Lipoprotein Measures Research Articles

Lipid changes across menopause status point to increased cardiovascular risk

Abstract Background While women develop cardiovascular disease (CVD) approximately ten years later than men, risk of CVD in women rises precipitously following menopause. The mechanisms underlying this acceleration in CVD risk are not well elucidated, but adverse changes in lipid measures are known to occur during the perimenopause period. Previous investigations have been largely restricted to traditional lipid measures and have not examined changes in lipoprotein particles including lipid subfractions and particle number. Purpose We sought to examine longitudinal changes in lipoprotein particles that occur during the menopause transition. Methods A total of 1305 participants in the Dallas Heart Study with known menopause status underwent measurement of LDL-P, HDL-P, sd-LDL, and ld-HDL by NMR LipoProfile LP4 algorithm (LabCorp, Raleigh Durham, NC, U.S.A.) at 2 examinations (between 7-8 years between DHS studies). We compared longitudinal changes in lipoprotein measures between pre-, peri-, post-menopausal women and men using multivariable adjusted linear regression models. For our analysis peri- is the group that was pre-menopause at DHS I and post-menopause at DHS 2, not to mean the period before menopause. Results There 1346 men (referent group) included in the study with a mean age of 43 ± 9.4 years. There was a total of 1246 women with a mean age of 42 ± 5.6 for peri-group, 54 ± 6.2 for post-group, and 34 ± 3.08 for the pre-group. Of the women 440 (35.3%) were pre-menopausal, 298 (23.9%) were peri-menopausal, and 508 (40.8%) were post-menopausal. Over a median follow-up time of 7 years. All three groups had an increase in LDL-P but the greatest percent change is between peri and post, 18.30 (SE 3.05, P<0.001). When compared to men the post-group has the greatest percent change of HDL-P with a negative change of 4.77 (SE 0.948 P<0.0001). Small-dense LDL had the highest percent change in the peri- group when compared to men with a change of 578.62 (SE 288.45, P<0.045). Large-dense HDL had greatest percent change in the post- group when compared to men with negative change of 37.84 (SE 12.83, P<0.0032). Conclusions We found that menopause is associated with adverse changes in lipoprotein profiles, with the most pronounced changes in LDL-particles and subfractions observed for peri-menopausal women. By contrast, post-menopausal women demonstrated the greatest reductions in HDL-particles and subfractions. Taken together, these changes suggest that menopause is associated with a transition to a more atherogenic lipoprotein profile. Further research is needed to investigate whether these adverse changes in lipoproteins translate to greater CV risk.

Associations Between High-Density Lipoprotein Cholesterol Efflux and Brain Grey Matter Volume.

Objective: High-density lipoprotein cholesterol efflux function may prevent brain amyloid beta deposition and neurodegeneration. However, the relevance of this finding has not been established in the diverse middle-aged population. Methods: We examined 1826 adults (47% Black adults) who participated in the Dallas Heart Study to determine associations between high-density lipoprotein (HDL) measures and brain structure and function. White matter hyperintensities (WMH) and whole-brain grey matter volume (GMV) were measured using brain MRI, and the Montreal Cognitive Assessment (MoCA) was used to measure neurocognitive function. HDL cholesterol efflux capacity (HDL-CEC) was assessed using fluorescence-labeled cholesterol efflux from J774 macrophages, and HDL particle size measures were assessed using nuclear magnetic resonance (NMR) spectroscopy (LipoScience). Multivariable linear regressions were performed to elucidate associations between HDL-CEC and brain and cognitive phenotypes after adjustment for traditional risk factors such as age, smoking status, time spent in daily physical activity, and education level. Results: Higher HDL-CEC and small HDL particle (HDL-P) concentration were positively associated with higher GMV normalized to total cranial volume (TCV) (GMV/TCV) after adjustment for relevant risk factors (β = 0.078 [95% CI: 0.029, 0.126], p = 0.002, and β = 0.063 [95% CI: 0.014, 0.111], p = 0.012, respectively). Conversely, there were no associations between HDL measures and WMH or MoCA (all p > 0.05). Associations of HDL-CEC and small HDL-P with GMV/TCV were not modified by ApoE-ε4 status or race/ethnicity. Interpretation: Higher HDL cholesterol efflux and higher plasma concentration of small HDL-P were associated with higher GMV/TCV. Additional studies are needed to explore the potential neuroprotective functions of HDL.

