Lipoprotein Measurements Research Articles

Lipoprotein(a) in progressive coronary artery disease: beyond classical cardiovascular risk parameters

Abstract Introduction Classical primary preventive cardiovascular disease (CVD) risk algorithms, such as the Framingham risk score and the widely used QRISK score in the UK, predate large-scale deep-phenotyped biomedical research resources. There is therefore the opportunity to identify novel predictors. In addition, whilst CVD risk profiling is well studied in the context of primary prevention, there is a paucity of data examining risk in regard to secondary prevention. Purpose To identify independent predictors of repeat coronary artery revascularisation, following index coronary angioplasty. Methods The UK Biobank is a large prospective multicentre study which recruited over 500,000 participants in the UK aged 37–73 years at entry between 2006–2010. Data are derived from an array of physical measurements, self-reported measures and biological samples, together with longitudinal linkage to hospital inpatient records and death registries. Procedural codes were used to identify patients who had undergone first coronary angioplasty from 2006 onwards. Repeat revascularisation (RR) was defined as angioplasty or bypass grafting occurring at least 9 months after the index angioplasty, in order to preclude instances of staged revascularisation and in-stent restenosis. Data were censored at January 2021 or date of death as appropriate. Results A total of 12,853 participants underwent a first coronary angioplasty during the study period, with 1,394 (10.8%) requiring RR over a median follow-up of 6.5 years. The average age was 64 years in the RR cohort and 1117 (80%) were male. Univariate analyses confirmed a number of established associations with RR, including for example diabetes mellitus and hypertension. Median lipoprotein(a) concentrations were 27.6 vs. 30.3nmol/L in the RR group, p=0.066. Cox regression analyses (n=7,216) incorporating 21 biometric and clinical parameters demonstrated that lipoprotein(a) >80nmol/L was one of six independent predictors of time to RR (HR 1.24, p=0.006), independent of other lipids. The strength and significance of this association persisted when the number of covariates was reduced to include only other lipids and classical cardiovascular risk parameters. LDL, HDL, and triglyceride levels were not significant predictors in this model. Conclusions Lipoprotein(a) is identified as a major independent driver of RR. However current European Society of Cardiology guidance does not recommend measurement of Lipoprotein(a) in the context of progressive coronary artery disease. Furthermore, it is known that strategies such as lifestyle advice and statins – recommended in all patients with established coronary artery disease - do no reduce lipoprotein(a), whilst niacin and PCSK9 inhibitors do have a significant effect. Indications for lipoprotein(a) measurement must therefore be broadened, so that specific treatments to lower it can be instituted in order to reduce the burden of progressive coronary artery disease. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Herefordshire Heart Fund

Towards SI-traceability of lipoprotein (a) measurements: Comparison of a candidate LC-MRM-MS RMP method with commercially available immunoassays for evaluating commutability of candidate reference materials

Background and Aims : Elevated concentrations of lipoprotein(a) (Lp(a)) are directly related to an increased risk of cardiovascular diseases, thus making its determination a crucial factor for clinical diagnosis. However, the lack of global standardisation of current immunoassay-based measuring procedures (MPs) for Lp(a) leads to inconsistent care of patients. The former Lp(a) reference method and the associated WHO-IFCC reference material are no longer available. Recently, it was decided to evolve to a next generation reference measurement system (RMS) with SI-traceability.

Lipoprotein(a) in the Korean Pediatric Population Visiting Local Clinics and Hospitals.

In this paper we investigate serum lipoprotein(a), an independent risk factor for cardiovascular disease in the Korean pediatric population. Visiting local clinics and hospitals, 600 lipoprotein(a) tests were performed on 416 Korean children and adolescents (124 boys and 292 girls), with a median age of 11.1 years (interquartile range, IQR, 9.8–13.9). The median lipoprotein(a) level was 21.5 nmol/L (IQR, 8.2–51.7). Among the 416 patients, the 90th percentile value of the initial lipoprotein(a) measurement was 107.8 nmol/L. The proportion of patients with lipoprotein(a) ≥ 100 nmol/L was 11.3%. The lipoprotein(a) level and the proportion of patients with lipoprotein(a) ≥ 100 nmol/L were not significantly different among sex, or age group. Among the 416 patients, 122 (29.3%, 21 boys and 101 girls) underwent at least two follow-up lipoprotein(a) measurements. The median follow-up period was 6.7 months (IQR, 5.5–11.8). The median lipoprotein(a) level across the 122 patients was 25 nmol/L (IQR 10.0–72.0). Among those patients, seven (5.7%) experienced an increase in serum lipoprotein(a) to ≥100 nmol/L during follow-up measurements. Further studies are needed in the Korean pediatric population in order to clarify the clinical significance of this change long-term.

