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Review

Lipoprotein(a): cardiovascular risk and emerging therapies

ORCID Icon &
Pages 259-268 | Received 11 Dec 2022, Accepted 28 Mar 2023, Published online: 03 Apr 2023

References

  • Kostner GM, Avogaro P, Cazzolato G, et al. Lipoprotein Lp(a) and the risk for myocardial infarction. Atherosclerosis. 1981 Jan;38(1–2):51–61.
  • Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular health study. J Am Coll Cardiol. 1997 Mar 1;29(3):630–634.
  • Gruneis R, Lamina C, Di Maio S, et al. The effect of LPA Thr3888Pro on lipoprotein(a) and coronary artery disease is modified by the LPA KIV-2 variant 4925g>a. Atherosclerosis. 2022 May;349:151–159.
  • Marco-Benedí V, Cenarro A, Laclaustra M, et al. Lipoprotein(a) in hereditary hypercholesterolemia: influence of the genetic cause, defective gene and type of mutation. Atherosclerosis. 2022 May;349:211–218.
  • Nissen SE, Wolski K, Balog C, et al. Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels. JAMA. 2022 May 3;327(17):1679–1687.
  • Rider DA, Eisermann M, Löffler K, et al. Pre-clinical assessment of SLN360, a novel siRNA targeting LPA, developed to address elevated lipoprotein (a) in cardiovascular disease. Atherosclerosis. 2022 May;349:240–247.
  • O’donoghue ML, Rosenson RS, Gencer B, et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N Engl J Med. 2022 Nov 17;387(20):1855–1864.
  • Marcovina SM, Albers JJ, Gabel B, et al. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem. 1995 Feb;41(2):246–255.
  • Nicholls SJ, Bubb KJ. The riskier lipid: what is on the HORIZON for lipoprotein (a) and should there be lp(a) screening for all? Curr Cardiol Rep. 2021 Jul 1;23(8):97.
  • Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009 Jul 22;302(4):412–423.
  • Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009 Dec 24;361(26):2518–2528.
  • Kille A, Nührenberg T, Franke K, et al. Association of lipoprotein(a) with intrinsic and on-clopidogrel platelet reactivity. J Thromb Thrombolysis. 2022 Jan;53(1):1–9.
  • Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017 Feb 14;69(6):692–711.
  • McCormick SPA, Schneider WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019 Feb;51(2):155–164.
  • Marcovina SM, Albers JJ, Scanu AM, et al. Use of a reference material proposed by the international federation of clinical chemistry and laboratory medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem. 2000 Dec;46(12):1956–1967.
  • Rosenson RS, López JAG, Monsalvo ML, et al. Quantification of LDL-Cholesterol corrected for molar concentration of lipoprotein(a). Cardiovasc Drugs Ther. 2022 Nov 26. DOI:10.1007/s10557-022-07407-y.
  • Tsimikas S, Marcovina SM. Ancestry, lipoprotein(a), and cardiovascular risk thresholds: jACC review topic of the week. J Am Coll Cardiol. 2022 Aug 30;80(9):934–946.
  • Wilson DP, Jacobson TA, Jones PH, et al. Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the national lipid association. J Clin Lipidol. 2022 Sep;16(5):e77–95.
  • Yeang C, Witztum JL, Tsimikas S. Novel method for quantification of lipoprotein(a)-cholesterol: implications for improving accuracy of LDL-C measurements. J Lipid Res. 2021;62:100053.
  • Tsimikas S, Stroes ESG. The dedicated “Lp(a) clinic”: a concept whose time has arrived? Atherosclerosis. 2020 May;300:1–9.
  • Nakamura T, Tokunaga K, Shimomura I, et al. Contribution of visceral fat accumulation to the development of coronary artery disease in non-obese men. Atherosclerosis. 1994 Jun;107(2):239–246.
  • Fujimoto WY, Bergstrom RW, Boyko EJ, et al. Visceral adiposity and incident coronary heart disease in Japanese-American men. The 10-year follow-up results of the Seattle Japanese-American community diabetes study. Diabetes Care. 1999 Nov;22(11):1808–1812.
  • Kronenberg F. Lipoprotein(a) measurement issues: are we making a mountain out of a molehill? Atherosclerosis. 2022 May;349:123–135.
  • Marcovina SM, Albers JJ. Lipoprotein (a) measurements for clinical application. J Lipid Res. 2016 Apr;57(4):526–537.
  • Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air force/texas coronary atherosclerosis prevention study. JAMA. 1998 May 27;279(20):1615–1622.
  • Deshmukh HA, Colhoun HM, Johnson T, et al. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). J Lipid Res. 2012 May;53(5):1000–1011.
  • Kollerits B, Drechsler C, Krane V, et al. Lipoprotein(a) concentrations, apolipoprotein(a) isoforms and clinical endpoints in haemodialysis patients with type 2 diabetes mellitus: results from the 4D Study. Nephrol Dial Transplant. 2016 Nov;31(11):1901–1908.
  • Khera AV, Everett BM, Caulfield MP, et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). Circulation. 2014 Feb 11;129(6):635–642.
  • Nestel PJ, Barnes EH, Tonkin AM, et al. Plasma lipoprotein(a) concentration predicts future coronary and cardiovascular events in patients with stable coronary heart disease. Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2902–2908.
  • Tsimikas S, Witztum JL, Miller ER, et al. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Circulation. 2004 Sep 14;110(11):1406–1412.
  • Berg K, Dahlén G, Christophersen B, et al. Lp(a) lipoprotein level predicts survival and major coronary events in the scandinavian simvastatin survival study. Clin Genet. 1997 Nov;52(5):254–261.
  • O’donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation. 2019 Mar 19;139(12):1483–1492.
  • Schwartz GG, Szarek M, Bittner VA, et al. Lipoprotein(a) and benefit of PCSK9 inhibition in patients with nominally controlled LDL cholesterol. J Am Coll Cardiol. 2021 Aug 3;78(5):421–433.
  • Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol. 2014 Feb 11;63(5):470–477.
  • Lamina C. Mendelian randomization: principles and its usage in Lp(a) research. Atherosclerosis. 2022 May;349:36–41.
  • Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013 Feb 7;368(6):503–512.
  • Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a mendelian randomization analysis. JAMA Cardiol. 2018 Jul 1;3(7):619–627.
  • Utermann G, Hoppichler F, Dieplinger H, et al. Defects in the low density lipoprotein receptor gene affect lipoprotein (a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4171–4174.
  • Kraft HG, Lingenhel A, Raal FJ, et al. Lipoprotein(a) in homozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2000 Feb;20(2):522–528.
  • Alonso R, Andres E, Mata N, et al. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol. 2014 May 20;63(19):1982–1989.
  • Funabashi S, Kataoka Y, Hori M, et al. Characterization of polyvascular disease in heterozygous familial hypercholesterolemia: its association with circulating lipoprotein(a) levels. J Am Heart Assoc. 2022 Aug 16;11(16):e025232.
  • Hedegaard BS, Bork CS, Kaltoft M, et al. Equivalent impact of elevated lipoprotein(a) and familial hypercholesterolemia in patients with atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2022 Nov 22;80(21):1998–2010.
  • Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the american college of cardiology/american heart association task force on clinical practice guidelines. Circulation. 2018 [2019Jun18];139(25):e1082–1143.
  • Mooser V, Mancini FP, Bopp S, et al. Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma. Hum Mol Genet. 1995 Feb;4(2):173–181.
  • Grüneis R, Weissensteiner H, Lamina C, et al. The kringle IV type 2 domain variant 4925g>a causes the elusive association signal of the LPA pentanucleotide repeat. J Lipid Res. 2022 Dec;63(12):100306.
  • Mehta A, Jain V, Saeed A, et al. Lipoprotein(a) and ethnicities. Atherosclerosis. 2022 May;349:42–52.
  • Abe A, Noma A. Studies on apolipoprotein(a) phenotypes. Part 1. Phenotype frequencies in a healthy Japanese population. Atherosclerosis. 1992 Sep;96(1):1–8.
  • Tsimikas S, Clopton P, Brilakis ES, et al. Relationship of oxidized phospholipids on apolipoprotein B-100 particles to race/ethnicity, apolipoprotein(a) isoform size, and cardiovascular risk factors: results from the Dallas Heart Study. Circulation. 2009 Apr 7;119(13):1711–1719.
  • Virani SS, Brautbar A, Davis BC, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the atherosclerosis risk in communities (ARIC) study. Circulation. 2012 Jan 17;125(2):241–249.
  • Guan W, Cao J, Steffen BT, et al. Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):996–1001.
  • Lee SR, Prasad A, Choi YS, et al. LPA gene, ethnicity, and cardiovascular events. Circulation. 2017 Jan 17;135(3):251–263.
  • Paré G, Çaku A, McQueen M, et al. Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups. Circulation. 2019 Mar 19;139(12):1472–1482.
  • Brandt EJ, Mani A, Spatz ES, et al. Lipoprotein(a) levels and association with myocardial infarction and stroke in a nationally representative cross-sectional US cohort. J Clin Lipidol. 2020 Sep;14(5):695–706.e4.
  • Patel AP, Wang M, Pirruccello JP, et al. Lp(a) (Lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank. Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):465–474.
  • Stefanutti C, Julius U, Watts GF, et al. Toward an international consensus-Integrating lipoprotein apheresis and new lipid-lowering drugs. J Clin Lipidol. 2017 Jul;11(4):858–871.e3.
  • Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the american college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol. 2018;73(24):3168–3209. 2019 Jun25. DOI:10.1016/j.jacc.2018.11.002.
  • 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis. 2019 Nov;290:140–205. DOI:10.1016/j.atherosclerosis.2019.08.014
  • Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American association of clinical endocrinologists and American college of endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm - 2020 executive summary. Endocr Pract. 2020 Oct;26(10):1196–1224.
  • Mach F, Baigent C, Catapano AL, et al. ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019;41(1):111–188. 2020Jan1. DOI:10.1093/eurheartj/ehz455.
