Novel Inflammatory Biomarkers as Additional Value to Traditional Risk-factors in Cardiovascular Risk Stratification

Authors

  • Ana Vavlukis Faculty of Pharmacy, Ss. Cyril and Methodius University, Skopje, Republic of Macedonia
  • Marija Vavlukis Professor aFaculty of Medicine, Ss. Cyril and Methodius University, Skopje, Republic of Macedonia
  • Aleksandar Dimovski Faculty of Pharmacy, Ss. Cyril and Methodius University, Skopje, Republic of Macedonia
  • Gordana Petrushevska Faculty of Medicine, Ss. Cyril and Methodius University, Skopje, Republic of Macedonia
  • Aleksandar Eftimov Faculty of Medicine, Ss. Cyril and Methodius University, Skopje, Republic of Macedonia
  • Sashka Domazetovska Faculty of Medicine, Ss. Cyril and Methodius University, Skopje, Republic of Macedonia
  • Almasa Demirovikj PZU Ena-Medikal, Skopje, Republic of Macedonia
  • Kristina Mladenovska Faculty of Pharmacy, Ss. Cyril and Methodius University, Skopje, Republic of Macedonia

DOI:

https://doi.org/10.3889/oamjms.2020.5119

Keywords:

Cardiovascular disease;, hsCRP;, Inflammatory biomarkers, IL-6, Risk-stratification

Abstract

BACKGROUND:: There is a growing interest in the possible role of inflammatory biomarkers, such as interleukins, chemokines, growth factors, and acute-phase proteins, in cardiovascular risk-stratification.

AIM: The aim of the study was to determine a possible correlation between the subjects’ cardiovascular risk profile and various inflammatory markers and to assess the sole use of IL-6 in CVD risk prediction.

MATERIALS AND METHODS: Seventy-five healthy subjects participated. EUROSCORE, lipid, glycemic, and inflammatory markers were analyzed. Сhi-square test, t-test, one-way ANOVA, Mann–Whitney, and Kruskal–Wallis tests were used. Significance was determined at <0.05.

RESULTS: A multivariate analysis revealed 12 markers to be independently associated with CVD risk – LDL-C, TG, ApoB, HbA1c, hsCRP, IL-6, and IL-1A as markers of higher, and HDL-C, IL-4, Il-10, VEGF, and EGF as markers of lower CVD risk. IL-6 levels > 1 pg/ml were positively correlated with female gender, age > 55 years, EUROSCORE ≥ 3, risk age, SBP, hsCRP > 2 mg/L, and IL-2 (p = 0.025, p = 0.013, p = 0.025, p = 0.011, p = 0.026, p = 0.046, and p = 0.018). Except for total CVD risk and risk age, the same variables were identified to be independently associated with IL-6.

CONCLUSION: Inflammatory biomarkers, especially hsCRP and IL-6, have a statistically significant, added predictive power in cardiovascular risk stratification.

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References

Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Murray CJ, et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: The global burden of disease 2010 study. Circulation. 2014;129(14):1483-92. https://doi.org/10.1161/circulationaha.113.004042 PMid:24573352

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: The sixth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European association for cardiovascular prevention and rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315-81. https://doi.org/10.1007/s12529-016-9583-6

Kavousi M, Elias-Smale S, Rutten JH, Leening MJ, Vliegenthart R, Verwoert GC, et al. Evaluation of newer risk markers for coronary heart disease risk classification: A cohort study. Ann Intern Med. 2012;156(6):438-44. https://doi.org/10.7326/0003-4819-156-6-201203200-00006 PMid:22431676

Yeboah J, Young R, McClelland RL, Delaney JC, Polonsky TS, Dawood FZ, et al. Utility of nontraditional risk markers in atherosclerotic cardiovascular disease risk assessment. J Am Coll Cardiol. 2016;67(2):139-47. PMid:26791059

Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: From pathophysiology to practice. J Am Coll Cardiol. 2009;54(23):2129-38. PMid:19942084

Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, et al. European guidelines on cardiovascular disease prevention in clinical practice: Full text. Fourth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2007;14(2):S1-113. https://doi.org/10.3410/f.718277733.793490996 PMid:17726407

Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple risk factor intervention trial. Am J Epidemiol. 1996;144(6):537-47. https://doi.org/10.1093/oxfordjournals.aje.a008963 PMid:8797513

Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557-65. https://doi.org/10.1056/nejmoa021993 PMid:12432042

Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease, stroke and mortality: An individual participant meta-analysis. Lancet. 2010;375(9790):132-40. https://doi.org/10.1016/s0140-6736(09)61717-7 PMid:20031199

