Lp Concentrations Research Articles

Impact of Lp(a) on lipid control in patients with acute coronary syndrome

Abstract Background The lipoprotein(a) (Lp[a]) is a genetically determined low-density lipoprotein (LDL)-like particle. Lp(a) levels above 50mg/dl have been correlated to an increased risk of atherosclerosis and major adverse cardiovascular events. Thus, treatments designed to reduce Lp(a) levels are currently under investigation. However, it is unknown how high Lp(a) concentrations affect the control of lipid profile. Purpose The purpose of this project is to investigate how Lp(a) impacts lipid profile control in individuals with acute coronary syndromes (ACS). Methods We designed a single-center prospective registry including consecutive patients admitted for ACS. Lp(a) levels were obtained from all enrolled patients during hospitalization; lipid profile (total cholesterol (TC), LDL-cholesterol, HDL-cholesterol, triglycerides) was obtained at admission and at the 6-month follow-up (6MFU). Patients were stratified according Lp(a) concentration (low-Lp(a): Lp(a) < 50 mg/dL; high-Lp(a): Lp(a) ≥ 50 mg/dL). LDL-cholesterol (LDLcorr) levels corrected for concentration of Lp(a) were calculated as LDLcorr= LDLmeasured – 30%Lp(a). At discharge cholesterol lowering drugs were introduced or titrated as standard of care. The primary endpoint was the percentage of patients reaching target LDL and LDLcorr (<55 mg/dL) at 6MFU. The secondary endpoints were the correlations between Lp(a) levels and lipid profile, both at baseline and at 6MFU, as well as the correlation between Lp(a) levels and the total number of traditional cardiovascular risk factors in the study population. Results From February 2020 through September 2023, a total of 409 patients were included: 305 (74.6%) with Lp(a) < 50 mg/dL; 104 (25.4%) with Lp(a) ≥ 50 mg/dL (Table 1). High-Lp(a) patients showed a lower prevalence of diabetes (14.2% vs 27.87%, P = 0.0055), an overall lower number of traditional cardiovascular risk factors (>2 in 25.9% vs 38.1%, P=0.0244). High-Lp(a) patients showed higher level of LDL-cholesterol compared to the low-Lp(a) population both at baseline (124±52 mg/dL vs 110.4±44 mg/dL, P= 0.0263) and at 6MFU (70.5±21 vs 63.8±29, P= 0.0208) with fewer patients achieving the target LDL cholesterol levels (21.57% vs 40.13%, P=0.0184). Estimating the true LDL concentration (LDLcorr) the percentage of patients reaching target LDL cholesterol levels at FU significantly increased in the high-Lp(a) group (from 21.57% to 76.5%), with a minimal increase noticeable in the low-Lp(a) population (from 40.13% to 48.41%, p 0,1870). Conclusions In ACS population, patients with high Lp(a) concentrations have fewer traditional CV risk factors and a lower prevalence of diabetes. High-Lp(a) patients, furthermore, seem more challenging to meet LDL target at 6 month follow up, but not when the LDL values are adjusted for Lp(a).

Polymorphic size of Lipoprotein (a) and structural bioprosthetic valve degeneration

Abstract Background The use of biological heart valves (BHV) is constantly growing for the treatment of patients with aortic stenosis and their durability arises as a main concern in the field. Structural valve deterioration (SVD) of the BHV occurs gradually post-implantation and seems to reiterate, at least in part, the pathophysiological processes described in native valve stenosis. Lipoprotein (a) [Lp(a)] is an important genetically determine cardiovascular risk factors, associated with native valve calcification. The shorter polymorphic sizes of Lp(a), defined as low of apolipoprotein (a) [apo(a)] Kringle-IV copy number, have been associated with more deleterious cardiovascular phenotype. However, the association of Lp(a) plasma levels and/or its polymorphic sizes with SVD remains unclear. Purpose To determine whether Lp(a) plasma levels and/or the Lp(a) polymorphic size were associated with SVD. Methods 332 patients who underwent aortic valve replacement (AVR) with BHV from the Translink trial were included in this study. Clinically significant SVD has been defined as Stage 3 SVD based on the VARC-3 definition. Lp(a) concentration was determine by immunoturbidimetry method and the apo(a) Kringle-IV copy number by liquid chromatography-tandem mass spectrometry. Univariable and multivariable models, adjusted for clinically relevant and statistically significant variables, were used to determine the independent association between Lp(a) concentrations or apo(a) Kringle-IV copy numbers with SVD. Results Among the 332 patients included in this study, the mean age was 78 ±8 years and 71% were males. 76 patients (23%) presented clinically significant SVD. Low apo(a) Kringle-IV copy number was associated with an increased risk of SVD (per log decrease: OR=2.71 [1.34-5.50], p=0.006), but not Lp(a) plasma concentration (OR=0.99 [0.84-1.15], p=0.85). This association remained significant after comprehensive multivariable adjustments, including Lp(a) concentration (OR=3.21 [1.31-7.84], p=0.01). The analysis of the transprosthetic mean gradient, as a surrogate marker of SVD, provided consistent results (all p≤0.03). Conclusion This cross-sectional study from the Translink trial demonstrates the association between Lp(a) polymorphic size and SVD, highlighting a potential therapeutic option to limit the occurrence of SVD in selected patients who underwent AVR with surgical or transcatheter BHV.

