Lp Concentrations Research Articles

The effect of LPA Thr3888Pro on lipoprotein(a) and coronary artery disease is modified by the LPA KIV-2 variant 4925G>A

Background and aimsHigh lipoprotein(a) [Lp(a)] concentrations are associated with increased coronary artery disease (CAD) risk. Lp(a) is regulated mainly genetically by the LPA gene but involved genetic variants have not been fully elucidated. Improved understanding of the entanglements of genetic Lp(a) regulation may enhance genetic prediction of Lp(a) and CAD risk. We investigated an interaction between the well-known LPA missense SNP rs41272110 (known as Thr3888Pro) and the frequent LPA splicing mutation KIV-2 4925G>A. MethodsEffects on Lp(a) concentrations were investigated by multiple quantile regression in the German Chronic Kidney Disease (GCKD) study, KORA-F3 and KORA-F4 (ntotal = 10,405) as well as in the UK Biobank (UKB) 200k exome dataset (n = 173,878). The impact of the interaction on CAD risk was assessed by survival analysis in UKB. ResultsWe observed a significant SNP-SNP interaction in all studies (p = 1.26e-05 to 3.03e-04). In quantile regression analysis, rs41272110 as a predictor shows no impact on Lp(a) (β = −0.06 [-0.79; 0.68], p = 0.879), but in a joint model including both SNPs as predictors, rs41272110 is associated with markedly higher Lp(a) (β = +9.40 mg/dL [6.45; 12.34], p = 4.07e-10). Similarly, rs41272110 shows no effect on CAD in UKB (HR = 1.01 [0.97; 1.04], p = 0.731), while rs41272110 carriers not carrying 4925G>A show an increased CAD risk (HR = 1.10 [1.04; 1.16], p = 6.9e-04). This group corresponds to 4% of the population. Adjustment for apolipoprotein(a) isoforms further modified the effect estimates markedly. ConclusionsThis work emphasizes the complexity of the genetic regulation of Lp(a) and the importance to account for genetic subgroups in Lp(a) association studies and when interpreting genetic cardiovascular risk profiles.

Cascade testing for elevated lipoprotein(a) in relatives of probands with high lipoprotein(a)

ObjectiveElevated lipoprotein(a) [Lp(a)] is a common inherited condition associated with cardiovascular disease. This study investigated whether cascade testing for Lp(a) was effective in detecting new cases of elevated Lp(a) in families. MethodsRelatives from adult probands with Lp(a) concentration ≥100 mg/dL were tested for elevated Lp(a) (≥50 mg/dL) via a cascade testing program in a tertiary hospital setting. The prevalence and yield of detecting new cases of elevated Lp(a) among the relatives were assessed. ResultsOf the 83 probands, 43.4% had familial combined hyperlipidemia (FCHL) and 34.9% common hypercholesterolemia (CH). Among 182 relatives tested (151 adults and 31 children), elevated Lp(a) was found in 68.1%, with 32.9% having Lp(a) between 50 and 99 mg/dL and 35.2% having Lp(a) ≥100 mg/dL. One new case of elevated Lp(a) ≥50 mg/dL was identified for every 1.5 relatives tested and 1 new case of elevated Lp(a) ≥100 mg/dL for every 2.8 relatives tested. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) >150 mg/dL compared with those with Lp(a) between 100 and 150 mg/dL (81.1% vs. 55.5%; P = 0.001). The concordance rates (kappa coefficient) for the detection of elevated Lp(a) with FCHL and CH were 34.8% (0.026) and 53.2% (0.099), respectively. ConclusionCascade testing for elevated Lp(a) from affected probands with phenotypic dyslipidemia is highly effective in identifying new cases of high Lp(a) in families. The yield of detecting elevated Lp(a) is greater when probands have higher levels of Lp(a) and exceeds the detection of relatives with FCHL and CH.

