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Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence., Methods: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis., Findings: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037)., Interpretation: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life., Funding: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health., Competing Interests: Declaration of interests BAH received a research grant from Silence Therapeutics. GKH reports research grants from the Klinkerpad fonds, and part-time employment at Novo Nordisk (Søborg, Denmark) since April, 2019. GKH is shareholder of Novo Nordisk. DJB reports clinical trial fees paid to their institution from LIB Therapeutics, Novartis, Silence Therapeutics, and IONIS; speaker fees from Amgen, Sanofi, Organon, MSD, Amryt, and Novartis; and consulting fees from Amryt. ALC has received research grants or support from Amarin, Amgen, Menarini, Mylan, Sanofi, and Sanofi Regeneron, and served as a consultant for or received honoraria from Akcea, Amarin, Amgen, Daiichi Sankyo, Esperion Therapeutics, Ionis, Kowa, Medco, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, Sanofi, and The Corpus. MC reports institutional support for the conduction of clinical trials from Regeneron Pharmaceuticals and Regenxbio, and consulting fees from Amryt Pharma. AG received grants and personal fees from Amgen, Sanofi–Regeneron, Mylan Viatris, MSD, Akcea Therapeutics, Amryt, Servier, Novartis, and Ultragenyx. FJR reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics. KKR reports grants from Amgen, Sanofi–Regeneron, Pfizer, Merck Sharp & Dohme, Daiichi Sankyo, and Ultragenyx; consulting fees from AstraZeneca, Kowa, Novartis, Sanofi, Amgen, Eli Lilly, Algorithm, Boehringer Ingelheim, Novo Nordisk, Silence Therapeutics, Bayer, Esperion, Daiichi Sankyo, Abbott, New Amsterdam, SCRIBE, CRISPR, VAXXINITY, EMENDOBIO, Cargene, Viatris, Amarin, Nodthera, and Resverlogix; honoraria for lectures from AstraZeneca, Novartis, Sanofi, Amgen, Algorithm, Boehringer Ingelheim, Novo Nordisk, Esperion, Daiichi Sankyo, and Amarin; and stock options in New Amsterdam, PEMI 31, and SCRIBE. HS reports research grants from Amgen, MSD, Synageva, Amryt, Alexion, and Akcea; consulting fees from Amgen, Alexion, Daiichi-Sankyo, Novartis, Pfizer, and Akcea; and speaker fees from Amgen, Daiichi-Sankyo, Sanofi, and Akcea. AW reports research grants from Amgen, Esperion, Novartis, Regeneron, Sanofi, Silence Therapeutics, and Ultragenyx; consulting fees from Chiesi and Novartis; and speaker fees from Algorithm, Sanofi, and Ultragenyx. All other authors declare no competing interests. The declaration of interests of individual collaborators are listed in the appendix (p 27)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose of Review: Genetic, experimental, epidemiologic, and clinical data support the causal role of elevated levels of low-density lipoprotein cholesterol (LDL-C) in atherosclerosis and cardiovascular disease (CVD). The recommendations of the 2019 European guidelines are based on the concept of differential CV risk, which in turn defines the LDL-C goals that should be achieved., Recent Findings: The 2019 ESC/EAS guidelines for dyslipidaemia use the Systematic COronary Risk Evaluation (SCORE) model to assess CV risk, which provides a 10-year risk of fatal CV event. The SCORE model has recently been updated to reflect current rates of cardiovascular disease in Europe. The new SCORE2 model provides estimates of the 10-year risk of fatal and non-fatal CVD events in people aged 40-69 years, thus improving the identification of individuals at higher risk of a CVD event. However, as in the SCORE age is the main determinant of risk, young people have a relatively low estimated 10-year risk of a CV event even with high levels of one or more causal risk factors. Individuals with familial hypercholesterolaemia, who have elevated LDL-C levels from birth and have a high risk of premature CVD, are one example. The concept of cumulative LDL exposure is thus becoming increasingly important. This is also supported by Mendelian randomisation studies showing that carrying genetic variants associated with lower LDL-C levels reduces CV risk. These observations have introduced the concept of "cholesterol-years", which takes into account both LDL-C levels and time of exposure. It is crucial that future European guidelines pay more attention to this point., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Over the last decade, several innovative therapeutic options have been developed and marketed for the management of hypercholesterolemia. However, the impossibility of a contextual update of international guidelines and the limits imposed by national regulatory authorities do not allow the use of these treatments in many patients, in particular in those at higher cardiovascular risk. Real-world studies show that the use of lipid-lowering therapies is inadequate even among patients at higher cardiovascular risk, with only 20% achieving recommended low-density lipoprotein cholesterol (LDL-C) levels and the use of combination therapies implemented in only 24% of patients. This review aims to highlight the benefits of an approach based on combination therapy and to propose a therapeutic algorithm that includes oral combination therapy, where necessary also in triple association (statin, ezetimibe and bempedoic acid), as an initial approach based on the most favorable cost-effectiveness ratio for patients at higher cardiovascular risk and the use of injectable anti-proprotein convertase subtilisin/kexin 9 therapies if the recommended LDL-C goal is not achieved.

Chronic low-degree inflammation is a hallmark of atherosclerotic cardiovascular (CV) disease. To assess the effect of lipid-lowering therapies on C-reactive protein (CRP), a biomarker of inflammation, we conducted a meta-analysis according to the PRISMA guidelines. Databases were searched from inception to July 2023. Inclusion criteria were: (i) randomized controlled trials (RCTs) in human, Phase II, III, or IV; (ii) English language; (iii) comparing the effect of lipid-lowering drugs vs. placebo; (iv) reporting the effects on CRP levels; (v) with intervention duration of more than 3 weeks; (vi) and sample size (for both intervention and control group) over than 100 subjects. The between-group (treatment-placebo) CRP absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 171 668 subjects from 53 RCTs were included. CRP levels (mg/L) were significantly decreased by statins [-0.65 (-0.87 to -0.43), bempedoic acid; -0.43 (-0.67 to -0.20), ezetimibe; -0.28 (-0.48 to -0.08)], and omega-3 fatty acids [omega3FAs, -0.27 (-0.52 to -0.01)]. CRP was reduced by -0.40 (-1.17 to 0.38) with fibrates, although not statistically significant. A slight increase of CRP concentration was observed for proprotein convertase subtilisin/kexin type 9 inhibitors [0.11 (0.07-0.14)] and cholesteryl-ester transfer protein inhibitors [0.10 (0.00-0.21)], the latter being not statistically significant. Meta-regression analysis did not show a significant correlation between changes in CRP and LDL cholesterol (LDL-C) or triglycerides. Statins, bempedoic acid, ezetimibe, and omega3FAs significantly reduce serum CRP concentration, independently of LDL-C reductions. The impact of this anti-inflammatory effect in terms of CV prevention needs further investigation., Competing Interests: Conflict of interest: S.X., F.G., E.O., S.C., and M.C. report no disclosures. A.L.C. received research funding and/or honoraria for advisory boards, consultancy, or speaker bureau from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Mediolanum, Merck, or MSD, Pfizer, Recordati, Rottapharm, Sanofi-Regeneron, Sigma-Tau. T.F.L. received honoraria and research grants from Roche, Basel Switzerland for running the Dal-Vessel trial. Outside this work, he has received educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Novartis, Sanofi, Servier, and Vifor., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated., Methods: DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated., Results: Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81-115) mg/dl and 32% (25-43%), respectively. Median LDL-C reductions of 24 (12-46) and 39 (27-91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7-25%) and 22% (15-32%), respectively, and ARRs of 4% (2-7%) and 6% (4-9%), respectively., Conclusion: In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach., (© 2022. The Author(s).)

