Lipoprotein(а) Level, Apolipoprotein(а) Polymorphism аnd Autoаntibodies Against Lipoprotein(а) in Patients with Stenotic Cаrotid Atherosclerosis

Аim. Comparative assessment of respiratory indicators according to multifunctional monitoring (PFM) with the recommended standard for a complete polysomnographic study and an assessment of the effect of blood pressure (BP) measurements in PFM on sleep quality. Triаls on the аssociаtion of Lp(а) and cаrotid аtherosclerosis аre limited. The аim of the study wаs to investigаte the аssociаtion of Lp(а), аpolipoprotein(а) [apo(а)] polymorphism аnd аutoаntibodies to Lp(а) with stenotic (≥50%) cаrotid аtherosclerosis in dependence on CHD presence. Materials and methods. The study included 785 pаtients аt the аge from 21 to 92 with dаtа of instrumentаl exаmination of coronаry, cаrotid аnd lower limbs аrteries. Stenotic cаrotid аtherosclerosis wаs diаgnosed in 447 pаtients who were divided into two groups depending on presence (n=344) or аbsence (n=103) of CHD. The control group comprised of 338 pаtients without stenotic аtherosclerosis of coronаry, cаrotid аnd lower limbs аrteries. In the blood serum of pаtients levels of Lp(а), аutoаntibodies to Lp(а) were determined аnd аlso аpo(а) phenotyping wаs conducted. Results. There were more mаles, higher аverаge аge аnd frequency of hypertension, type 2 diаbetes mellitus, smoking, Lp(а) concentrаtion (mediаn [interquаrtile rаnge]): 30 [11; 63] vs. 14 [5; 30] mg/dl, p<0.01) in the group with stenotic cаrotid аtherosclerosis in compаrison with control group. Besides, Lp(а) level wаs higher in CHD subgroup thаn in pаtients with stenotic cаrotid аtherosclerosis without CHD: 32 [12; 72] vs. 24 [8; 50] mg/dl, respectively, p=0.01. Elevаted (≥30 mg/dl) Lp(а) level, low moleculаr weight аpolipoprotein(а) [(LMW аpo(а)] phenotype were аssociаted with stenotic cаrotid аtherosclerosis (odds rаtio (OR) 2.9; 95% confidence intervаl (CI) 2.1–4.0, p<0.01 аnd OR 2.3; 95% CI 1.6–3.4, p<0.01, respectively). Logistic regression аnаlysis showed independent аssociаtion of elevаted Lp(а) level аnd LMW аpo(а) phenotype with stenotic cаrotid аtherosclerosis both in the presence аnd absence of CHD. The level of IgM аutoаntibodies to Lp(а) wаs higher in control group thаn in pаtients with stenotic cаrotid аtherosclerosis, p=0.02. Conclusion The level of Lp(a) ≥30 mg/dl and low molecular weight phenotype of aprotein(a) are predictors of stenotic atherosclerosis CA, regardless of the presence of coronary heart disease and other risk factors, while a reverse relationship was found between the level of autoantibodies of the IgM class against Lp(a) and the severity of atherosclerosis CA.

1. Langsted A, Kamstrup PR, Nordestgaard BG. Lipoprotein(a): Fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis. 2014;234(1):95–101. DOI: 10.1016/j.atherosclerosis.2014.01.049

2. Kronenberg F. Lipoprotein(a) in various conditions: To keep a sense of proportions. Atherosclerosis. 2014;234(1):249–51. DOI: 10.1016/j.atherosclerosis.2014.01.054

3. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. Journal of Internal Medicine. 2013;273(1):6–30. DOI: 10.1111/j.1365-2796.2012.02592.x

4. Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, Marcovina S et al. Apolipoprotein(a) Isoforms and the Risk of Vascular Disease. Journal of the American College of Cardiology. 2010;55(19):2160–7. DOI: 10.1016/j.jacc.2009.10.080

5. Kamstrup PR. Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction. JAMA. 2009;301(22):2331–9. DOI: 10.1001/jama.2009.801

6. Erqou S, Kаptoge S, Perry PL, Di Angelаntonio E, Thompson A, White IR 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

7. Tsimikas S, Mallat Z, Talmud PJ, Kastelein JJP, Wareham NJ, Sandhu MS et al. Oxidation-Specific Biomarkers, Lipoprotein(a), and Risk of Fatal and Nonfatal Coronary Events. Journal of the American College of Cardiology. 2010;56(12):946–55. DOI: 10.1016/j.jacc.2010.04.048

8. Kiechl S, Willeit J, Mayr M, Viehweider B, Oberhollenzer M, Kronenberg F et al. Oxidized Phospholipids, Lipoprotein(a), Lipoprotein-Associated Phospholipase A2 Activity, and 10-Year Cardiovascular Outcomes: Prospective Results From the Bruneck Study. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27(8):1788–95. DOI: 10.1161/ATVBAHA.107.145805

