Factors associated with levels of interleukins -18, -8, and -6 in hypertensive patients at high and very high cardiovascular risk

Aim. To identify the most significant factor influencing blood levels of cytokines in patients at high and very high cardiovascular risk. Materials and methods. A patient base from the “Management of chronic patients with multiple diseases” project was analyzed. 523 patients (mean age, 87±17.8) were included. Plasma samples were analyzed for concentrations of sodium, creatinine, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, and NT-proBNP. GFR was calculated using the CKD-EPI formula. Time-related CHF progression was assessed in one year; the time-related progression was considered an increase in CHF stage. Salt consumption was determined using the Charlton: SaltScreener questionnaire at the baseline visit and at one year. Low-salt diet containing 5 g of salt per day was recommended to all patients; 3.5 g of salt per day was recommended to patients with a documented diagnosis of CHF. Statistical analysis was performed using the Statistica 10.0 software. Results. 52.2 % of included patients consumed 6-10 g of salt per day; 43.4 % of patients consumed 10 g of salt or more per day; and only 4.4 % of patients consumed 5 g of salt or less per day. 21 % of included patients were at high risk of cardiovascular complications whereas for the vast majority of patients (79 %), the risk was stratified as very high. Two clusters of patients were formed based on the grade of hypertension, one-year CHF progression, and plasma levels of IL-6, -8, and -18. The one-year progression of CHF most significantly influenced the levels of IL-18, -8, and -6. The IL-6 level was correlated with the NT-proBNP level; an approximately similar degree of correlation was found for NT-proBNP and BP. Conclusion. Therefore, the performed statistical analysis determined correlations between the following factors: IL-6 level, NTproBNP level, and one-year CHF progression.

хроническая сердечная недостаточность, интерлейкин-18, интерлейкин-6, интерлекин-8, натрий, chronic heart failure, interleukin-18, interleukin-6, interleukin-8, sodium

1. Weinberger M.H., Fineberg N.S. Sodium and volume sensitivity of blood pressure. Age and pressure change over time. Hypertension. 1991; 18 (1): 67-71.

2. Rodriguez-Iturbe B., Franco M., Tapia E., Quiroz Y., Johnson R.J. Renal inflammation, autoimmunity and salt-sensitive hypertension. Clin Exp Pharmacol Physiol. 2012; 39 (1): 96-103. DOI: 10.1111/j.1440-1681.2011.05482.x.

3. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999; 340 (2): 115-26. DOI: 10.1056/NEJM199901143400207.

4. Pauletto P., Rattazzi M. Inflammation and hypertension: the search for a link. Nephrol Dial Transplant. 2006; 21 (4): 850-3. DOI: 10.1093/ndt/gfl019.

5. Crosswhite P., Sun Z. Ribonucleic Acid Interference Knockdown of Interleukin 6 Attenuates Cold-Induced Hypertension. Hypertension. 2010; 55 (6): 1484-91. DOI: 10.1161/HYPERTENSIONAHA.109.146902.

6. Rabkin S.W. The role of interleukin 18 in the pathogenesis of hypertension-induced vascular disease. Nature Clinical Practice Cardiovascular Medicine. 2009; 6 (3): 192-9. DOI: 10.1038/ncpcardio1453.

7. Madhur M.S., Lob H.E., McCann L.A., Iwakura Y., Blinder Y., Guzik T.J. et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension. 2010; 55 (2): 500-7. DOI: 10.1161/HYPERTENSIONAHA.109.145094.

8. Vm M., Al S., Aa A., As Z., Av K., Rs O. et al. Circulating interleukin-18: Association with IL-8, IL-10 and VEGF serum levels in patients with and without heart rhythm disorders. Int J Cardiol. 2016; 215: 105-9. DOI: 10.1016/j.ijcard.2016.04.002.

