Herz

, Volume 35, Issue 1, pp 11–16

Biomarker zur Diagnose der zellulären Abstoßung nach Herztransplantation

  • Matthias Frick
  • Herwig Antretter
  • Otmar Pachinger
  • Gerhard Pölzl
Article

Zusammenfassung

Die Herztransplantation hat sich zu einer etablierten Therapie bei Patienten mit terminaler, therapierefraktärer Herzinsuffizienz entwickelt. Im 1. Jahr nach Herztransplantation spielt dabei die akute Abstoßung nach wie vor eine wichtige Rolle. Die Diagnose der akuten Abstoßung erfolgt über die histologische Beurteilung von Herzmuskelgewebe und ist somit an die Durchführung einer Endomyokardbiopsie (EMB) gebunden, welche mit einem entsprechenden Risiko assoziiert ist und für einige Patienten eine unangenehme Prozedur darstellt. Neben den bildgebenden Verfahren (vor allem Echokardiographie und Magnetresonanztomographie) und dem intramyokardialen Elektrogramm als nichtinvasive Methoden zur Abstoßungsdiagnostik wurde auch eine große Anzahl zirkulierender Biomarker untersucht, wobei B-Typ-natriuretisches Peptid, Troponin und inflammatorische Marker zu den wichtigsten zählen. Obwohl der Einsatz dieser Biomarker hilfreich sein kann, hat keiner der diskutierten Parameter das Potential, die EMB als Goldstandard in der Abstoßungsdiagnostik nach Herztransplantation zu ersetzen. Interessant wird in den nächsten Jahren der Einsatz der Microarrays, mit deren Hilfe Genexpressionsmuster bestimmt werden können, welche mit einem höheren Risiko für eine Abstoßung assoziiert sind. Laufende Studien werden zeigen, ob dadurch die EMB zumindest in der Anzahl reduziert werden kann.

Schlüsselwörter:

Biomarker Abstoßung Herztransplantation 

Biomarker for Diagnosis of Rejection after Heart Transplantation

Abstract

Heart transplantation is an established therapeutic modality in patients with end-stage heart failure. In the 1st year after transplantation acute cellular rejection is still important. The diagnosis of acute cellular rejection is based on the histological evaluation of endomyocardial biopsy (EMB) specimens. EMB is an invasive procedure with a definite risk and poor tolerance in some patients. Imaging methods like echocardiography and magnetic resonance imaging as well as intracardiac ECG have been used for noninvasive diagnosis of acute cellular rejection. In addition, a large number of circulating biomarkers have been evaluated for noninvasive diagnosis of rejection. B-type natriuretic peptide, troponin and inflammatory markers are the most important biomarkers in this field. Although these parameters are useful, none of them has the potential to replace EMB as the gold standard for diagnosis of rejection. In the near future microarray technology might get important for diagnosis of acute cellular rejection. Using microarray technique gene expression profiles can be detected, which are associated with an increased risk for rejection. Ongoing studies will demonstrate, whether microarrays can at least reduce the number of EMBs.

Key Words:

Biomarker Rejection Heart transplantation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Caves PK, Stinson EB, Billingham M, et al. Percutaneous transvenous endomyocardial biopsy in human heart recipients. Experience with a new technique. Ann Thorac Surg 1973;16:325–36.CrossRefPubMedGoogle Scholar
  2. 2.
    Robbins RC, Barlow CW, Oyer PE, et al. Thirty years of cardiac transplantation at Stanford university. J Thorac Cardiovasc Surg 1999;117:939–51.CrossRefPubMedGoogle Scholar
  3. 3.
    Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003;349:847–58.CrossRefPubMedGoogle Scholar
  4. 4.
    Kobashigawa JA, Miller LW, Russell SD, et al. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant 2006;6:1377–86.CrossRefPubMedGoogle Scholar
  5. 5.
    Marboe CC, Billingham M, Eisen H, et al. Nodular endocardial infiltrates (Quilty lesions) cause significant variability in diagnosis of ISHLT grade 2 and 3A rejection in cardiac allograft recipients. J Heart Lung Transplant 2005;24:Suppl:S219–26.CrossRefPubMedGoogle Scholar
  6. 6.
    Winters GL, McManus BM. Consistencies and controversies in the application of the International Society for Heart and Lung Transplantation working formulation for heart transplant biopsy specimens. Rapamycin Cardiac Rejection Treatment Trial Pathologists. J Heart Lung Transplant 1996;15:728–35.PubMedGoogle Scholar
  7. 7.
    Mondillo S, Maccherini M, Galderisi M. Usefulness and limitations of transthoracic echocardiography in heart transplantation recipients. Cardiovasc Ultrasound 2008;6:2–13.CrossRefPubMedGoogle Scholar
  8. 8.
    Butler CR, Thompson R, Haykowsky M, et al. Cardiovascular magnetic resonance in the diagnosis of acute heart transplant rejection: a review. J Cardiovasc Magn Reson 2009;11:7–18.CrossRefPubMedGoogle Scholar
  9. 9.
    Auer T, Schreier G, Hutten H, et al. Intramyocardial electrograms for the monitoring of allograft rejection after heart transplantation using spontaneous and paced beats. Transplant Proc 1995;27:2621–4.PubMedGoogle Scholar
  10. 10.
    Bourge R, Eisen H, Hershberger R, et al. Noninvasive rejection monitoring of cardiac transplants using high resolution intramyocardial electrograms: initial US multicenter experience. Pacing Clin Electrophysiol 1998;21:2338–44.CrossRefPubMedGoogle Scholar
  11. 11.
    Mair J, Hammerer-Lercher A, Puschendorf B. The impact of cardiac natriuretic peptide determination on the diagnosis and management of heart failure. Clin Chem Lab Med 2001;39:571–88.CrossRefPubMedGoogle Scholar
  12. 12.
    Angermann CE, Ertl G. Natriuretic peptides — new diagnostic markers in heart disease. Herz 2004;29:609–17.CrossRefPubMedGoogle Scholar
  13. 13.
    Ang DS, Kong CF, Kao MP, et al. Serial bedside B-type natriuretic peptide strongly predicts prognosis in acute coronary syndrome independent of echocardiographic abnormalities. Am Heart J 2009;158:133–40.CrossRefPubMedGoogle Scholar
  14. 14.
    El Gamel A, Yonan NA, Keevil B, et al. Significance of raised natriuretic peptides after bicaval and standard cardiac transplantation. Ann Thorac Surg 1997;63:1095–100.CrossRefPubMedGoogle Scholar
  15. 15.
    Ationu A, Burch M, Singer D, et al. Cardiac transplantation affects ventricular expression of brain natriuretic peptide. Cardiovasc Res 1993;27:188–91.CrossRefPubMedGoogle Scholar
  16. 16.
    Buckley MG, Yacoub MH, Singer DR. Investigation of the plasma concentrations and circulating forms of BNP and ANP in orthotopic cardiac transplant recipients. J Hum Hypertens 1998;12:825–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Garrido IP, Pascual-Figal DA, Nicolás F, et al. Usefulness of serial monitoring of B-type natriuretic peptide for the detection of acute rejection after heart transplantation. Am J Cardiol 2009;103:1149–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Ogawa T, Veinot JP, Davies RA, et al. Neuroendocrine profiling of humans receiving cardiac allografts. J Heart Lung Transplant 2005;24:1046–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Kirchhoff WC, Gradaus R, Stypmann J, et al. Vasoactive peptides during long-term follow-up of patients after cardiac transplantation. J Heart Lung Transplant 2004;23:284–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Lan YT, Chang RK, Alejos JC, et al. B-type natriuretic peptide in children after cardiac transplantation. J Heart Lung Transplant 2004;23:558–63.CrossRefPubMedGoogle Scholar