The relationship between lipoprotein(a) and cardiovascular events in acute coronary syndrome patients with and without chronic kidney disease

Background and aimsPatients with chronic kidney disease (CKD) have high residual risk of cardiovascular events, whether the residual risk is associated with elevated level of lipoprotein(a) [Lp(a)] is unascertained. We aimed to explore the impact of Lp(a) levels on the risk of major adverse clinical events (MACEs) in CKD patients hospitalized for acute coronary syndrome (ACS) compared to those without CKD. MethodsThe data of patients hospitalized for ACS were collected at the China-Japan Friendship Hospital from January 2015 to December 2019. Patients were divided into 2 groups according to renal function: non-CKD group (eGFR≥60 ml/min/1.73 m2) and CKD group (eGFR <60 ml/min/1.73 m2). Multivariate Cox regression analysis and restricted cubic splines were performed to explore the relationship between Lp(a) levels and MACEs. ResultsA total of 1306 patients were enrolled. Patients with CKD had higher Lp(a) concentrations compared with those without CKD. During a median follow-up of 3.9 years, an elevated Lp(a) value was an independent predictor for MACEs in the overall population. Patients with a high Lp(a) level had higher risk of MACEs than those with a low Lp(a) level, regardless of renal function. The association between higher Lp(a) levels and MACEs remained consistent using the cut-off value of median (11.57 mg/dL), 30 mg/dL and 50 mg/dL in patients with CKD. On the contrary, Lp(a) higher than 50 mg/dL was associated with significantly higher risk of MACEs in patients without CKD. ConclusionsWe confirmed that a high Lp(a) level was associated with long term adverse outcomes in ASC patients, especially in those with CKD.

Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels

ImportanceLipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities.ObjectivesTo assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses.Design, Setting, and ParticipantsA single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021.InterventionsParticipants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously.Main Outcomes and MeasuresThe primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days.ResultsAmong 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were −20 (IQR, −61 to 3) nmol/L, −89 (IQR, −119 to −61) nmol/L, −185 (IQR, −226 to −163) nmol/L, −268 (IQR, −292 to −189) nmol/L, and −227 (IQR, −270 to −174) nmol/L, with maximal median percentage changes of −10% (IQR, −16% to 1%), −46% (IQR, −64% to −40%), −86% (IQR, −92% to −82%), −96% (IQR, −98% to −89%), and −98% (IQR, −98% to −97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration.Conclusions and RelevanceIn this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA.Trial RegistrationClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35

Genetic and Mechanistic Insights into the Modulation of Circulating Lipoprotein (a) Concentration by Apolipoprotein E Isoforms.

Lipoprotein (a) [Lp(a)] is a highly atherogenic lipoprotein species. A unique feature of Lp(a) is the strong genetic determination of its concentration. The LPA gene is responsible for up to 90% of the variance in Lp(a), but other genes also have an impact. Genome-wide associations studies indicate that the APOE gene, encoding apolipoprotein E (apoE), is the second most important locus modulating Lp(a) concentrations. Population studies clearly show that carriers of the apoE2 variant (ε2) display reduced Lp(a) levels, the lowest concentrations being observed in ε2/ε2 homozygotes. This genotype can lead predisposed adults to develop dysbetalipoproteinemia, a lipid disorder characterized by sharp elevations in cholesterol and triglycerides. However, dysbetalipoproteinemia does not significantly modulate circulating Lp(a). Mechanistically, apoE appears to impair the production but not the catabolism of Lp(a). These observations underline the complexity of Lp(a) metabolism and provide key insights into the pathways governing Lp(a) synthesis and secretion.

Low Molecular Weight Apolipoprotein(a) Phenotype Rather Than Lipoprotein(a) Is Associated With Coronary Atherosclerosis and Myocardial Infarction.

