Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement
Florian Kronenberg, Samia Mora, Erik S G Stroes, Brian A Ference, Benoit J Arsenault, Lars Berglund, Marc R Dweck, Marlys Koschinsky, Gilles Lambert, François Mach, Catherine J McNeal, Patrick M Moriarty, Pradeep Natarajan, Børge G Nordestgaard, Klaus G Parhofer, Salim S Virani, Arnold von Eckardstein, Gerald F Watts, Jane K Stock, Kausik K Ray, Lale S Tokgözoğlu, Alberico L Catapano, Florian Kronenberg, Samia Mora, Erik S G Stroes, Brian A Ference, Benoit J Arsenault, Lars Berglund, Marc R Dweck, Marlys Koschinsky, Gilles Lambert, François Mach, Catherine J McNeal, Patrick M Moriarty, Pradeep Natarajan, Børge G Nordestgaard, Klaus G Parhofer, Salim S Virani, Arnold von Eckardstein, Gerald F Watts, Jane K Stock, Kausik K Ray, Lale S Tokgözoğlu, Alberico L Catapano
Abstract
This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.
Keywords: Aortic stenosis; Cardiovascular risk; Clinical guidance; Consensus; Lipoprotein(a); Model of care; Testing; Treatment.
Conflict of interest statement
Conflict of interest: Potential conflicts of interest outside the submitted work are summarized as follows. The following authors report participation in trials; receipt of fellowships, or grants for travel, research or staffing support; and/or personal honoraria for consultancy or lectures/speaker’s bureau from: Abbott (K.K.R., L.S.T.), Abcentra (M.K.), Abdi-Ibrahim (L.S.T.), Actelion (L.S.T.), Aegerion (A.L.C., P.M.M.), Affiris AG (G.L.), Akcea (A.L.C., B.G.N., K.G.P., E.S.G.S.), Amarin (A.L.C., P.M.M., B.G.N., K.G.P.), Amgen (A.L.C., B.A.F., F.K., F.M., P.M.M., P.N., B.G.N., K.G.P., K.K.R., E.S.GS., L.S.T., G.F.W.), Amgen Germany (A.v.E.), Amgen Switzerland (A.v.E.), Amryt (A.L.C.), Amundsen/Amgen (F.M.), Apple (P.N.), Arrowhead (G.F.W.), Ayma Therapeutics (M.K.), AstraZeneca (A.L.C., P.N., B.G.N., K.K.R., G.F.W.), Bayer (L.S.T.), Berlin-Chemie (K.G.P.), Boehringer-Ingelheim (K.K.R.), Boston Scientific (P.N.), CiVi Pharma (B.A.F.), Daiichi-Sankyo (A.L.C., B.A.F., F.M., K.G.P., K.K.R., L.S.T.), Daiichi Switzerland (A.v.E.), dalCOR (B.A.F.), Denka (B.G.N.), Eli Lilly (A.L.C., B.A.F., M.K., K.K.R.), Esperion (A.L.C., B.A.F., P.M.M., B.G.N., K.K.R., E.S.G.S., G.F.W.), FH Foundation (P.M.M.), Foresite Labs (P.N.), Fresenius (F.K.), GB Life Sciences (P.M.M.), Genentech (P.N.), Genzyme (A.L.C.), Horizon/Novartis (F.M., B.G.N.), Ionis Pharmaceuticals (B.A., A.L.C., B.A.F., M.K., P.M.M.), Jupiter Bioventures (M.R.D.), Kaneka (F.K., P.M.M.), Kowa (A.L.C., B.G.N., K.K.R.), KrKa Phama (B.A.F.), Lupin (K.K.R.), Menarini (A.L.C.), Merck (A.L.C., B.A.F.), MSD (K.G.P.), Mylan (A.L.C., B.A.F., L.S.T.), New Amsterdam (K.K.R.), Noetic Insights (M.K.), Novartis (B.A., A.L.C., M.R.D., B.A.F., F.K., F.M., C.J.M.N., P.M.M., P.N., B.G.N., K.G.P., K.K.R., E.S.G.S., L.S.T., G.F.W.), Novartis Canada (M.K.), NovoNordisk (B.A.F., C.J.M.N., B.G.N., K.K.R., E.S., L.S.T.), Nyrada Inc (G.L.), Pfizer (B.A., M.R.D., B.A.F., M.K., S.M., K.K.R., L.S.T., G.F.W.), Quest Diagnostics (S.M.), Recordati (A.L.C., LS.T.), Regeneron (A.L.C., B.A.F., P.M.M., B.G.N., K.K.R., E.S.G.S.), Renew (P.M.M.), Resverlogix (K.K.R.), Sandoz (A.L.C.), Sanofi (A.L.C., B.A.F., F.M., B.G.N., K.G.P., K.K.R., E.S.G.S., L.S.T., G.F.W.), Sanofi-Aventis Switzerland (A.v.E.), Sanofi-Regeneron (G.L., E.S.G.S.), Servier (L.S.T.), Sigma Tau (A.L.C.), Silence Therapeutics (B.A., M.R.D., B.A.F., B.G.N., K.K.R., G.F.W.), and The Medicines Co (B.A.F.). P.N. declares spousal employment at Vertex and K.G.P. is a member of the Data Monitoring and Safety Board at Boehringer-Ingelheim. S.S.V. declares an honorarium from the American College of Cardiology (Associate Editor for Innovations, acc.org), and grant funding from the U.S. Department of Veterans Affairs, National Institutes of Health, World Heart Federation, and Tahir and Jooma Family. Manuscripts have been published in collaboration with non-academic co-authors by P.N. and L.S.T. (Fitbit), G.F.W. (Amgen), and B.A. (Pfizer). Equity interests including income from stocks, stock options, royalties, or from patents or copyrights were reported from AstraZeneca (J.K.S.), Boston Scientific (L.B.), Cargene Therapeutics (K.K.R.), Gilead Sciences (L.B)., J & J (L.B.), GSK (J.K.S.), Medtronic (L.B.), New Amsterdam Pharma (K.K.R.), NovoNordisk (L.B.), Pemi31 Therapeutics (K.K.R.), and Pfizer (L.B.). K.K.R. is President of the European Atherosclerosis Society. L.S.T. is past-president of the European Atherosclerosis Society and an Editorial Board Member, The European Heart Journal.
© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.
Figures
References
- Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GFet al. . Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844–2853.
- Osnabrugge RL, Mylotte D, Head SJ, Van Mieghem NM, Nkomo VT, LeReun CM, et al. . Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol 2013;62:1002–1012.
- Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–1011.
- Tsimikas S, Stroes ESG. The dedicated “Lp(a) clinic”: A concept whose time has arrived? Atherosclerosis 2020;300:1–9.
- Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao Let al. . Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation 2010; 121:1838–1847.
- Strandkjaer N, Hansen MK, Nielsen ST, Frikke-Schmidt R, Tybjaerg-Hansen A, Nordestgaard BG, et al. . Lipoprotein(a) levels at birth and in early childhood: the COMPARE study. J Clin Endocrinol Metab 2022;107:324–335.
- de Boer LM, Hof MH, Wiegman A, Stroobants AK, Kastelein JJP, Hutten BA. Lipoprotein(a) levels from childhood to adulthood: data in nearly 3,000 children who visited a pediatric lipid clinic. Atherosclerosis 2022;349:227–232.
- Kronenberg F, Utermann G. Lipoprotein(a) - resurrected by genetics. J Intern Med 2013;273:6–30.
- Kamstrup PR. Lipoprotein(a) and cardiovascular disease. Clin Chem 2021;67:154–166.
- Coassin S, Kronenberg F. Lipoprotein(a) beyond the kringle IV repeat polymorphism: the complexity of genetic variation in the LPA gene. Atherosclerosis 2022;349:17–35.
- Perombelon YFN, Soutar AK, Knight BL. Variation in lipoprotein(a) concentration associated with different apolipoprotein(a) alleles. J Clin Invest 1994;93:1481–1492.
- Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SCet al. . Genetic variants associated with lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361:2518–2528.
- Kronenberg F. Genetic determination of lipoprotein(a) and its association with cardiovascular disease. Convenient does not always mean better. J Intern Med 2014;276:243–247.
- Coassin S, Schoenherr S, Weissensteiner H, Erhart G, Forer L, Losso JLet al. . A comprehensive map of single base polymorphisms in the hypervariable LPA kringle IV-2 copy number variation region. J Lipid Res 2019;60:186–199.
- Coassin S, Erhart G, Weissensteiner H, Eca Guimaraes de Araújo M, Lamina C, Schönherr S, et al. . A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction. Eur Heart J 2017;38:1823–1831.
- Schachtl-Riess JF, Kheirkhah A, Grüneis R, Di Maio S, Schoenherr S, Streiter Get al. . Frequent LPA KIV-2 variants lower lipoprotein(a) concentrations and protect against coronary artery disease. J Am Coll Cardiol 2021;78:437–449.
- Mack S, Coassin S, Rueedi R, Yousri NA, Seppala I, Gieger C, et al. . A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms. J Lipid Res 2017;58:1834–1844.
- Hoekstra M, Chen HY, Rong J, Dufresne L, Yao J, Guo Xet al. . Genome-Wide association study highlights APOH as a novel locus for lipoprotein(a) levels-brief report. Arterioscler Thromb Vasc Biol 2021; 41:458–464.
- Said MA, Yeung MW, van de Vegte YJ, Benjamins JW, Dullaart RPF, Ruotsalainen S, et al. . Genome-wide association study and identification of a protective missense variant on lipoprotein(a) concentration: protective missense variant on lipoprotein(a) concentration. Arterioscler Thromb Vasc Biol 2021;41:1792–1800.
- Patel AP, Wang M, Pirruccello JP, Ellinor PT, Ng K, Kathiresan Set al. . Lp(a) (lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank. Arterioscler Thromb Vasc Biol 2021;41:465–474.
- Welsh P, Welsh C, Celis-Morales CA, Brown R, Ho FK, Ferguson LD, et al. . Lipoprotein(a) and cardiovascular disease: prediction, attributable risk fraction, and estimating benefits from novel interventions. Eur J Prev Cardiol 2022;28:1991–2000.
- Virani SS, Brautbar A, Davis BC, Nambi V, Hoogeveen RC, Sharrett ARet al. . Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the atherosclerosis risk in communities (ARIC) study. Circulation 2012;125:241–249.
- Pare G, Caku A, McQueen M, Anand SS, Enas E, Clarke R, et al. . Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups. Circulation 2019;139:1472–1482.
- Tsimikas S, Clopton P, Brilakis ES, Marcovina SM, Khera A, Miller ERet 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;119:1711–1719.
- Erhart G, Lamina C, Lehtimäki T, Marques-Vidal P, Kähönen M, Vollenweider P, et al. . Genetic factors explain a major fraction of the 50% lower lipoprotein[a] concentrations in Finns. Arterioscler Thromb Vasc Biol 2018;38:1230–1241.
- Deo RC, Wilson JG, Xing C, Lawson K, Kao WHL, Reich Det al. . Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in african Americans. PLoS One 2011;6:e14581.
- Chretien JP, Coresh J, Berthier-Schaad Y, Kao WH, Fink NE, Klag MJ, et al. . Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in african Americans compared with European Americans. J Med Genet 2006;43:917–923.
