Lp(a) (genetics/plasma) and CV Morbidity and Mortality Pia R. - - PowerPoint PPT Presentation

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Lp(a) (genetics/plasma) and CV Morbidity and Mortality Pia R. - - PowerPoint PPT Presentation

May 26, 2023 107 likes •519 views

Lp(a) (genetics/plasma) and CV Morbidity and Mortality Pia R. Kamstrup, MD PhD Herlev Hospital Gentofte Hospital Head of Dept of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark Faculty

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Herlev Hospital Pia R. Kamstrup, MD PhD Head of Dept of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark

Lp(a) (genetics/plasma) and CV Morbidity and Mortality

Gentofte Hospital

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Faculty 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:

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Faculty Disclosure

Declaration of non-financial interests:

  • Affiliation: Copenhagen University Hospital – Herlev and Gentofte
  • Position: Head of Department of Clinical Biochemistry
  • List of scientific or other organisations (including professional political
  • rganisations, self-regulatory bodies etc.), in which you are a member and/or

have a position : Danish Medical Society, Danish Society of Clinical Biochemistry, EAS, PCSK9 forum

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Lipoprotein(a) mg/dL Risk ratio and 95% CI Meta-analysis - 126 634 participants in 36 prospective studies

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Copenhagen General Population Study (CGPS) Copenhagen City Heart Study (CCHS)

N=11,000 N>100,000 26 yrs follow-up 13 yrs follow-up

No losses to follow-up 1976-2016

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N=9330

2008;117:176-84

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N=9330

2008;117:176-84

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N=9330

2008;117:176-84

Lp(a) levels >90th % predict 3-fold ↑ risk of MI 2-fold ↑ risk of IHD

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LPA gene

KIV-2 copy number variant: 2 to >40 repeats

Apolipo- protein(a) LDL-like particle

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Apolipo- protein(a) LDL-like particle

Lp(a) levels by LPA genotypes

Explains 45% of the total variation in plasma lipoprotein(a)

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Confounders evenly distributed

Randomized clinical trial Mendelian randomization study

Patients randomly assigned to placebo or active intervention group Random distribution of gene variants associated with high or low levels of Lp(a) in a genetically homogenous population Placebo

  • vs. Lp(a) lowering therapy

LPA gene variants associated with high Lp(a) levels

  • vs. LPA gene variants associated with low

Lp(a) levels Higher disease risk in placebo group than in the actively treated group with lowered Lp(a) indicates causality Higher disease risk in group with genetically determined high Lp(a) levels than in group with genetically determined low Lp(a) levels indicates causality

Randomization Intervention Outcome

No reverse causality

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Trend: p<0.001

Trend p<0.001

1.0 1.5 2.0 Hazard ratio for MI (95% CI)

Trend p<0.001

Genetic evidence

  • f

causality

50 40 30 20 10 1st 2nd 3rd 4th Lipoprotein(a) (mg/dL) LPA KIV-2 quartile

2009;301:2331-39

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Clarke R et al. NEJM 2009;361:2518-28

Lipoprotein(a), geometric mean, mg/dL

Genetic evidence

  • f causality
  • 2100 candidate genes; LPA strongest

association with chd

  • 2 LPA genetic variants (SNPs)

explained 36% of p-Lp(a) variation and associated with risk of chd

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Consistency with other custom- made chip/GWA Studies

Schunkert et al. 2011

  • confirmed association of LPA locus

with CAD in CAD case-control study

  • f 56 000 individuals

Trégouët et al. 2009

  • used a haplotype approach to

implicate the LPA locus in CVD (~ 9000 CVD cases & ~10 000 controls)

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AORTIC VALVE STENOSIS

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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.

