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Background Lipoprotein(a) [Lp(a)] is associated with increased risk of myocardial infarction, although the mechanism for this observation remains uncertain. Objectives This study aims to investigate whether Lp(a) is associated with adverse plaque progression. Methods Lp(a) was measured in patients with advanced stable coronary artery disease undergoing coronary computed tomography angiography at baseline and 12 months to assess progression of total, calcific, noncalcific, and low-attenuation plaque (necrotic core) in particular. High Lp(a) was defined as Lp(a) ≥ 70 mg/dL. The relationship of Lp(a) with plaque progression was assessed using linear regression analysis, adjusting for body mass index, segment involvement score, and ASSIGN score (a Scottish cardiovascular risk score comprised of age, sex, smoking, blood pressure, total and high-density lipoprotein [HDL]–cholesterol, diabetes, rheumatoid arthritis, and deprivation index). Results A total of 191 patients (65.9 ± 8.3 years of age; 152 [80%] male) were included in the analysis, with median Lp(a) values of 100 (range: 82 to 115) mg/dL and 10 (range: 5 to 24) mg/dL in the high and low Lp(a) groups, respectively. At baseline, there was no difference in coronary artery disease severity or plaque burden. Patients with high Lp(a) showed accelerated progression of low-attenuation plaque compared with low Lp(a) patients (26.2 ± 88.4 mm3 vs −0.7 ± 50.1 mm3; P = 0.020). Multivariable linear regression analysis confirmed the relation between Lp(a) and low-attenuation plaque volume progression (β = 10.5% increase for each 50 mg/dL Lp(a), 95% CI: 0.7%-20.3%). There was no difference in total, calcific, and noncalcific plaque volume progression. Conclusions Among patients with advanced stable coronary artery disease, Lp(a) is associated with accelerated progression of coronary low-attenuation plaque (necrotic core). This may explain the association between Lp(a) and the high residual risk of myocardial infarction, providing support for Lp(a) as a treatment target in atherosclerosis., Central Illustration

Visual Abstract, Highlights • This study is the first step towards the creation of a metabolomic map of calcified human aortic valves. • The study highlights an independent association of LysoPA with CAVS severity. • The study demonstrates that LysoPA levels are associated with faster CAVS progression rate., Summary This study outlines the first step toward creating the metabolite atlas of human calcified aortic valves by identifying the expression of metabolites and metabolic pathways involved at various stages of calcific aortic valve stenosis progression. Untargeted analysis identified 72 metabolites and lipids that were significantly altered (p

Visual Abstract, Highlights • Modulating LDL receptor expression genetically (in familial hypercholesterolemia) or pharmacologically (using statins or the PCSK9 inhibitor alirocumab) does not alter the cellular uptake of Lp(a) in primary human lymphocytes. • Lp(a) hepatic capture is not modulated by PCSK9 inhibition with alirocumab in liver-humanized mice. • LDLR does not appear to play a significant role in mediating Lp(a) plasma clearance in vivo., Summary Lipoprotein(a) (Lp[a]) is the most common genetically inherited risk factor for cardiovascular disease. Many aspects of Lp(a) metabolism remain unknown. We assessed the uptake of fluorescent Lp(a) in primary human lymphocytes as well as Lp(a) hepatic capture in a mouse model in which endogenous hepatocytes have been ablated and replaced with human ones. Modulation of LDLR expression with the PCSK9 inhibitor alirocumab did not alter the cellular or the hepatic uptake of Lp(a), demonstrating that the LDL receptor is not a major route for Lp(a) plasma clearance. These results have clinical implications because they underpin why statins are not efficient at reducing Lp(a).

Malignant coronary artery disease (CAD) refers to a severe and extensive atherosclerotic process involving multiple coronary arteries in young individuals (aged

Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy. Keywords: Lipoprotein(a), Oxidized phospholipids, Genetic risk factor, Indians, Acute myocardial infarction, Premature coronary artery disease, Cardiovascular disease, Kringles, Isoforms, Mendelian randomization, Single nucleotide polymorphism, Genome-wide association studies, meta-analysis

Objectives Measurement of lipoprotein(a) [Lp(a)] is used in risk assessment of atherosclerotic cardiovascular disease (ASCVD). The aim of the current study was to evaluate performance characteristic of five different Lp(a) assays using the cobas c501 (Roche Diagnostics) analyzer. Design and methods Lp(a) was measured using five Lp(a) assays (Diazyme, Kamiya, MedTest, Randox, and Roche) configured to mg/dL units. Assays from Diazyme and Kamiya were also configured using nmol/L units in separate experiments. Studies included sensitivity, imprecision, linearity, method comparison, and evaluation of healthy subjects. Imprecision (intra-day, 20 replicates; inter-day, duplicates twice daily for five days) and linearity were evaluated using patient pools. Linearity assessed a minimum of five patient splits spanning the analytical measurement range (AMR). Method comparison used 80 residual serum samples. Specimens from 120 self-reported healthy subjects (61 females / 59 males) were also tested. Method comparison for two assays in nmol/L units was conducted using 96 residual serum samples. Results Assay sensitivities met all manufacturer claims. Imprecision studies demonstrated %CVs ranging from 2.5 to 5.2% for the low pool (average concentration from 7.3 to 12.4 ​mg/dL); high pool %CVs ranged from 0.8 to 3.0% (average concentrations from 31.5–50.2 ​mg/dL). Linearity was confirmed for all assays. Variation in accuracy was observed when comparing results to an all method average. Lp(a) results were higher in females versus males in self-reported healthy subjects. Conclusions All assays performed according to manufacturer described performance characteristics, although differences were observed across Lp(a) assays tested when compared to an all method average., Highlights • Five automated assays for Lp(a) measurement (mg/dL units) were compared. • Differences in accuracy were observed across the methods investigated. • Two assays were also compared using nmol/L units. • More Lp(a) assay traceability to the international reference material is needed.

Visual Abstract, Highlights • Aortic stenosis was less prevalent in carriers of the PCSK9 R46L variant. • Variation at the PCSK9 locus influences LDL-C levels, but not Lp(a). • PCSK9 is produced and secreted by aortic valves. • In vitro, PCSK9 inhibition might lower calcification in aortic valve cells. • PCSK9 inhibition could represent a therapeutic strategy for aortic stenosis., Summary The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.

Visual Abstract, Highlights • Lp(a) significantly increased alkaline phosphatase activity, phosphate and calcium content, and matrix vesicle formation and induced apoptosis and calcification of normal human aortic valve interstitial cells. • The type of minerals induced by Lp(a) resembles that seen in calcified human aortic valves as shown by Raman spectroscopy. • Lp(a)-induced calcification of human aortic valve interstitial cells is mediated by activation of MAPK38, GSK3β, and Wnt signaling. • Inhibition of GSK3β and MAPK38 significantly reduced lipoprotein(a)-induced aortic valve interstitial cell calcification. • Lp(a)is abundant in calcified aortic valves, and lipoprotein(a) immunoreactivity colocalized with that of oxidized phospholipids., Summary Lipoprotein(a), or Lp(a), significantly increased alkaline phosphatase activity, release of phosphate, calcium deposition, hydroxyapatite, cell apoptosis, matrix vesicle formation, and phosphorylation of signal transduction proteins; increased expression of chondro-osteogenic mediators; and decreased SOX9 and matrix Gla protein (p

Calcific aortic valve disease (CAVD) occurs when subpopulations of valve cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein-lowering therapies have failed in clinical trials, and there are currently no pharmacological interventions available for this disease. Apolipoproteins are known promoters of atherosclerosis, but whether they possess pathogenic properties in CAVD is less clear. To search for a possible link, we assessed 12 apolipoproteins in nonfibrotic/noncalcific and fibrotic/calcific aortic valve tissues by proteomics and immunohistochemistry to understand if they were enriched in calcified areas. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific versus nonfibrotic/noncalcific tissues. Apo(a), apoB, apoC-III, apoE, and apoJ localized within the disease-prone fibrosa and colocalized with calcific regions as detected by immunohistochemistry. Circulating apoC-III on lipoprotein(a) is a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also induces aortic valve calcification is unknown. We found that apoC-III was increased in fibrotic and calcific tissues and observed within the calcification-prone fibrosa layer as well as around calcification. In addition, we showed that apoC-III induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated pathway. This study provides a first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active and modifiable driver of CAVD beyond its potential role as a biomarker.