Blood Lipids, Lipoproteins, and Apolipoproteins With Risk of Coronary Heart Disease: A Prospective Study Among Racially Diverse Populations.

Comprehensive blood lipoprotein profiles and their association with incident coronary heart disease (CHD) among racially and geographically diverse populations remain understudied. We conducted nested case-control studies of CHD among 3438 individuals (1719 pairs), including 1084 White Americans (542 pairs), 1244 Black Americans (622 pairs), and 1110 Chinese adults (555 pairs). We examined 36 plasma lipids, lipoproteins, and apolipoproteins, measured by nuclear magnetic resonance spectroscopy, with incident CHD among all participants and subgroups by demographics, lifestyle, and metabolic health status using conditional or unconditional logistic regression adjusted for potential confounders. Conventionally measured blood lipids, that is, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol, were each associated with incident CHD, with odds ratios (ORs) being 1.33, 1.32, 1.24, and 0.79 per 1-SD increase among all participants. Seventeen lipoprotein biomarkers showed numerically stronger associations than conventional lipids, with ORs per 1-SD among all participants ranging from 1.35 to 1.57 and a negative OR of 0.78 (all false discovery rate <0.05), including apolipoprotein B100 to apolipoprotein A1 ratio (OR, 1.57 [95% CI, 1.45-1.7]), low-density lipoprotein-triglycerides (OR, 1.55 [95% CI, 1.43-1.69]), and apolipoprotein B (OR, 1.49 [95% CI, 1.37-1.62]). All these associations were significant and consistent across racial groups and other subgroups defined by age, sex, smoking, obesity, and metabolic health status, including individuals with normal levels of conventionally measured lipids. Our study highlighted several lipoprotein biomarkers, including apolipoprotein B/ apolipoprotein A1 ratio, apolipoprotein B, and low-density lipoprotein-triglycerides, strongly and consistently associated with incident CHD. Our results suggest that comprehensive lipoprotein measures may complement the standard lipid panel to inform CHD risk among diverse populations.

Influence of age and sex on longitudinal metabolic profiles and body weight trajectories in the UK Biobank.

Accurate characterization of how age influences body weight and metabolism at different stages of life is important for understanding ageing processes. Here, we explore observational longitudinal associations between metabolic health and weight from the fifth to the seventh decade of life, using carefully adjusted statistical designs. Body measures and biochemical data from blood and urine (220 measures) across two visits were available from 10 104 UK Biobank participants. Participants were divided into stable (within ±4% per decade), weight loss and weight gain categories. Final subgroups were metabolically matched at baseline (48% women, follow-up 4.3 years, ages 41-70; n = 3368 per subgroup) and further stratified by the median age of 59.3 years and sex. Pulse pressure, haemoglobin A1c and cystatin-C tracked ageing consistently (P < 0.0001). In women under 59, age-associated increases in citrate, pyruvate, alkaline phosphatase and calcium were observed along with adverse changes across lipoprotein measures, fatty acid species and liver enzymes (P < 0.0001). Principal component analysis revealed a qualitative sex difference in the temporal relationship between body weight and metabolism: weight loss was not associated with systemic metabolic improvement in women, whereas both age strata converged consistently towards beneficial (weight loss) or adverse (weight gain) phenotypes in men. We report longitudinal ageing trends for 220 metabolic measures in absolute concentrations, many of which have not been described for older individuals before. Our results also revealed a fundamental dynamic sex divergence that we speculate is caused by menopause-driven metabolic deterioration in women.

HDL-C and apolipoprotein A-I are independently associated with skeletal muscle mitochondrial function in healthy humans.

