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

Lipoprotein(a) as a Cause of

Cardioborbobbvascular Disease

HDL

LDL

Rem

nant

Lp(a)

HDL

LDL

Rem-

nant

”GOOD”

BAD

UGLY

Genetic Lp(a)

=innocent

TGs

Lipid Lipoprotein

HDL

Remnants

LDL

Lipoprotein

HDL cholesterol

Remnant cholesterol

LDL cholesterol

Triglycerides

Lipid

Lp(a)

Lp(a) total mass

Lp(a)

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

F

raction o

f P

opula

tion

Men Women

20% 20%

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

Copenhagen General Population Study

Whites

Chinese

Japanese

Hispanics

Blacks

5 10 20 40

Uterman G 2001 &

Matthews KA et al. Am

Heart J 2005

Lipoprotein(a), mg/dL

Median (interquartile range)

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

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%

Kamstrup JACC 2013; 61: 1146-56

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

453 367 176 121 70 38 N

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

Pia Kamstrup.

JACC 2013;

61: 1146-56

Myocardial infarction

0

50

100

150

Lip

opro

tein

(a)

CO

BA

S,

nm

ol/

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

104 nmol/L

50 mg/dL

Nordestgaard,

Kamstrup &

Langsted 2016

Lp(a) nmol/L vs. Lp(a) mg/dL

Denka Seiken assay on Roche COBAS

Lp(a) ≤70 mg/dL N=2157

apolipo-

protein(a)

LDL-like

particle

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

Kringle IV-2

copy

number

variant:

2 to >40

repeats

Danish

kringle

Lipoprotein(a)

Randomization 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 causationNordestgaard 2015

Randomized trial vs. Mendelian randomization

Lipoprotein Cardiovascular

Disease Risk

Genotype

established but causal?

effect size?

pleiotropic effects?statistical power?

1

2 3

Causality: Instrumental Variable Analysis

Mendelian randomization hypotheses

Lp(a)Lp(a)↑

Atherosclerotic

stenosis

Myocardial

infarction

Aortic

stenosis

KIV-2↓

LDL

Apo(a)

Copenhagen General Population Study (CGPS)

N=15,000

N=110,000+

37 yrs follow-up

10 yrs follow-up

No losses to

follow-up

1977-2014

Copenhagen

Copenhagen City Heart Study (CCHS)

1

1.5

2

2.5

Haz

ard r

atio

(95%

CIs

)

0 50 100 150

Copenhagen General Population Study and

Copenhagen City Heart Study

N=58,340

1897 myocardial infarction (MI)

Emerging Risk Factor Collaboration

N=126,634

9336 MI + coronary death

1

1.5

2

2.5

Haz

ard

rat

io (

95

% C

Is)

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) Myocardial

Infarction

KIV-2 genotype

1

2 3

Causal association

large effect size,

pleiotropic effects

unlikely

adequate statistical

power

GWAS

SNPs

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

Hypotheses

Consistency with custom-made

chip/GWAStudies

Schunkert et al. 2011

•confirmed association of LPA locus

with CAD in CAD case-control study

of 56 000 individuals

Clarke et al. 2009

Trégouët et al. 2009

•LPA locus strongest association with CAD

of 48 000 tested SNPs

•2 LPA SNPs explained 36% of p-lp(a)

variation and associated ↑ risk of CAD

Atherosclerosis

through ”LDL”

depositionAtherosclerotic

stenosis through

wound healing

Thrombosis

through

fibrinolysis

inhibition

Nordestgaard 2015

Lp(a) SNP

rs10455872

Thanassoulis NEJM 2013; 369: 503-512

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

Copenhagen General Population Study

& Copenhagen City Heart Study

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

Hazard ratio (95%CI) for heart failure

Copenhagen City Heart Study &

Copenhagen General Population Study

Heart

failure

63%

21%

47%Lp(a)↑

Myocardial

infarction

Aortic

stenosis

Both

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

KIV-2↓

Mediation analysis (n=50,000)

0.9 1.0 1.1 1.2 1.3

Hazard 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

Nordestgaard & Langsted 2016

Copenhagen General Population Study and Copenhagen City Heart Study

Lp(a)

Lp(a)↑

Aortic valve

stenosis

KIV-2↓

Atherosclerosis

through ”LDL”

deposition

Stenosis

through wound

healing

Thrombosis

through

fibrinolysis

inhibition

Atherosclerotic

stenosis

Myocardial

infarction

HDL

LDL

Rem-

nant

BAD

UGLY

Genetic Lp(a)

=innocent

TGs

FH

”GOOD”

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

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

Heterozygous familial

hypercholesterolaemia

High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study

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

Cu

mu

lati

ve i

nci

den

ce o

f m

yo

card

ial

infa

rcti

on

20 40 60 80 100

Age, years

Clinical Lp(a)

FH mg/dL

Yes >50

Yes ≥50

No ≥50

No <50

Clinical Familial Hypercholesterolemia:

DLCN, Simon Broome and/or MEDPED

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

Copenhagen General Population Study

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

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

Copenhagen

General

Population

Study

N=46,200

FH

1:200

Ranked causes

of clinical FH

1. LDLR

2. Lp(a) (25%)

3. APOB

4. PCSK9

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

High lipoprotein(a) as a possible

cause of clinical familial

hypercholesterolemia (FH)

Conc

lusio

n

Atherosclerotic

stenosis

Myocardial

infarction

Aortic valve

stenosis

Clinical familial

hypercholesterolemia

25%

Lp(a)↑

KIV-2↓