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Dtsch Med Wochenschr 2004; 129(41): 2193-2197
DOI: 10.1055/s-2004-831864
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Kardiologie
© Georg Thieme Verlag Stuttgart · New York

Mechanismen der Transplantatvaskulopathie

Mechanisms of transplant vasculopathyH. Baron1 , G. Plenz2 , M. C. Deng1
  • 1Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York
  • 2Abteilung für Kardiologie and Angiologie, Klinik für Thorax-, Herz- und Gefäßchirurgie der Universität Münster
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Publication History

eingereicht: 7.6.2004

akzeptiert: 21.9.2004

Publication Date:
30 September 2004 (online)

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Zusammenfassung

Die Transplantatvaskulopathie des Spenderherzens ist eine diffuse, obliterative Form der Arteriosklerose, charakterisiert durch die Produktion einer Neointima reich an glatten Muskelzellen, die langfristig zu einer Obstruktion des Lumens führt. Pathophysiologisch werden nach Herztransplantation Alloantigene (z. B. auf Spender-Endothelzellen) durch antigen-präsentierende Zellen den T-Zellen des körpereigenen Immunsystemes präsentiert. Mit dem geeigneten kostimulatorischen Signal erzeugt dieses Muster eine differenzierte T-Zell-, B-Zell-Antwort und eine inflammatorische Antwort, während es ohne dieses Zweitsignal zur Apoptose der Immunzellen kommt. Im Falle einer Proliferation und Differenzierung der Immunzellen wird ein koordiniertes Zytokin-Muster initiiert. In diesen Prozess einbezogen sind Zellen der angeborenen Immunabwehr, von Monozyten abstammende Makrophagen. Die Zytokinfreisetzung führt zum Rolling, Sticking und der Diapedese von Immunzellen durch die koronare Endothelschicht und zu Migration der Media-ständigen glatten Muskelzellen und einem Wechsel ihres Phänotyps mit Produktion von wachstumsfördernden Zytokinen, die zur Intimahyperplasie beitragen.

Summary

Cardiac allograft vasculopathy is a diffuse, obliterative form of arteriosclerosis that is characterized by the production of a neointima rich in vascular smooth muscle cells that progressively obstructs the lumen. Pathophysiologically, after heart transplantation, alloantigens (e. g. on donor endothelial cells) are presented by antigen presenting cells to the T-cells of the body’s immune system. With the appropriate costimulatory signal, this signal pattern generates a differentiated T-cell, B-cell, and inflammatory cell response whereas without the second signal, the immune cells undergo apoptosis. In case of immune cell proliferation and differentiation, a coordinated pattern of cytokine release is initiated. Cells of innate immunity, monocyte-derived macrophages, are involved in this process. The inflammatory response culminates in rolling, sticking, and diapedesis through the coronary vascular endothelium and migration and phenotype switch of medial smooth muscle cells mediated by generation of growth-promoting cytokines.