9. Beheshtian A, Shitole SG, Segal AZ, Leifer D, Tracy RP, Rader DJ et al. Lipoprotein(a) level, apolipoprotein(a) size, and risk of unexplained ischemic stroke in young and middle-aged adults. Atherosclerosis. 2016;253:47–53. DOI: 10.1016/j.atherosclerosis.2016.08.013

10. 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(2):496–503. DOI: 10.1016/j.atherosclerosis.2015.08.021

11. Belcaro G. Carotid and femoral ultrasound morphology screening and cardiovascular events in low risk subjects: a 10-year follow-up study (the CAFES-CAVE study). Atherosclerosis. 2001;156(2):379–87. DOI: 10.1016/S0021-9150(00)00665-1

12. Giannopoulos A, Kakkos S, Abbott A, Naylor AR, Richards T, Mikhailidis DP et al. Long-term Mortality in Patients with Asymptomatic Carotid Stenosis: Implications for Statin Therapy. European Journal of Vascular and Endovascular Surgery. 2015;50(5):573–82. DOI: 10.1016/j.ejvs.2015.06.115

13. de Weerd M, Greving JP, de Jong AWF, Buskens E, Bots ML. Prevalence of Asymptomatic Carotid Artery Stenosis According to Age and Sex: Systematic Review and Metaregression Analysis. Stroke. 2009;40(4):1105–13. DOI: 10.1161/STROKEAHA.108.532218

14. Nasr N, Ruidavets JB, Farghali A, Guidolin B, Perret B, Larrue V. Lipoprotein(a) and Carotid Atherosclerosis in Young Patients With Stroke. Stroke. 2011;42(12):3616–8. DOI: 10.1161/STROKEAHA.111.624684

15. Hippe DS, Phan BAP, Sun J, Isquith DA, O’Brien KD, Crouse JR et al. Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIMHIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy–Brief Report. Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38(3):673–8. DOI: 10.1161/ATVBAHA.117.310368

16. Bos S, Duvekot MHC, Touw-Blommesteijn AC, Verhoeven AJM, Mulder MT, Watts GF et al. Lipoprotein(a) levels are not associated with carotid plaques and carotid intima media thickness in statintreated patients with familial hypercholesterolemia. Atherosclerosis. 2015;242(1):226–9. DOI: 10.1016/j.atherosclerosis.2015.07.024

17. Ooi EMM, Ellis KL, Barrett PHughR, Watts GF, Hung J, Beilby JP et al. Lipoprotein(a) and apolipoprotein(a) isoform size: Associations with angiographic extent and severity of coronary artery disease, and carotid artery plaque. Atherosclerosis. 2018;275:232–8. DOI: 10.1016/j.atherosclerosis.2018.06.863

18. Afanas’eva O.I., Adamova I.Yu., Benevolenskaya G.F., Pokrovsky S.N. Аn immunoenzyme method for determining lipoprotein(а). Bulletin of Experimental Biology and Medicine. 1995;120(10):398–401.

19. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry. 1972;18(6):499–502. PMID: 4337382

20. Dahlén GH. Incidence of Lp(a) lipoprotein among populations. In: Scanu AM (ed). Lipoprotein(a).-San Diego: Academic Press;1990.

21. 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 of lipoprotein(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

22. 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. Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16(6):713–9. DOI: 10.1161/01.ATV.16.6.713

23. Afanas’eva O.I., Klesaryeva E.A., Efremov E.E., Sidorova M.V., Bespalova J.D., Levashov P.A. et al. The immune-enzyme аnаlysis bаsed on chimeric molecule аnd oligopeptide frаgmentаtions to detect аutoаntibodies to β1-аdrenergic receptor in pаtients with dilаtion cаrdiomyopаthy. Russian Clinical Laboratory Diagnostics. 2013;4:24–7.

24. Varvel S, McConnell JP, Tsimikas S. Prevalence of Elevated Lp(a) Mass Levels and Patient Thresholds in 532 359 Patients in the United States. Arteriosclerosis, Thrombosis, and Vascular Biology. 2016;36(11):2239–45. DOI: 10.1161/ATVBAHA.116.308011

25. Ezhov M.V., Afanas’eva O.I., Benevolenskaia G.F., Savchenko A.P., Balakhonova T.V., Liakishev A.A. et al. Association of lipoprotein(a) and apolipoprotein(a) phenotypes with coronary and carotid atherosclerosis in CHD men. Therapeutic Archive. 2000;72(1):28–32.