Competing Interests: Disclosures J.H. Cornel reports membership on advisory boards for Amgen, Sanofi, Novo Nordisk en AstraZeneca. D. Gill and G.K. Hovingh are employed part-time by Novo Nordisk and own shares. A.L. Catapano reports consulting fees/lecturing fees from Akcea, Amgen, Amryt, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi Sankyo, Genzyme, Aegerion, and Sandoz. W. Koenig served on the Executive Steering Committee of SPIRE, which was funded by Pfizer. WK reports advisory board/lecturing fees from Novartis, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Genentech, Novo Nordisk, Esperion, OMEICOS, Sanofi, New Amsterdam Pharma, TenSixteen Bio and Bristol-Myers Squibb, grants and nonfinancial support from Abbott, Roche Diagnostics, Beckmann, and Singulex, outside the submitted work. Ridker served as the Trial Co-Chair for SPIRE, which was funded by Pfizer. Unrelated to the current project, P.M. Ridker has received additional institutional research grant support from Novartis, Amarin, Pfizer, Esperion, Novo Nordisk, and the NHLBI; has served as a consultant to Novartis, Flame, Agepha, AstraZeneca, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Uptton, Pfizer, Health Outlook, Montai Health, New Amsterdam, Boehringer-Ingelheim, Angiowave, RTI; Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). ESGS has received lecturing/advisory board fees from Amgen, Novartis, Esperion, Sanofi-Regenerion, and Akcea. NSN is co-founder of Lipid Tools. The other authors report no disclosures.

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.)

Given the limited accuracy of clinically used risk scores such as the Systematic COronary Risk Evaluation 2 system and the Second Manifestations of ARTerial disease 2 risk scores, novel risk algorithms determining an individual's susceptibility of future incident or recurrent atherosclerotic cardiovascular disease (ASCVD) risk are urgently needed. Due to major improvements in assay techniques, multimarker proteomic and lipidomic panels hold the promise to be reliably assessed in a high-throughput routine. Novel machine learning-based approaches have facilitated the use of this high-dimensional data resulting from these analyses for ASCVD risk prediction. More than a dozen of large-scale retrospective studies using different sets of biomarkers and different statistical methods have consistently demonstrated the additive prognostic value of these panels over traditionally used clinical risk scores. Prospective studies are needed to determine the clinical utility of a biomarker panel in clinical ASCVD risk stratification. When combined with the genetic predisposition captured with polygenic risk scores and the actual ASCVD phenotype observed with coronary artery imaging, proteomics and lipidomics can advance understanding of the complex multifactorial causes underlying an individual's ASCVD risk., Competing Interests: Conflict of interest N.S.N. is cofounder of Lipid Tools. S.J.N. has received research support from AstraZeneca, New Amsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience and is a consultant for AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, Vaxxinity, and Sequiris. W.K. reports advisory board/lecturing fees from Novartis, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Genentech, Novo Nordisk, Esperion, OMEICOS, Sanofi, New Amsterdam Pharma, TenSixteen Bio, and Bristol-Myers Squibb, and grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex, outside the submitted work. A.L.C. reports consulting fees/lecturing fees from Akcea, Amgen, Amryt, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi Sankyo, Genzyme, Aegerion, and Sandoz. E.S.G.S. reports advisory board/lecturing fees paid to the institution of E.S.G.S. by Novartis, AstraZeneca, Amgen, Sanofi, Esperion, Novo-Nordisk, IONIS, Amarin, and Merck. M.M. has licensed patents on cardiovascular biomarkers. J.M.K. reports no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: The European Atherosclerosis Society (EAS) Lipid Clinics Network promoted a survey in order to identify and understand how and when lipoprotein(a) [Lp(a)] is tested and clinically evaluated in lipid clinics throughout Europe, and the challenges that may prevent evaluation from being carried out., Methods: This survey was divided into three areas of inquiry: background and clinical setting information of clinicians, questions for doctors who claimed not to measure Lp(a), in order to understand what were the reasons for not ordering the test, and questions for doctors who measure Lp(a), to investigate the use of this value in the management of patients., Results: A total of 151 centres clinicians filled in the survey, out of 226 invited. The proportion of clinicians who declare to routinely measure Lp(a) in clinical practice was 75.5%. The most common reasons for not ordering the Lp(a) test were the lack of reimbursement or of treatment options, the non-availability of Lp(a) test, and the high cost of performing the laboratory test. The availability of therapies targeting this lipoprotein would result in a greater propensity of clinicians to start testing Lp(a). Among those who declared to routinely measure Lp(a), the Lp(a) measurement is mostly requested to further stratify patients' cardiovascular risk, and half of them recognized 50 mg/dL (approx. 110 nmol/L) as the threshold for increased cardiovascular risk due., Conclusions: These results warrant for a great deal of effort from scientific societies to address the barriers that limit the routine use of the measurement of Lp(a) concentration and to recognise the importance of Lp(a) as a risk factor., Competing Interests: Declaration of competing interest All authors declare no support from any organization for the submitted work; no other relationships or activities that could appear to have influenced the submitted work. E.O., M.G., and M.C. report no disclosures. A.L.C. received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Mediolanum, Merck or MSD, Pfizer, Recordati, Rottapharm, Sanofi-Regeneron, Sigma-Tau. L.T. received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Abbott, Astra Zeneca, Novartis, Sanofi, MSD, Novo Nordisk, Amgen, Bayer, Daiichi Sankyo, Janssen, Pfizer, Recordati. M.B. speakers bureau: Amgen, Daichii-Sankyo, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Pfizer, Sanofi-Aventis, Teva, Zentiva; consultant to Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, NewAmsterdam, Novartis, Novo-Nordisk, Polfarmex, Sanofi-Aventis; Grants from Amgen, Daichii-Sankyo, Mylan/Viatris, Sanofi and Valeant; CMDO at Longevity Group (Luxemburg). K.K.R. received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Amgen, Daiichi Sankyo, Regeneron, Sanofi, Novartis, Esperion, Abbott, Bayer, Eli Lilly, Silence Therapeutics, CSL Behring, New Amsterdam Pharma, Novo Nordisk, BI, Scribe, Vaxxinity, CRISPR, AZ, Kowa, Cargene and Viatris., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Although adequate clinical management of patients with hypercholesterolemia without a history of known cardiovascular disease is essential for prevention, these subjects are often disregarded. Furthermore, the scientific literature on primary cardiovascular prevention is not as rich as that on secondary prevention; finally, physicians often lack adequate tools for the effective management of subjects in primary prevention and have to face some unsolved relevant issues. This document aims to discuss and review the evidence available on this topic and provide practical guidance., Data Synthesis: Available algorithms and risk charts represent the main tool for the assessment of cardiovascular risk in patients in primary prevention. The accuracy of such an estimate can be substantially improved considering the potential contribution of some additional risk factors (C-reactive protein, lipoprotein(a), family history of cardiovascular disease) and conditions (environmental pollution, sleep quality, socioeconomic status, educational level) whose impact on the cardiovascular risk has been better understood in recent years. The availability of non-invasive procedures to evaluate subclinical atherosclerosis may help to identify subjects needing an earlier intervention. Unveiling the presence of these conditions will improve cardiovascular risk estimation, granting a more appropriate intervention., Conclusions: The accurate assessment of cardiovascular risk in subjects in primary prevention with the use of algorithms and risk charts together with the evaluation of additional factors will allow physicians to approach each patient with personalized strategies, which should translate into an increased adherence to therapy and, as a consequence, a reduced cardiovascular risk., Competing Interests: Declaration of competing interest ALC reports grant(s)/support from Akcea, Amarin, Amgen, Menarini, Mylan, Sanofi, and Sanofi/Regeneron; consultant for Akcea, Amgen, Amarin, Daiichi-Sankyo, Eli Lilly, Esperion, Kowa, Ionis Pharmaceuticals, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, and Sanofi, outside the submitted work. AFGC reports scientific advice and/or speaking fees from Servier Italia, Fidia Farmaceutici, and Sharper SpA; AC reports scientific advice and/or speaking fees from Servier, DOC, Fidia, Amgen, Sanofi, Daichi Sankyo, AstraZeneca, Novartis; DP reports scientific advice with Merck Serono and Boehringer; GS reports scientific advice and/or speaking fees from Novo Nordisk, Servier, MSD, Sanofi, Daiichi Sankyo, Eli Lilly, Sobi, Vifor Pharma, Amarin, Novartis, Sobi, Teva, and Amgen. Other authors report no conflict of interest related to the topic of this document., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell 'omics are providing new insights into cardiovascular development, inflammation, and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognized the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarize discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of crosstalk between hyperglycaemia, lipid mediators, and inflammation. The past 12 months also witnessed major advances in the field of cardiac arrhythmia including new mechanisms of fibrillation. We also focus on inducible pluripotent stem cell technology which has demonstrated disease causality for several genetic polymorphisms in long-QT syndrome and aortic valve disease, paving the way for personalized medicine approaches. Finally, the cardiovascular community has continued to better understand COVID-19 with significant advancement in our knowledge of cardiovascular tropism, molecular markers, the mechanism of vaccine-induced thrombotic complications and new anti-viral therapies that protect the cardiovascular system., Competing Interests: Conflicts of interest: C.G.T. has received funding from Amgen, and personal fees from VivaLyfe, and is listed as an inventor on two heart failure patents., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis., Competing Interests: Conflict of interest: Potential conflicts of interest outside the submitted work are summarized as follows. 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 (K.K.R., L.S.T.), Abcentra (M.K.), Abdi-Ibrahim (L.S.T.), Actelion (L.S.T.), Aegerion (A.L.C., P.M.M.), Affiris AG (G.L.), Akcea (A.L.C., B.G.N., K.G.P., E.S.G.S.), Amarin (A.L.C., P.M.M., B.G.N., K.G.P.), Amgen (A.L.C., B.A.F., F.K., F.M., P.M.M., P.N., B.G.N., K.G.P., K.K.R., E.S.GS., L.S.T., G.F.W.), Amgen Germany (A.v.E.), Amgen Switzerland (A.v.E.), Amryt (A.L.C.), Amundsen/Amgen (F.M.), Apple (P.N.), Arrowhead (G.F.W.), Ayma Therapeutics (M.K.), AstraZeneca (A.L.C., P.N., B.G.N., K.K.R., G.F.W.), Bayer (L.S.T.), Berlin-Chemie (K.G.P.), Boehringer-Ingelheim (K.K.R.), Boston Scientific (P.N.), CiVi Pharma (B.A.F.), Daiichi-Sankyo (A.L.C., B.A.F., F.M., K.G.P., K.K.R., L.S.T.), Daiichi Switzerland (A.v.E.), dalCOR (B.A.F.), Denka (B.G.N.), Eli Lilly (A.L.C., B.A.F., M.K., K.K.R.), Esperion (A.L.C., B.A.F., P.M.M., B.G.N., K.K.R., E.S.G.S., G.F.W.), FH Foundation (P.M.M.), Foresite Labs (P.N.), Fresenius (F.K.), GB Life Sciences (P.M.M.), Genentech (P.N.), Genzyme (A.L.C.), Horizon/Novartis (F.M., B.G.N.), Ionis Pharmaceuticals (B.A., A.L.C., B.A.F., M.K., P.M.M.), Jupiter Bioventures (M.R.D.), Kaneka (F.K., P.M.M.), Kowa (A.L.C., B.G.N., K.K.R.), KrKa Phama (B.A.F.), Lupin (K.K.R.), Menarini (A.L.C.), Merck (A.L.C., B.A.F.), MSD (K.G.P.), Mylan (A.L.C., B.A.F., L.S.T.), New Amsterdam (K.K.R.), Noetic Insights (M.K.), Novartis (B.A., A.L.C., M.R.D., B.A.F., F.K., F.M., C.J.M.N., P.M.M., P.N., B.G.N., K.G.P., K.K.R., E.S.G.S., L.S.T., G.F.W.), Novartis Canada (M.K.), NovoNordisk (B.A.F., C.J.M.N., B.G.N., K.K.R., E.S., L.S.T.), Nyrada Inc (G.L.), Pfizer (B.A., M.R.D., B.A.F., M.K., S.M., K.K.R., L.S.T., G.F.W.), Quest Diagnostics (S.M.), Recordati (A.L.C., LS.T.), Regeneron (A.L.C., B.A.F., P.M.M., B.G.N., K.K.R., E.S.G.S.), Renew (P.M.M.), Resverlogix (K.K.R.), Sandoz (A.L.C.), Sanofi (A.L.C., B.A.F., F.M., B.G.N., K.G.P., K.K.R., E.S.G.S., L.S.T., G.F.W.), Sanofi-Aventis Switzerland (A.v.E.), Sanofi-Regeneron (G.L., E.S.G.S.), Servier (L.S.T.), Sigma Tau (A.L.C.), Silence Therapeutics (B.A., M.R.D., B.A.F., B.G.N., K.K.R., G.F.W.), and The Medicines Co (B.A.F.). P.N. declares spousal employment at Vertex and K.G.P. is a member of the Data Monitoring and Safety Board at Boehringer-Ingelheim. S.S.V. 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 P.N. and L.S.T. (Fitbit), G.F.W. (Amgen), and B.A. (Pfizer). Equity interests including income from stocks, stock options, royalties, or from patents or copyrights were reported from AstraZeneca (J.K.S.), Boston Scientific (L.B.), Cargene Therapeutics (K.K.R.), Gilead Sciences (L.B)., J & J (L.B.), GSK (J.K.S.), Medtronic (L.B.), New Amsterdam Pharma (K.K.R.), NovoNordisk (L.B.), Pemi31 Therapeutics (K.K.R.), and Pfizer (L.B.). K.K.R. is President of the European Atherosclerosis Society. L.S.T. is past-president of the European Atherosclerosis Society and an Editorial Board Member, The European Heart Journal., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

