Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Chronic Rejection

  • Living reference work entry
  • First Online:
Contemporary Heart Transplantation

Part of the book series: Organ and Tissue Transplantation ((OTT))

  • 112 Accesses

Abstract

Chronic rejection is the culmination of many immune and nonimmune mechanisms that alter the structure and function of the allograft, thereby contributing to graft dysfunction in the long term. Chronic rejection remains a major limitation to allograft longevity and patient survival. The alterations in the heart include the following: (1) vascular changes (starting at the microvascular level and progressing to epicardial vessels), (2) allograft hypertrophy, and (3) allograft fibrosis. The vascular changes have been investigated extensively and currently represent most of our understanding of chronic rejection. Allograft hypertrophy and fibrosis are becoming more recognized as early markers of evolving changes with evidence reflecting that these changes could be independent of vascular changes. Current therapies may temporize the initiation and progression of chronic rejection, but have not made significant contributions to long-term survival beyond the first year posttransplant. This chapter will discuss the following: mechanisms contributing to chronic rejection, structural changes to the allograft, risk factors for chronic rejection, screening for allograft rejection, as well as preventive, suppressive, and interventional therapies.

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

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Agarwal S, Parashar A, Kapadia SR, Tuzcu EM, Modi D, Starling RC, Oliveira GH (2014) Long-term mortality after cardiac allograft vasculopathy: implications of percutaneous intervention. JACC Heart Fail 2(3): 281–288. https://doi.org/10.1016/j.jchf.2014.01.003

    Article  PubMed  Google Scholar 

  • Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, Jansson K, Solbu D, Karason K, Arora S, Dellgren G, Gullestad L, SCHEDULE Investigators (2016) Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: three-year results from the randomized SCHEDULE study. Am J Transplant 16(4):1238–1247. https://doi.org/10.1111/ajt.13588

    Article  CAS  PubMed  Google Scholar 

  • Armstrong AT, Binkley PF, Baker PB, Myerowitz PD, Leier CV (1998) Quantitative investigation of cardiomyocyte hypertrophy and myocardial fibrosis over 6 years after cardiac transplantation. J Am Coll Cardiol 32(3):704–710

    Article  CAS  Google Scholar 

  • Balk EM, Karas RH, Jordan HS, Kupelnick B, Chew P, Lau J (2004) Effects of statins on vascular structure and function: a systematic review. Am J Med 117(10): 775–790. https://doi.org/10.1016/j.amjmed.2004.05.026

    Article  CAS  PubMed  Google Scholar 

  • Benza RL, Zoghbi GJ, Tallaj J, Brown R, Kirklin JK, Hubbard M, Rayburn B, Foley B, McGiffin DC, Pinderski LJ, Misra V, Bourge RC (2004) Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. J Am Coll Cardiol 43(11):1973–1981. https://doi.org/10.1016/j.jacc.2004.02.045

    Article  PubMed  Google Scholar 

  • Berry GJ, Burke MM, Andersen C, Bruneval P, Fedrigo M, Fishbein MC, Goddard M, Hammond EH, Leone O, Marboe C, Miller D, Neil D, Rassl D, Revelo MP, Rice A, Rene Rodriguez E, Stewart S, Tan CD, Winters GL, West L, Mehra MR, Angelini A (2013) The 2013 International Society for Heart and Lung Transplantation working formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 32(12):1147–1162. https://doi.org/10.1016/j.healun.2013.08.011

    Article  PubMed  Google Scholar 

  • Bhama JK, Nguyen DQ, Scolieri S, Teuteberg JJ, Toyoda Y, Kormos RL, McCurry KR, McNamara D, Bermudez CA (2009) Surgical revascularization for cardiac allograft vasculopathy: is it still an option? J Thorac Cardiovasc Surg 137(6):1488–1492. https://doi.org/10.1016/j.jtcvs.2009.02.026

    Article  PubMed  Google Scholar 

  • Billingham ME (1987) Cardiac transplant atherosclerosis. Transplant Proc 19(4 Suppl 5):19–25

    CAS  PubMed  Google Scholar 

  • Braggion-Santos MF, Lossnitzer D, Buss S, Lehrke S, Doesch A, Giannitsis E, Korosoglou G, Katus HA, Steen H (2014) Late gadolinium enhancement assessed by cardiac magnetic resonance imaging in heart transplant recipients with different stages of cardiac allograft vasculopathy. Eur Heart J Cardiovasc Imaging 15(10): 1125–1132. https://doi.org/10.1093/ehjci/jeu090

    Article  PubMed  Google Scholar 

  • Bravo PE, Bergmark BA, Vita T, Taqueti VR, Gupta A, Seidelmann S, Christensen TE, Osborne MT, Shah NR, Ghosh N, Hainer J, Bibbo CF, Harrington M, Costantino F, Mehra MR, Dorbala S, Blankstein R, Desai A, Stevenson L, Givertz MM, Di Carli MF (2018) Diagnostic and prognostic value of myocardial blood flow quantification as non-invasive indicator of cardiac allograft vasculopathy. Eur Heart J 39(4): 316–323. https://doi.org/10.1093/eurheartj/ehx683