Visual Abstract, Highlights • Phosphorylcholine is a pro-inflammatory epitope in atherogenic oxidized phospholipids. • This study investigated effects of a novel monoclonal IgG1 antibody against PC on vascular function and atherosclerotic inflammation. • Treatment with phosphorylcholine antibody preserved coronary flow reserve and decreased uptake of 18F-FDG in atherosclerotic lesions in hypercholesterolemic mice. • Noninvasive imaging techniques represent translational tools to assess the efficacy of phosphorylcholine-targeted therapy on coronary artery function and atherosclerosis., Summary This study showed that treatment with a therapeutic monoclonal immunoglobulin-G1 antibody against phosphorylcholine on oxidized phospholipids preserves coronary flow reserve and attenuates atherosclerotic inflammation as determined by the uptake of 18F-fluorodeoxyglucose in atherosclerotic mice. The noninvasive imaging techniques represent translational tools to assess the efficacy of phosphorylcholine-targeted therapy on coronary artery function and atherosclerosis in clinical studies.

Lipoproteins are essential systemic lipid transport particles, composed of apolipoproteins embedded in a phospholipid and cholesterol monolayer surrounding a cargo of diverse lipid species. Many of the lipids present are susceptible to oxidative damage by lipid peroxidation, giving rise to the formation of reactive lipid peroxidation products (rLPPs). In view of the close proximity of the protein and lipid moieties within lipoproteins, the probability of adduct formation between rLPPs and amino acid residues of the proteins, a process called lipoxidation, is high. There has been interest for many years in the biological effects of such modifications, but the field has been limited to some extent by the availability of methods to determine the sites and exact nature of such modification. More recently, the availability of a wide range of antibodies to lipoxidation products, as well as advances in analytical techniques such as liquid chromatography tandem mass spectrometry (LC-MSMS), have increased our knowledge substantially. While most work has focused on LDL, oxidation of which has long been associated with pro-inflammatory responses and atherosclerosis, some studies on HDL, VLDL and Lipoprotein(a) have also been reported. As the broader topic of LDL oxidation has been reviewed previously, this review focuses on lipoxidative modifications of lipoproteins, from the historical background through to recent advances in the field. We consider the main methods of analysis for detecting rLPP adducts on apolipoproteins, including their advantages and disadvantages, as well as the biological effects of lipoxidized lipoproteins and their potential roles in diseases., Graphical abstract fx1, Highlights • Lipoproteins can be modified by reactive Lipid Peroxidation Products (rLPPs). • Lipoprotein lipoxidation is known to occur in several inflammatory diseases. • Biochemical, immunochemical and mass spectrometry methods can detect rLPP adducts. • Due to higher information output, MS can facilitate localization of modifications. • Antibodies against some rLPPs have been used to identify lipoxidation in vivo.

Graphical abstract, Highlights • Acute application of apo(a) to smooth muscle cells induced chemorepulsion. • Chronic application (>24 h) induced stress fibre formation and cell spreading. • Effects of apo(a) were mediated by integrin αVβ3, tyrosine kinases and RhoA/ROCK. • Apo(a) impaired SMC motility which potentially contributes to vascular dysfunction., Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease. Vascular smooth muscle cell (SMC) motility and plasticity, functions that are influenced by environmental cues, are vital to adaptation and remodelling in vascular physiology and pathophysiology. Lp(a) is reportedly damaging to SMC function via unknown molecular mechanisms. Apolipoprotein(a) (apo(a)), a unique glycoprotein moiety of Lp(a), has been demonstrated as its active component. The aims of this study were to determine functional effects of recombinant apo(a) on human vascular SMC motility and explore the underlying mechanism(s). Exposure of SMC to apo(a) in migration assays induced a potent, concentration-dependent chemorepulsion that was RhoA and integrin αVβ3-dependent, but transforming growth factor β-independent. SMC manipulation through RhoA gene silencing, Rho kinase inhibition, statin pre-treatment, αVβ3 neutralising antibody and tyrosine kinase inhibition all markedly inhibited apo(a)-mediated SMC migration. Our data reveal unique and potent activities of apo(a) that may negatively influence SMC remodelling in cardiovascular disease. Circulating levels of Lp(a) are resistant to lipid-lowering strategies and hence a greater understanding of the mechanisms underlying its functional effects on SMC may provide alternative therapeutic targets.