The risk of atherosclerotic cardiovascular disease (ASCVD) is strongly related to lifetime exposure to low-density lipoprotein (LDL)-cholesterol in longitudinal studies. Lipid-lowering therapy (using statins, ezetimibe and PCSK9 inhibitors) substantially ameliorates the risk and is associated with long-term reduction in cardiovascular (CV) events. The robust evidence supporting these therapies supports their continued (and expanding) role in risk reduction. In addition to these 'conventional' therapeutics, while waiting for other innovative therapies, growing evidence supports the use of a range of 'nutraceuticals' (constituents of food prepared as pharmaceutical formulations) including preparations of red yeast rice (RYR), the product of yeast (Monascus purpureus) grown on rice, which is a constituent of food and is used in traditional Chinese medicine. The major active ingredient, monacolin K, is chemically identical to lovastatin. RYR preparations have been demonstrated to be safe and effective in reducing LDL-C, and CV events. However, surprisingly, RYR has received relatively little attention in international guidelines - and conventional drugs with the strongest evidence for event reduction should always be preferred in clinical practice. Nevertheless, the absence of recommendations relating to RYR may preclude the use of a product which may have clinical utility in particular groups of patients (who may anyway self-prescribe this product), what in the consequence might help to reduce population CV risk. This Position Paper of the International Lipid Expert Panel (ILEP) will use the best available evidence to give advice on the use of red-yeast rice in clinical practice., Competing Interests: Conflict of Interest NA., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: REDUCE-IT demonstrated that adding 4 g/day of icosapent ethyl (IPE; purified ethyl ester of eicosapentaenoic acid [EPA]) to statins substantially reduced cardiovascular disease (CVD) events, with few adverse effects. These data prompted numerous leading medical societies across five continents, including the American College of Cardiology, the European Society of Cardiology, and the Japanese Circulation Society, to update their guidelines or scientific/consensus statements to recommend use of IPE for primary and secondary prevention of CVD events., Areas Covered: This review discusses the incorporation of IPE into international guidelines and scientific statements, noting areas of consensus and distinction. As background, this review also describes the CVD benefits and risks of IPE as a statin adjunct, and outlines current data regarding the potential mechanisms of CVD risk reduction by EPA (as IPE) beyond triglyceride reduction., Expert Opinion/commentary: IPE is unique among 'triglyceride-lowering' treatments in having strong CVD outcomes data and, therefore, a broad international consensus among professional medical society guidelines and statements endorsing its use for CVD risk reduction in patients generally meeting REDUCE-IT inclusion criteria. IPE should be considered for CVD prevention as a statin adjunct in all such patients., Plain Language SummaryCardiovascular disease (CVD) remains the leading cause of death worldwide. Statin monotherapy is conventionally used first-line to reduce the risk of CV events, such as heart attacks and strokes, in patients with elevated cholesterol. However, considerable risk remains despite appropriate control of cholesterol levels with a statin. Consequently, research has focused on treatment of additional therapeutic targets to reduce this remaining CV risk. One such target is elevated blood triglyceride levels. Unfortunately, most drugs that lower triglyceride levels, such as niacin, fibrates, and mixed omega-3 fatty acids, have not reduced the risk of cardiovascular events in clinical trials when added to statin therapy. However, the omega-3 fatty acid eicosapentaenoic acid ('EPA') administered in highly purified form as icosapent ethyl (IPE) has emerged as the first omega-3 fatty acid, and the first triglyceride-lowering agent to prevent CV events when added to statins. This was demonstrated most notably in the pivotal REDUCE-IT trial, in which IPE reduced the risk of major CV events by 25% in high-risk patients with mildly to moderately elevated triglyceride levels despite statin-controlled cholesterol levels. The mechanisms responsible for this reduction in CV events appear to go far beyond lowering triglyceride levels alone. In light of the positive results from the REDUCE-IT trial, IPE was approved for CV disease risk reduction globally, including in the United States, Canada, European Union, and the United Kingdom, and its use is being increasingly endorsed in United States and international statements and guidelines for managing CV risk. Despite minor differences among guidelines, there is strong consensus that IPE should be considered for use in CVD prevention in all patients who meet the proposed criteria.