- Mehta A, Jain V, Saeed A, Saseen JJ, Gulati M, Ballantyne CMet al. . Lipoprotein(a) and ethnicities. Atherosclerosis 2022;349:42–52.
- Mukamel RE, Handsaker RE, Sherman MA, Barton AR, Zheng Y, McCarroll SA, et al. . Protein-coding repeat polymorphisms strongly shape diverse human phenotypes. Science 2021;373:1499–1505.
- Varvel S, McConnell JP, Tsimikas S. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol 2016;36:2239–2245.
- Derby CA, Crawford SL, Pasternak RC, Sowers M, Sternfeld B, Matthews KA. Lipid changes during the menopause transition in relation to age and weight: the study of women’s health across the nation. Am J Epidemiol 2009;169:1352–1361.
- Enkhmaa B, Petersen KS, Kris-Etherton PM, Berglund L. Diet and Lp(a): does dietary change modify residual cardiovascular risk conferred by Lp(a)? Nutrients 2020;12:2024.
- Ebbeling CB, Knapp A, Johnson A, Wong JMW, Greco KF, Ma Cet al. . Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial. Am J Clin Nutr 2022;115:154–162.
- Langsted A, Kamstrup PR, Nordestgaard BG. Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis 2014;234:95–101.
- Enkhmaa B, Anuurad E, Berglund L. Lipoprotein (a): impact by ethnicity and environmental and medical conditions. J Lipid Res 2016;57:1111–1125.
- Kotwal A, Cortes T, Genere N, Hamidi O, Jasim S, Newman CBet al. . Treatment of thyroid dysfunction and serum lipids: a systematic review and meta-analysis. J Clin Endocrinol Metab 2020; 105:dgaa672.
- Edén S, Wiklund O, Oscarsson J, Rosén T, Bengtsson B-Å. Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb 1993;13:296–301.
- Zechner R, Desoye G, Schweditsch MO, Pfeiffer KP, Kostner GM. Fluctuations of plasma lipoprotein(a) concentrations during pregnancy and post partum. Metabolism 1986;35:333–336.
- Sattar N, Clark P, Greer IA, Shepherd J, Packard CJ. Lipoprotein (a) levels in normal pregnancy and in pregnancy complicated with pre-eclampsia. Atherosclerosis 2000;148:407–411.
- Salpeter SR, Walsh JME, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 2006;8:538–554.
- Kronenberg F. Causes and consequences of lipoprotein(a) abnormalities in kidney disease. Clin Exp Nephrol 2014;18:234–237.
- Hopewell JC, Haynes R, Baigent C. The role of lipoprotein (a) in chronic kidney disease. J Lipid Res 2018;59:577–585.
- Kronenberg F, König P, Lhotta K, Öfner D, Sandholzer C, Margreiter Ret al. . Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation. Arterioscler Thromb 1994;14:1399–1404.
- Feely J, Barry M, Keeling PW, Weir DG, Cooke T. Lipoprotein(a) in cirrhosis. BMJ 1992;304:545–546.
- Missala I, Kassner U, Steinhagen-Thiessen E. A systematic literature review of the association of lipoprotein(a) and autoimmune diseases and atherosclerosis. Int J Rheumatol 2012;2012:480784.
- Mooser V, Berger MM, Tappy L, Cayeux C, Marcovina SM, Darioli Ret al. . Major reduction in plasma Lp(a) levels during sepsis and burns. Arterioscler Thromb Vasc Biol 2000;20:1137–1142.
- Schultz O, Oberhauser F, Saech J, Rubbert-Roth A, Hahn M, Krone W, et al. . Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS One 2010; 5:e14328.
- Henriksson P, Angelin B, Berglund L. Hormonal regulation of serum lp (a) levels. Opposite effects after estrogen treatment and orchidectomy in males with prostatic carcinoma. J Clin Invest 1992;89:1166–1171.
- Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JBet al. . Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445–1451.
- Kronenberg F, Lingenhel A, Lhotta K, Rantner B, Kronenberg MF, König P, et al. . The apolipoprotein(a) size polymorphism is associated with nephrotic syndrome. Kidney Int 2004;65:606–612.
- Kronenberg F, König P, Neyer U, Auinger M, Pribasnig A, Lang Uet al. . Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 1995;6:110–120.
- Kronenberg F, Kuen E, Ritz E, Junker R, König P, Kraatz G, et al. . Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol 2000;11:105–115.
- Kraft HG, Menzel HJ, Hoppichler F, Vogel W, Utermann G. Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis. J Clin Invest 1989;83:137–142.
- Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PMet 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;129:635–642.
- Holm S, Oma I, Hagve TA, Saatvedt K, Brosstad F, Mikkelsen K, et al. . Levels of lipoprotein (a) in patients with coronary artery disease with and without inflammatory rheumatic disease: a cross-sectional study. BMJ Open 2019;9:e030651.
- Enkhmaa B, Anuurad E, Zhang W, Li CS, Kaplan R, Lazar Jet al. . Effect of antiretroviral therapy on allele-associated Lp(a) level in women with HIV in the women’s interagency HIV study. J Lipid Res 2018;59:1967–1976.
- Enkhmaa B, Anuurad E, Zhang W, Abbuthalha A, Li XD, Dotterweich W, et al. . HIV Disease activity as a modulator of lipoprotein(a) and allele-specific apolipoprotein(a) levels. Arterioscler Thromb Vasc Biol 2013;33:387–392.
- Wu XM, Broadwin R, Basu R, Malig B, Ebisu K, Gold EBet al. . Associations between fine particulate matter and changes in lipids/lipoproteins among midlife women. Sci Total Environ 2019;654:1179–1186.
- Jung I, Kwon H, Park SE, Park CY, Lee WY, Oh KW, et al. . Serum lipoprotein(a) levels and insulin resistance have opposite effects on fatty liver disease. Atherosclerosis 2020;308:1–5.