Prior animal and cell studies have demonstrated a direct role of high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-I) in enhancing skeletal muscle mitochondrial function and exercise capacity. However, the relevance of these animal and cell investigations in humans remains unknown. Therefore, a cross-sectional study was conducted in 48 adults (67% female, 8% Black participants, age 39 ± 15.4 yr old) to characterize the associations between HDL measures, ApoA-I, and muscle mitochondrial function. Forearm muscle oxygen recovery time (tau) from postexercise recovery kinetics was used to assess skeletal muscle mitochondrial function. Lipoprotein measures were assessed by nuclear magnetic resonance. HDL efflux capacity was assessed using J774 macrophages, radiolabeled cholesterol, and apolipoprotein B-depleted plasma both with and without added cyclic adenosine monophosphate. In univariate analyses, faster skeletal muscle oxygen recovery time (lower tau) was significantly associated with higher levels of HDL cholesterol (HDL-C), ApoA-I, and larger mean HDL size, but not HDL cholesterol efflux capacity. Slower recovery time (higher tau) was positively associated with body mass index (BMI) and fasting plasma glucose (FPG). In multivariable linear regression analyses, higher levels of HDL-C and ApoA-I, as well as larger HDL size, were independently associated with faster skeletal muscle oxygen recovery times that persisted after adjusting for BMI and FPG (all P < 0.05). In conclusion, higher levels of HDL-C, ApoA-I, and larger mean HDL size were independently associated with enhanced skeletal muscle mitochondrial function in healthy humans.NEW & NOTEWORTHY Our study provides the first direct evidence supporting the beneficial role of HDL-C and ApoA-I on enhanced skeletal muscle mitochondrial function in healthy young to middle-aged humans without cardiometabolic disease.

Lipoprotein Characteristics and Incident Coronary Heart Disease: Prospective Cohort of Nearly 90 000 Individuals in UK Biobank.

Background Associations of coronary heart disease (CHD) with plasma lipids are well described, but the associations with characteristics of lipoproteins (which transport lipids) remain unclear. Methods and Results UK Biobank is a prospective study of 0.5 million adults. Analyses were restricted to 89 422 participants with plasma lipoprotein and apolipoprotein measures from Nightingale nuclear magnetic resonance spectroscopy and without CHD at baseline. CHD risk was positively associated with concentrations of very-low-density lipoproteins, intermediate-density lipoproteins, and low-density lipoproteins (LDL), and inversely associated with high-density lipoproteins. Hazard ratios (99% CIs) per SD were 1.22 (1.17-1.28), 1.16 (1.11-1.21), 1.20 (1.15-1.25), and 0.90 (0.86-0.95), respectively. Larger subclasses of very-low-density lipoproteins were less strongly associated with CHD risk, but associations did not materially vary by size of LDL or high-density lipoprotein. Given lipoprotein particle concentrations, lipid composition (including cholesterol) was not strongly related to CHD risk, except for triglyceride in LDL particles. Apolipoprotein B was highly correlated with LDL concentration (r=0.99), but after adjustment for apolipoprotein B, concentrations of very-low-density lipoprotein and high-density lipoprotein particles remained strongly related to CHD risk. Conclusions This large-scale study reliably quantifies the associations of nuclear magnetic resonance-defined lipoprotein characteristics with CHD risk. CHD risk was most strongly related to particle concentrations, and separate measurements of lipoprotein concentrations may be of greater value than the measurement by apolipoprotein B, which was largely determined by LDL concentration alone. Furthermore, there was strong evidence of positive association with mean triglyceride molecules per LDL particle but little evidence of associations with total triglycerides or other lipid and lipoprotein fractions after accounting for lipoprotein concentrations.

Association between exposure to air pollution and blood lipids in the general population of Spain.

We aimed to assess the associations of exposure to air pollutants and standard and advanced lipoprotein measures, in a nationwide sample representative of the adult population of Spain. We included 4647 adults (>18 years), participants in the national, cross-sectional, population-based di@bet.es study, conducted in 2008-2010. Standard lipid measurements were analysed on an Architect C8000 Analyzer (Abbott Laboratories SA). Lipoprotein analysis was made by an advanced 1 H-NMR lipoprotein test (Liposcale®). Participants were assigned air pollution concentrations for particulate matter <10 μm (PM10 ), <2.5 μm (PM2.5 ) and nitrogen dioxide (NO2 ), corresponding to the health examination year, obtained by modelling combined with measurements taken at air quality stations (CHIMERE chemistry-transport model). In multivariate linear regression models, each IQR increase in PM10 , PM2.5 and NO2 was associated with 3.3%, 3.3% and 3% lower levels of HDL-c and 1.3%, 1.4% and 1.1% lower HDL particle (HDL-p) concentrations (p < .001 for all associations). In multivariate logistic regression, there was a significant association between PM10 , PM2.5 and NO2 concentrations and the odds of presenting low HDL-c (<40 mg/dL), low HDL-p (<p25) and higher LDL particle (LDL-p) concentrations (≥p75). In subgroup analyses there were stronger associations between PM10 and NO2 and low HDL-p in men (p for interaction .008 and .034), and between NO2 and low HDL-p in individuals with obesity (p for interaction .015). Our study shows an association between the exposure to air pollutants and blood lipids in the general population of Spain, suggesting a link to atherosclerosis.