Literatur

  • 1 Avery R K. Cardiac-allograft vasculopathy.  N Engl J Med. 2003;  349 829-830
    Search in Google Scholar
  • 2 Behrendt D, Ganz P, Fang J V. Cardiac allograft vasculopathy.  Curr Opin Cardiol. 2000;  15 422-429
    Search in Google Scholar
  • 3 Billingham M E. Histopathology of graft coronary disease.  J Heart Lung Transplant. 1992;  11 (Suppl) 38-42
    Search in Google Scholar
  • 4 Davis S F, Yeung A C, Meredith I T, Charbonneau F, Ganz P, Selwyn A P, Anderson T J. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant.  Circulation. 1996;  93 457-462
    Search in Google Scholar
  • 5 Deng M C, Bell S, Huie P, Pinto F, Hunt S A, Stinson E B, Sibley R, Hall B M, Valantine H A. Cardiac allograft vascular disease. Relationship to microvascular cell surface markers and inflammatory cell phenotypes on endomyocardial biopsy.  Circulation. 1995;  91 1647-1654
    Search in Google Scholar
  • 6 Deng M C, Mehra M, Hunt S, Valantine H, Miner R, Phillips J, Wohlgemuth J G, Chernoff D, Woodward E, Eisen H J. Leukocyte gene expression signature of CMV viremia in cardiac allograft recipients is distinct from that seen during allograft rejection (abstr).  Am J Transplant. 2004;  4 (suppl 8) 455
    Search in Google Scholar
  • 7 Deng M C, Mehra M R, Eisen H J, Billingham M, Berry G, Marboe C C, Itescu S, Johnson F L, Kobashigawa J, Wohlgemuth J G, Quertermous T, Hunt S. Cardiac allograft monitoring using a novel clinical algorithm based on peripheral leucocyte gene expression profiling.  Circulation. 2003;  108 (Supp IV) 389
    Search in Google Scholar
  • 8 Deng M C, Plenz G, Erren M, Wilhelm M J, Moennig G, Rothenburger M, Baba H A. Transplant vasculopathy: a model for coronary artery disease?.  Herz. 2000;  25 95-99
    Search in Google Scholar
  • 9 Deng M C, Tjan T DT, Asfour B, Roeder N, Scheld H H. Transplant vasculopathy.  Herz. 1998;  23 197-201
    Search in Google Scholar
  • 10 Eisen H J, Tuzcu E M, Dorent R, Kobashigawa J, Mancini D, von Valantine-Kaeppler H A, Starling R C, Sorensen K, Hummel M, Lind J M, Abeywickrama K H, Bernhardt P. RAD B253 Study Group . Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients.  N Engl J Med. 2003;  349 847-858
    Search in Google Scholar
  • 11 Everett J P, Hershberger R E, Norman D J, Chou S, Ratkovec R M, Cobanoglu A, Ott G Y, Hosenpud J D. Prolonged cytomegalovirus infection with viremia is associated with development of cardiac allograft vasculopathy.  J Heart Lung Transplant. 1992;  11 133-137
    Search in Google Scholar
  • 12 Germain R N. The art of the probable: system control in the adaptive immune system.  Science. 2001;  293 240-245
    Search in Google Scholar
  • 13 Grattan M T, Moreno-Cabral C E, Starnes V A, Oyer P E, Stinson E B, Shumway N E. Cytomegaly-virus infection is associated with cardiac allograft rejection and atherosclerosis.  J AmMed Assoc. 1989;  261 3561-3566
    Search in Google Scholar
  • 14 Grauhan O, Patzurek J, Hummel M, Lehmkuhl H, Dandel M, Pasic M, Weng Y, Hetzer R. Donor-transmitted coronary atherosclerosis.  J Heart Lung Transplant. 2003;  22 568-573
    Search in Google Scholar
  • 15 Hertz M I, Mohacsi P J, Taylor D O, Trulock E P, Boucek M M, Deng M C, Keck B M, Edwards L B, Rowe A W. The registry of the International Society for Heart and Lung Transplantation: introduction to the Twentieth Annual Reports - 2003.  J Heart Lung Transplant. 2003;  22 610-615
    Search in Google Scholar
  • 16 Hoffmann S C, Pearl J P, Blair P J, Kirk A D. Immune profiling: molecular monitoring in renal transplantation.  Front Biosci. 2003;  8 444-462
    Search in Google Scholar
  • 17 Hognestad A, Endresen K, Wergeland R, Stokke O, Geiran O, Holm T, Simonsen S, Kjekshus J K, Andreassen A K. Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients.  J Am Coll Cardiol. 2003;  42 477-482
    Search in Google Scholar
  • 18 Hollenberg S M, Klein L W, Parrillo J E, Scherer M, Burns D, Tamburro P, Oberoi M, Johnson M R, Costanzo M R. Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death.  Circulation. 2001;  104 3091-3096
    Search in Google Scholar
  • 19 Hollenberg S M, Klein L W, Parrillo J E, Scherer M, Burns D, Tamburro P, Bromet D, Satran A, Costanzo M R. Changes in coronary endothelial function predict progression of allograft vasculopathy after heart transplantation.  J Heart Lung Transplant. 2004;  23 265-271
