European Heart Journal (2020) 41, 2313–2330 CURRENT OPINION doi:10.1093/eurheartj/ehz962 Translational medicine Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, Downloaded from https://academic.oup.com/eurheartj/article-abstract/41/24/2313/5735221 by University of Glasgow user on 13 July 2020 genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel Jan Bore´n1†, M. John Chapman2,3*†, Ronald M. Krauss4, Chris J. Packard 5, Jacob F. Bentzon 6,7, Christoph J. Binder8, Mat J. Daemen 9, Linda L. Demer 10,11,12, Robert A. Hegele 13, Stephen J. Nicholls14, Børge G. Nordestgaard15, Gerald F. Watts16,17, Eric Bruckert18, Sergio Fazio19, Brian A. Ference20,21,22, Ian Graham23, Jay D. Horton24,25, Ulf Landmesser26,27, Ulrich Laufs28, Luis Masana29, Gerard Pasterkamp 30, Frederick J. Raal 31, Kausik K. Ray32, Heribert Schunkert33,34, Marja-Riitta Taskinen35, Bart van de Sluis36, Olov Wiklund 1, Lale Tokgozoglu 37, Alberico L. Catapano38, and Henry N. Ginsberg39 1Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; 2Endocrinology- Metabolism Division, Pitie´-Salpeˆtrie`re University Hospital, Sorbonne University, Paris, France; 3National Institute for Health and Medical Research (INSERM), Paris, France; 4Department of Atherosclerosis Research, Children’s Hospital Oakland Research Institute and UCSF, Oakland, CA 94609, USA; 5Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; 6Department of Clinical Medicine, Heart Diseases, Aarhus University, Aarhus, Denmark; 7Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; 8Department of Laboratory Medicine, Medical University of Vienna, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; 9Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; 10Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; 11Department of Physiology, University of California, Los Angeles, Los Angeles, CA, USA; 12Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA; 13Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; 14Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia; 15Department of Clinical Biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen, Denmark; 16School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia; 17Department of Cardiology, Lipid Disorders Clinic, Royal Perth Hospital, Perth, Australia; 18INSERM UMRS1166, Department of Endocrinology-Metabolism, ICAN - Institute of CardioMetabolism and Nutrition, AP-HP, Hopital de la Pitie, Paris, France; 19Departments of Medicine, Physiology and Pharmacology, Knight Cardiovascular Institute, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR, USA; 20Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, UK; 21Institute for Advanced Studies, University of Bristol, Bristol, UK; 22MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; 23Trinity College Dublin, Dublin, Ireland; 24Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA; 25Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; 26Department of Cardiology, Charite´ - University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, Germany; 27Berlin Institute of Health (BIH), Berlin, Germany; 28Klinik und Poliklinik fu¨r Kardiologie, Universita¨tsklinikum Leipzig, Liebigstraße 20, Leipzig, Germany; 29Research Unit of Lipids and Atherosclerosis, IISPV, CIBERDEM, University Rovira i Virgili, C. Sant Llorenc¸ 21, Reus 43201, Spain; 30Laboratory of Clinical Chemistry, University Medical Center Utrecht, Utrecht, The Netherlands; 31Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; 32Department of Primary Care and Public Health, Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, London, UK; 33Deutsches Herzzentrum Mu¨nchen, Klinik fu¨r Herz- und Kreislauferkrankungen, Faculty of Medicine, Technische Universita¨t Mu¨nchen, Lazarettstr, Munich, Germany; 34DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; 35Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. * Corresponding author. Tel: þ33 148 756 328, Email: [email protected] † These authors contributed equally as senior authors. VC The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 2314 J. Bore´n et al. Helsinki, Helsinki, Finland; 36Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 37Department of Cardiology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 38Department of Pharmacological and Biomolecular Sciences, Universita` degli Studi di Milano, and IRCCS MultiMedica, Milan, Italy; and 39Department of Medicine, Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA Received 9 July 2019; revised 10 November 2019; editorial decision 24 December 2019; accepted 8 January 2020; online publish-ahead-of-print 13 February 2020 . Introduction . research, and potentially for the development of innovative thera- . peutics to decrease the burgeoning clinical burden of ASCVD. Downloaded from https://academic.oup.com/eurheartj/article-abstract/41/24/2313/5735221 by University of Glasgow user on 13 July 2020 Atherosclerotic cardiovascular disease (ASCVD) starts early, even in . 1,2 . childhood. Non-invasive imaging in the PESA (Progression of Early . Subclinical Atherosclerosis) study revealed that 71% and 43% of . Trancytosis of low-density . middle-aged men and women, respectively, have evidence of subclin- . lipoprotein across the 3 . ical atherosclerosis. Extensive evidence from epidemiologic, genetic, . and clinical intervention studies has indisputably shown that low- . endothelium . density lipoprotein (LDL) is causal in this process, as summarized in . Apolipoprotein B-containing lipoproteins of up to 70 nm in diam- 4 . the first Consensus Statement on this topic. What are the key bio- . eter [i.e. chylomicron remnants, very low-density lipoproteins logical mechanisms, however, that underlie the central role of LDL in . (VLDL) and VLDL remnants, IDL, LDL, and Lp(a)] can cross the endo- the complex pathophysiology of ASCVD, a chronic and multifaceted . thelium (Figure 1).21–29 Low-density lipoprotein, as the most abundant . lifelong disease process, ultimately culminating in an atherothrom- . atherogenic lipoprotein in plasma, is the key deliverer of cholesterol botic event? . to the artery wall. Many risk factors modulate the propensity of LDL This second Consensus Statement on LDL causality discusses the . and other atherogenic lipoproteins to traverse the endothelium and established and newly emerging biology of ASCVD at the molecular, . 30 . enter the arterial intima. Despite the relevance of LDL endothelial cellular, and tissue levels, with emphasis on integration of the central . transport during atherogenesis, however, the molecular mechanisms pathophysiological mechanisms. Key components of this integrative . 31 . controlling this process are still not fully understood. approach include consideration of factors that modulate the athero- . A considerable body of evidence in recent years32 has chal- genicity of LDL at the arterial wall and downstream effects exerted . lenged the concept that movement of LDL occurs by passive filtra- by LDL particles on the atherogenic process within arterial tissue. tion (i.e. as a function of particle size and concentration) across a Although LDL is unequivocally recognized as the principal . 33 . compromised endothelium of high permeability. Studies have driving force in the development of ASCVD and its major clinic- . demonstrated that LDL transcytosis occurs through a vesicular al sequelae,4,5 evidence for the causal role of other apolipopro- . 34–36 37 . pathway, involving caveolae, scavenger receptor B1 (SR-B1), tein B (apoB)-containing lipoproteins in ASCVD is emerging. activin receptor-like kinase 1 (ALK1),38 and the LDL receptor.32 Detailed consideration of the diverse mechanisms by which . However, although the LDL receptor appears to mediate LDL these lipoproteins, including triglyceride (TG)-rich lipoproteins . transcytosis across