Characterization of Lipoprotein(a) Measurement in a Large US Healthcare Dataset

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Family Heart Foundation. Background/Synopsis Elevated lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is estimated to be present in 20% of the general population according to an NLA 2019 Scientific Statement, "Use of Lipoprotein(a) in Clinical Practice: A Biomarker Whose Time Has Come." Nonetheless, this genetic lipoprotein is rarely assessed. Objective/Purpose To characterize individuals receiving Lp(a) measurement and their providers using real-world data within the Family Heart Foundation integrated dataset of Americans screened or treated for ASCVD. Methods A cohort of individuals with at least one Lp(a) measurement and sufficient healthcare data was identified within an extensive dataset of >112 million individuals with laboratory data and diagnostic, procedural, and prescription claims from 2012-2019. Demographics (mean +/- standard deviation), ASCVD history, and healthcare provider at time of Lp(a) measurement were characterized. Probable familial hypercholesterolemia (FH) status was determined using a validated machine learning model. Results Lp(a) was rarely measured; 0.3% (n=335,726) of individuals had at least one Lp(a) measurement; they were aged 59.9 +/- 39.7 years, female (52.5%), Black (7.8%), Hispanic (7.1%), White (53.6%), and Other/Unknown (31.5%). Risk factors included hypertension (53.7%), hyperlipidemia (50.6%), and diabetes (24.6%). Cardiovascular history included ASCVD-only (29.1%), probable FH with ASCVD (1.2%), probable FH without ASCVD (1.7%), diagnosed FH with ASCVD (0.4%), diagnosed FH without ASCVD (0.6%), or no ASCVD or FH (70.8%). A small number of healthcare providers (n=629 of 810,119; <0.1%) were responsible for ordering the Lp(a) lab tests for 50% of individuals with a measurement; these providers most frequently specialized in internal medicine (26%), family medicine (23%), and internal medicine/CVD (14%), or were Physician Assistants & Advanced Practice Nursing Providers/Nurse Practitioner/Family (5%). Within this classification system, lipidology was not represented as a separate specialty. Conclusions Measurement of Lp(a) was rare within a large US healthcare dataset. Individuals who had Lp(a) assessed were older and had ASCVD risk factors; 31% had ASCVD. Ordering Lp(a) was concentrated within a very small number of all healthcare providers. Additional research is needed to characterize the barriers and facilitators related to ordering Lp(a) by healthcare providers for individuals with ASCVD and/or risk factors. Nothing to disclose.

Development and validation of an isoform-independent monoclonal antibody–based ELISA for measurement of lipoprotein(a)

The study aims were to develop a new isoform-independent enzyme-linked immunoassay (ELISA) for the measurement of lipoprotein(a) [Lp(a)], validate its performance characteristics, and demonstrate its accuracy by comparison with the gold-standard ELISA method and an LC-MS/MS candidate reference method, both developed at the University of Washington. The principle of the new assay is the capture of Lp(a) with monoclonal antibody LPA4 primarily directed to an epitope in apolipoprotein(a) KIV2 and its detection with monoclonal antibody LPA-KIV9 directed to a single antigenic site present on KIV9. Validation studies were performed following the guidelines of the Clinical Laboratory Improvement Amendments and the College of American Pathologists. The analytical measuring range of the LPA4/LPA-KIV9 ELISA is 0.27–1,402 nmol/L, and the method meets stringent criteria for precision, linearity, spike and recovery, dilutability, comparison of plasma versus serum, and accuracy. Method comparison with both the gold-standard ELISA and the LC-MS/MS method performed in 64 samples with known apolipoprotein(a) isoforms resulted in excellent correlation with both methods (r=0.987 and r=0.976, respectively). Additionally, the variation in apolipoprotein(a) size accounted for only 0.2% and 2.2% of the bias variation, respectively, indicating that the LPA4/LPA-KIV9 ELISA is not affected by apolipoprotein(a) size polymorphism. Peptide mapping and competition experiments demonstrated that the measuring monoclonal antibodies used in the gold-standard ELISA (a-40) and in the newly developed ELISA (LPA-KIV9) are directed to the same epitope, 4076LETPTVV4082, on KIV9. In conclusion, no statistically or clinically significant bias was observed between Lp(a) measurements obtained by the LPA4/LPA-KIV9 ELISA and those obtained by the gold-standard ELISA or LC-MS/MS, and therefore, the methods are considered equivalent.

