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
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
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
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, 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
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 <50
Clinical Familial Hypercholesterolemia: DLCN, Simon Broome and/or MEDPED
Copenhagen General Population Study
Langsted et al. 2016; Lancet DE; in press.
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, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; online May 12.
Atherosclerotic stenosis
Myocardial infarction
Aortic valve stenosis
Clinical familial hypercholesterolemia
25%
Lp(a)↑KIV-2↓
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