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Lipoprotein(a) as a Cause of Cardiovascular Disease Børge G Nordestgaard Professor, Chief Physician, MD, DMSc University of Copenhagen & Copenhagen University Hospital Conflict of Interest Disclosure Consultancies or talks sponsored by AstraZeneca, Merck, Omthera, Sanofi, Regeneron, IONIS, Aegerion, Dezima, Fresenius, B Braun, Kaneka, Amgen, Denka Seiken, Kowa

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

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Page 1: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Lipoprotein(a) as a Cause of Cardiovascular Disease

Børge 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

Page 2: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

HDL

LDL

Rem-nant

”GOOD”

BAD

UGLY

Genetic Lp(a)

=innocent

TGs

Page 3: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

HDL

Remnants

LDL

Lipoprotein

HDL cholesterol

Remnant cholesterol

LDL cholesterol

Triglycerides

Lipid

Lp(a)Lp(a) total mass

Page 4: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Atherosclerotic stenosis

Myocardial infarction

Aortic valve stenosis

Clinical familial hypercholesterolemia

25%

Lp(a)↑KIV-2↓

Page 5: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Lp(a) developed twice in evolution

Page 6: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 7: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 8: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 9: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

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

20%

Kamstrup JACC 2013; 61: 1146-56

Page 10: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

453 367 176 121 70 38 N

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

Myocardial infarction

Pia Kamstrup. JACC 2013; 61: 1146-56

Page 11: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 12: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 13: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 14: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Lipoprotein Cardiovascular Disease Risk

Genotype

Mendelian randomization hypotheses

established but causal?

effect size?pleiotropic effects?

statistical power?

1

2 3

Causality: Instrumental Variable Analysis

Page 15: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Lp(a)↑

Atherosclerotic stenosis

Myocardial infarction

Aortic stenosis

KIV-2↓

LDL

Apo(a)

Page 16: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 17: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 18: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 19: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 20: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Trégouët et al. 2009

•LPA locus strongest association with CADof 48 000 tested SNPs•2 LPA SNPs explained 36% of p-lp(a)variation and associated ↑ risk of CAD

Page 21: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Atherosclerosis through ”LDL” deposition

Atherosclerotic stenosis through

wound healing

Thrombosis through

fibrinolysis inhibition

Nordestgaard 2015

Page 22: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Lp(a) SNP rs10455872

Thanassoulis NEJM 2013; 369: 503-512

Page 23: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Kamstrup, Tybjærg-Hansen, Nordestgaard JACC 2015; 63; 470-477

Copenhagen General Population Study& Copenhagen City Heart Study

Page 24: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Copenhagen City Heart Study & Copenhagen General Population Study

Hazard ratio (95%CI) for heart failure

Page 25: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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↓

Page 26: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 27: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Lp(a)↑

Aortic valve stenosis

KIV-2↓

Atherosclerosisthrough ”LDL”

deposition

Stenosis through wound

healing

Thrombosisthrough

fibrinolysisinhibition

Atherosclerotic stenosis

Myocardial infarction

Page 28: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

HDL

LDL

Rem-nant

”GOOD”

BAD

UGLY

Genetic Lp(a)

=innocent

TGs

FH

Page 29: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 30: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

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

Page 31: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 32: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Copenhagen General Population Study by clinical FH

Page 33: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

Page 34: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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 <50

Clinical Familial Hypercholesterolemia: DLCN, Simon Broome and/or MEDPED

Copenhagen General Population Study

Langsted et al. 2016; Lancet DE; in press.

Page 35: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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

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

Page 36: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

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, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; online May 12.

Page 37: Universityof Copenhagen & Copenhagen UniversityHospital · Universityof Copenhagen & Copenhagen UniversityHospital Conflict of Interest Disclosure ... Lp(a)↑ Atherosclerotic stenosis

Atherosclerotic stenosis

Myocardial infarction

Aortic valve stenosis

Clinical familial hypercholesterolemia

25%

Lp(a)↑KIV-2↓