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Markers of Immune Function in Heart Transplantation: Implications for Immunosuppression and Screening for Rejection

  • Biomarkers of Heart Failure (W.H.W. Tang and J. Grodin, Section Editors)
  • Published:
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Abstract

Purpose of Review

Recent developments in high-throughput DNA and RNA sequencing technologies have facilitated the development of noninvasive assays to monitor heart transplant rejection. In this review, we summarize existing assays employed for the surveillance of allograft rejection, as well as promising future directions for such tests in the molecular biology field.

Recent Findings

The AlloMap genome expression profiling assay remains the only noninvasive test for rejection surveillance and is incorporated into the International Society of Heart and Lung Transplantation guidelines. Other efforts have focused on messenger RNA (mRNA), microRNA (miRNA), and donor-derived cell-free DNA (dd-cfDNA) as potential viable biomarkers. Mitochondrial pathways in allograft necroptosis and inflammation signaling may represent a novel direction for future research endeavors.

Summary

Although endomyocardial biopsy remains the gold standard, several converging areas of molecular biology could soon yield successful alternative methods of heart transplant rejection monitoring, with the distinct advantage of avoiding procedural complications.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914–56. https://doi.org/10.1016/j.healun.2010.05.034.

    Article  PubMed  Google Scholar 

  2. Saraiva F, Matos V, Goncalves L, Antunes M, Providencia LA. Complications of endomyocardial biopsy in heart transplant patients: a retrospective study of 2117 consecutive procedures. Transplant Proc. 2011;43(5):1908–12. https://doi.org/10.1016/j.transproceed.2011.03.010.

    Article  CAS  PubMed  Google Scholar 

  3. Singh V, Mendirichaga R, Savani G, Rodriguez A, Blumer V, Elmariah S, et al. Comparison of utilization trends, indications, and complications of endomyocardial biopsy in native versus donor hearts (from the nationwide inpatient sample 2002 to 2014). Am J Cardiol. 2018;121(3):356–63. https://doi.org/10.1016/j.amjcard.2017.10.021.

    Article  PubMed  Google Scholar 

  4. Peyster EG, Madabhushi A, Margulies KB. Advanced morphologic analysis for diagnosing allograft rejection: the case of cardiac transplant rejection. Transplantation. 2018;102(8):1230–9. https://doi.org/10.1097/TP.0000000000002189.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Churko JM, Mantalas GL, Snyder MP, Wu JC. Overview of high throughput sequencing technologies to elucidate molecular pathways in cardiovascular diseases. Circ Res. 2013;112(12):1613–23. https://doi.org/10.1161/CIRCRESAHA.113.300939.

    Article  CAS  PubMed  Google Scholar 

  6. Deng MC, Eisen HJ, Mehra MR, Billingham M, Marboe CC, Berry G, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant. 2006;6(1):150–60. https://doi.org/10.1111/j.1600-6143.2005.01175.x.

    Article  CAS  PubMed  Google Scholar 

  7. 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;36(8):1217–27. https://doi.org/10.1016/j.cjca.2019.11.017.

    Article  PubMed  Google Scholar 

  8. Kim JV, Lee B, Koitsopoulos P, Shannon CP, Chen V, Hollander Z, et al. Analytical validation of HEARTBiT: a blood-based multiplex gene expression profiling assay for exclusionary diagnosis of acute cellular rejection in heart transplant patients. Clin Chem. 2020;66(8):1063–71. https://doi.org/10.1093/clinchem/hvaa123.

    Article  PubMed  Google Scholar 

  9. Dewi IS, Torngren K, Gidlof O, Kornhall B, Ohman J. Altered serum miRNA profiles during acute rejection after heart transplantation: potential for non-invasive allograft surveillance. J Heart Lung Transplant. 2013;32(4):463–6. https://doi.org/10.1016/j.healun.2012.12.007.

    Article  Google Scholar 

  10. Constanso-Conde I, Hermida-Prieto M, Barge-Caballero E, Nunez L, Pombo-Otero J, Suarez-Fuentetaja N, et al. Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation. J Heart Lung Transplant. 2020;39(10):1100–8. https://doi.org/10.1016/j.healun.2020.05.018.

    Article  PubMed  Google Scholar 

  11. Van Huyen JD, Tible M, Gay A, Guillemain R, Aubert O, Varnous S, et al. MicroRNAs as non-invasive biomarkers of heart transplant rejection. Eur Heart J. 2014;35(45):3194–202. https://doi.org/10.1093/eurheartj/ehu346.

    Article  CAS  Google Scholar 

  12. Di Francesco A, Fedrigo M, Santovito D, Natarelli L, Castellani C, De Pascale F, et al. MicroRNA signatures in cardiac biopsies and detection of allograft rejection. J Heart Lung Transplant. 2018;37(11):1329–40. https://doi.org/10.1016/j.healun.2018.06.010.

