The Relationship of the Concentration of Lipoprotein(a) and Markers of Inflammation with Multifocal Atherosclerosis in Women

Purpose: to study relationship of lipoprotein(a) [Lp(a)], indicators of systemic inflammation and humoral immunity with severity of atherosclerotic involvement of various vascular beds in women.

Materials and methods. We included in this study 148 women aged 69±11 years with results of instrumental investigation of coronary, carotid arteries, and arteries of lower extremities. According to results of coronary angiography and ultrasound study patients were distributed into two groups: with stenosing atherosclerosis (those with hemodynamically significant [>50%] atherosclerotic lesions in any of these vascular beds, n=108), and control (those without hemodynamically significant stenoses, n=40). In dependence of extent of atherosclerotic involvement patients with stenosing atherosclerosis were divided into subgroups: with lesions in one vascular bed (subgroup 1, n=44) and with lesions in two and more vascular beds (subgroup 2, n=64). All patients with stenosing atherosclerosis and 78% of control patients took statins. In all patients we measured lipid spectrum, Lp(a) concentration, C-reactive protein (CRP). Preparations of oxidized lipoproteins [oxLp(a)] were obtained by Cu²⁺-induced free radical oxidation at 37 °С for 3 hours. Titer of autoantibodies to Lp(a), LDL and their oxidized modifications was determined by enzyme-linked immunosorbent assay (ELISA). Concentration of low-density lipoprotein cholesterol corrected on cholesterol in Lp(a) (LDLCh corr) was calculated by Dahlen modification of Friedewald formula.

Results. Stenosing atherosclerosis was diagnosed in 60 of 74 women (80%) with Lp(a) concentration above median - 33 mg/dl (in 38 multifical). Increase of blood serum Lp(a) concentration was associated with presence of isolated as well as multifocal atherosclerosis according to unifactorial, multifactorial, and logistic analysis, irrespective of other factors of risk and indicators of inflammation. According to results of logistic regression analysis increase of Lp(a) concentration by 1 mg/dl was associated with 1 % elevation of probability of appearance and development of multifocal atherosclerosis in women. Low level of class IgM autoantibodies to Lp(a) was linked with detection of stenosing atherosclerosis in any of 3 vascular beds (1^st vs. 4^th quartile of IgM autoantibodies concentration - OR 7.6., 95%CI 1.9-29.4; р=0.004) and had diagnostic significance. Indicators of systemic inflammation such as CRP and circulating immune complexes were high and had diagnostic significance for detection of multifocal atherosclerosis in studied women. However none of indicators was predictor of appearance of stenosing atherosclerosis according to data of logistic regression analysis.

Conclusion. Elevated concentration of Lp(a) is an independent predictor of risk of development stenosing atherosclerosis in various vascular beds and appearance of multifocal irrespective of other risk factors, indicators of systemic inflammation, and factors of humoral immunity in women. Markers of inflammation, as well as IgM autoantibodies against Lp(a) have diagnostic value for detection of patients stenosing lesions ib one or several vascular beds.

1. Aboyans V, Ricco J-B, Bartelink M-LEL, Bjorck M, Brodmann M, Cohnert T et al. Editor's Choice - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS). European Journal of Vascular and Endovascular Surgery. 2018;55(3):305-68. DOI: 10.1016/j.ejvs.2017.07.018

2. Ezhov M.V., Sergienko I.V., Aronov D.M., Arabidze G.G., Akhmedzhanov N. M., Bazhan S.S. et al. Diagnostics and correction of lipid metabolism disorders for the prevention and treatment of atherosclerosis. Russian recommendations VI revision. Atherosclerosis and Dyslipidemias. 2017;3:5-22.

3. Libby P, Loscalzo J, Ridker PM, Farkouh ME, Hsue PY, Fuster V et al. Inflammation, Immunity, and Infection in Atherothrombosis. Journal of the American College of Cardiology. 2018;72(17):2071-81. DOI: 10.1016/j.jacc.2018.08.1043

4. Avan A, Tavakoly Sany SB, Ghayour-Mobarhan M, Rahimi HR, Tajfard M, Ferns G. Serum C-reactive protein in the prediction of cardiovascular diseases: Overview of the latest clinical studies and public health practice. Journal of Cellular Physiology. 2018;233(11):8508-25. DOI: 10.1002/jcp.26791

5. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nature Reviews Immunology. 2008;8(10):802-15. DOI: 10.1038/nri2415

6. Azab B, Zaher M, Weiserbs KF, Torbey E, Lacossiere K, Gaddam S et al. Usefulness of Neutrophil to Lymphocyte Ratio in Predicting Short- and Long-Term Mortality After Non-ST-Elevation Myocardial Infarction. The American Journal of Cardiology. 2010;106(4):470-6. DOI: 10.1016/j.amjcard.2010.03.062

7. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. Journal of Lipid Research. 2016;57(11):1953-75. DOI: 10.1194/jlr.R071233

8. Burgess S, Ference BA, StaleyJR, 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 Cardiology. 2018;3(7):619-27. DOI: 10.1001/jamacardio.2018.1470

9. Orso E, Schmitz G. Lipoprotein (a) and its role in inflammation, atherosclerosis and malignancies. Clinical Research in Cardiology Supplements. 2017;12(S1):31-7. DOI: 10.1007/s11789-017-0084-1

10. Afanas'eva O.I., Ezhov M.V., Safarova M.S., Afanas'eva M.I., Adamova I.Yu., Pokrovsky S.N. Lipoprotein(a) polymorphism as a risk factor of coronary and carotid atherosclerosis and its complications in women. Cardiovascular Therapy and Prevention. 2010;9(6):10-6.