Deciphering lipoprotein(a) atherogenicity with use of high-throughput proteomics

Abstract Background Accumulating observational and genetic evidence suggests that lipoprotein(a) [Lp(a)], is significantly more atherogenic than other apolipoprotein-B containing particles. Systemic inflammation is thought to mediate the atherogenic effects of Lp(a). Previous studies have predominantly focused on single inflammatory biomarkers, an approach that fails to capture the broader molecular response to elevated Lp(a) levels. Purpose The aim of this study was to derive a proteome-wide signature of plasma Lp(a) concentrations and subsequently identify the pathways through which Lp(a) influences the risk of coronary artery disease (CAD). Methods This study included 41,123 UK Biobank participants with baseline Lp(a) measurements who also underwent a proteomic assessment. Relative concentration of 2,920 proteins was quantified in EDTA plasma samples using a high-throughput proximity extension assay. Lp(a)-associated proteins were identified in linear regression models, adjusting for age, sex, body mass index, race, smoking status, estimated glomerular filtration rate, medication use, and apolipoprotein B. Proteins linked with Lp(a) concentration were then evaluated for their association with incident CAD risk using Cox proportional hazards models. Significant traits were further included in pathway enrichment analysis. Results Out of 2,920 analyzed proteins (Figure 1), 140 showed a positive association with Lp(a) concentration, while 336 exhibited a negative association after adjustment for multiple testing (False discovery rate < 0.05). The strongest positive associations were observed for apolipoprotein F, group 10 secretory phospholipase A, and C4b-binding protein beta chain. The strongest negative associations were observed for asporin, aminoacylase-1, and retinol-binding protein 5. Among 140 proteins positively associated with Lp(a), 49 were associated with an increased risk of CAD. Conversely, among the 336 proteins negatively associated with Lp(a), 10 were associated with a decreased risk of CAD. Pathway enrichment analysis (Figure 2) indicated that proteins linked with both Lp(a) levels and CAD risk predominantly upregulated pathways related to peptide-ligand receptor signalling, platelet degranulation, neutrophil degranulation, and cytosolic calcium response. Conversely, pathways related to HDL remodeling, PI3K/AKT, KIT, and nuclear receptor signalling were downregulated. Conclusions The greater atherogenic potential of Lp(a) may be attributable to the modulation of several molecular pathways, particularly those involving platelet and neutrophil responses, cell signalling, and lipoprotein metabolism.

Study of lipoprotein(a) and its impact on atherosclerotic cardiovascular disease: design, rationale, and first results of the Zabrze-Lip(a)R Registry

Abstract Aims Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. Increased Lp(a) concentration >30 mg/dl may cause faster atherosclerosis. There is a need to characterize further the clinical phenotypes in patients at risk for ASVD with high Lp(a) levels. Material The Zabrze-Lip(a)R Registry was created on the basis of data from 2,001 patients with high- and very high cardiovascular risk treated in a tertiary hospital, and the Registry patients will be followed for many years. Mortality and cardiovascular events, such as known death, MI, and stroke, will be assessed. Results The median Lp(a) concentration in the entire population was 6.6 mg/dl (mean 14.3 ± 19.4 mg/dl). Preliminary results of the study group showed that 540 (27%) patients had elevated Lp(a) levels above 30 mg/dl, mainly in patients with established ASCVD after MI and/or coronary revascularization. Patients with elevated Lp(a) levels are older and have higher hematocrit and NT-proBNP and CRP levels. Conclusions Extensive observational studies are essential for further work that objectively collects information on the risks associated with Lp(a) values and cardiovascular disease. Additionally, developing a deeper understanding of the impact of Lp(a) on prognosis will be valuable in how Lp(a) interacts with other established risk factors in improving cardiovascular risk prediction.Distribution of Lp(a) concentrationsComparison of pts with different Lp(a)

Causal associations of insulin and Lp(a) levels: a Mendelian randomization study

Abstract Background Numerous observational studies have demonstrated circulating lipoprotein(a) [Lp(a)] to be inversely related to occurrence of type 2 diabetes [T2D]. However, this is not consistently supported by Mendelian randomization [MR] studies. In vitro studies have shown insulin to downregulate Lp(a) expression, which might be another mechanism behind the correlation observed between Lp(a) and T2D. Purpose In this MR study, we investigated the influence of genetically predicted levels of insulin on genetically predicted Lp(a) levels to elucidate the potential causal links between Lp(a) and diabetes. Methods Independent genetic variants associated with insulin levels were acquired from a meta-analysis of genome-wide association studies (GWAS, N=151,013). Summary data for Lp(a) were acquired from a GWAS study in the UK Biobank (N=361,194). Inverse-variance-weighted (IVM) method was used to perform a two sample MR study. Sensitivity analysis was conducted via MR Egger, weighted median (WME), as well as leave-one-out analysis. Results Genetically predicted insulin levels were negatively associated with Lp(a) levels according to IVM estimate (p=0.003). In sensitivity analysis, WME supported this result (p=0.0002), while MR-Egger was not statistically significant (p=0.11). Leave-one-out analysis did not show the results to depend on any single variant. Conclusion This MR study provides robust evidence supporting the association between plasma insulin levels and decreased Lp(a) concentration. These findings suggest that hyperinsulinemia triggered by insulin resistance can be in part responsible for the observed negative correlation between low Lp(a) and T2D risk. Figure 1. Genetic associations between insulin levels and Lp(a). Each genetic variant included in the analysis is represented as a point + 95% CI. Localization on the horizontal axis represents the correlation of the variant with exposure (plasma fasting insulin, inverse variance normal transformed values). Localization on the vertical axis represents the correlation of the variant with outcome (Lp(a), natural log transformed values). Lines represent estimates of different MR methods.Figure 1.

