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