ABSTRACT
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
KEYWORDS
ABBREVIATIONS:
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 accessOne-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:
Subscribe to The Journal of Heart and Lung TransplantationAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
REFERENCES
- 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: 1078-1094https://doi.org/10.1016/j.healun.2011.08.003
- Primary Graft Failure after Heart Transplantation.Journal of Transplantation. 2011; (2011)175768https://doi.org/10.1155/2011/175768
- 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: 1056-1066https://doi.org/10.1016/j.healun.2019.08.004
- Report from a consensus conference on primary graft dysfunction after cardiac transplantation.The Journal of Heart and Lung Transplantation. 2014; 33: 327-340https://doi.org/10.1016/j.healun.2014.02.027
- 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)521369https://doi.org/10.1155/2013/521369
- Multiorgan procurement increases systemic inflammation in brain dead donors.Clin Transplant. 2013; 27: 613-618https://doi.org/10.1111/ctr.12175
- Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure.Transplantation. 2001; 71: 1394-1400
- The Proinflammatory Environment in Potential Heart and Lung Donors: Prevalence and Impact of Donor Management and Hormonal Therapy.Transplantation. 2009; 88: 582https://doi.org/10.1097/TP.0b013e3181b11e5d
- Elevated tumor necrosis factor-alpha and interleukin-6 in myocardium and serum of malfunctioning donor hearts.Circulation. 2000; 102 (Suppl 3): III352-III358
- Reappraising the role of inflammation in heart failure.Nat Rev Cardiol. 2020; 17: 269-285https://doi.org/10.1038/s41569-019-0315-x
- Impact of Warm Ischemia Time on Survival After Heart Transplantation.Transplantation Proceedings. 2012; 44: 1385-1389https://doi.org/10.1016/j.transproceed.2011.12.075
- The role of donor age and ischemic time on survival following orthotopic heart transplantation.The Journal of Heart and Lung Transplantation. 1999; 18: 310-319https://doi.org/10.1016/S1053-2498(98)00059-X
- RADIAL: A novel primary graft failure risk score in heart transplantation.The Journal of Heart and Lung Transplantation. 2011; 30: 644-651https://doi.org/10.1016/j.healun.2011.01.721
- Trends in the utilization of marginal donors for orthotopic heart transplantation.J Cardiac Surg. 2021; 36: 1270-1276https://doi.org/10.1111/jocs.15359
- Cytokine gene expression in human cardiac allograft recipients.Transpl Immunol. 1994; 2: 199-207https://doi.org/10.1016/0966-3274(94)90061-2
- Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success.Front Immunol. 2020; 11599511https://doi.org/10.3389/fimmu.2020.599511
- Donor Simvastatin Treatment in Heart Transplantation: A Randomized and Blinded Clinical Trial.Circulation. 2019; 140: 627-640https://doi.org/10.1161/CIRCULATIONAHA.119.039932
- Validation of the International Society for Heart and Lung Transplantation primary graft dysfunction instrument in heart transplantation.J Hear Lung Transplant. 2019; 38: 260-266https://doi.org/10.1016/j.healun.2018.12.007
- 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: 263-270https://doi.org/10.1093/ejcts/ezw271
- Primary Cardiac Allograft Dysfunction—Validation of a Clinical Definition.Transplantation. 2015; 99: 1919https://doi.org/10.1097/TP.0000000000000620
- Primary graft dysfunction after heart transplantation: Incidence, trends, and associated risk factors.American Journal of Transplantation. 2018; 18: 1461-1470https://doi.org/10.1111/ajt.14588
- Primary graft dysfunction after heart transplantation: a thorn amongst the roses.Heart Fail Rev. 2019; 24: 805-820https://doi.org/10.1007/s10741-019-09794-1
- 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: 1217-1225https://doi.org/10.1016/j.healun.2017.02.014
- Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.J Hear Lung Transplant. 2021; 40: 970-980https://doi.org/10.1016/j.healun.2021.06.002
- A Role for Fractalkine and Its Receptor (CX3CR1) in Cardiac Allograft Rejection.The Journal of Immunology. 2000; 165: 6067-6072https://doi.org/10.4049/jimmunol.165.11.6067
- Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity.Scientific Reports. 2018; 8: 2461https://doi.org/10.1038/s41598-018-20858-4
- Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival.J Immunol Baltim Md. 1996; 156 (1950): 2316-2323
- Gene transfer of interleukin-18-binding protein attenuates cardiac allograft rejection*.Transplant International. 2007; 20: 460-466https://doi.org/10.1111/j.1432-2277.2007.00457.x
- 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: 1941-1955https://doi.org/10.4049/jimmunol.177.3.1941
- CCR6 Regulates the Migration of Inflammatory and Regulatory T Cells.J Immunol. 2008; 181: 8391-8401https://doi.org/10.4049/jimmunol.181.12.8391
- Elevated donor cardiac troponin T and procalcitonin indicate two independent mechanisms of early graft failure after heart transplantation.Int J Cardiol. 2003; 92: 163-167https://doi.org/10.1016/s0167-5273(03)00083-4
- Donor Serum SMARCAL1 Concentrations Predict Primary Graft Dysfunction in Cardiac Transplantation.Circulation. 2009; 120 (_suppl_1): S198-S205https://doi.org/10.1161/circulationaha.108.842971
- Methylprednisolone Therapy in Deceased Donors Reduces Inflammation in the Donor Liver and Improves Outcome After Liver Transplantation.Ann Surg. 2008; 248: 1042-1050https://doi.org/10.1097/sla.0b013e318190e70c
- Critical Role of Proinflammatory Cytokine IL-6 in Allograft Rejection and Tolerance.Am J Transplant. 2012; 12: 90-101https://doi.org/10.1111/j.1600-6143.2011.03770.x
- IL-6 Directed Therapy in Transplantation.Curr Transplant Reports. 2021; 8: 1-14https://doi.org/10.1007/s40472-021-00331-4
- Targeting Inflammation and Alloimmunity in Heart Transplant Recipients With Tocilizumab (RTB-004).ClinicalTrials.gov Identifier NCT03644667. May 16, 2021 (Available at) (Accessed)
Article info
Publication history
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation.