Role of lipoprotein (a) in pathogenesis of ischemic heart disease, degenerative aortic stenosis, and heart failure
DOI:
https://doi.org/10.6016/ZdravVestn.3057Keywords:
lipoprotein (a), ischaemic heart disease, degenerative aortic stenosis and heart failureAbstract
Lipoprotein (a) [Lp (a)] is a well-established risk factor for atherosclerotic cardiovascular disease. Lp(a) shows unique proatherogenic and thrombogenic properties that are important in atherothrombosis, and its elevated concentrations have shown a causal relationship with an increased risk of myocardial infarction/ ischaemic heart diseases and stroke, independent of classical risk factors. Degenerative valvular aortic stenosis is the most prevalent valvular heart disease, and it shares common risk factors with ischaemic heart disease. Lp(a) has been shown to promote valve calcification and disease progression. A mechanistic link between Lp(a) and aortic stenosis was further confirmed in observational and genetic studies of patients with increased Lp(a) concentrations. On the other hand, the role of Lp(a) in the development of heart failure is less clear. Two polymorphisms of Lp(a), rs3798220 and rs10455872, have emerged as predictors of the development of heart failure. Lp(a)-related risk for heart failure is mostly associated with ischaemic heart disease and valvular aortic stenosis. However, the association of the rs3798220 polymorphism with heart failure can not be explained by either ischemic heart disease or valvular aortic stenosis. The present review aims to summarize and discuss the current state of the literature on pathophysiological and clinical aspects of Lp(a), with a focus on ischaemic heart disease, degenerative aortic valve stenosis, and heart failure.
Downloads
References
1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al.; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119-77.
DOI: 10.1093/eurheartj/ehx393
PMID: 28886621
2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al.; ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-200.
DOI: 10.1093/eurheartj/ehw128
PMID: 27206819
3. Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al.; CHARGE Extracoronary Calcium Working Group. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368(6):503-12.
DOI: 10.1056/NEJMoa1109034
PMID: 23388002
4. Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer G, et al.; SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24(11):987-1003.
DOI: 10.1016/S0195-668X(03)00114-3
PMID: 12788299
5. Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313-30.
DOI: 10.1093/eurheartj/ehz962
PMID: 32052833
6. Smith JG, Luk K, Schulz CA, Engert JC, Do R, Hindy G, et al.; Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Extracoronary Calcium Working Group. Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis. JAMA. 2014;312(17):1764-71.
DOI: 10.1001/jama.2014.13959
PMID: 25344734
7. Aronow WS, Ahn C, Kronzon I, Goldman ME. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol. 2001;88(6):693-5.
DOI: 10.1016/S0002-9149(01)01821-5
PMID: 11564402
8. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al.; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-81.
DOI: 10.1016/S0140-6736(10)61350-5
PMID: 21067804
9. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J; ASTRONOMER Investigators. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010;121(2):306-14.
DOI: 10.1161/CIRCULATIONAHA.109.900027
PMID: 20048204
10. Cowell SJ, Newby DE, Prescott RJ, Bloomfield P, Reid J, Northridge DB, et al.; Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005;352(23):2389-97.
DOI: 10.1056/NEJMoa043876
PMID: 15944423
11. Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al.; SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343-56.
DOI: 10.1056/NEJMoa0804602
PMID: 18765433
12. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, et al.; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357(22):2248-61.
DOI: 10.1056/NEJMoa0706201
PMID: 17984166
13. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al.; Gissi-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1223-30.
DOI: 10.1016/S0140-6736(08)61239-8
PMID: 18757090
14. Kamstrup PR. Lipoprotein(a) and ischemic heart disease—a causal association? A review. Atherosclerosis. 2010;211(1):15-23.
DOI: 10.1016/j.atherosclerosis.2009.12.036
PMID: 20106478
15. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301(22):2331-9.
DOI: 10.1001/jama.2009.801
PMID: 19509380
16. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, et al.; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361(26):2518-28.
DOI: 10.1056/NEJMoa0902604
PMID: 20032323
17. 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;63(5):470-7.
DOI: 10.1016/j.jacc.2013.09.038
PMID: 24161338
18. Kamstrup PR, Nordestgaard BG. Elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population. JACC Heart Fail. 2016;4(1):78-87.
DOI: 10.1016/j.jchf.2015.08.006
PMID: 26656145
19. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al.; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-22.
DOI: 10.1056/NEJMoa1615664
PMID: 28304224
20. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al.; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-107.
DOI: 10.1056/NEJMoa1801174
PMID: 30403574
21. Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R, Edelberg JM, et al.; ODYSSEY OUTCOMES Committees and Investigators. Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome. J Am Coll Cardiol. 2020;75(2):133-44.
DOI: 10.1016/j.jacc.2019.10.057
PMID: 31948641
22. Berg K. A new serum type system in man—the Ld system. Vox Sang. 1965;10(5):513-27.
PMID: 4955857
23. Rehberger Likozar A, Zavrtanik M, Šebeštjen M. Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options. Ann Med. 2020;52(5):162-77.
DOI: 10.1080/07853890.2020.1775287
PMID: 32453609
24. Utermann G. The mysteries of lipoprotein(a). Science. 1989;246(4932):904-10.
DOI: 10.1126/science.2530631
PMID: 2530631
25. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69(6):692-711.
DOI: 10.1016/j.jacc.2016.11.042
PMID: 28183512
26. Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30(12):2311-6.
DOI: 10.1161/ATVBAHA.108.179697
PMID: 21084697
27. Spence JD, Koschinsky M. Mechanisms of lipoprotein(a) pathogenicity: prothrombotic, proatherosclerotic, or both? Arterioscler Thromb Vasc Biol. 2012;32(7):1550-1.
DOI: 10.1161/ATVBAHA.112.251306
PMID: 22699275
28. Kostner GM, Avogaro P, Cazzolato G, Marth E, Bittolo-Bon G, Qunici GB. Lipoprotein Lp(a) and the risk for myocardial infarction. Atherosclerosis. 1981;38(1-2):51-61.
DOI: 10.1016/0021-9150(81)90103-9
PMID: 7470205
29. Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F, Watts GF, et al.; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844-53.
DOI: 10.1093/eurheartj/ehq386
PMID: 20965889
30. 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. 2019;•••.
PMID: 31504418
31. Marcovina SM, Albers JJ. Lipoprotein (a) measurements for clinical application. J Lipid Res. 2016;57(4):526-37.
DOI: 10.1194/jlr.R061648
PMID: 26637278
32. Cegla J, Neely RD, France M, Ferns G, Byrne CD, Halcox J, et al.; HEART UK Medical, Scientific and Research Committee. HEART UK consensus statement on Lipoprotein(a): A call to action. Atherosclerosis. 2019;291:62-70.
DOI: 10.1016/j.atherosclerosis.2019.10.011
PMID: 31704552
33. 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(5):1313-23.
DOI: 10.1016/j.jacl.2018.07.003
PMID: 30100157
34. Lawn RM. How often has Lp(a) evolved? Clin Genet. 1996;49(4):167-74.
DOI: 10.1111/j.1399-0004.1996.tb03281.x
PMID: 8828980
35. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273(1):6-30.
DOI: 10.1111/j.1365-2796.2012.02592.x
PMID: 22998429
36. Helgadottir A, Gretarsdottir S, Thorleifsson G, Holm H, Patel RS, Gudnason T, et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol. 2012;60(8):722-9.
DOI: 10.1016/j.jacc.2012.01.078
PMID: 22898070
37. Enkhmaa B, Anuurad E, Zhang W, Tran T, Berglund L. Lipoprotein(a): genotype-phenotype relationship and impact on atherogenic risk. Metab Syndr Relat Disord. 2011;9(6):411-8.