Background and AimsCurrent evidence suggests that lipoprotein(a) [Lp(a)] level above 50 mg/dL is associated with increased cardiovascular risk. Our study aim was to determine the relationship of apolipoprotein(a) [apo(a)] phenotypes and Lp(a) concentration below and above 50 mg/dL with coronary atherosclerosis severity and myocardial infarction (MI).Material and MethodsThe study population consisted of 540 patients (mean age 54.0 ± 8.8 years, 82% men) who passed through coronary angiography. The number of diseased major coronary arteries assessed atherosclerosis severity. Lipids, glucose, Lp(a) levels and apo(a) phenotypes were determined in all patients. All patients were divided into four groups: with Lp(a) <50 mg/dL [ “normal” Lp(a)] or ≥50 mg/dL [hyperLp(a)], and with low-molecular (LMW) or high-molecular weight (HMW) apo(a) phenotypes.ResultsBaseline clinical and biochemical characteristics were similar between the groups. In groups with LMW apo(a) phenotypes, the odds ratio (OR; 95% confidence interval) of multivessel disease was higher [10.1; 3.1–33.5, p < 0.005 for hyperLp(a) and 2.2; 1.0–4.9, p = 0.056 for normal Lp(a)], but not in the group with HMW apo(a) and hyperLp(a) [1.1; 0.3–3.3, p = 0.92] compared with the reference group with HMW apo(a) and normal Lp(a). Similarly, MI was observed more often in patients with LMW apo(a) phenotype and hyperLp(a) and normal Lp(a) than in groups with HMW apo(a) phenotype.ConclusionThe LMW apo(a) phenotype is associated with the severity of coronary atherosclerosis and MI even when Lp(a) level is below 50 mg/dL. The combination of Lp(a) level above 50 mg/dL and LMW apo(a) phenotype increases the risk of severe coronary atherosclerosis, regardless of other risk factors.

Association between lipoprotein(a) concentrations and atherosclerotic cardiovascular disease risk in patients with familial hypercholesterolemia: an analysis from the HELLAS-FH.

Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, such a role in patients with familial hypercholesterolemia (FH) is less documented. The purpose of this study was to evaluate the association between Lp(a) concentrations and ASCVD prevalence in adult patients with FH. This was a cross-sectional study from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Patients were categorized into 3 tertiles according to Lp(a) levels. A total of 541 adult patients (249 males) with possible/probable/definite FH heterozygous FH (HeFH) were included (mean age 48.5 ± 15.0 years at registration, 40.8 ± 15.9 years at diagnosis). Median (interquartile range) Lp(a) concentrations in the 1st, 2nd and 3rd Lp(a) tertile were 6.4 (3.0-9.7), 22.4 (16.0-29.1) and 77.0 (55.0-102.0) mg/dL, respectively. There was no difference in lipid profile across Lp(a) tertiles. The overall prevalence of ASCVD was 9.4% in the first, 16.1% in the second and 20.6% in the third tertile (p = 0.012 among tertiles). This was also the case for premature ASCVD, with prevalence rates of 8.5, 13.4 and 19.8%, respectively (p = 0.010 among tertiles). A trend for increasing prevalence of coronary artery disease (8.3, 12.2 and 16.1%, respectively; p = 0.076 among tertiles) was also observed. No difference in the prevalence of stroke and peripheral artery disease was found across tertiles. Elevated Lp(a) concentrations are significantly associated with increased prevalence of ASCVD in patients with possible/probable/definite HeFH.

How should public health recommendations address Lp(a) measurement, a causative risk factor for cardiovascular disease (CVD)?

Background and aimsElevated concentrations of Lipoprotein (a) [Lp(a)] is an inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD). This study aims to investigate the clinical utility for patients, and the economic benefit to healthcare systems and society of measuring Lp(a) concentrations more widely today. MethodsWe conducted a structured literature review to identify the economic and health benefits and costs of measuring the Lp(a) concentration, potential barriers hindering the uptake of the measure, and potential solutions to address them. These findings were then discussed in an advisory board attended by experts and patient organisations. ResultsIt was found that if Lp(a) concentration is measured more widely today, patients, healthcare system and society would experience clinical and economic benefits even before specific Lp(a) lowering pharmacological treatments become available. Furthermore, a wider uptake of the Lp(a) measurement would support the development of epidemiological data. ConclusionsFor Lp(a) measurement to be more widely used, key barriers which are hindering its uptake need to be addressed. These include i) the perception that the measure may have limited clinical value, ii) lack of awareness on Lp(a), iii) lack of data on the CV benefit of reducing Lp(a), iv) technical and clinical guidelines barriers, and v) healthcare system barriers. Scientific communities and industry should collaborate to address technical challenges and deficiencies in clinical guidelines. However, policy intervention will be crucial for national ASCVD plans to acknowledge the importance of Lp(a).

