Skip to main content
SpringerLink
Log in

Coronary Artery Vasculopathy in Pediatric Cardiac Transplant Patients

The Therapeutic Potential of Immunomodulators

  • Leading Article
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

The single largest cause of late graft loss in pediatric cardiac transplantation is transplant coronary artery vasculopathy (CAV). The mechanism of CAV remains unknown; it appears to have both immune and non-immune causes. The final common pathway of these mechanisms is endothelial activation, a prothrombotic environment, and endothelial damage with subsequent diffuse intimal proliferation. The disease process has largely been thought to be progressive and unresponsive to treatment. Re-transplantation has been advocated as the only definitive treatment. The appropriate management is largely unknown; intervention or surgical management has had limited utility, while medical management appears to have the most promise. Improvement in outcome can be achieved by optimizing non-immune factors and aggressive management of the immune mechanisms. Long-term survival of transplant patients after diagnosis with CAV is now being reported.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Fig. 1
Table III
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Boucek MM, Faro A, Novick RJ, et al. The registry of the International Society of Heart and Lung Transplantation: third official pediatric report, 1999. J Heart Lung Transplant 1999; 18(12): 1151–72

    Article  PubMed  CAS  Google Scholar 

  2. Pahl E. Transplant coronary artery disease in children. Prog Pediatr Cardiol 2000; 11: 137–43

    Article  PubMed  Google Scholar 

  3. Yun JJ, Fischbein MP, Laks H, et al. Chronic rejection of transplanted hearts. Curr Opin Organ Transplant 2001; 6: 205–10

    Article  Google Scholar 

  4. Costanzo MR, Naftel DC, Pritzker MR, et al. Heart transplant coronary artery disease detected by coronary angiography: a multi-institutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 1998; 17(8): 744–53

    PubMed  CAS  Google Scholar 

  5. Wilhelm MJ, Pratschke J, Laskowski IA, et al. Brain death and its impact on the donor heart-lessons from animal models. J Heart Lung Transplant 2000; 19(5): 414–8

    Article  PubMed  CAS  Google Scholar 

  6. Ardehali A, Laks H, Drinkwater Jr DC, et al. Expression of major histocompatibility antigens and vascular adhesion molecules on human cardiac allografts preserved in University of Wisconsin solution. J Heart Lung Transplant 1993; 12 (6 Pt 1): 1044–51

    PubMed  CAS  Google Scholar 

  7. Day JD, Rayburn BK, Gaudin PB, et al. Cardiac allograft vasculopathy: the central pathogenetic role of ischemia-induced endothelial cell injury. J Heart Lung Transplant 1995; 14 (6 Pt 2): S142–9

    PubMed  CAS  Google Scholar 

  8. Grattan MT, Moreno-Cabral CE, Starnes VA, et al. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA 1989; 261(24): 3561–6

    Article  PubMed  CAS  Google Scholar 

  9. Mehra MR, Ventura HO, Smart FW, et al. Impact of converting enzyme inhibitors and calcium entry blockers on cardiac allograft vasculopathy: from bench to bedside. J Heart Lung Transplant 1995; 14 (6 Pt 2): S246–9

    PubMed  CAS  Google Scholar 

  10. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995; 333(10): 621–7

    Article  PubMed  CAS  Google Scholar 

  11. Kobashigawa J, Wener L, Johnson J, et al. Longitudinal study of vascular remodeling in coronary arteries after heart transplantation. J Heart Lung Transplant 2000; 19(6): 546–50

    Article  PubMed  CAS  Google Scholar 

  12. Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345(22): 1593–600

    Article  PubMed  CAS  Google Scholar 

  13. Miner SE, Cole DE, Evrovski J, et al. Hyperhomocysteinemia and transplant coronary artery disease in cardiac transplant recipients. Clin Transplant 2001; 15(4): 258–62

    Article  PubMed  CAS  Google Scholar 

  14. Labarrere CA, Nelson DR, Faulk WP. Endothelial activation and development of coronary artery disease in transplanted human hearts. JAMA 1997; 278(14): 1169–75