Abstract P453: Apolipoprotein B, Low-Density Lipoprotein Particle Number, Non-High-Denisity Lipoprotein Cholesterol, Low-Density Lipoprotein Cholesterol, and Total Cholesterol for Atherosclerotic Cardiovascular Disease Risk Prediction in Young Adults

Introduction: Measures of atherogenic particle number (apoB and LDL particle number [LDL-P]) are stronger predictors of atherosclerotic cardiovascular disease (ASCVD) risk than measures of cholesterol concentration (LDL-C, non-HDL-C, total cholesterol [TC]) in middle-aged adults. It is unclear if this is true for younger adults. Methods: Among CARDIA participants (ppts), NMR was used to measure apoB and LDL-P. Non-HDL-C and TC were measured using standard assays; LDL-C was calculated using the Friedewald equation. We stratified the ppts into two age windows: age 20-30y (n=1645) and age 30-40y (n=2922). We used adjusted Cox proportional hazards models to assess the associations of 1SD higher apoB, LDL-P, non-HDL-C, LDL-C, or TC with incident ASCVD events. We substituted each measure of atherogenic lipid burden for TC in a modified Pooled Cohort Equation (PCE) model (with and without HDL-C); and model performance (discrimination and reclassification) was evaluated. Results: There were 81 and 163 ASCVD events over (median [IQR]) 31.8y (31.1-32.0y) for the age 20-30 age window and over 26.8y (19.1-27.1y) for the 30-40y age window, respectively. In ppts age 20-30y, a 1SD higher apoB, LDL-P, non-HDL-C, and LDL-C were significantly associated with incident ASCVD in demographic adjusted models. The strengths of associations with ASCVD were not significantly different across these measures. For the 30-40y age window, all measures of atherogenic lipoproteins were significantly associated with ASCVD; the strengths of association were not significantly different across atherogenic lipid measures in all models. There were no significant differences in the C-statistic and no improvement in reclassification when each measure was used to replace TC in the PCE model. Conclusions: ApoB, LDL-P, LDL-C or non-HDL-C may be slightly better markers of long-term ASCVD risk than TC in adults &lt; 30y. However, in adults between 30-40y all measures of atherogenic lipid burden appeared to be equivalent predictors of long-term risk.

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.

Associations of clinical and circulating metabolic biomarkers with low physical fitness and function in adults with chronic lymphocytic leukemia.

Many patients with chronic lymphocytic leukemia (CLL) experience physical dysfunction and low overall fitness. It remains unknown what factors drive CLL physical dysfunction. We assessed physical function and metabolic lipoprotein panels in 106 patients with CLL. In univariate analyses of clinical factors, a longer time since diagnosis was associated with a higher likelihood of dysfunctional aerobic fitness (OR = 3.56, 95% CI: 1.37–9.22; p = 0.002) and physical performance (SPPB: OR = 2.03, 95% CI: 1.20–3.44; p = 0.004). Having received treatment was associated with a higher likelihood of dysfunctional aerobic fitness (OR = 1.57, 95% CI: 1.02–2.40; p = 0.036), SPPB (OR = 1.85, 95% CI: 1.13–3.03; p = 0.011) and grip strength (OR = 1.67, 95% CI: 1.10–2.55; p = 0.015). We found that several small HDL particle parameters, higher levels of citrate (OR = 2.01, 95% CI: 1.22–3.31; p = 0.030), and lower levels of hemoglobin (OR = 0.50, 95% CI: 0.31–0.82; p = 0.030) were associated with a higher likelihood of dysfunctional aerobic fitness. Multivariable least absolute shrinkage and selection operator (LASSO)-penalized regression analyses using variable importance measures (VIM) showed that 7.8-nm HDL particles (VIM = 1.000) and total HDL particle levels (VIM = 1.000) were more informative than clinical measures for the odds of dysfunctional aerobic fitness and 6-min walk functional fitness, respectively, while 10.3-nm HDL particles (VIM = 0.383) were more informative for grip strength. Time since diagnosis (VIM = 0.680) and having received treatment (VIM = 0.490) were more informative than lipoprotein measures for the odds of having dysfunctional SPPB. Taken together, we establish significant relationships between clinical and metabolic factors and physical characteristics that might prompt early use of ancillary support services.

