Атеросклероз и воспаление: терапевтические мишени и пути воздействия

Атеросклероз (АС) – это хроническое воспалительное заболевание сосудов, обусловленное различными факторами риска, в частности курением, ожирением, артериальной гипертензией, дислипидемией. Кроме того, в патогенез АС вовлечены такие сигнальные пути, как инфламмасома NLRP3, Toll-подобные рецепторы, пропротеин конвертаза субтилизина/кексина 9-го типа, Notch и Wnt, которые связаны с воспалительной реакцией в организме человека. Терапевтическое воздействие на воспалительные пути, особенно на каскад реакций, регулируемый инфламмасомой NLRP3 и приводящий к продукции воспалительного интерлейкина-1β, может представлять собой новый путь лечения АС-заболеваний. В статье обобщены знания о клеточных участниках и ключевых сигнальных путях воспаления при АС, обсуждаются доклинические исследования, нацеленные на эти ключевые пути развития АС, клинические испытания, которые будут направлены на некоторые из этих процессов и эффекты подавления воспаления и атерогенеза.

1. Basatemur G.L., Jørgensen H.F., Clarke M.C.H. et al. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol 2019;16(12):727–44. DOI: 10.1038/s41569-019-0227-9

2. Soehnlein O., Libby P. Targeting inflammation in atherosclerosis – from experimental insights to the clinic. Nat Rev Drug Discov 2021;20(8):589–610. DOI: 10.1038/s41573-021-00198-1

3. Roy P., Orecchioni M., Ley K. How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat Rev Immunol 2022;22(4):251–65. DOI: 10.1038/s41577-021-00584-1

4. Hansson G.K., Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011;12(3):204–12. DOI: 10.1038/ni.2001

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

6. Wolf D., Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019;124(2):315–27. DOI: 10.1161/CIRCRESAHA.118.313591

7. Miller Y.I., Choi S.H., Wiesner P. et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res 2011;108(2):235–48. DOI: 10.1161/CIRCRESAHA.110.223875

8. Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 2010;10(1):36–46. DOI: 10.1038/nri2675

9. Fernandez D.M., Rahman A.H., Fernandez N.F. et al. Single-cell immune landscape of human atherosclerotic plaques. Nat Med 2019;25(10):1576–88. DOI: 10.1038/s41591-019-0590-4

10. Bornfeldt K.E., Linton M.F., Fisher E.A., Guyton J.R. JCL roundtable: lipids and inflammation in atherosclerosis. J Clin Lipido 2021;15(1):3–17. DOI: 10.1016/j.jacl.2021.01.005

11. Mauricio D., Castelblanco E., Alonso N. Cholesterol and inflammation in atherosclerosis: an immune-metabolic hypothesis. Nutrients 2020;12(8):2444. DOI: 10.3390/nu12082444

12. Libby P. Inflammation in atherosclerosis – no longer a theory. Clin Chem 2021;67(1):131–42. DOI: 10.1093/clinchem/hvaa275

13. Clark B.C., Arnold W.D. Strategies to prevent serious fall injuries: a commentary on Bhasin et al. A randomized trial of a multifactorial strategy to prevent serious fall injuries. Adv Geriatr Med Res 2021;3(1):e210002. DOI: 10.20900/agmr20210002

14. Shao C., Wang J., Tian J., Tang Y.D. Coronary artery disease: from mechanism to clinical practice. Adv Exp Med Biol 2020;1177:1–36. DOI: 10.1007/978-981-15-2517-9_1

15. Gao Y., Galis Z.S. Exploring the role of endothelial cell resilience in cardiovascular health and disease. Arterioscler Thromb Vasc Biol 2021;41(1):179–85. DOI: 10.1161/ATVBAHA.120.314346

16. Grootaert M.O.J., Bennett M.R. Vascular smooth muscle cells in atherosclerosis: time for a re-assessment. Cardiovasc Res 2021;117(11):2326–39. DOI: 10.1093/cvr/cvab046

