Артериальная гипертензия: современные достижения метаболомики

Ранняя диагностика и эффективная фармакотерапия артериальной гипертензии являются актуальными задачами, значительный вклад в  решение которых может внести метаболомика. Этиология артериальной гипертензии остается неизвестной для большей части пациентов с повышенным артериальным давлением; диагноз для 90% определяется как эссенциальная (первичная) гипертензия. Для  данной популяции пациентов характерны нарушения путей метаболизма липидов, глюкозы, биогенных аминов и аминокислот, что находит проявление в виде гиперлипидемии, гипергликемии, снижения чувствительности к инсулину с возможным последующим развитием сахарного диабета второго типа. Изучение метаболомного профиля может дать ключ к определению метаболитов – маркеров гипертензии и способствовать эффективному развитию доклинической диагностики и определению групп риска, равно как и более полному пониманию этиологических и патогенетических механизмов повышения артериального давления. Осуществленные исследования указывают на существование характерных для пациентов с гипертензией метаболомных профилей, отличающих их от субъектов с нормотензией. Наиболее типичными являются случаи изменения содержания ряда аминокислот, полиненасыщенных жирных кислот, карнитинов, фосфатидилхолинов и ацилглицеринов.
Вариабельность ответа на  гипотензивную терапию не  позволяет достичь эффективного контроля величин артериального давления у значимой части пациентов. Особенности изменения метаболомного профиля на фоне приема препаратов различных фармакологических групп могут быть использованы для идентификации метаболитов – маркеров ответа на применение основных классов гипотензивных средств, а также маркеров развития побочных эффектов лекарственной терапии. Таким образом, индивидуализация фармакотерапевтического подхода на основе данных фармакометаболомики может значительно повысить эффективность и безопасность гипотензивной терапии.
Настоящий обзор направлен на  изучение основных групп метаболитов, определенных в  опубликованных исследованиях в качестве предикторов развития гипертензии, а также метаболитов – маркеров ответа на гипотензивную терапию.

1. Fuchs F.D., Whelton P.K. High Blood Pressure and Cardiovascular Disease. Hypertension. 2020;75(2):285–292. https://doi.org/10.1161/HYPERTENSIONAHA.119.14240.

2. Oparil S., Acelajado M.C., Bakris G.L. Berlowitz D.R., Cífková R., Dominiczak A.F. et al. Hypertension. Nat Rev Dis Primers. 2018;4:18014. https://doi.org/10.1038/nrdp.2018.14.

3. Lu Y.T., Fan P., Zhang D., Zhang Y., Meng X., Zhang Q.Y. et al. Overview of Monogenic Forms of Hypertension Combined With Hypokalemia. Front Pediatr. 2021;8:543309. https://doi.org/10.3389/fped.2020.543309.

4. Schrover I.M., Dorresteijn J.A. N., Smits J.E., Danser A.H. J., Visseren F.L. J., Spiering W. Identifying treatment response to antihypertensives in patients with obesity-related hypertension. Clin Hypertens. 2017;23:20. https://doi.org/10.1186/s40885-017-0077-x.

5. Trivedi D.K., Hollywood K.A., Goodacre R. Metabolomics for the masses: The future of metabolomics in a personalized world. New Horiz Transl Med. 2017;3(6):294–305. Available at: https://pubmed.ncbi.nlm.nih.gov/29094062.

6. Kaddurah-Daouk R., Kristal B.S., Weinshilboum R.M. Metabolomics: a global biochemical approach to drug response and disease. Annu Rev Pharmacol Toxicol. 2008;48:653–683. https://doi.org/10.1146/annurev.pharmtox.48.113006.094715.

7. Currie G., Delles C. The Future of “Omics” in Hypertension. Can J Cardiol. 2017;33(5):601–610. https://doi.org/10.1016/j.cjca.2016.11.023.

8. Zhong L., Zhang J.P., Nuermaimaiti A.G., Yunusi K.X. Study on plasmatic metabolomics of Uygur patients with essential hypertension based on nuclear magnetic resonance technique. Eur Rev Med Pharmacol Sci. 2014;18(23):3673–3680. Available at: https://pubmed.ncbi.nlm.nih.gov/25535139.

