Post on 09-Nov-2020
Herlev Hospital Pia R. Kamstrup, MD PhD
Head of Dept of Clinical Biochemistry,
Herlev and Gentofte Hospital,
Copenhagen University Hospital,
Denmark
Lp(a) as a target in cardiovascular
prevention:
Why worry and how to assess?
Gentofte Hospital
Lp(a), a new lipid frontier in CV risk management & target for therapy
Disclosure
I I have received a research grant(s)/ in kind support
A From current sponsor(s) NO
B From any institution NO
II I have been a speaker or participant in accredited CME/CPD
A From current sponsor(s) YES
B From any institution YES
III I have been a consultant/strategic advisor etc
A For current sponsor(s) NO
B For any institution NO
IV I am a holder of (a) patent/shares/stock ownerships
A Related to presentation NO
B Not related to presentation NO
Declaration of financial interests
For the last 3 years and the subsequent 12 months:
Lipoprotein(a) mg/dL
Ris
k r
atio a
nd 9
5%
CI
Meta-analysis - 126 634 participants in 36 prospective studies
Non-fatal MI and coronary death:
8362 cases
Ischaemic stroke:
1684 cases
Copenhagen General Population Study (CGPS)
Copenhagen City
Heart Study (CCHS)
N=11,000
N>100,000
26 yrs follow-up
14 yrs follow-up
No losses to
follow-up
1976-2018
N = 9 330
Lipoprotein(a) Participants Events Age and sex adjusted Multivariable adjusted
Age, years
Cu
mu
lati
ve i
ncid
en
ce,
%
Myocardial Infarction
Hazard ratio (95% CI)Hazard ratio (95% CI)
Lp(a) and recurrent MACE in the CGPS, N=2527
Madsen CM, Kamstrup PR, Langsted A, Varbo A, Nordestgaard BG, ATVB 2020
LPA geneKIV-2 copy number variant:
2 to >40 repeats
Apolipo-
protein(a)
LDL-like
particle
Apolipo-
protein(a)
LDL-like
particleLp(a) levels by LPA
genotypes
Apolipo-
protein(a)
LDL-like
particleLp(a) levels by LPA
genotypes
Explains 45% of the total
variation in plasma lipoprotein(a)
Lipoprotein(a) KIV-2 quartile
(mg/dL)
Multifactorially adjusted hazard ratio
(95% confidence interval)
Trend: p<0.001 Trend: p<0.001
1st
2nd
3rd
4th
50 40 30 20 10 1.0 1.5 2.0
Figure. Levels of lipoprotein(a) and risk of myocardial infarction by KIV-2 genotype.
Trend p<0.001
1.0 1.5 2.0
Hazard ratio for MI (95% CI)
Trend p<0.001
Genetic
evidence
of
causality
50 40 30 20 10
1st
2nd
3rd
4th
Lipoprotein(a) (mg/dL)
LPA KIV-2
quartile
2009;301:2331-39
Lp(a) SNP
rs10455872
Metaanalysis of GWAS data on 7k
individuals with aortic valve CT
scans implicates the LPA gene in
aortic valve calcification.
Appears mediated via elevated lp(a)
levels.
2014;63:470-7
Multivariable adjusted
hazard ratio (95%CI)
N = 29 016
Lp(a) >90th % predicts
2-3 fold ↑ risk of AVS
Relative risk/hazard ratio (95%CI) of AVS per 10-fold higher lipoprotein(a)
Observational
Genetic (individual participant data,
N=28845)
1.0 2.0 3.0
1.4 (1.2-1.7)
1.6 (1.2-2.1)
1.0 2.0 3.0 4.0 5.0
Haz
ard
rat
ioCardiovascular mortality
2636 deaths All-cause mortality
10180 deaths
>90th: 1.32(1.12-1.56)
>95th: 1.50(1.28-1.76) >95th: 1.20(1.10-1.30)
>90th: 1.07(0.98-1.17)
Frac
tio
n o
f p
op
ula
tio
n
Relative risk/hazard ratio (95%CI) of cardiovascular/all-cause mortality per 50 mg/dL higher lipoprotein(a)
Plasma lipoprotein(a) Plasma lipoprotein(a)
Observational
Genetic LPA KIV2
LPA rs10455872
1.16(1.09-1.23)
1.23(1.08-1.41)0.98(0.88-1.09)
1.05(1.01-1.09)
1.10(1.04-1.18)0.97(0.92-1.02)
HR for cardiovascular mortality HR for all-cause mortality
N/events P interactionN/events P interaction
Lp(a) risk estimates independent of other risk factors
Why worry?
AS
Heart
Failure
MI
PAD
Ischemic
stroke
Mortality
Why worry?
AS
Heart
Failure
MI
PAD
Ischemic
stroke
Mortality
Lp(a) > 90th %
2-3 fold ↑ risk
Lp(a)
Why worry?
AS
Heart
Failure
MI
PAD
Ischemic
stroke
Mortality
Lp(a) > 90th %
2-3 fold ↑ risk
Lp(a)
LPA risk genotypes
√
√
√
√
√
√
Interpretation 2020:
Strong, independent and likely causal risk factor for CVD
Perc
en
tag
e o
f p
op
ula
tio
n, %
Plasma lipoprotein(a) concentration
0 51 107 160 214 269 323 378 432
mg/dL
nmol/L
N = 79 718
80th
percentile
90th
percentile 95th
percentile 99th
percentile
50th
percentile
0
5
10
15
20
How to assess?
Perc
en
tag
e o
f p
op
ula
tio
n, %
Plasma lipoprotein(a) concentration
0 51 107 160 214 269 323 378 432
mg/dL
nmol/L
N = 79 718
80th
percentile
90th
percentile 95th
percentile 99th
percentile
50th
percentile
0
5
10
15
20Lp(a) measurement challenges
Biology
• Wide concentration range
• Apo(a) isoform size variation
• ApoB & plasminogen-like components
Lack of assay standardization hinders
common thresholds for increased CVD
risk
P-L
p(a
) %
bia
s
Apolipoprotein(a) isoform size
<calibrator =calibrator >calibrator
≥80th % ≤20th %
Lp(a), In-house assay, N=9670
Lp(a), DiaSys assay, N=11348
Lp(a), Denka Seiken – frozen, N=12541
Lp(a), Denka Seiken – fresh, N=20619
Lp(a) measurements – Danish general population studies
48 122 mg/dL 4
50 107 mg/dL 9
41 97 mg/dL 5
33 76 mg/dL 4
>95th %
Kamstrup & Nordestgaard, unpublished data
How to assess?
• Well-validated assays
(i.e. with acceptable precision (CV<4%) and linearity
also above dilution limits)
• Documented insensitivity to apo(a) isoform size
• Traceability to an internationally recognized calibrator
(e.g. WHO SRM 2B primary reference material) to
ensure common cutpoints for increased risk
• Fresh samples are preferred
• Report using same unit as calibrator
(preferably as number of particles i.e. nmol/L)
Plasma Lp(a)
LPA genotyping not necessary for risk assessment
Acknowledgments
Authors
Børge G. Nordestgaard
Anne Langsted
Christian Medum Madsen
Technicians
Depts Clin Biochem,
Herlev Hospital and
Rigshospitalet
Participants and staff in
The Copenhagen City Heart Study
The Copenhagen General Population Study
Funded by (non-profit)
The Danish Heart Foundation
IMK Almene Fund
The Danish Council for Independent Research