    Article  CAS  PubMed  Google Scholar 

  • Carlsen J, Toft JC, Mortensen SA, Arendrup H, Aldershvile J, Hesse B (2000) Myocardial perfusion scintigraphy as a screening method for significant coronary artery stenosis in cardiac transplant recipients. J Heart Lung Transplant 19(9):873–878. https://doi.org/10.1016/s1053-2498(00)00167-4

    Article  CAS  PubMed  Google Scholar 

  • Cassar A, Matsuo Y, Herrmann J, Li J, Lennon RJ, Gulati R, Lerman LO, Kushwaha SS, Lerman A (2013) Coronary atherosclerosis with vulnerable plaque and complicated lesions in transplant recipients: new insight into cardiac allograft vasculopathy by optical coherence tomography. Eur Heart J 34(33): 2610–2617. https://doi.org/10.1093/eurheartj/eht236

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheng R, Vanichsarn C, Patel JK, Currier J, Chang DH, Kittleson MM, Makkar R, Kobashigawa JA, Azarbal B (2017) Long-term clinical and angiographic outcomes of percutanenous coronary intervention with everolimus-eluting stents for the treatment of cardiac allograft vasculopathy. Catheter Cardiovasc Interv 90(1):48–55. https://doi.org/10.1002/ccd.26830

    Article  PubMed  Google Scholar 

  • Chih S, Ross HJ, Alba AC, Fan CS, Manlhiot C, Crean AM (2016) Perfusion cardiac magnetic resonance imaging as a rule-out test for cardiac allograft vasculopathy. Am J Transplant 16(10):3007–3015. https://doi.org/10.1111/ajt.13839

    Article  CAS  PubMed  Google Scholar 

  • Chirakarnjanakorn S, Starling RC, Popovic ZB, Griffin BP, Desai MY (2015) Dobutamine stress echocardiography during follow-up surveillance in heart transplant patients: diagnostic accuracy and predictors of outcomes. J Heart Lung Transplant 34(5):710–717. https://doi.org/10.1016/j.healun.2014.11.019

    Article  PubMed  Google Scholar 

  • Ciliberto GR, Ruffini L, Mangiavacchi M, Parolini M, Sara R, Massa D, De Maria R, Gronda E, Vitali E, Parodi O (2001) Resting echocardiography and quantitative dipyridamole technetium-99m sestamibi tomography in the identification of cardiac allograft vasculopathy and the prediction of long-term prognosis after heart transplantation. Eur Heart J 22(11):964–971. https://doi.org/10.1053/euhj.2000.2422

    Article  CAS  PubMed  Google Scholar 

  • Clausell N, Butany J, Molossi S, Lonn E, Gladstone P, Rabinovitch M, Daly PA (1995) Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries. J Am Coll Cardiol 26(1):110–119

    Article  CAS  Google Scholar 

  • Clemmensen TS, Molgaard H, Andersen NF, Baerentzen S, Poulsen SH (2016) Exercise-stress echocardiography reveals systolic anterior motion of the mitral valve as a cause of syncopes in a cardiac amyloidosis patient. Case Rep Cardiol 2016:3198715. https://doi.org/10.1155/2016/3198715

    Article  PubMed  PubMed Central  Google Scholar 

  • Clemmensen TS, Holm NR, Eiskjaer H, Logstrup BB, Christiansen EH, Dijkstra J, Barkholt TO, Terkelsen CJ, Maeng M, Poulsen SH (2017) Layered fibrotic plaques are the predominant component in cardiac allograft vasculopathy: systematic findings and risk stratification by OCT. JACC Cardiovasc Imaging 10:773. https://doi.org/10.1016/j.jcmg.2016.10.021

    Article  PubMed  Google Scholar 

  • Clerkin KJ, Farr MA, Restaino SW, Ali ZA, Mancini DM (2016) Dobutamine stress echocardiography is inadequate to detect early cardiac allograft vasculopathy. J Heart Lung Transplant 35(8):1040–1041. https://doi.org/10.1016/j.healun.2016.05.012

    Article  PubMed  PubMed Central  Google Scholar 

  • Clerkin KJ, Farr MA, Restaino SW, Zorn E, Latif F, Vasilescu ER, Marboe CC, Colombo PC, Mancini DM (2017) Donor-specific anti-HLA antibodies with antibody-mediated rejection and long-term outcomes following heart transplantation. J Heart Lung Transplant 36(5):540–545. https://doi.org/10.1016/j.healun.2016.10.016

    Article  PubMed  Google Scholar 

  • Cohn JM, Wilensky RL, O’Donnell JA, Bourdillon PD, Dillon JC, Feigenbaum H (1996) Exercise echocardiography, angiography, and intracoronary ultrasound after cardiac transplantation. Am J Cardiol 77(14):1216–1219. https://doi.org/10.1016/s0002-9149(96)00165-8