Lipoprotein(a) and atherosclerotic cardiovascular disease in a Brazilian tertiary hospital population

Abstract Background/Introduction Elevated levels of lipoprotein(a) [Lp(a)] are a strong risk marker of atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction (MI), ischemic stroke, and peripheral arterial disease, as well as of aortic valve calcification and stenosis. However, few studies have assessed the prevalence of high Lp(a) levels in patients followed at a tertiary hospital specialized in cardiovascular diseases (CVD). In addition, there is scant information about Lp(a) concentrations in Brazilian individuals. Purpose The aim of the study was to describe the demographic characteristics and comorbidities of patients with at least one measure of Lp(a) at a tertiary treatment center for CVD in our city – Brazil. Methods Patients treated at a heart institute had their data extracted between the years 1999 and 2021. Data were obtained through direct electronic extraction of patients' medical records. The patients were categorized according to different Lp(a) cutoff levels (> 50 and < 70, > 70 and < 90, and > 90 mg/dL) and by quartiles. Results Of 4,970 unique patients included in the study, the mean age at baseline was 59.9 years (SD ± 14.5), 2,634 (53%) were male, and the median Lp(a) was 23.2 mg/dL (interquartile range 8.9 - 56.8 mg/dL). In the whole cohort, 460 (9.3%) had Lp(a) > 50 and < 70, 344 (6.9%) > 70 and < 90, 612 (12.3%) > 90 mg/dl and 138 (2.8%) > 150 mg/dL. Established ASCVD was reported in 1,223 (24%) of the individuals, with a progressively higher prevalence across the Lp(a) categories above (31.2%, 33.8%, 34.2%, respectively) (table 1). Moreover, the Lp(a) median (interquartile range) in mg/dL was significantly higher in those with baseline history of ASCVD (31.4 [10.8-71.2] vs 21.2 [8.3-52]), MI (27.8 [10.6-65.9] vs 22.3 [8.5-54.7]) and stroke (24.9 [10-69.5] vs 23.1 [8.9-56.5]), all p < 0.05 (table 2). Lp(a) was also significantly higher among those with LDL-C ≥ 100 mg/dL relative to LDL-C < 100 mg/dl (25.5[9.5-63.2] vs 21.4[8.4 vs 52.2] p < 0.05). Conclusions In this cohort of patients followed at a tertiary center specialized in CVD, approximately a third had Lp(a) levels above 50 mg/dL, a cutoff robustly associated with ASCVD. This finding likely represents an important source of cardiovascular residual risk, particularly in those with established ASCVD, exposing the need of further therapies.

Comparison of cardiovascular disease risk assessment tools in primary prevention patients with raised lipoprotein(a)

Abstract Background Genetically inherited lipoprotein (a) (lp(a)) is an independent cardiac risk factor. The approach to cardiovascular disease (CVD) risk modification is, however, uncertain. Current CVD risk calculators do not take lp(a) into account and guidance suggests binary treatment decisions based on presentation of lp(a) without considering other risk factors. A new CVD risk assessment tool has been developed which includes lp(a) concentration, Lp(a) Clinical Guidance (lpaclinicalguidance.com). Purpose The aim was to compare the CVD risk estimations and management impact, over both 10 years and lifetime, using the HEART UK consensus statement, QRISK3, Lp(a) Score, Score-2, Score-2 OP, and LIFE-CVD assessment tools in 20 primary prevention patients with raised lp(a). Methods This was a retrospective analysis from an existing database, recruited through lipid and cardiology outpatient services, with raised lp(a), and no history of CVD. A random selection with a broad range of lp(a) concentrations were chosen. The 10-year risk threshold to treat was based on current NICE guidance at 10% and, in the absence of consensus, a lifetime risk threshold of 25%. Lp(a) was measured by a reference clinical laboratory using a Roche platform (Denka Seiken reagent, isoform insensitive). Results The subset (n=20) included patients with lp(a) ranging from 64 nmol/L to >720 nmol/L, aged 20 to 78 (12 females). Risk assessment tool age restrictions prohibited risk estimation in all patients (explaining the variation in denominator below). Figure 1 shows a comparison of 10-year risk assessment tools, figure 2 lifetime risk. HEART UK guidance would indicate 90% of patients (18/20) were eligible to commence lipid lowering therapy, however, all patients would have treatment indicated based on Lp(a) Score (16/16). Using Score-2, no patients would have treatment indicated (0/6). Only 25% of patients (1/4) would have treatment indicated using Score-2 OP despite a minimum age criterion that alone introduces a major CVD risk factor. Of the remaining risk estimation tools: LIFE-CVD, QRISK3 lifetime risk, and QRISK3 10-year risk indicated 85% (11/13), 50% (8/16), and 38% (6/16) of patients, respectively, would have treatment indicated. Conclusions In primary prevention patients with raised lp(a), CVD risk estimation and decision-making is impaired by discrepancies in risk assessment tools. There may be underestimation in CVD risk, and subsequently under-treatment, with principal use of QRISK3 10-year risk to guide lipid lowering therapy. Lifetime CVD risk may be underestimated by QRISK and LIFE-CVD proportionally to the degree of elevation of lp(a). Risk assessment is imperfect; population data can only provide limited information when applied to an individual and the wide discrepancy found here calls into question the validity of risk estimation formulae in this population, or alternatively provides a range of tools for clinicians to select to suit the question asked.

Does the LPA genotype have a role in coronary artery disease risk beyond Lp(a) values?

Abstract Introduction High lipoprotein(a) [Lp(a)] concentrations are one of the most important genetically determined risk factors for coronary artery disease (CAD). Many functional single nucleotide polymorphisms (SNPs) of the LPA gene have pronounced effects on Lp(a) concentrations. Studies show that rs3798220 polymorphism is strongly associated with Lp(a) concentration and also with risk of CAD. Goal: To evaluate if LPA rs3798220 T>C is associated with CAD beyond its effect on Lp(a) levels. Methods We performed a case-control study with 3,157 individuals (1,721 CAD patents and 1,436 controls). The LPA rs3798220 T>C was genotyped with the TaqMan PCR assay (Applied Biosystems 7300 Real-Time). This variant has a minor allele frequency (MAF) <2%; hence, the risk homozygous CC is a rare genotype, and we used the heterozygous CT in our analysis. Laboratory analysis was performed, and Lp(a) biochemical levels were measured in the cases and controls. Chi-squared tests were used to determine differences by genotype in CAD association (in cases and controls). We also reported a multivariate logistic regression to test if this LPA variant is still independently associated with CAD after adjustment to Lp(a) levels and traditional risk factors for CAD. Results Wild-type genotype TT was increased in the group without CAD, whereas the genotype TC was higher in patients with CAD (p<0.0001). After multivariate logistic regression, adjusted for traditional risk factors, the TC genotype remained in the equation as an independent risk factor for CAD (OR=2.36; 95%CI: 1.54–3.61; p<0.0001). When the multivariate regression analysis is adjusted for traditional risk factors plus Lp(a) levels, the TC genotype remains in the equation as independently associated with CAD despite being substantially attenuated (OR=1.67; 95%CI: 1.07–2.60; p=0.025). Conclusion LPA rs3798220 T>C may be an independent risk factor for CAD beyond the effect of rising Lp(a) levels. Perhaps testing for the genetic determinants of Lp(a) relative to direct measurement of Lp(a) level could provide additional prognostic utility.

High intensity statin-ezetimibe combination therapy reduces mortality in patients with ischaemic heart disease and elevated Lipoprotein(a)

Abstract Background Early and prompt reduction of low-density lipoprotein cholesterol concentrations (LDL-C) using combination lipid-lowering therapy (LLT) is recommended to lower cardiovascular risk in patients with ischaemic heart disease (IHD) and elevated LDL-C. Lowering LDL-C is also an important cardiovascular risk mitigation strategy in patients with elevated lipoprotein(a) [Lp(a)]. However, it is unknown if combination LLT reduces mortality in patients with elevated Lp(a). Aim To undertake an observational study to investigate the effect of combination LLT using high intensity statin with ezetimibe on cardiovascular outcomes in patients with and without elevated Lp(a). Methods Serum Lp(a) concentrations were measured in 520 consecutively recruited patients with IHD admitted to hospital, half of whom were admitted for acute myocardial infarction. Patients treated with high intensity statin and ezetimibe within the 1st year from admission to hospital (‘HI statin-ezetimibe group’, n=157) were compared with the rest of patients who had less intensive lipid lowering regimen (‘Others group’, n=363) for cardiovascular outcomes. Results During the 2-year follow-up period, 14.6%, 6.5%, and 53.1% of patients had all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE) respectively. Median age was 63.5 years and 82.3% were male. Multivariable Cox regression showed that baseline Lp(a) ≥70 nmol/L was associated with increased risk of all-cause mortality (HR 1.97, 95% CI 1.20-3.22, P=0.007). Compared with a less intensive regimen, HI statin-ezetimibe was associated with reduced risk of all-cause mortality (HR 0.44 [0.21-0.89], P=0.023) and MACE (HR 0.71 [0.52-0.95], P=0.027), with no statistically significant effect on cardiovascular mortality (HR 0.43, P=0.142). Notably, the cardiovascular benefits of HI statin-ezetimibe were more pronounced in patients with elevated Lp(a); a greater reduction in risk of MACE was seen for patients with Lp(a) ≥70 nmol/L (HR 0.51, P=0.007) or Lp(a) ≥100 nmol/L (HR 0.36, P=0.009), and in all-cause mortality risk for those with Lp(a) ≥70 nmol/L (HR 0.24, P=0.025). Although LDL-C reduction >50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibe use in patients with or without elevated Lp(a). Conclusion Intensification of lipid-lowering therapy with high-intensity statin and ezetimibe improves cardiovascular outcomes in patients at very high cardiovascular risk, particularly those with elevated Lp(a). Larger studies are required to confirm our findings that this cardiovascular benefit is partially independent of LDL-C lowering.

Lipoprotein (a) as a Cardiovascular Risk Factor in Controversial Clinical Scenarios: A Narrative Review

Lipoprotein (a) is a complex lipid molecule that has sparked immense interest in recent years, after studies demonstrated its significant association with several cardiovascular conditions. Lp(a) promotes cardiovascular disease through its combined proatherogenic, pro-inflammatory, and prothrombotic effects. While the measurement of Lp(a) has become widely available, effective methods to reduce its concentration are currently limited. However, emerging data from ongoing clinical trials involving antisense oligonucleotides have indicated promising outcomes in effectively reducing Lp(a) concentrations. This may serve as a potential therapeutic target in the management and prevention of myocardial infarction, calcific aortic stenosis, and cerebrovascular accidents. In contrast, the role of Lp(a) in atrial fibrillation, in-stent restenosis, cardiac allograft vasculopathy, and bioprosthetic aortic valve degeneration remains unclear. This review article aims to thoroughly review the existing literature and provide an updated overview of the evidence surrounding the association of Lp(a) and these cardiovascular diseases. We seek to highlight controversies in the existing literature and offer directions for future investigations to better understand Lp(a)’s precise role in these conditions, while providing a summary of its unique molecular characteristics.