    Article  PubMed  CAS  Google Scholar 

  15. Labarrere CA, Nelson DR, Park JW. Pathologic markers of allograft arteriopathy: insight into the pathophysiology of cardiac allograft chronic rejection. Curr Opin Cardiol 2001; 16(2): 110–7

    Article  PubMed  CAS  Google Scholar 

  16. Miller L, Kobashigawa J, Valantine H, et al. The impact of cyclosporine dose and level on the development and progression of allograft coronary disease. Sandoz/CVIS Investigators. J Heart Lung Transplant 1995; 14 (6 Pt 2): S227–34

    PubMed  CAS  Google Scholar 

  17. Jutte NH, Groeneveld K, Balk AH, et al. The development of transplant coronary artery disease after cardiac transplantation is correlated with a predominance of CD8+ T lymphocytes in endomyocardial biopsy derived T cell cultures. Clin Exp Immunol 1994; 98(1): 158–62

    Article  PubMed  CAS  Google Scholar 

  18. Nakagawa T, Sukhova GK, Rabkin E, et al. Acute rejection accelerates graft coronary disease in transplanted rabbit hearts. Circulation 1995; 92(4): 987–93

    Article  PubMed  CAS  Google Scholar 

  19. Hosenpud JD, Everett JP, Morris TE, et al. Cardiac allograft vasculopathy: association with cell-mediated but not humoral alloimmunity to donor-specific vascular endothelium. Circulation 1995; 92(2): 205–11

    Article  PubMed  CAS  Google Scholar 

  20. Mulla NF, Johnston JK, Vander Dussen L, et al. Late rejection is a predictor of transplant coronary artery disease in children. J Am Coll Cardiol 2001; 37(1): 243–50

    Article  PubMed  CAS  Google Scholar 

  21. Russell PS, Chase CM, Winn HJ, et al. Coronary atherosclerosis in transplanted mouse hearts (II): importance of humoral immunity. J Immunol 1994; 152(10): 5135–41

    PubMed  CAS  Google Scholar 

  22. Russell ME, Hancock WW, Akalin E, et al. Chronic cardiac rejection in the LEW to F344 rat model: blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. J Clin Invest 1996; 97(3): 833–8

    Article  PubMed  CAS  Google Scholar 

  23. Russell ME. Graft arteriosclerosis: molecular features of macrophage activation. Transplant Proc 1997; 29(6): 2542–3

    Article  PubMed  CAS  Google Scholar 

  24. Tellides G, Tereb DA, Kirkiles-Smith NC, et al. Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature 2000; 403(6766): 207–11

    Article  PubMed  CAS  Google Scholar 

  25. Pattison JM, Nelson PJ, Huie P, et al. RANTES chemokine expression in transplant-associated accelerated atherosclerosis. J Heart Lung Transplant 1996; 15(12): 1194–9

    PubMed  CAS  Google Scholar 

  26. Yun JJ, Fischbein MP, Laks H, et al. Rantes production during development of cardiac allograft vasculopathy. Transplantation 2001; 71(11): 1649–56

    Article  PubMed  CAS  Google Scholar 

  27. Gao W, Topham PS, King JA, et al. Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection. J Clin Invest 2000; 105(1): 35–44

    Article  PubMed  CAS  Google Scholar 

  28. Sata M, Luo Z, Walsh K. Fas ligand overexpression on allograft endothelium inhibits inflammatory cell infiltration and transplant-associated intimal hyperplasia. J Immunol 2001; 166(11): 6964–71

    PubMed  CAS  Google Scholar 

  29. Hsu DT, Lamour JM, Korsin R, et al. Long term incidence of graft vasculopathy in children. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions; 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 173

    Google Scholar 

  30. Dent CL, Canter CE, Hirsch R, et al. Transplant coronary artery disease in pediatric heart transplant recipients. J Heart Lung Transplant 2000; 19(3): 240–8

    Article  PubMed  CAS  Google Scholar 

  31. Dearani JA, Razzouk AJ, Gundry SR, et al. Pediatric cardiac retransplantation: intermediate-term results. Ann Thorac Surg 2001; 71(1): 66–70

    Article  PubMed  CAS  Google Scholar 

  32. Fortuna RS, Chinnock RB, Bailey LL. Heart transplantation among 233 infants during the first six months of life: the Loma Linda experience. Loma Linda Pediatric Heart Transplant Group. Clin Transpl 1999: 263–72

    Google Scholar 

  33. Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant 1992; 11 (3 Pt 2): S38–44

    PubMed  CAS  Google Scholar 

  34. Hirsch R, Balzer DT, Dent CL, et al. Outcome after diagnosis of moderate-severe transplant coronary artery disease (TCAD) in pediatric heart transplant recipients. J Heart Lung Transplant 2001; 20(2): 261–2

    Article  PubMed  Google Scholar 

  35. Kuhn MA, Hashmi A, Deming DD, et al. Management of post-transplant coronary artery disease (PTCAD) using intravascular ultrasound (IVUS) improves outcome in pediatric heart transplant (htx) recipients. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions. 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 64

    Google Scholar 

  36. Pahl E, Duffy CE, Chaudhry FA. The role of stress echocardiography in children. Echocardiography 2000; 17(5): 507–12

    Article  PubMed  CAS  Google Scholar 

  37. DiFilippo S, Roboisson M, Sassolas F, et al. Non-invasive detection of coronary artery disease by dobutamine stress echocardiography in children after heart transplant. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions. 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 83

    Google Scholar 

  38. Kobashigawa JA. Statins as immunosuppressive agents. Liver Transpl 2001; 7(6): 559–61

    Article  PubMed  CAS  Google Scholar 

  39. Pietra BA, Wiseman A, Bolwerk A, et al. CD4 T cell-mediated cardiac allograft rejection requires donor but not host MHC class II. J Clin Invest 2000; 106(8): 1003–10

    Article  PubMed  CAS  Google Scholar 

  40. Russell PS, Chase CM, Sykes M, et al. Tolerance, mixed chimerism, and chronic transplant arteriopathy. J Immunol 2001; 167(10): 5731–40

    PubMed  CAS  Google Scholar 

  41. Labarrere CA, Benner RW, Fuerst H, et al. Interleukin-1β and risk of coronary artery disease in heart transplant patients. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions; 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 59

    Google Scholar 

  42. Densem CG, Hutchinson IV, Yonan N, et al. Influence of tumor necrosis factor-alpha gene-308 polymorphism on the development of coronary vasculopathy after cardiac transplantation. J Heart Lung Transplant 2001; 20(12): 1265–73

    Article  PubMed  CAS  Google Scholar 

  43. Rose EA, Smith CR, Petrossian GA, et al. Humoral immune responses after cardiac transplantation: correlation with fatal rejection and graft atherosclerosis. Surgery 1989; 106(2): 203–7

    PubMed  CAS  Google Scholar 

  44. Rose ML. Role of antibody and indirect antigen presentation in transplant-associated coronary artery vasculopathy. J Heart Lung Transplant 1996; 15(4): 342–9

    PubMed  CAS  Google Scholar 

  45. Leendert PC. Current controversies in cardiac transplantation: calcium channel blockers and angiotensin-converting enzyme inhibitors in the prevention of graft vasculopathy. J Heart Lung Transplant 2000; 19(5): 409–13

    Article  Google Scholar 

  46. Ballantyne CM. Statins after cardiac transplantation: which statin, what dose, and how low should we go. J Heart Lung Transplant 2000; 19(6): 515–7

    Article  PubMed  CAS  Google Scholar 

  47. Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6(12): 1399–402

    Article  PubMed  CAS  Google Scholar 

  48. Labarrere CA, Nelson DR, Faulk WP. Myocardial fibrin deposits in the first month after transplantation predict subsequent coronary artery disease and graft failure in cardiac allograft recipients. Am J Med 1998; 105(3): 207–13

    Article  PubMed  CAS  Google Scholar 

  49. 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(4): 457–64

    Article  PubMed  CAS  Google Scholar 

  50. Faulk WP, Labarrere CA. Modulation of vascular antithrombin III in human cardiac allografts. Haemostasis 1993; 23Suppl. 1: 194–201

    PubMed  Google Scholar 

  51. Aziz S, Tada Y, Gordon D, et al. A reduction in accelerated graft coronary disease and an improvement in cardiac allograft survival using low molecular weight heparin in combination with cyclosporine. J Heart Lung Transplant 1993; 12(4): 634–43

    PubMed  CAS  Google Scholar 

  52. Teranishi K, Poston RS, Reitz BA, et al. Effect of low molecular weight heparin on suppression of chronic graft vascular disease in a rat cardiac allograft model. Transplant Proc 1998; 30(4): 1009–11

    Article  PubMed  CAS  Google Scholar 

  53. Schlaifer JD, Mills RM. Effect of low molecular weight heparin on coronary endothelial function in acute cellular heart transplant rejection. Am J Cardiol 2000; 86(1): 117–20

    Article  PubMed  CAS  Google Scholar 

  54. Ambrosi P, Barlatier A, Habib G, et al. Hyperhomocysteinaemia in heart transplant recipients. Eur Heart J 1994; 15(9): 1191–5

    PubMed  CAS  Google Scholar 

  55. Cooke GE, Eaton GM, Whitby G, et al. Plasma atherogenic markers in congestive heart failure and posttransplant (heart) patients. J Am Coll Cardiol 2000; 36(2): 509–16

    Article  PubMed  CAS  Google Scholar 

  56. Jourdheuil-Rahmani D, Rolland PH, Rosset E, et al. Homocysteine induces synthesis of a serine elastase in arterial smooth muscle cells from multi-organ donors. Cardiovasc Res 1997; 34(3): 597–602

    Article  PubMed  CAS  Google Scholar 

  57. Potena L, Grigioni F, Viggiani M, et al. Interplay between methylenetetrahydrofolate reductase gene polymorphism 677C->T and serum folate levels in determining hyperhomocysteinemia in heart transplant recipients. J Heart Lung Transplant 2001; 20(12): 1245–51

    Article  PubMed  CAS  Google Scholar 

  58. Pethig K, Hoffmann A, Heublein B, et al. Cardiac allograft vascular disease after orthotopic heart transplantation: methylenetetrahydrofolate reductase gene polymorphism C677T does not account for rapidly progressive forms. Transplantation 2000; 69(3): 442–5

    Article  PubMed  CAS  Google Scholar 

  59. Cook RC, Parker S, Kingsbury K, et al. Effective treatment of hyperhomocysteinemia in heart transplant recipients with and without renal failure. J Heart Lung Transplant 2001; 20(3): 310–5

    Article  PubMed  CAS  Google Scholar 

  60. Miner SE, Cole DE, Evrovski J, et al. Pyridoxine improves endothelial function in cardiac transplant recipients. J Heart Lung Transplant 2001; 20(9): 964–9

    Article  PubMed  CAS  Google Scholar 

  61. Parisi F, Kost-Byerly S, Saponara I, et al. Elevated plasma homocysteine concentrations after pediatric heart transplantations. Transpl Int 2000; 13Suppl. 1: S235–9

    PubMed  Google Scholar 

  62. Fang JC, Kinlay S, Beltrame J, et al. Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial. Lancet 2002; 359(9312): 1108–13

    Article  PubMed  CAS  Google Scholar 

  63. Wu GD, Jin Y-S, Barr ML, et al. Vascular endothelial cell apoptosis induced by non-MHC alloantibodies: an important injury mechanism in the development of chronic graft rejection. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions. 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 72

    Google Scholar 

  64. Miniati DN, Lijkwan MA, Murata S, et al. Adenoviral upregulation of Bcl-2 decreases oxidative stress and graft coronary artery disease in rat heart transplants. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions. 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 71

    Google Scholar 

  65. Cantin B, Gao SZ, Kwok BWK, et al. Mild cardiac allograft coronary disease does not change the prognosis of patients after heart transplantation. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions. 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 89

    Google Scholar 

  66. Cantin B, Gao SZ, Kwok BWK, et al. Prognosis of patients with significant angiographically diagnosed cardiac allograft coronary disease. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions. 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 96

    Google Scholar 

  67. Raisanen-Sokolowski A, Vuoristo P, Myllarniemi M, et al. Mycophenolate mofetil (MMF, RS-61443) inhibits inflammation and smooth muscle cell proliferation in rat aortic allografts. Transpl Immunol 1995; 3(4): 342–51

    Article  PubMed  CAS  Google Scholar 

  68. Dipchand AI, Benson L, McCrindle BW, et al. Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience. Pediatr Transplant 2001; 5(2): 112–8

    Article  PubMed  CAS  Google Scholar 

  69. Gao SZ, Kwok BWK, Cantin B, et al. Does late switch to mycophenolate mofetil affect development of transplant coronary artery disease. In: Kirklin JK, editor. The International Society for Heart and Lung Transplantation 22nd Annual Meeting and Scientific Sessions. 2002 Apr 10–13; Washington, DC: Elsevier, 2002: 89

    Google Scholar 

  70. Dipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001; 20(10): 1035–43

    Article  PubMed  CAS  Google Scholar 

  71. Schutz E, Shipkova M, Armstrong VW, et al. Therapeutic drug monitoring of mycophenolic acid: comparison of HPLC and immunoassay reveals new MPA metabolites. Transplant Proc 1998; 30(4): 1185–7

    Article  PubMed  CAS  Google Scholar 

  72. Gregory CR. Immunosuppressive approaches to the prevention of graft vascular disease. Transplant Proc 1998; 30(3): 878–80

    Article  PubMed  CAS  Google Scholar 

  73. Poston RS, Billingham M, Hoyt EG, et al. Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model. Circulation 1999; 100(1): 67–74

    Article  PubMed  CAS  Google Scholar 

  74. Braun-Dullaeus RC, Mann MJ, Seay U, et al. Cell cycle protein expression in vascular smooth muscle cells in vitro and in vivo is regulated through phospha-tidylinositol 3-kinase and mammalian target of rapamycin. Arterioscler Thromb Vasc Biol 2001; 21(7): 1152–8

    Article  PubMed  CAS  Google Scholar 

  75. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 2001; 104(17): 2007–11

    Article  PubMed  CAS  Google Scholar 

  76. Paul LC. Immunologic risk factors for chronic renal allograft dysfunction. Transplantation 2001; 71(11 Suppl.): SS17–23

    PubMed  CAS  Google Scholar 

  77. Kahan BD. Potential therapeutic interventions to avoid or treat chronic allograft dysfunction. Transplantation 2001; 71(11 Suppl.): SS52–7

    PubMed  CAS  Google Scholar 

  78. Straatman LP, Coles JG. Pediatric utilization of rapamycin for severe cardiac allograft rejection. Transplantation 2000; 70(3): 541–3

    Article  PubMed  CAS  Google Scholar 

  79. Pappas PA, Weppler D, Pinna AD, et al. Sirolimus in pediatric gastrointestinal transplantation: the use of sirolimus for pediatric transplant patients with tacrolimus-related cardiomyopathy. Pediatr Transplant 2000; 4(1): 45–9

    Article  PubMed  CAS  Google Scholar 

  80. Kaplan B, Meier-Kriesche HU, Napoli KL, et al. Correlation between pretrans-plantation test dose cyclosporine pharmacokinetic profiles and posttransplantation sirolimus blood levels in renal transplant recipients. Ther Drug Monit 1999; 21(1): 44–9

    Article  PubMed  CAS  Google Scholar 

  81. Trepanier DJ, Gallant H, Legatt DF, et al. Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update. Clin Biochem 1998; 31(5): 345–51

    Article  PubMed  CAS  Google Scholar 

  82. Shaddy RE, Revenaugh JA, Orsmond GS, et al. Coronary interventional procedures in pediatric heart transplant recipients with cardiac allograft vasculopathy. Am J Cardiol 2000; 85(11): 1370–2

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Dr Pietra is supported by grant NIH RO1 HL 67976-02. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Pediatrics, The Children’s Hospital, Denver, Colorado, USA

    Biagio A. Pietra & Mark M. Boucek

  2. Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado, USA

    Biagio A. Pietra

Authors
  1. Biagio A. Pietra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark M. Boucek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Biagio A. Pietra.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pietra, B.A., Boucek, M.M. Coronary Artery Vasculopathy in Pediatric Cardiac Transplant Patients. Pediatr-Drugs 5, 513–524 (2003). https://doi.org/10.2165/00148581-200305080-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00148581-200305080-00002

Keywords

Search

Navigation