Молекулярная диагностика отторжения трансплантата у реципиентов сердца: векторы развития и перспективы клинического применения

Современные достижения в области молекулярных методов диагностики открывают возможность интег- рировать генетические и эпигенетические биомаркеры в клиническую практику. Последние годы получили развитие такие направления исследований, как анализ профиля экспрессии генов, определение внеклеточ- ной ДНК и оценка экспрессии микроРНК. Показан диагностический потенциал молекулярно-генетических биомаркеров при различных патологических состояниях. Появляются первые данные клинических иссле- дований об использовании молекулярных методов диагностики для выявления посттрансплантационных осложнений у реципиентов солидных органов. У реципиентов сердца оценка молекулярно-генетических, эпигенетических и клинических показателей необходима для персонифицированного подбора иммуносуп- рессивной терапии и предотвращения развития дисфункции и васкулопатии трансплантата. В настоящем обзоре суммированы современные представления о молекулярной диагностике отторжения трансплантата у реципиентов сердца и перспективах ее клинического применения.

1. Готье СВ. Трансплантология: итоги и перспективы. Том XV. 2023 год. М.–Тверь: Триада, 2024; 320.

2. Singh TP, Cherikh WS, Hsich E, Lewis A, Perch M, Kian S et al. Graft survival in primary thoracic organ transplant recipients: A special report from the International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2023 Oct; 42 (10): 1321–1333. doi: 10.1016/j.healun.2023.07.017.

3. Wu MY, Ali Khawaja RD, Vargas D. Heart Transplantation: Indications, Surgical Techniques, and Complications. Radiol Clin North Am. 2023 Sep; 61 (5): 847–859. doi: 10.1016/j.rcl.2023.04.011.

4. Fitzsimons SJ, Evans JDW, Rassl DM, Lee KK, Strachan FE, Parameshwar J et al. High-sensitivity Cardiac Troponin Is Not Associated With Acute Cellular Rejection After Heart Transplantation. Transplantation. 2022 May 1; 106 (5): 1024–1030. doi: 10.1097/TP.0000000000003876.

5. Zhu V, Perry LA, Plummer M, Segal R, Smith J, Liu Z. Diagnostic accuracy of brain natriuretic peptide and Nterminal-pro brain natriuretic peptide to detect complications of cardiac transplantation in adults: A systematic review and meta-analysis. Transplant Rev (Orlando). 2023 Jul; 37 (3): 100774. doi: 10.1016/j.trre.2023.100774.

6. Суспицын ЕН, Раупов РК, Кучинская ЕМ, Костик ММ. Анализ профиля экспрессии интерферонзависимых генов для дифференциальной диагностики заболеваний иммунной системы (обзор литературы). Клиническая лабораторная диагностика. 2021; 66 (5): 279–284. https://doi.org/10.51620/0869-2084-2021-66-5-279-284.

7. Михайлов АМ, Каравай МФ, Сивцов ВА, Курникова МА. Машинное обучение для диагностики заболеваний по полному профилю экспрессии генов. Автоматика и телемеханика. 2023; (7): 83–92.

8. Алиева АМ, Теплова НВ, Кисляков ВА, Валиев РК, Рахаев АМ, Сарыев МН и др. Внеклеточная ДНК и сердечно-сосудистые заболевания. РМЖ. 2022; 5: 26–29.

9. Стоногина ДА, Желанкин АВ, Васильев СВ, Генерозов ЭВ, Аксельрод АС. Диагностические возможности профилей циркулирующих микроРНК у пациентов с острым коронарным синдромом и стабильной ИБС. Кардиология и сердечно-сосудистая хирургия. 2024; 17 (2): 125–132. https://doi.org/10.17116/kardio202417021125.

10. Villaseñor-Altamirano AB, Balderas-Martínez YI, Medina-Rivera A. Chapter 8 – Review of gene expression using microarray and RNA-seq. Rigor and Reproducibility in Genetics and Genomics: Peer-reviewed, Published, Cited (Translational and Applied Genomics). Eds: D.F. Dluzen, M.H.M. Schmidt. Academic Press, 2024: 159–187. https://doi.org/10.1016/B978-0-12-817218-6.00008-5.