Nanopore sequencing with unique molecular identifiers enables accurate mutation analysis and haplotyping in the complex lipoprotein(a) KIV-2 VNTR.

Repetitive genome regions, such as variable number of tandem repeats (VNTR) or short tandem repeats (STR), are major constituents of the uncharted dark genome and evade conventional sequencing approaches. The protein-coding LPA kringle IV type-2 (KIV-2) VNTR (5.6kb per unit, 1-40 units per allele) is a medically highly relevant example with a particularly intricate structure, multiple haplotypes, intragenic homologies, and an intra-VNTR STR. It is the primary regulator of plasma lipoprotein(a) [Lp(a)] concentrations, an important cardiovascular risk factor. Lp(a) concentrations vary widely between individuals and ancestries. Multiple variants and functional haplotypes in the LPA gene and especially in the KIV-2 VNTR strongly contribute to this variance. We evaluated the performance of amplicon-based nanopore sequencing with unique molecular identifiers (UMI-ONT-Seq) for SNP detection, haplotype mapping, VNTR unit consensus sequence generation, and copy number estimation via coverage-corrected haplotypes quantification in the KIV-2 VNTR. We used 15 human samples and low-level mixtures (0.5 to 5%) of KIV-2 plasmids as a validation set. We then applied UMI-ONT-Seq to extract KIV-2 VNTR haplotypes in 48 multi-ancestry 1000 Genome samples and analyzed at scale a poorly characterized STR within the KIV-2 VNTR. UMI-ONT-Seq detected KIV-2 SNPs down to 1% variant level with high sensitivity, specificity, and precision (0.977 ± 0.018; 1.000 ± 0.0005; 0.993 ± 0.02) and accurately retrieved the full-length haplotype of each VNTR unit. Human variant levels were highly correlated with next-generation sequencing (R2 = 0.983) without bias across the whole variant level range. Six reads per UMI produced sequences of each KIV-2 unit with Q40 quality. The KIV-2 repeat number determined by coverage-corrected unique haplotype counting was in close agreement with droplet digital PCR (ddPCR), with 70% of the samples falling even within the narrow confidence interval of ddPCR. We then analyzed 62,679 intra-KIV-2 STR sequences and explored KIV-2 SNP haplotype patterns across five ancestries. UMI-ONT-Seq accurately retrieves the SNP haplotype and precisely quantifies the VNTR copy number of each repeat unit of the complex KIV-2 VNTR region across multiple ancestries. This study utilizes the KIV-2 VNTR, presenting a novel and potent tool for comprehensive characterization of medically relevant complex genome regions at scale.

Serum Lipoprotein(a) Levels and Their Association with Atherosclerotic Cardiovascular Disease in Japan.

To investigate the distribution of lipoprotein(a) (Lp(a)) and its association with atherosclerotic cardiovascular disease (ASCVD) in Japanese patients at high risk for ASCVD using a health insurance database. Between July 2013 and June 2021, patients eligible for ASCVD prevention according to the 2017 Japan Atherosclerosis Society (JAS) guidelines with documented Lp(a) test results were extracted from the Medical Data Vision claims database and divided into three groups: primary prevention high-risk (Group I), secondary prevention (Group II) and secondary prevention high-risk (Group III). Data on lipid levels, cardiovascular morbidity risk factors and lipid-lowering treatments were extracted. Of 700,580 patients with documented low-density lipoprotein cholesterol (LDL-C), 2,967 (0.42%) were tested for Lp(a). In 2,170 eligible patients, the median [interquartile range] serum concentration of Lp(a) was 13.9 [7.5-24.6] mg/dL, with 151 patients (7.0%) above the recommended risk threshold of ≥ 50 mg/dL. Lp(a) levels increased with risk across all prevention groups. Being in the highest Lp(a) quintile (Q5) was associated with an increased frequency of ASCVD (28.9% versus 18.9% in the lowest quintile (Q1) for unstable angina; 18.7% versus 10.1% for myocardial infarction; 27.9% versus 17.0% for ischemic stroke). In the secondary prevention groups, the proportion of patients meeting an LDL-C target of ＜70 mg/dL decreased from 30.2% in Q1 to 19.0% in Q5 for Group II and from 32.9% to 16.3% for Group III. Despite a high prevalence of Lp(a) ≥ 50mg/dL in Japanese patients at high risk for ASCVD, it found that the Lp(a) testing rate was very low.