    Article  PubMed  Google Scholar 

  13. Dengu F. Next-generation sequencing methods to detect donor-derived cell-free DNA after transplantation. Transplant Rev (Orlando). 2020;34(3):100542. https://doi.org/10.1016/j.trre.2020.100542.

    Article  Google Scholar 

  14. Khush KK, Patel J, Pinney S, Kao A, Alharethi R, DePasquale E, et al. Non-invasive detection of graft injury after heart transplant using donor derived cell-free DNA: a prospective multicenter study. Am J Transplant. 2019;19(10):2889–99. https://doi.org/10.1111/ajt.15339The authors demonstrate the clinical utility of AlloSure, a donor derived cell-free DNA assay commonly used in renal transplant recipients, in the discrimination of cardiac allograft rejection.

  15. Richmond ME, Zangwill SD, Kindel SJ, Deshpande SR, Schroder JN, Bichell DP, et al. Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation. J Heart Lung Transplant. 2020;39(5):454–63. https://doi.org/10.1016/j.healun.2019.11.015.

    Article  PubMed  Google Scholar 

  16. Valujskikh A. Runaway powerhouse: donor mitochondria promote rejection. Am J Transplant. 2019;19(7):1875–6. https://doi.org/10.1111/ajt.15349.

    Article  PubMed  Google Scholar 

  17. Dela Cruz CS, Kang M. Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases. Mitochondrion. 2018;41:37–44. https://doi.org/10.1016/j.mito.2017.12.001.

    Article  CAS  Google Scholar 

  18. Land WG, Agostinis P, Gasser S, Garg AD, Linkermann A. Transplantation and damage-associated molecular patterns (DAMPs). Am J Transplant. 2016;16(12):3338–61. https://doi.org/10.1111/ajt.13963.

    Article  CAS  PubMed  Google Scholar 

  19. Gan I, Jiang J, Lian D, Huang X, Fuhrmann B, Liu W, et al. Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection. Am J Transplant. 2019;19(3):686–98. https://doi.org/10.1111/ajt.15112In this study, cyclophilin D (Cyp-D), a mitochondrial permeability transition pore (mPTP) molecule, was implicated in a murine cardiac allograft rejection model via endothelial cell necroptosis. The authors also hypothesize that some of the beneficial immunosuppressive effects of cyclosporine may occur via inhibition of the Cyp-D pathway.

    Article  CAS  PubMed  Google Scholar 

  20. Tarazon E, Ortega A, Gil-Cayuela C, Sanchez-Lacuesta E, Marin P, Lago F, et al. SERCA2a: a potential non-invasive biomarker of cardiac allograft rejection. J Heart Lung Transplant. 2017;36(12):1322–8. https://doi.org/10.1016/j.healun.2017.07.003The authors demonstrate the discriminatory ability of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in detecting cardiac allograft rejection. This study also raises a potential intriguing link between SERCA2a-mediated calcium dysregulation in congestive heart failure, and a possible similar role in declining allograft function and associated rejection.

    Article  PubMed  Google Scholar 

  21. Tarazon E, Gil-Cayuela C, Manzanares MG, Roca M, Lago F, Gonzalez-Juanatey JR, et al. Circulating sphingosine-1-phosphate as a non-invasive biomarker of heart transplant rejection. Sci Rep. 2019;9(1):13880. https://doi.org/10.1038/s41598-019-50413-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Deng MC. The AlloMap genomic biomarker story: 10 years after. Clin Transpl. 2017;31(3). https://doi.org/10.1111/ctr.12900.

  23. Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010;362(20):1890–900. https://doi.org/10.1056/NEJMoa0912965.

    Article  CAS  PubMed  Google Scholar 

  24. Crespo-Leiro MG, Stypmann J, Schulz U, Zuckermann A, Mohacsi P, Bara C, et al. Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II. Eur Heart J. 2016;37(33):2591–601. https://doi.org/10.1093/eurheartj/ehv682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Moayedi Y, Foroutan F, Miller RJH, et al. Risk evaluation using gene expression screening to monitor for acute cellular rejection in heart transplant recipients. J Heart Lung Transplant. 2019;38(1):51–8. https://doi.org/10.1016/j.healun.2018.09.004This study provides additional longitudinal data supporting the screening use of AlloMap outside clinical trials, in a contemporary cohort of stable transplant recipients at low risk of acute cellular rejection.

  26. Kransdorf EP, Kobashigawa JA. Genetic and genomic approaches to the detection of heart transplant rejection. Per Med. 2012;9(7):693–705. https://doi.org/10.2217/pme.12.84.

    Article  CAS  PubMed  Google Scholar 

  27. Shah KS, Kittleson MM, Kobashigawa JA. Updates on heart transplantation. Curr Heart Fail Rep. 2019;16(5):150–6. https://doi.org/10.1007/s11897-019-00432-3.

