids, lipoprotein subclasses, and HOMA-IR. Linear regression models evaluated the associations of VAT-area, HOMA-IR, and BMI with lipid cardiometabolic risk factors. Sex-stratified analyses further explored these associations. Included were 127 adolescents (age=14.4±1.5years; 53.5% female; 88.2% African-American), mean BMI=34.0±5.1kg/m(2). VAT-area was negatively associated with low-density lipoprotein particle (LDL-P) size (β=-0.28, P=.0001), high-density lipoprotein particle (HDL-P) size (β=-0.33, P<.0001), and large HDL-P concentration (β=-0.29, P<.0001) and positively associated with small LDL-P concentration (β=0.23, P=.0005) and small HDL-P concentration (β=0.25, P=.05). When VAT-area, HOMA-IR, and BMI associations were compared, VAT-area had the strongest associations with most of the lipoprotein subclasses. After sex stratification, the associations of VAT-area with HDL cholesterol, LDL-P size, and large LDL-P concentration were significant only for females (all P<.05). In a cohort of largely African-American obese adolescents, VAT-area was associated with a more atherogenic lipoprotein subclass profile. When compared with HOMA-IR and BMI, VAT-area had the strongest associations with most lipoprotein subclasses. The relationships between VAT-area and certain lipoprotein subclasses are significantly different in males vs females.

The effect of acute endurance exercise on lipoproteins: a comparison of the nuclear magnetic resonance technique with the conventional lipid profile in healthy men

Nuclear magnetic resonance (NMR) of lipoprotein particle size and number may provide greater sensitivity to detecting cardiovascular disease risk compared with the conventional lipid profile in some individuals. The salubrious effect of cardiovascular exercise on blood lipids using the conventional profile is well documented; however, NMR analysis is lacking. The purpose of this study was to examine the effect of a 60-min bout of dynamic exercise on lipoprotein particle size and number as measured by NMR and compare it with the conventional blood lipid profile. Eight active, healthy men (26 ± 5.17 years) ran for 60 min at 70% maximal oxygen uptake on a motor-driven treadmill. Fasting blood samples were drawn at pre-exercise and 5-10 min and 24 h postexercise. The conventional lipid profile showed a significant change in triglycerides (p = 0.019) immediately after exercise with an increase of 22% and a nonsignificant decrease of 13% from baseline after 24 h. The NMR profile showed a significant change in the large high-density lipoprotein particle concentration (p = 0.046) with an increase of 5.8% immediately after exercise, and a decrease of 6.7% at 24 h after exercise. None of the NMR profile changes were significantly different from the baseline value. These data suggest that sensitivity differences between techniques depend on the variable considered; however, they do not warrant concomitant analysis in future studies using this population. Finally, no appreciable favorable or adverse effect was observed in the overall cardiovascular disease risk profile in active, normolipidemic males.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Plasma High Density Lipoprotein and Anticoagulant Response to Activated Protein C (APC) and Protein S