  21. 21.
    Arnau-Vives MA, Almenar L, Hervas I, et al. Predictive value of brain natriuretic peptide in the diagnosis of heart transplant rejection. J Heart Lung Transplant 2004;23:850–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Wu AH, Johnson ML, Aaronson KD, et al. Brain natriuretic peptide predicts serious cardiac allograft rejection independent of hemodynamic measurements. J Heart Lung Transplant 2005;24:52–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Hammerer-Lercher A, Mair J, Antretter H, et al. B-type natriuretic peptide as a marker of allograft rejection after heart transplantation. J Heart Lung Transplant 2005;24:1444–8.PubMedGoogle Scholar
  24. 24.
    O’Neill JO, McRae AT 3rd, Troughton RW, et al. Brain natriuretic peptide levels do not correlate with acute cellular rejection in de novo orthotopic heart transplant recipients. J Heart Lung Transplant 2005;24:416–20.CrossRefPubMedGoogle Scholar
  25. 25.
    Mehra MR, Uber PA, Potluri S, et al. Usefulness of an elevated B-type natriuretic peptide to predict allograft failure, cardiac allograft vasculopathy, and survival after heart transplantation. Am J Cardiol 2004;94:454–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Martinez-Dolz L, Almenar L, Moro J, et al. Prognostic value of brain natriuretic peptide in heart transplant patients. J Heart Lung Transplant 2007;26:986–91.CrossRefPubMedGoogle Scholar
  27. 27.
    Martínez-Dolz L, Almenar L, Hervás I, et al. Prognostic relationship between two serial determinations of B-type natriuretic peptide and medium-long-term events in heart transplantation. J Heart Lung Transplant 2008;27:735–40.CrossRefPubMedGoogle Scholar
  28. 28.
    Zimmermann R, Baki S, Dengler TJ, et al. Troponin T release after heart transplantation. Br Heart J 1993;69:395–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Hossein-Nia M, Mascaro J, McKenna WJ, et al.Troponin T as a non-invasive marker of cardiac allograft rejection. Lancet 1993;341:838.CrossRefPubMedGoogle Scholar
  30. 30.
    Dengler TJ, Zimmermann R, Braun K, et al. Elevated serum concentrations of cardiac troponin T in acute allograft rejection after human heart transplantation. J Am Coll Cardiol 1998;32:405–12.CrossRefPubMedGoogle Scholar
  31. 31.
    Chance JJ, Segal JB, Wallerson G, et al. Cardiac troponin T and C-reactive protein as markers of acute cardiac allograft rejection. Clin Chim Acta 2001;312:31–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang CW, Steinhubl SR, Castellani WJ, et al. Inability of serum myocyte death markers to predict acute cardiac allograft rejection. Transplantation 1996;62:1938–41.CrossRefPubMedGoogle Scholar
  33. 33.
    Alexis JD, Lao CD, Selter JG, et al. Cardiac troponin T: a noninvasive marker for heart transplant rejection? J Heart Lung Transplant 1998;17:395–8.PubMedGoogle Scholar
  34. 34.
    Mullen JC, Bentley MJ, Scherr KD, et al. Troponin T and I are not reliable markers of cardiac transplant rejection. Eur J Cardiothorac Surg 2002;22:233–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Billingham ME, Cary NR, Hammond ME, et al.A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 1990;9:587–93.PubMedGoogle Scholar
  36. 36.
    Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005;24:1710–20.CrossRefPubMedGoogle Scholar
  37. 37.