A-216 Prevalence and status of Lipoprotein(a) in the Korean population visiting local clinics and hospitals

Abstract Background Lipoprotein a (Lp(a)) is a risk factor for cardiovascular disease (CVD) and has pro-atherogenic and pro-inflammatory effects. According to the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, a sub-analysis was published showing that the risk of residual CVD after sufficiently lowering low-density lipoprotein cholesterol can be explained by Lp(a) concentration. The purpose of this study is to determine the prevalence of elevated Lp(a) and to analyze the characteristics of Lp(a) results by age, gender, and region in the Korean population visiting local clinics and hospitals. Methods We retrospectively reviewed Lp(a) test results from the Korean population who visited 117 local clinics and hospitals nationwide between February 2023 and January 2024. Serum levels of Lp(a) were measured by immunoturbidimetric assay. Lp(a) was analyzed to three age groups (<20, 20-59, ≥60 years) according to Lp(a) values (<30 or ≥30 mg/dl). One hundred seventeen local clinics and hospitals across the country were reclassified into 7 regions. Results A total of 15,523 patients (7,702 males and 7,821 females), aged 12-104 years, were included. The median (interquartile range, IQR) age of the population was 59 (49-69) years; the median (IQR) Lp(a) concentration was 9.7 (4.2-21.6) mg/dl. The prevalence of elevated Lp(a) levels (≥30 mg/dl) in this study was 16.7% (13.9% for males, 19.5% for females, p <0.001). Prevalence of elevated Lp(a) levels by age groups were as follows: <20 (8.9%, 5/56), 20-59 (13.9%, 1,071/7,724), ≥60 years (19.6%, 1,516/7,743). The correlation coefficient r between Lp(a) and age was 0.139 (p <0.001). No significant relationship was found between Lp(a) and region. Among 15,523 patients, the number of patients with Lp (a) level ≥100 mg/dl was 174 (n=70 for males, n=104 for females, p=0.128), and median (IQR) Lp(a) concentration was 115.1 (106.8-131.6) mg/dl. Of them, four patients showed extremely high Lp(a) levels (>180 mg/dL). Conclusions The prevalence of elevated Lp(a) in our population visiting local clinics and hospitals nationwide was 14.4% and differed by gender and age group. For successful management and establishment of the policy of CVD, it is important to identify the prevalence of elevated Lp(a). Future study is needed including the clinical information to confirm the present findings.

A-225 Validation of self-collected capillary dried plasma spot collection for lipoprotein(a) testing

Abstract Background Cardiovascular disease is prominent among socially disadvantaged populations that do not have the resources for standard health screening. Self-collected capillary Advance Dx (ADX) dried plasma spot cards could address these issues by offering access to clinically acceptable lipid screening from remote collections. Our laboratory currently uses ADX specimens to screen for cholesterol, calculated LDL, HDL, glucose, lipoprotein (a) (LP(a)), and triglycerides, however, the current study will focus on the validation of self-collected capillary ADX specimens for LP(a) testing. Methods ADX LP(a) was measured using the Tina-quant Lipoprotein (a) Gen.2 assay on the Roche cobas c702 closed development channel. All closed development channel assay parameters followed the standard assay, except sample volume increased from 2 to 18uL. Calibration was performed using Roche LP(a) calibrators diluted 1:10 with water. Patient specimens were prepared by collecting four 6mm punches from the plasma portion of the ADX card. Samples were resuspended in 400uL of 0.1% bovine serum albumin and incubated for 30 minutes at room temperature (RT) while shaking at 250 RPM. Non-biological materials were diluted 1:13 with water to match the sample-to-diluent ratio of the extracted patient ADX specimens. A correction factor (CF) was derived and challenged using total protein (TP) as an internal standard. BioRad Lipids Control (BRLC) and ADX patient specimens were run for wet and dry matrices to establish imprecision. Accuracy was determined using BRLC and ADX patient specimens. Linearity was confirmed by running 5 levels of Maine Standards Linearity Cardiac CM3 Kit. ADX stability was observed at RT and under summer/winter conditions to account for shipping to the laboratory. Results Specimens tested between venous and ADX LP(a) to derive the CF (n=70) had a bias of 21.92 mg/dL (132.28%) and a linear equation of (y=2.40x -1.23; R=0.985). Average card TP was 4.36 g/dL. The resulting CF is: reported ADX LP(a) = ((4.36/card TP)*card LP(a)*2.397)-1.23. Matched venous and ADX specimens that challenged the CF (n=50) had a bias of -1.00 mg/dL (-3.33%) and a linear equation of (y=0.98x -0.25; R=0.994) at the medical decision point of 30.00 mg/dL. Imprecision was 2.4% and 2.4% for BRLC specimens with mean concentrations of 15.04 and 29.40 mg/dL, respectively. Imprecision was 4.2% and 10.5% for ADX patient control specimens with mean venous target concentrations of 66.85 and 14.81 mg/dL, respectively. BRLC had an average bias of -0.31 mg/dL (-2.03%) and 0.41 mg/dL (1.40%) for levels 1 and 2, respectively. ADX patient specimens (n=3) had average biases of -1.47 mg/dL (-3.83%), 1.43 mg/dL (2.15%), and -1.58 mg/dL (-10.64%). ADX LP(a) concentrations from 6.0-80.0 mg/dL were linear (y=1.04x -0.45; R=0.999). The ADX specimen is stable for at least 7 days at RT and at least 5 days under summer and winter shipping conditions. Conclusions All assay parameters met acceptability criteria and were less than the total allowable error of 28.8%. Self-collected capillary ADX specimens are acceptable for the clinical measurement of LP(a), and effectively improve access to testing and identifying high-risk individuals as therapeutic strategies for treatment of elevated LP(a) continue to emerge.

The prevalence of hyperlipoproteinemia(a) in outpatient cardiology clinic patients of European ancestry: results from a STAR-Lp(a) cross-sectional study.