    Article  CAS  PubMed  Google Scholar 

  • Collings CA, Pinto FJ, Valantine HA, Popylisen S, Puryear JV, Schnittger I (1994) Exercise echocardiography in heart transplant recipients: a comparison with angiography and intracoronary ultrasonography. J Heart Lung Transplant 13(4):604–613

    CAS  PubMed  Google Scholar 

  • Costanzo MR, Naftel DC, Pritzker MR, Heilman JK 3rd, Boehmer JP, Brozena SC, Dec GW, Ventura HO, Kirklin JK, Bourge RC, Miller LW (1998) Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 17(8): 744–753

    CAS  PubMed  Google Scholar 

  • Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, Kao W, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J, Johnson M, Keogh A, Lewis C, O’Connell J, Rogers J, Ross H, Russell S, Vanhaecke J, International Society of Heart and Lung Transplantation Guidelines (2010) The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 29(8): 914–956. https://doi.org/10.1016/j.healun.2010.05.034

    Article  PubMed  Google Scholar 

  • Cutts JL, Bankhurst AD (1990) Reversal of lovastatin-mediated inhibition of natural killer cell cytotoxicity by interleukin 2. J Cell Physiol 145(2):244–252. https://doi.org/10.1002/jcp.1041450208

    Article  CAS  PubMed  Google Scholar 

  • Dasari TW, Saucedo JF, Krim S, Alkhouli M, Fonarow GC, Alvarez R, Ibrahim H, Dai D, Wang TY, Costa M, Lindenfeld J, Messenger JC (2015) Clinical characteristics and in hospital outcomes of heart transplant recipients with allograft vasculopathy undergoing percutaneous coronary intervention: insights from the National Cardiovascular Data Registry. Am Heart J 170(6):1086–1091. https://doi.org/10.1016/j.ahj.2015.09.021

    Article  PubMed  Google Scholar 

  • Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT (1996) C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271(5247):348–350

    Article  CAS  Google Scholar 

  • Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, Starling RC, Sorensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P, RAD B253 Study Group (2003) Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 349(9):847–858. https://doi.org/10.1056/NEJMoa022171

    Article  CAS  PubMed  Google Scholar 

  • Eisen HJ, Kobashigawa J, Starling RC, Pauly DF, Kfoury A, Ross H, Wang SS, Cantin B, Van Bakel A, Ewald G, Hirt S, Lehmkuhl H, Keogh A, Rinaldi M, Potena L, Zuckermann A, Dong G, Cornu-Artis C, Lopez P (2013) Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant 13(5):1203–1216. https://doi.org/10.1111/ajt.12181

    Article  CAS  PubMed  Google Scholar 

  • Elhendy A, Sozzi FB, van Domburg RT, Vantrimpont P, Valkema R, Krenning EP, Roelandt JR, Maat LP, Balk AH (2000) Accuracy of dobutamine tetrofosmin myocardial perfusion imaging for the noninvasive diagnosis of transplant coronary artery stenosis. J Heart Lung Transplant 19(4):360–366. https://doi.org/10.1016/s1053-2498(00)00068-1

    Article  CAS  PubMed  Google Scholar 

  • el-Sawy T, Fahmy NM, Fairchild RL (2002) Chemokines: directing leukocyte infiltration into allografts. Curr Opin Immunol 14(5):562–568

    Article  CAS  Google Scholar 

  • Escobar A, Ventura HO, Stapleton DD, Mehra MR, Ramee SR, Collins TJ, Jain SP, Smart FW, White CJ (1994) Cardiac allograft vasculopathy assessed by intravascular ultrasonography and nonimmunologic risk factors. Am J Cardiol 74(10):1042–1046

    Article  CAS  Google Scholar 

  • Fearon WF, Hirohata A, Nakamura M, Luikart H, Lee DP, Vagelos RH, Hunt SA, Valantine HA, Fitzgerald PJ, Yock PG, Yeung AC (2006) Discordant changes in epicardial and microvascular coronary physiology after cardiac transplantation: Physiologic Investigation for Transplant Arteriopathy II (PITA II) study. J Heart Lung Transplant 25(7):765–771. https://doi.org/10.1016/j.healun.2006.03.003

    Article  PubMed  Google Scholar 

  • Gao SZ, Alderman EL, Schroeder JS, Silverman JF, Hunt SA (1988) Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coll Cardiol 12(2):334–340

    Article  CAS  Google Scholar 

  • Garrido IP, Garcia-Lara J, Pinar E, Pastor-Perez F, Sanchez-Mas J, Valdes-Chavarri M, Pascual-Figal DA (2012) Optical coherence tomography and highly sensitivity troponin T for evaluating cardiac allograft vasculopathy. Am J Cardiol 110(5):655–661. https://doi.org/10.1016/j.amjcard.2012.04.047

