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  1. Article ; Online: Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

    Halloran, Philip F / Madill-Thomsen, Katelynn / Aliabadi-Zuckermann, Arezu Z / Cadeiras, Martin / Crespo-Leiro, Marisa G / Depasquale, Eugene C / Deng, Mario / Gökler, Johannes / Hall, Shelley / Jamil, Aayla / Kim, Daniel H / Kobashigawa, Jon / Macdonald, Peter / Melenovsky, Vojtech / Patel, Jignesh / Potena, Luciano / Shah, Keyur / Stehlik, Josef / Zuckermann, Andreas

    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

    2024  

    Abstract: The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) ... ...

    Abstract The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.
    Language English
    Publishing date 2024-03-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2060594-8
    ISSN 1600-6143 ; 1600-6135
    ISSN (online) 1600-6143
    ISSN 1600-6135
    DOI 10.1016/j.ajt.2024.03.031
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  2. Article ; Online: Assessing the Relationship Between Molecular Rejection and Parenchymal Injury in Heart Transplant Biopsies.

    Madill-Thomsen, Katelynn S / Reeve, Jeff / Aliabadi-Zuckermann, Arezu / Cadeiras, Martin / Crespo-Leiro, Marisa G / Depasquale, Eugene C / Deng, Mario / Goekler, Johannes / Kim, Daniel H / Kobashigawa, Jon / Macdonald, Peter / Potena, Luciano / Shah, Keyur / Stehlik, Josef / Zuckermann, Andreas / Halloran, Philip F

    Transplantation

    2022  Volume 106, Issue 11, Page(s) 2205–2216

    Abstract: Background: The INTERHEART study (ClinicalTrials.gov #NCT02670408) used genome-wide microarrays to detect rejection in endomyocardial biopsies; however, many heart transplants with no rejection have late dysfunction and impaired survival. We used the ... ...

    Abstract Background: The INTERHEART study (ClinicalTrials.gov #NCT02670408) used genome-wide microarrays to detect rejection in endomyocardial biopsies; however, many heart transplants with no rejection have late dysfunction and impaired survival. We used the microarray measurements to develop a molecular classification of parenchymal injury.
    Methods: In 1320 endomyocardial biopsies from 645 patients previously studied for rejection-associated transcripts, we measured the expression of 10 injury-induced transcript sets: 5 induced by recent injury; 2 reflecting macrophage infiltration; 2 normal heart transcript sets; and immunoglobulin transcripts, which correlate with time. We used archetypal clustering to assign injury groups.
    Results: Injury transcript sets correlated with impaired function. Archetypal clustering based on the expression of injury transcript sets assigned each biopsy to 1 of 5 injury groups: 87 Severe-injury, 221 Late-injury, and 3 with lesser degrees of injury, 376 No-injury, 526 Mild-injury, and 110 Moderate-injury. Severe-injury had extensive loss of normal transcripts (dedifferentiation) and increase in macrophage and injury-induced transcripts. Late-injury was characterized by high immunoglobulin transcript expression. In Severe- and Late-injury, function was depressed, and short-term graft failure was increased, even in hearts with no rejection. T cell-mediated rejection almost always had parenchymal injury, and 85% had Severe- or Late-injury. In contrast, early antibody-mediated rejection (AMR) had little injury, but late AMR often had the Late-injury state.
    Conclusions: Characterizing heart transplants for their injury state provides new understanding of dysfunction and outcomes and demonstrates the differential impact of T cell-mediated rejection versus AMR on the parenchyma. Slow deterioration from AMR emerges as a major contributor to late dysfunction.
    MeSH term(s) Humans ; Graft Rejection/diagnosis ; Kidney Transplantation ; Biopsy ; Heart Transplantation/adverse effects ; Antibodies
    Chemical Substances Antibodies
    Language English
    Publishing date 2022-10-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 208424-7
    ISSN 1534-6080 ; 0041-1337
    ISSN (online) 1534-6080
    ISSN 0041-1337
    DOI 10.1097/TP.0000000000004231
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  3. Article ; Online: Molecular states associated with dysfunction and graft loss in heart transplants.

