Universityof Copenhagen Copenhagen UniversityHospital Copenhagen Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis Myocardial

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  • Lipoprotein(a) as a Cause of Cardiovascular Disease

    Brge G NordestgaardProfessor, Chief Physician, MD, DMSc

    University of Copenhagen & Copenhagen University Hospital

    Conflict of Interest DisclosureConsultancies or talks sponsored by AstraZeneca, Merck, Omthera, Sanofi, Regeneron,

    IONIS, Aegerion, Dezima, Fresenius, B Braun, Kaneka, Amgen, Denka Seiken, Kowa

  • HDL

    LDL

    Rem-nant

    GOOD

    BAD

    UGLY

    Genetic Lp(a)

    =innocent

    TGs

  • HDL

    Remnants

    LDL

    Lipoprotein

    HDL cholesterol

    Remnant cholesterol

    LDL cholesterol

    Triglycerides

    Lipid

    Lp(a)Lp(a) total mass

  • Atherosclerotic stenosis

    Myocardial infarction

    Aortic valve stenosis

    Clinical familial hypercholesterolemia

    25%

    Lp(a)KIV-2

  • Lp(a) developed twice in evolution

  • 0 50 100 150 200Lp(a), mg/dL

    0 50 100 150 200Lp(a), mg/dL

    Fra

    ctio

    n of

    Pop

    ulat

    ion

    Men Women

    20% 20%

    Copenhagen General Population Study

    Low number of Kringle IV-2

    repeats

    High number of Kringle IV-2

    repeats

    Nordestgaard et al. EAS Consensus Panel. Eur Heart J 2010;31:2844-2853

    80-90% genetically determined

  • Whites

    Chinese

    Japanese

    Hispanics

    Blacks

    Lipoprotein(a), mg/dLMedian (interquartile range)

    5 10 20 40

    Uterman G 2001 &

    Matthews KA et al. Am Heart J 2005

  • Whom to screen for Lp(a) Premature CVD Familial hypercholesterolemia Family history premature CVD or Lp(a) Recurrent CVD despite statins 3% 10-year risk of fatal CVD 10% 10-year risk of fatal/nonfatal CHD Aortic valve calcification or stenosis?

    Nordestgard et al. EAS Consensus Panel. Eur Heart J 2010;31:2844-2853 - updated

  • Emerging Risk Factor Collaboration. JAMA 2012; 307: 2499-2506

    0 50 100 150 200Lp(a), mg/dL

    20%

    Kamstrup JACC 2013; 61: 1146-56

  • 453 367 176 121 70 38 N

    2% 3% 11% 16% 16% 23% NRI

    Myocardial infarction

    Pia Kamstrup. JACC 2013; 61: 1146-56

  • 0

    50

    100

    150Li

    popr

    otei

    n(a)

    CO

    BA

    S, n

    mol

    /L

    0 20 40 60 80Lipoprotein(a) COBAS, mg/dL

    R2 = 0.99. Lp(a), nmol/L = 2.14 * lp(a), mg/dL 3.15

    Lp(a) nmol/L vs. Lp(a) mg/dLDenka Seiken assay on Roche COBAS

    Lp(a) 70 mg/dL N=2157

    104 nmol/L

    50 mg/dL

    Nordestgaard, Kamstrup &

    Langsted 2016

  • Lipoprotein(a)

    apolipo-protein(a)

    LDL-likeparticle

    Koschinsky et al. Cur Opin Lipidol 2004;15:167-174

    Kringle IV-2 copy number variant:2 to >40 repeats

    Danish kringle

  • Randomized trial vs. Mendelian randomizationRandomization methods

    Placebo Drug: lipoprotein levels or

    Cardiovascular disease or

    Confounders evenly distributed

    Random distribution of alleles

    Confounders evenly distributed

    Cardiovascular disease or

    Normal allele

    Allele: lipoprotein levels or

    Reverse causation Nordestgaard 2015

  • Lipoprotein Cardiovascular Disease Risk

    Genotype

    Mendelian randomization hypotheses

    established but causal?

    effect size?pleiotropic effects?

    statistical power?

    1

    2 3

    Causality: Instrumental Variable Analysis

  • Lp(a)

    Atherosclerotic stenosis

    Myocardial infarction

    Aortic stenosis

    KIV-2

    LDL

    Apo(a)

  • Copenhagen General Population Study (CGPS)

    Copenhagen City Heart Study (CCHS)

    N=15,000

    N=110,000+

    37 yrs follow-up

    10 yrs follow-up

    No losses to follow-up

    1977-2014

    Copenhagen

  • 1

    1.5

    2

    2.5

    Haz

    ard

    ratio

    (95%

    CIs

    )0 50 100 150

    Copenhagen General Population Study andCopenhagen City Heart Study

    N=58,3401897 myocardial infarction (MI)

    Emerging Risk Factor Collaboration

    N=126,6349336 MI + coronary death

    1

    1.5

    2

    2.5

    Haz

    ard

    ratio

    (95%

    CIs

    )

    0 50 100 150

    Lipoprotein(a), mg/dL Lipoprotein(a), mg/dL

    Nordestgaard & Langsted 2016

  • Instrumental variable analysis: causality

    Risk of myocardial infarction for a doubling of lipoprotein(a) levels

    Hazard Ratio (95% CI)

    Kamstrup et al. JAMA 2009; 301: 2331-9

  • Lipoprotein(a) MyocardialInfarction

    KIV-2 genotype

    Hypotheses

    1

    2 3

    Causal association

    large effect size,pleiotropic effectsunlikely

    adequate statisticalpower

    GWAS

    SNPs

    Kamstrup et al. JAMA 2009; 301: 2331-9

  • Consistency with custom-made chip/GWAStudies

    Schunkert et al. 2011

    confirmed association of LPA locuswith CAD in CAD case-control study of 56 000 individuals

    Clarke et al. 2009

    Trgout et al. 2009

    LPA locus strongest association with CADof 48 000 tested SNPs2 LPA SNPs explained 36% of p-lp(a)variation and associated risk of CAD

  • Atherosclerosis through LDL deposition

    Atherosclerotic stenosis through

    wound healing

    Thrombosis through

    fibrinolysis inhibition

    Nordestgaard 2015

  • Lp(a) SNP rs10455872

    Thanassoulis NEJM 2013; 369: 503-512

  • Kamstrup, Tybjrg-Hansen, Nordestgaard JACC 2015; 63; 470-477

    Copenhagen General Population Study& Copenhagen City Heart Study

  • Kamstrup & Nordestgaard JACC Heart Failure 2016; 4: 78-87

    Copenhagen City Heart Study & Copenhagen General Population Study

    Hazard ratio (95%CI) for heart failure

  • Mediation analysis (n=50,000)

    Heart failure

    63%21%

    47%Lp(a)

    Myocardial infarction

    Aortic stenosis

    Both

    Kamstrup & Nordestgaard JACC Heart Failure 2016; 4: 78-87

    KIV-2

  • 0.9 1.0 1.1 1.2 1.3Hazard ratio or causal risk ratio (95% CI) for a doubling in lipoprotein(a)

    Myocardial infarctionPlasma lipoprotein(a) 58,232/1894

    LPA KIV-2 98,941/4604

    LPA rs10455872 104,366/4825

    Aortic valve stenosisPlasma lipoprotein(a) 48,564/459

    LPA KIV-2 98,817/1022

    LPA rs10455872 99,226/1023

    Venous thromboembolismPlasma lipoprotein(a) 58,459/1470

    LPA KIV-2 94,638/4303

    LPA rs10455872 104,601/4590

    HR or CRR(95% CI)

    1.09(1.07;1.12)

    1.15(1.11;1.20)

    1.10(1.06;1.13)

    1.14(1.08;1.20)

    1.13(1.04;1.22)

    1.21(1.14;1.29)

    1.00(0.98;1.03)

    1.01(0.96;1.06)

    1.03(0.99;1.07)

    N/events

    Copenhagen General Population Study and Copenhagen City Heart Study

    Nordestgaard & Langsted 2016

  • Lp(a)

    Aortic valve stenosis

    KIV-2

    Atherosclerosisthrough LDL

    deposition

    Stenosis through wound

    healing

    Thrombosisthrough

    fibrinolysisinhibition

    Atherosclerotic stenosis

    Myocardial infarction

  • HDL

    LDL

    Rem-nant

    GOOD

    BAD

    UGLY

    Genetic Lp(a)

    =innocent

    TGs

    FH

  • Atherosclerosis

    Myocardial infarction

    Angina pectoris

    Elevated LDL cholesterol

    Mutations in LDL receptor, apolipoproteinB or PCSK9

    Liver with only 50% functional LDL receptors

    Coronary heart disease

    Heterozygous familial hypercholesterolaemia

    Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490

  • Langsted et al. 2016; Lancet DE; online May 12.

    Raul D. Santos. 2016; Lancet DE; online May 12.

  • Langsted et al. 2016; Lancet DE; online May 12.

  • Langsted et al. 2016; Lancet DE; online May 12.

    Copenhagen General Population Study by clinical FH

  • Langsted et al. 2016; Lancet DE; online May 12.

  • 0

    0.2

    0.4

    0.6

    0.8

    Cum

    ulat

    ive

    inci

    denc

    e of

    myo

    card

    ial i

    nfar

    ctio

    n

    20 40 60 80 100Age, years

    Clinical Lp(a)FH mg/dL

    Yes >50

    Yes 50

    No 50No

  • Langsted et al. 2016; Lancet DE; online May 12.

    Copenhagen General Population Study by clinical FH, n=46,200

  • High lipoprotein(a) as a possible cause of clinical familial

    hypercholesterolemia (FH)

    Copenhagen General

    Population Study

    N=46,200

    FH 1:200

    Ranked causesof clinical FH

    1. LDLR2. Lp(a) (25%)3. APOB4. PCSK9

    Langsted, Kamstrup, Benn, Tybjrg-Hansen, Nordestgaard 2016; Lancet DE; online May 12.

  • Atherosclerotic stenosis

    Myocardial infarction

    Aortic valve stenosis

    Clinical familial hypercholesterolemia

    25%

    Lp(a)KIV-2