    Article  CAS  PubMed  Google Scholar 

  • Goodroe R, Bonnema DD, Lunsford S, Anderson P, Ryan-Baille B, Uber W, Ikonomidis J, Crumbley AJ, VanBakel A, Zile MR, Pereira N (2007) Severe left ventricular hypertrophy 1 year after transplant predicts mortality in cardiac transplant recipients. J Heart Lung Transplant 26(2):145–151. https://doi.org/10.1016/j.healun.2006.11.003

    Article  PubMed  Google Scholar 

  • Gregory SA, Ferencik M, Achenbach S, Yeh RW, Hoffmann U, Inglessis I, Cury RC, Nieman K, McNulty IA, Laffan JA, Pomerantsev EV, Brady TJ, Semigran MJ, Jang IK (2006) Comparison of sixty-four-slice multidetector computed tomographic coronary angiography to coronary angiography with intravascular ultrasound for the detection of transplant vasculopathy. Am J Cardiol 98(7):877–884. https://doi.org/10.1016/j.amjcard.2006.04.027

    Article  PubMed  Google Scholar 

  • Halle AA 3rd, DiSciascio G, Massin EK, Wilson RF, Johnson MR, Sullivan HJ, Bourge RC, Kleiman NS, Miller LW, Aversano TR et al (1995) Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. J Am Coll Cardiol 26(1):120–128

    Article  Google Scholar 

  • Hiemann NE, Wellnhofer E, Knosalla C, Lehmkuhl HB, Stein J, Hetzer R, Meyer R (2007) Prognostic impact of microvasculopathy on survival after heart transplantation: evidence from 9713 endomyocardial biopsies. Circulation 116(11):1274–1282. https://doi.org/10.1161/CIRCULATIONAHA.106.647149

    Article  PubMed  Google Scholar 

  • Hollenberg SM, Klein LW, Parrillo JE, Scherer M, Burns D, Tamburro P, Oberoi M, Johnson MR, Costanzo MR (2001) Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death. Circulation 104(25): 3091–3096

    Article  CAS  Google Scholar 

  • Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ (2001) The Registry of the International Society for Heart and Lung Transplantation: eighteenth official report-2001. J Heart Lung Transplant 20(8): 805–815

    Article  CAS  Google Scholar 

  • Hunt J, Bedánová H, Starling RC, Rabágo G, Banner NR, Kobashigawa J, Keogh A, Kormos R, Mehra M, Wahlers T, Noeldeke J (2007) 398: Premature termination of a prospective, open label, randomized, multicenter study of sirolimus to replace calcineurin inhibitors (CNI) in a standard care regimen of CNI, MMF and corticosteroids early after heart transplantation. J Heart Lung Transplant 26(2):S203. https://doi.org/10.1016/j.healun.2006.11.419

    Article  Google Scholar 

  • Johnson MR, Aaronson KD, Canter CE, Kirklin JK, Mancini DM, Mehra MR, Radovancevic B, Taylor DO, Webber SA (2007) Heart retransplantation. Am J Transplant 7(9):2075–2081. https://doi.org/10.1111/j.1600-6143.2007.01902.x

    Article  CAS  PubMed  Google Scholar 

  • Kapessidou Y, Habran C, Buonocore S, Flamand V, Barvais L, Goldman M, Braun MY (2006) The replacement of graft endothelium by recipient-type cells conditions allograft rejection mediated by indirect pathway CD4+ T cells. Transplantation 82(4):582–591

    Article  Google Scholar 

  • Keogh A, Richardson M, Ruygrok P, Spratt P, Galbraith A, O’Driscoll G, Macdonald P, Esmore D, Muller D, Faddy S (2004) Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation 110(17):2694–2700. https://doi.org/10.1161/01.CIR.0000136812.90177.94

    Article  CAS  PubMed  Google Scholar 

  • Kfoury AG, Hammond ME, Snow GL, Drakos SG, Stehlik J, Fisher PW, Reid BB, Everitt MD, Bader FM, Renlund DG (2009) Cardiovascular mortality among heart transplant recipients with asymptomatic antibody-mediated or stable mixed cellular and antibody-mediated rejection. J Heart Lung Transplant 28(8):781–784. https://doi.org/10.1016/j.healun.2009.04.035

    Article  PubMed  Google Scholar 

  • Khalifian S, Broyles JM, Tuffaha SH, Alrakan M, Ibrahim Z, Sarhane KA (2013) Immune mechanisms of ischemia-reperfusion injury in transplantation. Open J Immunol 03(03):158–164. https://doi.org/10.4236/oji.2013.33020

    Article  CAS  Google Scholar 

  • Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA et al (1995) Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 333(10):621–627. https://doi.org/10.1056/NEJM199509073331003

    Article  CAS  PubMed  Google Scholar 

  • Kobashigawa JA, Tobis JM, Starling RC, Tuzcu EM, Smith AL, Valantine HA, Yeung AC, Mehra MR, Anzai H, Oeser BT, Abeywickrama KH, Murphy J, Cretin N (2005) Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol 45(9): 1532–1537. https://doi.org/10.1016/j.jacc.2005.02.035