Limited data exist on the long-term safety and efficacy of bempedoic acid, an adenosine triphosphate-citrate lyase inhibitor, for lowering low-density lipoprotein cholesterol (LDL-C). This 78-week, phase 3, open-label extension (OLE) study followed the CLEAR Harmony phase 3 study, in which patients were randomized 2:1 to bempedoic acid or placebo for 52 weeks; during the OLE, patients who received bempedoic acid continued treatment (≤130 weeks) and patients who received placebo initiated bempedoic acid (≤78 weeks). Safety assessments included treatment-emergent adverse events, adverse events of special interest, and clinical laboratory abnormalities. Efficacy assessments included % change from the parent study baseline in LDL-C, other lipid parameters, and high-sensitivity C-reactive protein (hsCRP). Of 1,462 patients who enrolled in the OLE study, 970 received bempedoic acid in the parent study; laboratory abnormalities and reductions in LDL-C, other lipid parameters, and hsCRP observed in the parent study remained stable through 130 weeks of treatment. On initiation of bempedoic acid treatment, 492 patients who received placebo in the parent study experienced reductions in LDL-C, other lipid parameters, and hsCRP, mirroring reductions observed in patients who received bempedoic acid in the parent study who remained stable through 78 weeks of therapy. During the OLE, incidence of treatment-emergent adverse events and adverse events of special interest were comparable in patients who received 130 weeks (78%) versus 78 weeks (78%) of bempedoic acid treatment. In conclusion, bempedoic acid was generally well tolerated and demonstrated sustained efficacy with up to 2.5 years of continuous treatment. Bempedoic acid safety profiles were similar between the parent and OLE studies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Elevated 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., Methods: We 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., Results: It 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., Conclusions: For 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)., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: Little is known about the role of Lp(a) in the assessment of cardiovascular risk in the paediatric population. Trying to clarify the clinical relevance of Lp(a) in risk stratification, the aim of the study is to evaluate the association between Lp(a) plasma levels in children with familial hypercholesterolaemia (FH) and positive family history for premature cardiovascular disease (pCVD) in first- and second-degree relatives., Methods: 653 Caucasian children and adolescents (334 females and 319 males), aged 2-17 years, with diagnosis of FH from a paediatric cohort included in the LIPIGEN Network, were selected. We compared family history of pCVD, lipid and genetic profile in two groups based on Lp(a) levels below or above 30 mg/dL. To determine the independent predictors of pCVD, a multivariate logistic regression was used, with all clinical characteristics and blood measurements as predictors., Results: Subjects with Lp(a) > 30 mg/dl more frequently reported positive family history of pCVD compared to subjects with Lp(a)≤30 mg/dl (69.90% vs 36.66%, p < 0.0001), while did not show differences in terms of median [interquartile range] LDL-cholesterol level (153.00 [88.00 vs 164.50 [90.25] mg/dL, p = 0.3105). In the regression analysis, Lp(a) > 30 mg/dl was an independent predictor of family history of pCVD. Comparing subjects with or without family history of pCVD, we reported significant differences for Lp(a) > 30 mg/dl (46.25% vs 17.65%, p < 0.0001), FH genetic mutation (50.48% vs 40.75%, p = 0,0157), as well as for LDL-cholesterol (p = 0.0013) and total cholesterol (p = 0.0101)., Conclusions: Children/adolescents with FH and Lp(a) > 30 mg/dl where more likely to have a positive family history of pCVD. Lp(a) screening in children and adolescents with FH may enhance risk assessment and help identify those subjects, children and relatives, at increased pCVD risk., (Copyright © 2022. Published by Elsevier B.V.)

Aims: Current risk scores do not accurately identify patients at highest risk of recurrent atherosclerotic cardiovascular disease (ASCVD) in need of more intensive therapeutic interventions. Advances in high-throughput plasma proteomics, analysed with machine learning techniques, may offer new opportunities to further improve risk stratification in these patients., Methods and Results: Targeted plasma proteomics was performed in two secondary prevention cohorts: the Second Manifestations of ARTerial disease (SMART) cohort (n = 870) and the Athero-Express cohort (n = 700). The primary outcome was recurrent ASCVD (acute myocardial infarction, ischaemic stroke, and cardiovascular death). Machine learning techniques with extreme gradient boosting were used to construct a protein model in the derivation cohort (SMART), which was validated in the Athero-Express cohort and compared with a clinical risk model. Pathway analysis was performed to identify specific pathways in high and low C-reactive protein (CRP) patient subsets. The protein model outperformed the clinical model in both the derivation cohort [area under the curve (AUC): 0.810 vs. 0.750; P < 0.001] and validation cohort (AUC: 0.801 vs. 0.765; P < 0.001), provided significant net reclassification improvement (0.173 in validation cohort) and was well calibrated. In contrast to a clear interleukin-6 signal in high CRP patients, neutrophil-signalling-related proteins were associated with recurrent ASCVD in low CRP patients., Conclusion: A proteome-based risk model is superior to a clinical risk model in predicting recurrent ASCVD events. Neutrophil-related pathways were found in low CRP patients, implying the presence of a residual inflammatory risk beyond traditional NLRP3 pathways. The observed net reclassification improvement illustrates the potential of proteomics when incorporated in a tailored therapeutic approach in secondary prevention patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

The past year was an exciting time for clinical lipidology when we learnt more about existing therapies as well as therapies targeting novel pathways discovered through genetic studies. LDL cholesterol remained the main target and a variety of drugs to lower LDL cholesterol through different mechanisms were explored. Emerging evidence on the atherogenity of triglyceride-rich lipoproteins led to renewed interest in lowering them with new treatments. Lp(a) was back in focus with evidence on causality and new targeted therapeutics which dramatically lower Lp(a) levels. We will be able to personalise lipid lowering therapy further with this enriched armamentarium once we have the results of the cardiovascular outcome studies with some of these new agents., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The recent ESC/EAS 2019 Guidelines for the management of dyslipidaemias are centred on the causal role of low density lipoprotein (LDL), or more generally apolipoprotein B (apoB)-containing lipoproteins, in atherosclerosis as an essential principle. Despite updated goals and recommendations, that have further highlighted the importance of a powerful reduction in LDL-C levels to reduce the individual CV risk, some challenges remain to be addressed in view of future guideline elaboration. In this review, we will summarize the new evidence from clinical trials since 2019 guideline release and discuss the possible challenges for the future., (Copyright © 2021. Published by Elsevier B.V.)

