Lipoprotein(A) As a Cause of Cardioborbobbvascular Disease Børge G Nordestgaard Professor, Chief Physician, MD, Dmsc

University of Copenhagen & Copenhagen University Hospital

Lipoprotein(a) as a Cause of Cardioborbobbvascular Disease Børge G Nordestgaard Professor, Chief Physician, MD, DMSc

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 ”GOOD” =innocent HDL HDL BAD LDLLDL Rem Remnant - UGLY TGs Lp(a) nant Genetic Lp(a) Lipid Lipid LipoproteinLipoprotein

HDL HDL cholesterol

LDL LDL cholesterol

Remnants

Triglycerides Remnant cholesterol

Lp(a) Lp(a) total mass Atherosclerotic stenosis Lp(a)↑ Lp(a) KIV-2↓

Myocardial infarction

25%

Clinical familial Aortic valve hypercholesterolemia stenosis Lp(a) developed twice in evolution Copenhagen General Population Study

Men Women High number of Kringle IV-2 80-90% repeats genetically determined Low number of Kringle IV-2 repeats

20% 20% Fraction of Population of Fraction 0 50 100 150 200 0 50 100 150 200 Lp(a), mg/dL Lp(a), mg/dL

Nordestgaard et al. EAS Consensus Panel. Eur Heart J 2010;31:2844-2853 Uterman G 2001 & Lipoprotein(a), mg/dL Matthews KA et al. Am Heart J 2005 Median (interquartile range) Whites Chinese Japanese Hispanics Blacks 5 10 20 40 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

Men Women

20% 20% Fraction of Population of Fraction 0 50 100 150 200 0 50 100 150 200 Lp(a), mg/dL Lp(a), mg/dL Kamstrup JACC 2013; 61: 1146-56 Myocardial infarction

453 367 176 121 70 38 N Pia Kamstrup. JACC 2013; 2% 3% 11% 16% 16% 23% NRI 61: 1146-56 Lp(a) nmol/L vs. Lp(a) mg/dL 150 Denka Seiken assay on Roche COBAS Lp(a) ≤70 mg/dL N=2157

104 nmol/L 100

Nordestgaard, Kamstrup & Langsted 2016

50 Lipoprotein(a) COBAS, nmol/L Lipoprotein(a)

0 50 mg/dL 0 20 40 60 80 Lipoprotein(a) COBAS, mg/dL R2 = 0.99. Lp(a), nmol/L = 2.14 * lp(a), mg/dL – 3.15 Danish Lipoprotein(a) kringle

Kringle IV-2 copy number variant: 2 to >40 repeats LDL-like particle apolipo- protein(a)

Koschinsky et al. Cur Opin Lipidol 2004;15:167-174 Randomized trial vs. Mendelian randomization Randomization methods Random distribution of alleles

Placebo Drug: lipoprotein Normal Allele: lipoprotein levels  or  allele levels  or 

Confounders Confounders evenly distributed evenly distributed

Cardiovascular disease  or  Cardiovascular disease  or 

Reverse causation Nordestgaard 2015 Mendelian randomization hypotheses

established but causal?

Lipoprotein Cardiovascular 1 Disease Risk

2 3 effect size? statistical power? pleiotropic effects?

Genotype

Causality: Instrumental Variable Analysis Atherosclerotic stenosis Lp(a) Lp(a)↑ LDL

Myocardial infarction

Apo(a) KIV-2↓ Aortic stenosis Copenhagen City Heart Study (CCHS)

37 yrs follow-up N=15,000 No losses to Copenhagen follow-up 1977-2014

N=110,000+ 10 yrs follow-up

Copenhagen General Population Study (CGPS) Copenhagen General Population Study and Emerging Risk Factor Collaboration Copenhagen City Heart Study

N=58,340 N=126,634 1897 myocardial infarction (MI) 9336 MI + coronary death

2.5 2.5

2 2

1.5 1.5

Hazard ratio (95% CIs) (95% ratio Hazard Hazard ratio (95% CIs) (95% ratio Hazard

