Circulating culprit or therapeutic bullseye: lipoprotein(a) in cardiovascular risk assessment and novel therapeutic prospects

Abstract

Lipoprotein(a) [Lp(a)] has emerged as a significant player in the realm of cardiovascular disease (CVD), exerting a pivotal role in atherosclerotic cardiovascular disease (ASCVD), aortic valve stenosis (AVS), and overall cardiovascular (CV) and all-cause mortality. Since its discovery in 1963 by Kåre Berg, our understanding of Lp(a) has undergone significant evolution. This comprehensive review delves into the genetics, structure, assembly, and inter-population differences of Lp(a), shedding light on its intricate involvement in CVD. Genetically, Lp(a) is primarily influenced by variations in the LPA gene. The LPA gene encodes apo(a) and the variation in the kringle domains is the main determinant of plasma Lp(a) levels. Other genetic variants, such as SNPs in the LPA gene region, the pentanucleotide repeat polymorphism, and specific SNPs in the coding sequences of kringle domains, have also been associated with varying Lp(a) concentrations. Additionally, genes outside the LPA locus, including APOE, APOH, and CEPT gene regions, contribute to Lp(a) variability across different populations. Inter-population differences in Lp(a) levels are evident, with ethnicity and sex playing significant roles. Racial disparities in median Lp(a) concentration have been observed, with black individuals often displaying higher levels compared to their white counterparts. The review underscores Lp(a) as an independent, heritable CV risk factor in both primary and secondary settings. High Lp(a) levels are closely linked to the recurrence of myocardial infarction, AVS, and CV events. The necessity of measuring Lp(a) concentration at least once in life to assess an individual's absolute global CV risk is emphasized. Despite substantial progress, many questions remain unanswered about Lp(a), including its physiological role in the cardiovascular system and its involvement in inflammatory and thrombotic processes. Ongoing research holds promise for the development of therapeutic interventions, such as pharmacological agents and apheresis, to mitigate the cardiovascular risks associated with elevated Lp(a) levels. This review highlights the multifaceted nature of Lp(a) in the context of cardiovascular health, emphasizing the importance of continued research efforts to unravel its complexities and develop innovative strategies for managing its associated risks.

Keywords

Lp(a) / CV risk / myocardial infarction / aortic stenosis / emerging therapies

References

[1] Berg K.A new serum type system in man-the L_p system.Acta Pathol Microbiol Scand1963;59:369-82

[2] Kronenberg F,Stroes ESG.Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European atherosclerosis society consensus statement.Eur Heart J2022;43:3925-46 PMCID:PMC9639807

[3] Lau F, Giugliano RP. Lipoprotein(a) and its significance in cardiovascular disease: a review.JAMA Cardiol2022;7:760-9

[4] Schmidt K,Kronenberg F.Structure, function, and genetics of lipoprotein(a).J Lipid Res2016;57:1339-59 PMCID:PMC4959873

[5] Kraft HG,Hoppichler F,Utermann G.Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis.J Clin Invest1989;83:137-42 PMCID:PMC303653

[6] Tsimikas S.A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies.J Am Coll Cardiol2017;69:692-711

[7] Kratzin H,Niehaus M,Seidel D.Structural relationship of an apolipoprotein(a) phenotype (570 kDa) to plasminogen: homologous kringle domains are linked by carbohydrate-rich regions.Biol Chem Hoppe Seyler1987;368:1533-44

[8] Kalaivani V.Apolipoprotein(a), an enigmatic anti-angiogenic glycoprotein in human plasma: a curse or cure?.Pharmacol Res2020;158:104858

[9] Kalaivani V,Kumar AA,Jaleel A.O-glycan structures in apo(a) subunit of human lipoprotein(a) suppresses the pro-angiogenic activity of galectin-1 on human umbilical vein endothelial cells.FASEB J2023;37:e22813

[10] White AL,Lanford RE.Influence of allelic variation on apolipoprotein(a) folding in the endoplasmic reticulum.J Biol Chem1997;272:5048-55

[11] Rader DJ,Ikewaki K.The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate.J Clin Invest1994;93:2758-63 PMCID:PMC294537

[12] Reyes-Soffer G,Berglund L.Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the american heart association.Arterioscler Thromb Vasc Biol2022;42:e48-60 PMCID:PMC9989949

[13] Enkhmaa B,Kris-Etherton PM.Diet and Lp(a): does dietary change modify residual cardiovascular risk conferred by Lp(a)?.Nutrients2020;12:2024 PMCID:PMC7400957

[14] Hopewell JC,Baigent C.The role of lipoprotein(a) in chronic kidney disease.J Lipid Res2018;59:577-85 PMCID:PMC5880503