The causal relation between elevated levels of LDL-C and cardiovascular disease has been largely established by experimental and clinical studies. Thus, the reduction of LDL-C levels is a major target for the prevention of cardiovascular disease. In the last decades, statins have been used as the main therapeutic approach to lower plasma cholesterol levels; however, the presence of residual lipid-related cardiovascular risk despite maximal statin therapy raised the need to develop additional lipid-lowering drugs to be used in combination with or in alternative to statins in patients intolerant to the treatment. Several new drugs have been approved which have mechanisms of action different from statins or impact on different lipoprotein classes., (© 2020. The Author(s).)

Objective: In primary hypercholesterolemia many people treated with statins do not reach their plasma LDL-C goals and are at increased risk of cardiovascular disease (CVD). This study aimed to evaluate efficacy and safety of a new fixed-dose combination (FDC) formulation of rosuvastatin/ezetimibe (R/E) in this population., Methods: This was a multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR) or high risk (HR) of CVD, inadequately controlled with 20 mg or 10 mg stable daily dose of rosuvastatin or equipotent dose of another statin. The primary objective was to demonstrate superiority of FDC R/E versus rosuvastatin monotherapy uptitrated to 40 mg (R40) or 20 mg (R20) in reduction of LDL-C after 6 weeks., Results: Randomized VHR participants (n = 244) were treated with R40, R40/E10, or R20/E10; randomized HR participants (n = 208) received R10/E10 or R20. In VHR participants, superiority of R40/E10 and R20/E10 versus R40 was demonstrated on LDL-C percent change from baseline to Week 6 with least squares mean differences (LSMD) of -19.66% (95% CI: -29.48% to -9.84%; P < .001) and -12.28% (95% CI: -22.12% to -2.44%; P = .015), respectively. In HR participants, superiority of R10/E10 over R20 was not demonstrated (LSMD -5.20%; 95% CI: -15.18% to 4.78%; P = .306), despite clinically relevant LDL-C reduction with R10/E10. No unexpected safety findings were reported., Conclusions: The results from this study suggest that R/E FDCs improve LDL-C reduction and goal achievement in people with primary hypercholesterolemia inadequately controlled with statins and at VHR/HR of CVD.

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To provide contemporary data on the implementation of European guideline recommendations for lipid-lowering therapies (LLTs) across different settings and populations and how this impacts low-density lipoprotein cholesterol (LDL-C) goal achievement., Methods and Results: An 18 country, cross-sectional, observational study of patients prescribed LLT for primary or secondary prevention in primary or secondary care across Europe. Between June 2017 and November 2018, data were collected at a single visit, including LLT in the preceding 12 months and most recent LDL-C. Primary outcome was the achievement of risk-based 2016 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C goal while receiving stabilized LLT; 2019 goal achievement was also assessed. Overall, 5888 patients (3000 primary and 2888 secondary prevention patients) were enrolled; 54% [95% confidence interval (CI) 52-56] achieved their risk-based 2016 goal and 33% (95% CI 32-35) achieved their risk-based 2019 goal. High-intensity statin monotherapy was used in 20% and 38% of very high-risk primary and secondary prevention patients, respectively. Corresponding 2016 goal attainment was 22% and 45% (17% and 22% for 2019 goals) for very high-risk primary and secondary prevention patients, respectively. Use of moderate-high-intensity statins in combination with ezetimibe (9%), or any LLT with PCSK9 inhibitors (1%), was low; corresponding 2016 and 2019 goal attainment was 53% and 20% (ezetimibe combination), and 67% and 58% (PCSK9i combination)., Conclusion: Gaps between clinical guidelines and clinical practice for lipid management across Europe persist, which will be exacerbated by the 2019 guidelines. Even with optimized statins, greater utilization of non-statin LLT is likely needed to reduce these gaps for patients at highest risk., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of immune-inflammatory response thus paving the road to investigate their involvement in other diseases beyond those related to the CV system. HDL-C levels and HDL composition are indeed altered in patients with autoimmune diseases and usually associated to disease severity. At molecular levels, HDL have been shown to modulate the anti-inflammatory potential of endothelial cells and, by controlling the amount of cellular cholesterol, to interfere with the signaling through plasma membrane lipid rafts in immune cells. These findings, coupled to observations acquired from subjects carrying mutations in genes related to HDL system, have helped to elucidate the contribution of HDL beyond cholesterol efflux thus posing HDL-based therapies as a compelling interventional approach to limit the inflammatory burden of immune-inflammatory diseases.