DOI: 10.1089/met.2011.0026
PMID: 21749171
38. 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(5):1003-9.
DOI: 10.1161/ATVBAHA.115.306683
PMID: 26941019
39. 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(4):996-1001.
DOI: 10.1161/ATVBAHA.114.304785
PMID: 25810300
40. Virani SS, Brautbar A, Davis BC, Nambi V, Hoogeveen RC, Sharrett AR, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2012;125(2):241-9.
DOI: 10.1161/CIRCULATIONAHA.111.045120
PMID: 22128224
41. Tipping RW, Ford CE, Simpson LM, Walldius G, Jungner I, Folsom AR, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412-23.
DOI: 10.1001/jama.2009.1063
PMID: 19622820
42. Kamstrup PR, Benn M, Tybjaerg-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(2):176-84.
DOI: 10.1161/CIRCULATIONAHA.107.715698
PMID: 18086931
43. Agarwala A, Pokharel Y, Saeed A, Sun W, Virani SS, Nambi V, et al. The association of lipoprotein(a) with incident heart failure hospitalization: Atherosclerosis Risk in Communities study. Atherosclerosis. 2017;262:131-7.
DOI: 10.1016/j.atherosclerosis.2017.05.014
PMID: 28554015
44. Kamstrup PR, Nordestgaard BG. Elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population. JACC Heart Fail. 2016;4(1):78-87.
DOI: 10.1016/j.jchf.2015.08.006
PMID: 26656145
45. Steffen BT, Duprez D, Bertoni AG, Guan W, Tsai MY. Lp(a) [lipoprotein(a)]-related risk of heart failure is evident in whites but not in other racial/ethnic groups the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2018;38(10):2498-504.
DOI: 10.1161/ATVBAHA.118.311220
PMID: 30354212
46. O’Donoghue ML, Fazio S, Giugliano RP, Stroes ES, Kanevsky E, Gouni-Berthold I, et al. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019;139(12):1483-92.
DOI: 10.1161/CIRCULATIONAHA.118.037184
PMID: 30586750
47. Smith GD, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1-22.
DOI: 10.1093/ije/dyg070
PMID: 12689998
48. Smith GD, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004;33(1):30-42.
DOI: 10.1093/ije/dyh132
PMID: 15075143
49. Langsted A, Kamstrup PR, Nordestgaard BG. High lipoprotein(a) and high risk of mortality. Eur Heart J. 2019;40(33):2760-70.
DOI: 10.1093/eurheartj/ehy902
PMID: 30608559
50. Šebeštjen M, Žegura B, Gužič-Salobir B, Keber I. Fibrinolytic parameters and insulin resistance in young survivors of myocardial infarction with heterozygous familial hypercholesterolemia. Wien Klin Wochenschr. 2001;113(3-4):113-8.
PMID: 11253736
51. Boffa MB, Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res. 2016;57(5):745-57.
DOI: 10.1194/jlr.R060582
PMID: 26647358
52. Iung B, Vahanian A. Epidemiology of valvular heart disease in the adult. Nat Rev Cardiol. 2011;8(3):162-72.
DOI: 10.1038/nrcardio.2010.202
PMID: 21263455
53. Li C, Xu S, Gotlieb AI. The response to valve injury. A paradigm to understand the pathogenesis of heart valve disease. Cardiovasc Pathol. 2011;20(3):183-90.
DOI: 10.1016/j.carpath.2010.09.008
PMID: 21075649
54. Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, et al. Calcific aortic valve disease: not simply a degenerative process: A review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: Calcific aortic valve disease-2011 update. Circulation. 2011;124(16):1783-91.
DOI: 10.1161/CIRCULATIONAHA.110.006767
PMID: 22007101
55. Pawade TA, Newby DE, Dweck MR. Calcification in Aortic Stenosis: The Skeleton Key. J Am Coll Cardiol. 2015;66(5):561-77.