- Reyes-Soffer G, Westerterp M. Beyond lipoprotein(a) plasma measurements: lipoprotein(a) and inflammation. Pharmacol Res 2021;169:105689.
- Muller N, Schulte DM, Turk K, Freitag-Wolf S, Hampe J, Zeuner Ret al. . IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans. J Lipid Res 2015;56:1034–1042.
- Enkhmaa B, Berglund L. Non-genetic influences on lipoprotein(a) concentrations. Atherosclerosis 2022;349:53–62.
- Stenvinkel P, Berglund L, Heimbürger O, Pettersson E, Alvestrand A. Lipoprotein(a) in nephrotic syndrome. Kidney Int 1993;44:1116–1123.
- Dieplinger H, Lackner C, Kronenberg F, Sandholzer C, Lhotta K, Hoppichler Fet al. . Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a). J Clin Invest 1993;91:397–401.
- Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, 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;392:1311–1320.
- Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J 2020;41:2275–2284.
- Trinder M, Paruchuri K, Haidermota S, Bernardo R, Zekavat SM, Gilliland T, et al. . Repeat measures of lipoprotein(a) molar concentration and cardiovascular risk. J Am Coll Cardiol 2022; 79:617–628.
- de Boer LM, Oorthuys AOJ, Wiegman A, Langendam MW, Kroon J, Spijker Ret al. . Statin therapy and lipoprotein(a) levels: a systematic review and meta-analysis. Eur J Prev Cardiol 2022;29:779–792.
- Kamstrup PR, Benn M, Tybaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen city heart study. Circulation 2008;117:176–184.
- Kamstrup PR, Nordestgaard BG. Elevated lipoprotein(a) levels, LPA risk genotypes, elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population. JACC Heart Fail 2016;4:78–87.
- Langsted A, Kamstrup PR, Nordestgaard BG. High lipoprotein(a) and high risk of mortality. Eur Heart J 2019;40:2760–2770.
- Langsted A, Nordestgaard BG, Kamstrup PR. Elevated lipoprotein(a) and risk of ischemic stroke. J Am Coll Cardiol 2019;74:54–66.
- Erqou S, Kaptoge S, Perry PL, Di AE, Thompson A, White IRet al. . Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412–423.
- Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;301:2331–2339.
- Trinder M, Uddin MM, Finneran P, Aragam KG, Natarajan P. Clinical utility of lipoprotein(a) and LPA genetic risk score in risk prediction of incident atherosclerotic cardiovascular disease. JAMA Cardiol 2020;6:287–295.
- Gudbjartsson DF, Thorgeirsson G, Sulem P, Helgadottir A, Gylfason A, Saemundsdottir J, et al. . Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J Am Coll Cardiol 2019;74:2982–2994.
- Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res 2016;57:1953–1975.
- Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis. Arterioscler Thromb Vasc Biol 2012;32:1732–1741.
- Rifai N, Ma J, Sacks FM, Ridker PM, Hernandez WJ, Stampfer MJet al. . Apolipoprotein(a) size and lipoprotein(a) concentration and future risk of angina pectoris with evidence of severe coronary atherosclerosis in men: the physicians’ health study. Clin Chem 2004;50:1364–1371.
- Aronis KN, Zhao D, Hoogeveen RC, Alonso A, Ballantyne CM, Guallar Eet al. . Associations of lipoprotein(a) levels with incident atrial fibrillation and ischemic stroke: the ARIC (atherosclerosis risk in communities) study. J Am Heart Assoc 2017;6:e007372.
- Pan Y, Li H, Wang Y, Meng X, Wang Y. Causal effect of Lp(a) [lipoprotein(a)] level on ischemic stroke and Alzheimer disease a Mendelian randomization study. Stroke 2019;50:3532–3539.
- Arnold M, Schweizer J, Nakas CT, Schutz V, Westphal LP, Inauen Cet al. . Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study. Eur Heart J 2021;42:2186–2196.
- Nave AH, Lange KS, Leonards CO, Siegerink B, Doehner W, Landmesser U, et al. . Lipoprotein (a) as a risk factor for ischemic stroke: a meta-analysis. Atherosclerosis 2015;242:496–503.
- Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, Santer P, Oberhollenzer F, et al. . Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the bruneck study. Circulation 1999;100:1154–1160.
- Palmer MR, Kim DS, Crosslin DR, Stanaway IB, Rosenthal EA, Carrell DSet al. . Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network. Genet Epidemiol 2021;45:4–15.
- Klarin D, Lynch J, Aragam K, Chaffin M, Assimes TL, Huang Jet al. . Genome-wide association study of peripheral artery disease in the million veteran program. Nat Med 2019;25:1274–1279.
- Laschkolnig A, Kollerits B, Lamina C, Meisinger C, Rantner B, Stadler M, et al. . Lipoprotein(a) concentrations, apolipoprotein(a) phenotypes and peripheral arterial disease in three independent cohorts. Cardiovasc Res 2014;103:28–36.
- van Zuydam NR, Stiby A, Abdalla M, Austin E, Dahlstrom EH, McLachlan S, et al. . Genome-wide association study of peripheral artery disease. Circ Genom Precis Med 2021; 14:e002862.
- Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GMet al. . Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013;368:503–512.
- Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014;63:470–477.
- Arsenault BJ, Boekholdt SM, Dube MP, Rheaume E, Wareham NJ, Khaw KTet al. . Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case-control cohort. Circ Cardiovasc Genet 2014;7:304–310.
- Vongpromek R, Bos S, Ten Kate GJR, Yahya R, Verhoeven AJM, De Feyter PJ, et al. . Lipoprotein(a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia. J Intern Med 2015;278:166–173.