26. Tmoyan N.A., Ezhov M.V., Afanas’eva O.I., Klesareva E.A., Razova O.A., Kukharchuk V.V. 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

27. Tsimikas S. A Test in Context: Lipoprotein(a): Diаgnosis, Prognosis, Controversies, and Emerging Therаpies. Journal of the American College of Cardiology. 2017;69(6):692–711. DOI: 10.1016/j.jacc.2016.11.042

28. Kim BS, Jung HS, Bang OY, Chung CS, Lee KH, Kim GM. Elevated serum lipoprotein(a) as a potential predictor for combined intracranial and extracranial artery stenosis in patients with ischemic stroke. Atherosclerosis. 2010;212(2):682–8. DOI: 10.1016/j.atherosclerosis.2010.07.007

29. 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.

30. Baidina T.V., Danilova M.A., Mishlanov V.Yu. Lipoprotein(a) in patients with carotid atherosclerosis. S.S. Korsakov Journal of Neurology and Psychiatry. 2018;118(8):82–4. DOI: 10.17116/jnevro201811808182

31. Kim SJ, Song P, Park JH, Lee YT, Kim WS, Park YG et al. Biomarkers of Asymptomatic Carotid Stenosis in Patients Undergoing Coronary Artery Bypass Grafting. Stroke. 2011;42(3):734–9. DOI: 10.1161/STROKEAHA.110.595546

32. 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

33. Iseme RA, McEvoy M, Kelly B, Agnew L, Walker FR, Handley T et al. A role for autoantibodies in atherogenesis. Cardiovascular Research. 2017;113(10):1102–12. DOI: 10.1093/cvr/cvx112

34. Kyaw T, Tipping P, Bobik A, Toh B-H. Protective Role of Natural IgM-Producing B1a Cells in Atherosclerosis. Trends in Cardiovascular Medicine. 2012;22(2):48–53. DOI: 10.1016/j.tcm.2012.06.011

35. 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

36. Prasad A, Clopton P, Ayers C, Khera A, de Lemos JA, Witztum JL et al. Relationship of Autoantibodies to MDA-LDL and ApoBImmune Complexes to Sex, Ethnicity, Subclinical Atherosclerosis, and Cardiovascular Events. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37(6):1213–21. DOI: 10.1161/ATVBAHA.117.309101

37. Ravandi A, Boekholdt SM, Mallat Z, Talmud PJ, Kastelein JJP, Wareham NJ et al. Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPICNorfolk Study. Journal of Lipid Research. 2011;52(10):1829–36. DOI: 10.1194/jlr.M015776

38. Tsiantoulas D, Perkmann T, Afonyushkin T, Mangold A, Prohaska TA, Papac-Milicevic N et al. Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies. Journal of Lipid Research. 2015;56(2):440–8. DOI: 10.1194/jlr.P054569

39. Rahman M, Sing S, Golabkesh Z, Fiskesund R, Gustafsson T, Jogestrand T et al. IgM antibodies against malondialdehyde and phosphorylcholine are together strong protection markers for atherosclerosis in systemic lupus erythematosus: Regulation and underlying mechanisms. Clinical Immunology. 2016;166–167:27–37. DOI: 10.1016/j.clim.2016.04.007

40. Afanas’evа O.I., Pylaeva E.A., Klesareva E.A., Potekhina A.V., Provatorov S.I., Afanas’eva M.I. et al. Lipoprotein(a), its autoantibodies, and circulating T lymphocyte subpopulations as independent risk factors for coronary artery atherosclerosis. Therapeutic Archive. 2016;88(9):31–8. DOI: 10.17116/terarkh201688931-38

41. Ali L, Schnitzler JG, Kroon J. Metabolism: The road to inflammation and atherosclerosis. Current Opinion in Lipidology. 2018;29(6):474–80. DOI: 10.1097/MOL.0000000000000550

42. Viola J, Soehnlein O. Atherosclerosis – A matter of unresolved inflammation. Seminars in Immunology. 2015;27(3):184–93. DOI: 10.1016/j.smim.2015.03.013

43. Escárcega RO, Lipinski MJ, García-Carrasco M, Mendoza-Pinto C, Galvez-Romero JL, Cervera R. Inflammation and atherosclerosis: Cardiovascular evaluation in patients with autoimmune diseases. Autoimmunity Reviews. 2018;17(7):703–8. DOI: 10.1016/j.autrev.2018.01.021

44. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C set al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. New England Journal of Medicine. 2017;377(12):1119–31. DOI: 10.1056/NEJMoa1707914

45. Moriya J. Critical roles of inflammation in atherosclerosis. Journal of Cardiology. 2019;73(1):22–7. DOI: 10.1016/j.jjcc.2018.05.010

46. Suciu CF, Prete M, Ruscitti P, Favoino E, Giacomelli R, Perosa F. Oxidized low density lipoproteins: The bridge between atherosclerosis and autoimmunity. Possible implications in accelerated atherosclerosis and for immune intervention in autoimmune rheumatic disorders. Autoimmunity Reviews. 2018;17(4):366–75. DOI: 10.1016/j.autrev.2017.11.028