9. Zhao H., Liu Y., Li Z., Song Y., Cai X,. Liu Y. et al. Identification of essential hypertension biomarkers in human urine by non-targeted metabolomics based on UPLC-Q-TOF/MS. Clin Chim Acta. 2018;486:192–198. https://doi.org/10.1016/j.cca.2018.08.006.

10. Bai Q., Peng B., Wu X., Cao Y., Sun X., Hong M. et al. Metabolomic study for essential hypertension patients based on dried blood spot mass spectrometry approach. IUBMB Life. 2018;70(8):777–785. https://doi.org/10.1002/iub.1885.

11. Yang M., Yu Z., Deng S., Chen X., Chen L., Gu Z. et al. A Targeted Metabolomics MRM-MS Study on Identifying Potential Hypertension Biomarkers in Human Plasma and Evaluating Acupuncture Effects. Sci Rep. 2016;6:25871. https://doi.org/10.1038/srep25871.

12. Chachaj A., Matkowski R., Gröbner G., Szuba A., Dudka I. Metabolomics of Interstitial Fluid, Plasma and Urine in Patients with Arterial Hypertension: New Insights into the Underlying Mechanisms. Diagnostics (Basel). 2020;10(11):936. https://doi.org/10.3390%2Fdiagnostics10110936.

13. Ameta K., Gupta A., Kumar S., Sethi R., Kumar D., Mahdi A. Essential hypertension: A filtered serum based metabolomics study. Sci Rep. 2017;7(1):2153. https://doi.org/10.1038/s41598-017-02289-9.

14. Dietrich S., Floegel A., Weikert C., Prehn C., Adamski J., Pischon T. et al. Identification of Serum Metabolites Associated With Incident Hypertension in the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. Hypertension. 2016;68(2):471–477. https://doi.org/10.1161/HYPERTENSIONAHA.116.07292.

15. Hao Y., Wang Y., Xi L., Li G., Zhao F., Qi Y. et al. A Nested Case-Control Study of Association between Metabolome and Hypertension Risk. Biomed Res Int. 2016;2016:7646979. https://doi.org/10.1155/2016/7646979.

16. Kulkarni H., Meikle P.J., Mamtani M., Weir J.M., Barlow C.K., Jowett J.B. et al. Plasma lipidomic profile signature of hypertension in Mexican American families: specific role of diacylglycerols. Hypertension. 2013;62(3):621–626. https://doi.org/10.1161/HYPERTENSIONAHA.113.01396.

17. Wang L., Hou E., Wang L., Wangd Y., Yange L., Zheng X. et al. Reconstruction and analysis of correlation networks based on GC-MS metabolomics data for young hypertensive men. Anal Chim Acta. 2015;854:95–105. https://doi.org/10.1016/j.aca.2014.11.009.

18. Lin Y.T., Salihovic S., Fall T., Hammar U., Ingelsson E., Ärnlöv J. et al. Global Plasma Metabolomics to Identify Potential Biomarkers of Blood Pressure Progression. Arterioscler Thromb Vasc Biol. 2020;40(8):e227-e237. https://doi.org/10.1161/ATVBAHA.120.314356.

19. Goïta Y., Chao de la Barca J.M., Keïta A., Diarra M., Dembélé K., Chabrun F. et al. Sexual Dimorphism of Metabolomic Profile in Arterial Hypertension. Sci Rep. 2020;10(1):7517. https://doi.org/10.1038/s41598-020-64329-1.

20. Menni C., Graham D., Kastenmüller G., Alharbi N.H., Alsanosi S.M., McBride M. et al. Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate. Hypertension. 2015;66(2):422–429. https://doi.org/10.1161/HYPERTENSIONAHA.115.05544.

21. Mels C.M., Delles C., Louw R., Schutte A.E. Central systolic pressure and a nonessential amino acid metabolomics profile: the African Prospective study on the Early Detection and Identification of Cardiovascular disease and Hypertension. J Hypertens. 2019;37(6):1157–1166. https://doi.org/10.1097/hjh.0000000000002040.