    Search in Google Scholar
  • 20 Hosenpud J D, Bennett L E, Keck B M, Fiol B, Boucek M M, Novick R J. The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Report-1999.  J Heart Lung Transplant. 1999;  18 611-626
    Search in Google Scholar
  • 21 Johnson M R. Transplant coronary disease: nonimmunologic risk factors.  J Heart Lung Transplant. 1992;  11 S124-132
    Search in Google Scholar
  • 22 Kobashigawa J A, Katznelson S, Laks H, Johnson J A, Yeatman L, Wang X M, Chia D, Terasaki P I, Sabad A, Cogert G A, Trosian K, Hamilton M A, Moriguchi J D, Kawata N, Hage A, Drinkwater D C, Stevenson L W. Effect of pravastatin on outcomes after cardiac transplantation.  N Engl J Med. 1995;  333 621-627
    Search in Google Scholar
  • 23 Koglin J, Glysing-Jensen T, Mudgett J S, Russell M E. NOS2 mediates opposing effects in models of acute and chronic cardiac rejection. Insights from NOS2-knockout mice.  Am J Pathol. 1998;  153 1371-1376
    Search in Google Scholar
  • 24 Koglin J, Glysing-Jensen T, Räisänen-Sokolowski A, Russell M E. Immune sources of transforming growth factor-β1 reduce transplant arteriosclerosis. Insight derived from a knockout mouse model.  Circ Res. 1998;  83 652-660
    Search in Google Scholar
  • 25 Labarrere C A, Lee J B, Miller S J, Siddiqui R A, Brizendine E J, Pitts D E, Hormuth D A, Deng M C. Interleukin-6 and risk of coronary artery disease and graft failure in heart transplant recipients (abstr).  J Heart Lung Transplant. 2003;  22 S164
    Search in Google Scholar
  • 26 Labarrere C A, Pitts D, Nelson D R, Faulk W P. Vascular tissue plasminogen activator and the development of coronary artery disease in heart-transplant recipients.  N Engl J Med. 1995;  333 1111-1116
    Search in Google Scholar
  • 27 Loebe M, Schüler S, Zais O, Warnecke H, Fleck E, Hetzer R. Role of cytomegalovirus infection in the development of coronary artery disease in the transplanted heart.  J Heart Transplant. 1990;  9 707-711
    Search in Google Scholar
  • 28 Luckraz H, Charman S C, Wreghitt T, Wallwork J, Parameshwar J, Large S R. Does cytomegalovirus status influence acute and chronic rejection in heart transplantation during the ganciclovir prophylaxis era?.  J Heart Lung Transplant. 2003;  22 1023-1027
    Search in Google Scholar
  • 29 Mancini D, Pinney S, Burkhoff D, LaManca J, Itescu S, Burke E, Edwards N, Oz M, Marks A R. Use of rapamycin slows progression of cardiac transplantation vasculopathy.  Circulation. 2003;  108 48-53
    Search in Google Scholar
  • 30 Marboe C C, Billingham M, Eisen H J, Feller E, Deng M C, Mehra M R, Hunt S, Wohlgemuth J G, Mahmood I, Morris M S, Berry G. Refining pathological classification of acute rejection in cardiac allograft recipients: a multicenter study using peripheral blood gene expression profiling (abstr).  J Heart Lung Transplant. 2004;  23 S42
    Search in Google Scholar
  • 31 Matzinger P. The immune system’s role in graft loss: theoretical considerations.  Transplant Proc. 1997;  29 11S-12S (Suppl 8A)
    Search in Google Scholar
  • 32 Mehra M C, Kobashigawa J, Hunt S, Eisen H J, Starling R, Johnson F, Murali S, Zeevi A, Pauly D, Wohlgemuth J G, Morris M S, Woodward R, Deng M C. Molecular testing and prediction of clinical outcome in heart transplantation: A prospective multicenter trial (abstr).  J Heart Lung Transplant. 2004;  23 S106
    Search in Google Scholar
  • 33 Mehra M R, Uber P A, Ventura H O, Scott R L, Park M H. The impact of mode of donor brain death on cardiac allograft vasculopathy: an intravascular ultrasound study.  J Am Coll Cardiol. 2004;  43 806-810
    Search in Google Scholar
  • 34 Orosz C G. Networked alloimmunity: a brief reexamination of some basic concepts in transplantation biology.  J Heart Lung Transplant. 1996;  15 1063-1068
    Search in Google Scholar
  • 35 Parameshwar J, Foote J, Sharples L, Wallwork J, Large S, Schofield P. Lipids, lipoprotein (a) and coronary artery disease in patients following cardiac transplantation.  Transplant Int. 1996;  9 481-485
    Search in Google Scholar
  • 36 Pethig K, Heublein B, Meliss R R, Haverich A. Volumetric remodeling of the proximal left coronary artery: early versus late after heart transplantation.  J Am Coll Cardiol. 1999;  34 197-203