Metabolic syndrome prevalence and patterns among rural women: a community-based study in Cilongok, Central Java, Indonesia

MetS (MetS) is a predictor of cardiovascular disease and type 2 Diabetes mellitus. The prevalence of MetS increases not only in the urban area but also in the rural area. Women have a greater risk of MetS than men in some studies. This study was purposed to describe MetS prevalence and pattern of rural area women in the Integrated Development Post of Non-communicable Disease (Posbindu PTM) in Cilongok Rural Area. A population-based cross-sectional study was conducted in Cilongok, Banyumas rural area of Central Java among 63 rural women. Data were collected by interviews; measurement of fasting blood glucose, high-density lipoprotein, and triacylglycerol; measurement of blood pressure and abdominal circumference. Food consumption data were collected by multiply 24-hours food recalls. MetS were categorized by NCEP ATP III 2001 criteria. The prevalence of MetS in rural area women was 31.75%. Age was associated with MetS (p-value 0.038 ;95% CI : 0.983-23.63). Women with MetS have significant differences with women without MetS in the value of fasting blood glucose, high-density lipoprotein, triacylglycerol, blood pressure, and abdominal circumference (p-value &lt;0.05). About 95% of MetS women have a high waist circumference and 80% have a low high-density lipoprotein. MetS women consumed higher energy than women without MetS (p-value &lt;0.05). Conclusion: Prevalence of MetS in Cilongok rural area women was high. High in fasting blood glucose, high-density lipoprotein, triacylglycerol, blood pressure, and abdominal circumference were found to be a predictor of MetS. High energy consumption becomes a risk factor for MetS.&#x0D; &#x0D;

Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk.

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.

M265 Towards SI-traceability of lipoprotein (A) measurements: Comparison of a candidate LC-MRM-MS RMP method with commercially available immunoassays for evaluating commutability of candidate reference materials

M265 Towards SI-traceability of lipoprotein (A) measurements: Comparison of a candidate LC-MRM-MS RMP method with commercially available immunoassays for evaluating commutability of candidate reference materials

Familial Hypercholesterolemia and Lipoprotein(a): Two Partners in Crime?

Familial hypercholesterolemia is a high cardiovascular risk disorder. We will review the role of lipoprotein(a) in cardiovascular risk and in aortic valve stenosis in familial hypercholesterolemia, as well as its association with their phenotype, and strategies to identify this high-risk population. Patients with familial hypercholesterolemia have higher lipoprotein(a) levels mainly due to an increased frequency of LPA variants, and the cardiovascular risk is increased twofolds when both conditions coexist. Also, an increased risk for aortic valve stenosis and valve replacement has been observed with high lipoprotein(a) levels. Assessment of lipoprotein(a) during the cascade screening for familial hypercholesterolemia is a good opportunity to identify this high-risk population. High cardiovascular risk in familial hypercholesterolemia is increased even more when lipoprotein(a) is also elevated. Measurement of lipoprotein(a) in these patients is crucial to identify those subjects who need to intensify LDL-cholesterol reduction pending availability of lipoprotein(a)-specific treatments.

Value of Genetic Testing for Lipoprotein(a) Variants

Value of Genetic Testing for Lipoprotein(a) Variants

Apolipoprotein A-V is a potential target for treating coronary artery disease: evidence from genetic and metabolomic analyses

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73–0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.

Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection.

SARS-CoV-2 infection causes a significant reduction in lipoprotein-bound serum phospholipids give rise to supramolecular phospholipid composite (SPC) signals observed in diffusion and relaxation edited 1H NMR spectra. To characterize the chemical structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent analytical techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 positive and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR experiment. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS).