22. Zheng Y., Yu B., Alexander D., Mosley T.H., Heiss G., Nettleton J.A., Boerwinkle E. Metabolomics and incident hypertension among blacks: the atherosclerosis risk in communities study. Hypertension. 2013;62(2):398–403. https://doi.org/10.1161/hypertensionaha.113.01166.

23. Deventer C.A., Lindeque J.Z., van Rensburg P.J., Malan L., van der Westhuizen F.H., Louw R. Use of metabolomics to elucidate the metabolic perturbation associated with hypertension in a black South African male cohort: the SABPA study. J Am Soc Hypertens. 2015;9(2):104–114. https://doi.org/10.1016/j.jash.2014.11.007.

24. Unger T., Borghi C., Charchar F., Khan N.A., Poulter N.R., Prabhakaran D. et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75(6):1334–1357. https://doi.org/10.1161/HYPERTENSIONAHA.120.15026.

25. Materson B.J. Variability in response to antihypertensive drugs. Am J Med. 2007;120(4);1 Suppl.:10–20. https://doi.org/10.1016/j.amjmed.2007.02.003.

26. Paz M.A., de-La-Sierra A., Sáez M., Barceló M.A., Rodríguez J.J., Castro S. et al. Treatment efficacy of anti-hypertensive drugs in monotherapy or combination: ATOM systematic review and meta-analysis of randomized clinical trials according to PRISMA statement. Medicine (Baltimore). 2016;95(30):e4071. https://doi.org/10.1097/md.0000000000004071.

27. Pathan M.K., Cohen D.L. Resistant Hypertension: Where are We Now and Where Do We Go from Here? Integr Blood Press Control. 2020;13:83–93. Available at: https://pubmed.ncbi.nlm.nih.gov/32801854.

28. Carey R.M., Calhoun D.A., Bakris G.L., Brook R.D., Daugherty S.L., DennisonHimmelfarb C.R. et al. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension. 2018;72(5):e53-e90. https://doi.org/10.1161/HYP.0000000000000084.

29. Egan B.M., Zhao Y., Axon R.N., Brzezinski W.A., Ferdinand K.C. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011;124(9):1046–1058. https://doi.org/10.1161/CIRCULATIONAHA.111.030189.

30. Gupta A.K., Nasothimiou E.G., Chang C.L., Sever P.S., Dahlöf B., Poulter N.R.; ASCOT investigators. Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J Hypertens. 2011;29(10):2004–2013. https://doi.org/10.1097/hjh.0b013e32834a8a42.

31. Altmaier E., Fobo G., Heier M., Thorand B., Meisinger C., Römisch-Margl W. et al. Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism. Eur J Epidemiol. 2014;29(5):325–336. https://doi.org/10.1007%2Fs10654-014-9910-7.

32. Hiltunen T.P., Rimpelä J.M., Mohney R.P., Stirdivant S.M., Kontula K.K. Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension. PLoS ONE. 2017;12(11):e0187729. https://doi.org/10.1371/journal.pone.0187729.

33. Shahin M.H., Gong Y., McDonough C. W., Rotroff D., Beitelshees A., Garrett T. et al. A Genetic Response Score for Hydrochlorothiazide Use: Insights From Genomics and Metabolomics Integration. Hypertension. 2016;68(3):621–629. https://doi.org/10.1161/HYPERTENSIONAHA.116.07328.

34. Campbell D., Aman A., Iniesta R., Menni C., Gong Y., Cooper-DeHoff R. et al. Pharmaco-metabolomics of blood pressure response to beta-blockers and diuretics. J Hypertens. 2018;36:e124-e125. https://doi.org/10.1097/01.hjh.0000539324.49196.87.

35. Sonn B.J., Saben J.L., McWilliams G., Shelton S., Flaten H., D’Alessandro A., Monte A. Predicting response to lisinopril in treating hypertension: a pilot study. Metabolomics. 2019;15(10):133. https://doi.org/10.1007/s11306-019-1601-7.

