Prevalence and relevance of Lp(a) in familial ... · Atherosclerosis Myocardial infarction Angina...
Transcript of Prevalence and relevance of Lp(a) in familial ... · Atherosclerosis Myocardial infarction Angina...
Prevalence and relevance of Lp(a)
in familial hypercholesterolemia
Børge G Nordestgaard
Professor, Chief Physician, MD, DMSc
University of Copenhagen & Copenhagen University Hospital
Conflict of Interest Disclosure: the Danish tax payerConsultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa,
Denka Seiken, Novartis, Novo Nordisk
Early studies
FH-Lp(a) association
• Guo HC et al. Atherosclerosis 1991; 86:
69-83
• Leitersdorf E et al. L Lipid Res 1991;
32: 1513-1519
• Mbewe AD et al. Arterioscler Thromb
1991; 11: 940-946
• Soutar AK et al. J Clin Invest 1991; 88:
483-492
• Bowden JF et al. Arterioscler Thromb
1994; 14: 1561-1568
Other early studies on
elevated Lp(a) in FH
Role of ascertainment bias
FH
Lipid
clinicLp(a) + FH
High
LDL-C
+
prema-
ture MI
FH pathophysiology &
genetics
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. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)
LDLR >95%
APOB 2-5%
PCSK9 <1%
0
50
100
150
200
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Cu
mu
lati
ve L
DL-
C (
mm
ol)
Years Age
HOZ Untreated Treat at 10yrs Non FH Treat at 18yrs
35yrs
53yrs
48yrs
55yr
12.5yrs
Start high dose statin
Start lowdose statin
Threshold
for CHD
Female sex
Smoking
Hypertension
Diabetes
Triglycerides
HDL-C
Lipoprotein(a)
Without FH
Homozygous FH Heterozygous FH
Age in years
Coronary disease & death before age 20
Untreated coronary disease before age 55/60
Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)
FH diagnosis
DUTCH FH CRITERIA
Death 76 yrs
No CHD
LDL 3.8 mmol/L
Age 78 yrs
CHD 58 yrs
LDL 7.4 mmol/L
Age 48 yrs
CHD 48 yrs
LDL 8.3 mmol/L
Age 47 yrs
No CHD
LDL 2.4 mmol/L
Age 50 yrs
No CHD
LDL 3.3 mmol/L
Index case:
start of
cascade
screening
Age 18 yrs
LDL 2.2 mmol/L
Age 8 yrs
LDL 5.6 mmol/L
Age 15 yrs
LDL 6.1 mmol/L
FH FH
FH
FH
Man Woman
Family pedigree
Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)
Study Definition Country HeFH HoFH
Benn JCEM 2012 Clinical Denmark 1:223 1:200,000
Sjouke EHJ 2015 Genetic Netherlands 1:244 1:300,000
Pajak AMC 2016 Clinical Poland 1:250 1:250,000
Benn EHJ 2016 Genetic Denmark 1:217 1:190,000
deFerranti Circ 2016 Clinical USA 1:250 1:250,000
Safarova JCL 2016 Clinical USA 1:310 1:385,000
Wald NEJM 2016 Gen+Clin UK 1:250 1:250,000
Frequency of FH in general population
Nordestgaard 2016
Clin
ical dia
gnosis
Muta
tion d
iagnosis
Mutation without
clinical diagnosis
Clinical diagnosis
without mutation
Patient: treat LDL
Family: monitor LDL & consider treatment
Patient: treat LDL
Family: mutation test, monitor LDL,
& consider treatment
Patient: monitor LDL & consider treatment
Family: monitor LDL & consider treatment
Adapted from Luis Masana
Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)
High Lp(a)?
Does FH cause high
Lp(a)?
LDL cholesterol, mmol/L0 3 6 9 12 15 18
Adapted from Brown & Goldstein Scientific American 1984; 251: 52-60
0
50
100Relative number of LDL receptors
FH heterozygote
FH homozygote
”Normal” adults
Adult animals & newborn humans
Nobel Prize 1985
131I-LDL
125I-Lp(a)
Homozygous FH
Heterozygous FH
2 Controls
Role of LDL receptor in Lp(a) removal is unclear
JBC 2015; 290: 11649-62
Cells
Cohorts
Turnover
Does high Lp(a)
cause FH?