Abstract 2249Previously we reported that plasma high density lipoprotein (HDL) enhances activated protein C (APC)/protein S (PS) anticoagulant action in plasma clotting and factor Va inactivation assays (APC/PS enhancement) and that lower HDL levels are found in male venous thrombosis patients or in patients with recurrent venous thrombosis versus controls, giving rise to our hypothesis that HDL helps protect against venous thrombosis. In this study, we sought (1) to identify which HDL particles enhance APC/PS activity, (2) to assess correlations between this activity and HDL particle size, and (3) to evaluate the recent challenge to our HDL anticoagulant activity hypothesis (Oslakovic et al, J Clin Invest, 2010). To identify HDL subfractions with APC/PS enhancing activity, we subfractionated HDL by sequential density gradient ultracentrifugation over the HDL density range of 1.063–1.21 mg/dl. When the anticoagulant property of these HDL subtractions was studied, we found that the less dense HDL subfractions corresponding to HDL2 particles enhanced APC/PS anticoagulant activity much more than other HDL fractions. Thus, we identified larger HDL particles as the key subfraction for this anticoagulant property of HDL. Hence, we hypothesized that plasma levels of large HDL particles would correlate with plasma sensitivity of APC/protein S. To test this hypothesis, we used proton NMR to quantify the levels of large, medium and small HDL particles and to determine the average size of HDL particles in plasmas from 39 normal adults. We performed dilute tissue factor-induced clotting assays in the absence or presence of APC/protein S to define APC/PS sensitivity and assessed correlations. There was a positive correlation between large HDL particle concentration and plasma sensitivity to APC/protein S (r=0.40, p=0.02). The size of HDL particles was also positively correlated with plasma sensitivity to APC/protein S (r=0.42, p=0.01). As previously reported, apoAI concentrations which is major apolipoprotein in HDL correlated with plasma sensitivity to APC/protein S (r=0.52, p=0.0007). Thus, as hypothesized, apoAI-containing large HDL particle concentrations in plasma correlate very well with the anticoagulant response to APC/PS. Recently Oslakovic et al purported to show that APC/PS enhancement was not an intrinsic property of HDL and claimed that this activity was due to negatively charged phospholipid contaminants of HDL based on gel filtration (Superose 6) analysis of their frozen HDL preparation. Therefore, we applied Superose 6 gel filtration analyses to four different fresh, never-frozen HDL preparations coming either from commercial sources or from in-house preparations. Our studies showed that when each HDL prep was subjected to Superose 6 fractionation, the column fractions containing large HDL (apoAI positive fractions) enhanced APC/protein S anticoagulant activity in plasma clotting assays and also for the inactivation of factor Va in purified systems. Moreover, immobilized anti-apoAI-antibodies removed the APC/PS enhancing effect, further establishing the fact that apoAI-containing HDL particles enhance APC/PS activity. When we analyzed HDL preps stored at 4 °C over successive weeks, we found that HDL fractions lost the ability to enhance APC/PS, showing the relatively labile nature of this activity. Freezing and thawing HDL was also deleterious for this activity. Thus, the APC/PS enhancing activity of fresh, never-frozen HDL preps is primarily due to HDL particles. All of our new findings confirm our previous conclusion that HDL enhances APC/PS anticoagulant actions. Our extensive data set strongly contradicts the conclusions from the recent HDL study by Oslakovic et al who unfortunately performed their bioassays using frozen HDL made from previously frozen lipidmic plasma. In summary, freshly purified, non-frozen large HDL particles made from fresh plasma enhance APC/PS activity. The sensitivity of plasma of healthy adults to APC/PS anticoagulant effects is significantly correlated with the plasma levels of large HDL particles, suggesting the physiological importance of large HDL particles as enhancing the anticoagulant APC/PS system and supporting our hypothesis that large HDL particles may be protective against venous thrombosis, at least in part, via this activity. Disclosures:No relevant conflicts of interest to declare.

Differences in lipoprotein particle subclass distribution for Japanese Americans in Hawaii and Japanese in Japan: The INTERLIPID Study

Current data suggest that low density lipoprotein (LDL) and high density lipoprotein (HDL) subclass concentrations relate directly to the risk of coronary heart disease (CHD). Earlier Studies indicated that Japanese in Japan had lower rates of CHD than Japanese Americans in Hawaii. Rates of CHD appear to continue to be lower in Japan despite increasing cholesterol levels in Japan and decreasing CHD rates in the United States. To provide insight into CHD rate differences. Nuclear Magnetic Resonance (NMR) measurements of lipoprotein subclasses were used to assess lipoprotein particle concentration and size in samples from these two genetically similar populations in Japan and Hawaii. Japanese Americans had significantly higher age- and risk factor- adjusted concentrations of lipoprotein particles implicated in atherogenesis, including large very low density lipoprotein (VLDL; P < 0.001), small LDL (P < 0.001), and small HDL (women, P < 0.001; men, P < 0.01), and significantly lower concentrations of large LDL (P < 0.001) and the putative cardio-protective large HDL (P < 0.05) than Japanese in Japan. Average age- and risk factor- adjusted LDL and HDL particle sizes were also significantly (P < 0.001) smaller in Japanese Americans. Adjustment for body mass index markedly reduced the differences in some lipoprotein measures, including total LDL and large HDL particle concentrations for both genders, total VLDL particle concentration for women, and large VLDL concentration and average HDL particle size for men. Differences in lipoprotein subclass distributions and lifestyle factors such as body weight may contribute to differences in CHD incidence for Japanese in Japan and Japanese Americans.