Profoundly Disturbed Lipoproteins in Cirrhotic Patients: Role of Lipoprotein-Z, a Hepatotoxic LDL-like Lipoprotein.

Detailed information regarding lipoprotein concentrations and subfractions in cirrhotic patients before and after orthotopic liver transplantation (OLT) is lacking. Lipoprotein-Z (LP-Z) is a recently characterised abnormal, hepatotoxic free cholesterol-rich low-density lipoprotein (LDL)-like lipoprotein. We determined the lipoprotein profiles, including LP-Z, in cirrhotic patients and OLT recipients and assessed the prognostic significance of LP-Z on the OLT waiting list. We performed analyses in cirrhotic transplant candidates and non-cirrhotic OLT recipients. A population-based cohort was used as reference. The setting was a University hospital. Lipoprotein particle concentrations and subfractions were measured by nuclear magnetic resonance spectroscopy. In the cirrhotic patients (N = 130), most measures of triglyceride-rich lipoproteins (TRL), LDL, and high-density lipoproteins (HDL) were much lower compared to the OLT recipients (N = 372) and controls (N = 6027) (p < 0.01). In the OLT recipients, many lipoprotein variables were modestly lower, but HDL-cholesterol, triglycerides, and TRL and HDL size were greater vs. the control population. LP-Z was measurable in 40 cirrhotic patients and 3 OLT recipients (30.8% vs. 0.8%, p < 0.001). The cirrhotic patients with measurable LP-Z levels had profoundly lower HDL-cholesterol and particle concentrations (p < 0.001), and worse Child Pugh Turcotte classifications and MELD scores. The presence of LP-Z (adjusted for age, sex, and MELD score) predicted worse survival in cirrhotic patients (HR per 1 LnSD increment: 1.11, 95%CI 1.03–1.19, p = 0.003). In conclusion, cirrhotic patients have considerably lower plasma concentrations of all major lipoprotein classes with changes in lipoprotein subfraction distribution. After OLT, these lipoprotein abnormalities are in part reversed. LP-Z is associated with cirrhosis. Its presence may translate in disturbed HDL metabolism and worse survival.

Associations of lipoprotein particle profile and objectively measured physical activity and sedentary time in schoolchildren: a prospective cohort study

BackgroundOur understanding of the mechanisms through which physical activity might benefit lipoprotein metabolism is inadequate. Here we characterise the continuous associations between physical activity of different intensities, sedentary time, and a comprehensive lipoprotein particle profile.MethodsOur cohort included 762 fifth grade (mean [SD] age = 10.0 [0.3] y) Norwegian schoolchildren (49.6% girls) measured on two separate occasions across one school year. We used targeted proton nuclear magnetic resonance (1H NMR) spectroscopy to produce 57 lipoprotein measures from fasted blood serum samples. The children wore accelerometers for seven consecutive days to record time spent in light-, moderate-, and vigorous-intensity physical activity, and sedentary time. We used separate multivariable linear regression models to analyse associations between the device-measured activity variables—modelled both prospectively (baseline value) and as change scores (follow-up minus baseline value)—and each lipoprotein measure at follow-up.ResultsHigher baseline levels of moderate-intensity and vigorous-intensity physical activity were associated with a favourable lipoprotein particle profile at follow-up. The strongest associations were with the larger subclasses of triglyceride-rich lipoproteins. Sedentary time was associated with an unfavourable lipoprotein particle profile, the pattern of associations being the inverse of those in the moderate-intensity and vigorous-intensity physical activity analyses. The associations with light-intensity physical activity were more modest; those of the change models were weak.ConclusionWe provide evidence of a prospective association between time spent active or sedentary and lipoprotein metabolism in schoolchildren. Change in activity levels across the school year is of limited influence in our young, healthy cohort.Trial registrationClinicalTrials.gov, #NCT02132494. Registered 7th April 2014

Abstract 9971: Longitudinal Lipoprotein(a) Concentrations and Cardiovascular Risk: A Prospective Cohort Study

