Ассоциация между адипокинами и ремоделированием сердца у пациентов с ожирением на доклинических стадиях сердечной недостаточности

Введение. Ассоциация между гипертрофией левого желудочка (ГЛЖ) при ожирении и сопутствующих метаболических рисках с уровнем адипокинов на различных стадиях сердечной недостаточности (СН) в настоящее время обсуждается.

Цель – изучить взаимосвязь уровней циркулирующих адипокинов с ГЛЖ у пациентов с ожирением на доклинических стадиях СН. Материалы и методы. Исследованы 74  пациента с ожирением: 43% без маркеров ГЛЖ  (стадия A СН) – группа 1, 57% с ГЛЖ (стадия B СН) – группа 2. Проведена трансторакальная эхокардиография, оценка N-концевого предшественника мозгового натрийуретического пептида (Nt-proBNP), стимулирующего фактора роста, экспрессируемого геном 2, растворимая форма (sST2), уровней лептина и адипонектина, расчет индекса инсулинорезистентности HOMA-IR. Применен статистический метод согласованных пар – matched pairs analysis.

Результаты. Установлены отрицательные корреляции маркеров ГЛЖ с уровнем лептина в группе 1 (стадия А СН) и с уровнем адипонектина в группе 2 (стадия В СН) (все p < 0,05). Наблюдались положительные корреляции между соотношением sST2/ адипонектин и HOMA-IR с параметрами ГЛЖ в группе 2 (стадия В СН) (все p >< 0,05). Заключение. Направленность ассоциаций между циркулирующим уровнем адипокинов и ГЛЖ различается в зависимости от доклинической стадии СН. Полученные данные могут отражать взаимосвязь между ремоделированием сердца в ответ на  молекулярные механизмы воспаления и инсулинорезистентность с ожирением на определенной стадии сердечнососудистого континуума. Ключевые слова: лептин, адипонектин, инсулинорезистентность, HOMA-IR, воспаление, sST2, гипертрофия левого желудочка>˂ 0,05). Наблюдались положительные корреляции между соотношением sST2/ адипонектин и HOMA-IR с параметрами ГЛЖ в группе 2 (стадия В СН) (все p ˂ 0,05).

Заключение. Направленность ассоциаций между циркулирующим уровнем адипокинов и ГЛЖ различается в зависимости от доклинической стадии СН. Полученные данные могут отражать взаимосвязь между ремоделированием сердца в ответ на  молекулярные механизмы воспаления и инсулинорезистентность с ожирением на определенной стадии сердечнососудистого континуума. 

1. Badimon L., Bugiardini R., Cenko E., Cubedo J., Dorobantu M., Duncker D.J. et al. Position paper of the European Society of Cardiology-working group of coronary pathophysiology and microcirculation: obesity and heart disease. Eur Heart J. 2017;38(25):1951–1958. https://doi.org/10.1093/eurheartj/ehx181.

2. Heidenreich P.A., Bozkurt B., Aguilar D., Allen L.A., Byun J.J., Colvin M.M. et al. AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895– e1032. https://doi.org/10.1161/CIR.0000000000001063.

3. Bozkurt B., Aguilar D., Deswal A., Dunbar S.B., Francis G.S., Horwich T. et al. Contributory Risk and Management of Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and Metabolic Syndrome in Chronic Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016;134(23):e535–e578. https://doi.org/10.1161/CIR.0000000000000450.

4. Prenner S.B., Mather P.J. Obesity and heart failure with preserved ejection fraction: A growing problem. Trends Cardiovasc Med. 2018;28(5):322–327. https://doi.org/10.1016/j.tcm.2017.12.003.

5. Albakri A. Obesity cardiomyopathy: a review of literature on clinical status and meta-analysis of diagnostic and clinical management. Med Clin Arch. 2018;2(3):1–13. https://doi.org/10.15761/MCA.1000134.

6. Abel E.D., Litwin S.E., Sweeney G. Cardiac remodeling in obesity. Physiol Rev. 2008;88(2):389–419. https://doi.org/10.1152/physrev.00017.2007.

7. Sletten A.C., Peterson L.R., Schaffer J.E. Manifestations and mechanisms of myocardial lipotoxicity in obesity. J Intern Med. 2018;284(5):478–491. https://doi.org/10.1111/joim.12728.

8. Ashrafian H., Athanasiou T., le Roux C.W. Heart remodelling and obesity: the complexities and variation of cardiac geometry. Heart. 2011;97(3):171–172. https://doi.org/10.1136/hrt.2010.207092.

