Hyperlipoprotein(a) and the low-molecular-weight apoprotein(a) phenotype in patients with atherosclerotic cardiovascular diseases and their complications

Aim. To study the association between lipoprotein(a) [Lp(a)] and apoprotein(a) [apo(a)] phenotypes with atherosclerosis of various locations and a history of cardiovascular events.

Material and methods. This cross-sectional, single-center study included 819 patients over 18 years of age with available paraclinical data on the coronary, carotid, and lower extremity arteries (LEA). Atherosclerosis was considered significant with stenosis of at least one main artery by more than 50%, as determined by carotid duplex ultrasound, LEA, and coronary angiography. Patients were divided into 4 following groups depending on their Lp(a) level and apo(a) phenotype: group 1 — Lp(a) <30 mg/dL and high-molecular-weight apo(a) phenotype (n=314); group 2 — Lp(a) <30 mg/dL and low-molecular-weight (LMW) apo(a) phenotype (n=122); group 3 — Lp(a) ≥30 mg/dL and high-molecularweight apo(a) phenotype (n=126); group 4 — Lp(a) ≥30 mg/dL and LMW apo(a) (n=257). In all patients, serum lipid and Lp(a) concentrations were determined, and apo(a) phenotyping was performed.

Results. The study groups were comparable by age and sex. In the studied sample, as the concentration of Lp(a) and LMW apo(a) increased from group 1 to group 4, the proportion of individuals without significant atherosclerosis decreased (58, 36, 29 and 20%, respectively), and multifocal atherosclerosis incidence increased (16, 34, 44 and 45%, respectively). LMW apo(a) with Lp(a) <30 mg/dl (group 2) was associated with multifocal atherosclerosis with an odds ratio (OR) of 2,6 (95% confidence interval (CI): 1,6-4,3 (p<0,01)), while hyperlipoproteinemia(a) (Lp(a) concentration ≥30 mg/dL) was associated with a 4-fold increase in the odds of multifocal atherosclerosis (groups 3 and 4) when compared with group 1 — OR 4,0; 95% CI: 2,5-6,4 (p<0,01) and OR 4,0; 95% CI: 2,7-5,9 (p<0,01), respectively. Independent association of Lp(a) and LMW apo(a) levels with atherosclerotic cardiovascular diseases and history of myocardial infarction (MI) was confirmed by logistic regression analysis including age, sex, hypertension, type 2 diabetes, smoking status, and obesity in the model. The odds of coronary, carotid, and multifocal atherosclerosis and history of MI were highest with a combination of hyperlipoproteinemia(a) and LMW apo(a) as follows: OR 4,5; 95% CI: 3,0-6,8 (p<0,01), OR 3,5; 95% CI: 2,2-5,6 (p<0,01), OR 10,9; 95% CI: 5,8-20,5 (p<0,01), OR 2,9; 95% CI: 2,0-4,2 (p<0,01), respectively. No significant association was found between Lp(a) and LMW apo(a) levels with a history of ischemic stroke.

Conclusion. Hyperlipoproteinemia(a) and LMW apo(a) are associated with significant coronary, carotid and LEA atherosclerosis, with isolated and multifocal atherosclerosis and a history of MI, independent of both conventional risk factors and each other. LMW apo(a) was associated with atherosclerotic cardiovascular disease and a history of MI, but not with ischemic stroke, regardless of Lp(a) levels.

1. Afanasieva OI, Arefieva TI, Tyurina AV, et al. Lipoprotein(a) and triglyceride-rich lipoproteins — association with recurrent nonfatal myocardial infarction in patients with early manifestation of coronary artery disease. Russian Cardiology Bulletin. 2024;19(1):29-37. (In Russ.) doi:10.17116/Cardiobulletin20241901129.

2. Afanasieva OI, Pokrovsky SN. Hyperlipoproteinemia(a) as a dangerous genetically determined violation of lipid metabolism and a risk factor for atherothrombosis and cardiovascular diseases. Russian Journal of Cardiology. 2019;(5):101-8. (In Russ.) doi:10.15829/1560-4071-2019-5-101-108.

3. Tmoyan NA, Afanasieva OI, Ezhov MV. The Role of Lipoprotein(a) in the Development of Peripheral and Carotid Atherosclerosis. Kardiologiia. 2018;58(6):70-8. (In Russ.) doi:10.18087/cardio.2018.6.10135.

4. Langlois MR, Nordestgaard BG, Langsted A, et al; European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Joint Consensus Initiative. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM. Clin Chem Lab Med. 2020;58(4):496-517. doi:10.1515/cclm-20191253.

5. 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.

6. Sandholzer C, Saha N, Kark JD, et al. Apo(a) isoforms predict risk for coronary heart disease. A study in six populations. Arterioscler Thromb. 1992;12(10):1214-26. doi:10.1161/01.atv.12.10.1214.

7. Afanasieva OI, Ezhov MV, Tmoyan NA, et al. Low Molecular Weight Apolipoprotein(a) Phenotype Rather Than Lipoprotein(a) Is Associated With Coronary Atherosclerosis and Myocardial Infarction. Front Cardiovasc Med. 2022;9:843602. doi:10.3389/fcvm.2022.843602.

8. Clarke SL, Huang RDL, Hilliard AT, et al; VA Million Veteran Program. Genetically predicted lipoprotein(a) associates with coronary artery plaque severity independent of low-density lipoprotein cholesterol. Eur J Prev Cardiol. 2025;32(2):116-27. doi:10.1093/eurjpc/zwae271.