Introduction: When indicated, current guidelines recommend a single measurement of lipoprotein(a) for cardiovascular risk assessment. However, temporal variability in lipoprotein(a) concentration is not well understood, and it is unclear if repeat testing may help refine risk prediction of coronary artery disease (CAD). Hypothesis: We examined the longitudinal stability of lipoprotein(a) measurements and tested whether instability in lipoprotein(a) molar concentration was associated with incident CAD. Methods: We assessed the correlation between baseline and first follow-up measurements of lipoprotein(a) in the UK Biobank (molar concentration n=16,017) and Mass General Brigham cohorts (molar concentration n=271; mass n=1,748; cholesterol n=1,237). The association between change in lipoprotein(a) molar concentration and incident CAD was assessed among 15,432 UK Biobank participants using Cox proportional-hazards models. Results: Baseline and follow-up lipoprotein(a) molar concentration were significantly correlated in the UK Biobank over a median 4.42 years (IQR: 1.24 years) and Mass General Brigham cohorts over a median 0.94 years (IQR: 0.60 years) (Spearman correlations: 0.96 and 0.92, respectively; p-values &lt;0.0001). Similar results were observed for lipoprotein(a) mass and cholesterol. Follow-up lipoprotein(a) molar concentration was significantly associated with risk of incident CAD (HR [95% CI] per 120 nmol/L: 1.31 [1.14-1.51], p-value=0.0002). However, delta lipoprotein(a) was not significantly associated with incident CAD independent of follow-up lipoprotein(a) (p-value=0.98). Conclusions: These findings suggest that, in the absence of therapies substantially altering lipoprotein(a) measures, longitudinal assessments of lipoprotein(a) are likely unnecessary for CAD risk assessment in the context of primary prevention.

A Novel Immunoassay for Malondialdehyde-Conjugated Low-Density Lipoprotein Measures Dynamic Changes in the Blood of Patients Undergoing Coronary Artery Bypass Graft Surgery.

Oxidized low-density lipoproteins play an important role in tissue pathology. In this study, we report a sensitive novel enzyme-linked immunosorbent assay for the detection of malondialdehyde-modified low-density lipoprotein (MDA-LDL), a key component of oxidized LDL. The assay is capable of measuring a variable presence of MDA-LDL within human plasma and serum. We demonstrate the robust nature of the assay on samples stored for over 20 months, as well as high inter-operator reproducibility (r = 0.74, p < 0.0001). The assay was capable of detecting dynamic changes in patient blood samples after coronary artery bypass graft surgery, indicating synthesis or release of MDA-LDL with the oxidative stress of surgery, followed by homeostatic clearance. This robust, sensitive and specific assay for circulating MDA-LDL will serve as a valuable translational tool for the improved detection of oxidative forms of LDL in response to a range of physiological or pathological stimuli, with potential clinical applicability.

Risk Markers for Limited Coronary Artery Calcium in Persons With Significant Aortic Valve Calcium (From the Multi-ethnic Study of Atherosclerosis)

The early stages of aortic valve calcification (AVC) and coronary artery calcification (CAC) include shared ASCVD risk factors, yet there is considerable heterogeneity between the burden of AVC, and CAC. We sought to identify the markers associated with limited CAC among persons with significant AVC. There were 325 participants from the Multi-Ethnic Study of Atherosclerosis without clinical ASCVD and with AVC ≥100 Agatston units (AU) at Visit 1. Multivariable-adjusted prevalence ratios for limited CAC (0 to 99 AU) were calculated using modified Poisson regression. Participants had a mean age of 72.1 years, median AVC score of 209, and 34% were women. A total of 133 (41%) participants had CAC <100, of whom 46/133 had CAC=0. Younger age (PR=1.40, 95% CI: 1.22 to 1.62, per 10-years), female gender (PR=1.68, 95% CI: 1.28 to 2.20), and low 10-year ASCVD risk (PR=2.30, 95% CI: 1.85 to 2.85) were most strongly associated with limited CAC. Neither a normal lipoprotein(a) nor normal measures of inflammation were significantly associated with limited CAC. Lower serum phosphate (PR=1.15, 95% CI: 1.01 to 1.31; per 0.5 mg/dl lower) and calcium-phosphate product (PR=1.16, 95% CI: 1.02 to 1.34; per SD lower) were associated with an approximately 15% higher prevalence of limited CAC. In conclusion, more than 40% of persons with significant AVC had CAC. Beyond traditional risk factors, lower serum phosphate, and lower calcium-phosphate product were associated with a higher prevalence of limited CAC.

Increased apolipoprotein-B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE.

BackgroundCardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR biomarkers are needed for JSLE patient stratification and to identify therapeutic approaches to reduce cardiovascular morbidity and mortality in JSLE.MethodsSerum metabolomic analysis (including >200 lipoprotein measures) was performed on a discovery (n=31, median age 19) and validation (n=31, median age 19) cohort of JSLE patients. Data was analysed using cluster, receiver operating characteristic analysis and logistic regression. RNA-sequencing assessed gene expression in matched patient samples.FindingsHierarchical clustering of lipoprotein measures identified and validated two unique JSLE groups. Group-1 had an atherogenic and Group-2 had an atheroprotective lipoprotien profile. Apolipoprotein(Apo)B:ApoA1 distinguished the two groups with high specificity (96.2%) and sensitivity (96.7%). JSLE patients with high ApoB:ApoA1 ratio had increased CD8+ T-cell frequencies and a CD8+ T-cell transcriptomic profile enriched in genes associated with atherogenic processes including interferon signaling. These metabolic and immune signatures overlapped statistically significantly with lipid biomarkers associated with sub-clinical atherosclerosis in adult SLE patients and with genes overexpressed in T-cells from human atherosclerotic plaque respectively. Finally, baseline ApoB:ApoA1 ratio correlated positively with SLE disease activity index (r=0.43, p=0.0009) and negatively with Lupus Low Disease Activity State (r=-0.43, p=0.0009) over 5-year follow-up.InterpretationMulti-omic analysis identified high ApoB:ApoA1 as a potential biomarker of increased cardiometabolic risk and worse clinical outcomes in JSLE. ApoB:ApoA1 could help identify patients that require increased disease monitoring, lipid modification or lifestyle changes.FundingLupus UK, The Rosetrees Trust, British Heart Foundation, UCL & Birkbeck MRC Doctoral Training Programme and Versus Arthritis.

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis.

Aims Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement.Methods and results Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function.Conclusions Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.

Association of the Mediterranean Diet With Onset of Diabetes in the Women’s Health Study

Higher Mediterranean diet (MED) intake has been associated with reduced risk of type 2 diabetes, but underlying biological mechanisms are unclear. To characterize the relative contribution of conventional and novel biomarkers in MED-associated type 2 diabetes risk reduction in a US population. This cohort study was conducted among 25 317 apparently healthy women. The participants with missing information regarding all traditional and novel metabolic biomarkers or those with baseline diabetes were excluded. Participants were invited for baseline assessment between September 1992 and May 1995. Data were collected from November 1992 to December 2017 and analyzed from December 2018 to December 2019. MED intake score (range, 0 to 9) was computed from self-reported dietary intake, representing adherence to Mediterranean diet intake. Incident cases of type 2 diabetes, identified through annual questionnaires; reported cases were confirmed by either telephone interview or supplemental questionnaire. Proportion of reduced risk of type 2 diabetes explained by clinical risk factors and a panel of 40 biomarkers that represent different physiological pathways was estimated. The mean (SD) age of the 25 317 female participants was 52.9 (9.9) years, and they were followed up for a mean (SD) of 19.8 (5.8) years. Higher baseline MED intake (score ≥6 vs ≤3) was associated with as much as a 30% lower type 2 diabetes risk (age-adjusted and energy-adjusted hazard ratio, 0.70; 95% CI, 0.62-0.79; when regression models were additionally adjusted with body mass index [BMI]: hazard ratio, 0.85; 95% CI, 0.76-0.96). Biomarkers of insulin resistance made the largest contribution to lower risk (accounting for 65.5% of the MED-type 2 diabetes association), followed by BMI (55.5%), high-density lipoprotein measures (53.0%), and inflammation (52.5%), with lesser contributions from branched-chain amino acids (34.5%), very low-density lipoprotein measures (32.0%), low-density lipoprotein measures (31.0%), blood pressure (29.0%), and apolipoproteins (23.5%), and minimal contribution (≤2%) from hemoglobin A1c. In post hoc subgroup analyses, the inverse association of MED diet with type 2 diabetes was seen only among women who had BMI of at least 25 at baseline but not those who had BMI of less than 25 (eg, women with BMI <25, age- and energy-adjusted HR for MED score ≥6 vs ≤3, 1.01; 95% CI, 0.77-1.33; P for trend = .92; women with BMI ≥25: HR, 0.76; 95% CI, 0.67-0.87; P for trend < .001). In this cohort study, higher MED intake scores were associated with a 30% relative risk reduction in type 2 diabetes during a 20-year period, which could be explained in large part by biomarkers of insulin resistance, BMI, lipoprotein metabolism, and inflammation.