    Halloran, Philip F / Madill-Thomsen, Katelynn / Mackova, Martina / Aliabadi-Zuckermann, Arezu Z / Cadeiras, Martin / Crespo-Leiro, Marisa G / Depasquale, Eugene C / Deng, Mario / Gökler, Johannes / Hall, Shelley A / Kim, Daniel H / Kobashigawa, Jon / Macdonald, Peter / Potena, Luciano / Shah, Keyur / Stehlik, Josef / Zuckermann, Andreas / Reeve, Jeff

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

    2023  Volume 43, Issue 3, Page(s) 508–518

    Abstract: Background: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies.: Methods: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ... ...

    Abstract Background: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies.
    Methods: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ventricular ejection fraction [LVEF] ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival.
    Results: Dysfunction is correlated with dedifferentiation-decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection. Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury. Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB). Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest.
    Conclusions: Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia.
    MeSH term(s) Humans ; Stroke Volume ; Ventricular Function, Left ; Heart Transplantation ; Hypoxia ; Inflammation
    Language English
    Publishing date 2023-11-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1062522-7
    ISSN 1557-3117 ; 1053-2498
    ISSN (online) 1557-3117
    ISSN 1053-2498
    DOI 10.1016/j.healun.2023.11.013
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  4. Article ; Online: Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes.

    Halloran, Philip F / Madill-Thomsen, Katelynn / Aliabadi-Zuckermann, Arezu Z / Cadeiras, Martin / Crespo-Leiro, Marisa G / Depasquale, Eugene C / Deng, Mario / Gökler, Johannes / Kim, Daniel H / Kobashigawa, Jon / Macdonald, Peter / Potena, Luciano / Shah, Keyur / Stehlik, Josef / Zuckermann, Andreas

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

    2021  Volume 41, Issue 3, Page(s) 334–344

    Abstract: Background: The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). ... ...

    Abstract Background: The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.
    Methods: Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).
    Results: Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.
    Conclusions: Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).
    MeSH term(s) Antibodies/immunology ; Biopsy ; Cross-Sectional Studies ; Graft Rejection/immunology ; Graft Rejection/pathology ; Heart Transplantation ; Humans ; Microscopy ; Molecular Diagnostic Techniques ; Myocardium/pathology ; Prospective Studies
    Chemical Substances Antibodies
    Language English
    Publishing date 2021-08-26
    Publishing country United States
    Document type Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 1062522-7
    ISSN 1557-3117 ; 1053-2498
    ISSN (online) 1557-3117
    ISSN 1053-2498
    DOI 10.1016/j.healun.2021.08.004
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  5. Article ; Online: Cardiac Amyloidosis: Diagnosis and Treatment Strategies.

    Tuzovic, Mirela / Yang, Eric H / Baas, Arnold S / Depasquale, Eugene C / Deng, Mario C / Cruz, Daniel / Vorobiof, Gabriel

    Current oncology reports

    2017  Volume 19, Issue 7, Page(s) 46

    Abstract: Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends ... ...

    Abstract Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective.
    Language English
    Publishing date 2017-07
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2057359-5
    ISSN 1534-6269 ; 1523-3790
    ISSN (online) 1534-6269
    ISSN 1523-3790
    DOI 10.1007/s11912-017-0607-4
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  6. Article ; Online: An integrated molecular diagnostic report for heart transplant biopsies using an ensemble of diagnostic algorithms.

    Parkes, Michael D / Aliabadi, Arezu Z / Cadeiras, Martin / Crespo-Leiro, Maria G / Deng, Mario / Depasquale, Eugene C / Goekler, Johannes / Kim, Daniel H / Kobashigawa, Jon / Loupy, Alexandre / Macdonald, Peter / Potena, Luciano / Zuckermann, Andreas / Halloran, Philip F

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

    2019  Volume 38, Issue 6, Page(s) 636–646

    Abstract: Background: We previously reported a microarray-based diagnostic system for heart transplant endomyocardial biopsies (EMBs), using either 3-archetype (3AA) or 4-archetype (4AA) unsupervised algorithms to estimate rejection. In the present study we ... ...