[15] Schmidt H,Kolm R.Lipoprotein(a) in cirrhosis.BMJ1992;304:1180 PMCID:PMC1882140

[16] Mack S,Rueedi R.A genome-wide association meta-analysis on lipoprotein(a) concentrations adjusted for apolipoprotein(a) isoforms.J Lipid Res2017;58:1834-44 PMCID:PMC5580897

[17] Ferreira H,Vieira E.Pentanucleotide repeat (TTTTA)n polymorphism in the 5′ control region of the apoliprotein (A) gene and atherothrombotic serum lipoprotein (A) concentration, in a pediatric population.Haematologica2003;88:ELT07

[18] Ichinose A.Detection of polymorphisms in the 5′-flanking region of the gene for apolipoprotein(a).Biochem Biophys Res Commun1995;209:372-8

[19] Ichinose A.Characterization of the apolipoprotein(a) gene.Biochem Biophys Res Commun1995;209:365-71

[20] Suzuki K,Saito T.Plasma lipoprotein(a) levels and expression of the apolipoprotein(a) gene are dependent on the nucleotide polymorphisms in its 5′-flanking region.J Clin Invest1997;99:1361-6 PMCID:PMC507952

[21] Puckey LH,Knight BL.Polymorphisms in the apolipoprotein(a) gene and their relationship to allele size and plasma lipoprotein(a) concentration.Hum Mol Genet1997;6:1099-107

[22] Ogorelkova M,Ehnholm C.Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6 to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians.Hum Mol Genet2001;10:815-24

[23] Prins J,Bouma BN.The identification of polymorphisms in the coding region of the apolipoprotein (a) gene-association with earlier identified polymorphic sites and influence on the lipoprotein (a) concentration.Thromb Haemost1999;82:1709-17

[24] Clarke R,Hopewell JC.Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N Engl J Med2009;361:2518-28

[25] Said MA,van de Vegte YJ.Genome-wide association study and identification of a protective missense variant on lipoprotein(a) concentration: protective missense variant on lipoprotein(a) concentration-brief report.Arterioscler Thromb Vasc Biol2021;41:1792-800

[26] Hoekstra M,Rong J.Genome-wide association study highlights APOH as a novel locus for lipoprotein(a) levels-brief report.Arterioscler Thromb Vasc Biol2021;41:458-64 PMCID:PMC7769958

[27] Virani SS,Davis BC.Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the atherosclerosis risk in communities (ARIC) study.Circulation2012;125:241-9 PMCID:PMC3760720

[28] Patel AP,Pirruccello JP.Lp(a) (lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank.Arterioscler Thromb Vasc Biol2021;41:465-74 PMCID:PMC7769893

[29] Derby CA,Pasternak RC,Sternfeld B.Lipid changes during the menopause transition in relation to age and weight: the study of women’s health across the nation.Am J Epidemiol2009;169:1352-61 PMCID:PMC2727246

[30] Cesaro A,Moscarella E.Lipoprotein(a): a genetic marker for cardiovascular disease and target for emerging therapies.J Cardiovasc Med2021;22:151-61

[31] Banerjee D,Shin J,Palaniappan L.Racial and ethnic variation in lipoprotein(a) levels among Asian Indian and Chinese patients.J Lipids2011;2011:291954 PMCID:PMC3108091

[32] Kronenberg F,Stroes ESG.Frequent questions and responses on the 2022 lipoprotein(a) consensus statement of the European atherosclerosis society.Atherosclerosis2023;374:107-20

[33] Madsen CM,Langsted A,Nordestgaard BG.Lipoprotein(a)-lowering by 50 mg/dL (105 nmol/L) may be needed to reduce cardiovascular disease 20% in secondary prevention: a population-based study.Arterioscler Thromb Vasc Biol2020;40:255-66

[34] Kamstrup PR,Nordestgaard BG.Extreme lipoprotein(a) levels and improved cardiovascular risk prediction.J Am Coll Cardiol2013;61:1146-56

[35] Rikhi R,Ashburn N.Relationship of low-density lipoprotein-cholesterol and lipoprotein(a) to cardiovascular risk: the multi-ethnic study of atherosclerosis (MESA).Atherosclerosis2022;363:102-8 PMCID:PMC9964094

[36] Yao Y,Wang B.Baseline low-density-lipoprotein cholesterol modifies the risk of all-cause death associated with elevated lipoprotein(a) in coronary artery disease patients.Front Cardiovasc Med2021;8:817442 PMCID:PMC8792964

[37] Di Fusco SA, Maggioni AP, Scicchitano P, Zuin M, D’Elia E, Colivicchi F. Lipoprotein(a), inflammation, and atherosclerosis.J Clin Med2023;12:2529 PMCID:PMC10095203