    Article  PubMed  Google Scholar 

  28. Stehlik J, Kobashigawa J, Hunt SA, Reichenspurner H, Kirklin JK. Honoring 50 years of clinical heart transplantation in circulation: in-depth state-of-the-art review. Circulation. 2018;137(1):71–87. https://doi.org/10.1161/CIRCULATIONAHA.117.029753.

    Article  PubMed  Google Scholar 

  29. Dallaire F, Greenway SC. Advancing heart transplantation and the detection of rejection, Bit by BiT. Can J Cardiol. 2020;36(8):1189–90. https://doi.org/10.1016/j.cjca.2019.11.023.

    Article  PubMed  Google Scholar 

  30. Hamdorf M, Kawakita S, Everly M. The potential of microRNAs as novel biomarkers for transplant rejection. J Immunol Res. 2017;2017:4072364–12. https://doi.org/10.1155/2017/4072364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mas VR, Dumur CI, Scian MJ, Gehrau RC, Maluf DG. MicroRNAs as biomarkers in solid organ transplantation. Am J Transplant. 2013;13(1):11–9. https://doi.org/10.1111/j.16000-6143.2012.01313.x.

    Article  CAS  PubMed  Google Scholar 

  32. Harris A, Krams SM, Martinez OM. MicroRNAs as immune regulators: implications for transplantation. Am J Transplant. 2010;10(4):713–9. https://doi.org/10.1111/j.1600-6143.2010.03032.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang J, Chen J, Sen S. MicroRNA as biomarkers and diagnostics. J Cell Physiol. 2016;231(1):25–30. https://doi.org/10.1002/jcp.25056.

    Article  CAS  PubMed  Google Scholar 

  34. Seeto RK, Fleming JN, Dholakia S, Dale BL. Understanding and using Allosure donor derived cell-free DNA. Biophys Rev. 2020;12(4):917–24. https://doi.org/10.1007/s12551-020-00713-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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;6(241):241ra77. https://doi.org/10.1126/scitranslmed.3007803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ragalie WS, Stamm K, Mahnke D, Liang HL, Simpson P, Katz R, et al. Noninvasive assay for donor fraction of cell-free DNA in pediatric heart transplant recipients. J Am Coll Cardiol. 2018;71(25):2982–3. https://doi.org/10.1016/j.jacc.2018.04.026.

    Article  PubMed  Google Scholar 

  37. Annesley SJ, Fisher PR. Mitochondria in health and disease. Cells. 2019;8(7):680. https://doi.org/10.3390/cells80700680.

    Article  CAS  PubMed Central  Google Scholar 

  38. Tian R, Colucci WS, Arany Z, Bachschmid MM, Ballinger SW, Boudina S, et al. Unlocking the secrets of mitochondria in the cardiovascular system: path to a cure in heart failure- a report from the 2018 National Heart, Lung, and Blood Institute Workshop. Circulation. 2019;140(14):1205–16. https://doi.org/10.1161/CIRCULATIONAHA.119.040551.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lin L, Xu H, Bishawi M, Feng F, Samy K, Truskey G, et al. Circulating mitochondria in organ donors promote allograft rejection. Am J Transplant. 2019;19(7):1917–29. https://doi.org/10.1111/ajt.15309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gomez L, Raisky O, Chalabreysse L, Verschelde C, Bonnefoy-Berard N, Ovize M. Link between immune cell infiltration and mitochondria-induced cardiomyocyte death during acute cardiac graft rejection. Am J Transplant. 2006;6(3):487–95. https://doi.org/10.1111/j.1600-6143.2005.01219.x.

    Article  CAS  PubMed  Google Scholar 

  41. Samuel TJ, Rosenberry RP, Lee S, Pan Z. Correcting calcium dysregulation in chronic heart failure using SERCA2a gene therapy. Int J Mol Sci. 2018;19(4):1086. https://doi.org/10.3390/ijms19041086.

    Article  CAS  PubMed Central  Google Scholar 

  42. Eisner D, Caldwell J, Trafford A. Sarcoplasmic reticulum Ca-ATPase and heart failure 20 years later. Circ Res. 2013;113(8):958–61. https://doi.org/10.1161/CIRCRESAHA.113.302187.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Fellow, Advanced Heart Failure and Transplant Cardiology, Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9047, USA

    David X. Zhuo

  2. Nurse Practitioner, Advanced Heart Failure, Transplant, LVAD, Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Katie Ginder

  3. Internal Medicine, Advanced Heart Failure and Transplant Cardiology, Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Ste #HP.8.110, Dallas, TX, 75390-9047, USA

    E. Ashley Hardin

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Correspondence to E. Ashley Hardin.

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Zhuo, D.X., Ginder, K. & Hardin, E.A. Markers of Immune Function in Heart Transplantation: Implications for Immunosuppression and Screening for Rejection. Curr Heart Fail Rep 18, 33–40 (2021). https://doi.org/10.1007/s11897-020-00499-3

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