Stronger associations of sagittal abdominal diameter with atherogenic lipoprotein subfractions than waist circumference in middle-aged US white and Japanese men

Both sagittal abdominal diameter (SAD) and waist circumference (WC) highly correlate with visceral adipose tissue (VAT) being linked to an atherogenic lipoprotein profile. However, it is uncertain whether SAD is a better correlate of atherogenic lipoprotein subfractions than WC. We examined relative associations of SAD vs WC with lipoprotein subfractions for US white and Japanese men, concurrently examining the associations of VAT vs subcutaneous adipose tissue with lipoprotein subfractions. A population-based sample of 260 white and 282 Japanese men aged 40 to 49 years was examined for VAT and subcutaneous adipose tissue by computed tomography; SAD and WC by a portable sliding-beam caliper and a measuring tape, respectively; and lipoprotein subfractions by nuclear magnetic resonance spectroscopy. Both SAD and WC were significantly and positively associated with large very low-density lipoprotein and total and small low-density lipoprotein particle concentrations, and inversely associated with large high-density lipoprotein particle concentration for both white and Japanese men. In body mass index–adjusted regression models, the significant associations of SAD remained for both white and Japanese men, whereas those of WC became nonsignificant for white men. When SAD and WC were simultaneously included into the body mass index–adjusted models, the associations of SAD remained significant and statistically stronger than those of WC for both white and Japanese men. Furthermore, the pattern of the associations of SAD with those lipoprotein subfractions was comparable to that of the associations of VAT. Sagittal abdominal diameter was comparable to VAT and stronger than WC in the associations with atherogenic lipoprotein subfractions for middle-aged, nondiabetic, white and Japanese men.

Abstract 3645: Alcohol Volume, Not Drinking Frequency, Increases Plasma High-Density Lipoprotein Sub-Class Particle Concentration

Introduction: Alcohol intake is positively associated with high-density lipoprotein (HDL) cholesterol, however no studies have investigated the association with lipoprotein sub-classes using nuclear magnetic resonance spectroscopy (NMR). Hypothesis: We assessed the hypothesis that usual daily alcohol intake (volume), beverage type and drinking frequency influence plasma HDL sub-class concentrations as determined by NMR. Methods: Six hundred and ninety volunteers (389 women) aged 40 – 69 years at baseline (1990 –1994) participated in a cross-sectional study using the Melbourne Collaborative Cohort Study, Australia. Measures included self-reported alcohol intake using beverage-specific quantity-frequency questions (volume) and a drinking diary for previous week (frequency). Results: Median alcohol intake was 15.2 g/d (2.7, 32.0) for men and 1.0 g/d (0, 9.6) for women. Alcohol volume was positively associated with total HDL particle concentration in men and women. For men, a 10 g/d increment in alcohol intake increased total HDL particle concentration by 0.62 μmol/L (95% CI: 0.27, 0.98) and small HDL particle concentration by 0.34 μmol/L (0.01, 0.68). For women, total HDL particle concentration increased 1.06 μmol/L (0.60, 1.53) for every 10 g/d increment in alcohol intake. Alcohol volume was positively associated with large HDL particle concentration in premenopausal women [0.67 μmol/L (0.19, 1.15)] and small HDL particle concentration in postmenopausal women [0.82 μmol/L (0.14, 1.51)]. Beer, wine and spirits were all positively associated with total HDL concentration for men. Beer and wine were both positively associated with total HDL concentration for women. Drinking frequency was not associated with total HDL particle concentration or any of its’ sub-classes. Conclusions: Alcohol volume (and not drinking frequency) was positively associated with NMR-determined plasma total HDL particle concentration for men and women. These associations appeared to be regardless of beverage type, although comparison of beverage types was not possible for women. These results suggest that for any given weekly volume of alcohol, the number of drinking days does not influence HDL particle concentration.