9. Selthofer-Relatić K., Belovari T., Bijelić N., Kibel A., Rajc J. Presence of Intramyocardial Fat Tissue in the Right Atrium and Right Ventricle – Postmortem Human Analysis. Acta Clin Croat. 2018;57(1):122–129. https://doi.org/10.20471/acc.2018.57.01.15.

10. Packer M., Kitzman D.W. Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2. JACC Heart Fail. 2018;6(8):633–639. https://doi.org/10.1016/j.jchf.2018.01.009.

11. Oh A., Okazaki R., Sam F., Valero-Muñoz M. Heart Failure With Preserved Ejection Fraction and Adipose Tissue: A Story of Two Tales. Front Cardiovasc Med. 2019;6:110. https://doi.org/10.3389/fcvm.2019.00110.

12. Packer M. Leptin-Aldosterone-Neprilysin Axis: Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity. Circulation. 2018;137(15):1614–1631. https://doi.org/10.1161/CIRCULATIONAHA.117.032474.

13. Trayhurn P., Wood I.S. Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans. 2005;33(Pt 5):1078–1081. https://doi.org/10.1042/BST0331078.

14. Bahrami H., Bluemke D.A., Kronmal R., Bertoni A.G., Lloyd-Jones D.M., Shahar E. et al. Novel metabolic risk factors for incident heart failure and their relationship with obesity: the MESA (Multi-Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol. 2008;51(18):1775–1783. https://doi.org/10.1016/j.jacc.2007.12.048.

15. Rosen B.D., Cushman M., Nasir K., Bluemke D.A., Edvardsen T., Fernandes V. et al. Relationship between C-reactive protein levels and regional left ventricular function in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis. J Am Coll Cardiol. 2007;49(5):594–600. https://doi.org/10.1016/j.jacc.2006.09.040.

16. Wu H., Ballantyne C.M. Metabolic Inflammation and Insulin Resistance in Obesity. Circ Res. 2020;126(11):1549–1564. https://doi.org/10.1161/CIRCRESAHA.119.315896.

17. Witteles R.M., Fowler M.B. Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol. 2008;51(2):93–102. https://doi.org/10.1016/j.jacc.2007.10.021.

18. Cauwenberghs N., Knez J., Thijs L., Haddad F., Vanassche T., Yang W.Y. et al. Relation of Insulin Resistance to Longitudinal Changes in Left Ventricular Structure and Function in a General Population. J Am Heart Assoc. 2018;7(7):e008315. https://doi.org/10.1161/JAHA.117.008315.

19. Velagaleti R.S., Gona P., Chuang M.L., Salton C.J., Fox C.S., Blease S.J. et al. Relations of insulin resistance and glycemic abnormalities to cardiovascular magnetic resonance measures of cardiac structure and function: the Framingham Heart Study. Circ Cardiovasc Imaging. 2010;3(3):257–263. https://doi.org/10.1161/CIRCIMAGING.109.911438.

20. Shah R.V., Abbasi S.A., Heydari B., Rickers C., Jacobs D.R. Jr, Wang L. et al. Insulin resistance, subclinical left ventricular remodeling, and the obesity paradox: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2013;61(16):1698–1706. https://doi.org/10.1016/j.jacc.2013.01.053.

21. Wong C., Marwick T.H. Obesity cardiomyopathy: pathogenesis and pathophysiology. Nat Clin Pract Cardiovasc Med. 2007;4(8):436–443. https://doi.org/10.1038/ncpcardio0943.

22. Ghantous C.M., Azrak Z., Hanache S., Abou-Kheir W., Zeidan A. Differential Role of Leptin and Adiponectin in Cardiovascular System. Int J Endocrinol. 2015:534320. https://doi.org/10.1155/2015/534320.

23. Ebong I.A., Goff D.C. Jr, Rodriguez C.J., Chen H., Bertoni A.G. Mechanisms of heart failure in obesity. Obes Res Clin Pract. 2014;8(6):e540–548. https://doi.org/10.1016/j.orcp.2013.12.005.

24. Rajapurohitam V., Gan X.T., Kirshenbaum L.A., Karmazyn M. The obesityassociated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res. 2003;93(4):277–279. https://doi.org/10.1161/01.RES.0000089255.37804.72.

25. Smith C.C., Yellon D.M. Adipocytokines, cardiovascular pathophysiology and myocardial protection. Pharmacol Ther. 2011;129(2):206–219. https://doi.org/10.1016/j.pharmthera.2010.09.003.