Abstract P059: Effects Of Saturated Fatty Acid On Lipoprotein(a): A Systematic Review And Meta-analysis

Background: Elevated lipoprotein(a) [Lp(a)] is a significant contributor to residual CVD risk. Replacement of saturated fatty acids (SFA) with mono- and polyunsaturated fatty acids (MUFA and PUFA), carbohydrates (CHO) has established effects on traditional lipid parameters related to CVD; however, the evidence for Lp(a) is inconsistent. Moreover, some evidence suggests replacing SFA with other macronutrients increases Lp(a). Objective: The aim was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of replacing SFA with MUFA, PUFA, trans fatty acids (TFA) and CHO on Lp(a). Methods: PubMed, Cochrane Central, ClinicalTrials.gov, and Web of Science were searched for RCTs with a duration of ≥13 days that included healthy adults ages 20-65 y and examined the effect of diets differing in SFA, MUFA, PUFA, or CHO on Lp(a). Exclusion criteria included changes in protein/alcohol and &gt;10% weight loss in last 6 months. Diet comparisons were extracted from trials to assess the effect of substitution of SFA for other macronutrients. Data are presented as weighted means. Data were analyzed using a mixed model approach (SAS 9.4). Results: Twenty-seven articles met criteria for inclusion and data were available for analysis for 15 articles. There were 39 comparisons between SFA and other macronutrients. Lp(a) was measured by macra, polyclonal, or sandwich enzyme linked immunosorbent assay (ELISA), particle enhanced turbidimetric immunoassay, or radioimmunoassay. SFA was substituted for TFA ( k =6), MUFA ( k =9), and PUFA ( k =3). Five trials compared a high SFA diet with a high CHO diet. A total of 539 adults (44.7 + 31.6 y) were included in the pooled sample. Overall, the mean displacement of SFA for other macronutrients was 6.7% of kcals. Mean Lp(a) across the included studies was 100.5 + 100.3 mg/dl. Replacement of SFA with MUFA, PUFA or CHO did not significantly affect Lp(a). Lp(a) was 6.1 mg/dl (p=0.021; 95% CI: -11.3, -0.9) lower when SFA replaced TFA. Conclusions: Overall, substitution of SFA for other macronutrients did not impact Lp(a) concentrations. Lower levels of Lp(a) were observed when 5% of kcals from TFA were replaced with SFA, although the clinical relevance of this finding is unclear. Further research examining the effect of SFA replacement on Lp(a) is needed due to the methodological quality of the available data and heterogeneity in Lp(a) measurement methods utilized.

Lipoprotein (a) levels in newly diagnosed treatment naive type 2 diabetics &amp; it’s correlation with glycemic &amp; lipid parameters

Type 2 diabetes mellitus (T2DM) has a high morbidity and mortality mainly due to cardiovascular diseases. Besides traditional risk factors, Lp(a) has recently been emerged as an independent risk factor. This study aimed to evaluate the incidences of elevated Lp(a) levels in newly diagnosed T2DM Pts and to find the pattern of lipid profile abnormalities associated with elevated Lp(a) group of pts &amp; it’s correlation with glycemic &amp; lipid parameters.This present study was conducted in newly diagnosed treatment naïve type 2 diabetic patients. After obtaining informed consent, all participants completed a survey to obtain anthropometric &amp; clinical information. Venous blood samples were drawn for fasting plasma glucose, postprandial glucose, HbA1c,lipid profile &amp; Lp(a) measurements.A total 70 newly diagnosed type 2 diabetic pts &amp; 50 healthy controls were studied. The mean Lp(a)level measured among diabetics was 34.17 ±33.25 mg/dl. The mean concentration of Lp(a) in diabetics was significantly higher than control group(&amp;#60;0.001). Lp(a) was positively correlated with 2hr PP glucose, HbA1c and these correlations were statistically significant. The Lp(a) was negatively correlated with HDLc &amp; this correlation was statistically significant(0.04).Our study demonstrated Type 2 diabetics had statistically significant higher levels of Lp(a). The residual lipid risk is probably contributed by this molecule So, every diabetic should have checked their level at least once in a lifetime to predict CV risk.