17. Vengrenyuk Y., Nishi H, Long X. et al. Cholesterol loading reprograms the microRNA-143/145 – myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler Thromb Vasc Biol 2015;35(3):535–46. DOI: 10.1161/ATVBAHA.114.304029

18. Tinajero M.G., Gotlieb A.I. Recent developments in vascular adventitial pathobiology: the dynamic adventitia as a complex regulator of vascular disease. Am J Pathol 2020;190(3):520–34. DOI: 10.1016/j.ajpath.2019.10.021

19. Hu D., Yin C., Luo S. et al. Vascular smooth muscle cells contribute to atherosclerosis immunity. Front Immunol 2019;10:1101. DOI: 10.3389/fimmu.2019.01101

20. Lordan R., Tsoupras A., Zabetakis I. Platelet activation and prothrombotic mediators at the nexus of inflammation and atherosclerosis: Potential role of antiplatelet agents. Blood Rev 2021;45:100694. DOI: 10.1016/j.blre.2020.100694

21. van der Pol E., Böing A.N., Harrison P. et al. Classification, functions, and clinical relevance of extracellular vesicles. Pharm Rev 2012;64(3):676–705. DOI: 10.1124/pr.112.005983

22. Lee M.K.S., Kraakman M.J., Dragoljevic D. et al. Apoptotic ablation of platelets reduces atherosclerosis in mice with diabetes. Arterioscler Thromb Vasc Biol 2021;41(3):1167–78. DOI: 10.1161/ATVBAHA.120.315369

23. Theofilis P., Sagris M., Antonopoulos A.S. et al. Inflammatory mediators of platelet activation: focus on atherosclerosis and COVID-19. Int J Mol Sci 2021;22:11170. DOI: 10.3390/ijms222011170

24. Barrett T.J. Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol 2020;40(1):20–33. DOI: 10.1161/ATVBAHA.119.312802

25. Gerlach B.D., Ampomah P.B., Yurdagul Jr.A. et al. Efferocytosis induces macrophage proliferation to help resolve tissue injury. Cell Metab 2021;33(12):2445–63.e8. DOI: 10.1016/j.cmet.2021.10.015

26. Huang X., Liu C., Kong N. et al. Synthesis of siRNA nanoparticles to silence plaque-destabilizing gene in atherosclerotic lesional macrophages. Nat Protoc 2022;17(3):748–80. DOI: 10.1038/s41596-021-00665-4

27. Tao W., Yurdagul A.Jr., Kong N. et al. siRNA nanoparticles targeting CaMKIIγ in lesional macrophages improve atherosclerotic plaque stability in mice. Sci Transl Med 2020;12(553):1063. DOI: 10.1126/scitranslmed.aay1063

28. Dworacka M., Winiarska Н., Borowska М. et al. Pro-atherogenic alterations in T-lymphocyte subpopulations related to acute hyperglycaemia in type 2 diabetic patients. Circ J 2007;71(6):962–7. DOI: 10.1253/circj.71.962

29. Smith E., Prasad K.-M. R., Butcher M. et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 2010;121:1746–55. DOI: 10.1161/CIRCULATIONAHA.109.924886

30. Madhur M.S., Funt S.A, Li L. et al. Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol 2011;31(7):1565–72. DOI: 10.1161/ATVBAHA.111.227629

31. Taleb S., Romain M., Ramkhelawon B. et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med 2009;206(10):2067–77. DOI: 10.1084/jem.20090545

32. Xia M., Wu Q., Chen P., Qian C. Regulatory T cell-related gene biomarkers in the deterioration of atherosclerosis. Front Cardiovasc Med 2021;8:661709. DOI: 10.3389/fcvm.2021.661709

33. Mangge H., Prüller F., Schnedl W. et al. Beyond macrophages and T cells: B cells and immunoglobulins determine the fate of the atherosclerotic plaque. Int J Mol Sci 2020;21(11):4082. DOI: 10.3390/ijms21114082