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases., Competing Interests: Author Disclosures This study was funded by the Bill and Melinda Gates Foundation. Dr. Benjamin has received funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) (R01HL092577, 1R01HL128914) and American Heart Association (18SFRN34110082). Dr. Brauer has received a grant from the Bill and Melinda Gates Foundation. Dr. Catapano has received support from Fondazione Cariplo 2015-0524 and 2015-0564, H2020 REPROGRAM PHC-03-2015/667837-2, ERA NET ER-2017-2364981, GR-2011-02346974, Ministry of Health - Ricerca Corrente Multimedica; has received research grant/support from Sanofi, Sanofi Regeneron, Amgen, Mylan, Menarini, and Eli Lilly; has served on the speakers bureau for Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron, Daiichi-Sankyo, AstraZeneca, Aegerion, Amryt, and Sandoz; has received honoraria from Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi-Sankyo, AstraZeneca, Aegerion, Amryt, and Sandoz; and has served as a consultant/on the Advisory Board for Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi-Sankyo, Genzyme, Aegerion, and Sandoz. Dr. Coresh has received funding from the NIH and National Kidney Foundation; and has served as an advisor to Healthy.io. Dr. Fowkes has served on the Advisory Board for AstraZeneca. Dr. Muntner has received grants and personal fees from Amgen Inc. Dr. Ribeiro has received partial support by CNPq (310679/2016-8 and 465518/2014-1) and by FAPEMIG (PPM-00428-17). Dr. Zuhlke has received funding by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and the National Research Foundation of South Africa. Dr. Rigotti has served as a consultant to Achieve Life Sciences; and has received royalties from UpToDate, Inc. Dr. Rodgers is employed by The George Institute for Global Health (TGI) and seconded part time to George Medicines Pty Ltd (GM); TGI has submitted patent applications with respect to low-fixed-dose combination products for the treatment of cardiovascular or cardiometabolic disease and is listed as one of the inventors; George Health Enterprises Pty. Ltd. (GHE) and its subsidiary, GM, have received investment funds to develop fixed-dose combination products, including combinations of blood pressure-lowering drugs; GHE is the social enterprise arm of TGI (Dr. Rodgers does not have a direct financial interest in these patent applications or investments). Dr. Sundström holds ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Bayer, Pfizer, and AstraZeneca, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The widespread use of statins has largely improved the treatment of hypercholesterolemia, but many patients still fail to achieve the LDL-C targets recommended by guidelines. Furthermore, some patients continue to present a very high cardiovascular (CV) risk or even an extreme risk despite being well treated, mainly due to the presence of co-morbidities such as diabetes or peripheral artery disease, which significantly increase their global CV risk. For these very high CV risk patients, the most recent European guidelines have reviewed the LDL-C goals and recommend an LDL-C reduction of at least 50% and a goal of <55 mg/dL or even <40 mg/dL. Recent clinical trials have shown that patient stratification based on the presence or absence of atherothrombotic risk factors may represent a valuable tool to identify patients at extremely high CV risk who may benefit more from an aggressive LDL-C-lowering approach. In these patients it may be appropriate to aim for the lowest LDL-C level, independently of recommended goals, with all the available pharmacological approaches., Competing Interests: Declaration of competing interest GFW reports honorary expenses from Amgen, Kowa, MSD, Sanofi; Consulting/Advisory board for Amgen, Sanofi, Regeneron, Gemphire; funded Research from Amgen, Sanofi, Regeneron, Pfizer; ALC reports grants from Amgen, Sanofi, Regeneron personal fees from Merck, Sanofi, Regeneron, AstraZeneca, Amgen, Novartis, outside the submitted work; LM reports fees for lectures and advisory work from: Amgen; Sanofi-Regeneron; Mylan; Servier; Danone; AZ reports grants, consulting fees and/or honoraria and delivering lectures for Abbott, AstraZeneca, Merck Sharp & Dohme, Amgen, Sanofi, Lilly, Mylan, Chiesi Amryt e Daiichi Sankyo; A. Pirillo reports no conflict of interest; LT is Company consultant for Abbott, Amgen, Bayer, MSD, Mylan, Sanofi, and has received honorarium as speaker from Abbott, Actelion, Amgen, Astra, Bayer, Daiichi Sankyo MSD, Mylan, Novartis, Novo Nordisk, Sanofi, Servier, Pfizer, Recordati., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aim: To estimate the prevalence of cardiovascular (CV) disease and CV risk factors among Polish patients., Methods: A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the 4th quarter of 2015 and 1st and 2nd quarters of 2016; 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices., Results: Nearly 19% of men and approximately 12% of women had cardiovascular disease (CVD). Over 60% of the recruited patients had hypertension (HTN), >80% had dyslipidaemia and <15% of patients were diagnosed with diabetes (DM). All of these disorders were more frequent in men. In 80% of patients the waist circumference exceed norm for the European population. Less than half of the patients were current smokers or had smoked in the past. Patients with CVD had significantly higher blood pressure and glucose levels but lower low density lipoprotein-cholesterol level., Conclusions: The prevalence of CVD and CV risk factors among patients in Poland is high. CVD is more common in men than in women. The most common CV risk factors are excess waist circumference, dyslipidaemia and HTN. Family physicians should conduct activities to prevent, diagnose early and treat CVD in the primary health care population., Competing Interests: Declaration of competing interest JJJ has received research grant/support from Valeant, and has served as a consultant or speaker for Valeant, Amgen, Teva, Servier, Boehringer Ingelheim, Celgene, Bioton, Microlife and ALAB Laboratories. TT has served as a consultant or speaker for Boehringer Ingelheim, Novartis, Shire, Biofarm, Eli Lilly. AW has served as a consultant or speaker for Merck, Boehringer Ingelheim, Sanofi Aventis, Bausch Health. ALC reports grants from Amgen, Sanofi, Regeneron personal fees from Merck, Sanofi, Regeneron, AstraZeneca, Amgen, Novartis, outside the submitted work. DPM has given talks and attended conferences sponsored by Amgen, Novonordisk and Libytec. MTM has no direct competing interests in regards to this paper. His dept holds or has held research grants from Pfizer, Amgen, Ipsen, Shire, Teijin & Menarini. He was or has been the principal investigator on trials paid for by: Pfizer, Novartis, Ipsen, Teijin & Menarini. In the last 5 years have been paid consulting or speakers fees by Novartis, Takeda, Shire, &AstraZeneca. ŁS has given talks and attended conferences sponsored by Janssen-Cilag, Pfizer, Krka. SK has served as a speaker for Novartis. MB has received research grant(s)/support from Amgen, Mylan, Sanofi and Valeant, and has served as a consultant for Amgen, Daiichi-Sankyo, Esperion, Freia Pharmaceuticals, Herbapol, Kogen, KRKA, Mylan, Novartis, Novo-Nordisk, Polfarmex, Polpharma, Sanofi-Aventis, Servier, and Zentiva., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aim: The metabolic syndrome (MetS) has become one of the most important clinical issues in the cardiovascular field for this decade because of the marked increase in cardiovascular (CV) risk associated with a clustering of risk factors. The aim of the current study was to evaluate the relationship between MetS and its components and cardiovascular disease (CVD)., Methods: This population-based cross-sectional study was based on data from two studies carried out in Russia (ESSE-RF) and Italy (PLIC). One sample from each cohort was selected, matching individuals by sex and age. A comparison between samples of MetS components distribution and CV risk, according to SCORE chart, has been conducted., Results: A total of 609 individuals (mean [SD] age 55 [8] years, about 39% males) for each cohort were selected. Almost half of PLIC cohort participants belonged to the moderate CV risk group (47% vs 27%), while in ESSE-RF cohort a relatively higher prevalence of individuals classified in the high and very high risk group was observed (19% vs 11%, 21% vs 6%, respectively). Overall, 43% of ESSE-RF participants were diagnosed with MetS, compared with the 27% of PLIC members (the difference in prevalence becomes 37% vs 21%, considering a more conservative cut-off for waist circumference). Both cohorts showed a trend towards the increase of MetS components moving from the lowest to the highest CV risk class, with a high prevalence of patients with four or five MetS determinants allocated in the high/very high CV risk group., Conclusions: Developing effective public health strategies for the prevention, detection and treatment of MetS should be an urgent priority to reduce the burden of CVD, not only in subjects at high/very high CV risk, but also in those characterized by a lower risk, as even rare CV events that come from low risk group bring a tangible burden to healthcare systems., Competing Interests: Declaration of competing interest All authors declare no support from any organization for the submitted work; no other relationships or activities that could appear to have influenced the submitted work. EO, AB, LG, FP, ET, MC, OVR report no disclosures. ALC reports grants from Amgen, Sanofi, Regeneron personal fees from Merck, Sanofi, Regeneron, AstraZeneca, Amgen, Novartis, outside the submitted work AA received research funding and/or honoraria for speaker bureau from Abbott, Amgen, KRKA, Pfizer, Recordati, Sanofi-Regeneron, Servier. OPR received research funding and/or honoraria for speaker bureau from KRKA, Pfizer, Recordati, Sanofi-Regeneron, Servier, Stada, Teva, Sandoz. AK received research funding and/or honoraria for speaker bureau from Servier, Novartis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The 2018 American Heart Association/American College of Cardiology/Multi-Society (AHA/ACC/MS) Guideline on the Management of Blood Cholesterol and the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines for the Management of Dyslipidemias: Lipid Modification to Reduce Cardiovascular Risk, that were recently released by the United States and Europe, provide new recommendations for the management of blood lipid levels based on the latest evidence. Despite many common points, there are several differences in the recommendations, including the definition of very-high-risk patient category, the recommendations for some categories of patients, such as those with diabetes, familial hypercholesterolemia, chronic kidney disease, and aged patients, and the use of ezetimibe and PCSK9 inhibitors. These differences suggest that multiple approaches can be used to manage lipid abnormalities in the context of cardiovascular risk reduction., Competing Interests: Declaration of competing interest LT has received consulting fees/honoraria from Abbott, Amgen, Bayer, Daiichi-Sankyo, Jansen, MSD, Mylan, NovoNordisk, Pfizer, Recordati, Sanofi, Servier; MC and AP have nothing to disclose; ALC reports grants from Amgen, Sanofi, Regeneron personal fees from Merck, Sanofi, Regeneron, AstraZeneca, Amgen, Novartis, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The availability of efficient lipid-lowering drugs has substantially reduced the incidence and mortality for cardiovascular disease (CVD). Despite that, CVD still represents a major cause of death and disability; efforts are thus required to prevent this disease, since reducing the established CV risk factors may slow or prevent the onset of cardiovascular events. Current guidelines recommend a healthier lifestyle for all CV risk categories, as it may have a beneficial impact on several risk factors; in individuals with a low-to-moderate hypercholesterolemia, which are not eligible for a pharmacological approach and are not far from the cholesterol target recommended for their risk category, functional foods or nutraceuticals may be considered as supplement to reduce their CV risk status. Of note, counseling and lifestyle intervention in people at moderate CV risk represents a major issue for both preventing a further risk increase and reducing the need for drugs. Studies on general populations have clearly indicated that lifestyle interventions translate into a clinical benefit, with reduction of the incidence of myocardial infarction and the risk of developing type 2 diabetes., Competing Interests: Declaration of competing interest B.F. has received lecture fees from MEDA pharmaceuticals; C.J. and A.P. report no conflicts of interest; L.T. is Company consultant for Abbott, Amgen, Bayer, MSD, Mylan, Sanofi, and has received honorarium as speaker from Abbott, Actelion, Amgen, Astra, Bayer, Daiichi Sankyo MSD, Mylan, Novartis, Novo Nordisk, Sanofi, Servier, Pfizer, Recordati; M.P. reports no conflicts of interest; ALC reports grants from Amgen, Sanofi, Regeneron personal fees from Merck, Sanofi, Regeneron, AstraZeneca, Amgen, Novartis, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite consensus that excessive circulating concentrations of apoB-lipoproteins is a key driver for the atherosclerotic process and that treatments that low-density lipoprotein cholesterol lowering by up-regulation of low-density lipoprotein cholesterol receptor expression reduces that risk, divergent viewpoints on interpretation of study data have resulted in substantial differences in European and American lipid guideline recommendations. This article explores those differences and highlights the importance of understanding guideline-based lipid management to improve patient care and reduce the risk of clinical atherosclerotic cardiovascular disease.