- Capoulade R, Chan KL, Yeang C, Mathieu P, Bosse Y, Dumesnil JGet al. . Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis. J Am Coll Cardiol 2015;66:1236–1246.
- Langsted A, Nordestgaard BG, Benn M, Tybjaerg-Hansen A, Kamstrup PR. PCSK9 R46l loss-of-function mutation reduces lipoprotein(a), LDL cholesterol, and risk of aortic valve stenosis. J Clin Endocrinol Metab 2016;101:3281–3287.
- Cairns BJ, Coffey S, Travis RC, Prendergast B, Green J, Engert JCet al. . A replicated, genome-wide significant association of aortic stenosis with a genetic variant for lipoprotein(a): meta-analysis of published and novel data. Circulation 2017;135:1181–1183.
- Chen HY, Dufresne L, Burr H, Ambikkumar A, Yasui N, Luk K, et al. . Association of LPA variants with aortic stenosis: a large-scale study using diagnostic and procedural codes from electronic health records. JAMA Cardiol 2018;3:18–23.
- Perrot N, Theriault S, Dina C, Chen HY, Boekholdt SM, Rigade Set al. . Genetic variation in LPA, calcific aortic valve stenosis in patients undergoing cardiac surgery, and familial risk of aortic valve microcalcification. JAMA Cardiol 2019;4:620–627.
- Cao J, Steffen BT, Budoff M, Post WS, Thanassoulis G, Kestenbaum B, et al. . Lipoprotein(a) levels are associated with subclinical calcific aortic valve disease in white and black individuals: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 2016;36:1003–1009.
- Arsenault BJ, Pelletier W, Kaiser Y, Perrot N, Couture C, Khaw KTet al. . Association of long-term exposure to elevated lipoprotein(a) levels with parental life span, chronic disease-free survival, and mortality risk: a Mendelian randomization analysis. JAMA Netw Open 2020;3:e200129.
- Cao YX, Zhang HW, Jin JL, Liu HH, Zhang Y, Zhang M, et al. . Lipoprotein(a) and cardiovascular outcomes in patients with previous myocardial infarction: a prospective cohort study. Thromb Haemost 2021;121:1161–1168.
- Deelen J, Evans DS, Arking DE, Tesi N, Nygaard M, Liu Xet al. . A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat Commun 2019;10:3669.
- Genser B, Dias KC, Siekmeier R, Stojakovic T, Grammer T, Maerz W. Lipoprotein (a) and risk of cardiovascular disease–a systematic review and meta analysis of prospective studies. Clin Lab 2011;57:143–156.
- Dentali F, Gessi V, Marcucci R, Gianni M, Grandi AM, Franchini M. Lipoprotein(a) as a risk factor for venous thromboembolism: a systematic review and meta-analysis of the literature. Semin Thromb Hemost 2017;43:614–620.
- Larsson SC, Gill D, Mason AM, Jiang T, Bäck M, Butterworth ASet al. . Lipoprotein(a) in Alzheimer, atherosclerotic, cerebrovascular, thrombotic, and valvular disease: Mendelian randomization investigation. Circulation 2020;141:1826–1828.
- Boffa MB, Stranges S, Klar N, Moriarty PM, Watts GF, Koschinsky ML. Lipoprotein(a) and secondary prevention of atherothrombotic events: a critical appraisal. J Clin Lipidol 2018;12:1358–1366.
- O’Donoghue ML, Morrow DA, Tsimikas S, Sloan S, Ren AF, Hoffman EBet al. . Lipoprotein(a) for risk assessment in patients with established coronary artery disease. J Am Coll Cardiol 2014;63:520–527.
- Madsen CM, Kamstrup PR, Langsted A, Varbo A, Nordestgaard BG. Lp(a) (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 Biol 2020;40:255–266.
- Albers JJ, Slee A, O’Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jret al. . Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (atherothrombosis intervention in metabolic syndrome with low HDL/high triglyceride and impact on global health outcomes). J Am Coll Cardiol 2013;62:1575–1579.
- Despres AA, Perrot N, Poulin A, Tastet L, Shen M, Chen HYet al. . Lipoprotein(a), oxidized phospholipids, and aortic valve microcalcification assessed by 18F-sodium fluoride positron emission tomography and computed tomography. CJC Open 2019;1:131–140.
- Kaiser Y, Nurmohamed NS, Kroon J, Verberne HJ, Tzolos E, Dweck MR, et al. . Lipoprotein(a) has no major impact on calcification activity in patients with mild to moderate aortic valve stenosis. Heart 2022;108:61–66.
- Kaiser Y, Singh SS, Zheng KH, Verbeek R, Kavousi M, Pinto SJet al. . Lipoprotein(a) is robustly associated with aortic valve calcium. Heart 2021;107:1422–1428.
- Zheng KH, Tsimikas S, Pawade T, Kroon J, Jenkins WSA, Doris MK, et al. . Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis. J Am Coll Cardiol 2019;73:2150–2162.
- Mohammadi-Shemirani P, Chong M, Narula S, Perrot N, Conen D, Roberts JDet al. . Elevated lipoprotein(a) and risk of atrial fibrillation. J Am Coll Cardiol 2022;79:1579–1590.
- Satterfield BA, Dikilitas O, Safarova MS, Clarke SL, Tcheandjieu C, Zhu X, et al. . Associations of genetically predicted Lp(a) (lipoprotein [a]) levels with cardiovascular traits in individuals of European and african ancestry. Circ Genom Precis Med 2021;14:e003354.
- Wilson DP, Jacobson TA, Jones PH, Koschinsky ML, McNeal CJ, Nordestgaard BGet 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 2019;13:374–392.
- Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP, Kamstrup PR, et al. . 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 Biol 2022; 42:e48–e60.