34. Nahrendorf M., Swirski F.K. Immunology. Neutrophil-macrophage communication in inflammation and atherosclerosis. Science. 2015;349(6245):237–8. DOI: 10.1126/science.aac7801

35. Josefs T., Barrett T.J., Brown E.J. et al. Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice. JCI Insight 2020;5:e134796. DOI: 10.1172/jci.insight.134796

36. Hermans M., Lennep J.R.V., van Daele P., Bot I. Mast cells in cardiovascular disease: from bench to bedside. Int J Mol Sci 2019;20(14):3395. DOI: 10.3390/ijms20143395

37. Li Y., Wang F., Imani S. et al. Natural killer cells: friend or foe in metabolic diseases? Front Immunol 2021;12:614429. DOI: 10.3389/fimmu.2021.614429

38. Zhao Y., Zhang J., Zhang W., Xu Y. A myriad of roles of dendritic cells in atherosclerosis. Clin Exp Immunol 2021;206(1):12–27. DOI: 10.1111/cei.13634

39. Clement M., Raffort J., Lareyre F. et al. Impaired autophagy in CD11b(+) dendritic cells expands CD4(+) regulatory T cells and limits atherosclerosis in mice. Circ Res 2019;125(11):1019–34. DOI: 10.1161/CIRCRESAHA.119.315248

40. Sun Y., Long J., Chen W. et al. Alisol B 23-acetate, a new promoter for cholesterol flux from dendritic cells, alleviates dyslipidemia and inflammation in advanced atherosclerotic mice. Int Immunopharmacol 2021;99:107956. DOI: 10.1016/j.intimp.2021.107956

41. Curtiss L.K., Black A.S., Bonnet D.J., Tobias P.S. Atherosclerosis induced by endogenous and exogenous toll-like receptor (TLR)1 or TLR6 agonists. J Lipid Res 2012;53(10):2126–32. DOI: 10.1194/jlr.M028431

42. Roshan M.H., Tambo A., Pace N.P. The role of TLR2, TLR4, and TLR9 in the pathogenesis of atherosclerosis. Int J Inflam 2016;1532832. DOI: 10.1155/2016/1532832

43. Kim J., Yoo J.Y., Suh J.M. et al. The flagellin-TLR5-Nox4 axis promotes the migration of smooth muscle cells in atherosclerosis. Exp Mol Med 2019;51(7):1–13. DOI: 10.1038/s12276-019-0275-6

44. Kapelouzou A., Giaglis S., Peroulis M. et al. Overexpression of toll-like receptors 2, 3, 4, and 8 is correlated to the vascular atherosclerotic process in the hyperlipidemic rabbit model: the effect of statin treatment. J Vasc Res 2017;54(3):156–69. DOI: 10.1159/000457797

45. Fukuda D., Nishimoto S., Aini K. et al. Toll-like receptor 9 plays a pivotal role in angiotensin II-induced therosclerosis. J Am Heart Assoc 2019;8(7):e010860. DOI: 10.1161/JAHA.118.010860

46. Li B., Xia Y., Hu B. Infection and atherosclerosis: TLR-dependent pathways. Cell Mol Life Sci 2020;77(14):2751–69. DOI: 10.1007/s00018-020-03453-7

47. Lehr H.A., Sagban T.A., Ihling C. et al. Immunopathogenesis of atherosclerosis: endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet. Circulation 2001;104(8):914–20. DOI: 10.1161/hc3401.093153

48. Bahrami A., Parsamanesh N., Atkin S.L. et al. Effect of statins on toll-like receptors: a new insight to pleiotropic effects. Pharm Res 2018;135:230–8. DOI: 10.1016/j.phrs.2018.08.014

49. Pothineni N.V.K., Subramany S., Kuriakose K. et al. Infections, atherosclerosis, and coronary heart disease. Eur Heart J 2017; 38(43):3195–201. DOI: 10.1093/eurheartj/ehx362

50. Li B., Xia Y., Hu B. Infection and atherosclerosis: TLR-dependent pathways. Cell Mol Life Sci 2020;77(14):2751–69. DOI: 10.1007/s00018-020-03453-7