    Article  PubMed  Google Scholar 

  • Kobashigawa J, Crespo-Leiro MG, Ensminger SM, Reichenspurner H, Angelini A, Berry G, Burke M, Czer L, Hiemann N, Kfoury AG, Mancini D, Mohacsi P, Patel J, Pereira N, Platt JL, Reed EF, Reinsmoen N, Rodriguez ER, Rose ML, Russell SD, Starling R, Suciu-Foca N, Tallaj J, Taylor DO, Van Bakel A, West L, Zeevi A, Zuckermann A, Consensus Conference Participants (2011) Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 30(3):252–269. https://doi.org/10.1016/j.healun.2010.11.003

    Article  PubMed  Google Scholar 

  • Kwak B, Mulhaupt F, Myit S, Mach F (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6(12):1399–1402. https://doi.org/10.1038/82219

    Article  CAS  PubMed  Google Scholar 

  • Lemahieu WP, Maes BD, Verbeke K, Vanrenterghem Y (2004) CYP3A4 and P-glycoprotein activity in healthy controls and transplant patients on cyclosporin vs. tacrolimus vs. sirolimus. Am J Transplant 4(9): 1514–1522. https://doi.org/10.1111/j.1600-6143.2004.00539.x

    Article  CAS  PubMed  Google Scholar 

  • Loupy A, Toquet C, Rouvier P, Beuscart T, Bories MC, Varnous S, Guillemain R, Pattier S, Suberbielle C, Leprince P, Lefaucheur C, Jouven X, Bruneval P, Duong Van Huyen JP (2016) Late failing heart allografts: pathology of cardiac allograft vasculopathy and association with antibody-mediated rejection. Am J Transplant 16(1):111–120. https://doi.org/10.1111/ajt.13529

    Article  CAS  PubMed  Google Scholar 

  • Luk A, Alba AC, Butany J, Tinckam K, Delgado D, Ross HJ (2015) C4d immunostaining is an independent predictor of cardiac allograft vasculopathy and death in heart transplant recipients. Transpl Int 28(7):857–863. https://doi.org/10.1111/tri.12560

    Article  CAS  PubMed  Google Scholar 

  • Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, Dobbels F, Kirk R, Rahmel AO, Yusen RD, Stehlik J, International Society for Heart and Lung Transplantation (2013) The registry of the International Society for Heart and Lung Transplantation: thirtieth official adult heart transplant report – 2013; focus theme: age. J Heart Lung Transplant 32(10):951–964. https://doi.org/10.1016/j.healun.2013.08.006

    Article  PubMed  Google Scholar 

  • Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, Dobbels F, Goldfarb SB, Levvey BJ, Meiser B, Yusen RD, Stehlik J, International Society of Heart and Lung Transplantation (2014) The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report – 2014; focus theme: retransplantation. J Heart Lung Transplant 33(10): 996–1008. https://doi.org/10.1016/j.healun.2014.08.003

    Article  PubMed  Google Scholar 

  • Lund LH, Edwards LB, Dipchand AI, Goldfarb S, Kucheryavaya AY, Levvey BJ, Meiser B, Rossano JW, Yusen RD, Stehlik J, International Society for Heart and Lung Transplantation (2016) The registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report-2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant 35(10): 1158–1169. https://doi.org/10.1016/j.healun.2016.08.017

    Article  PubMed  Google Scholar 

  • Mancini D, Pinney S, Burkhoff D, LaManca J, Itescu S, Burke E, Edwards N, Oz M, Marks AR (2003) Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 108(1):48–53. https://doi.org/10.1161/01.CIR.0000070421.38604.2B

    Article  CAS  PubMed  Google Scholar 

  • Manrique A, Bernard M, Hitzel A, Bubenheim M, Tron C, Agostini D, Cribier A, Vera P, Bessou JP, Redonnet M (2010) Diagnostic and prognostic value of myocardial perfusion gated SPECT in orthotopic heart transplant recipients. J Nucl Cardiol 17(2):197–206. https://doi.org/10.1007/s12350-009-9166-x

    Article  PubMed  Google Scholar 

  • Mc Ardle BA, Davies RA, Chen L, Small GR, Ruddy TD, Dwivedi G, Yam Y, Haddad H, Mielniczuk LM, Stadnick E, Hessian R, Guo A, Beanlands RS, deKemp RA, Chow BJ (2014) Prognostic value of rubidium-82 positron emission tomography in patients after heart transplant. Circ Cardiovasc Imaging 7(6):930–937. https://doi.org/10.1161/CIRCIMAGING.114.002184

    Article  PubMed  Google Scholar 

  • Mehra MR, Uber PA, Ventura HO, Scott RL, Park MH (2004) The impact of mode of donor brain death on cardiac allograft vasculopathy: an intravascular ultrasound study. J Am Coll Cardiol 43(5):806–810. https://doi.org/10.1016/j.jacc.2003.08.059