Lipoprotein(a), Immune Cells and Cardiovascular Outcomes in Patients with Premature Coronary Heart Disease.

The detection of lipoprotein(a) [Lp(a)] in the artery wall at the stage of lipid-bands formation may indicate that it participates in the atherosclerosis local nonspecific inflammatory process. Innate immune cells are involved in atherogenesis, with monocytes playing a major role in the initiation of atherosclerosis, while neutrophils can contribute to plaque destabilization. This work studies the relationship between Lp(a), immune blood cells and major adverse cardiovascular events (MACE) in patients with the early manifestation of coronary heart disease (CHD). The study included 200 patients with chronic CHD, manifested up to the age of 55 in men and 60 in women. An increased Lp(a) concentration [hyperLp(a)] was shown to predict cardiovascular events in patients with premature CHD with long-term follow-up. According to the logistic regression analysis results, an increase in the monocyte count with OR = 4.58 (95% CI 1.04–20.06) or lymphocyte-to-monocyte ratio with OR = 0.82 (0.68–0.99), (p < 0.05 for both) was associated with MACE in patients with early CHD, regardless of gender, age, classical risk factors, atherogenic lipoproteins concentration and statin intake. The combination of an increased monocyte count and hyperLp(a) significantly increased the proportion of patients with early CHD with subsequent development of MACE (p = 0.02, p trend = 0.003). The odds of cardiovascular events in patients with early CHD manifestation were highest in patients with an elevated lymphocyte-to-monocyte ratio and an elevated Lp(a) level. A higher neutrophil blood count and an elevated neutrophil-to-lymphocyte ratio determined the faster development of MACE in patients with a high Lp(a) concentration. The data obtained in this study suggest that the high atherothrombogenicity of Lp(a) is associated with the “inflammatory” component and the innate immune cells involvement in this process. Thus, the easily calculated immunological ratios of blood cells and Lp(a) concentrations can be considered simple predictors of future cardiovascular events.

PCSK9 inhibition with alirocumab decreases plasma lipoprotein(a) concentration by a dual mechanism of action in statin‐treated patients with very high apolipoprotein(a) concentration

Inhibition of proprotein convertase subtilisin/kexin type 9 with alirocumab decreases plasma lipoprotein(a) [Lp(a)] levels. The kinetic mechanism for lowering Lp(a) by alirocumab may differ according to pre-treatment apolipoprotein(a) [apo(a)] levels. The effect of 12-week alirocumab (150 mg subcutaneously fortnightly) on the kinetics of apo(a) was compared in statin-treated patients with high (n = 10) and very high Lp(a) concentrations (n = 11). In patients with high apo(a) concentrations, alirocumab lowered plasma apo(a) pool size (-17%, p < 0.01) chiefly by increasing the fractional catabolic rate (FCR) of apo(a) (+27%, p < 0.001). By contrast in patients with very high apo(a) concentrations, alirocumab significantly lowered plasma apo(a) pool size (-32%, p < 0.001) by both increasing apo(a) FCR (+30%, p < 0.001) and lowering production rate (-11%, p < 0.05). In statin-treated patients with very high apo(a) concentrations, alirocumab lowers plasma Lp(a) concentration by a dual mode of action that increases the clearance and decreases the production of Lp(a) particles.

Genome-Wide Characterization of a Highly Penetrant Form of Hyperlipoprotein(a)emia Associated With Genetically Elevated Cardiovascular Risk.

Background:Lp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype.Methods:A large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed.Results:Seventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside the LPA locus. The extreme Lp(a) phenotype segregated with the presence of a short apo(a) isoform containing 21 Kringle IV domains. This allele was characterized by the presence of three rare strongly Lp(a) increasing single nucleotide polymorphisms and a significantly increased load of oxidized phospholipids per Lp(a) particle. An Lp(a) GRS consisting of 48 single nucleotide polymorphisms that represent 2001 genome-wide significant LPA single nucleotide polymorphisms, efficiently captured the hyper-Lp(a) phenotype and discriminated affected and nonaffected individuals with great accuracy. The genome-wide GRS for CAD, encompassing 6.6 million single nucleotide polymorphisms, was very high for most family members (>97.5 percentile of the reference population), but this observation was no longer valid when the contribution of the LPA locus was omitted.Conclusions:High-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals, LPA can be a major locus driving a very high CAD GRS. This underpins the large contribution of the LPA locus to the cardiovascular genetic risk in families.

