Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement fromthe European Atherosclerosis Society Consensus Panel

Brian A. Ference, Henry N. Ginsberg, Ian Graham, Kausik K. Ray, Chris J. Packard, Eric Bruckert, Robert A. Hegele, Ronald M. Krauss, Frederick J. Raal, Heribert Schunkert, Gerald F. Watt, Jan Borén, Sergio Fazio, Jay D. Horton, Luis Masana, Stephen J. Nicholls, Børge G. Nordestgaard, Bart Van De Sluis, Marja Riitta Taskinen, Lale TokgözoǧluUlf Landmesser, Ulrich Laufs, Olov Wiklund, Jane K. Stock, M. John Chapman, Alberico L. Catapano

    Research output: Contribution to journalArticle

    429 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)2459-2472
    Number of pages14
    JournalEuropean Heart Journal
    Volume38
    Issue number32
    DOIs
    StatePublished - Aug 21 2017

    Fingerprint

    LDL Lipoproteins
    Epidemiologic Studies
    Cardiovascular Diseases
    Random Allocation
    Clinical Studies
    Cohort Studies
    Prospective Studies
    LDL Receptors
    HDL Lipoproteins
    Causality
    LDL Cholesterol
    Meta-Analysis

    Keywords

    • Atherosclerosis
    • Cardiovascular disease
    • Causality
    • Clinical trials
    • Ezetimibe
    • Low-density lipoprotein
    • Mendelian randomization
    • PCSK9
    • Recommendations
    • Statin

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Cite this

    Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement fromthe European Atherosclerosis Society Consensus Panel. / Ference, Brian A.; Ginsberg, Henry N.; Graham, Ian; Ray, Kausik K.; Packard, Chris J.; Bruckert, Eric; Hegele, Robert A.; Krauss, Ronald M.; Raal, Frederick J.; Schunkert, Heribert; Watt, Gerald F.; Borén, Jan; Fazio, Sergio; Horton, Jay D.; Masana, Luis; Nicholls, Stephen J.; Nordestgaard, Børge G.; Van De Sluis, Bart; Taskinen, Marja Riitta; Tokgözoǧlu, Lale; Landmesser, Ulf; Laufs, Ulrich; Wiklund, Olov; Stock, Jane K.; Chapman, M. John; Catapano, Alberico L.

    In: European Heart Journal, Vol. 38, No. 32, 21.08.2017, p. 2459-2472.

    Research output: Contribution to journalArticle

    Ference, BA, Ginsberg, HN, Graham, I, Ray, KK, Packard, CJ, Bruckert, E, Hegele, RA, Krauss, RM, Raal, FJ, Schunkert, H, Watt, GF, Borén, J, Fazio, S, Horton, JD, Masana, L, Nicholls, SJ, Nordestgaard, BG, Van De Sluis, B, Taskinen, MR, Tokgözoǧlu, L, Landmesser, U, Laufs, U, Wiklund, O, Stock, JK, Chapman, MJ & Catapano, AL 2017, 'Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement fromthe European Atherosclerosis Society Consensus Panel', European Heart Journal, vol. 38, no. 32, pp. 2459-2472. https://doi.org/10.1093/eurheartj/ehx144
    Ference, Brian A. ; Ginsberg, Henry N. ; Graham, Ian ; Ray, Kausik K. ; Packard, Chris J. ; Bruckert, Eric ; Hegele, Robert A. ; Krauss, Ronald M. ; Raal, Frederick J. ; Schunkert, Heribert ; Watt, Gerald F. ; Borén, Jan ; Fazio, Sergio ; Horton, Jay D. ; Masana, Luis ; Nicholls, Stephen J. ; Nordestgaard, Børge G. ; Van De Sluis, Bart ; Taskinen, Marja Riitta ; Tokgözoǧlu, Lale ; Landmesser, Ulf ; Laufs, Ulrich ; Wiklund, Olov ; Stock, Jane K. ; Chapman, M. John ; Catapano, Alberico L. / Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement fromthe European Atherosclerosis Society Consensus Panel. In: European Heart Journal. 2017 ; Vol. 38, No. 32. pp. 2459-2472.
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    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.",
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    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 - Watt, 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 - Tokgözoǧlu, Lale

    AU - Landmesser, Ulf

    AU - Laufs, Ulrich

    AU - Wiklund, Olov

    AU - Stock, Jane K.

    AU - Chapman, M. John

    AU - Catapano, Alberico L.

    PY - 2017/8/21

    Y1 - 2017/8/21

    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.

    AB - 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.

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    KW - Cardiovascular disease

    KW - Causality

    KW - Clinical trials

    KW - Ezetimibe

    KW - Low-density lipoprotein

    KW - Mendelian randomization

    KW - PCSK9

    KW - Recommendations

    KW - Statin

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