Repeat Measures of Lipoprotein(a) Molar Concentration and Cardiovascular Risk

BackgroundWhen indicated, guidelines recommend measurement of lipoprotein(a) for cardiovascular risk assessment. However, temporal variability in lipoprotein(a) is not well understood, and it is unclear if repeat testing may help refine risk prediction of coronary artery disease (CAD). ObjectivesThe authors examined the stability of repeat lipoprotein(a) measurements and the association between instability in lipoprotein(a) molar concentration with incident CAD. MethodsThe authors assessed the correlation between baseline and first follow-up measurements of lipoprotein(a) in the UK Biobank (n = 16,017 unrelated individuals). The association between change in lipoprotein(a) molar concentration and incident CAD was assessed among 15,432 participants using Cox proportional hazards models. ResultsBaseline and follow-up lipoprotein(a) molar concentration were significantly correlated over a median of 4.42 years (IQR: 3.69-4.93 years; Spearman rho = 0.96; P < 0.0001). The correlation between baseline and follow-up lipoprotein(a) molar concentration were stable across time between measurements of <3 (rho = 0.96), 3-4 (rho = 0.97), 4-5 (rho = 0.96), and >5 years (rho = 0.96). Although there were negligible-to-modest associations between statin use and changes in lipoprotein(a) molar concentration, statin usage was associated with a significant increase in lipoprotein(a) among individuals with baseline levels ≥70 nmol/L. Follow-up lipoprotein(a) molar concentration was significantly associated with risk of incident CAD (HR per 120 nmol/L: 1.32 [95% CI: 1.16-1.50]; P = 0.0002). However, the delta between follow-up and baseline lipoprotein(a) molar concentration was not significantly associated with incident CAD independent of follow-up lipoprotein(a) (P = 0.98). ConclusionsThese findings suggest that, in the absence of therapies substantially altering lipoprotein(a), a single accurate measurement of lipoprotein(a) molar concentration is an efficient method to inform CAD risk.

Value of repeated measurements of lipoprotein (a) to assess cardiovascular risk: a retrospective study

Background: High plasma concentrations of lipoprotein (a) [Lp(a)] are associated with an increased cardiovascular risk. Current guidelines recommend measurement of only a single Lp(a) in an individual’s lifetime under specific circumstances to improve cardiovascular risk prediction. Accordingly, the question raised is the number of false positives and negatives missed through only a single measurement. Methods: All Lp(a) measurements between 2004 and March 2021 were retrieved from the laboratory database of the Erasme hospital. Only patients with repeated measurement were included. The first and subsequent Lp(a) measurement were compared. Two different cohorts were studied as a result of a change in Lp(a) determination methodology (n = 2049 and n = 309, respectively). The effects of a third Lp(a) measurement were assessed through binary analyses (n = 678). The 180 mg/dl (430 nmol/L) threshold recommended in the ESC guidelines was assessed first. Analysis was repeated for 100, 70 and 50 mg/dl thresholds of raised Lp(a) levels. Results: A low rate of false negatives (0.8%–1%) and false positives (0.6–0.3%) were revealed with two Lp(a) measurements. There was no difference in regards to the divergent Lp(a) thresholds nor the measurement of Lp(a) on two or three occasions. Conclusion: The present study showed Lp(a) determination to be reproducible. A single measurement is sufficient to assess if a patient exceeds various cut-off values of elevated Lp(a) levels.

A Comparative Study of the Levels of Heat Shock Protein 70, Some Biochemical and Hormonal in the Blood of Cows Suffering from Follicular Cystic Ovarian and Endometritis

Twenty- four reproductive systems of Frisian cross breed cows, aged between (3-5years) were obtained from Basrah abattoir during the period of (2nd March 2020 - 30th June, 2020). They were divided into 3 groups of cows with ovarian follicular cystic (n=8), cows with endometritis (n = 8), and healthy cows (n=8) depending on clinical signs. The main gall of this paper compare and report the different values of heat shock protein 70 (HSP70), some biochemical and hormonal levels in those cows in the native Basrah climate. Samples of blood were collected from all cows subjected to this study and serum was harvested from each individual sample by centrifugation. Heat shock protein 70 (Hsp70), total protein (TP), albumin(Alb), globulin, total cholesterol (Cho), triglyceride (TG), low density lipo-protein(LDL), aspartate aminotransferase (AST), cortisol, testosterone, thyroid stimulation hormone (TSH), thyroxin (T4) and triiodothyronine hormones(T3) were measured in serum samples. Results revealed a significant increase (p≤0.05) in the level of Hsp70, and thyroid stimulation hormones (TSH) of cows with two pathological cases (endometritis and follicular cysts) compared with those healthy cow. Significant decrease (p≤0.05) in the measurement of total protein, albumin, globulin, thyroxin (T4), triiodothyronine (T3) hormones, cholesterol, triglyceride, and low density lipoprotein (LDL) in cows having those two genital diseases compared with normal cows. The results also were revealed a significant increase (p≤0.05) in the level of testosterone hormone in cows with follicular cystic ovarian case compared with endometritis case and control ones. Finally, significant increase (p≤0.05) in cortisol hormone level and aspartate aminotransferase (AST) activity in cows with endometritis case compared with the control one and follicular cystic ovarian cases.