9. Luengo-Fernandez R, Walli-Attaei M, Gray A, et al. Economic burden of cardiovascular diseases in the European Union: a population-based cost study. Eur Heart J. 2023;44(45):4752-67. doi:10.1093/eurheartj/ehad583.

10. Arutyunov GP, Tarlovskaya EI, Arutyunov AG, et al. Real-world data on managing patients with coronary artery disease and multifocal atherosclerosis. Results of the 12-month international clinical registry of patients with identified multifocal atherosclerosis in the Russian Federation and Eurasian countries (KAMMA). Russian Journal of Cardiology. 2025;30(3):6152. (In Russ.) doi:10.15829/1560-40712025-6152.

11. Arutyunov GP, Tarlovskaya EI, Arutyunov AG, et al. Peculiarities of polyvascular disease and the diagnostic significance of the ankle-brachial index in patients with coronary artery disease: results from the real-world registry KAMMA (Clinical registry on patient population with polyvascular disease in the Russian Federation and Eurasian countries). Russian Journal of Cardiology. 2024;29(4):5837. (In Russ.) doi:10.15829/1560-40712024-5837.

12. Reyes-Soffer G, Ginsberg HN, Berglund L, et al.; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; and Council on Peripheral Vascular Disease. 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(1):e48-e60. doi:10.1161/ATV.0000000000000147.

13. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022; 43(39):3925-46. doi:10.1093/eurheartj/ehac361.

14. Langsted A, Nordestgaard BG. Value of Genetic Testing for Lipoprotein(a) Variants. Circ Genom Precis Med. 2022;15(2):e003737. doi:10.1161/CIRCGEN.122.003737.

15. Raitakari O, Kartiosuo N, Pahkala K, et al. Lipoprotein(a) in Youth and Prediction of Major Cardiovascular Outcomes in Adulthood. Circulation. 2023;147(1):23-31. doi:10.1161/CIRCULATIONAHA.122.060667.

16. Garg PK, Guan W, Karger AB, et al. 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(2):154-60. doi:10.1016/j.jcct.2020.06.002.

17. Jackson CL, Garg PK, Guan W, et al. Lipoprotein(a) and coronary artery calcium in comparison with other lipid biomarkers: The multi-ethnic study of atherosclerosis. J Clin Lipidol. 2023;17(4): 538-48. doi:10.1016/j.jacl.2023.06.002.

18. 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;41(1):465-74. doi:10.1161/ATVBAHA.120.315291.

19. Amiri M, Raeisi-Dehkordi H, Verkaar AJCF, et al. Circulating lipoprotein (a) and all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis. Eur J Epidemiol. 2023;38(5):485-99. doi:10.1007/s10654-022-00956-4.

20. Klesareva EA, Afanasieva OI, Sherstyuk EE, et al. The relationship between the level of Lp(а) and the prevalence of atherosclerosis among young patients. Terapevticheskii arkhiv (Ter. Arkh.). 2022; 94(4):479-84. (In Russ.) doi:10.26442/00403660.2022.04.201454.

21. Afanasyeva OI, Pokrovsky SN. Lipoprotein(a) as underestimated cardiovascular risk factor in Russia. Time to introduce into clinical practice. Russian Journal of Cardiology. 2024;29(8):6035. (In Russ.) doi:10.15829/1560-4071-2024-6035.

22. 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; 16(5):e77-e95. doi:10.1016/j.jacl.2022.08.007.

23. van Buuren F, Horstkotte D, Knabbe C, et al. Incidence of elevated lipoprotein (a) levels in a large cohort of patients with cardiovascular disease. Clin Res Cardiol Suppl. 2017;12(Suppl 1):55-9. doi:10.1007/s11789-017-0087-y.

24. Raitakari O, Kivelä A, Pahkala K, et al. Long-term tracking and population characteristics of lipoprotein (a) in the Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2022;356:18-27. doi:10.1016/j.atherosclerosis.2022.07.009.

25. Kouvari M, Panagiotakos DB, Chrysohoou C, et al. Lipoprotein (a) and 10-year Cardiovascular Disease Incidence in Apparently Healthy Individuals: A Sex-based Sensitivity Analysis from ATTICA Cohort Study. Angiology. 2019;70(9):819-29. doi:10.1177/0003319719854872.

26. Ezhov MV, Shalnova SA, Yarovaya EB, et al. Lipoprotein(a) in an adult sample from the Russian population: distribution and association with atherosclerotic cardiovascular diseases. Arch Med Sci. 2021;19(4):995-1002. doi:10.5114/aoms/131089.

27. Kumar P, Swarnkar P, Misra S, et al. Lipoprotein (a) level as a risk factor for stroke and its subtype: A systematic review and meta-analysis. Sci Rep. 2021;11(1):15660. doi:10.1038/s41598-021-95141-0.

28. Kosmas CE, Bousvarou MD, Papakonstantinou EJ, et al. Lipoprotein (a) and cerebrovascular disease. J Int Med Res. 2024; 52(7):3000605241264182. doi:10.1177/03000605241264182.

29. Tmoyan NA, Ezhov MV, Afanasieva OI, et al. Association of lipoprotein (a) with ischemic stroke and stenotic carotid atherosclerosis. S. S. Korsakov Journal of Neurology and Psychiatry. 2020;120(3 2):42 48. (In Russ.) doi:10.17116/jnevro202012003242.