    Article  PubMed  Google Scholar 

  • Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE, Kobashigawa JA, Madsen J, Parameshwar J, Starling RC, Uber PA (2010) International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant 29(7):717–727. https://doi.org/10.1016/j.healun.2010.05.017

    Article  PubMed  Google Scholar 

  • Miller CA, Sarma J, Naish JH, Yonan N, Williams SG, Shaw SM, Clark D, Pearce K, Stout M, Potluri R, Borg A, Coutts G, Chowdhary S, McCann GP, Parker GJ, Ray SG, Schmitt M (2014) Multiparametric cardiovascular magnetic resonance assessment of cardiac allograft vasculopathy. J Am Coll Cardiol 63(8):799–808. https://doi.org/10.1016/j.jacc.2013.07.119

    Article  PubMed  Google Scholar 

  • Mitchell RN (2009) Graft vascular disease: immune response meets the vessel wall. Annu Rev Pathol 4:19–47. https://doi.org/10.1146/annurev.pathol.3.121806.151449

    Article  CAS  PubMed  Google Scholar 

  • Mittal TK, Panicker MG, Mitchell AG, Banner NR (2013) Cardiac allograft vasculopathy after heart transplantation: electrocardiographically gated cardiac CT angiography for assessment. Radiology 268(2): 374–381. https://doi.org/10.1148/radiol.13121440

    Article  PubMed  Google Scholar 

  • Monsinjon T, Gasque P, Chan P, Ischenko A, Brady JJ, Fontaine MC (2003) Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells. FASEB J 17(9):1003–1014. https://doi.org/10.1096/fj.02-0737com

    Article  CAS  PubMed  Google Scholar 

  • Peng Q, Li K, Patel H, Sacks SH, Zhou W (2006) Dendritic cell synthesis of C3 is required for full T cell activation and development of a Th1 phenotype. J Immunol 176(6):3330–3341

    Article  CAS  Google Scholar 

  • Pichler M, Rainer PP, Schauer S, Hoefler G (2012) Cardiac fibrosis in human transplanted hearts is mainly driven by cells of intracardiac origin. J Am Coll Cardiol 59(11):1008–1016. https://doi.org/10.1016/j.jacc.2011.11.036

    Article  PubMed  Google Scholar 

  • Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE, O’Donnell J, Thomas C, Bourge RC, Naftel DC (2003) Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study. J Heart Lung Transplant 22(8):862–868. https://doi.org/10.1016/s1053-2498(02)00803-3

    Article  PubMed  Google Scholar 

  • Raichlin E, Bae JH, Kushwaha SS, Lennon RJ, Prasad A, Rihal CS, Lerman A (2009a) Inflammatory burden of cardiac allograft coronary atherosclerotic plaque is associated with early recurrent cellular rejection and predicts a higher risk of vasculopathy progression. J Am Coll Cardiol 53(15):1279–1286. https://doi.org/10.1016/j.jacc.2008.12.041

    Article  PubMed  Google Scholar 

  • Raichlin E, Villarraga HR, Chandrasekaran K, Clavell AL, Frantz RP, Kushwaha SS, Rodeheffer RJ, McGregor CG, Daly RC, Park SJ, Kremers WK, Edwards BS, Pereira NL (2009b) Cardiac allograft remodeling after heart transplantation is associated with increased graft vasculopathy and mortality. Am J Transplant 9(1):132–139. https://doi.org/10.1111/j.1600-6143.2008.02474.x

    Article  CAS  PubMed  Google Scholar 

  • Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ (2005) Cardiac allograft vasculopathy: a review. Can J Surg 48(4):319–327

    PubMed  PubMed Central  Google Scholar 

  • Rodrigues AC, Frimm Cde C, Bacal F, Andreolli V, Tsutsui JM, Bocchi EA, Mathias W Jr, Lage SG (2005) Coronary flow reserve impairment predicts cardiac events in heart transplant patients with preserved left ventricular function. Int J Cardiol 103(2):201–206. https://doi.org/10.1016/j.ijcard.2004.12.017

    Article  PubMed  Google Scholar 

  • Rodriguez ER, Skojec DV, Tan CD, Zachary AA, Kasper EK, Conte JV, Baldwin WM 3rd (2005) Antibody-mediated rejection in human cardiac allografts: evaluation of immunoglobulins and complement activation products C4d and C3d as markers. Am J Transplant 5(11):2778–2785. https://doi.org/10.1111/j.1600-6143.2005.01074.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saadi S, Platt JL (1995) Transient perturbation of endothelial integrity induced by natural antibodies and complement. J Exp Med 181(1):21–31

    Article  CAS  Google Scholar 

  • Saadi S, Holzknecht RA, Patte CP, Stern DM, Platt JL (1995) Complement-mediated regulation of tissue factor activity in endothelium. J Exp Med 182(6): 1807–1814