36. Altmaier E., MennjLoS ONE. 2016;11(4):e0153163. https://doi.org/10.1371/journal.pone.0153163.

37. Weng L., Gong Y., Culver J., Gardell S., Petucci C., Morse A. et al. Presence of arachidonoyl-carnitine is associated with adverse cardiometabolic responses in hypertensive patients treated with atenolol. Metabolomics. 2016;12(10):160. https://doi.org/10.1007/s11306-016-1098-2.

38. Wikoff W.R., Frye R.F., Zhu H., Gong Y., Boyle S., Churchill E. et al.; Pharmacometabolomics Research Network. Pharmacometabolomics reveals racial differences in response to atenolol treatment. PLoS ONE. 2013;8(3):e57639. https://doi.org/10.1371/journal.pone.0057639.

39. Rotroff D.M., Shahin M.H., Gurley S.B., Zhu H., Motsinger-Reif A., Meisner M. et al. Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes. CPT Pharmacometrics Syst Pharmacol. 2015;4(11):669–679. https://doi.org/10.1002/psp4.12017.

40. Shahin M.H., Gong Y., Frye R.F., Rotroff D., Beitelshees A., Baillie R. et al. Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics. J Am Heart Assoc. 2017;7(1):e006656. https://doi.org/10.1161/JAHA.117.006656.

41. Ogawa M., Takahara A., Ishijima M., Tazaki S. Decrease of plasma sulfur amino acids in essential hypertension. Jpn Circ J. 1985;49(12):1217–1224. https://doi.org/10.1253/jcj.49.1217.

42. Altorf-van der Kuil W., Engberink M.F., De Neve M., van Rooij F.J., Hofman A., van’t Veer P. et al. Dietary amino acids and the risk of hypertension in a Dutch older population: The Rotterdam Study. Am J Clin Nutr. 2013;97(2):403–410. https://doi.org/10.3945/ajcn.112.038737.

43. Jennings A., MacGregor A., Pallister T., Spector T., Cassidy A. Associations between branched chain amino acid intake and biomarkers of adiposity and cardiometabolic health independent of genetic factors: A twin study. Int J Cardiol. 2016;223:992–998. https://doi.org/10.1016/j.ijcard.2016.08.307.

44. Oomen C.M., van Erk M.J., Feskens E.J., Kok F.J., Kromhout D. Arginine intake and risk of coronary heart disease mortality in elderly men. Arterioscler Thromb Vasc Biol. 2000;20(9):2134–2139. https://doi.org/10.1161/01.ATV.20.9.2134.

45. Stamler J., Brown I.J., Daviglus M.L., Chan Q., Kesteloot H., Ueshima H. et al. INTERMAP Research Group. Glutamic acid, the main dietary amino acid, and blood pressure: The INTERMAP Study (International Collaborative Study of Macronutrients, Micronutrients and Blood Pressure) Circulation. 2009;120(3):221–228. https://doi.org/10.1161/CIRCULATIONAHA.108.839241.

46. Teymoori F., Asghari G., Mirmiran P., Azizi F. High dietary intake of aromatic amino acids increases risk of hypertension. J Am Soc Hypertens. 2018;12(1):25–33. https://doi.org/10.1016/j.jash.2017.11.004.

47. Venho B., Voutilainen S., Valkonen V.P., Virtanen J., Lakka T.A., Rissanen T.H. et al. Arginine intake, blood pressure, and the incidence of acute coronary events in men: The Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2002;76(2):359–364. https://doi.org/10.1093/ajcn/76.2.359.

48. Luiking Y.C., Ten Have G.A., Wolfe R.R., Deutz N.E. Arginine de novo and nitric oxide production in disease states. Am J Physiol Endocrinol Metab. 2012;303(10):E1177-1189. https://doi.org/10.1152/ajpendo.00284.2012.

49. Cynober L., Moinard C., De Bandt J.P. The 2009 ESPEN Sir David Cuthbertson. Citrulline: a new major signaling molecule or just another player in the pharmaconutrition game? Clin Nutr. 2010;29(5):545–551. https://doi.org/10.1016/j.clnu.2010.07.006.

50. Hsu C.N., Tain Y.L. Amino Acids and Developmental Origins of Hypertension. Nutrients. 2020;12(6):1763. https://doi.org/10.3390%2Fnu12061763.