9. Shim A.L., Aksyonov A.A., Mitrokhin V.M., Lovchikova I.B., Konoplyannikov M.A., Konev A.V. et al. Serum interleukin-6: Association with circulating cytokine serum levels in patients with sinus arrhythmia and patients with coronary artery disease. Cell Immunol. 2016; 310: 178-83. DOI: 10.1016/j.cellimm.2016.09.007.

10. Charlton K.E., Steyn K., Levitt N.S., Jonathan D., Zulu J.V., Nel J.H. Development and validation of a short questionnaire to assess sodium intake. Public Health Nutrition. 2008; 11 (01): 83-94. DOI: 10.1017/S1368980007000146.

11. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016; 388 (10053): 1459-544. DOI: 10.1016/S0140-6736 (16) 31012-1.

12. Lim S.S., Vos T., Flaxman A.D., Danaei G., Shibuya K., Adair-Rohani H. et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380 (9859): 2224-60. DOI: 10.1016/S0140-6736 (12) 61766-8.

13. Frame A.A., Wainford R.D. Renal sodium handling and sodium sensitivity. Kidney Res Clin Pract. 2017; 36 (2): 117-31. DOI: 10.23876/j.krcp.2017.36.2.117.

14. Franco M., Tapia E., Bautista R., Pacheco U., Santamaria J., Quiroz Y. et al. Impaired pressure natriuresis resulting in salt-sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney. Am J Physiol Renal Physiol. 2013; 304 (7): F982-90. DOI: 10.1152/ajprenal.00463.2012.

15. Арутюнов Г.П., Драгунов Д.О., Соколова А.В. Взаимосвязь между натрийурезом, показателями центральной гемодинамики и плазменной концентрацией ангиотензина II. Клиническая нефрология. 2013; (6): 24-8 [Arutyunov G. P., Dragunov D. O., Sokolova A. V. Vzaimosvyaz' mezhdu natrijurezom, pokazatelyami czentral'noj gemodinamiki i plazmennoj konczentracziej angioten-zina II. Klinicheskaya nefrologiya. 2013; (6): 24-8].

16. Арутюнов Г.П., Драгунов Д.О., Соколова А.В., Моросанова Е.И. Влияние диуретиков с различным периодом полувыведения на изменение натрийурезаи показатели центральной гемодинамики у пациентов с гипертонической болезнью, осложненной хронической сердечной недостаточностью. Сердце: журнал для практикующих врачей. 2014; 13 (2): 107-13 [Arutyunov G. P., Dragunov D. O., Sokolova A. V., Morosanova E. I. Vliyanie diure-tikov s razlichny'm periodom poluvy'vedeniya na izmenenie natrijurezai pokazateli czentral'noj gemodinamiki u paczientov s gipertonicheskoj bolezn'yu,oslozhnennoj xronicheskoj serdech-noj nedostatochnost'yu. Serdcze: zhurnal dlya praktikuyushhix vrachej. 2014; 13 (2): 107-13].

17. Suzuki K., Miyashita A., Inoue Y., Iki S., Enomoto H., Takahashi Y. et al. Interleukin-6-producing pheochromocytoma. Acta Haematol. 1991; 85 (4): 217-9.

18. Fernandez-Real J.M., Vayreda M., Richart C., Gutierrez C., Broch M., Vendrell J. et al. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab. 2001; 86 (3): 1154-9. DOI: 10.1210/jcem.86.3.7305.

19. Chae C.U., Lee R.T., Rifai N., Ridker P.M. Blood pressure and inflammation in apparently healthy men. Hypertension. 2001; 38 (3): 399-403.

20. Zhang W., Wang W., Yu H., Zhang Y., Dai Y., Ning C. et al. Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage. Hypertension. 2012; 59 (1): 136-44. DOI: 10.1161/HYPERTENSIONAHA.111.173328.

21. Hulthe J., McPheat W., Samnegård A., Tornvall P., Hamsten A., Eriksson P. Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6. Atherosclerosis. 2006; 188 (2): 450-4. DOI: 10.1016/j.atherosclerosis.2005.11.013.

22. Woldbaek P.R., Sande J.B., Strømme T.A., Lunde P.K., Djurovic S., Lyberg T. et al. Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice. AmJ Physiol Heart Circ Physiol. 2005; 289 (2): H708-714. DOI: 10.1152/ajpheart.01179.2004.

23. Colston J.T., Boylston W.H., Feldman M.D., Jenkinson C.P., de la Rosa S.D., Barton A. et al. Interleukin-18 Knockout Mice Display Maladaptive Cardiac Hypertrophy in Response to Pressure Overload. Biochem Biophys Res Commun. 2007; 354 (2): 552-8. DOI: 10.1016/j.bbrc.2007.01.030.

24. ÖZzbïçer S., Uluçam Z.M. Association Between Interleukin-18 Level and Left Ventricular Mass Index in Hypertensive Patients. Korean Circ J. 2017; 47 (2): 238-44. DOI: 10.4070/kcj.2016.0351.

25. Naito Y., Tsujino T., Fujioka Y., Ohyanagi M., Okamura H., Iwasaki T. Increased circulating interleukin-18 in patients with congestive heart failure. Heart. 2002; 88 (3): 296-7. DOI: 10.1136/heart.88.3.296.

26. Seta Y., Kanda T., Tanaka T., Arai M., Sekiguchi K., Yokoyama T. et al. Interleukin-18 in patients with congestive heart failure: induction of atrial natriuretic peptide gene expression. Res Commun Mol Pathol Pharmacol. 2000; 108 (1-2): 87-95.

27. Арутюнов Г.П., Драгунов Д.О., Арутюнов А.Г., Соколова А.В. Влияние уровня общего натрия, депонированного в миокарде, на его жесткость. Терапевтический архив. 2017; 89 (1): 32-7 [Arutyunov G. P., Dragunov D. O., Arutyunov A. G., Sokolova A. V. Vliyanie urovnya obshhego natriya, deponirovannogo v miokarde, na ego zhestkost'. Terapevticheskij arxiv. 2017; 89 (1): 32-7].

28. Арутюнов Г.П., Драгунов Д.О., Соколова А.В. Влияние петлевых диуретиков с различным периодом полувыведения на динамику изменения натрийуреза у гипертоников с разным профилем артериального давления. Системные гипертензии. 2014; 11 (2): 23-8 [Arutyunov G. P., Dragunov D. O., Sokolova A. V. Vliyanie petlevy'x diuretikov s razlichny'm periodom poluvy'vedeniya na dinamiku izmeneniya natrijureza u gipertonikov s razny' m profilem arterial'nogo davleniya. Sistemny'e gipertenzii. 2014; 11 (2): 23-8].

29. Titze J. A different view on sodium balance. Curr Opin Nephrol Hypertens. 2015; 24 (1): 14-20. DOI: 10.1097/MNH.0000000000000085.

30. Titze J., Müller D.N., Luft F.C. Taking another “look” at sodium. Can J Cardiol. 2014; 30 (5): 473-5. DOI: 10.1016/j.cjca.2014.02.006.

31. Schatz V., Neubert P., Schröder A., Binger K., Gebhard M., Müller D.N. et al. Elementary immunology: Na+ as a regulator of immunity. Pediatr Nephrol. 2017; 32 (2): 201-10. DOI: 10.1007/s00467-016-3349-x.

32. Cohen T., Nahari D., Cerem L.W., Neufeld G., Levi B.Z. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996; 271 (2): 736-41.

33. Ebrahem Q., Minamoto A., Hoppe G., Anand-Apte B., Sears J.E. Triamcinolone Acetonide Inhibits IL-6 and VEGF-Induced Angiogenesis Downstream of the IL-6 and VEGF Receptors. Invest Ophthalmol Vis Sci. 2006; 47 (11): 4935-41. DOI: 10.1167/iovs.05-1651.