Elevated lipoprotein(a) [Lp(a)] is independently associated with an increased risk of cardiovascular disease (CVD). Evaluating the levels of Lp(a) among patients of European ancestry referred to outpatient cardiology clinics. We included 2475 consecutive patients referred to outpatient cardiology clinics between March 2022 and January 2024. We excluded all patients with atherosclerotic cardiovascular disease, heart failure, significant valve disease, and aortic aneurysm. The median age of the 2475 study participants (of which 1724 [69.7%] were women) was 66.0 years [53.0-73.0 years]). An Lp(a) level of ≥30 mg/dL (≥75 nmol/L) was recorded in 21.5% and a level of ≥50 mg/dL (≥125 nmol/L) was recorded in 13.5% of patients. In univariable analysis the level of Lp(a) was significantly associated with hypertension, sleep apnea, migraine, polycystic ovary syndrome, physical activity, fasting blood glucose, HbA1c, LDL, and non-HDL cholesterol. Being female (β±SE 0.06±0.02), atrial fibrillation (0.05±0.02), HbA1c (0.14±0.02), and LDL cholesterol (0.09±0.02) were independently related to the level of Lp(a). Atrial fibrillation (odds ratio [OR] 1.80, 95%CI:1.01-3.19), migraine (0.51, 0.32-0.83) and hyperlipidemia (1.56, 1.22-1.99) were related to Lp(a) ≥30 mg/dL (≥75 nmol/L), while being female (1.46, 1.10-1.92), hyperlipidemia (1.49, 1.12-1.97), hypertension (1.42, 1.10-1.84) and HbA1c (0.84, 0.72-0.96) were related to Lp(a) ≥50 mg/dL (≥125 nmol/L). The prevalence of increased Lp(a) concentration among patients of European ancestry consulting with cardiologists is 21.5%. Being female, hypertension, atrial fibrillation, migraine, LDL-C, and HbA1c concentration are independently related to the level of Lp(a) in this population.

Hierarchical porous ACNF/MIL-68(In)–NH2 composites for rapid and efficient removal of losartan from water: Unveiling adsorption mechanisms and superior performance

Losartan (LP), a medication commonly used to treat hypertension, has emerged as a potential environmental pollutant. Despite its widespread use, research on the efficient and rapid removal of LP from the environment remains very scarce. The limited studies on LP adsorption indicate that the adsorption capacity and rate of LP need improvement. In this study, we successfully prepared a hierarchical porous nitric acid-treated carbon nanofiber (ACNF)/MIL-68(In)–NH2 composite with a robust three-dimensional support structure using a simple hydrothermal method for the first time to adsorb LP. The resulting ACNF/MIL-68(In)–NH2 composite demonstrated exceptional adsorption capabilities, achieving an equilibrium absorption capacity of 259.87 mg/g within just 64 min, significantly outperforming previously reported results. Langmuir fitting indicated a maximum theoretical adsorption capacity exceeding 630 mg/g at 55 °C. For actual wastewater with low LP concentrations, complete removal was achieved with a minimal dose of the ACNF/MIL-68(In)–NH2 adsorbent. DFT calculations and Multiwfn wavefunction analysis revealed that the adsorption behavior of LP onto ACNF/MIL-68(In)–NH2 is primarily driven by electrostatic interactions, multiple hydrogen bonds, π-π stacking interactions, and van der Waals forces. This work presents an innovative strategy for the efficient and rapid removal of residual LP from water environments.

Efficacy of Traditional Anti-lipidemic Drugs in Lowering Lipoprotein(a) Levels: A Systematic Review.

Lipoprotein(a), or Lp(a), was identified in the early 1960.Its role as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) became widely recognized by the late 20th century, regardless of other traditional risk markers such as low-density lipoproteins and high-density lipoproteins. This study aimed to systematically review available literature and compare the efficacy of different lipid-lowering drugs, both approved for clinical use and currently undergoing trials, in lowering Lp(a) levels. A comprehensive search of medical databases including PubMed, PubMed Central (PMC), Medline, ScienceDirect, Cochrane Library, and Google Scholar was conducted to identify relevant studies. A total of 29 research papers met the inclusion criteria, focusing on the impact of various lipid-lowering drugs on Lp(a) concentration in patients with significantly elevated baseline Lp(a) levels. Plasma Lp(a) levels exceeding 30 mg/dL are associated with a higher risk of ASCVD, including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and increased all-cause mortality. Most commonly used lipid-lowering agents, such as statins, fibrates, ezetimibe, and nutraceuticals like coenzyme Q10 (CoQ10), showed no significant effect on Lp(a) plasma levels. However, Lp(a) apheresis and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors were found to effectively reduce plasma Lp(a) concentrations. Emerging therapies targeting apolipoprotein(a) RNA, including anti-sense oligonucleotides (ASO) and small interfering RNA (siRNA), significantly reduced Lp(a) levels in Phase 2 trials. While several lipid-lowering agents have minimal impact on Lp(a) levels, therapies like Lp(a) apheresis, PCSK-9 inhibitors, and novel RNA-targeting drugs show promise in effectively reducing Lp(a) concentrations. However, whether these reductions translate into decreased cardiovascular events remains to be determined.