Clinical Utility of Lipoprotein(a) and LPA Genetic Risk Score in Risk Prediction of Incident Atherosclerotic Cardiovascular Disease

Lipoprotein(a) is a highly heritable biomarker independently associated with atherosclerotic cardiovascular disease (ASCVD). It is unclear whether measured lipoprotein(a) or genetic factors associated with lipoprotein(a) can provide comparable or additional prognostic information for primary prevention. To determine whether a genetic risk score (GRS) comprising 43 variants at the LPA gene, which encodes apolipoprotein(a), has clinical utility in assessing ASCVD risk compared with and in addition to lipoprotein(a) measurement. The UK Biobank is a prospective observational study of approximately 500 000 volunteers aged 40 to 69 years who were recruited from 22 sites across the United Kingdom between 2006 and 2010. Using externally derived weights, an LPA GRS was calculated for 374 099 unrelated individuals with array-derived genotypes and lipoprotein(a) measures. Data were analyzed from April 2020 to March 2020. Measured lipoprotein(a) and LPA GRS. We estimated the associations between measured lipoprotein(a) and LPA GRS with the incidence of ASCVD (peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) using Cox proportional hazards models. To determine the utility of using measured lipoprotein(a) and LPA GRS as risk enhancers for ASCVD, we assessed the potential improvement in ASCVD risk discrimination by QRISK3 and Pooled Cohort Equations among individuals with borderline to intermediate risk (n = 113 703 and 144 350, respectively). The mean age of the overall study population was 57.6 years, and 204 355 individuals were female (54.6%). During a median follow-up of 11.1 years (interquartile range, 1.4 years), 15 444 individuals developed an incident ASCVD event (5.1%). The LPA GRS explained approximately 60% of the variation in measured lipoprotein(a) for White/European individuals. Independently, both lipoprotein(a) and LPA GRS were associated with incident, composite ASCVD (hazard ratio per 120 nmol/L increase, 1.26; 95% CI, 1.23-1.28 vs hazard ratio, 1.29; 95% CI, 1.26-1.33; P < .001). The association between LPA GRS and ASCVD was substantially attenuated after adjusting for measured lipoprotein(a). Adding measured lipoprotein(a) or LPA GRS to QRISK3 provided modest improvements to the risk discrimination of incident ASCVD events (area under the receiver operating curve, 0.640; 95% CI, 0.633-0.647 vs 0.642; 95% CI, 0.635-0.649 for both; P = .005 and P = .01, respectively). When indicated, cardiovascular risk assessment with lipoprotein(a) at middle-age may include direct measurement or an LPA GRS.

Role of Bempedoic Acid in Dyslipidemia Management.

Statins remain the preferred agent to reduce low-density lipoprotein cholesterol (LDL-C) and lower atherosclerotic cardiovascular disease (ASCVD) risk. Additional nonstatin agents are recommended to further lower LDL-C among patients at high-risk of ASCVD or those with heterozygous familial hypercholesterolemia, despite statin therapy. Patients unable to tolerate recommended doses of statin therapy due to adverse effects, including statin-associated muscle symptoms, may also require additional nonstatin agents to lower LDL-C and ASCVD risk. Bempedoic acid is a first-in-class, once-daily oral agent, recently approved as monotherapy and in combination with ezetimibe, as an adjunct to maximally tolerated statin therapy in patients with ASCVD or heterozygous familial hypercholesterolemia who require additional LDL-C lowering. Its novel mechanism is reported to avoid adverse muscle symptoms associated with statins. The effectiveness and safety of bempedoic acid and bempedoic acid/ezetimibe combination have been reported in multiple phase 2 and 3 trials. In this review, we report the lipid-lowering effects associated with bempedoic acid, and the safety profile from multiple clinical trials. Based on available data, bempedoic acid significantly lowers LDL-C and other atherogenic lipoprotein measures, and high-sensitivity C-reactive protein when added to background lipid-lowering therapy in patients with and without statin intolerance. Overall safety of bempedoic acid seems to be comparable to placebo, except for increased serum uric acid and tendon rupture. Ongoing clinical trials assessing the long-term safety and cardiovascular outcomes will provide additional insight into the role of bempedoic acid as an adjunct lipid-lowering medication.