51. Hsu C.N., Tain Y.L. Hydrogen Sulfide in Hypertension and Kidney Disease of Developmental Origins. Int J Mol Sci. 2018;19(5):1438. https://doi.org/10.3390/ijms19051438.

52. McCarty M. F., O’Keefe J.H., DiNicolantonio J.J. Dietary Glycine Is RateLimiting for Glutathione Synthesis and May Have Broad Potential for Health Protection. Ochsner J. 2018;18(1):81–87. Available at: https://pubmed.ncbi.nlm.nih.gov/29559876.

53. Cicero A.F., Derosa G., Di Gregori V., Bove M., Gaddi A.V., Borghi C. Omega 3 polyunsaturated fatty acids supplementation and blood pressure levels in hypertriglyceridemic patients with untreated normal-high blood pressure and with or without metabolic syndrome: a retrospective study. Clin Exp Hypertens. 2010;32(2):137–144. https://doi.org/10.3109/10641960903254448.

54. Cabo J., Alonso R., Mata P. Omega-3 fatty acids and blood pressure. Br J Nutr. 2012;107(2 Suppl.):195–200. https://doi.org/10.1017/s0007114512001584.

55. Colussi G., Catena C., Novello M., Bertin N., Sechi L.A. Impact of omega-3 polyunsaturated fatty acids on vascular function and blood pressure: Relevance for cardiovascular outcomes. Nutr Metab Cardiovasc Dis. 2017;27(3):191–200. https://doi.org/10.1016/j.numecd.2016.07.011.

56. Miller P.E., Van Elswyk M., Alexander D.D. Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. Am J Hypertens. 2014;27(7):885–896. https://doi.org/10.1093/ajh/hpu024.

57. Polonis K., Wawrzyniak R., Daghir-Wojtkowiak E., Szyndler A., Chrostowska M., Melander O. et al. Metabolomic Signature of Early Vascular Aging (EVA) in Hypertension. Front Mol Biosci. 2020;7:12. https://doi.org/10.3389/fmolb.2020.00012.

58. Li H., Junk P., Huwiler A., Burkhardt C., Wallerath T., Pfeilschifter J., Förstermann U. Dual effect of ceramide on human endothelial cells: induction of oxidative stress and transcriptional upregulation of endothelial nitric oxide synthase. Circulation. 2002;106(17):2250–2256. https://doi.org/10.1161/01.CIR.0000035650.05921.50.

59. Guan Z., Singletary S.T., Cook A.K., Hobbs J.L., Pollock J.S., Inscho E.W. Sphingosine-1-phosphate evokes unique segment-specific vasoconstriction of the renal microvasculature. J Am Soc Nephrol. 2014;25(8):1774–1785. https://doi.org/10.1681/ASN.2013060656.

60. Wang L., Szklo M., Folsom A.R., Cook N.R., Gapstur S.M., Ouyang P. Endogenous sex hormones, blood pressure change, and risk of hypertension in postmenopausal women: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2012;224(1):228–234. https://doi.org/10.1016/j.atherosclerosis.2012.07.005.

61. Caulin-Glaser T., García-Cardeña G., Sarrel P., Sessa W.C., Bender J.R. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circ Res. 1997;81(5):885–892. https://doi.org/10.1161/01.res.81.5.885.

62. Qiao X., McConnell K. R., Khalil R.A. Sex steroids and vascular responses in hypertension and aging. Gend Med. 2008;5(1 Suppl.):46–64. https://doi.org/10.1016/j.genm.2008.03.006.

63. Kim C., Cushman M., Kleindorfer D., Lisabeth L., Redberg R.F., Safford M.M. A review of the relationships between endogenous sex steroids and incident ischemic stroke and coronary heart disease events. Curr Cardiol Rev. 2015;11(3):252–260. https://doi.org/10.2174/1573403x1103150515110749.

64. Jarrell Z.R., Smith M.R., Hu X., Orr M., Liu K., Quyyumi A. et al. Plasma acylcarnitine levels increase with healthy aging. Aging (Albany NY). 2020;12(13):13555-13570. https://doi.org/10.18632/aging.103462.