    Article  CAS  Google Scholar 

  • Sade LE, Eroglu S, Yuce D, Bircan A, Pirat B, Sezgin A, Aydinalp A, Muderrisoglu H (2014) Follow-up of heart transplant recipients with serial echocardiographic coronary flow reserve and dobutamine stress echocardiography to detect cardiac allograft vasculopathy. J Am Soc Echocardiogr 27(5):531–539. https://doi.org/10.1016/j.echo.2014.01.020

    Article  PubMed  Google Scholar 

  • Sanchez Lazaro IJ, Almenar Bonet L, Moro Lopez J, Sanchez Lacuesta E, Martinez-Dolz L, Aguero Ramon-Llin J, Andres Lalaguna L, Cano Perez O, Ortiz Martinez V, Buendia Fuentes F, Salvador Sanz A (2008) Influence of traditional cardiovascular risk factors in the recipient on the development of cardiac allograft vasculopathy after heart transplantation. Transplant Proc 40(9):3056–3057. https://doi.org/10.1016/j.transproceed.2008.08.115

    Article  CAS  PubMed  Google Scholar 

  • Sato T, Seguchi O, Ishibashi-Ueda H, Yanase M, Okada N, Kuroda K, Hisamatsu E, Sunami H, Watanabe T, Nakajima S, Wada K, Hata H, Fujita T, Fukushima N, Kobayashi J, Nakatani T (2016) Risk stratification for cardiac allograft vasculopathy in heart transplant recipients – annual intravascular ultrasound evaluation. Circ J 80(2):395–403. https://doi.org/10.1253/circj.CJ-15-1037

    Article  PubMed  Google Scholar 

  • Spes CH, Mudra H, Schnaack SD, Klauss V, Reichle FM, Uberfuhr P, Theisen K, Angermann CE (1996) Dobutamine stress echocardiography for noninvasive diagnosis of cardiac allograft vasculopathy: a comparison with angiography and intravascular ultrasound. Am J Cardiol 78(2):168–174

    Article  CAS  Google Scholar 

  • Spes CH, Klauss V, Mudra H, Schnaack SD, Tammen AR, Rieber J, Siebert U, Henneke KH, Uberfuhr P, Reichart B, Theisen K, Angermann CE (1999) Diagnostic and prognostic value of serial dobutamine stress echocardiography for noninvasive assessment of cardiac allograft vasculopathy: a comparison with coronary angiography and intravascular ultrasound. Circulation 100(5):509–515

    Article  CAS  Google Scholar 

  • Srivastava R, Keck BM, Bennett LE, Hosenpud JD (2000) The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. Transplantation 70(4):606–612

    Article  CAS  Google Scholar 

  • Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, Dobbels F, Kirk R, Rahmel AO, Hertz MI, International Society of Heart and Lung Transplantation (2012) The registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report – 2012. J Heart Lung Transplant 31(10): 1052–1064. https://doi.org/10.1016/j.healun.2012.08.002

    Article  PubMed  Google Scholar 

  • Stetson SJ, Perez-Verdia A, Mazur W, Farmer JA, Koerner MM, Weilbaecher DG, Entman ML, Quinones MA, Noon GP, Torre-Amione G (2001) Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor-alpha. Circulation 104(6):676–681

    Article  CAS  Google Scholar 

  • Stovin PG, Sharples LD, Schofield PM, Cary NR, Mullins PA, English TA, Wallwork J, Large SR (1993) Lack of association between endomyocardial evidence of rejection in the first six months and the later development of transplant-related coronary artery disease. J Heart Lung Transplant 12(1 Pt 1):110–116

    CAS  PubMed  Google Scholar 

  • Tanaka K, Zou JP, Takeda K, Ferrans VJ, Sandford GR, Johnson TM, Finkel T, Epstein SE (1999) Effects of human cytomegalovirus immediate-early proteins on p53-mediated apoptosis in coronary artery smooth muscle cells. Circulation 99(13):1656–1659

    Article  CAS  Google Scholar 

  • Tomai F, De Luca L, Petrolini A, Di Vito L, Ghini AS, Corvo P, De Persio G, Parisi F, Pongiglione G, Giulia Gagliardi M, Prati F (2016) Optical coherence tomography for characterization of cardiac allograft vasculopathy in late survivors of pediatric heart transplantation. J Heart Lung Transplant 35(1):74–79. https://doi.org/10.1016/j.healun.2015.08.011

    Article  PubMed  Google Scholar 

  • von Ziegler F, Leber AW, Becker A, Kaczmarek I, Schonermarck U, Raps C, Tittus J, Uberfuhr P, Becker CR, Reiser M, Steinbeck G, Knez A (2009) Detection of significant coronary artery stenosis with 64-slice computed tomography in heart transplant recipients: a comparative study with conventional coronary angiography. Int J Cardiovasc Imaging 25(1): 91–100. https://doi.org/10.1007/s10554-008-9343-z