[38] Verbeek R,Langsted A.Cardiovascular disease risk associated with elevated lipoprotein(a) attenuates at low low-density lipoprotein cholesterol levels in a primary prevention setting.Eur Heart J2018;39:2589-96 PMCID:PMC6287703

[39] Afshar M,Dufresne L,Thanassoulis G.Lipoprotein(a) interactions with low-density lipoprotein cholesterol and other cardiovascular risk factors in premature acute coronary syndrome (ACS).J Am Heart Assoc2016;5:e003012 PMCID:PMC4859285

[40] Tromp TR,Nurmohamed NS.Use of lipoprotein(a) to improve diagnosis and management in clinical familial hypercholesterolemia.Atherosclerosis2023;365:27-33

[41] Kronenberg F,Stroes ESG.Consensus and guidelines on lipoprotein(a) - seeing the forest through the trees.Curr Opin Lipidol2022;33:342-52 PMCID:PMC9643632

[42] Kronenberg F.Human genetics and the causal role of lipoprotein(a) for various diseases.Cardiovasc Drugs Ther2016;30:87-100 PMCID:PMC4789197

[43] Sandholzer C,Kark JD.Apo(a) isoforms predict risk for coronary heart disease. A study in six populations.Arterioscler Thromb1992;12:1214-26

[44] Coassin S.Lipoprotein(a) beyond the kringle IV repeat polymorphism: the complexity of genetic variation in the LPA gene.Atherosclerosis2022;349:17-35 PMCID:PMC7613587

[45] Lampsas S,Oikonomou E.Lipoprotein(a) in Atherosclerotic diseases: from pathophysiology to diagnosis and treatment.Molecules2023;28:969 PMCID:PMC9918959

[46] Schnitzler JG,Ali L.Atherogenic lipoprotein(a) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation.Circ Res2020;126:1346-59

[47] Bartrons R,Simon-Molas H,Manzano A.The potential utility of PFKFB3 as a therapeutic target.Expert Opin Ther Targets2018;22:659-74

[48] Tsimikas S,Beyer RW.Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes.J Am Coll Cardiol2003;41:360-70

[49] Bergmark C,Orsoni A.A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma.J Lipid Res2008;49:2230-9

[50] Tsimikas S,Tselepis AD.New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease.Arterioscler Thromb Vasc Biol2007;27:2094-9

[51] Tsimikas S.The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity.Curr Opin Lipidol2008;19:369-77

[52] Després AA,Poulin A.Lipoprotein(a), oxidized phospholipids, and aortic valve microcalcification assessed by 18F-sodium fluoride positron emission tomography and computed tomography.CJC Open2019;1:131-40 PMCID:PMC7063623

[53] Kaiser Y,Zheng KH.Lipoprotein(a) is robustly associated with aortic valve calcium.Heart2021;107:1422-8 PMCID:PMC8372399

[54] Kaiser Y,Kroon J.Lipoprotein(a) has no major impact on calcification activity in patients with mild to moderate aortic valve stenosis.Heart2022;108:61-6

[55] Kaiser Y,Singh SS.Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification.Eur Heart J2022;43:3960-7 PMCID:PMC9840475

[56] Zheng KH,Pawade T.Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis.J Am Coll Cardiol2019;73:2150-62 PMCID:PMC6494952

[57] Bouchareb R,Nsaibia MJ.Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve.Circulation2015;132:677-90

[58] Federico L,Smyth SS.Therapeutic potential of autotaxin/lysophospholipase d inhibitors.Curr Drug Targets2008;9:698-708 PMCID:PMC3724932

[59] Nordestgaard BG.Lipoprotein(a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology.J Lipid Res2016;57:1953-75 PMCID:PMC5087876

[60] Boffa MB.Beyond fibrinolysis: the confounding role of Lp(a) in thrombosis.Atherosclerosis2022;349:72-81

[61] Boffa MB,Yeang C.Potent reduction of plasma lipoprotein(a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis.J Lipid Res2019;60:2082-9 PMCID:PMC6889713

[62] Sultan SM,Dowling MM,Kirton A.Review of lipid and lipoprotein(a) abnormalities in childhood arterial ischemic stroke.Int J Stroke2014;9:79-87 PMCID:PMC3869879

[63] Tsimikas S.Elevated lipoprotein(a) and the risk of stroke in children, young adults, and the elderly.Eur Heart J2021;42:2197-200

[64] Dzobo KE,Stroes ESG,Kroon J.Lipoprotein(a): an underestimated inflammatory mastermind.Atherosclerosis2022;349:101-9

[65] Puri R,Arsenault BJ.Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial.JAMA Cardiol2020;5:1136-43 PMCID:PMC7344788