11. Kobashigawa J, Patel J, Azarbal B, Kittleson M, Chang D, Czer L et al. Randomized pilot trial of gene expression profiling versus heart biopsy in the first year after heart transplant: early invasive monitoring attenuation through gene expression trial. Circ Heart Fail. 2015 May; 8 (3): 557–564. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001658.

12. Horwitz PA, Tsai EJ, Putt ME, Gilmore JM, Lepore JJ, Parmacek MS et al. Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression. Circulation. 2004 Dec 21; 110 (25): 3815–3821.

13. Deng MC, Eisen HJ, Mehra MR, Billingham M, Marboe CC, Berry G et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene ex pression profiling. Am J Transplant. 2006 Jan; 6 (1): 150–160.

14. Fang KC. Clinical utilities of peripheral blood gene expression profiling in the management of cardiac transplant patients. J Immunotoxicol. 2007 Jul; 4 (3): 209– 217.

15. Deng MC. The AlloMap™ genomic biomarker story: 10 years after. Clin Transplant. 2017 Mar; 31 (3): e12900. https://doi.org/10.1111/ctr.12900.

16. Shannon CP, Hollander Z, Dai DLY, Chen V, Assadian S, Lam KK et al. HEARTBiT: A transcriptomic signature for excluding acute cellular rejection in adult heart allograft patients. Can J Cardiol. 2020 Aug; 36 (8): 1217– 1227.

17. Loupy A, van Huyen JPD, Hidalgo L, Reeve J, Racapé M, Aubert O et al. Gene expression profiling for the identification and classification of antibody-mediated heart rejection. Circulation. 2017 Mar 7; 135 (10): 917–935. https://doi.org/10.1161/CIRCULATIONAHA.116.022907.

18. Afzali B, Chapman E, Racapé M, Adam B, Bruneval P, Gil F et al. Molecular assess ment of microcirculation injury in formalin-fixed human cardiac allograft biopsies with antibody-mediated rejection. Am J Transplant. 2017 Feb; 17 (2): 496–505. https://doi.org/10.1111/ajt.13956.

19. Tarazon E, Perez-Carrillo L, Garcia-Bolufer P, Triviño JC, Feijóo-Bandín S, Lago F et al. Circulating mitochondrial genes detect acute cardiac allograft rejection: role of the mitochondrial calcium uniporter complex. Am J Transplant. 2021 Jun; 21 (6): 2056–2066.

20. Deuse T, Hu X, Agbor-Enoh S, Koch M, Spitzer MH, Gravina A et al. De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans. Nat Biotechnol. 2019 Oct; 37 (10): 1137–1144.

21. Shah P, Valantine HA, Agbor-Enoh S. Transcriptomics in transplantation: more than just biomarkers of allograft rejection. Am J Transplant. 2021 Jun; 21 (6): 2000–2001.

22. Lo YMD, Han DSC, Jiang P, Chiu RWK. Epigenetics, fragmentomics, and topology of cell-free DNA in liquid biopsies. Science. 2021 Apr 9; 372 (6538): eaaw3616. doi: 10.1126/science.aaw3616.

23. Khush KK, Patel J, Pinney S, Kao A, Alharethi R, DePasquale E et al. Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: A prospective multicenter study. Am J Transplant. 2019 Oct; 19 (10): 2889–2899. doi: 10.1111/ajt.15339.

24. Snyder TM, Khush KK, Valantine HA, Quake SR. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci USA. 2011 Apr 12; 108 (15): 6229–6234. doi: 10.1073/pnas.1013924108.

25. Sorbini M, Togliatto GM, Simonato E, Boffini M, Cappuccio M, Gambella A et al. HLA DRB1 mismatchbased identification of donor-derived cell free DNA (dd cfDNA) as a marker of rejection in heart transplant recipients: A single-institution pilot study. J Heart Lung Transplant. 2021 Aug; 40 (8): 794–804. doi: 10.1016/j.healun.2021.05.001.

26. Knüttgen F, Beck J, Dittrich M, Oellerich M, Zittermann A, Schulz U et al. Graft-derived Cell-free DNA as a Noninvasive Biomarker of Cardiac Allograft Rejection: A Cohort Study on Clinical Validity and Confounding Factors. Transplantation. 2022 Mar 1; 106 (3): 615–622. doi: 10.1097/TP.0000000000003725.