26. Karmazyn M., Purdham D.M., Rajapurohitam V., Zeidan A. Leptin as a cardiac hypertrophic factor: a potential target for therapeutics. Trends Cardiovasc Med. 2007;17(6):206–211. https://doi.org/10.1016/j.tcm.2007.06.001.

27. Bantulà M., Roca-Ferrer J., Arismendi E., Picado C. Asthma and Obesity: Two Diseases on the Rise and Bridged by Inflammation. J Clin Med. 2021;10(2):169. https://doi.org/10.3390/jcm10020169.

28. Kamareddine L., Ghantous C.M., Allouch S., Al-Ashmar S.A., Anlar G., Kannan S. et al. Between Inflammation and Autophagy: The Role of Leptin-Adiponectin Axis in Cardiac Remodeling. J Inflamm Res. 2021;14:5349–5365. https://doi.org/10.2147/JIR.S322231.

29. Hall M.E., Harmancey R., Stec D.E. Lean heart: Role of leptin in cardiac hypertrophy and metabolism. World J Cardiol. 2015;7(9):511–524. https://doi.org/10.4330/wjc.v7.i9.511.

30. Woodward L., Akoumianakis I., Antoniades C. Unravelling the adiponectin paradox: novel roles of adiponectin in the regulation of cardiovascular disease. Br J Pharmacol. 2017;174(22):4007–4020. https://doi.org/10.1111/bph.13619.

31. Shibata R., Ouchi N., Ito M., Kihara S., Shiojima I., Pimentel D.R. et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 2004;10(12):1384–1389. https://doi.org/10.1038/nm1137.

32. Anthony S.R., Guarnieri A.R., Gozdiff A., Helsley R.N., Phillip Owens A., Tranter M. Mechanisms linking adipose tissue inflammation to cardiac hypertrophy and fibrosis. Clin Sci (Lond). 2019;133(22):2329–2344. https://doi.org/10.1042/CS20190578.

33. Norvik J.V., Schirmer H., Ytrehus K., Jenssen T.G., Zykova S.N., Eggen A.E. et al. Low adiponectin is associated with diastolic dysfunction in women: a cross-sectional study from the Tromsø Study. BMC Cardiovasc Disord. 2017;17(1):79. https://doi.org/10.1186/s12872-017-0509-2.

34. Biolo A., Shibata R., Ouchi N., Kihara S., Sonoda M., Walsh K., Sam F. Determinants of adiponectin levels in patients with chronic systolic heart failure. Am J Cardiol.;105(8):1147–1152. https://doi.org/10.1016/j.amjcard.2009.12.015.

35. Villarreal-Molina M.T., Antuna-Puente B. Adiponectin: anti-inflammatory and cardioprotective effects. Biochimie. 2012;94(10):2143–2149. https://doi.org/10.1016/j.biochi.2012.06.030.

36. López-Jaramillo P., Gómez-Arbeláez D., López-López J., López-López C., Martínez-Ortega J,. Gómez-Rodríguez A., Triana-Cubillos S. The role of leptin/ adiponectin ratio in metabolic syndrome and diabetes. Horm Mol Biol Clin Investig. 2014;18(1):37–45. https://doi.org/10.1515/hmbci-2013-0053.

37. Williams B., Mancia G., Spiering W., Agabiti Rosei E., Azizi M., Burnier M. et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104. https://doi.org/10.1093/eurheartj/ehy339.

38. Marwick T.H., Gillebert T.C., Aurigemma G., Chirinos J., Derumeaux G., Galderisi M. et al. Recommendations on the Use of Echocardiography in Adult Hypertension: A Report from the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE). J Am Soc Echocardiogr. 2015;28(7):727–754. https://doi.org/10.1016/j.echo.2015.05.002.

39. McClatchey M.W., Cohen S.J., Reed F.M. The usefulness of matched pair randomization for medical practice-based research. Fam Pract Res J. 1992;12(3):235–243. Available at: https://pubmed.ncbi.nlm.nih.gov/1414427/.

40. Zhang Z. Introduction to machine learning: k-nearest neighbors. Ann Transl Med. 2016;4(11):218. https://doi.org/10.21037/atm.2016.03.37.

41. Liu T., Moore A. W., Gray A. New algorithms for efficient high-dimensional nonparametric classification. J Mach Learn Res. 2006;7(41):1135–1158. Available at: http://people.ee.duke.edu/~lcarin/liu06a.pdf.

