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Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
Eur Heart J. 2017 Aug 21; 38(32):2459-2472.EH

Abstract

AIMS

To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).

METHODS AND RESULTS

We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects.

CONCLUSION

Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.

Links

Authors+Show Affiliations

Division of Translational Research and Clinical Epidemiology, Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, MI 48202, USA.

Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA.

Trinity College Dublin, Ireland.

Department of Primary Care and Public Health, Imperial Centre for Cardiovascular Disease Prevention, Imperial College, London, UK.

College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK.

INSERM UMRS1166, Department of Endocrinology-Metabolism, ICAN - Institute of CardioMetabolism and Nutrition, AP-HP, Hôpital de la Pitié, Paris, France.

Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.

Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.

Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany. Deutsches Zentrum für Herz und Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich 81377, Germany.

Lipid Disorders Clinic, Centre for Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.

Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.

Department of Medicine, Center for Preventive Cardiology of the Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA.

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Research Unit of Lipids and Atherosclerosis, University Rovira i Virgili, C. Sant Llorenç 21, Reus 43201, Spain.

South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.

Nordestgaard BG

Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark.

Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen AV 9713, The Netherlands.

Helsinki University Central Hospital and Research Programs' Unit, Diabetes and Obesity, Heart and Lung Centre, University of Helsinki, Helsinki, Finland.

Hacettepe University, Ankara, Turkey.

Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA. INSERM UMRS1166, Department of Endocrinology-Metabolism, ICAN - Institute of CardioMetabolism and Nutrition, AP-HP, Hôpital de la Pitié, Paris, France. Department of Cardiology, Charité-Universitätsmedizin Berlin (CBF), Hindenburgdamm 30, Berlin 12203, Germany.

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg, Saar, Germany.

Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden. Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.

European Atherosclerosis Society, Gothenburg, Sweden.

INSERM, Dyslipidemia and Atherosclerosis Research, and University of Pierre and Marie Curie, Pitié-Sâlpetrière University Hospital, Paris, France.

Department of Pharmacological and Biomolecular Sciences, University of Milan and IRCCS Multimedica, Milan, Italy.

MeSH

Anticholesteremic AgentsAtherosclerosisCholesterol, HDLCholesterol, LDLConsensusEpidemiologic MethodsEzetimibeGenetic Predisposition to DiseaseHydroxymethylglutaryl-CoA Reductase InhibitorsHyperlipidemiasLipoproteins, LDLPCSK9 Inhibitors

Pub Type(s)

Journal Article

Review

Consensus Development Conference

Language

eng

PubMed ID

28444290

Clinical Trial Links

Cholesterol Self-testing in Patients Post Acute Coronary Syndrome

OptimiZation Of Lipid Lowering Therapies Using a Decision Support System In Patients With Acute Coronary Syndrome.

Effects of Statin for Elderly Patients With Atherosclerotic Cardiovascular Disease

Citation

Ference, Brian A., et al. "Low-density Lipoproteins Cause Atherosclerotic Cardiovascular Disease. 1. Evidence From Genetic, Epidemiologic, and Clinical Studies. a Consensus Statement From the European Atherosclerosis Society Consensus Panel." European Heart Journal, vol. 38, no. 32, 2017, pp. 2459-2472.

Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472.

Ference, B. A., Ginsberg, H. N., Graham, I., Ray, K. K., Packard, C. J., Bruckert, E., Hegele, R. A., Krauss, R. M., Raal, F. J., Schunkert, H., Watts, G. F., Borén, J., Fazio, S., Horton, J. D., Masana, L., Nicholls, S. J., Nordestgaard, B. G., van de Sluis, B., Taskinen, M. R., ... Catapano, A. L. (2017). Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal, 38(32), 2459-2472. https://doi.org/10.1093/eurheartj/ehx144

Ference BA, et al. Low-density Lipoproteins Cause Atherosclerotic Cardiovascular Disease. 1. Evidence From Genetic, Epidemiologic, and Clinical Studies. a Consensus Statement From the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Aug 21;38(32):2459-2472. PubMed PMID: 28444290.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. AU - Ference,Brian A, AU - Ginsberg,Henry N, AU - Graham,Ian, AU - Ray,Kausik K, AU - Packard,Chris J, AU - Bruckert,Eric, AU - Hegele,Robert A, AU - Krauss,Ronald M, AU - Raal,Frederick J, AU - Schunkert,Heribert, AU - Watts,Gerald F, AU - Borén,Jan, AU - Fazio,Sergio, AU - Horton,Jay D, AU - Masana,Luis, AU - Nicholls,Stephen J, AU - Nordestgaard,Børge G, AU - van de Sluis,Bart, AU - Taskinen,Marja-Riitta, AU - Tokgözoglu,Lale, AU - Landmesser,Ulf, AU - Laufs,Ulrich, AU - Wiklund,Olov, AU - Stock,Jane K, AU - Chapman,M John, AU - Catapano,Alberico L, PY - 2016/11/30/received PY - 2017/03/08/accepted PY - 2017/4/27/pubmed PY - 2018/7/18/medline PY - 2017/4/27/entrez KW - Atherosclerosis KW - Cardiovascular disease KW - Causality KW - Clinical trials KW - Ezetimibe KW - Low-density lipoprotein KW - Mendelian randomization KW - PCSK9 KW - Recommendations KW - Statin SP - 2459 EP - 2472 JF - European heart journal JO - Eur Heart J VL - 38 IS - 32 N2 - AIMS: To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. CONCLUSION: Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD. SN - 1522-9645 UR - https://www.unboundmedicine.com/medline/citation/28444290/full_citation DB - PRIME DP - Unbound Medicine ER -