    Abstract Background: We previously reported a microarray-based diagnostic system for heart transplant endomyocardial biopsies (EMBs), using either 3-archetype (3AA) or 4-archetype (4AA) unsupervised algorithms to estimate rejection. In the present study we examined the stability of machine-learning algorithms in new biopsies, compared 3AA vs 4AA algorithms, assessed supervised binary classifiers trained on histologic or molecular diagnoses, created a report combining many scores into an ensemble of estimates, and examined possible automated sign-outs.
    Methods: We studied 889 EMBs from 454 transplant recipients at 8 centers: the initial cohort (N = 331) and a new cohort (N = 558). Published 3AA algorithms derived in Cohort 331 were tested in Cohort 558, the 3AA and 4AA models were compared, and supervised binary classifiers were created.
    Results: A`lgorithms derived in Cohort 331 performed similarly in new biopsies despite differences in case mix. In the combined cohort, the 4AA model, including a parenchymal injury score, retained correlations with histologic rejection and DSA similar to the 3AA model. Supervised molecular classifiers predicted molecular rejection (areas under the curve [AUCs] >0.87) better than histologic rejection (AUCs <0.78), even when trained on histology diagnoses. A report incorporating many AA and binary classifier scores interpreted by 1 expert showed highly significant agreement with histology (p < 0.001), but with many discrepancies, as expected from the known noise in histology. An automated random forest score closely predicted expert diagnoses, confirming potential for automated signouts.
    Conclusions: Molecular algorithms are stable in new populations and can be assembled into an ensemble that combines many supervised and unsupervised estimates of the molecular disease states.
    MeSH term(s) Adolescent ; Adult ; Aged ; Algorithms ; Child ; Child, Preschool ; Cohort Studies ; Female ; Graft Rejection/etiology ; Graft Rejection/pathology ; Heart Failure/etiology ; Heart Failure/pathology ; Heart Failure/surgery ; Heart Transplantation ; Humans ; Machine Learning ; Male ; Middle Aged ; Myocardium/pathology ; Pathology, Molecular ; Predictive Value of Tests ; ROC Curve ; Risk Assessment ; Young Adult
    Language English
    Publishing date 2019-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1062522-7
    ISSN 1557-3117 ; 1053-2498
    ISSN (online) 1557-3117
    ISSN 1053-2498
    DOI 10.1016/j.healun.2019.01.1318
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  7. Article ; Online: Exploring the cardiac response to injury in heart transplant biopsies.

    Halloran, Philip F / Reeve, Jeff / Aliabadi, Arezu Z / Cadeiras, Martin / Crespo-Leiro, Marisa G / Deng, Mario / Depasquale, Eugene C / Goekler, Johannes / Jouven, Xavier / Kim, Daniel H / Kobashigawa, Jon / Loupy, Alexandre / Macdonald, Peter / Potena, Luciano / Zuckermann, Andreas / Parkes, Michael D

    JCI insight

    2018  Volume 3, Issue 20

    Abstract: Background: Because injury is universal in organ transplantation, heart transplant endomyocardial biopsies present an opportunity to explore response to injury in heart parenchyma. Histology has limited ability to assess injury, potentially confusing it ...

