The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.


Published:January 18, 2023DOI:



      Heart transplant results have constantly improved but primary left ventricle graft dysfunction (LV-PGD) remains a devastating complication early after transplantation. Donor and recipient systemic inflammatory response may be involved in immune activation of the transplant, and LV-PGD development. Here, we investigated donor and recipient plasma and intragraft cytokine profiles preoperatively and during LV-PGD and searched for predictive markers for LV-PGD.


      Donor and recipient plasma samples (n = 74) and myocardial biopsies of heart transplants (n = 64) were analyzed. Plasma and intragraft cytokine levels were determined by multiplexed and next-generation sequencing platforms, respectively. The development of LV-PGD during the first 24 hours, and graft function and mortality up to 1 year after transplantation, were examined.


      Severe LV-PGD, but not mild or moderate LV-PGD, was significantly associated with early mortality, plasma high-sensitivity troponin elevation, and an increase in intragraft and plasma proinflammatory cytokines during reperfusion. Preoperative donor and recipient plasma cytokine levels failed to predict LV-PGD. Cytokine network analysis identified interleukins -6, -8, -10, and -18 as key players during reperfusion. Prolonged cold and total ischemia time, and increased need for red blood cell transfusions during operation were identified as clinical risk factors for severe LV-PGD.


      Severe LV-PGD was associated with a poor clinical outcome. Donor and recipient plasma cytokine profile failed to predict LV-PGD, but severe LV-PGD was associated with an increase in post-reperfusion intragraft and recipient plasma proinflammatory cytokines. Identified key cytokines may be potential therapeutic targets to improve early and long-term outcomes after heart transplantation.



      CKMBm (creatine kinase MB isoenzyme mass), hsCRP (high-sensitivity C-reactive protein), HTx (heart transplantation), IL (interleukin), LV (left ventricular), MAP (mean arterial pressure), NT-proBNP (N-terminal pro b-type natriuretic peptide), PGD (primary graft dysfunction), RV (right ventricular), SGD (secondary graft dysfunction), TnT (troponin T)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Heart and Lung Transplantation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Stehlik J.
        • Edwards LB.
        • Kucheryavaya AY.
        • et al.
        The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Report—2011.
        The Journal of Heart and Lung Transplantation. 2011; 30: 1078-1094
        • Iyer A.
        • Kumarasinghe G.
        • Hicks M.
        • et al.
        Primary Graft Failure after Heart Transplantation.
        Journal of Transplantation. 2011; (2011)175768
        • Khush KK.
        • Cherikh WS.
        • Chambers DC.
        • et al.
        The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report — 2019; focus theme: Donor and recipient size match.
        J Hear Lung Transplant. 2019; 38: 1056-1066
        • Kobashigawa J.
        • Zuckermann A.
        • Macdonald P.
        • et al.
        Report from a consensus conference on primary graft dysfunction after cardiac transplantation.
        The Journal of Heart and Lung Transplantation. 2014; 33: 327-340
        • Watts RP.
        • Thom O.
        • Fraser JF.
        Inflammatory signalling associated with brain dead organ donation: from brain injury to brain stem death and posttransplant ischaemia reperfusion injury.
        Journal of Transplantation. 2013; (2013)521369
        • Auråen H.
        • Mollnes TE.
        • Bjørtuft Ø.
        • et al.
        Multiorgan procurement increases systemic inflammation in brain dead donors.
        Clin Transplant. 2013; 27: 613-618
        • Potapov EV.
        • Ivanitskaia EA.
        • Loebe M.
        • et al.
        Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure.
        Transplantation. 2001; 71: 1394-1400
        • Venkateswaran RV.
        • Dronavalli V.
        • Lambert PA.
        • et al.
        The Proinflammatory Environment in Potential Heart and Lung Donors: Prevalence and Impact of Donor Management and Hormonal Therapy.
        Transplantation. 2009; 88: 582
        • Birks EJ.
        • Burton PB.
        • Owen V.
        • et al.
        Elevated tumor necrosis factor-alpha and interleukin-6 in myocardium and serum of malfunctioning donor hearts.
        Circulation. 2000; 102 (Suppl 3): III352-III358
        • Adamo L.
        • Rocha-Resende C.
        • Prabhu SD.
        • Mann DL.
        Reappraising the role of inflammation in heart failure.
        Nat Rev Cardiol. 2020; 17: 269-285
        • Marasco SF.
        • Kras A.
        • Schulberg E.
        • Vale M.
        • Lee GA.
        Impact of Warm Ischemia Time on Survival After Heart Transplantation.
        Transplantation Proceedings. 2012; 44: 1385-1389
        • Rizzo DFD.
        • Menkis AH.
        • Pflugfelder PW.
        • et al.
        The role of donor age and ischemic time on survival following orthotopic heart transplantation.
        The Journal of Heart and Lung Transplantation. 1999; 18: 310-319
        • Segovia J.
        • Cosío MDG.
        • Barceló JM.
        • et al.
        RADIAL: A novel primary graft failure risk score in heart transplantation.
        The Journal of Heart and Lung Transplantation. 2011; 30: 644-651
        • Huckaby LV.
        • Hickey G.
        • Sultan I.
        • Kilic A.
        Trends in the utilization of marginal donors for orthotopic heart transplantation.
        J Cardiac Surg. 2021; 36: 1270-1276
        • Wu CJ.
        • Kurbegov D.
        • Lattin B.
        • et al.
        Cytokine gene expression in human cardiac allograft recipients.
        Transpl Immunol. 1994; 2: 199-207
        • Silvis MJM.
        • Dengler SEK genaamd.
        • Odille CA.
        • et al.
        Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success.
        Front Immunol. 2020; 11599511
        • Nykänen AI.
        • Holmström EJ.
        • Tuuminen R.
        • et al.
        Donor Simvastatin Treatment in Heart Transplantation: A Randomized and Blinded Clinical Trial.
        Circulation. 2019; 140: 627-640
        • Foroutan F.
        • Alba AC.
        • Stein M.
        • et al.
        Validation of the International Society for Heart and Lung Transplantation primary graft dysfunction instrument in heart transplantation.
        J Hear Lung Transplant. 2019; 38: 260-266
        • Squiers JJ.
        • Saracino G.
        • Chamogeorgakis T.
        • et al.
        Application of the International Society for Heart and Lung Transplantation (ISHLT) criteria for primary graft dysfunction after cardiac transplantation: outcomes from a high-volume centre†.
        European Journal of Cardio-Thoracic Surgery. 2017; 51: 263-270
        • Dronavalli VB.
        • Rogers CA.
        • Banner NR.
        Primary Cardiac Allograft Dysfunction—Validation of a Clinical Definition.
        Transplantation. 2015; 99: 1919
        • Nicoara A.
        • Ruffin D.
        • Cooter M.
        • et al.
        Primary graft dysfunction after heart transplantation: Incidence, trends, and associated risk factors.
        American Journal of Transplantation. 2018; 18: 1461-1470
        • Singh SSA.
        • Dalzell JR.
        • Berry C.
        • Al-Attar N.
        Primary graft dysfunction after heart transplantation: a thorn amongst the roses.
        Heart Fail Rev. 2019; 24: 805-820
        • Sabatino M.
        • Vitale G.
        • Manfredini V.
        • et al.
        Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: Epidemiology, risk factors, and outcomes.
        The Journal of Heart and Lung Transplantation. 2017; 36: 1217-1225
        • Benck L.
        • Kransdorf EP.
        • Emerson DA.
        • et al.
        Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.
        J Hear Lung Transplant. 2021; 40: 970-980
        • Robinson LA.
        • Nataraj C.
        • Thomas DW.
        • et al.
        A Role for Fractalkine and Its Receptor (CX3CR1) in Cardiac Allograft Rejection.
        The Journal of Immunology. 2000; 165: 6067-6072
        • Uehara M.
        • Solhjou Z.
        • Banouni N.
        • et al.
        Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity.
        Scientific Reports. 2018; 8: 2461
        • Qin L.
        • Chavin KD.
        • Ding Y.
        • et al.
        Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival.
        J Immunol Baltim Md. 1996; 156 (1950): 2316-2323
        • Dudler J.
        • Simeoni E.
        • Fleury S.
        • et al.
        Gene transfer of interleukin-18-binding protein attenuates cardiac allograft rejection*.
        Transplant International. 2007; 20: 460-466
        • Bosco MC.
        • Puppo M.
        • Santangelo C.
        • et al.
        Hypoxia Modifies the Transcriptome of Primary Human Monocytes: Modulation of Novel Immune-Related Genes and Identification Of CC-Chemokine Ligand 20 as a New Hypoxia-Inducible Gene.
        J Immunol. 2006; 177: 1941-1955
        • Yamazaki T.
        • Yang XO.
        • Chung Y.
        • et al.
        CCR6 Regulates the Migration of Inflammatory and Regulatory T Cells.
        J Immunol. 2008; 181: 8391-8401
        • Potapov EV.
        • Wagner FD.
        • Loebe M.
        • et al.
        Elevated donor cardiac troponin T and procalcitonin indicate two independent mechanisms of early graft failure after heart transplantation.
        Int J Cardiol. 2003; 92: 163-167
        • Aharinejad S.
        • Andrukhova O.
        • Gmeiner M.
        • et al.
        Donor Serum SMARCAL1 Concentrations Predict Primary Graft Dysfunction in Cardiac Transplantation.
        Circulation. 2009; 120 (_suppl_1): S198-S205
        • Kotsch K.
        • Ulrich F.
        • Reutzel-Selke A.
        • et al.
        Methylprednisolone Therapy in Deceased Donors Reduces Inflammation in the Donor Liver and Improves Outcome After Liver Transplantation.
        Ann Surg. 2008; 248: 1042-1050
        • Zhao X.
        • Boenisch O.
        • Yeung M.
        • et al.
        Critical Role of Proinflammatory Cytokine IL-6 in Allograft Rejection and Tolerance.
        Am J Transplant. 2012; 12: 90-101
        • Miller CL.
        • Madsen JC.
        IL-6 Directed Therapy in Transplantation.
        Curr Transplant Reports. 2021; 8: 1-14
        • Kobashigawa J.
        • Madsen JC.
        Targeting Inflammation and Alloimmunity in Heart Transplant Recipients With Tocilizumab (RTB-004). Identifier NCT03644667. May 16, 2021 (Available at) (Accessed)