Causal associations between insulin and Lp(a) levels in Caucasian population: a Mendelian randomization study

BackgroundNumerous observational studies have demonstrated that circulating lipoprotein(a) [Lp(a)] might be inversely related to the risk of type 2 diabetes (T2D). However, recent Mendelian randomization (MR) studies do not consistently support this association. The results of in vitro research suggest that high insulin concentrations can suppress Lp(a) levels by affecting apolipoprotein(a) [apo(a)] synthesis. This study aimed to identify the relationship between genetically predicted insulin concentrations and Lp(a) levels, which may partly explain the associations between low Lp(a) levels and increased risk of T2D.MethodsIndependent genetic variants strongly associated with fasting insulin levels were identified from meta-analyses of genome-wide association studies in European populations (GWASs) (N = 151,013). Summary level data for Lp(a) in the population of European ancestry were acquired from a GWAS in the UK Biobank (N = 361,194). The inverse-variance weighted (IVW) method approach was applied to perform two-sample summary-level MR. Robust methods for sensitivity analysis were utilized, such as MR‒Egger, the weighted median (WME) method, MR pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out analysis, and MR Steiger.ResultsGenetically predicted fasting insulin levels were negatively associated with Lp(a) levels (β = − 0.15, SE = 0.05, P = 0.003). The sensitivity analysis revealed that WME (β = − 0.26, SE = 0.07, P = 0.0002), but not MR‒Egger (β = − 0.22, SE = 0.13, P = 0.11), supported a causal relationship between genetically predisposed insulin levels and Lp(a).ConclusionOur MR study provides robust evidence supporting the association between genetically predicted increased insulin concentrations and decreased concentrations of Lp(a). These findings suggest that hyperinsulinaemia, which typically accompanies T2D, can partially explain the inverse relationship between low Lp(a) concentrations and an increased risk of T2D.

Deciphering the associations of selenium distribution in serum GPx-3 and selenoprotein P with cardiovascular risk factors in a healthy population with moderate levels of selenium: The ATTICA study

BackgroundSelenium (Se) is an essential micronutrient, important for human health. The relationship of Se with cardiovascular risk factors is still inconclusive, especially regarding the role of different selenoproteins. The present study evaluated the relation of total serum Se as well as its distribution in plasma selenoproteins, namely glutathione peroxidase 3 (GPx3) and selenoprotein P (SelP) with cardiovascular risk factors in a sex-specific manner, in a healthy population with moderate levels of Se. Methods: A sub-sample from the ATTICA Study’s database, consisting of 398 participants (160 females and 238 males) with data on Se and selenoproteins levels, was considered. GPx3, SelP and the main non-specific serum selenium containing protein, selenoalbumin (SeAlb) were simultaneously determined in human plasma by high-performance liquid chromatography (HPLC) coupled with inductively coupled plasma mass spectrometry (ICP-MS) at baseline. Results: Participants that belong to the highest tertiles of GPx3 and SelP presented the lowest blood pressure. Homocysteine was inversely associated with SelP and its ratio SelP/TSe in both sexes. In males, the lowest tertile of GPx3 showed lower adiponectin levels (0.66 ± 0.21 μg/mL) in comparison to the 2nd tertile of GPx3 (p=0.002), SelP was inversely associated with visceral adipose index (VAI) (-2.29 ± 0.81, p=0.005). Particularly, in males, the middle tertile of SelP had the lowest VAI values. Regarding females, lower Lp(a) concentration by 11.96 ± 5.84 mg/dL was observed in low SelP levels while higher leptin concentration by 2.30 ± 0.73 μg/L and lower fibrinogen concentration by 27.32 ± 13.30 mg/dL was detected in low GPx3 levels. Conclusion: Circulating selenoproteins exert differentiated effects on cardiovascular risk factors, some of them in a sex-specific manner.

Lipoprotein (a) and the Occurrence of Lipid Disorders and Other Cardiovascular Risk Factors in Patients without Diagnosed Cardiovascular Disease.

Background: Elevated lipoprotein (a) [Lp(a)] concentrations are linked mainly to genetic factors. The relationship between Lp(a) and other lipid disorders or cardiovascular (CV) risk factors has been less investigated. The aim of this study was to assess the occurrence of lipid disorders and other CV risk factors according to Lp(a) concentrations. Methods: A cross-sectional analysis of 200 primary-care patients who had not been diagnosed with CV disease was conducted. The following risk factors were assessed: older age, history of hypertension, diabetes mellitus or dyslipidemia, smoking, lack of physical activity, body mass index (BMI), and waist circumference. The following lipid parameters were measured: total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and small, dense LDL (sdLDL-C). Patients were divided into two groups based on their Lp(a) concentrations: <30 mg/dL and ≥30 mg/dL. Results: In 70% of patients, the Lp(a) concentration was <30 mg/dL. The concentrations of lipid parameters did not differ between the groups. The rate of patients with sdLDL-C >1.0 mmol/L was higher in the low-Lp(a) group (10.0 vs. 1.7%, p = 0.04), with no significant differences regarding the other analyzed lipid disorders (p > 0.05). Both in the low- and high-Lp(a) group, most patients had two other abnormal lipid factors (45.0% and 60.0%, respectively). The distribution of impaired lipid parameters (p = 0.41) and other CV risk factors (p = 0.16) was similar in both groups. There was a lower rate of patients >60 years old (15.0% vs. 32.9%, p = 0.01) and with a BMI ≥ 25 kg/m2 (46.7% vs. 63.6%, p = 0.026) in the high-Lp(a) group, and previously diagnosed hyperlipidemia was more prevalent in this group (65.0% vs. 47.1%, p = 0.02). The occurrence of other cardiovascular risk factors did not differ significantly between the Lp(a) groups (p > 0.05). In the high-Lp(a) group, the highest proportion (25.0%) had two CV risk factors, and in the low-Lp(a) group, 31.4% had four CV risk factors. Conclusions: An elevated Lp(a) concentration is not related to the number of conventional CV risk factors or other impairment major lipid parameters.