- Emdin CA, Khera AV, Natarajan P, Klarin D, Won HH, Peloso GMet al. . Phenotypic characterization of genetically lowered human lipoprotein(a) levels. J Am Coll Cardiol 2016;68:2761–2772.
- Sandholzer C, Saha N, Kark JD, Rees A, Jaross W, Dieplinger H, et al. . Apo(a) isoforms predict risk for coronary heart disease: a study in six populations. Arterioscler Thromb 1992;12:1214–1226.
- Erqou S, Thompson A, Di Angelantonio AE, Saleheen D, Kaptoge S, Marcovina Set al. . Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol 2010;55:2160–2167.
- Kraft HG, Lingenhel A, Köchl S, Hoppichler F, Kronenberg F, Abe A, et al. . Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol 1996;16:713–719.
- Lim ET, Würtz P, Havulinna AS, Palta P, Tukiainen T, Rehnstrom Ket al. . Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet 2014;10:e1004494.
- Guan W, Cao J, Steffen BT, Post WS, Stein JH, Tattersall MC, 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;35:996–1001.
- Lee SR, Prasad A, Choi YS, Xing C, Clopton P, Witztum JLet al. . LPA Gene, ethnicity, and cardiovascular events. Circulation 2017;135:251–263.
- Brandt EJ, Mani A, Spatz ES, Desai NR, Nasir K. Lipoprotein(a) levels and association with myocardial infarction and stroke in a nationally representative cross-sectional US cohort. J Clin Lipidol 2020;14:695–706.
- Loh WJ, Chang X, Aw TC, Phua SK, Low AF, Chan MYet al. . Lipoprotein(a) as predictor of coronary artery disease and myocardial infarction in a multi-ethnic Asian population. Atherosclerosis 2022;349:160–165.
- Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. . 2019. ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–188.
- Verbeek R, Hoogeveen RM, Langsted A, Stiekema LCA, Verweij SL, Hovingh GKet al. . Cardiovascular disease risk associated with elevated lipoprotein(a) attenuates at low low-density lipoprotein cholesterol levels in a primary prevention setting. Eur Heart J 2018;39:2589–2596.
- 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.
- Marston NA, Gurmu Y, Melloni GEM, Bonaca M, Gencer B, Sever PSet al. . The effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of venous thromboembolism. Circulation 2020;9:1600–1607.
- Boffa MB. Beyond fibrinolysis: the confounding role of Lp(a) in thrombosis. Atherosclerosis 2022;349:72–81.
- Di Maio S, Lamina C, Coassin S, Forer L, Wurzner R, Schonherr Set al. . Lipoprotein(a) and SARS-CoV-2 infections: susceptibility to infections, ischemic heart disease and thromboembolic events. J Intern Med 2022;291:101–107.
- deVeber G, Kirkham F, Shannon K, Brandao L, Strater R, Kenet G, et al. . Recurrent stroke: the role of thrombophilia in a large international pediatric stroke population. Haematologica 2019;104:1676–1681.
- Nowak-Göttl U, Sträter R, Heinecke A, Junker R, Koch HG, Schuierer Get al. . Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood 1999;94:3678–3682.
- Sultan SM, Schupf N, Dowling MM, deVeber GA, Kirton A, Elkind MS. Review of lipid and lipoprotein(a) abnormalities in childhood arterial ischemic stroke. Int J Stroke 2014;9:79–87.
- Mora S, Kamstrup PR, Rifai N, Nordestgaard BG, Buring JE, Ridker PM. Lipoprotein(a) and risk of type 2 diabetes. Clin Chem 2010;56:1252–1260.
- Tolbus A, Mortensen MB, Nielsen SF, Kamstrup PR, Bojesen SE, Nordestgaard BG. Kringle IV type 2. Not low lipoprotein(a), as a cause of diabetes: a novel genetic approach using SNPs associated selectively with lipoprotein(a) concentrations or with kringle IV type;2, repeats. Clin Chem 2017;63:1866–1876.
- Kamstrup PR, Nordestgaard BG. Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol 2013;1:220–227.
- 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;42:1147–1156.
- Ye Z, Haycock PC, Gurdasani D, Pomilla C, Boekholdt SM, Tsimikas Set al. . The association between circulating lipoprotein(a) and type 2 diabetes: is it causal? Diabetes 2014;63:332–342.
- Kaya A, Onat A, Yuksel H, Can G, Yuksel M, Ademoglu E. Lipoprotein(a)-activated immunity, insulin resistance and new-onset diabetes. Postgrad Med 2017;129:611–618.
- Paige E, Masconi KL, Tsimikas S, Kronenberg F, Santer P, Weger Set al. . Lipoprotein(a) and incident type-2 diabetes: results from the prospective bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol 2017;16:38.
- Ding L, Song A, Dai M, Xu M, Sun W, Xu B, et al. . Serum lipoprotein (a) concentrations are inversely associated with T2D, prediabetes, and insulin resistance in a middle-aged and elderly Chinese population. J Lipid Res 2015;56:920–926.
- Lamina C, Kronenberg F. The mysterious lipoprotein(a) is still good for a surprise. Lancet Diabetes Endocrinol 2013;1:170–172.
- Tsimikas S. In search of a physiological function of lipoprotein(a): causality of elevated Lp(a) levels and reduced incidence of type 2 diabetes. J Lipid Res 2018;59:741–744.
- Farukhi ZM, Mora S. Lifelong low Lp(a) levels: genetics give a green light? Eur Heart J 2021;42:1157–1159.
- White AL, Guerra B, Wang J, Lanford RE. Presecretory degradation of apolipoprotein[a] is mediated by the proteasome pathway. J Lipid Res 1999;40:275–286.