51. Shah P.K., Chyu K.Y., Dimayuga P.C., Nilsson J. Vaccine for atherosclerosis. J Am Coll Cardiol 2014;64(25):2779–91. DOI: 10.1016/j.jacc.2014.10.018

52. Liaqat A., Asad M., Shoukat F., Khan A.U. A spotlight on the underlying activation mechanisms of the NLRP3 inflammasome and its role in atherosclerosis: a review. Inflammation 2020;43(6):2011–20. DOI: 10.1007/s10753-020-01290-1

53. Burger F., Baptista D., Roth A. et al. NLRP3 inflammasome activation controls vascular smooth muscle cells phenotypic switch in atherosclerosis. Int J Mol Sci 2021;23(1):340. DOI: 10.3390/ijms23010340

54. Seok J.K., Kang H.C., Cho Y.Y. et al. Regulation of the NLRP3 inflammasome by post-translational modifications and small molecules. Front Immunol 2020;11:618231. DOI: 10.3389/fimmu.2020.618231

55. Li Y., Niu X., Xu H. et al. VX-765 attenuates atherosclerosis in ApoE deficient mice by modulating VSMCs pyroptosis. Exp Cell Res 2020;389:111847. DOI: 10.1016/j.yexcr.2020.111847

56. Stigliano C., Ramirez M.R., Singh J.V. et al. Methotraxate-loaded hybrid nanoconstructs target vascular lesions and inhibit atherosclerosis progression in ApoE(-/-) mice. Adv Healthc Mater 2017;6(13). DOI: 10.1002/adhm.201601286

57. Momtazi-Borojeni A.A., Sabouri-Rad S., Gotto A.M. et al. PCSK9 and inflammation: a review of experimental and clinical evidence. Eur Heart J Cardiovasc Pharmacother 2019;5(4):237–45. DOI: 10.1093/ehjcvp/pvz022

58. Ding Z., Liu S., Wang X. et al. Hemodynamic shear stress via ROS modulates PCSK9 expression in human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxid Redox Signal 2015;22(9):760–71. DOI: 10.1089/ars.2014.6054

59. Ferri N., Tibolla G., Pirillo A. et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 2012;220(2):381–6. DOI: 10.1016/j.atherosclerosis.2011.11.026

60. Ding Z., Pothineni N.V.K., Goel A. et al. PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1. Cardiovasc Res 2020;116(5):908–15. DOI: 10.1093/cvr/cvz313

61. Walley K.R., Thain K.R., Russell J.A. et al. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med 2014;6(258):258ra143. DOI: 10.1126/scitranslmed.3008782

62. Leander K., Mälarstig A., van’t Hooft F.M. et al. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) predicts future risk of cardiovascular events independently of established risk factors.Circulation 2016;133(13):1230–9. DOI: 10.1161/CIRCULATIONAHA.115.018531

63. Qi Z., Hu L., Zhang J. et al. PCSK9 enhances platelet activation, thrombosis and myocardial infarction expansion by binding to platelet CD36. Circulation 2020;143(1):45–61. DOI: 10.1161/CIRCULATIONAHA.120.046290

64. Seidah N.G., Prat A., Pirillo A. et al. Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. Cardiovasc Res 2019;115(3):510–18. DOI: 10.1093/cvr/cvz003

65. Momtazi-Borojeni A. A., Jaafari M. R., Badiee A. & Sahebkar A. Long-term generation of antiPCSK9 antibody using a nanoliposome-based vaccine delivery system. Atherosclerosis 2019;283:69–78. DOI: 10.1016/j.atherosclerosis.2019.02.001

66. Ummarino D. Dyslipidaemia: anti-PCSK9 vaccines to halt atherosclerosis. Nat Rev Cardiol 2017;14(8):442–3. DOI: 10.1038/nrcardio.2017.106