    Search in Google Scholar
  • 37 Petrossian G A, Nichols A B, Marboe C C, Sciacca R, Rose E A, Smith C R, Cannon P J, Reemtsma K, Powers E R. Relation between survival and development of coronary artery disease and anti-HLA antibodies after cardiac transplantation.  Circulation. 1989;  80 III122-125
    Search in Google Scholar
  • 38 Pinney S P, Mancini D. Cardiac allograft vasculopathy: advances in understanding its pathophysiology, prevention, and treatment.  Curr Opin Cardiol. 2004;  19 170-176
    Search in Google Scholar
  • 39 Radio S, Wood S, Wilson S, Lin H, Winters G. et al . Allograft vascular disease: comparison of heart and other grafted organs.  Transplant Proc. 1996;  28 496-499
    Search in Google Scholar
  • 40 Räisänen-Sokolowski A, Glysing-Jensen T, Koglin J, Russell M E. Reduced transplant arteriosclerosis in murine cardiac allografts placed in interferon-( knockout recipients.  Am J Pathol. 1998;  152 359-365
    Search in Google Scholar
  • 41 Ross R. Atherosclerosis - an inflammatory disease.  N Engl J Med. 1999;  340 115-126
    Search in Google Scholar
  • 42 Schnetzler B, Drobinski G, Dorent R, Camproux A C, Ghossoub J, Thomas D, Gandjbakhch I. The role of percutaneous transluminal coronary angioplasty in heart transplant recipients.  J Heart Lung Transplant. 2000;  19 557-565
    Search in Google Scholar
  • 43 Shirali G S, Ni J, Chinnock R E, Johnston J K, Rosenthal G L, Bowles N F, Towbin J A. Association of viral genome with graft loss in children after cardiac transplantation.  N Engl J Med. 2001;  344 1498-1503
    Search in Google Scholar
  • 44 Taylor D O, Edwards L B, Boucek M M, Trulock E P, Keck B M, Hertz M I. The registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant report-2004.  J Heart Lung Transplant. 2004;  23 796-803
    Search in Google Scholar
  • 45 Ueland T, Sikkeland L I, Yndestad A, Eiken H G, Holm T, Guevara C, Haug T, Endresen K, Froland S S, Gullestad L, Andreassen A K, Geiran O, Simonsen S, Aukrust P. Myocardial gene expression of inflammatory cytokines after heart transplantation in relation to the development of transplant coronary artery disease.  Am J Cardiol. 2003;  92 715-717
    Search in Google Scholar
  • 46 Valantine H. Cardiac allograft vasculopathy after heart transplantation: Risk factors and management.  J Heart Lung Transplant. 2004;  23 187-193 (Suppl)
    Search in Google Scholar
  • 47 Valantine H A. The role of viruses in cardiac allograft vasculopathy.  Am J Transplant. 2003;  4 169-177
    Search in Google Scholar
  • 48 Webber S, Bernstein D, Mital S, Addonizio L, Bentlejewski C, Byno A, Boyle G, Phillips J, Wohlgemuth J, Zeevi A. Discovery and validation of molecular pathways and diagnostic testing for cardiac rejection in pediatric patients: a multicenter study. Annual Scientific Sessions of the ISHLT, San Francisco 2004
    Search in Google Scholar
  • 49 Weis M, Hartmann A, Olbrich H G, Hor G, Zeiher A M. Prognostic significance of coronary flow reserve on left ventricular ejection fraction in cardiac transplant recipients.  Transplantation. 1998;  65 103-108
    Search in Google Scholar
  • 50 Weis M, Kledal T N, Lin K Y, Panchal S N, Gao S Z, Valantine H A, Mocarski E S, Cooke J P. Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis.  Circulation. 2004;  109 500-505
    Search in Google Scholar
  • 51 Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Steinbeck G, Seidel D, Reichart B. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial.  Circulation. 1997;  96 1398-1402
    Search in Google Scholar
  • 52 Yousufuddin M, Cook D J, Starling R C, Abdo A, Paul P, Tuzcu E M, Ratliff N B, McCarthy P M, Young J B, Yamani M H. Angiotensin II receptors from peritransplantation through first-year post-transplantation and the risk of transplant coronary artery disease.  J Am Coll Cardiol. 2004;  43 1565-1573
    Search in Google Scholar
  • 53 Yun J J, Whiting D, Fischbein M P, Banerji A, Irie Y, Stein D, Fishbein M C, Proudfoot A E, Laks H, Berliner J A, Ardehali A. Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection.  Circulation. 2004;  109 932-937
    Search in Google Scholar

Mario C. Deng

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