[66] Tsimikas S,Nora C,Witztum JL.Statin therapy increases lipoprotein(a) levels.Eur Heart J2020;41:2275-84

[67] de Boer LM,Wiegman A.Statin therapy and lipoprotein(a) levels: a systematic review and meta-analysis.Eur J Prev Cardiol2022;29:779-92

[68] Yahya R,Verhoeven A.Statin treatment increases lipoprotein(a) levels in subjects with low molecular weight apolipoprotein(a) phenotype.Atherosclerosis2019;289:201-5

[69] Sahebkar A,Pirro M.Impact of ezetimibe on plasma lipoprotein(a) concentrations as monotherapy or in combination with statins: a systematic review and meta-analysis of randomized controlled trials.Sci Rep2018;8:17887 PMCID:PMC6294784

[70] Boden WE,Anderson T.Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.N Engl J Med2011;365:2255-67

[71] Landray MJ,Hopewell JC.Effects of extended-release niacin with laropiprant in high-risk patients.N Engl J Med2014;371:203-12

[72] Thomas T,Karmally W.CETP (cholesteryl ester transfer protein) inhibition with anacetrapib decreases production of lipoprotein(a) in mildly hypercholesterolemic subjects.Arterioscler Thromb Vasc Biol2017;37:1770-5 PMCID:PMC5567403

[73] Nicholls SJ,Brewer HB.Evacetrapib alone or in combination with statins lowers lipoprotein(a) and total and small LDL particle concentrations in mildly hypercholesterolemic patients.J Clin Lipidol2016;10:519-27.e4

[74] Nicholls SJ,Kastelein JJ.Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial.Nat Med2022;28:1672-8

[75] Sabatine MS,Keech AC.Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med2017;376:1713-22

[76] Schwartz GG,Szarek M.Alirocumab and cardiovascular outcomes after acute coronary syndrome.N Engl J Med2018;379:2097-107

[77] Schwartz GG,Bittner VA.Lipoprotein(a) and benefit of PCSK9 inhibition in patients with nominally controlled LDL cholesterol.J Am Coll Cardiol2021;78:421-33

[78] O’Donoghue ML,Giugliano RP.Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.Circulation2019;139:1483-92

[79] Moriarty PM,Gorby LK.Lipoprotein apheresis for lipoprotein(a) and cardiovascular disease.J Clin Lipidol2019;13:894-900

[80] Leebmann J,Julius U.Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study.Circulation2013;128:2567-76

[81] Cupido AJ.Inclisiran for the treatment of hypercholesterolaemia: implications and unanswered questions from the ORION trials.Cardiovasc Res2020;116:e136-9 PMCID:PMC7449556

[82] Ray KK,Kallend D.Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.N Engl J Med2020;382:1507-19

[83] Ray KK,Kallend DG.Inclisiran and cardiovascular events: a patient-level analysis of phase III trials.Eur Heart J2023;44:129-38 PMCID:PMC9825807

[84] Thompson PD,Janik MJ.Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance.J Clin Lipidol2015;9:295-304

[85] Ballantyne CM,Mancini GBJ.Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.Atherosclerosis2018;277:195-203

[86] Ray KK,Catapano AL.Safety and efficacy of bempedoic acid to reduce LDL cholesterol.N Engl J Med2019;380:1022-32

[87] Goldberg AC,Stroes ESG.Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.JAMA2019;322:1780-8 PMCID:PMC6865290

[88] Laufs U,Mancini GBJ.Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance.J Am Heart Assoc2019;8:e011662 PMCID:PMC6509724

[89] Merki E,Mullick AE.Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice.Circulation2008;118:743-53

[90] Santos RD,Catapano AL,Steinhagen-Thiessen E.Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials.Arterioscler Thromb Vasc Biol2015;35:689-99 PMCID:PMC4344404

[91] Tsimikas S,Hughes SG.Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study.Lancet2015;386:1472-83

[92] Yu RZ,Post N.Disposition and pharmacology of a GalNAc3-conjugated ASO targeting human lipoprotein(a) in mice.Mol Ther Nucleic Acids2016;5:e317 PMCID:PMC5014512

[93] Tsimikas S,Gouni-Berthold I.Lipoprotein(a) reduction in persons with cardiovascular disease.N Engl J Med2020;382:244-55

[94] Koren MJ,Baum SJ.Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a).Nat Med2022;28:96-103

[95] O’Donoghue ML,Gencer B.Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease.N Engl J Med2022;387:1855-64

[96] Nicholls SJ,Fleming C.Muvalaplin, an oral small molecule inhibitor of lipoprotein(a) formation: a randomized clinical trial.JAMA2023;330:1042-53 PMCID:PMC10463176