Lipoprotein(a) and Pulmonary Embolism Severity-A Retrospective Data Analysis.

AimWe aimed to investigate a correlation between PE severity and Lp(a) levels.MethodsWe performed a retrospective data analysis from our medical records of PE patients admitted to the University Hospital Graz, Austria. Patients with an Lp(a) reading within a 1-year interval before and after PE diagnosis were included. In accordance with the 2019 ESC guidelines for the diagnosis and management of acute PE, severity assessment was carried out classifying patients into four groups: low risk (LR), intermediate low risk (IML), intermediate high risk (IMH) and high risk (HR). The study period of interest was between January 1, 2002 and August 1, 2020.ResultsWe analyzed 811 patients with PE, of whom 323 (40%) had low-risk PE, 343 (42%) had intermediate-low-risk PE, 64 (8%) had intermediate-high-risk PE, and 81 (10%) had high-risk PE, respectively. We did not observe an association between PE severity and Lp(a) concentrations. In detail, median Lp(a) concentrations were 17 mg/dL [25–75th percentile: 10-37] in low-risk PE patients, 16 mg/dL [10–37] in intermediate-low-risk PE patients, 15mg/dL [10–48] in intermediate-high-risk PE patients, and 13mg/dL [10–27] in high-risk PE patients, respectively (Kruskal-Wallis p = 0.658, p for linear trend = 0.358).ConclusionThe current findings suggest no correlation between PE severity and Lp(a) levels.

The relationship between lipoprotein A and other lipids with prostate cancer risk: A multivariable Mendelian randomisation study.

Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk, though findings remain inconclusive to date. The ongoing research has mainly involved observational studies, which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa. Data for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)), and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample summary-level Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB, and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis, but adjustment for HDL, TG, and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (ORweighted median per standard deviation (SD) = 1.091; 95% CI 1.028 to 1.157; P = 0.004) and MVMR analyses after adjustment for the other lipid traits (ORIVW per SD = 1.068; 95% CI 1.005 to 1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR ORIVW per SD = 1.078; 95% CI 0.999 to 1.163; P = 0.055) and early age onset PCa (MVMR ORIVW per SD = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilised to minimise the effect of pleiotropy, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings. We observed that genetically predicted Lp(a) concentrations were associated with an increased PCa risk. Future studies are required to understand the underlying biological pathways of this finding, as it may inform PCa prevention through Lp(a)-lowering strategies.

Impact of Lipoprotein(a) as a Residual Risk Factor in Long-Term Cardiovascular Outcomes in Patients With Acute Coronary Syndrome Treated With Statins

The association between lipoprotein(a) (Lp[a]) levels and cardiovascular disease has been reported. However, it is still uncertain whether Lp(a) concentration could be a residual risk factor for cardiovascular events after acute coronary syndrome (ACS). The aim of the present study is to evaluate the impact of Lp(a) on long-term cardiovascular outcomes in patients with ACS treated with statins. We studied 1,758 consecutive patients with ACS who underwent emergency percutaneous coronary intervention between 2008 and 2017. We finally enrolled 1,131 patients for whom Lp(a) data were available and who were treated with statins at discharge. Patients were divided into 2 groups according to Lp(a) levels (median Lp(a) 15.0 mg/100 ml). The primary end points were major adverse cardiac events (MACEs), composite of all-cause death, and myocardial infarction up to 5 years. Overall, 107 MACEs (9.5%) were identified. The cumulative incidence of MACE was significantly higher in the high Lp(a) group than the low Lp(a) group (log-rank p=0.01). After adjustment for other cardiovascular risk factors, the high Lp(a) group had a significantly higher risk of MACE (hazard ratio 1.66, 95% confidence interval 1.05 to 2.61, p=0.03). Multivariate Cox hazard analysis also showed that increasing Lp(a) as a continuous variable was associated with the incidence of MACE (hazard ratio 1.35 per log Lp[a] 1 increase, 95% confidence interval 1.07 to 1.72, p=0.01). In conclusion, high Lp(a) level is significantly associated with long-term cardiovascular outcomes in patients with ACS treated with statins after primary percutaneous coronary intervention and is likely to be a potential biomarker for residual risk prediction of future clinical events.