1 1

0 50 100 150 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 Hypotheses Causal association Lipoprotein(a) Myocardial Infarction 1 GWAS 2 3 large effect size, pleiotropic effects adequate statistical unlikely power SNPs KIV-2 genotype

Kamstrup et al. JAMA 2009; 301: 2331-9 Consistency with custom-made chip/GWAStudies

Schunkert et al. 2011 Trégouët et al. 2009 •confirmed association of LPA locus with CAD in CAD case-control study of 56 000 individuals

Clarke 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 Thrombosis through fibrinolysis inhibition

Atherosclerosis through ”LDL” deposition Atherosclerotic stenosis through Nordestgaard 2015 wound healing Lp(a) SNP rs10455872

Thanassoulis NEJM 2013; 369: 503-512 Copenhagen General Population Study & Copenhagen City Heart Study

Kamstrup, Tybjærg-Hansen, Nordestgaard JACC 2015; 63; 470-477 Copenhagen City Heart Study & Copenhagen General Population Study

Hazard ratio (95%CI) for heart failure

Kamstrup & Nordestgaard JACC Heart Failure 2016; 4: 78-87 Mediation analysis (n=50,000) Myocardial infarction Heart failure Lp(a)↑ 47% Both 63% 21% KIV-2↓ Aortic stenosis Kamstrup & Nordestgaard JACC Heart Failure 2016; 4: 78-87 Copenhagen General Population Study and Copenhagen City Heart Study HR or CRR(95% CI) Myocardial infarction N/events Plasma lipoprotein(a) 58,232/1894 1.09(1.07;1.12)

LPA KIV-2 98,941/4604 1.15(1.11;1.20)

LPA rs10455872 104,366/4825 1.10(1.06;1.13)

Aortic valve stenosis 1.14(1.08;1.20) Plasma lipoprotein(a) 48,564/459 1.13(1.04;1.22) LPA KIV-2 98,817/1022 1.21(1.14;1.29) LPA rs10455872 99,226/1023

Venous thromboembolism 1.00(0.98;1.03) Plasma lipoprotein(a) 58,459/1470 1.01(0.96;1.06) LPA KIV-2 94,638/4303 1.03(0.99;1.07) LPA rs10455872 104,601/4590

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

Nordestgaard & Langsted 2016 Atherosclerotic stenosis Atherosclerosis Lp(a) through ”LDL” deposition

Myocardial Lp(a)↑ infarction Thrombosis through fibrinolysis inhibition KIV-2↓

Stenosis through wound healing Aortic valve stenosis ”GOOD” =innocent HDL

BAD FH LDL

Rem- UGLY TGs nant Genetic Lp(a) Elevated LDL cholesterol Atherosclerosis

Coronary heart disease Liver with only 50% functional LDL receptors Myocardial infarction Angina pectoris

Mutations in LDL receptor, apolipoproteinB or PCSK9 Heterozygous familial hypercholesterolaemia

Nordestgaard et al. Eur Heart J 2013; 34: 3478-3490 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. Copenhagen General Population Study by clinical FH

Langsted et al. 2016; Lancet DE; online May 12. Langsted et al. 2016; Lancet DE; online May 12. Copenhagen General Population Study 0.8 Clinical Familial Hypercholesterolemia: Clinical Lp(a) DLCN, Simon Broome and/or MEDPED FH mg/dL

0.6 Yes >50

Yes ≥50 0.4

No ≥50 0.2 No <50

Cumulative incidence of myocardial infarction myocardial of incidence Cumulative 20 40 60 80 100 Age, years

Langsted et al. 2016; Lancet DE; in press. Copenhagen General Population Study by clinical FH, n=46,200

Langsted et al. 2016; Lancet DE; online May 12. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolemia (FH)

Ranked causes Copenhagen of clinical FH General FH Population 1. LDLR 1:200 Study 2. Lp(a) (25%) N=46,200 3. APOB 4. PCSK9

Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; online May 12. Atherosclerotic Conc stenosis Lp(a)↑ lusio n KIV-2↓

Myocardial infarction

25%

Clinical familial Aortic valve hypercholesterolemia stenosis