    Labarrere CA, Nelson DR, Cox CJ, et al. Cardiac-specific troponin I levels and risk of coronary artery disease and graft failure following heart transplantation. JAMA 2000;284:457–64.CrossRefPubMedGoogle Scholar
  38. 38.
    Ridker PM, Haughie P. Prospective studies of C-reactive protein as a risk factor for cardiovascular disease. J Invest Med 1998;46:391–5.Google Scholar
  39. 39.
    Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 1994;331:417–4.CrossRefPubMedGoogle Scholar
  41. 41.
    Harkiss GD. Serial study of C reactive protein concentrations in cardiac allograft recipients. J Clin Pathol 1985;38:193–7.Google Scholar
  42. 42.
    Sánchez-Soriano RM, Almenar L, Martínez-Dolz L, et al. Diagnostic usefulness of inflammatory markers in acute cellular rejection after heart transplantation. Transplant Proc 2006;38:2569–71.CrossRefPubMedGoogle Scholar
  43. 43.
    Martínez-Dolz L, Almenar L, Reganon E, et al. What is the best biomarker for diagnosis of rejection in heart transplantation? Clin Transplant 2009;23:672–80.Google Scholar
  44. 44.
    Van Gelder T, Balk AH, Zondervan PE, et al. C-reactive protein in the monitoring of acute rejection after heart transplantation. Transpl Int 1998;11:361–4.CrossRefPubMedGoogle Scholar
  45. 45.
    Balduini A, Campana C, Ceresa M, et al. Utility of biochemical markers in the follow-up of heart transplant recipients. Transplant Proc 2003;35:3075–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Assicot M, Gendrel D, Carsin H, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993;341:515–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Nijsten MW, Olinga P, The TH, et al. Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro. Crit Care Med 2000;28:458–61.CrossRefPubMedGoogle Scholar
  48. 48.
    Hammer S, Fraunberger P, Meiser B, et al. Procalcitonin, a new indicator for non-viral infections in heart, lung or liver transplant patients. Ann Transplant 1999;4:5–9.PubMedGoogle Scholar
  49. 49.
    Boeken U, Feindt P, Micek M, et al. Procalcitonin (PCT) in cardiac surgery: diagnostic value in systemic inflammatory response syndrome (SIRS), sepsis and after heart transplantation (HTX). Cardiovasc Surg 2000;8:550–4.CrossRefPubMedGoogle Scholar
  50. 50.
    Hammer S, Meisner F, Dirschedl P, et al. Procalcitonin for differential diagnosis of graft rejection and infection in patients with heart and/or lung grafts. Intensive Care Med 2000;26:Suppl 2:S182–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Eisenberg MS, Chen HJ, Warshofsky MK, et al. Elevated levels of plasma C-reactive protein are associated with decreased graft survival in cardiac transplant recipients. Circulation 2000;102:2100–4.PubMedGoogle Scholar
  52. 52.
    Schena M, Shalon D, Davis RW, et al. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 1995;270:467–70.CrossRefPubMedGoogle Scholar
  53. 53.
    Jun AS, Liu SH, Koo EH, et al. Microarray analysis of gene expression in human donor corneas. Arch Ophthalmol 2001;119:1629–34.PubMedGoogle Scholar
  54. 54.
    Deng MC, Eisen HJ, Mehra MR, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant 2006;6:150–60.CrossRefPubMedGoogle Scholar
  55. 55.
    Mehra MR, Kobashigawa JA, Deng MC, et al. Clinical implications and longitudinal alteration of peripheral blood transcriptional signals indicative of future cardiac allograft rejection. J Heart Lung Transplant 2008;27:297–301.CrossRefPubMedGoogle Scholar

Copyright information

© Urban & Vogel, Muenchen 2010

Authors and Affiliations

  • Matthias Frick
    • 1
    • 3
  • Herwig Antretter
    • 2
  • Otmar Pachinger
    • 1
  • Gerhard Pölzl
    • 1
  1. 1.Universitätsklink für Innere Medizin III – KardiologieMedizinische Universität InnsbruckInnsbruckÖsterreich
  2. 2.Universitätsklinik für HerzchirurgieMedizinische Universität InnsbruckInnsbruckÖsterreich
  3. 3.Universitätsklinik für Innere Medizin III – KardiologieMedizinische Universität InnsbruckInnsbruckÖsterreich

Personalised recommendations