67. Zeitlinger M., Bauer M., Reindl-Schwaighofer R. et al. A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9. Eur J Clin Pharm 2021;77(10):1473–84. DOI: 10.1007/s00228-021-03149-2

68. Quillard T., Charreau B. Impact of notch signaling on inflammatory responses in cardiovascular disorders. Int J Mol Sci 2013;14(4):6863–88. DOI: 10.3390/ijms14046863

69. Fior R., Henrique D. “Notch-Off”: a perspective on the termination of Notch signalling. Int J Dev Biol 2009;53(8–10): 1379–84. DOI: 10.1387/ijdb.072309rf

70. Nus M., Martínez-Poveda В., MacGrogan D. et al. Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis. Cardiovasc Res 2016;112(2):568–80. DOI: 10.1093/cvr/cvw193

71. Mack J.J., Iruela-Arispe M.L. NOTCH regulation of the endothelial cell phenotype. Curr Opin Hematol 2018;25(3):212– 18. DOI: 10.1097/MOH.0000000000000425

72. Martos-Rodriguez C.J., Albarrán-Juárez J., Morales-Cano D. et al. Fibrous caps in atherosclerosis form by notch dependent mechanisms common to arterial media development. Arterioscler Thromb Vasc Biol 2021;41(9):e427–39. DOI: 10.1161/ATVBAHA.120.315627

73. Christopoulos P. F., Gjølberg T.T., Krüger S. et al. Targeting the Notch signaling pathway in chronic inflammatory diseases. Front Immunol 2021;12:668207. DOI: 10.3389/fimmu.2021.668207

74. Lorzadeh S., Kohan L., Ghavami S., Azarpira N. Autophagy and the Wnt signaling pathway: a focus on Wnt/beta-catenin signaling. Biochim Biophys Acta Mol Cell Res 2021;1868(3):118926. DOI: 10.1016/j.bbamcr.2020.118926

75. Terenzi D.C., Verma S., Hess D.A. Exploring the clinical implications of Wnt signaling in enucleated erythrocytes. Arterioscler Thromb Vasc Biol 2021;41(5):1654–6. DOI: 10.1161/ATVBAHA.121.316169

76. Mach F., Baigent C., Catapano A.L. et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41(1):111–88. DOI: 10.1093/eurheartj/ehz455

77. Kolovou V., Katsiki N., Makrygiannis S. et al. Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors in patients with heterozygous familial hypercholesterolemia: a one center study. J Cardiovasc Pharm Ther 2021;26(1):51–8. DOI: 10.1177/1074248420943079

78. AlTurki A., Marafi M., Dawas A. et al. Meta-analysis of randomized controlled trials assessing the impact of proprotein convertase subtilisin/kexin type 9 antibodies on mortality and cardiovascular outcomes. Am J Cardiol 2019;124(12):1869–75. DOI: 10.1016/j.amjcard.2019.09.011

79. Rifai M. A., Ballantyne C. M. PCSK9-targeted therapies: present and future approaches. Nat Rev Cardiol 2021;18(12):805–6. DOI: 10.1038/s41569-021-00634-0

80. Graham M.J., Lee R.G., Brandt T.A. et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017;377(3):222–32. DOI: 10.1056/ NEJMoa1701329

81. Su X., Peng D.Q. New insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases. Lipids Health Dis 2018;17(1):12. DOI: 10.1186/s12944-018-0659

82. Gaudet D., Gipe D.A., Pordy R. et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017;377(3):296–7. DOI: 10.1056/NEJMc1705994

83. Pinkosky S.L., Groot P.H., Lalwani N.D., Steinberg G.R. Targeting ATP-Citrate Lyase in hyperlipidemia and metabolic disorders. Trends Mol Med 2017;23(11):1047–63. DOI:10.1016/j.molmed.2017.09.001

84. Ballantyne C.M., Banach M., Mancini J. et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis 2018;277:195–203. DOI: 10.1016/j.atherosclerosis.2018.06.002

85. Goldberg A.C., Leiter L.A., Stroes E. et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom Randomized Clinical trial. JAMA 2019;322(18):1780–88. DOI: 10.1001/jama.2019.16585