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr., Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207. https://doi.org/10.1016/j.jvs.2008.12.037 PMid:18997196

Kaul S, Morrissey RP, Diamond GA. By Jove? What is a clinician to make of JUPITER? Arch Intern Med. 2010;170(12):1073-77. https://doi.org/10.1001/archinternmed.2010.189 PMid:20585074

Lubrano V, Balzan S. Consolidated and emerging inflammatory markers in coronary artery disease. World J Exp Med. 2015;5(1):21-32. PMid:25699231

Lubrano V, Balzan S. Enzymatic antioxidant system in vascular inflammation and coronary artery disease. World J Exp Med. 2015;5(4):218-24. https://doi.org/10.5493/wjem.v5.i4.218 PMid:26618108

Subirana I, Montserrat F, Diaz O, Vila J, Francés A, Delpon E, et al. Prediction of coronary disease incidence by biomarkers of inflammation, oxidation, and metabolism. Sci Rep. 2018;8:3191.

Karu I, Starkopf J, Zilmer K, Zilmer M. Growth factors serum levels in coronary artery disease patients scheduled for bypass surgery: Perioperative dynamics and comparisons with healthy volunteers. Biomed Res Int. 2013;2013:985404. https://doi.org/10.1155/2013/985404 PMid:23984427

Kleveland O, Kunszt G, Bratlie M, Ueland T, Broch K, Holte E, et al. Effect of a Single Dose of the Interleukin-6 Receptor Antagonist on Inflammation and Troponin Release in Patients with Non-STEMI. Tamil Nadu: ESC; 2015.

Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: Moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118(1):145-56. https://doi.org/10.1161/circresaha.115.306656 PMid:26837745

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;41(1):111-88. https://doi.org/10.3410/f.718277728.793490990 PMid:31504418

Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-22. https://doi.org/10.1016/s0140-6736(10)60484-9 PMid:20609967

Odegaard AO, Jacobs DR Jr., Sanchez OA, Goff DC Jr., Reiner AP, Gross MD. Oxidative stress, inflammation, endothelial dysfunction and incidence of Type 2 diabetes. Cardiovasc Diabetol. 2016;15:51. https://doi.org/10.1186/s12933-016-0369-6 PMid:27013319

Shu L, Chan KH, Zhang G, Huan T, Kurt Z, Zhao Y, et al. Shared genetic regulatory networks for cardiovascular disease and Type 2 diabetes in multiple populations of diverse ethnicities in the United States. PLoS Genet. 2017;13(9):e1007040. https://doi.org/10.1371/journal.pgen.1007040 PMid:28957322

Ridker PM, Bhatt DL, Bavry AA. Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin- JUPITER. United States: American Heart Association Annual Scientific Sessions; 2015.

Jing Y, Zhu D, Bi Y, Yang D, Hu Y, Shen S. Monocyte chemoattractant protein 1-2518 A/G polymorphism and susceptibility to Type 2 diabetes in a Chinese population. Clin Chim Acta. 2011;412(5-6):466-9. https://doi.org/10.1016/j.cca.2010.11.030

Khera A, McGuire DK, Murphy SA, Stanek HG, Das SR, Vongpatanasin W, et al. Race and gender differences in C-reactive protein levels. J Am Coll Cardiol. 2005;46(3):464-9. PMid:16053959

Milan-Mattos JC, Anibal FF, Perseguini NM, Minatel V, Rehder- Santos P, Castro CA, et al. Effects of natural aging and gender on pro-inflammatory markers. Braz J Med Biol Res. 2019;52(9):e8392. https://doi.org/10.1590/1414-431x20198392 PMid:31411315

Kumari R, Kumar S, Ahmad MK, Singh R, Pradhan A, Chandra S, et al. TNF-α/IL-10 ratio: An independent predictor for coronary artery disease in North Indian population. Diabetes Metab Syndr. 2018;12(3):221-5. https://doi.org/10.1016/j.dsx.2017.09.006 PMid:28988596

Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295. https://doi.org/10.1101/cshperspect.a016295 PMid:25190079

Huang YH, Yang HY, Huang SW, Ou G, Hsu YF, Hsu MJ. Interleukin-6 induces vascular endothelial growth factor-C expression via src-FAK-STAT3 signaling in lymphatic endothelial cells. PLoS One. 2016;11(7):e0158839. https://doi.org/10.1371/journal.pone.0158839 PMid:27383632

Zepeda-Orozco D, Wen HM, Hamilton BA, Raikwar NS, Thomas CP. EGF regulation of proximal tubule cell proliferation and VEGF-A secretion. Physiol Rep. 2017;5(18):e13453. https://doi.org/10.14814/phy2.13453 PMid:28963126

Rosenson RS, Brewer HB, Ansell B, Barter P, Chapman MJ, Heinecke JW, et al. Translation of high-density lipoprotein function into clinical practice: Current prospects and future challenges. Circulation. 2013;128(11):1256-67. https://doi.org/10.1161/circulationaha.113.000962 PMid:24019446

Asztalos BF, Tani M, Schaefer EJ. Metabolic and functional relevance of HDL subspecies. Curr Opin Lipidol. 2011;22(3):176- 85. https://doi.org/10.1097/mol.0b013e3283468061 PMid:21537175

White CR, Datta G, Mochon P, Zhang Z, Kelly O, Curcio C, et al. Vasculoprotective effects of apolipoprotein mimetic peptides: An evolving paradigm in HDL therapy (vascular disease prevention, In Press). Vasc Dis Prev. 2009;6:122-30. https://doi.org/10.2174/1567270000906010122 PMid:20084185

Wojdasiewicz P, Poniatowski LA, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014;2014:561459. https://doi.org/10.1155/2014/561459 PMid:24876674

Woodward EA, Prêle CM, Nicholson CE, Kolesnik TB, Hart PH. The anti-inflammatory effects of interleukin-4 are not mediated by suppressor of cytokine signalling-1 (SOCS1). Immunology. 2010;131(1):118-27. https://doi.org/10.1111/j.1365-2567.2010.03281.x PMid:20406299

Lee YW, Kim PH, Lee WH, Hirani AA. Interleukin-4, oxidative stress, vascular inflammation and atherosclerosis. Biomol Ther (Seoul). 2010;18(2):135-44. PMid:21072258

Orsó E, Schmitz G. Lipoprotein(a) and its role in inflammation, atherosclerosis and malignancies. Clin Res Cardiol Suppl. 2017;12(1):31-7. https://doi.org/10.1007/s11789-017-0084-1 PMid:28188431

Lyngdoh T, Marques-Vidal P, Paccaud F, Preisig M, Waeber G, Bochud M, et al. Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study. PLoS One. 2011;6(5):e19901. https://doi.org/10.1371/journal.pone.0019901 PMid:21625475

Panee J. Monocyte chemoattractant protein 1 (MCP-1) in obesity and diabetes. Cytokine. 2012;60(1):1-12. https://doi.org/10.1016/j.cyto.2012.06.018 PMid:22766373

Ferrante G, Condorelli G. Interleukin-6 trans-signaling and risk of future cardiovascular events: A new avenue of atheroprotection? Cardiovasc Res. 2019;115(1):8-9. https://doi.org/10.1093/cvr/cvy233 PMid:30219834

Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: Moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118(1):145-56. https://doi.org/10.1161/circresaha.115.306656 PMid:26837745

Wannamethee SG, Whincup PH, Rumley A, Lowe GD. Inter-relationships of interleukin-6, cardiovascular risk factors and the metabolic syndrome among older men. J Thromb Haemost. 2007;5(8):1637-43. https://doi.org/10.1111/j.1538-7836.2007.02643.x PMid:17596140

Bacchiega BC, Bacchiega AB, Usnayo MJ, Bedirian R, Singh G, da Rocha Castelar Pinheiro G. Interleukin-6 inhibition and coronary artery disease in a high-risk population: A prospective community-based clinical study. J Am Heart Assoc. 2017;6(3):e005038. https://doi.org/10.1161/jaha.116.005038 PMid:28288972

Lin YH, Glei D, Weinstein M, Wu SI, Chien KL. Additive value of interleukin-6 and C-reactive protein in risk prediction for all-cause and cardiovascular mortality among a representative adult cohort in Taiwan. J Form Med Assoc. 2017;116(12):982- 92. https://doi.org/10.1016/j.jfma.2017.02.002

Garofallo SB, Portal VL, Markoski MM, Dias LD, de Quadrosa AS, Marcadenti A. Correlations between traditional and nontraditional indicators of adiposity, inflammation, and monocyte subtypes in patients with stable coronary artery disease. J Obes. 2019;2019:3139278. https://doi.org/10.1155/2019/3139278 PMid:31354986

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Published

2020-11-02

How to Cite

1.
Vavlukis A, Vavlukis M, Dimovski A, Petrushevska G, Eftimov A, Domazetovska S, Demirovikj A, Mladenovska K. Novel Inflammatory Biomarkers as Additional Value to Traditional Risk-factors in Cardiovascular Risk Stratification. Open Access Maced J Med Sci [Internet]. 2020 Nov. 2 [cited 2021 Dec. 4];8(B):1092-104. Available from: https://oamjms.eu/index.php/mjms/article/view/5119

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