    Article  Google Scholar 

  • Watanabe T, Seguchi O, Yanase M, Fujita T, Murata Y, Sato T, Sunami H, Nakajima S, Kataoka Y, Nishimura K, Hisamatsu E, Kuroda K, Okada N, Hori Y, Wada K, Hata H, Ishibashi-Ueda H, Miyamoto Y, Fukushima N, Kobayashi J, Nakatani T (2017) Donor-transmitted atherosclerosis associated with worsening cardiac allograft vasculopathy after heart transplantation: serial volumetric intravascular ultrasound analysis. Transplantation 101(6): 1310–1319. https://doi.org/10.1097/TP.0000000000001322

    Article  PubMed  Google Scholar 

  • Weiss MJ, Madsen JC, Rosengard BR, Allan JS (2008) Mechanisms of chronic rejection in cardiothoracic transplantation. Front Biosci 13:2980–2988

    Article  CAS  Google Scholar 

  • Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, Cottens S, Takada Y, Hommel U (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7(6):687–692. https://doi.org/10.1038/89058

    Article  CAS  PubMed  Google Scholar 

  • Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K, Steinbeck G, Seidel D, Reichart B (2003) Simvastatin initiated early after heart transplantation: 8-year prospective experience. Circulation 107(1): 93–97

    Article  CAS  Google Scholar 

  • Wever-Pinzon O, Romero J, Kelesidis I, Wever-Pinzon J, Manrique C, Budge D, Drakos SG, Pina IL, Kfoury AG, Garcia MJ, Stehlik J (2014) Coronary computed tomography angiography for the detection of cardiac allograft vasculopathy: a meta-analysis of prospective trials. J Am Coll Cardiol 63(19): 1992–2004. https://doi.org/10.1016/j.jacc.2014.01.071

    Article  PubMed  Google Scholar 

  • Wong C, Ganz P, Miller L, Kobashigawa J, Schwarzkopf A, Valantine von Kaeper H, Wilensky R, Ventura H, Yeung AC (2001) Role of vascular remodeling in the pathogenesis of early transplant coronary artery disease: a multicenter prospective intravascular ultrasound study. J Heart Lung Transplant 20(4):385–392

    Article  CAS  Google Scholar 

  • Wu GD, Tuan TL, Bowdish ME, Jin YS, Starnes VA, Cramer DV, Barr ML (2003) Evidence for recipient derived fibroblast recruitment and activation during the development of chronic cardiac allograft rejection. Transplantation 76(3):609–614. https://doi.org/10.1097/01.TP.0000066362.37931.6D

    Article  PubMed  Google Scholar 

  • Wu AH, Ballantyne CM, Short BC, Torre-Amione G, Young JB, Ventura HO, Eisen HJ, Radovancevic B, Rayburn BK, Lake KD, Yancy CW Jr, Taylor DO, Mehra MR, Kubo SH, Fishbein DP, Zhao XQ, O’Brien KD (2005a) Statin use and risks of death or fatal rejection in the Heart Transplant Lipid Registry. Am J Cardiol 95(3):367–372. https://doi.org/10.1016/j.amjcard.2004.09.035

    Article  PubMed  Google Scholar 

  • Wu YW, Yen RF, Lee CM, Ho YL, Chou NK, Wang SS, Huang PJ (2005b) Diagnostic and prognostic value of dobutamine thallium-201 single-photon emission computed tomography after heart transplantation. J Heart Lung Transplant 24(5):544–550. https://doi.org/10.1016/j.healun.2003.12.004

    Article  PubMed  Google Scholar 

  • Wu GW, Kobashigawa JA, Fishbein MC, Patel JK, Kittleson MM, Reed EF, Kiyosaki KK, Ardehali A (2009) Asymptomatic antibody-mediated rejection after heart transplantation predicts poor outcomes. J Heart Lung Transplant 28(5):417–422. https://doi.org/10.1016/j.healun.2009.01.015

    Article  PubMed  Google Scholar 

  • Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13(8):952–961. https://doi.org/10.1038/nm1613

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Newark Beth Israel Medical Center, Newark, NJ, USA

    Laurie Letarte

  2. Houston Methodist Hospital, Houston, TX, USA

    Arvind Bhimaraj

Authors
  1. Laurie Letarte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arvind Bhimaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laurie Letarte .

Editor information

Editors and Affiliations

  1. AdventHealth Transplant Institute, Orlando, FL, USA

    Linda Bogar

  2. Division of Cardiology, University of Washington, Seattle, WA, USA

    April Stempien-Otero

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Letarte, L., Bhimaraj, A. (2020). Chronic Rejection. In: Bogar, L., Stempien-Otero, A. (eds) Contemporary Heart Transplantation. Organ and Tissue Transplantation. Springer, Cham. https://doi.org/10.1007/978-3-319-33280-2_37-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-33280-2_37-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-33280-2

  • Online ISBN: 978-3-319-33280-2

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation