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

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 Disclosure Declaration of financial interests For the last 3 years and the subsequent 12 months: 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

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 organisations, 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

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

No losses to 26 yrs follow-up follow-up N=11,000 1976-2016 Copenhagen City Heart Study (CCHS) N>100,000 13 yrs follow-up Copenhagen General Population Study (CGPS)

2008;117:176-84 N=9330

2008;117:176-84 N=9330

2008;117:176-84 N=9330 Lp(a) levels >90th % predict 3- fold ↑ risk of MI 2- fold ↑ risk of IHD

LDL-like particle Apolipo- protein(a) LPA gene KIV-2 copy number variant: 2 to >40 repeats

Lp(a) levels by LPA LDL-like particle genotypes Apolipo- protein(a) Explains 45% of the total variation in plasma lipoprotein(a)

Randomized Mendelian clinical randomization trial study Patients randomly assigned to Random distribution of gene variants Randomization placebo or active intervention associated with high or low levels of Lp(a) group in a genetically homogenous population Confounders evenly distributed Placebo LPA gene variants associated with high Intervention Lp(a) levels vs. Lp(a) lowering therapy vs. LPA gene variants associated with low Lp(a) levels Higher disease risk in placebo Higher disease risk in group with Outcome group than in the actively treated genetically determined high Lp(a) levels No reverse group with lowered Lp(a) than in group with genetically determined causality indicates causality low Lp(a) levels indicates causality

2009;301:2331-39 Hazard ratio for MI (95% CI) Lipoprotein(a) (mg/dL) 1.0 1.5 2.0 50 40 30 20 10 LPA KIV-2 quartile 1st Genetic evidence 2nd of 3rd causality 4th Trend p<0.001 Trend: p<0.001 Trend p<0.001

Clarke R et al. NEJM 2009;361:2518-28 • 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 Genetic evidence of causality Lipoprotein(a), geometric mean, mg/dL

Consistency with other custom- made chip/GWA Studies Schunkert et al. 2011 Trégouët et al. 2009 • confirmed association of LPA locus with CAD in CAD case-control study • used a haplotype approach to of 56 000 individuals implicate the LPA locus in CVD (~ 9000 CVD cases & ~10 000 controls)

AORTIC VALVE STENOSIS

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

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

Lp(a) levels and aortic stenosis progression 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) 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)

HEART FAILURE

JACC HF 2016;4:78-87

JACC HF 2016;4:78-87

JACC HF 2016;4:78-87 Lp(a) levels >90th % predict 1.6- 1.8 fold ↑ risk of HF

Lp(a) and heart failure 1.6 to 1.8-fold ↑ risk Heart Lipoprotein(a) failure (top 10%) LIKELY CAUSAL 63% mediated via MI or AVS Lp(a) and HF: population attributable risk = 9%

ISCHEMIC STROKE

PERIPHERAL ARTERIAL DISEASE

2012;32:1732-41

• Measured p-Lp(a) and apo(a) phenotypes in 100 cases with intermittent claudication and in 100 controls ATVB 1992;12:895-901 • Measured p-Lp(a) and apo(a) phenotypes in 213 cases with symptomatic PAD and in 213 controls Clin Chem 2007;53:1298-1305 • 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 Cardiovasc Res 2014;103:28-36

MORTALITY

Cardiovascular mortality All-cause mortality 2636 deaths 10180 deaths Hazard ratio Combined CGPS and CCHS: 69764 participants with p-Lp(a) 98809 participants with LPA KIV-2 119094 participants with LPA rs10455872

Mortality Cardiovascular All-cause Lipoprotein(a) (N= 69764) Percentile mg/dL 1-50 <10 51-80 10-42 81-90 43-68 91-95 69-93 >95 >93 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 Rs10455872 (N=119094) Non-carrier Carrier 0.8 1.0 1.2 1.4 1.6 0.8 1.0 1.2 1.4 1.6 Hazard ratio (95% Confidence interval)

Risk estimates independent of other risk factors N/events P interaction N/events P interaction Hazard ratio Hazard ratio Cardiovascular mortality All-cause mortality

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

Summary PAD MI 2- 3 fold ↑ risk PAD MI Top 10% AS AS Ischemic stroke ↑ Lipoprotein(a) Ischemic 2- 3 fold ↑ risk 1.2- 1.6 fold ↑ risk stroke Heart Mortality Failure Heart failure Mortality 1.6- 1.8 fold ↑ risk 1.2- 1.4 fold ↑ risk

Summary √ PAD MI PAD √ MI √ √ AS AS Ischemic stroke ↑ Lipoprotein(a) LPA risk genotypes √ √ Mortality Heart failure Mortality Interpretation 2019: Independent and likely causal risk factor

Treatment options in high Lp(a) Lp(a) lowering therapy Therapy Reduction in Lp(a) Mechanism/problem Likely slight increase 0 % (+) Statins No CVD reduction. 20% Niacin Adverse events. CETP inhibitor 24-45% Decreased hepatic apoa production. Decrease hepatic apoB synthesis. 26-27% ApoB antisense Hepatotoxicity. Decreased apoa/Lp(a) formation? 10-30% PCSK9 inhibitor Uptake by LDLRs? Approved for FH. Up to 70% Apheresis Removal of apoB lipoproteins. Apo(a) antisense Up to 90% Decrease hepatic apo(a) synthesis.

Acknowledgments Participants and staff in Authors The Copenhagen City Heart Børge G. Nordestgaard Study Anne Langsted The Copenhagen General Population Study Christian Medom Madsen Funded by (non-profit) Technicians The Danish Heart Foundation Depts Clin Biochem, IMK Almene Fund Herlev Hospital and The Danish Council for Independent Research Rigshospitalet