Association of Lipoprotein(a) Concentrations and Apolipoprotein(a) isoform with Coronary Artery Disease Stratification in Han Chinese.

The purpose of this study was to investigate the association between lipoprotein(a) [Lp(a)] concentrations, apolipoprotein(a) [apo(a)] isoform, and coronary artery disease (CAD) stratification in Han Chinese. Logistic regression analysis was performed to analyze the association between Lp(a) concentrations, apo(a) isoform and CAD stratification. Lp(a) concentrations and apo(a) isoforms were combined with other risk factors to establish the optimal prediction model of CAD risk. Individuals with the top quarter of Lp(a) concentrations had more than a two-fold higher risk of stable CAD and three-fold higher risk of acute coronary syndrome (ACS) compared with those in the bottom quarter. This association was no longer significant after adjustment for apo(a) isoforms in stable CAD (OR 2.198, 95% CI 0.991 - 4.875, p = 0.053), but remained significant in the ACS (OR 3.583, 95% CI 1.278 - 5.614, p < 0.05). Individuals with small apo(a) isoforms had more than a two-fold higher risk of stable CAD and almost three-fold higher risk of ACS compared with those carrying larger apo(a) isoforms; however, this association was significantly alleviated after adjustment for Lp(a) concentrations (OR 2.133, 95% CI 0.964 - 4.742, p = 0.098; OR 2.642, 95% CI 1.032 - 5.833, p = 0.298, respectively). A combination of Lp(a) concentrations and apo(a) isoforms with other risk factors was the optimal prediction model of CAD risk (AUC 0.800, 95% CI 0.752 - 0.848, p < 0.001). Elevated Lp(a) concentrations and small apo(a) isoforms were significant risk factors for CAD stratification, and their effects on CAD risk were mediated by each other. Combined application of Lp(a) concentrations and apo(a) isoform with conventional risk factors could aid in the assessment and prediction of CAD.

Dyslipidaemia in Sri Lanka

Cardiovascular diseases (CVDs) are the leading cause of mortality in South Asia. Although well-recognized as a major risk factor, dyslipidemia in such populations is not well-reviewed. To review the trends in dyslipidemia, phenotypes, underlying causes, treatment modalities, and management gaps in Sri Lanka. A narrative review was undertaken on published literature on dyslipidemia in Sri Lanka from 2000 to 2020, extracted using PubMed, Google Scholar, and locally published literature. Out of the 33 documents reviewed, only a limited number was available on large-scale population-based studies. High prevalence of metabolic syndrome along with moderately high low-density lipoprotein-cholesterol, low high-density lipoprotein-cholesterol, high triglycerides, and high ApoB and Lp(a) concentrations was seen. Familial hypercholesterolemia was an understudied area with a need for a national screening program. With dyslipidemia guidelines limited to the management of special disease groups, there is a chasm between guidelines and practice at present in Sri Lanka. Unlike in primary prevention, prescribing high-dose statins in secondary prevention of CVD has been satisfactory. Treatment gaps are identified, with room for improvements in lipid screening and achieving lipid goals. Considering the substantial burden identified, education of physicians, optimizing lipid testing, and aggressive treatment of lipids are key initiatives toward optimizing management of dyslipidemia.

Quantifying the Contribution of Lipoprotein (a) to Atherogenic Lipoprotein Burden: A Novel Particle-Based Approach