  • Pearson GJ, Thanassoulis G, Anderson TJ, et al. Canadian cardiovascular society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can J Cardiol. 2021 Aug;37(8):1129–1150.
  • Watts GF, Sullivan DR, Hare DL, et al. Integrated guidance for enhancing the care of familial hypercholesterolaemia in Australia. Heart Lung Circ. 2021 Mar;30(3):324–349.
  • Pederiva C, Capra ME, Biasucci G, et al. Lipoprotein(a) and family history for cardiovascular disease in paediatric patients: a new frontier in cardiovascular risk stratification. Data from the LIPIGEN paediatric group. Atherosclerosis. 2022 May;349:233–239.
  • Willeit P, Ridker PM, Nestel PJ, et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018 Oct 13;392(10155):1311–1320.
  • Taimela S, Viikari JS, Porkka KV, et al. Lipoprotein (a) levels in children and young adults: the influence of physical activity. The cardiovascular risk in young finns study. Acta Paediatr. 1994 Dec;83(12):1258–1263.
  • Drowatzky KL, Durstine JL, Irwin ML, et al. The association between physical activity, cardiorespiratory fitness, and lipoprotein(a) concentrations in a tri-ethnic sample of women: the cross-cultural activity participation study. Vasc Med. 2001;6(1):15–21. DOI:10.1177/1358836X0100600104
  • Silaste ML, Rantala M, Alfthan G, et al. Changes in dietary fat intake alter plasma levels of oxidized low-density lipoprotein and lipoprotein(a). Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):498–503.
  • Haring B, von Ballmoos MC, Appel LJ, et al. Healthy dietary interventions and lipoprotein (a) plasma levels: results from the Omni Heart Trial. PLoS ONE. 2014;9(12):e114859. DOI:10.1371/journal.pone.0114859
  • Perrot N, Verbeek R, Sandhu M, et al. Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: the EPIC-Norfolk prospective population study. Atherosclerosis. 2017 Jan;256:47–52.
  • Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA. 2000 Apr 12;283(14):1845–1852.
  • Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255–2267.
  • Yeang C, Hung MY, Byun YS, et al. Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein(a). J Clin Lipidol. 2016 May;10(3):594–603.
  • Awad K, Mikhailidis DP, Katsiki N, et al. Effect of ezetimibe monotherapy on plasma lipoprotein(a) concentrations in patients with primary hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials. Drugs. 2018 Mar;78(4):453–462.
  • Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010 Dec 16;363(25):2406–2415.
  • Roeseler E, Julius U, Heigl F, et al. Lipoprotein apheresis for lipoprotein(a)-associated cardiovascular disease: prospective 5 years of follow-up and apolipoprotein(a) characterization. Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):2019–2027.
  • Leebmann J, Roeseler E, Julius U, et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation. 2013 Dec 17;128(24):2567–2576.
  • Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020 Apr 16;382(16):1520–1530.
  • Ray KK, Raal FJ, Kallend DG, et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J. 2022 Nov 4;44:129–138.
  • Santos RD, Raal FJ, Catapano AL, et al. 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 Biol. 2015 Mar;35(3):689–699.
  • Nandakumar R, Matveyenko A, Thomas T, et al. Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects. J Lipid Res. 2018 Dec;59(12):2397–2402.
  • Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016 Nov 5;388(10057):2239–2253.
  • Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020 Jan 16;382(3):244–255.
  • Yeang C, Karwatowska-Prokopczuk E, Su F, et al. Effect of pelacarsen on lipoprotein(a) cholesterol and corrected low-density lipoprotein cholesterol. J Am Coll Cardiol. 2022 Mar 22;79(11):1035–1046.
  • Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017 Mar 21;16(1):38.
  • Kamstrup PR, Nordestgaard BG. Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol. 2013 Nov;1(3):220–227.
  • Langsted A, Nordestgaard BG, Kamstrup PR. Low lipoprotein(a) levels and risk of disease in a large, contemporary, general population study. Eur Heart J. 2021 Mar 21;42(12):1147–1156.
  • García-Gómez C, Martín-Martínez MA, Castañeda S, et al. Lipoprotein(a) concentrations in rheumatoid arthritis on biologic therapy: results from the CARdiovascular in rheuMatology study project. J Clin Lipidol. 2017 May;11(3):749–756.e3.
  • Meroni M, Longo M, Lombardi R, et al. Low lipoprotein(a) levels predict hepatic fibrosis in patients with nonalcoholic fatty liver disease. Hepatol Commun. 2022 Mar;6(3):535–549.
  • Rikhi R, Bhatia HS, Schaich CL, et al. Association of Lp(a) (Lipoprotein[a]) and hypertension in primary prevention of cardiovascular disease: the MESA. Hypertension. 2023 Feb;80(2):352–360.
  • Agarwala A, Ballantyne C, Stone NJ. Primary prevention management of elevated Lipoprotein(a). JAMA Cardiol. 2022 Nov 16;8:96. DOI:10.1001/jamacardio.2022.4063.
  • Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015 Mar 26;161(1):161–172.

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