11. Ezhov M.V., Afanas'eva O.I., Benevolenskaia G.F., Savchenko A.P., Balakhonova TV., Liakishev A.A. et al. Association oflipoprotein(a) and apolipoprotein(a) phenotypes with coronary and carotid atherosclerosis in CHD men. Therapeutic Archive. 2000;72(1):28-32.

12. Dahlen GH. Incidence of Lp(a) lipoprotein among populations. In: In: Scanu AM (ed). Lipoprotein(a).-San Diego: Academic Press;

13. Afanas'eva O.I., Adamova I.Yu., Benevolenskaya G.F., Pokrovskiy S.N. Enzyme immunoassay of lipoprotein(a). Bulletin of Experimental Biology and Medicine. 1995;120(4):1030-3. DOI: 10.1007/BF02444976

14. Cho KI, Cho SH, Her A-Y, Singh GB, Shin E-S. Prognostic Utility of Neutrophil-to-Lymphocyte Ratio on Adverse Clinical Outcomes in Patients with Severe Calcific Aortic Stenosis. PLOS ONE. 2016;11(8):e0161530. DOI: 10.1371/journal.pone.0161530

15. Afanas'eva O.I., Ezhov M.V., Afanas'eva M.I., Safarova M.S., Berestetskaya Yu.V., Pokrovsky S.N. Correlations of low molecular weight phenotype of apoprotein(a) and serum level oflipoprotein(a) with multifocal atherosclerosis in patients with coronary heart disease. Rational Pharmacotherapy in Cardiology. 2010;6(4):474-80. DOI: 10.20996/1819-6446-2010-6-4-474-480

16. Tmoyan NA, Ezhov MV, Afanasieva OI, Klesareva EA, Razova OA, Kukharchuk VV et al. The association of lipoprotein(a) and apolipoprotein(a) phenotypes with peripheral artery disease. Therapeutic Archive. 2018;90(9):31-6. DOI: 10.26442/terarkh201890931-36

17. van Capelleveen JC, van der Valk FM, Stroes ESG. Current therapies for lowering lipoprotein (a). Journal of Lipid Research. 2016;57(9):1612-8. DOI: 10.1194/jlr.R053066

18. Rao F, Schork AJ, Maihofer AX, Nievergelt CM, Marcovina SM, Miller ER et al. Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35(7):1704-11. DOI: 10.1161/ATVBAHA.115.305306

19. Tsimikas S, Willeit P, Willeit J, Santer P, Mayr M, Xu Q et al. Oxidation-Specific Biomarkers, Prospective 15-Year Cardiovascular and Stroke Outcomes, and Net Reclassification of Cardiovascular Events. Journal of the American College of Cardiology. 2012;60(21):2218-29. DOI: 10.1016/j.jacc.2012.08.979

20. Miller YI, Choi S-H, Wiesner P, Fang L, Harkewicz R, Hartvigsen K et al. Oxidation-Specific Epitopes Are Danger-Associated Molecular Patterns Recognized by Pattern Recognition Receptors of Innate Immunity. Circulation Research. 2011;108(2):235-48. DOI: 10.1161/CIRCRESAHA.110.223875

21. Menees SB, Powell C, Kurlander J, Goel A, Chey WD. A MetaAnalysis of the Utility of C-Reactive Protein, Erythrocyte Sedimentation Rate, Fecal Calprotectin, and Fecal Lactoferrin to Exclude Inflammatory Bowel Disease in Adults With IBS: American Journal of Gastroenterology. 2015;110(3):444-54. DOI: 10.1038/ajg.2015.6

22. Ridker PM. A Test in Context: high-sensitivity C-reactive protein. Journal of the American College of Cardiology. 2016;67(6):712-23. DOI: 10.1016/j.jacc.2015.11.037

23. Coffman E, Richmond-Bryant J. Multiple biomarker models for improved risk estimation of specific cardiovascular diseases related to metabolic syndrome: a cross-sectional study. Population Health Metrics. 2015;13(1):7. DOI: 10.1186/s12963-015-0041-5

24. Peng Y, Dong B, Wang Z. Overall and Gender-specific Associations between C-reactive Protein and Stroke Occurrence: A Crosssectional Study in US. Journal of Stroke. 2016;18(3):355-7. DOI: 10.5853/jos.2016.00451

25. Gong S, Gao X, Xu F, Shang Z, Li S, Chen W et al. Association of lymphocyte to monocyte ratio with severity of coronary artery disease: Medicine. 2018;97(43):e12813. DOI: 10.1097/MD.0000000000012813