Aims: In the era of personalized medicine, it is of utmost importance to be able to identify subjects at the highest cardiovascular (CV) risk. To date, single biomarkers have failed to markedly improve the estimation of CV risk. Using novel technology, simultaneous assessment of large numbers of biomarkers may hold promise to improve prediction. In the present study, we compared a protein-based risk model with a model using traditional risk factors in predicting CV events in the primary prevention setting of the European Prospective Investigation (EPIC)-Norfolk study, followed by validation in the Progressione della Lesione Intimale Carotidea (PLIC) cohort., Methods and Results: Using the proximity extension assay, 368 proteins were measured in a nested case-control sample of 822 individuals from the EPIC-Norfolk prospective cohort study and 702 individuals from the PLIC cohort. Using tree-based ensemble and boosting methods, we constructed a protein-based prediction model, an optimized clinical risk model, and a model combining both. In the derivation cohort (EPIC-Norfolk), we defined a panel of 50 proteins, which outperformed the clinical risk model in the prediction of myocardial infarction [area under the curve (AUC) 0.754 vs. 0.730; P < 0.001] during a median follow-up of 20 years. The clinically more relevant prediction of events occurring within 3 years showed an AUC of 0.732 using the clinical risk model and an AUC of 0.803 for the protein model (P < 0.001). The predictive value of the protein panel was confirmed to be superior to the clinical risk model in the validation cohort (AUC 0.705 vs. 0.609; P < 0.001)., Conclusion: In a primary prevention setting, a proteome-based model outperforms a model comprising clinical risk factors in predicting the risk of CV events. Validation in a large prospective primary prevention cohort is required to address the value for future clinical implementation in CV prevention., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose of Review: Hypertriglyceridaemia is a highly prevalent disorder worldwide. Genetic and Mendelian randomization studies have suggested that triglyceride (TG)-rich lipoproteins are causal risk factors for coronary heart disease and contribute to the residual cardiovascular risk observed in patients optimally treated with statins. However, clinical trials failed to show cardiovascular benefits of TG-lowering; in this context, trials with omega-3 fatty acids provided contrasting results. Few trials have tested the supplementation of EPA alone rather than the combination of EPA + DHA. The JELIS study showed that EPA 1.8 g/day significantly reduced CV events in hypercholesterolaemic patients given statins, an effect that was independent on lipid reduction., Recent Findings: The REDUCE-IT trial showed that high-dose (4 g/day) EPA significantly reduces the incidence of major cardiovascular events compared with placebo in patients with elevated TG levels. The clinical benefit was higher than expected by the reduction of TG-rich lipoprotein levels. Recent data support the efficacy of high-dose EPA supplementation on a background of optimal LDL-C-lowering therapy as a key approach to achieve a further and significant reduction of CV events in very-high CV risk patients with persistent hypertriglyceridaemia. The effect on lipids does not appear to fully explain the CV benefit, and additional mechanisms of action of EPA likely contribute to the cardiovascular protection, including the reduction of inflammation and platelet aggregation. Current guidelines recommend using high-dose EPA in combination with a statin in high/very-high CV risk patients with mild-to-moderate elevation of plasma TG to reduce the residual CV risk.