- Chan DC, Watts GF, Coll B, Wasserman SM, Marcovina SM, Barrett PHR. Lipoprotein(a) particle production as a determinant of plasma lipoprotein(a) concentration across varying apolipoprotein(a) isoform sizes and background cholesterol-lowering therapy. J Am Heart Assoc 2019;8:e011781.
- Ying Q, Chan DC, Pang J, Marcovina SM, Barrett PHR, Watts GF. PCSK9 Inhibition with alirocumab decreases plasma lipoprotein(a) concentration by a dual mechanism of action in statin-treated patients with very high apolipoprotein(a) concentration. J Intern Med 2022;291:870–876.
- McCormick SPA, Schneider WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology 2019;51:155–164.
- Romagnuolo R, Scipione CA, Boffa MB, Marcovina SM, Seidah NG, Koschinsky ML. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem 2015;290:11649–11662.
- McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease. SA:R236553. /REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344–2353.
- Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Blom D, Seidah NGet al. . PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res 2016;57:1086–1096.
- Villard EF, Thedrez A, Blankenstein J, Croyal M, Tran T-T-T, Poirier B, et al. . PCSK9 Modulates the secretion but not the cellular uptake of lipoprotein(a) ex vivo. JACC Basic Transl Sci 2016;1:419–427.
- Sharma M, Redpath GM, Williams MJ, McCormick SP. Recycling of apolipoprotein(a) after PlgRKT-mediated endocytosis of lipoprotein(a). Circ Res 2017;120:1091–1102.
- Chemello K, Beeské S, Trang Tran TT, Blanchard V, Villard EF, Poirier Bet al. . Lipoprotein(a) cellular uptake ex vivo and hepatic capture in vivo is insensitive to PCSK9 inhibition with alirocumab. JACC Basic Transl Sci 2020;5:549–557.
- Chemello K, Chan DC, Lambert G, Watts GF. Recent advances in demystifying the metabolism of lipoprotein(a). Atherosclerosis 2022;349:82–91.
- Reyes-Soffer G, Pavlyha M, Ngai C, Thomas T, Holleran S, Ramakrishnan Ret al. . Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans. Circulation 2017;135:352–362.
- Watts GF, Chan DC, Somaratne R, Wasserman SM, Scott R, Marcovina SM, et al. . Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics. Eur Heart J 2018;39:2577–2585.
- Langsted A, Nordestgaard BG. Lipoprotein(a): is it more, less or equal to LDL as a causal factor for cardiovascular disease and mortality? Curr Opin Lipidol 2020;31:125–131.
- van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JDet al. . Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 2016;134:611–624.
- Garg PK, Guan W, Karger AB, Steffen BT, Budoff M, Tsai MY. Lipoprotein (a) and risk for calcification of the coronary arteries, mitral valve, and thoracic aorta: the multi-ethnic study of atherosclerosis. J Cardiovasc Comput Tomogr 2021;15:154–160.
- Kaiser Y, Daghem M, Tzolos E, Meah MN, Doris MK, Moss AJet al. . Association of lipoprotein(a) with atherosclerotic plaque progression. J Am Coll Cardiol 2022;79:223–233.
- Bouchareb R, Mahmut A, Nsaibia MJ, Boulanger MC, Dahou A, Lepine JL, et al. . Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve. Circulation 2015;132:677–690.
- Bourgeois R, Bourgault J, Despres AA, Perrot N, Guertin J, Girard Aet al. . Lipoprotein proteomics and aortic valve transcriptomics identify biological pathways linking lipoprotein(a) levels to aortic stenosis. Metabolites 2021;11:459.
- Leibundgut G, Scipione C, Yin H, Schneider M, Boffa MB, Green S, et al. . Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J Lipid Res 2013;54:2815–2830.
- Schnitzler JG, Hoogeveen RM, Ali L, Prange KHM, Waissi F, van Weeghel Met al. . Atherogenic lipoprotein(a) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation. Circ Res 2020;126:1346–1359.
- Boffa MB, Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res 2016;57:745–757.
- Boffa MB, Marar TT, Yeang C, Viney NJ, Xia S, Witztum JLet al. . Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis. J Lipid Res 2019;60:2082–2089.
- Burgess S, Ference BA, Staley JR, Freitag DF, Mason AM, Nielsen SF, 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;3:619–627.
- Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol 2013;61:1146–1156.
- Willeit P, Kiechl S, Kronenberg F, Witztum JL, Santer P, Mayr Met al. . Discrimination and net reclassification of cardiovascular risk with lipoprotein (a): prospective 15-year outcomes in the Bruneck study. J Am Coll Cardiol 2014;64:851–860.
- Delabays B, Marques-Vidal P, Kronenberg F, Waeber G, Vollenweider P, Vaucher J. Use of lipoprotein(a) for refining cardiovascular risk prediction in a low-risk population: the CoLaus/PsyCoLaus study. Eur J Prev Cardiol 2021;28:e18–e20.
- Perrot N, Verbeek R, Sandhu M, Boekholdt SM, Hovingh GK, Wareham NJet al. . Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: the EPIC-Norfolk prospective population study. Atherosclerosis 2017; 256:47–52.
- Jeong A, Eze IC, Vienneau D, de Hoogh K, Keidel D, Rothe T, et al. . Residential greenness-related DNA methylation changes. Environ Int 2022;158:106945.
- Pearson GJ, Thanassoulis G, Anderson TJ, Barry AR, Couture P, Dayan N, et al. . 2021 Canadian cardiovascular society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can J Cardiol 2021;37:1129–1150.
- Nurmohamed NS, Kaiser Y, Schuitema PCE, Ibrahim S, Nierman M, Fischer JCet al. . Finding very high lipoprotein(a): the need for routine assessment. Eur J Prev Cardiol 2022;29:769–776.
- Chakraborty A, Pang J, Chan DC, Ellis KL, Hooper AJ, Bell DA, et al. . Cascade testing for elevated lipoprotein(a) in relatives of probands with familial hypercholesterolaemia and elevated lipoprotein(a). Atherosclerosis 2022;349:219–226.
- Vuorio A, Watts GF, Kovanen PT. Familial hypercholesterolaemia and COVID-19: triggering of increased sustained cardiovascular risk. J Intern Med 2020;287:746–747.
- Watts GF, Gidding SS, Mata P, Pang J, Sullivan DR, Yamashita Set al. . Familial hypercholesterolaemia: evolving knowledge for designing adaptive models of care. Nat Rev Cardiol 2020;17:360–377.
- Ellis KL, Perez d I, Alonso R, Fuentes F, Watts GF, Mata P. Value of measuring lipoprotein(a) during cascade testing for familial hypercholesterolemia. J Am Coll Cardiol 2019;73:1029–1039.
- Kronenberg F. Lipoprotein(a) measurement issues: are we making a mountain out of a molehill? Atherosclerosis 2022;349:123–135.
- Scharnagl H, Stojakovic T, Dieplinger B, Dieplinger H, Erhart G, Kostner GMet al. . Comparison of lipoprotein(a) serum concentrations measured by six commercially available immunoassays. Atherosclerosis 2019;289:206–213.
- Cobbaert CM, Althaus H, Begcevic Brkovic I, Ceglarek U, Coassin S, Delatour V, et al. . Towards an SI-traceable reference measurement system for seven serum apolipoproteins using bottom-up quantitative proteomics: conceptual approach enabled by cross-disciplinary/cross-sector collaboration. Clin Chem 2021;67:478–489.
- Marcovina SM, Clouet-Foraison N, Koschinsky ML, Lowenthal MS, Orquillas A, Boffa MBet al. . Development of an LC-MS/MS proposed candidate reference method for the standardization of analytical methods to measure lipoprotein(a). Clin Chem 2021;67:490–499.
- Lassman ME, McLaughlin TM, Zhou H, Pan Y, Marcovina SM, Laterza O, et al. . Simultaneous quantitation and size characterization of apolipoprotein(a) by ultra-performance liquid chromatography/mass spectrometry. Rapid Commun Mass Spectrom 2014;28:1101–1106.
- Tsimikas S, Fazio S, Viney NJ, Xia S, Witztum JL, Marcovina SM. Relationship of lipoprotein(a) molar concentrations and mass according to lipoprotein(a) thresholds and apolipoprotein(a) isoform size. J Clin Lipidol 2018;12:1313–1323.
- Collet J-P, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DLet al. . 2020. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289–1367.
- Kostner GM, Ibovnik A, Holzer H, Grillhofer H. Preparation of a stable fresh frozen primary lipoprotein[a] (lp[a]) standard. J Lipid Res 1999;40:2255–2263.
- Marcovina SM, Albers JJ, Scanu AM, Kennedy H, Giaculli F, Berg Ket 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;46:1956–1967.
- Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. . Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European atherosclerosis society. Eur Heart J 2013;34:3478–3490.
- Langsted A, Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study. Lancet Diabetes Endocrinol 2016;4:577–587.
- Chan DC, Pang J, Hooper AJ, Bell DA, Burnett JR, Watts GF. Effect of lipoprotein(a) on the diagnosis of familial hypercholesterolemia: does it make a difference in the clinic? Clin Chem 2019;65:1258–1266.
- Hopewell JC, Parish S, Offer A, Link E, Clarke R, Lathrop Met al. . Impact of common genetic variation on response to simvastatin therapy among 18,705 participants in the heart protection study. Eur Heart J 2013;34:982–992.
- Kronenberg F. Prediction of cardiovascular risk by Lp(a) concentrations or genetic variants within the LPA gene region. Clin Res Cardiol Suppl 2019;14:5–12.
- Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, et al. . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–2207.
- Waldmann E, Parhofer KG. Lipoprotein apheresis to treat elevated lipoprotein (a). J Lipid Res 2016;57:1751–1757.
- Nugent AK, Gray JV, Gorby LK, Moriarty PM. Lipoprotein apheresis: first FDA indicated treatment for elevated lipoprotein(a). J Clin Cardiol 2020;1:16–21.
- O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold Iet al. . Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–1492.
- Szarek M, Bittner VA, Aylward P, Baccara-Dinet M, Bhatt DL, Diaz R, et al. . Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J 2020;41:4245–4255.
- Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz Ket al. . Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–2267.
- Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, et al. . Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203–212.
- Chasman DI, Shiffman D, Zee RY, Louie JZ, Luke MM, Rowland CMet al. . Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 2009;203:371–376.
- Tsimikas S. Potential causality and emerging medical therapies for lipoprotein(a) and its associated oxidized phospholipids in calcific aortic valve stenosis. Circ Res 2019;124:405–415.
- Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen Eet al. . Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244–255.
- Koren MJ, Moriarty PM, Baum SJ, Neutel J, Hernandez-Illas M, Weintraub HS, et al. . Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a). Nat Med 2022;28:96–103.
- Nissen SE, Wolski K, Balog C, Swerdlow DI, Scrimgeour AC, Rambaran 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;327:1679–1687.
- Lamina C, Kronenberg F. Estimation of the required lipoprotein(a)-lowering therapeutic effect size for reduction in coronary heart disease outcomes: a Mendelian randomization analysis. JAMA Cardiol 2019;4:575–579.
- Powell BJ, Waltz TJ, Chinman MJ, Damschroder LJ, Smith JL, Matthieu MMet al. . A refined compilation of implementation strategies: results from the expert recommendations for implementing change (ERIC) project. Implement Sci 2015;10:21.
Source: PubMed