86. Berberich A.J., Hegele R.A. Lomitapide for the treatment of hypercholesterolemia. Expert Opin Pharmacother 2017;18(12):1261–8. DOI: 10.1080/14656566.2017.1340941

87. Harada-Shiba M., Ikewaki K., Nohara A. et al. Efficacy and safety of Lomitapide in Japanese patients with homozygous familial hypercholesterolemia. J Atheroscler Thromb 2017;24(4):402–11. DOI: 10.5551/jat.38216

88. Meyers C.D., Tremblay K., Amer A. et al. Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome. Lipids Health Dis 2015;14:8. DOI: 10.1186/s12944-015-0006-5

89. Meyers C.D., Amer A., Majumdar T. & Chen J. Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects. J Clin Pharm 2015;55(9): 1031–41. DOI: 10.1002/jcph.509

90. Merki E., Graham M., Taleb A. et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol 2011;57(15):1611–21. DOI: 10.1016/j.jacc.2010.10.052

91. Viney N.J., van Capelleveen J.C., Geary R.S. et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016;388(10057):2239–53. DOI:10.1016/S0140-6736(16)31009-1

92. Fogacci F., Ferri N., Toth P.P. et al. Efficacy and safety of mipomersen: a systematic review and meta-analysis of randomized clinical trials. Drugs 2019;79(7):751–66. DOI: 10.1007/s40265-019-01114-z

93. Astaneh B., Makhdami N., Astaneh V., Guyatt G. The effect of mipomersen in the management of patients with familial hypercholesterolemia: a systematic review and meta-analysis of clinical trials. J Cardiovasc Dev Dis 2021;8(7):82. DOI: 10.3390/jcdd8070082

94. Yang X., Lee S.R., Choi Y.S. et al. Reduction in lipoproteinassociated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. J Lipid Res 2016;57(4):706–13. DOI: 10.1194/jlr.M066399

95. Apolipoprotein A-I [human] (apoA-I) for Acute Coronary Syndrome (AEGIS-II Trial). Available at: https://www.withpower.com/trial/phase-3-acute-coronary-syndrome-2-2018-9d541

96. Shamburek R.D., Bakker-Arkema R., Auerbach B.J. et al. Familial lecithin: cholesterol acyltransferase deficiency: first-in-human treatment with enzyme replacement. J Clin Lipidol 2016;10(2):356–67. DOI: 10.1016/j.jacl.2015.12.007

97. Yamashita S., Masuda D., Matsuzawa Y. Pemafibrate, a new selective PPAR-alpha modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep 2020;22(1):5. DOI: 10.1007/s11883-020-0823-5

98. Stein E., Bays H., Koren M. et al. Efficacy and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients. J Clin Lipidol 2016;10(5):1212–22. DOI: 10.1016/j.jacl.2016.08.002

99. Larsen L.E., Stoekenbroek R.M., Kastelein J.J.P., Holleboom A.G. Moving targets: recent advances in lipid-lowering therapies. Arterioscler Thromb Vasc Biol 2019;39(3):349–59. DOI: 10.1161/ATVBAHA.118.312028

100. Bhatt D L., Steg P.G., Miller M. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380(1):11–22. DOI: 10.1056/NEJMoa1812792

101. Bhaskar V., Yin J., Mirza A.M. et al. Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice. Atherosclerosis 2011;216(2):313–20. DOI: 10.1016/j.atherosclerosis.2011.02.026

102. Ridker P. M., Everett B.M., Thuren T. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377(12):1119–31. DOI: 10.1056/NEJMoa1707914

103. Hoffman H.M., Broderick L. The role of the inflammasome in patients with autoinflammatory diseases. J Allergy Clin Immunol 2016;138(1):3–14. DOI: 10.1016/j.jaci.2016.05.001

104. Pergola P.E., Devalaraja M., Fishbane S. et al. Ziltivekimab for treatment of anemia of inflammation in patients on hemodialysis: results from a phase 1/2 multicenter, randomized, double-blind, placebo-controlled trial. J Am Soc Nephrol 2021;32(1):211–22. DOI: 10.1681/ASN.2020050595

105. Lee E. B. A review of sarilumab for the treatment of rheumatoid arthritis. Immunotherapy 2018;10(1):57–65. DOI: 10.2217/imt-2017-0075

106. Castagne B., Viprey M., Martin J. et al. Cardiovascular safety of tocilizumab: a systematic review and network meta-analysis. PLoS One 2019;14(8):e0220178. DOI: 10.1371/journal.pone.0220178

107. Micha R., Imamura F., Wyler von Ballmoos M. et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 2011;108(9):1362–70. DOI: 10.1016/j.amjcard.2011.06.054

108. Broz P., Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 2016;16(7):407–20. DOI: 10.1038/nri.2016.58

109. Dinarello C.A., Simon A., van der Meer J.W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012;11(8):633–52. DOI: 10.1038/nrd3800

110. Dinarello C.A. The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol 2019;15(10):612–32. DOI: 10.1038/s41584-019-0277-8

111. Насонов Е.Л., Елисеев М.С. Роль интерлейкина 1 в развитии заболеваний человека. Научно-практическая ревматология 2016;54(1):60–77. DOI: 10.14412/1995-4484-2016-60-77

112. Leung Y.Y., Yao Hui L.L., Kraus V.B. Colchicine – update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum 2015;45(3):341–50. DOI: 10.1016/j.semarthrit.2015.06.013

113. Angelidis C., Kotsialou Z., Kossyvakis C. et al. Colchicine pharmacokinetics and mechanism of action. Curr Pharm Des 2018;24(6):659–63. DOI: 10.2174/138161282466618012 Nidorf S.M., Fiolet A.T., Mosterd A. et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383(19):1838–47. DOI: 10.1056/NEJMoa2021372

114. Denise Martin E., De Nicola G.F., Marber M.S. New therapeutic targets in cardiology: p38 alpha mitogen-activated protein kinase for ischemic heart disease. Circulation 2012;126(3):357–68. DOI: 10.1161/CIRCULATIONAHA.111.071886

115. Wohlford G. F., Van Tassell B., Billingsley H.E. et al. Phase 1B, randomized, double-blinded, dose escalation, single-center, repeat dose safety and pharmacodynamics study of the oral NLRP3 inhibitor dapansutrile in subjects with NYHA II–III systolic heart failure. J Cardiovasc Pharmacol 2020;77(1):49–60. DOI: 10.1097/FJC.0000000000000931

116. O’Donoghue M.L. Glaser R., Aylward P.E. et al. Rationale and design of the LosmApimod to Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial. Am Heart J 2015;169(5):622–30.e6. DOI: 10.1016/j.ahj.2015.02.012

117. Casella I.B., Presti C. A new era of medical therapy for peripheral artery disease. J Vasc Bras 2020;19:e20190056. DOI: 10.1590/1677-5449.190056

118. Santoso A., Heriansyah T. & Rohman M.S. Phospholipase A2 is an inflammatory predictor in cardiovascular diseases: is there any spacious room to prove the causation? Curr Cardiol Rev 2020;16(1):3–10. DOI: 10.2174/1573403X15666190531111932

119. Toledo-Ibelles P., Mas-Oliva J. Antioxidants in the fight against atherosclerosis: is this a dead end? Curr Atheroscler Rep 2018;20(7):36. DOI: 10.1007/s11883-018-0737-7

120. Tardif J.C., Grégoire J., L’Allier P.L. et al. Effects of the antioxidant succinobucol (AGI-1067) on human atherosclerosis in a randomized clinical trial. Atherosclerosis 2008;197(1):480–6. DOI: 10.1016/j.atherosclerosis.2006.11.039

121. Tardif J.C., Kouz S., Waters D.D. et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381(26):2497–505. DOI: 10.1056/NEJMoa1912388