The recent publication of the REDUCE-IT study has reopened the debate about the efficacy of omega-3 fatty acids in reducing the risk of cardiovascular (CV) events. This meta-analysis aims at investigating the effect of omega-3 long-chain polyunsaturated fatty acids (n-3 PUFA) administration on CV outcomes in published randomized clinical trials (RCTs), with a focus on the role of dose, type of n-3 PUFA, and different CV risk at baseline. This meta-analysis was conducted according to the PRISMA reporting guidelines. PubMed, Cochrane and EMBASE were searched since inception to March 2020. Inclusion criteria were: (1) RCTs; (2) including subjects with previous CV events; (3) administration of n-3 PUFA ≥ 1 g/day dosage for ≥1 year; (4) effects on all-cause mortality, cardiac death, major adverse cardiovascular events (MACE), fatal/nonfatal myocardial infarction (MI), or fatal/nonfatal stroke reported. Odds ratios (ORs) with 95 % confident intervals (95 %CI) were estimated. 16 RCTs were included in the meta-analysis accounting for 81,073 participants. Supplementation of n-3 PUFA was associated with a significant risk reduction of cardiac mortality (OR 0.91 [95 % CI, 0.85-0.98]), MACE (OR 0.90 [95 % CI, 0.82-0.99]), and MI (OR 0.83 [95 % CI, 0.71-0.98]). In subgroup analyses, the risk reduction of cardiac mortality and MI was confirmed only in RCTs that enrolled patients in secondary prevention (-21 % and -31 %, respectively). Moreover, only the administration of more than 1 g per day of n-3 PUFA was effective in reducing the risk of cardiac death (-35 %), MACE (-24 %), and MI (-33 %). Finally, EPA + DHA supplementation was only associated with a significant risk reduction of cardiac death compared with EPA administered alone (-8 %). Conversely, the efficacy of EPA administered alone seemed to be greater in terms of risk reduction of MACE (-25 %) or MI (-30 %) than the combined EPA + DHA supplementation. The pharmacological approach with n-3 PUFA significantly improves cardiovascular outcomes, with higher benefit achieved by patients in secondary CV prevention, using more than 1 g/day, and taking EPA administered alone., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: To provide information on the balance between the cardiovascular (CV) benefit and the diabetogenic harm of statin therapy in the current clinical practice., Methods: All the 115,939 residents (older than 50 years) in the Italian Lombardy Region newly treated with statins between 2003 and 2005, were followed from the first statin prescription until 2012 to identify those experiencing a macrovascular complication and those with at least one sign suggestive of new onset diabetes. The proportion of days of follow-up covered by statin prescriptions measured adherence with statins. Hazard ratio, and relative 95% confidence interval (CI), for the two considered outcomes associated with statin adherence, were separately estimated (proportional hazard models). Number needed to treat (NNT) and number needed to harm (NNH), i.e., number of individuals who must be treated with statins in order to prevent a macrovascular complication, or to generate a new onset diabetes, respectively, were calculated to evaluate the balance between CV benefit and diabetogenic harm of statin therapy., Results: Compared to those at very low adherence with statins, patients at high adherence showed a significant reduction of macrovascular risk (28%, 95% CI: 23%-33%) and a greater risk of developing diabetic condition (67%, 50%-86%). In the whole cohort, the NNT was 26, whereas the NNH 65. NNT was lower than NNH also in all considered strata of age, gender, clinical profile., Conclusions: This large cohort investigation provides real-world evidence that the balance between CV benefit and diabetogenic harm of statin therapy is largely favourable to treatment benefits., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Although bisphosphonates have been suggested to protect against atherosclerotic cardiovascular (CV) events, evidence is still conflicting. We aimed at investigating the effect of bisphosphonates on hospitalizations for atherosclerotic CV events., Methods: We carried out a retrospective cohort study selecting subjects aged>40 years, incident users of bisphosphonates. Exposure to bisphosphonates was characterized based on cumulative doses (proportion of days covered, PDC). Treatment's adherence was classified as low (PDC≤40%), intermediate (PDC 41%-80%), or high (PDC>80%). A multivariate Cox model was fitted to estimate the association between cumulative time-dependent exposure to bisphosphonates and hospitalization for atherosclerotic CV events (hazard ratio [HR] and 95% confidence interval)., Results: Among 82,704 new bisphosphonates users (females 87.0%, mean age 70.7 ± 10.6 years), 16.1% had a CV hospitalization during a mean follow-up of 6.5 + 2.6 years. Compared with individuals with PDC ≤40%, those exposed for 41-80% or more than 80% showed HRs of CV hospitalization of 0.95 [0.91-0.99] and 0.75 [0.71-0.81], respectively. In the sub-analysis by type of event, a PDC >80% was associated with a reduced incidence for both coronary and cerebrovascular events (HRs 0.75 [0.68-0.83] and 0.76 [0.70-0.83], respectively). The protective effect was confirmed in stratified analyses by sex and age classes, and in those performed at 1 and 3 years of follow-up., Conclusions: Strict adherence to bisphosphonate treatment was associated with a better CV outcome. Although further studies to investigate possible mechanisms are warranted, bisphosphonates could be considered as having a potential CV benefit beyond the effect on bones., Competing Interests: Declaration of competing interest All authors declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. MC, EO, FG, ET, and LS report no disclosures. ALC received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Mediolanum, Merck or MSD, Pfizer, Recordati, Rottapharm, Sanofi-Regeneron, Sigma-Tau. GC received research support from the European Community (EC), the Italian Agency of Drug (AIFA), and the Italian Ministry of Education, University and Research (MIUR). He took part in a variety of projects funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, AMGEN, and BMS). He also received honoraria as member of Advisory Board from Roche., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Despite the invaluable efficacy of statins, adherence to therapy is extremely poor in clinical practice. Improvement interventions should be as personalized as possible, but it is necessary to know factors that most influence adherence, and sex seems to be a key determinant. Thus, we aimed at exploring potential areas of sex-differences in statin adherence in a real-world population. For this purpose, we assessed adherence (as proportion of days covered) on a wide cohort of new statin users aged >40 years, and we evaluated its association with several covariates through sex-stratified log-binomial regression models. In addition, to compare also the benefits of optimal statin adherence in primary prevention of cardiovascular disease between men and women, we implemented sex-stratified Cox proportional hazard models. Our study showed that women are more likely to stop or be less adherent to statin treatment than men. Moreover, we observed significant sex-differences on effect size of several factors associated with adherence that should be taken into consideration for the management of patients. Finally, we observed no significant difference between men and women regarding statin efficacy in terms of reduction of incident hospitalization for ischemic heart disease and/or non-haemorrhagic cerebrovascular disease. These results invoke the responsibility of physicians to a prompt and personalized intervention. Physicians should consider routine screening for non-adherence in their clinical practice, target patients at higher risk of non-adherence, and improved motivation and communication., Competing Interests: Declaration of Competing Interest EO, MTB, MC, ET, LM and FR report no disclosures. ALC received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Mediolanum, Merck or MSD, Pfizer, Recordati, Rottapharm, Sanofi-Regeneron, Sigma-Tau. GC received research support from the European Community (EC), the Italian Agency of Drug (AIFA), and the Italian Ministry of Education, University and Research (MIUR). He took part in a variety of projects that were funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, Amgen, and BMS). He also received honoraria as member of Advisory Board from Roche., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aims: The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy., Methods: This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol., Results: Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); P  < 0.001), ezetimibe alone (-23.2%; P  < 0.001) or bempedoic acid alone (-17.2%; P  < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo., Conclusion: The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk., Trial Registration: ClinicalTrials.gov identifier: NCT03337308.

Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear., Methods and Results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration ( n  = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events., Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.

European guidelines on cardiovascular prevention in clinical practice were first published in 1994 and have been regularly updated, most recently in 2016, by the Sixth European Joint Task Force. Given the amount of new information that has become available since then, components from the task force and experts from the European Association of Preventive Cardiology of the European Society of Cardiology were invited to provide a summary and critical review of the most important new studies and evidence since the latest guidelines were published. The structure of the document follows that of the previous document and has six parts: Introduction (epidemiology and cost effectiveness); Cardiovascular risk; How to intervene at the population level; How to intervene at the individual level; Disease-specific interventions; and Settings: where to intervene? In fact, in keeping with the guidelines, greater emphasis has been put on a population-based approach and on disease-specific interventions, avoiding re-interpretation of information already and previously considered. Finally, the presence of several gaps in the knowledge is highlighted.

This narrative review aims to discuss the more relevant evidence on the role of linoleic acid (LA), a n-6 essential fatty acid that constitutes the predominant proportion of dietary polyunsaturated fatty acids (PUFA), in cardiovascular health. Although LA can be metabolized into Arachidonic Acid (AA), a 20 carbon PUFA which is the precursor of eicosanoids, including some with proinflammatory or prothrombotic-vasoconstrictor action, the large majority of experimental and clinical studies have assessed the potential benefit of increasing dietary intake of LA. Overall, data from clinical studies and meta-analyses suggest an association between high dietary intakes or tissue levels of n-6 PUFA, and specifically LA, and the improvement of cardiovascular risk (mainly of the plasma lipid profile), as well as long-term glycaemic control and insulin resistance. Most observational data show that elevated/increased dietary intake or tissue levels of LA is associated with a reduced incidence of cardiovascular diseases (mainly coronary artery diseases) and of new onset metabolic syndrome or type 2 diabetes. The effects of LA (or n-6 PUFA) in other physio-pathological areas are less clear. High quality clinical trials are needed to assess both the actual amplitude and the underlying mechanisms of the health effects related to dietary intake of this essential fatty acid., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose of Review: Cellular cholesterol content influences the structure and function of lipid rafts, plasma membrane microdomains essential for cell signaling and activation. HDL modulate cellular cholesterol efflux, thus limiting cholesterol accumulation and controlling immune cell activation. Aim of this review is to discuss the link between HDL and cellular cholesterol metabolism in immune cells and the therapeutic potential of targeting cholesterol removal from cell membranes., Recent Findings: The inverse relationship between HDL-cholesterol (HDL-C) levels and the risk of cardiovascular disease has been recently challenged by observations linking elevated levels of HDL-C with increased risk of all-cause mortality, infections and autoimmune diseases, paralleled by the failure of clinical trials with HDL-C-raising therapies. These findings suggest that improving HDL function might be more important than merely raising HDL-C levels. New approaches aimed at increasing the ability of HDL to remove cellular cholesterol have been assessed for their effect on immune cells, and the results have suggested that this could be a new effective approach., Summary: Cholesterol removal from plasma membrane by different means affects the activity of immune cells, suggesting that approaches aimed at increasing the ability of HDL to mobilize cholesterol from cells would represent the next step in HDL biology.