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Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles., Methods: Participants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model., Results: Out of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97-5.0) to 12.0 (95%CI 5.5-24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively., Conclusions: This study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LFR is cofounder of Lipid Tools and reports speakers fee from Ultragenyx, Novartis, and Daiichi Sankyo. JJPK is part time CSO of New Amsterdam Pharma and part time CMO of Staten Biotech and a consultant to AgBio, Scribe, Cincor, CSL Behring, CiVi Biopharma, Draupnir, Esperion Therapeutics, Madrigal, Menarini, Omeicos, Silence Therapeutics, Sirnaomics, TTxD and North Sea Therapeutics. GKH reports research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445), CardioVascular Research Initiative, European Union and the Klinkerpad fonds, institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker's bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron until April 2019 (fees paid to the academic institution); and part-time employment and stock holder of at Novo Nordisk A/S, Denmark since April 2019. ESGS has received ad-board/lecturing fees, paid to the institution, from: Amgen, Sanofi, Astra-Zeneca, Esperion, Daiichi Sankyo, NovoNordisk, Ionis/Akcea, Amarin. The other authors report no disclosures., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: Systemic low-grade inflammation, measured by plasma high-sensitivity C-reactive protein (hsCRP) levels, is an important risk factor for atherosclerotic cardiovascular disease (ASCVD). To date, however, it is unknown whether plasma hsCRP is associated with adverse histological plaque features., Methods: Plaques were derived during carotid endarterectomy. Patients with hsCRP levels ≥2 mg/L were evaluated for pro-inflammatory and adverse plaque characteristics, as well as future ASCVD events, and compared with patients with low hsCRP levels. Logistic and linear regression analyses in addition to subdistribution hazard ratios were conducted, adjusted for cardiovascular risk factors., Results: A total of 1096 patients were included, of which 494 (46.2 %) had hsCRP levels ≥2 mg/L. Elevated hsCRP levels 2 mg/L were independently associated with levels of plaque interleukin 6, beta coefficient of 109.8 (95 % confidence interval (CI): 33.4, 186.5; p = 0.005) pg/L, interleukin 8 levels, 194.8 (110.4, 378.2; p = 0.03) pg/L and adiponectin plaque levels, -16.8 (-30.1, -3.6; p = 0.01) μg/L, compared with plaques from patients with low hsCRP levels. Histological analysis revealed increased vessel density in high hsCRP patients, odds ratio (OR) of 1.57 (1.20, 2.09; p = 0.001), larger lipid core, 1.35 (1.02, 1.73; p = 0.04), and increased macrophage content, 1.32 (1.02, 1.73; p = 0.04). Over a 3-year follow-up period, hsCRP levels ≥2 mg/L were associated with a hazard ratio of 1.81 (1.03, 3.16; p = 0.04) for coronary artery disease event risk., Conclusions: The distinct inflammatory and histological features observed in carotid plaques among individuals with hsCRP levels ≥2 mg/L underscore the utility of plasma hsCRP as a potent identifier for patients harboring high-risk plaques., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolemia (FH) is a highly prevalent genetic disorder resulting in markedly elevated LDL cholesterol levels and premature coronary artery disease. FH underdiagnosis and undertreatment require novel detection methods. This study evaluated the effectiveness of using an LDL cholesterol cut-off ≥99.5th percentile (sex- and age-adjusted) to identify clinical and genetic FH, and investigated underutilization of genetic testing and undertreatment in FH patients., Methods: Individuals with at least one prior LDL cholesterol level ≥99.5th percentile were selected from a laboratory database containing lipid profiles of 590,067 individuals. The study comprised three phases: biochemical validation of hypercholesterolemia, clinical identification of FH, and genetic determination of FH., Results: Of 5614 selected subjects, 2088 underwent lipid profile reassessment, of whom 1103 completed the questionnaire (mean age 64.2 ± 12.7 years, 48% male). In these 1103 subjects, mean LDL cholesterol was 4.0 ± 1.4 mmol/l and 722 (65%) received lipid-lowering therapy. FH clinical diagnostic criteria were met by 282 (26%) individuals, of whom 85% had not received guideline-recommended genetic testing and 97% failed to attain LDL cholesterol targets. Of 459 individuals consenting to genetic validation, 13% carried an FH-causing variant, which increased to 19% in clinically diagnosed FH patients., Conclusions: The identification of a substantial number of previously undiagnosed and un(der)treated clinical and genetic FH patients within a central laboratory database highlights the feasibility and clinical potential of this targeted screening strategy; both in identifying new FH patients and in improving treatment in this high-risk population., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Cardiovascular disease (CVD) remains the largest cause of death globally due to various risk factors. One novel potential contributor to CVD might be the metabolism of the essential amino acid tryptophan (Trp), which through many pathways can produce immunomodulatory metabolites such as kynurenine, indole-3-propionate and serotonin. We aim to identify the metabolites with the strongest association with cardiovascular disease, utilizing a substantial and diverse cohort of individuals. In our pursuit of this aim, our primary focus is to validate and reinforce the findings from previous cross-sectional studies., Methods: We used the community-based EPIC-Norfolk cohort (46.3 % men, age 59.8 ± 9.0) with a median follow-up of 22.1 (17.6-23.3) years to study associations between the relative levels of Trp metabolites measured with untargeted metabolomics and incident development of CVD. Serum from n = 11,972 apparently healthy subjects was analysed, of which 6982 individuals had developed CVD at the end of follow-up. Cox proportional hazard models were used to study associations, adjusted for sex, age, conventional cardiovascular risk factors and CRP. All metabolites were Ln-normalised prior to analysis., Results: Higher levels of Trp were inversely associated with mortality (HR 0.73; CI 0.64-0.83) and fatal CVD (HR 0.76; CI 0.59-0.99). Higher levels of kynurenine (HR 1.33; CI 1.19-1.49) and the [Kynurenine]/[Tryptophan]-ratio (HR 1.24; CI 1.14-1.35) were associated with a higher incident development of CVD. Serotonin was not associated with overall CVD, but we did find associations for myocardial infarction and stroke. Adjustment for CRP did not yield any discernible differences in effect size., Conclusions: Tryptophan levels were inversely correlated with CVD, while several of its major metabolites (especially kynurenine and serotonin) were positively correlated. These findings indicate that mechanistic studies are required to understand the role of Trp metabolism in CVD with the goal to identify new therapeutic targets., Competing Interests: Declaration of competing interest C.J.T. has nothing to disclose. M.N. is founder, holds stock in and is a member of the Scientific Advisory Board of Caelus Health, the Netherlands. N.M.J.H. has received honorarium from Novo Nordisk and Boehringer Ingelheim. For both, none of these conflicts of interest are relevant for this publication. S.L.H. reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and/or therapeutics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, a wholly owned subsidiary of Quest Diagnostics, P&G, and Zehna Therapeutics. S.L.H also reports being a paid consultant for Zehna Therapeutics, having received research funds from