27. Agbor-Enoh S, Shah P, Tunc I, Hsu S, Russell S, Feller E et al. Cell-Free DNA to Detect Heart Allograft Acute Rejection. Circulation. 2021 Mar 23; 143 (12): 1184–1197. doi: 10.1161/CIRCULATIONAHA.120.049098.

28. De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H et al. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014 Jun 18; 6 (241): 241ra77. doi: 10.1126/scitranslmed.3007803.

29. Holzhauser L, Clerkin KJ, Fujino T, Alenghat FJ, Raikhelkar J, Kim G et al. Donor-derived cell-free DNA is associated with cardiac allograft vasculopathy. Clin Transplant. 2021 Mar; 35 (3): e14206. doi: 10.1111/ctr.14206.

30. DePasquale EC, Kobashigawa J, Hall S, Wolf-Doty T, Teuteberg J, Khush KK. Donor derived cell free DNA as a risk factor for initiating de-novo donor specific antibodies in heart transplantation. J Heart Lung Transplant. 2021 Apr; 40 (4): S217–S218.

31. Shah P, Bristow MR, Port JD. MicroRNAs in Heart Failure, Cardiac Transplantation, and Myocardial Recovery: Biomarkers with Therapeutic Potential. Curr Heart Fail Rep. 2017 Dec; 14 (6): 454–464. doi: 10.1007/s11897-017-0362-8.

32. Nováková T, Macháčková T, Novák J, Hude P, Godava J, Žampachová V et al. Identification of a Diagnostic Set of Endomyocardial Biopsy microRNAs for Acute Cellular Rejection Diagnostics in Patients after Heart Transplantation Using Next-Generation Sequencing. Cells. 2019 Nov 6; 8 (11): 1400. doi: 10.3390/cells8111400.

33. Великий ДА, Гичкун ОЕ, Шарапченко СО, Можейко НП, Курабекова РМ, Шевченко ОП. Диагностическое значение микроРНК-101 и микроРНК-27 при остром отторжении трансплантированного сердца. Вестник трансплантологии и искусственных органов. 2020; 22 (4): 20–26. https://doi.org/10.15825/1995-1191-2020-4-20-26.

34. Шевченко ОП, Великий ДА, Шарапченко СО, Гичкун ОЕ, Марченко АВ, Улыбышева АА и др. МикроРНК-27 и -339 при фиброзе миокарда трансплантированного сердца: анализ диагностической значимости. Вестник трансплантологии и искусственных органов. 2021; 23 (3): 73–81. https://doi.org/10.15825/1995-1191-2021-3-73-81.

35. Shevchenko O, Sharapchenko S, Gichkun O, Velikiy D, Mozheiko N, Makarova L et al. Diagnostic value of microRNA-27, microRNA-101 and ST2 for heart trans plant acute rejection. Clinica Chimica Acta. 2022; 530: S452.

36. Pérez-Carrillo L, Sánchez-Lázaro I, Triviño JC, Feijóo-Bandín S, Lago F, González-Juanatey JR et al. Diagnostic value of serum miR 144-3p for the detection of acute cellular rejection in heart transplant patients. J Heart Lung Transplant. 2022 Feb; 41 (2): 137–147. doi: 10.1016/j.healun.2021.10.004.

37. Pérez-Carrillo L, Sánchez-Lázaro I, Triviño JC, FeijóoBandín S, Lago F, González-Juanatey JR et al. Combining Serum miR 144-3p and miR 652-3p as Potential Biomarkers for the Early Diagnosis and Stratification of Acute Cellular Rejection in Heart Transplantation Patients. Transplantation. 2023 Sep 1; 107 (9): 2064–2072. doi: 10.1097/TP.0000000000004622.

38. Hinkel R, Ramanujam D, Kaczmarek V, Howe A, Klett K, Beck C et al. AntimiR 21 Prevents Myocardial Dysfunction in a Pig Model of Ischemia/Reperfusion Injury. J Am Coll Cardiol. 2020 Apr 21; 75 (15): 1788–1800. doi: 10.1016/j.jacc.2020.02.041.

39. Lu J, Liu Y, Wang W, Li P, Qi F. Knockdown of miR 146a in regulatory T cells suppresses heart transplantation rejection in mice by increasing autophagy. Transpl Immunol. 2021 Apr; 65: 101372. doi: 10.1016/j.trim.2021.101372.

40. Gavroy B, Timmermans T, Van Caenegem O, Mastrobuoni S, Jacquet L, Latinne D, Poncelet AJ. Significance of HLA matching and anti-HLA antibodies in heart transplant patients receiving induction therapy? Transpl Immunol. 2022 Dec; 75: 101706. doi: 10.1016/j.trim.2022.101706.

41. Sciaccaluga C, Natali BM, Righini FM, Sorini Dini C, Landra F, Mandoli GE et al. Heart transplantation and anti-HLA antibodY: myocardial dysfunction and prognosis – HeartLAy study. ESC Heart Fail. 2023 Oct; 10 (5): 2853–2864. doi: 10.1002/ehf2.14442.

42. Kobashigawa J, Colvin M, Potena L, Dragun D, Crespo-Leiro MG, Delgado JF et al. The management of antibodies in heart transplantation: An ISHLT consensus document. J Heart Lung Transplant. 2018 May; 37 (5): 537–547. doi: 10.1016/j.healun.2018.01.1291.

43. Moreno JD, Verma AK, Kopecky BJ, Dehner C, Kostelecky N, Vader JM et al. Angiotensin II Type 1 Receptor Antibody-mediated Rejection Following Orthotopic Heart Transplant: A Single-center Experience. Transplantation. 2022 Feb 1; 106 (2): 373–380. doi: 10.1097/TP.0000000000003712.

44. Nair N. Vascular rejection in cardiac allograft vasculopathy: Impact on graft survival. Front Cardiovasc Med. 2022 Aug 4; 9: 919036. doi: 10.3389/fcvm.2022.919036.

45. Giarraputo A, Barison I, Fedrigo M, Burrello J, Castellani C, Tona F et al. A Changing Paradigm in Heart Transplantation: An Integrative Approach for Invasive and Non-Invasive Allograft Rejection Monitoring. Biomolecules. 2021 Feb 1; 11 (2): 201. doi: 10.3390/biom11020201.

46. Castellani C, Burrello J, Fedrigo M, Burrello A, Bolis S, Di Silvestre D et al. Circulating extracellular vesicles as non-invasive biomarker of rejection in heart transplant. J Heart Lung Transplant. 2020 Oct; 39 (10): 1136–1148. doi: 10.1016/j.healun.2020.06.011.

47. Hu RW, Korutla L, Reddy S, Harmon J, Zielinski PD, Bueker A et al. Circulating Donor Heart Exosome Profiling Enables Noninvasive Detection of Antibody-mediated Rejection. Transplant Direct. 2020 Oct 19; 6 (11): e615. doi: 10.1097/TXD.0000000000001057.

48. Корнева ЛО, Осипова МА, Борцова МА, Мусаева ББ, Симоненко МА, Акино АД и др. Уровень некоторых микровезикул у пациентов с отторжением сердечного трансплантата. Российский кардиологический журнал. 2024; 29 (S8): 307.

49. Qian X, Shah P, Agbor-Enoh S. Noninvasive biomarkers in heart transplant: 2020–2021 year in review. Curr Opin Organ Transplant. 2022 Feb 1; 27 (1): 7–14. doi: 10.1097/MOT.0000000000000945.

50. Khachatoorian Y, Khachadourian V, Chang E, Sernas ER, Reed EF, Deng M et al. Noninvasive biomarkers for prediction and diagnosis of heart transplantation rejection. Transplant Rev (Orlando). 2021 Jan; 35 (1): 100590. doi: 10.1016/j.trre.2020.100590.

51. Benck L, Sato T, Kobashigawa J. Molecular Diagnosis of Rejection in Heart Transplantation. Circ J. 2022 Jun 24; 86 (7): 1061–1067. doi: 10.1253/circj.CJ-21-0591.

52. Holzhauser L, DeFilippis EM, Nikolova A, Byku M, Contreras JP, De Marco T et al. The End of Endomyocardial Biopsy?: A Practical Guide for Noninvasive Heart Transplant Rejection Surveillance. JACC Heart Fail. 2023 Mar; 11 (3): 263–276. doi: 10.1016/j.jchf.2022.11.002.