POSA170 Prevalence of Elevated Lipoprotein(A) Among Atherosclerotic Cardiovascular Disease Patients with Lipoprotein(A) Measurements: Evidence from a Systematic Literature Review

Lipoprotein(a) [Lp(a)] is an inherited, independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD). A systematic assessment of evidence on Lp(a) from literature is lacking. We aim to describe the distribution of Lp(a) in secondary prevention ASCVD patients among geographies.

Lipoprotein (a) and Hypertension.

To provide an overview of the associations between elevated blood pressure and lipoprotein (a) and possible causal links, as well as data on the prevalence of elevated lipoprotein (a) in a cohort of hypertensive patients. Elevated lipoprotein (a) is now considered to be an independent and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Despite this, there are limited data demonstrating an association between elevated lipoprotein (a) and hypertension. Further, there is limited mechanistic data linking lipoprotein (a) and hypertension through either renal impairment or direct effects on the vasculature. Despite the links between lipoprotein (a) and atherosclerosis, there are limited data demonstrating an association with hypertension. Evidence from our clinic suggests that ~ 30% of the patients in this at-risk, hypertensive cohort had elevated lipoprotein (a) levels and that measurement of lipoprotein (a) maybe useful in risk stratification.

Lipidomic signatures for APOE genotypes provides new insights about mechanisms of resilience in Alzheimer’s disease

AbstractBackgroundThe apolipoprotein E gene (APOE) genotype is the first and strongest genetic risk factor for late‐onset Alzheimer’s disease and has emerged as a novel therapeutic target for AD. The encoded protein (Apolipoprotein E, APOE) is well‐known to be involved in lipoprotein transport and metabolism, but its effect on lipid metabolic pathways and the potential mediating effect of these on disease risk have not been fully defined.MethodWe performed lipidomic analysis on three independent cohorts (AIBL, n = 693; ADNI, n=207; BHS, n=4,384) and defined the association between APOE polymorphisms (ε4 and ε2) and plasma lipid species. To identify associations independent of lipoprotein metabolism, the analyses was performed with adjustment for clinical lipids (total cholesterol, HDL‐C and triglycerides). Causal mediation analysis was performed to estimate the proportion of risk in the outcome model explained by a direct effect of APOE genotype on prevalent AD — the average direct effect (ADE) — and the proportion that was mediated by lipid species or lipidomic risk models — the average causal mediation effect (ACME).ResultWe identified multiple associations of species from lipid classes such as ceramide, hexosylceramide, sphingomyelin, plasmalogens, alkyldiacylglycerol and cholesteryl esters with APOE polymorphisms (ε4 and ε2) that were independent of clinical lipoprotein measurements. There were 104 and 237 lipid species associated with APOE ε4 and ε2 respectively which were largely discordant. Of these 116 were also associated with Alzheimer’s disease. Individual lipid species (notably the alkyldiacylglycerol subspecies) or lipidomic risk models of APOE genotypes mediated up to 10% and 30% of APOE ε4 and ε2 treatment effect on AD risks respectively.ConclusionWe demonstrate a strong relationship between APOE polymorphisms and peripheral lipid species. Lipids species mediate a proportion of the effects of APOE genotypes in risk of AD, particularly resilience with e2. Our results highlight the involvement of lipids in how APOE e2 mediates its resilience to AD and solidify their involvement with the disease pathway.

Effect of Methadone on Lipid Profile, Serum Leptin and Liver Enzymes Levels in Male and Female Rats

Methadone Maintenance Therapy (MMT) has been accepted as a gold-standard treatment for opioid therapy. It may associate with adverse effects. This study aimed to affect methadone on serum lipid profile, leptin levels, and liver enzymes in male and female rats. 41 Wistar rats weighing 200-300gr were randomly assigned into four groups, including two methadone treatments and two control groups, both male and female, that received 5mg/kg methadone or 1cc normal saline daily for 8 weeks respectively by gavage method. All animals were weighed weekly. Fasting blood sugar (FBS) was measured by a glucometer, and blood samples were taken by cardiac puncture for triglyceride, low-density lipoprotein (LDL),high-density lipoprotein (HDL), total cholesterol, Aspartate transaminase (AST), Alanine transaminase (ALT), alkaline phosphatase (ALP) and leptin levels measurement after 12h fasting. One-way ANOVA showed no significant difference in mean FBS, total cholesterol, triglyceride, and LDL levels among the four groups. Moreover, there was a statistically significant difference in the mean of HDL, ALT, AST, and ALP levels. Furthermore, repeated measures ANOVA indicated a significant increase in body weight of rats during 8 weeks. Our findings indicated changes in some metabolic effects associated with methadone treatment in a gender-dependent manner.

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.