P&G, Roche Diagnostics, and Zehna Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal association with atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. One of the novelties of this statement is a new risk calculator showing how Lp(a) influences lifetime risk for ASCVD and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentration. The statement also provides practical advice on how knowledge about Lp(a) concentration can be used to modulate risk factor management, given that specific and highly effective mRNA-targeted Lp(a)-lowering therapies are still in clinical development. This advice counters the attitude: "Why should I measure Lp(a) if I can't lower it?". Subsequent to publication, questions have arisen relating to how the recommendations of this statement impact everyday clinical practice and ASCVD management. This review addresses 30 of the most frequently asked questions about Lp(a) epidemiology, its contribution to cardiovascular risk, Lp(a) measurement, risk factor management and existing therapeutic options., Competing Interests: Declaration of competing interest Potential conflicts of interest outside the submitted work are summarized below. The following authors report participation in trials; receipt of fellowships, or grants for travel, research or staffing support; and/or personal honoraria for consultancy or lectures/speaker’s bureau from: Abbott (KKR, LST, BG Nordestgaard [BGN]), Abcentra (M Koschinsky [MK]), Abdi-Ibrahim (LST), Actelion (LST), Aegerion (ALC, PM Moriarty [PMM]), Affiris AG (G Lambert [GL]), Akcea (ALC, BGN, KG Parhofer [KGP], ESGS), Amarin (ALC, PMM, BGN, KGP), Amgen (ALC, BA Ference [BAF], F Kronenberg [FK], F Mach [FM], PMM, P Natarajan [PN], BGN, KGP, KKR, ESGS, LST, GF Watts [GFW]), Amgen Germany (A von Eckardstein [AvE]), Amgen Switzerland (AvE), Amryt (ALC), Amundsen/Amgen (FM), Apple (PN), Arrowhead (GFW), Ayma Therapeutics (MK), AstraZeneca (ALC, PN, BGN, KKR, GFW), Bayer (LST), Berlin-Chemie (KGP), Boehringer-Ingelheim (KKR), Boston Scientific (PN), CiVi Pharma (BAF), Daiichi-Sankyo (ALC, BAF, FM, KGP, KKR, LST), Daiichi Switzerland (AvE), dalCOR (BAF), Denka (BGN), Eli Lilly (ALC, BAF, MK, KKR), Esperion (ALC, BAF, PMM, BGN, KKR, ESGS, GFW), FH Foundation (PMM), Foresite Labs (PN), Fresenius (FK), GB Life Sciences (PMM), Genentech (PN), Genzyme (ALC), Horizon/Novartis (FM, BGN), Ionis Pharmaceuticals (BA, ALC, BAF, BGN, MK, PMM), Jupiter Bioventures (MR Dweck [MRD]), Kaneka (FK, PMM), Kowa (ALC, BGN, KKR), KrKa Phama (BAF), Lupin (KKR), Menarini (ALC), Merck (ALC, BAF), MSD (KGP), Mylan (ALC, BAF, LST), New Amsterdam (KKR), Noetic Insights (MK), Novartis (B Arsenault [BA], ALC, MRD, BAF, FK, FM, CJ McNeal [CJMN], PMM, PN, BGN, KGP, KKR, ESGS, LST, GFW), Novartis Canada (MK), NovoNordisk (BAF, CJMN, BGN, KKR, ES, LST), Nyrada Inc (GL), Pfizer (BA, MRD, BAF, MK,SM, KKR, LST, GFW), Quest Diagnostics (SM), Recordati (ALC, LST), Regeneron (ALC, BAF, PMM, BGN, KKR, ESGS), Renew (PMM), Resverlogix (KKR), Sandoz (ALC), Sanofi (ALC, BAF, FM, BGN, KGP, KKR, ESGS, LST, GFW), Sanofi-Aventis Switzerland (AvE), Sanofi-Regeneron (GL, ESGS), Servier (LST), Sigma Tau (ALC), Silence Therapeutics (BA, MRD, BAF, BGN, KKR, GFW), The Medicines Co (BAF) and UltraGenyx (BGN). PN declares spousal employment at Vertex and KGP is a member of the Data Monitoring and Safety Board at Boehringer-Ingelheim. SSV declares an honorarium from the American College of Cardiology (Associate Editor for Innovations, acc.org), and grant funding from the U.S. Department of Veterans Affairs, National Institutes of Health, World Heart Federation, and Tahir and Jooma Family. Manuscripts have been published in collaboration with non-academic co-authors by PN and LST (Fitbit), GFW (Amgen), and BA (Pfizer). Equity interests including income from stocks, stock options, royalties, or from patents or copyrights were reported from AstraZeneca (JKS), Boston Scientific (L Berglund [LB]), Cargene Therapeutics (KKR), Gilead Sciences (LB), J & J (LB), GSK (JKS), Medtronic (LB), New Amsterdam Pharma (KKR), NovoNordisk (LB), Pemi31 Therapeutics (KKR), and Pfizer (LB).KKR is President of the European Atherosclerosis Society. LST is Past-President of the European Atherosclerosis Society and an Editorial Board Member, The European Heart Journal., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: High-sensitivity C-reactive protein (hsCRP), a marker for atherosclerotic cardiovascular disease risk, is reduced by bempedoic acid. We assessed the relationship between changes in low-density lipoprotein cholesterol (LDL-C) and hsCRP in relation to baseline statin use., Methods: Pooled data from four phase 3 trials (patients on maximally tolerated statins [Pool 1] and patients receiving no or low-dose statins [Pool 2]) were used to determine the proportion of patients with baseline hsCRP ≥2 mg/L who achieved hsCRP <2 mg/L at week 12. The percentage of patients who achieved hsCRP <2 mg/L and guideline-recommended LDL-C (Pool 1, <70 mg/dL; Pool 2, <100 mg/dL) was determined for patients on statins in Pool 1 and those not on statins in Pool 2, as was the correlation between percent changes in hsCRP and LDL-C., Results: Overall, 38.7% in Pool 1 and 40.7% in Pool 2 with baseline hsCRP ≥2 mg/L achieved hsCRP <2 mg/L with bempedoic acid, with little effect from background statin. Among patients taking a statin in Pool 1 or not taking a statin in Pool 2, 68.6% and 62.4% achieved hsCRP <2 mg/L. Both hsCRP <2 mg/L and United States guideline-recommended LDL-C were achieved more often with bempedoic acid vs. placebo (20.8% vs. 4.3%, respectively, in Pool 1 and 32.0% vs. 5.3%, in Pool 2). Changes in hsCRP and LDL-C were only weakly correlated (Pool 1, r = 0.112; Pool 2, r = 0.173)., Conclusions: Bempedoic acid significantly reduced hsCRP irrespective of background statin therapy; the effect was largely independent of LDL-C lowering., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Stroes has received research grant(s)/support to his institution from Amgen, Sanofi, Resverlogix, and Athera and has received lecturing/advisory board fees from Amgen, Sanofi, Akcea/IONIS, Esperion Therapeutics, Inc., and Novartis. Dr. Bays’s research site has received research grants from 89Bio, Acasti, Akcea, Allergan, Alon Medtech/Epitomee, Amarin, Amgen, AstraZeneca, Axsome, Boehringer Ingelheim, Civi, Eli Lilly, Esperion Therapeutics, Inc., Evidera, Gan and Lee, Home Access, Janssen, Johnson and Johnson, Lexicon, Matinas, Merck, Metavant, Novartis, NovoNordisk, Pfizer, Regeneron, Sanofi, Selecta, TIMI, and Urovant. He has served as a consultant/advisor for 89Bio, Amarin, Esperion Therapeutics, Inc., Matinas, and Gelesis and as a speaker for Esperion. Dr. Banach has received research grant(s)/support from Amgen, Sanofi, Valeant, and Viatris, has served as a consultant for or received honoraria from Abbott Medical, Abbott Vascular, Amgen, Esperion Therapeutics, Inc., Freia Pharmaceuticals, Herbapol, Kogen, KRKA, Mylan/Viatris, Novartis, Novo Nordisk, Polpharma, Polfarmex, Regeneron, Sanofi-Aventis, Servier, Valeant, Daichii Sankyo, Teva, and Zentiva, and is CMO at Nomi Biotech Corporation Ltd. Dr. Catapano has received research grant(s)/support from Sanofi, Sanofi Regeneron, Amgen, Amarin, Mylan, and Menarini (all paid to the institution, not to the individual), and has served as a consultant for or received honoraria from Akcea, Amarin, Amgen, Sanofi, Esperion Therapeutics, Inc., Kowa, Novartis, Ionis Pharmaceuticals, Medco, Mylan, Menarini, MSD, Recordati, Regeneron, and Daiichi Sankyo. Dr. Duell has received institutional research grant(s)/support from Travere/Retrophin and Regenxbio, and served as a consultant for Akcea/Ionis, Kaneka, Novo Nordisk, Retrophin, and Regeneron. Dr. Laufs has served as a consultant for Amgen, Daiichi Sankyo, Esperion