N= 42,934 3082 184
Copenhagen General Population Study
Dutch Lipid Clinic Network
Unlikely Possible Probable/definite
Lip
opro
tein
(a),
mg
/dL
Unadjusted: P<0·0001
Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.
Adjusted LDL-C: P=0.46
N= 42,934 43,699 3082 2360 184 141
Dutch Lipid Clinic Network
Unlikely Possible Probable/definite
Lip
opro
tein
(a),
mg
/dL
Unadjusted LDL-C: P<0·0001
Adjusted LDL-C=
LDL-C minus (Lp(a)*0.30)
Copenhagen General Population Study
Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.
High lipoprotein(a) as a cause of
clinical familial hypercholesterolemia
(FH)
Copenhagen
General
Population
Study
N=46,200
FH
1:220
Ranked genetic
causes of
clinical FH
1. LDLR
2. Lp(a) (25%)
3. APOB
4. PCSK9
Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.
Does high Lp(a)
misclassify FH?
Adjusted LDL-C: P=0.46
N= 42,934 43,699 3082 2360 184 141
Dutch Lipid Clinic Network
Unlikely Possible Probable/definite
Lip
opro
tein
(a),
mg
/dL
Unadjusted LDL-C: P<0·0001
Adjusted LDL-C=
LDL-C minus (Lp(a)*0.30)
Copenhagen General Population Study
Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.
High Lp(a) in FH
causes CHD!
Lp(a)
mg/dL
< 50
< 50
≥ 50
≥ 50
Women
Men
0
0.2
0.4
0.6
0.8
20 40 60 80 100Age, years
Log-rank trend <0·0001
Clinical Lipo-
FH protein(a)
Yes >50mg/dL
Yes ≤50mg/dL
No >50mg/dLNo ≤50mg/dL
Cum
ula
tive
inci
den
ce o
f m
yoca
rdia
l in
farc
tion Copenhagen General Population Study
Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.
1 2 3 4 5 6 7 8
Number/events
35,153/502
6921/137
2300/89
715/42
28,144/478
6917/133
1985/84
575/43
Hazard ratio for myocardial infarction (95%CI)
Clinical
FH
KIV-2
Lipo-
protein(a)NoNoYes
Yes
≤50mg/dL
≤50mg/dL>50mg/dL
>50mg/dL
Clinical
FH
NoNoYes
Yes
>20%
>20%
≤20%
≤20%
Copenhagen General Population Study
Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.
Consensus – Guidelines
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
Screen for Lp(a) in FH
• EAS EU 2010 Yes
• ESC/EAS EU 2016 Yes
• CCS Can 2016 Unclear
• AACE/ACE US 2017 Unclear
• NICE UK 2017 Unclear
• AHA/ACC US 2018 Unclear
• NLA US 2019 Yes
0
5
20
15
10
LDL Cholesterol
mmol/L mg/dL
0
190
770
580
390
Homozygous FH
Heterozygous FH
Common
hypercholesterolemia
Clinical
diagnosis Mutation diagnosis
Homozygous
LDL-receptor
negative
Homozygous
LDL-receptor
defective or
homozygous
LDLRAP1/ARH
Homozygous
APOB defect/
PCSK9 gain of
function
Compound
heterozygous
LDL-receptor/
APOB/ PCSK913 500
Cuchel et al. EAS consensus. Eur Heart J 2014; 35: 2146-2157 (open access)
Danish clinical quality
database on FH
Funded 100% by the Danish Government:
Nationwide Danish clinical quality databases
All hospitals must report patients to registries:
• Breast cancer
• Acute surgery
• Schizophrenia
• Heart failure
• ..and 80 other nationwide disease registries
Starting 2019/20 also a nationwide Danish
clinical quality database on:
• Familial hypercholesterolemia
Nationwide Danish clinical quality database on
Familial Hypercholesterolemia: 14 standards
Monitor and benchmark hospital regions
1. FH diagnoses
2. Family cascade screening
3. Non-pharmacological treatment
4. Pharmacological treatment
5. LDL cholesterol target attainment
6. Prognosis
1.5 Fraction of FH patients with Lp(a)
measurement. Standard >80%
Conclusion
1980 2000 2020
Evolution of FH understanding
Clinical FH
Nordestgaard 2019
LDL-R
APOB
LDLRAP1
PCSK9
LPA
Multiallele
Recessive
Codominant