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2014;63:470-7

Multivariable adjusted hazard ratio (95%CI) N = 29 016 Lp(a) >90th % predicts 2-3 fold ↑ risk of AVS

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Observational vs. genetic risk scores for elevated Lp(a)

1 2 3 Relative risk (95%CI) of aortic valve stenosis per 10-fold increase in lipoprotein(a) levels Measured lipoprotein(a), N=29106 Genetically elevated lipoprotein(a) according to LPA KIV-2, N=28490 according to LPA rs10455872, N=28496 according to LPA rs3798220, N=28498 according to LPA genotypes combined, N=28485 1.6(1.2-2.1) 1.4(1.2-1.7)

<

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Zheng et al. 2019

  • In AS pts. Lp(a) and OxPL drive

valve calcification and disease progression (N=145, mean age 70, follow-up up to 5 yrs) Capoulade et al. 2015

  • In AS pts. increased Lp(a) and OxPL

associate with hemodynamic AS progression and valve replacement (N=220, mean age 58, 48% bicuspid, mean follow-up 3.5 yrs)

Lp(a) levels and aortic stenosis progression

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HEART FAILURE

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JACC HF 2016;4:78-87

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JACC HF 2016;4:78-87

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JACC HF 2016;4:78-87

Lp(a) levels >90th % predict 1.6-1.8 fold ↑ risk of HF

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Lipoprotein(a) (top 10%) 63% mediated via MI or AVS Heart failure 1.6 to 1.8-fold ↑ risk

LIKELY CAUSAL

Lp(a) and heart failure

Lp(a) and HF: population attributable risk = 9%

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ISCHEMIC STROKE

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PERIPHERAL ARTERIAL DISEASE

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2012;32:1732-41

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ATVB 1992;12:895-901 Clin Chem 2007;53:1298-1305 Cardiovasc Res 2014;103:28-36

  • Measured p-Lp(a), apo(a) phenotypes,

and 1 LPA SNP rs10455872 (~ 585 PAD cases & ~6500 controls) → all associated with increased risk of PAD in support of a causal association

  • Measured p-Lp(a) and apo(a)

phenotypes in 100 cases with intermittent claudication and in 100 controls

  • Measured p-Lp(a) and apo(a)

phenotypes in 213 cases with symptomatic PAD and in 213 controls

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MORTALITY

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Combined CGPS and CCHS: 69764 participants with p-Lp(a) 98809 participants with LPA KIV-2 119094 participants with LPA rs10455872

Hazard ratio

Cardiovascular mortality 2636 deaths All-cause mortality 10180 deaths

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0.8 1.0 1.2 1.4 1.6 1.4 1.6 0.8 1.0 1.2

All-cause Cardiovascular

Mortality

Hazard ratio (95% Confidence interval)

Rs10455872 (N=119094)

Non-carrier Carrier

KIV-2 No.of (N=98809)

Percentile repeats 51-100 >35 21-50 29-35 11-20 25-28 6-10 22-24 <6 <22

Lipoprotein(a) (N= 69764)

Percentile mg/dL 1-50 <10 51-80 10-42 81-90 43-68 91-95 69-93 >95 >93

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Hazard ratio Cardiovascular mortality Hazard ratio All-cause mortality N/events P interaction N/events P interaction

Risk estimates independent of other risk factors

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Emdin et al. JACC 2016;68:2761-72

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Summary

↑ Lipoprotein(a)

AS Heart Failure Mortality MI Ischemic stroke PAD

Top 10%

2-3 fold ↑ risk 2-3 fold ↑ risk 1.6-1.8 fold ↑ risk 1.2-1.6 fold ↑ risk 1.2-1.4 fold ↑ risk

AS MI Heart failure PAD Ischemic stroke Mortality

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Summary

↑ Lipoprotein(a)

√ √

LPA risk genotypes Interpretation 2019: Independent and likely causal risk factor

AS

√

Mortality

√

MI PAD

√ √

AS MI Heart failure PAD Ischemic stroke Mortality

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Lp(a) lowering therapy

Therapy Reduction in Lp(a) Mechanism/problem Statins 0 % (+)

Likely slight increase

Niacin 20%

No CVD reduction. Adverse events.

CETP inhibitor 24-45%

Decreased hepatic apoa production.

ApoB antisense 26-27%

Decrease hepatic apoB synthesis. Hepatotoxicity.

PCSK9 inhibitor 10-30%

Decreased apoa/Lp(a) formation? Uptake by LDLRs? Approved for FH.

Apheresis

Removal of apoB lipoproteins.

Up to 70% Apo(a) antisense Up to 90%

Decrease hepatic apo(a) synthesis.

Treatment options in high Lp(a)

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Acknowledgments

Authors Børge G. Nordestgaard Anne Langsted Christian Medom 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