Therapeutics, Inc., and Sanofi. Dr. Mancini received research grant(s)/support from Merck, AstraZeneca, Amgen, Sanofi, Novo Nordisk, Boehringer Ingelheim, Lilly, Pfizer, HLS Therapeutics, and Bayer and has served as a consultant for these companies as well as for Esperion Therapeutics, Inc., Novartis, and Servier. Dr. Ray has received research grant(s)/support from Amgen, Daiichi Sankyo, MSD, Pfizer, Regeneron, and Sanofi (all paid to the institution, not to the individual), and served as a consultant for or received honoraria from AbbVie, Akcea, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cerenis, Cipla, Daiichi Sankyo, Dr. Reddy’s Laboratories, Lilly, Esperion Therapeutics, Inc., Kowa, Medco, MSD, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Takeda, and Zuellig Pharma. Dr. Gotto is an Esperion Therapeutics, Inc. board member and Akcea DSMB chair. He has also served as a consultant for Kowa. Dr. Sasiela is a former employee of Esperion Therapeutics, Inc., and may hold stock and/or stock options. He is currently the principal of Cardiometabolic Consulting, LLC. Dr. Zhang was an employee of Esperion Therapeutics, Inc. when the analysis was carried out and may hold stock and/or stock options., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Lipoprotein(a) (Lp(a)) is an LDL-like particle whose plasma levels are largely genetically determined. The impact of measuring Lp(a) in patients with clinical familial hypercholesterolemia (FH) referred for genetic testing is largely unknown. We set out to evaluate the contribution of (genetically estimated) Lp(a) in a large nation-wide referral population of clinical FH., Methods: In 1504 patients referred for FH genotyping, we used an LPA genetic instrument (rs10455872 and rs3798220) as a proxy for plasma Lp(a) levels. The genetic Lp(a) proxy was used to correct LDL-cholesterol and reclassify patients with clinical FH based on Dutch Lipid Criteria Network (DLCN) scoring. Finally, we used estimated Lp(a) levels to reclassify ASCVD risk using the SCORE and SMART risk scores., Results: LPA SNPs were more prevalent among mutation-negative compared with mutation-positive patients (296/1280 (23.1%) vs 35/224 (15.6%), p = 0.016). Among patients with genetically defined high Lp(a) levels, 9% were reclassified to the DLCN category 'unlikely FH' using Lp(a)-corrected LDL-cholesterol (LDL-C cor ) and all but one of these patients indeed carried no FH variant. Furthermore, elevated Lp(a) reclassified predicted ASCVD risk into a higher category in up to 18% of patients., Conclusions: In patients referred for FH molecular testing, we show that taking into account (genetically estimated) Lp(a) levels not only results in reclassification of probability of genetic FH, but also has an impact on individual cardiovascular risk evaluation. However, to avoid missing the diagnosis of an FH variant, clear thresholds for the use of Lp(a)-cholesterol adjusted LDL-cholesterol levels in patients referred for genetic testing of FH must be established., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TRT, SI, JP, LZ and JCD declare no conflicts of interest. NSN and LFR are co-founders of Lipid Tools. GKH reports research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445), CardioVascular Research Initiative, EU, and the Klinkerpad fonds; institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker's bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron until April 2019 (fees paid to the academic institution). ESGS reports consulting fees from Amgen, Sanofi, Regeneron, Esperion, Novartis, Ionis/Akcea (all paid to the institution)., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Lipoprotein(a) [Lp(a)] has been established as an independent and causal risk factor for cardiovascular disease. Individuals with elevated levels of Lp(a) (>125 nmol/L; >50 mg/dl) display increased arterial wall inflammation characterized by activation of the endothelium by Lp(a)-carried oxidized phospholipids and recruitment of circulating monocytes. This results in increased secretion of chemoattractants and cytokines, upregulation of adhesion molecules and increased migration of leukocytes through the vessel wall. In addition, Lp(a) is also pivotal in the initiation phase of aortic valve stenosis. The oxidized phospholipids associated, in part, with the apolipoprotein(a) [apo(a)] moiety of Lp(a) stimulate the aortic valve residential cell, the valve interstitial cells (VICs), to either induce osteoblastic differentiation or apoptosis, thereby initiating the process of aortic valve calcification. Lastly, Lp(a) has been linked to systemic inflammation, including the acute phase response. Specifically, the cytokine interleukin 6 (IL-6) has a unique relationship with Lp(a), since the LPA gene contains IL-6 response elements. In this review, we will discuss the pathways and cell types affected by Lp(a) in the context of atherosclerosis, aortic valve stenosis and the acute phase response, highlighting the role of Lp(a) as an inflammatory mastermind., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Backgrounds and Aims: Elevated lipoprotein(a) (Lp[a]) has been identified as a causal risk factor for cardiovascular disease including peripheral arterial disease (PAD). Although Lp(a) is associated with the diagnosis of PAD, it remains elusive whether there is an association of Lp(a) with cardiovascular and limb events in patients with severe PAD., Methods: Preoperative plasma Lp(a) levels were measured in 384 consecutive patients that underwent iliofemoral endarterectomy and were included in the Athero-Express biobank. Our primary objective was to assess the association of Lp(a) levels with Major Adverse Limb Events (MALE). Our secondary objective was to relate Lp(a) levels to Major Adverse Cardiovascular Events (MACE) and femoral plaque composition that was acquired from baseline surgery., Results: During a median follow-up time of 5.6 years, a total of 225 MALE were recorded in 132 patients. Multivariable analysis, including history of peripheral intervention, age, diabetes mellitus, end stage renal disease and PAD disease stages, showed that Lp(a) was independently associated with first (HR of 1.36 (95% CI 1.02-1.82) p = .036) and recurrent MALE (HR 1.36 (95% CI 1.10-1.67) p = .004). A total of 99 MACE were recorded but Lp(a) levels were not associated with MACE.sLp(a) levels were significantly associated with a higher presence of smooth muscle cells in the femoral plaque, although this was not associated with MALE or MACE., Conclusions: Plasma Lp(a) is independently associated with first and consecutive MALE after iliofemoral endarterectomy. Hence, in patients who undergo iliofemoral endarterectomy, Lp(a) could be considered as a biomarker to enhance risk stratification for future MALE., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Severe obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular disease. Experimental evidence suggests that this risk may be mediated by chronic sympathetic hyperactivation and systemic inflammation, but the precise mechanisms remain to be unraveled. Our aim was to evaluate whether severe OSA patients are characterized by increased sympathetic and hematopoietic activity, potentially driving atherosclerosis., Methods: Untreated patients with severe OSA (apnea-hypopnea index (AHI) > 30 per hour) were matched with mild OSA patients (AHI<15 & >5 per hour) according to age, sex, and body mass index. Study objectives were to assess baroreflex sensitivity (BRS) and heart-rate variability (HRV) using continuous finger blood pressure measurements, hematopoietic activity in the bone marrow and spleen, and arterial inflammation with 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT)., Results: A total of 34 subjects, 17 per group, were included in the analysis. Mean age was 60.7 ± 6.2 