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> David and June Trone Family Foundation AHA NIH. <h3>Background/Synopsis</h3> LDL cholesterol [LDL-C] on clinical lipid panels includes cholesterol from LDL, IDL, and Lipoprotein (a). Contributions from Lp(a) cholesterol [Lp(a)-C] to LDL-C can influence the diagnosis and management of dyslipidemias. Currently, there is no commercially available assay to accurately measure Lp(a)-C and we showed previously that estimating Lp(a)-C using fixed conversion factors tends to overestimate the contribution of Lp(a)-C to LDL-C. Moreover, comparing Lp(a)-C with LDL-C alone may miss contributions of other atherogenic lipoproteins to overall atherosclerotic cardiovascular disease risk. <h3>Objective/Purpose</h3> To more accurately quantify how Lp(a) compares to the overall atherogenic burden and circumvent inaccuracies associated with cholesterol mass estimation, we demonstrate a novel particle-based approach to compare Lp(a) concentration [Lp(a)-P] with all atherogenic particles (referred to as non-HDL-P), making use of widely available assays already employed in clinical practice. <h3>Methods</h3> Using the Very Large Database of Lipids, we extracted data from individuals with measured Lp(a)-P (nmol/L) and apoB (mg/dL). The concentration of all atherogenic particles (non-HDL-P) was calculated using the molecular weight of apoB which is preserved across individuals, enabling accurate conversion from mass to molar concentration. The fraction of Lp(a)-P/non-HDL-P was calculated and stratified by increasing Lp(a)-P deciles across sex, age, triglycerides, LDL-C, and non-HDL-C. <h3>Results</h3> 158,260 patients from the Very Large Database of Lipids were included. The percentage of Lp(a)-P/non-HDL-P increased at higher Lp(a)-P concentrations. Mean Lp(a)-P/non-HDL-P for the study population was approximately 3%, but was as high as 15% in the top Lp(a)-P decile. When stratified by sex, fractions mirrored those seen in the general population. When stratified by age, the highest fractions of Lp(a)-P/non-HDL-P were observed among the youngest and oldest ages. We observed that Lp(a)-P/non-HDL-P decreased with rising LDL-C and triglycerides, owing to larger contributions from LDL and VLDL to the total atherogenic population. <h3>Conclusions</h3> We demonstrate the feasibility and simplicity of comparing Lp(a) particles with the total atherogenic particle population, making use of commercially available assays widely used in clinical practice. Importantly, a molar approach avoids previously demonstrated inaccuracies associated with Lp(a)-C estimations. Moreover, this approach may enrich assessment of residual risk mediated by Lp(a) by comparing it against the sum total of atherogenic particles encompassed by the non-HDL family. Future investigation is needed to identify clinically meaningful thresholds for Lp(a)-P/non-HDL-P, particularly with the ongoing development of targeted Lp(a) therapies.

Lipoprotein (a)-mediated vascular calcification: population-based and in vitro studies

BackgroundLipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular diseases, while its role in vascular calcification has not been well-established. Here, we investigated an association of Lp(a) with vascular calcification using population-based and in vitro study designs. MethodsA total of 2806 patients who received coronary computed tomography were enrolled to assess the correlation of Lp(a) with the severity of coronary artery calcification (CAC). Human aortic smooth muscle cells (HASMCs) were used to explore mechanisms of Lp(a)-induced vascular calcification. ResultsIn the population study, Lp(a) was independently correlated with the presence and severity of CAC (all p < 0.05). In vitro study showed that cell calcific depositions and alkaline phosphatase (ALP) activity were increased and the expression of pro-calcific proteins, including bone morphogenetic protein-2 (BMP2) and osteopontin (OPN), were up-regulated by Lp(a) stimulation. Interestingly, Lp(a) activated Notch1 signaling, resulting in cell calcification, which was inhibited by the Notch1 signaling inhibitor, DAPT. Lp(a)-induced Notch1 activation up-regulated BMP2-Smad1/5/9 pathway. In contrast, Noggin, an inhibitor of BMP2-Smad1/5/9 pathway, significantly blocked Lp(a)-induced HASMC calcification. Notch1 activation also induced translocation of nuclear factor-κB (NF-κB) accompanied by OPN overexpression and elevated inflammatory cytokines production, while NF-κB silencing alleviated Lp(a)-induced vascular calcification. ConclusionsElevated Lp(a) concentrations are independently associated with the presence and severity of CAC and the impact of Lp(a) on vascular calcification is involved in the activation of Notch1-NF-κB and Notch1-BMP2-Smad1/5/9 pathways, thus implicating Lp(a) as a potential novel therapeutic target for vascular calcification.