DOI: 10.1016/j.jacc.2015.05.066
PMID: 26227196
56. The Copenhagen city heart study. Eur Heart J Suppl. 2001;3:H1-83.
DOI: 10.1016/S1520-765X(01)90110-5
57. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298(3):299-308.
DOI: 10.1001/jama.298.3.299
PMID: 17635890
58. Capoulade R, Chan KL, Yeang C, Mathieu P, Bossé Y, Dumesnil JG, et al. Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis. J Am Coll Cardiol. 2015;66(11):1236-46.
DOI: 10.1016/j.jacc.2015.07.020
PMID: 26361154
59. Arsenault BJ, Boekholdt SM, Dubé MP, Rhéaume E, Wareham NJ, Khaw KT, et 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(3):304-10.
DOI: 10.1161/CIRCGENETICS.113.000400
PMID: 24704946
60. Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF. A potential basis for the thrombotic risks associated with lipoprotein(a). Nature. 1989;339(6222):301-3.
DOI: 10.1038/339301a0
PMID: 2542796
61. Zheng KH, Tsimikas S, Pawade T, Kroon J, Jenkins WS, Doris MK, et al. Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. J Am Coll Cardiol. 2019;73(17):2150-62.
DOI: 10.1016/j.jacc.2019.01.070
PMID: 31047003
62. Khatibzadeh S, Farzadfar F, Oliver J, Ezzati M, Moran A. Worldwide risk factors for heart failure: a systematic review and pooled analysis. Int J Cardiol. 2013;168(2):1186-94.
DOI: 10.1016/j.ijcard.2012.11.065
PMID: 23201083
63. Atchley AE, Kitzman DW, Whellan DJ, Iskandrian AE, Ellis SJ, Pagnanelli RA, et al.; HF-ACTION Investigators. Myocardial perfusion, function, and dyssynchrony in patients with heart failure: baseline results from the single-photon emission computed tomography imaging ancillary study of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) Trial. Am Heart J. 2009;158(4):S53-63.
DOI: 10.1016/j.ahj.2009.07.009
PMID: 19782789
64. Bell SP, Adkisson DW, Ooi H, Sawyer DB, Lawson MA, Kronenberg MW. Impairment of subendocardial perfusion reserve and oxidative metabolism in nonischemic dilated cardiomyopathy. J Card Fail. 2013;19(12):802-10.
DOI: 10.1016/j.cardfail.2013.10.010
PMID: 24331202
65. Bohl S, Kassner U, Eckardt R, Utz W, Mueller-Nordhorn J, Busjahn A, et al. Single lipoprotein apheresis session improves cardiac microvascular function in patients with elevated lipoprotein(a): detection by stress/rest perfusion magnetic resonance imaging. Ther Apher Dial. 2009;13(2):129-37.
DOI: 10.1111/j.1744-9987.2009.00667.x
PMID: 19379152
66. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, et al.; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382(3):244-55.
DOI: 10.1056/NEJMoa1905239
PMID: 31893580
Downloads
Published
Issue
Section
License
The Author transfers to the Publisher (Slovenian Medical Association) all economic copyrights following form Article 22 of the Slovene Copyright and Related Rights Act (ZASP), including the right of reproduction, the right of distribution, the rental right, the right of public performance, the right of public transmission, the right of public communication by means of phonograms and videograms, the right of public presentation, the right of broadcasting, the right of rebroadcasting, the right of secondary broadcasting, the right of communication to the public, the right of transformation, the right of audiovisual adaptation and all other rights of the author according to ZASP.
The aforementioned rights are transferred non-exclusively, for an unlimited number of editions, for the term of the statutory
The Author can make use of his work himself or transfer subjective rights to others only after 3 months from date of first publishing in the journal Zdravniški vestnik/Slovenian Medical Journal.
The Publisher (Slovenian Medical Association) has the right to transfer the rights of acquired parties without explicit consent of the Author.
The Author consents that the Article be published under the Creative Commons BY-NC 4.0 (attribution-non-commercial) or comparable licence.