years, 24 (70.6%) were male. Mean AHI was 40.5 ± 12.6 per hour in the severe OSA group, and 10.5 ± 3.4 per hour in the mild OSA group. Participants with severe OSA were characterized by reduced BRS (5.7 [4.6-7.8] ms/mmHg in severe vs 8.2 [6.9-11.8] ms/mmHg in mild OSA, p = 0.033) and increased splenic activity (severe OSA 18 F-FDG uptake 3.56 ± 0.77 vs mild OSA 3.01 ± 0.68; p = 0.036). HRV, bone marrow activity and arterial inflammation were comparable between groups., Conclusions: Patients with severe OSA are characterized by decreased BRS and increased splenic activity. Randomized controlled trials are warranted to assess whether OSA treatment reduces sympathetic and splenic activity., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: Thrombosis is a major driver of adverse outcome and mortality in patients with Coronavirus disease 2019 (COVID-19). Hypercoagulability may be related to the cytokine storm associated with COVID-19, which is mainly driven by interleukin (IL)-6. Plasma lipoprotein(a) [Lp(a)] levels increase following IL-6 upregulation and Lp(a) has anti-fibrinolytic properties. This study investigated whether Lp(a) elevation may contribute to the pro-thrombotic state hallmarking COVID-19 patients., Methods: Lp(a), IL-6 and C-reactive protein (CRP) levels were measured in 219 hospitalized patients with COVID-19 and analyzed with linear mixed effects model. The baseline biomarkers and increases during admission were related to venous thromboembolism (VTE) incidence and clinical outcomes in a Kaplan-Meier and logistic regression analysis., Results: Lp(a) levels increased significantly by a mean of 16.9 mg/dl in patients with COVID-19 during the first 21 days after admission. Serial Lp(a) measurements were available in 146 patients. In the top tertile of Lp(a) increase, 56.2% of COVID-19 patients experienced a VTE event compared to 18.4% in the lowest tertile (RR 3.06, 95% CI 1.61-5.81; p < 0.001). This association remained significant after adjusting for age, sex, IL-6 and CRP increase and number of measurements. Increases in IL-6 and CRP were not associated with VTE. Increase in Lp(a) was strongly correlated with increase in IL-6 (r = 0.44, 95% CI 0.30-0.56, p < 0.001)., Conclusions: Increases in Lp(a) levels during the acute phase of COVID-19 were strongly associated with VTE incidence. The acute increase in anti-fibrinolytic Lp(a) may tilt the balance to VTE in patients hospitalized for COVID-19., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Low-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype., Methods: First, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data., Results: The mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10-0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk., Conclusions: This 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Both plasma low-density lipoprotein (LDL) cholesterol levels and risk for premature cardiovascular disease are extremely elevated in patients with homozygous familial hypercholesterolemia (HoFH), despite the use of multiple cholesterol lowering treatments. Given its inborn nature, atherosclerotic plaques are commonly observed in young HoFH patients. Whether intensive lipid lowering strategies result in plaque regression in adolescent patients is unknown., Methods: Two HoFH patients with null/null LDLR variants, who participated in the R1500-CL-1629 randomized clinical trial (NCT03399786) evaluating the LDL cholesterol lowering effect of evinacumab (a human antibody directed against ANGPTL3; 15 mg/kg intravenously once monthly), were included in this study. Patients underwent coronary computed tomography angiography (CCTA) before randomization and after 6 months of treatment., Results: Both patient A (aged 12) and B (aged 16) were treated with a statin, ezetimibe and weekly apheresis. Evinacumab decreased mean pre-apheresis LDL cholesterol levels from 5.51 ± 0.75 and 5.07 ± 1.45 mmol/l to 2.48 ± 0.31 and 2.20 ± 0.13 mmol/l and post-apheresis LDL levels from 1.45 ± 0.26 and 1.37 ± 39 mmol/l to 0.80 ± 0.16 and 0.78 ± 0.13 mmol/l in patient A and B, respectively. Total plaque volumes were reduced by 76% and 85% after 6 months of evinacumab treatment in patient A and B, respectively., Conclusions: We describe two severely affected young HoFH patients in whom profound plaque reduction was observed with CCTA after intensive lipid lowering therapy with statins, ezetimibe, LDL apheresis, and evinacumab. This shows that atherosclerotic plaques possess the ability to regress at young age, even in HoFH patients., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Statins suppress hepatic mRNA expression of ANGPTL3 encoding angiopoietin-like 3 in healthy subjects, but it is unknown if plasma ANGPTL3 concentrations are affected by statins prescribed to hypercholesterolemic patients in clinical practice. We therefore investigated the effect of statin treatment on plasma ANGPTL3 concentrations in hypercholesterolemic patients. In addition, we explored the underlying mechanism by which statins regulate ANGPTL3 in vitro., Methods: Plasma ANGPTL3 concentrations were measured in 93 genetically confirmed familial hypercholesterolemia (FH) patients who were using statin therapy and 61 statin naïve FH patients. Moreover, concentrations were measured in 14 hypercholesterolemic patients who discontinued their statin treatment for 4 weeks. In vitro studies were performed with Huh7 human hepatoma cells., Results: Plasma ANGPTL3 concentrations were 15% lower in statin treated FH patients compared to statin naïve FH patients (145 (120-193) vs. 167 (135-220) ng/ml, p = 0.012). Statin discontinuation resulted in a 21% (p<0.001) increase of plasma ANGPTL3 concentrations. Simvastatin reduced ANGPTL3 mRNA expression and ANGPTL3 secretion of Huh7 cells. Liver X receptor (LXR) activation with T0901317 increased ANGPTL3 mRNA expression and ANGPTL3 secretion by 6- and 3-fold, respectively. Adding simvastatin did not mitigate this effect but adding the LXR antagonist GSK2230 to simvastatin-incubated Huh7 cells diminished simvastatin-induced reductions in ANGPTL3 mRNA expression and ANGPTL3 secretion. Simvastatin reduced intracellular oxysterol concentrations. Oxysterols are endogenous LXR ligands, implying that simvastatin suppresses ANGPTL3 secretion via reduced oxysterol-mediated LXR activation., Conclusions: Statins lower plasma ANGPTL3 concentrations in hypercholesterolemic patients, likely due to decreased oxysterol-mediated LXR activation., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

The endothelium is crucial for maintaining vascular homeostasis and functions as a barrier between blood components and tissue. In atherosclerosis, this barrier function is impaired, which is characterized by secretion of chemoattractants and cytokines, upregulation of adhesion molecules and increased vascular permeability. This facilitates enhanced leukocyte migration through the vessel wall. Fortunately, we can utilize these features to our advantage by using nanomedicine to deliver drugs and imaging tracers into the interstitial space. This provides us with targeted, local delivery of therapeutic agents, which enhances the specificity and efficacy of these agents and thus, could be used to inhibit disease progression. Additionally, delivery of imaging tracers in the interstitial space will give us insight into the vulnerability of atherosclerotic plaques by targeting resident macrophages and activated endothelial cells, providing pivotal information that is currently lacking in the clinic. In this review, we discuss how the endothelial barrier is affected during atherosclerosis and how to surmount this barrier for successful delivery of nanomedicine carrying drugs and imaging tracers to both the endothelium and macrophages., (Copyright © 2020. Published by Elsevier B.V.)

Background and Aims: Smoking causes cardiovascular disease. AHRR hypomethylation at the cg05575921 site is associated with active and former smoking status at baseline, and cumulative amount of tobacco smoked. We tested the hypothesis that AHRR cg05575921 hypomethylation as an epigenetic marker of smoking history predicts the risk of myocardial infarction in former smokers., Methods: We included 10,510 individuals with methylation extent measurements and information on smoking status from the Copenhagen City Heart Study (CCHS), a prospective, cohort study of the general population carried out from 1991 to 2003. The endpoint myocardial infarction was retrieved from the national Danish Patient Registry and the national Danish Causes of Death Registry., Results: For individuals in the 1st (lowest) quartile of AHRR cg05575921 methylation (≤49% methylation extent), 99% were ever smokers at baseline (active and former smokers combined) compared to 42% in the 4th (highest) quartile (>62% methylation extent). For former smokers, the cumulative incidence of myocardial infarction was higher in the lowest methylation extent (1st-50th percentile) compared to the highest methylation extent (51st-100th percentile). Compared to never smokers, the multivariable adjusted subhazard ratio for myocardial infarction was 1.09 (95%CI:0.88-1.35) for former smokers with the highest methylation degree, 1.38 (1.06-1.80) for active smokers with the highest methylation extent, 1.39 (1.08-1.78) for former smokers with the lowest methylation extent, and 1.61 (1.35-1.92) for active smokers with the lowest methylation extent., Conclusions: AHRR cg05575921 hypomethylation as an epigenetic marker of smoking history predicts risk of myocardial infarction, particularly in former smokers. Further, AHRR hypomethylation, regardless of smoking status, was associated with increased risk of myocardial infarction., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol., Methods: In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and 18 F-FDG PET/CT to quantify arterial wall inflammation., Results: A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm 2 , p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks., Conclusion: In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolemia (FH) is an inherited disorder associated with increased risk of coronary heart disease as a result of high LDL-cholesterol (LDL-C). The clinical diagnosis can be made with the Dutch Lipid Clinic Network criteria (DLCN criteria). FH is an underdiagnosed disorder, possibly due to false negative LDL-C interpretation during lipid lowering therapy (LLT). We hypothesized that automated health record-based integration of data can provide a signal to facilitate identification of FH patients., Methods: We included patients with LDL-C ≥6.5 mmol/l after correction for LLT in all patients testing LDL-C in Northwest Clinics, The Netherlands. Patients previously diagnosed with FH were excluded. The primary endpoint was the additional number of patients with DLCN criteria ≥6 points after correction for LLT. Secondary endpoints were the additional number of patients with DLCN criteria ≥6 points after also adding data on patient- and family history, and LDL-C before and after correction for LLT. Analysis was performed in a daily automated routine (HiX ChipSoft)., Results: In a total of 41,937 individual LDL-C measurements during 26 weeks, we found 351 patients with LDL-C ≥6.5 mmol/l after automated correction for LLT. FH had previously been diagnosed in 42 patients. In the remaining 309 patients (58.3% female; age: 66 ± 11 yrs (mean ± SD); 85.8% on LLT), the number of patients with DLCN criteria ≥6 points increased from 9 to 95 after correction for LLT, and to 127 after also adding patient and family history. The mean LDL-C before and after correction for LLT was 4.69 ± 1.42 mmol/l and 8.16 ± 1.68 mmol/l, respectively (mean ± SD; p < 0.001)., Conclusions: We conclude that automated medical record-based integration of LDL-C, LLT and patient- and family history can provide a crucial signal to facilitate identification of FH. Whether this signal results in subsequent genetic identification of FH patients and their relatives requires further study., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: The rare ASGR1 del12 variant is associated with a beneficial effect on coronary artery disease (CAD) that is disproportionate to the small reductions in plasma LDL cholesterol (LDLc). This unexplained benefit has sparked the debate on potential additional pleiotropic effects of ASGR1 variants. Since ASGR1 has also been implicated in platelet homeostasis, we evaluated platelet function in heterozygous ASGR1 del12 carriers and controls. In addition, we compared the magnitude of various LDLc lowering genetic scores in the UK-biobank using Mendelian randomization., Methods: Desialylation of platelet surface glycoproteins and platelet aggregation capacity were measured in 12 carriers and 10 controls. We selected 3 common genetic variants in the ASGR1 locus that were significantly associated with plasma LDLc and assessed the association with coronary artery disease (CAD) and compared it with the effects of HMCGR, LDLR, NCI1L1 and PCSK9 gene scores., Results: Platelet surface GlcNAC residues were significantly lower in carriers but platelet aggregation did not differ. The relative risk reduction of ASGR1 GRS on CAD and myocardial infarction per 10 mg/dl LDLc reduction was 23% (OR 0.77, 95% CI 0.62-0.96). This risk reduction was proportionally similar to the gene risk scores in HMCGR, NPC1L1, PCSK9, and LDLR., Conclusions: Unlike previous reports, we did not find any evidence for a pleiotropic effect of the rare del12 variant in the ASGR1 locus on CAD, as platelet function did not differ between carriers and controls. Moreover, the observed effect of ASGR1 variants on CAD risk was proportional to the reduction in plasma LDLc levels., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

The emergence of pathophysiological, epidemiologic, and genetic data strongly supports the causality for lipoprotein(a) [Lp(a)] in cardiovascular disease (CVD) and calcific aortic valve disease (CAVD). In parallel, novel Lp(a) lowering approaches have been developed that have re-invigorated clinical interest in Lp(a). Because Lp(a) is the most prevalent monogenetic lipid disorder globally, with prevalence of Lp(a) > 50 mg/dL estimated at >1.4 billion people, the rationale for diagnosing and managing Lp(a)-mediated risk is now stronger than ever. Patients with elevated Lp(a) are significantly under-diagnosed and the diagnosis is frequently made ad hoc rather than systematically. Elevated Lp(a) levels are associated with atherothrombotic risk and patients present with varied clinical phenotypes, ranging from stroke in pediatric age groups, to ST-segment elevation myocardial infarction in young males, to CAVD in elderly individuals. A new clinical care paradigm of a dedicated "Lp(a) Clinic" would serve to evaluate and manage such patients who have elevated Lp(a) as the pathophysiological etiology. Such a clinic would include multidisciplinary expertise in lipid metabolism, clinical cardiology, vascular medicine, valvular disease, thrombosis, and pediatric aspects of clinical care. This viewpoint argues for the rationale of an Lp(a) outpatient clinic where patients with elevated Lp(a) and their affected relatives can be referred, evaluated, managed and followed, to ultimately reduce Lp(a)-mediated CVD and CAVD risk., Competing Interests: Declaration of competing interest ST is a co-inventor, receives royalties from patents owned by the University of California San Diego on oxidation-specific antibodies, is a co-founder of Oxitope, Inc and Kleanthi Diagnostics and currently has a dual appointment at UCSD and as an employee of Ionis Pharmaceuticals. ESGS is a consultant for Akcea Therapeutics, Amgen, Sanofi, Esperion, and has received research grants from Sanofi., (Copyright © 2020. Published by Elsevier B.V.)

Notwithstanding the intense efforts into the understanding and prevention of cardiovascular disease (CVD), its complex pathology remains the leading cause of mortality worldwide. The pivotal role of epigenetic changes in the control of gene expression has been profiled in several diseases, such as cancer and inflammatory disorders. In the last decade, increasing evidence has also linked aberrant epigenetic modulation as a contributor to CVD development. Differential profiles of DNA methylation, histone methylation and acetylation have consistently been observed in tissues and cells (comprising the aortic lesions, vascular endothelium and monocytes) from patients with CVD. This highlights the therapeutic potential of epigenetic drugs for cardiovascular treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: In clinical trials, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors robustly lowered LDL-cholesterol (LDL-c) and had a favorable tolerability and safety profile. Based on these findings, PCSK9 inhibitors are incorporated in updates of clinical treatment guidelines. However, trial results do not necessarily predict the effectiveness under real-world conditions. The aim of the current study is to determine the efficacy and tolerability of PCSK9 inhibitors in routine outpatient care., Methods: The cohort comprised all patients who were prescribed evolocumab or alirocumab at the outpatient clinic of a large university hospital in the Netherlands. Eligible patients required additional lipid-lowering despite maximally tolerated statin therapy and ezetimibe, or were statin intolerant. Data were systematically collected during routine outpatient visits., Results: The study included 238 patients of whom 67.2% had familial hypercholesterolemia (FH) and 42.9% were statin intolerant. The mean LDL-c reduction was 55.0% from a baseline of 4.4 mmol/L. LDL-c goals were attained by 62.3% of patients. Side effects were reported by 15.5% of patients and 2.5% discontinued treatment. No meaningful differences in efficacy or tolerability were observed between patients with FH or statin intolerance, or across treatment regimens., Conclusions: The observed lipid reductions and side effects profile of PCSK9 inhibitors in a routine care setting were comparable to observations in clinical trials., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients., Methods: CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001., Results: One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI., Conclusions: Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis., Clinical Trial Registration: Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Introduction: There is discussion about incorporating a family history (FamHis) of premature coronary artery disease (CAD) in risk score algorithms. However, FamHis provides information on individual risk. Coronary artery calcification score (CACS) is a metric of atherosclerosis that may determine the individual risk within families at high risk of premature CAD., Methods: In asymptomatic individuals (n = 704), we assessed the association between FamHis of CAD and elevated CACS. To assess the predictive value of CACS in individuals with a FamHis of CAD, we performed a post-hoc analysis on the St. Francis Heart Study (n = 834). We assessed, in a case control design, the risk of future CAD in individuals with a FamHis of CAD and either CACS >80th percentile or no CACS at all., Results: Individuals with a FamHis for CAD had an increased risk for elevated CACS (adjusted odds ratio (OR) 2.23 (95% CI 1.48-3.36); p < 0.05), compared to those without a FamHis. In the prospective study (3.5 years follow-up), the event rate equally low in those with a positive FamHis and a negative FamHis (0% vs. 1%), if they had a CAC of 0. However, in those with CACS >80(th) percentile, a FamHis of CAD doubled the CAD event rate (positive FamHis 12.5% vs. negative FamHis 6.8%; adjusted HR 2.08 (95% CI 1.09-3.87; p < 0.05)., Conclusion: CAC scoring leads to risk discrimination among those with a positive FamHis for premature CAD. These results support testing CAC score in asymptomatic individuals with a positive FamHis to identify a high risk population., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Blocking the interleukin-6 pathway by tocilizumab (TCZ) has been associated with changes in the lipoprotein profile, which could adversely impact cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). In the present study, we addressed the effect of TCZ on lipoproteins in both fasting and non-fasting state in RA patients and tested the effect of TCZ on LDL receptor (LDLr) expression in vitro., Methods: Twenty patients with active RA and an inadequate response to TNF blockers received monthly TCZ intravenously. On week 0, 1 and 6 blood was drawn before and after an oral fat load, the lipid profiles and HDL antioxidative capacity were measured. Effects of TCZ on LDLr expression in transfected HepG2 cells were subjected., Results: After 6 weeks of TCZ, total cholesterol increased by 22% (4.8 ± 0.9 to 5.9 ± 1.3 mmol/L; p < 0.001), LDLc by 22% (3.0 ± 0.6 to 3.6 ± 0.8 mmol/L; p < 0.001) and HDLc by 17% (1.4 ± 0.4 to 1.7 ± 0.7 mmol/L; p < 0.016). Fasting triglycerides (TG) increased by 48% (1.0 ± 0.4 to 1.4 ± 0.8 mmol/L; p = 0.011), whereas postprandial incremental area under the curve TG increased by 62% (p = 0.002). Lipid changes were unrelated to the change in disease activity or inflammatory markers. No difference in HDL antioxidative capacity was found. In vitro, LDLr expression in cultured liver cells was significantly decreased following TCZ incubation (P < 0.001)., Conclusions: TCZ adversely impacts on both LDLc as well as fasting and postprandial TG in patients with RA. The changes in hepatic LDLr expression following TCZ imply that adverse lipid changes may be a direct hepatic effect of TCZ. The net effect of TCZ on CV-morbidity has to be confirmed in future clinical trials., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: The pathophysiology of hypertriglyceridemia is complex hampering effective therapeutic strategies. Increased central parasympathetic nerve activity was shown to inhibit hepatic triglyceride (TG) excretion via modulation of liver stearyl-CoA desaturase (SCD)-1 activity in rodents. We evaluated the impact of 7-h lactate clamping on VLDL-TG homeostasis in humans., Methods: Eight normolipidemic, male subjects were subjected to a continuous infusion of l-lactate (target concentration 3 mmol/L) or saline for 7 h in random order on two separate occasions. TG kinetics in very low density lipoproteins (VLDL1 and 2) were measured after a bolus injection of [1,1,2,3,3]-(2)H5-glycerol. Palmitic acid (16:0) and palmitoleic acid (16:1) in VLDL1 and VLDL2 were measured as a reflection of liver SCD1 activity., Results: Plasma TG levels changed by 0.16 ± 0.09 mmol/L during lactate vs -0.15 ± 0.08 mmol/L during saline (P < 0.05). VLDL1 16:1/16:0 ratio increased to 1.2 ± 0.7 during lactate versus a decrease during saline by -1.5 ± 0.6 (p = 0.01). During lactate VLDL1-TG excretion was higher compared to saline (1604 [827-2870] versus 1285 [505-2155] μmol glycerol; p < 0.05), trending toward higher VLDL1-TG pool sizes during lactate (28%; p = 0.07 versus saline)., Conclusions: In normolipidemic men, 7-h l-lactate clamp increases, rather than decreases SCD1 activity and hepatic TG secretion leading to elevated plasma TG levels. These conflicting data between human and rodents on central regulation of hepatic TG excretion illustrate that experimental findings on the role of the central nervous system in lipid metabolism should be interpreted with caution., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Carriers of a functional mutation in LCAT, encoding lecithin:cholesterol acyl transferase, are exposed to lifelong low high-density lipoprotein cholesterol (HDL-c) levels. We investigated whether LCAT mutation carriers have increased arterial stiffness as a marker of cardiovascular disease and whether arterial stiffness was associated with carotid wall thickening., Methods: We assessed 45 carriers of LCAT mutations (mean age ± SD 46 ± 13 yrs) and 45 age-matched controls. Probands referred with established cardiovascular disease were excluded. We measured carotid-fermoral pulse wave velocity (PWV) and carotid artery wall thickening by ultrasound and 3.0 T magnetic resonance imaging., Results: In carriers, HDL-c was lower (32 ± 12 vs. 59 ± 16 mg/dl; p < 0.0001) and triglycerides were higher (median 116 [IQR 80-170] vs. 71 [IQR 53-89] mg/dl; p < 0.001) vs. controls. PWV was higher in carriers vs. controls (7.9 ± 2.0 m/s vs. 7.1 ± 1.6 m/s; p < 0.01). This difference retained significance in multivariate analysis including age, sex, mean arterial pressure and body mass index, and after exclusion of carriers and controls with cardiovascular disease. Both in carriers and controls, PWV was correlated with wall thickening of the carotid arteries as assessed by ultrasound (R 0.50, p < 0.001 for carriers and R 0.36, p < 0.04 for controls) and 3.0 T magnetic resonance imaging (R 0.54, p < 0.001 for carriers and R 0.58, p < 0.001 for controls)., Conclusion: Pulse wave velocity is increased in LCAT mutation carriers with low HDL-c and is associated with carotid wall thickening., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Genetic variation in the gene ALOX5AP, encoding arachidonate 5-lipoxygenase-activating protein, have been suggested to increase risk for myocardial infarction and stroke. Leukotrienes (LTs) that derive from the 5-lipoxygenase (5-LO) cascade have been implicated in the pathogenesis of abdominal aortic aneurysm (AAA)., Methods and Results: The association of the ALOX5AP haplotypes with AAA was assessed in a large population-based cohort of 613 men aged ≥65 years with screen-detected AAAs and 707 randomly selected age-matched controls without AAA. Taqman assays were used to assess seven previously described single nucleotide polymorphisms (SNPs) of ALOX5AP. Haplotypes A and B were defined by the four SNPs (SG13S25, SG13S114, SG13S89, SG13S32) and (SG13S377, SG13S114, SG13S41, SG13S35), respectively. After adjustment for cardiovascular risk factors, there were no significant differences in the distribution of ALOX5AP haplotypes between cases and controls., Conclusion: A genetic predisposition to up-regulation of LT mediators is unlikely to play a dominant role in the pathogenesis of AAA., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Fecal bile acid and neutral sterol excretion are the obligate endpoints of the reverse cholesterol transport pathway (RCT). In studies in mice, no evidence was found for a relation between HDL-cholesterol (HDL-c) levels and fecal sterol excretion. In this study, we have evaluated this relationship in patients with isolated low HDL-c versus controls., Results: Fecal sterol excretion was studied in 12 subjects with familial hypoalphalipoproteinemia (FHA) and 11 healthy controls. Compared to the controls (8.9+/-6.3mg/kg/day), neutral sterol excretion was significantly lower in the FHA group (4.0+/-2.4mg/kg/day). Fecal bile acid excretion showed a similar pattern. Across the groups, a strong positive correlation between HDL-c and fecal neutral sterol excretion was found (r=0.53; p=0.01)., Conclusions: Isolated low HDL-c levels in humans are associated with reduced fecal sterol excretion suggesting that in humans HDL regulates the final step in the RCT pathway at low HDL-c levels.

Surrogate markers have recently come under scrutiny since a few of the considered most reliable intermediate endpoints (LDL-c, HDL-c and HbA(1c)) have failed to predict clinical benefit following pharmacological intervention in the causal pathway. However, it follows that comprehending the pathophysiological complexity of atherosclerotic vascular disease, no single surrogate is likely to be omniscient in the translation of benefit or harm of a certain therapy. Especially surrogates that are assessed in the circulation merely reflect a part of the complex multipathway disease. Such markers do not have the ability to monitor potential side effects of interventions or assess the activation of unknown pro-atherogenic pathways. Contrary to such soluble endpoints, vascular imaging data can provide information on atherosclerosis as a continuous variable, since the disease process of the vascular wall itself is assessed. Understanding this continuity from the earliest stages through to the vascular complications is essential, as the arterial wall reflects the net effect of either known or yet to be discovered hereditary as well as environmental factors. In this review we will focus on challenges and pitfalls using plasma biomarkers as surrogate endpoints for the assessment of cardiovascular drug efficacy. Subsequently, we will focus on vascular imaging modalities as tools to investigate atherosclerosis.

Objective: To evaluate the association between HDL particle size measured by gradient gel electrophoresis and risk of incident coronary heart disease (CHD) in apparently healthy men and women., Methods: We performed a prospective case-control study nested in the EPIC-Norfolk cohort. Cases were apparently healthy men and women aged 45-79 years who developed fatal or nonfatal CHD (n=1035). They were matched to 1920 controls who remained free of CHD over the follow-up period of 6 years., Results: Participants with the smallest HDL particles had the most unfavourable cardiometabolic risk profile whereas those with the largest HDL particles had the most favourable risk profile. Plasma HDL cholesterol levels were found to be the best correlate of HDL particle size (r=0.58 and r=0.62, respectively, for men and women, p<0.001). Men in the highest quartile of HDL particle size had an unadjusted odds ratio (OR) for future CHD of 0.75 (95% CI, 0.57-0.97) compared to those in the bottom quartile. For women, the equivalent OR was 0.50 (0.35-0.71). After additional adjustment for diabetes, body mass index, systolic blood pressure, LDL and HDL cholesterol levels, the ORs were 1.43 (1.01-2.03) in men and 0.84 (0.52-1.35) in women., Conclusions: A decreased HDL particle size is associated with an adverse cardiometabolic risk profile. Small HDL particle size was also associated with an increased CHD risk, but this association was largely explained by traditional risk factors.

Background: Prolonged exposure to protease inhibitor (PI)-, but not non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing combination antiretroviral therapy (CART) has been associated with an increased cardiovascular risk, partly explained by the different effects of these drugs on plasma lipids. Most markedly, NNRTIs have been associated with increases in high density lipoprotein cholesterol (HDL-C), which may be atheroprotective., Methods: In a cross-sectional study we investigated the impact of PI- vs. NNRTI-based CART in 130 HIV-1-infected patients with plasma virus suppressed to below the limit of detection, whom had been continuously exposed for at least 2 years to either one of such regimens, but not both. Carotid intima-media thickness (C-IMT) and fasting metabolic parameters were measured., Results: Mean (+/-S.D.) C-IMT in patients treated with PI-based CART was 0.81 (+/-0.17) mm as compared to 0.71 (+/-0.14)mm in NNRTI treated patients (p=0.0003). HDL-C and apolipoprotein A-I (apoA-I) levels were higher in the NNRTI than in the PI group (1.39 mmol/L vs. 1.03 mmol/L; p<0.0001, and 1.44 mmol/L vs. 1.33 mmol/L; p=0.0008, respectively). Framingham Risk Score, body mass index, duration of CART, and use of PI-based CART were positively correlated with C-IMT whereas HDL-C and apoA-I were inversely correlated with C-IMT., Conclusions: Treatment of HIV-1-infected patients for 2 years or more with PI-based compared to NNRTI-based CART is associated with greater C-IMT, consistent with the reported higher risk of CVD in patients using PI. However, this difference seems not fully explained by a more favorable impact of NNRTI-based CART on HDL-C and apoA-I levels.

Introduction: Myeloperoxidase (MPO), an antimicrobial enzyme of the innate immune system, has been proposed to exert a wide array of pro-atherogenic effects throughout all stages of the atherosclerotic process. In view of the potent anti-inflammatory effects of statins in vitro, we evaluated the impact of statin therapy on plasma MPO levels in patients with heterozygous familial hypercholesterolemia (FH), treated with either intensive or conventional lipid-lowering therapy. Furthermore, we evaluated the relation between MPO levels and atherosclerosis progression, as determined by intima media thickness (IMT)., Methods: We measured plasma MPO levels, lipoprotein profiles, high sensitivity-C-reactive protein (hs-CRP) as well as IMT of carotid artery segments in 122 FH patients at baseline and after 2-year treatment with atorvastatin 80 mg or simvastatin 40 mg QD., Results: Baseline median MPO values were 147pM (interquartile range (IQR) 122-217) and 144pM (IQR 118-216) and these increased significantly to 221pM (IQR 144-290) and 255pM (IQR 152-324) during 2-year follow-up in both the atorvastatin 80 mg and simvastatin 40 mg group, respectively. There was no correlation between MPO levels and IMT progression, change in lipoproteins or hs-CRP., Conclusion: In FH patients, statins do not prevent an increase in MPO levels during follow-up. Moreover, MPO levels are not associated with atherosclerosis progression in these patients.

In recent years, it has become increasingly clear that arterial inflammation represents a key feature determining the course of atherogenesis. The consecutive stages in the evolution of atherosclerotic lesions are respectively, plaque buildup and growth, and destabilization, predisposing to plaque rupture and intravascular thrombosis. This chain of events leading from lesion formation to clinical events has been carefully elucidated during the last three decades. C-reactive protein (CRP) has been directly implicated in the pathogenesis of atherosclerosis. In the present review, we will focus on a potentially causal role of CRP during the various stages of atherogenesis.

Rationale: Lipoprotein lipase (LPL) X447 homozygotes are characterized by enhanced conversion of TRL apoB100. Here, we set out to investigate whether this LPL variant is also associated with enhanced apoB48 clearance. Therefore, we evaluated apoB48 kinetics in X447 homozygotes in the fed state by infusion of isotope L-[1-(13)C]-valine and subsequent compartmental modeling., Methods and Results: ApoB48 metabolism was assessed in five X447 homozygotes (X/X genotype) and five S447 homozygotes (S/S genotype). Subjects were continuously fed and received infusion of stable isotope L-[1-(13)C]-valine. Results were analyzed by SAAM II modeling. Fasting (2.4-fold, p=0.02) as well as non-fasting (1.6-fold, p=0.09) apoB48 concentration was increased in the X447 homozygotes compared to S447 homozygotes. In addition, the X447 homozygotes exhibited a 1.7-fold higher apoB48 poolsize (p=0.04). Interestingly, apoB48 fractional catabolic rate (FCR) was 1.9-fold higher (p=0.007) and apoB48 synthesis was more than two-fold higher (p=0.006) in the X447 homozygotes compared to S447 homozygotes., Conclusion: In the present study, we show that X447 homozygotes exhibit enhanced apoB48 clearance. Previously, these homozygotes were shown to present with enhanced apoB100 TRL conversion. Combined, this LPLS447X gain of function variant affects apoB48 as well as apoB100 TRL metabolism.

Objectives: in patients with familial hypercholesterolemia (FH), the propensity towards atherosclerosis may vary considerably. In the general population, a positive family history is associated with an increased risk for cardiovascular events. Since endothelial dysfunction is predictive for future cardiovascular events, we evaluated whether FH-children with a positive family history of premature cardiovascular disease have more pronounced endothelial dysfunction compared to children with a negative family history., Study Design: 50 FH children, 10-18 years, participated in this study. Thirty-one children had a positive family history for cardiovascular events (fh(+)) and 19 children had no events in the family (fh(-)). Nineteen matched siblings participated as controls. Endothelial function was assessed by testing the flow mediated dilatation (FMD) of the brachial artery., Results: baseline characteristics were comparable for fh(+), fh(-) and controls. Lipid levels were significantly higher in FH children. In FH, FMD was impaired compared to controls (11.7+/-4.4 vs. 15.6+/-6.8%, P<0.03). In addition, FMD was significantly lower in fh(+) compared to fh(-) (10.7+/-9.9 vs. 13.3+/-4.6%, P<0.05)., Conclusion: In FH-children, endothelial function is impaired compared to matched controls. This impairment is most pronounced in FH children with a positive family history of premature cardiovascular disease.

Based on studies in diabetic and hypertensive populations it has been postulated that early endothelial dysfunction is the mechanism responsible for the increased cardiovascular risk in microalbuminuric subjects. We evaluated the relation between microalbuminuria and endothelial dysfunction, assessed as flow-mediated dilation of the brachial artery, in an apparently healthy population. Within the framework of the PREVEND Intervention Trial non-hypertensive and non-hypercholesterolemic subjects were recruited on the basis of reproducible microalbuminuria. Using high-resolution ultrasound, flow-mediated dilation and nitroglycerin-mediated dilation of the brachial artery was assessed to measure endothelium-dependent and endothelium-independent responses, respectively. For the current study subjects with diabetes mellitus, clinical atherosclerosis, and macroalbuminuria were excluded from the analyses. We studied 421 men and 233 women (mean age (SD) 50 (12)). Increasing levels of urinary albumin excretion were accompanied by a significant increase in age, percentage men, systolic and diastolic blood pressure, body mass index, and serum triglycerides, whereas there was no decrease of flow-mediated vasodilation or nitroglycerin-mediated vasodilation. Adjusted for age and sex, urinary albumin excretion was significantly related to systolic (r=0.19, P<0.001) and diastolic (r=0.16, P<0.001) blood pressure, body mass index (r=0.18, P<0.001), and triglycerides (r=0.13, P=0.001), but not to flow-mediated vasodilation (r=-0.01, P=0.8). In contrast to blood pressure, body mass index, and triglycerides, there was no relation between urinary albumin excretion and flow-mediated vasodilation in apparently healthy subjects. These data suggest that the presence of atherogenic risk factors precedes the development of endothelial dysfunction in microalbuminuric, but otherwise healthy subjects.