42. Perego L., Pizzocri P., Corradi D., Maisano F., Paganelli M., Fiorina P. et al. Circulating leptin correlates with left ventricular mass in morbid (grade III) obesity before and after weight loss induced by bariatric surgery: a potential role for leptin in mediating human left ventricular hypertrophy. J Clin Endocrinol Metab. 2005;90(7):4087–4093. https://doi.org/10.1210/jc.2004-1963.

43. Barouch L.A., Berkowitz D.E., Harrison R.W., O’Donnell C.P., Hare J.M. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003;108(6):754–759. https://doi.org/10.1161/01.CIR.0000083716.82622.FD.

44. Hall M.E., Maready M.W., Hall J.E., Stec D.E. Rescue of cardiac leptin receptors in db/db mice prevents myocardial triglyceride accumulation. Am J Physiol Endocrinol Metab. 2014;307(3):E316–325. https://doi.org/10.1152/ajpendo.00005.2014.

45. Pladevall M., Williams K., Guyer H., Sadurní J., Falces C., Ribes A. et al. The association between leptin and left ventricular hypertrophy: a populationbased cross-sectional study. J Hypertens. 2003;21(8):1467–1473. https://doi.org/10.1097/00004872-200308000-00009.

46. Lieb W., Sullivan L.M., Aragam J., Harris T.B., Roubenoff R., Benjamin E.J., Vasan R.S. Relation of serum leptin with cardiac mass and left atrial dimension in individuals >70 years of age. Am J Cardiol. 2009;104(4):602–605. https://doi.org/10.1016/j.amjcard.2009.04.026.

47. Paduszyńska A., Sakowicz A., Banach M., Maciejewski M., Dąbrowa M., Bielecka-Dąbrowa A. Cardioprotective properties of leptin in patients with excessive body mass. Ir J Med Sci. 2020;189(4):1259–1265. https://doi.org/10.1007/s11845-020-02211-9.

48. Kamimura D., Suzuki T., Wang W., deShazo M., Hall J.E., Winniford M.D. et al. Higher plasma leptin levels are associated with reduced left ventricular mass and left ventricular diastolic stiffness in black women: insights from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Hypertens Res. 2018;41(8):629–638. https://doi.org/10.1038/s41440-018-0062-0.

49. Melhem S., Steven S., Taylor R., Al-Mrabeh A. Effect of Weight Loss by LowCalorie Diet on Cardiovascular Health in Type 2 Diabetes: An Interventional Cohort Study. Nutrients. 2021;13(5):1465. https://doi.org/10.3390/nu13051465.

50. Fujita Y., Kouda K., Ohara K., Nakamura H., Iki M. Leptin mediates the relationship between fat mass and blood pressure: The Hamamatsu Schoolbased health study. Medicine (Baltimore). 2019;98(12):e14934. https://doi.org/10.1097/MD.0000000000014934.

51. D’souza A.M., Neumann U.H., Glavas M.M., Kieffer T.J. The glucoregulatory actions of leptin. Mol Metab. 2017;6(9):1052–1065. https://doi.org/10.1016/j.molmet.2017.04.011.

52. Pereira S., Cline D.L., Glavas M.M., Covey S.D., Kieffer T.J. Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism. Endocr Rev. 2021;42(1):1–28. https://doi.org/10.1210/endrev/bnaa027.

53. Isidori A.M., Strollo F., Morè M., Caprio M., Aversa A., Moretti C. et al. Leptin and aging: correlation with endocrine changes in male and female healthy adult populations of different body weights. J Clin Endocrinol Metab. 2000;85(5):1954–1962. https://doi.org/10.1210/jcem.85.5.6572.

54. Sahu A. Minireview: A hypothalamic role in energy balance with special emphasis on leptin. Endocrinology. 2004;145(6):2613–2620. https://doi.org/10.1210/en.2004-0032.

55. Unger R.H. Hyperleptinemia: protecting the heart from lipid overload. Hypertension. 2005;45(6):1031–1034. https://doi.org/10.1161/01.HYP.0000165683.09053.02.

56. Faxén U.L., Hage C., Andreasson A., Donal E., Daubert J.C., Linde C. et al. HFpEF and HFrEF exhibit different phenotypes as assessed by leptin and adiponectin. Int J Cardiol. 2017;228:709–716. https://doi.org/10.1016/j.ijcard.2016.11.194.

57. Reinmann M., Meyer P. B-type natriuretic peptide and obesity in heart failure: a mysterious but important association in clinical practice. Cardiovasc Med. 2020;23:w02095. https://doi.org/10.4414/cvm.2020.02095.

58. Sarhene M., Wang Y., Wei J., Huang Y., Li M., Li L. et al. Biomarkers in heart failure: the past, current and future. Heart Fail Rev. 2019;24(6):867–903. https://doi.org/10.1007/s10741-019-09807-z.

59. Ghali R., Altara R., Louch W.E., Cataliotti A., Mallat Z., Kaplan A. et al. IL-33 (Interleukin 33)/sST2 Axis in Hypertension and Heart Failure. Hypertension. 2018;72(4):818–828. https://doi.org/10.1161/HYPERTENSIONAHA.118.11157.

60. Altara R., Ghali R., Mallat Z., Cataliotti A., Booz G.W., Zouein F.A. Conflicting vascular and metabolic impact of the IL-33/sST2 axis. Cardiovasc Res. 2018;114(12):1578–1594. https://doi.org/10.1093/cvr/cvy166.

61. Zeyda M., Wernly B., Demyanets S., Kaun C., Hämmerle M., Hantusch B. et al. Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue. Int J Obes (Lond). 2013;37(5):658–665. https://doi.org/10.1038/ijo.2012.118.

62. Ojji D.B., Opie L.H., Lecour S., Lacerda L., Adeyemi O., Sliwa K. Relationship between left ventricular geometry and soluble ST2 in a cohort of hypertensive patients. J Clin Hypertens (Greenwich). 2013;15(12):899–904. https://doi.org/10.1111/jch.12205.

63. Zhang Z., Xie Y., Shen B., Nie Y., Cao X., Xiang F., Zou J. Relationship between Soluble ST2 and Left Ventricular Geometry in Maintenance Hemodialysis Patients. Blood Purif. 2021;50(1):84–92. https://doi.org/10.1159/000508402.

64. Ibrahim N.E., Januzzi J.L. Jr. Established and Emerging Roles of Biomarkers in Heart Failure. Circ Res. 2018;123(5):614–629. https://doi.org/10.1161/ CIRCRESAHA.118.312706.

65. Sarhene M., Wang Y., Wei J., Huang Y., Li M., Li L. et al. Biomarkers in heart failure: the past, current and future. Heart Fail Rev. 2019;24(6):867–903. https://doi.org/10.1007/s10741-019-09807-z.

66. Lebedev D.A., Lyasnikova E.A., Vasilyeva E.Yu., Babenko A.Yu., Shlyakhto E.V. Type 2 Diabetes Mellitus and Chronic Heart Failure with Midrange and Preserved Ejection Fraction: A Focus on Serum Biomarkers of Fibrosis. J Diabetes Res. 2020:6976153. https://doi.org/10.1155/2020/6976153.

67. Miller A.M. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011;8(1):22. https://doi.org/10.1186/1476-9255-8-22.

68. Rana B.M.J., Jou E., Barlow J.L., Rodriguez-Rodriguez N., Walker J.A., Knox C. et al. A stromal cell niche sustains ILC2-mediated type-2 conditioning in adipose tissue. J Exp Med. 2019;216(9):1999–2009. https://doi.org/10.1084/jem.20190689.

69. Zhou Z., Yan F., Liu O. Interleukin (IL)-33: an orchestrator of immunity from host defence to tissue homeostasis. Clin Transl Immunology. 2020;9(6):e1146. https://doi.org/10.1002/cti2.1146.

70. Celic V., Majstorovic A., Pencic-Popovic B., Sljivic A., Lopez-Andres N., Roy I. et al. Soluble ST2 Levels and Left Ventricular Structure and Function in Patients With Metabolic Syndrome. Ann Lab Med. 2016;36(6):542–549. https://doi.org/10.3343/alm.2016.36.6.542.

71. Tseng C.C.S., Huibers M.M.H., van Kuik J., de Weger R.A., Vink A., de Jonge N. The Interleukin-33/ST2 Pathway Is Expressed in the Failing Human Heart and Associated with Pro-fibrotic Remodeling of the Myocardium. J Cardiovasc Transl Res. 2018;11(1):15–21. https://doi.org/10.1007/s12265-017-9775-8.

72. Wu M.X., Wang S.H., Xie Y., Chen Z.T., Guo Q., Yuan W.L. et al. Interleukin-33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin-like growth factor-binding protein 3. J Cell Physiol. 2021;236(6):4403–4419. https://doi.org/10.1002/jcp.30158.