Sex differences in 5-year risk of major adverse cardiovascular events in patients with coronary artery disease and elevated lipoprotein(a) levels

Aim. To evaluate 5-year major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) and high lipoprotein(a) (Lp(a)) levels in the Uzbek population.
Material and methods. The study included 216 patients (96 men and 120 women) hospitalized with a diagnosis of "CAD. Progressive angina", in whom MACE (cardiovascular death, non-fatal myocardial infarction and stroke) was assessed during 5 years of follow-up. The 2-∆∆Сt value, correlating with the number of LPA KIV-2 repeats, was determined in genomic DNA using quantitative real-time polymerase chain reaction (qPCR).
Results. In patients with CAD with elevated Lp(a) in the quartile 4 ≥48 mg/dL, the MACE risk was 2 times higher (relative risk 2,0; 95% confidence interval 1,04-3,87, P<0,05) than in quartile 1 ≤6 mg/dl. Moreover, among men it was 2,6 times higher (P<0,05), while in women — 1,4 times higher without significant difference. In contrast, in the study cohort, the MACE risk in quartile 1 <3,9 of 2-∆∆Сt was 3 times higher than in quartile 4 (>6) (P<0,01) in men, and 3,3 times higher among women (P<0,05). Lp(a) concentration in the examined subjects was inversely dependent on the 2-∆∆Сt value. We also observed a decreased MACE risk in women with high Apolipoprotein A-I (apoA) levels in quartile 4 (>175 mg/dL) versus quartile 1 (<140 mg/dL) with relative risk of 0,30 (95% confidence interval 0,10-0,98, P<0,05).
Conclusion. The 2-∆∆Сt value in the lower quartile associated with a low number of LPA KIV-2 repeats more accurately reflects the MACE risk in women with CAD. Also, the relative risk in women was lower in the upper quartile of apoA compared to the lower one.

1. Ezhov MV, Kukharchuk VV, Sergienko IV, et al. Disorders of lipid metabolism. Clinical Guidelines 2023. Russian Journal of Cardiology. 2023;28(5):5471. (In Russ.) doi: 10.15829/1560-4071-2023-5471. EDN YVZOWJ.

2. 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. 2023;19(4):995-102 doi: 10.5114/aoms/131089.

3. 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.

4. Guertin J, Kaiser Y, Manikpurage H, et al. Sex-Specific Associations of Genetically Predicted Circulating Lp(a) (Lipoprotein(a)) and Hepatic LPA Gene Expression Levels with Cardiovascular Outcomes: Mendelian Randomization and Observational Analyses. Circ Genom Precis Med. 2021;14(4):485-94. doi: 10.1161/CIRCGEN.120.003271.

5. Simony SB, Mortensen MB, Langsted A, et al. Sex differences of lipoprotein(a) levels and associated risk of morbidity and mortality by age: the Copenhagen General Population Study. Atherosclerosis. 2022;355:76-82. doi: 10.1016/j.atherosclerosis.2022.06.1023.

6. Lanktree MB, Rajakumar C, Brunt JH, et al. Determination of lipoprotein(a) kringle repeat number from genomic DNA: copy number variation genotyping using qPCR. J Lipid Res. 2009;50(4):768-72. doi: 10.1194/jlr.D800050-JLR200.

7. Untergasser A, Cutcutache I, Koressaar T, et al. Primer3—new capabilities and interfaces. Nucleic Acids Res. 2012;40(15):2-12. doi: 10.1093/nar/gks596.

8. Sticchi E, Magi A, Kamstrup PR, et al. Apolipoprotein(a) Kringle-IV Type 2 Copy Number Variation Is Associated with Venous Thromboembolism. PLoS ONE. 2016;11(2):1-14. doi: 10.1371/journal.pone.0149427.

9. Fogacci F, Di Micoli V, Avagimyan A, et al. Assessment of Apolipoprotein(a) Isoform Size Using Phenotypic and Genotypic Methods. Int. J. Mol. Sci. 2023;24:1-14. doi: 10.3390/ijms241813886.

10. Cook NR, Mora S, Ridker PM. Lipoprotein(a) and Cardiovascular Risk Prediction among Women. J Am Coll Cardiol. 2018;72(3):287-96. doi: 10.1016/j.jacc.2018.04.060.

11. 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.

12. Razavi AC, Jain V, Gowtham R, et al. Does Elevated High-Density Lipoprotein Cholesterol Protect Against Cardiovascular Disease? The Journal of Clinical Endocrinology & Metabolism. 2024;109(2):321-32. doi: 10.1210/clinem/dgad406.

13. Matthews KA, Crawford SL, Chae CU, et al. Are Changes in Cardiovascular Disease Risk Factors in Midlife Women due to Chronological Aging or to the Menopausal Transition? J Am Coll Cardiol. 2009;54(25):2366-73. doi: 10.1016/j.jacc.2009.10.009.

14. Liu AC, Lawn RM, Verstuyft JG, Rubin EM. Human apolipoprotein A-I prevents atherosclerosis associated with apolipoprotein (a) in transgenic mice. Journal of Lipid Research.1994;35:2263-67.

15. 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;9:1-7. doi: 10.3389/fcvm.2022.843602.