    Abstract Background: Because injury is universal in organ transplantation, heart transplant endomyocardial biopsies present an opportunity to explore response to injury in heart parenchyma. Histology has limited ability to assess injury, potentially confusing it with rejection, whereas molecular changes have potential to distinguish injury from rejection. Building on previous studies of transcripts associated with T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), we explored transcripts reflecting injury.
    Methods: Microarray data from 889 prospectively collected endomyocardial biopsies from 454 transplant recipients at 14 centers were subjected to unsupervised principal component analysis and archetypal analysis to detect variation not explained by rejection. The resulting principal component and archetype scores were then examined for their transcript, transcript set, and pathway associations and compared to the histology diagnoses and left ventricular function.
    Results: Rejection was reflected by principal components PC1 and PC2, and by archetype scores S2TCMR, and S3ABMR, with S1normal indicating normalness. PC3 and a new archetype score, S4injury, identified unexplained variation correlating with expression of transcripts inducible in injury models, many expressed in macrophages and associated with inflammation in pathway analysis. S4injury scores were high in recent transplants, reflecting donation-implantation injury, and both S4injury and S2TCMR were associated with reduced left ventricular ejection fraction.
    Conclusion: Assessment of injury is necessary for accurate estimates of rejection and for understanding heart transplant phenotypes. Biopsies with molecular injury but no molecular rejection were often misdiagnosed rejection by histology.TRAIL REGISTRATION. ClinicalTrials.gov NCT02670408FUNDING. Roche Organ Transplant Research Foundation, the University of Alberta Hospital Foundation, and Alberta Health Services.
    MeSH term(s) Adolescent ; Adult ; Aged ; Biopsy ; Child ; Child, Preschool ; Endocardium/injuries ; Endocardium/pathology ; Female ; Gene Expression Profiling ; Graft Rejection/etiology ; Heart Injuries/diagnosis ; Heart Injuries/etiology ; Heart Injuries/pathology ; Heart Transplantation/adverse effects ; Humans ; Male ; Middle Aged ; Myocardium/pathology ; Prospective Studies ; Tissue Array Analysis ; Transplant Recipients ; Young Adult
    Language English
    Publishing date 2018-10-18
    Publishing country United States
    Document type Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.123674
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  8. Article ; Online: Heart Failure Therapies for End-Stage Chemotherapy-Induced Cardiomyopathy.

    Mukku, Roy B / Fonarow, Gregg C / Watson, Karol E / Ajijola, Olujimi A / Depasquale, Eugene C / Nsair, Ali / Baas, Arnold S / Deng, Mario C / Yang, Eric H

    Journal of cardiac failure

    2016  Volume 22, Issue 6, Page(s) 439–448

    Abstract: With ongoing advancements in cancer-related treatments, the number of cancer survivors continues to grow globally, with numbers in the United States predicted to reach 18 million by 2020. As a result, it is expected that a greater number of patients will ...

    Abstract With ongoing advancements in cancer-related treatments, the number of cancer survivors continues to grow globally, with numbers in the United States predicted to reach 18 million by 2020. As a result, it is expected that a greater number of patients will present with chemotherapy-related side effects. One entity in particular, chemotherapy-related cardiomyopathy (CCMP), is a known cardiotoxic manifestation associated with agents such as anthracyclines, trastuzumab, and tyrosine kinase inhibitors. Although such effects have been described in the medical literature for decades, concrete strategies for screening, prevention, and management of CCMP continue to be elusive owing to limited studies. Late recognition of CCMP is associated with a poorer prognosis, including a lack of clinical response to pharmacologic therapy, and end-stage heart failure. A number of advanced cardiac therapies, including cardiac resynchronization therapy, ventricular assist devices, and orthotopic cardiac transplantation, are available to for end-stage heart failure; however, the role of these therapies in CCMP is unclear. In this review, management of end-stage CCMP with the use of advanced therapies and their respective effectiveness are discussed, as well as clinical characteristics of patients undergoing these treatments. The relative paucity of data in this field highlights the importance and need for larger-scale longitudinal studies and long-term registries tracking the outcomes of cancer survivors who have received cardiotoxic cancer therapy to determine the overall incidence of end-stage CCMP, as well as prognostic factors that will ultimately guide such patients toward receiving appropriate end-stage care.
    MeSH term(s) Adrenergic beta-Antagonists/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Antineoplastic Agents/adverse effects ; Cardiomyopathies/chemically induced ; Cardiomyopathies/complications ; Cardiomyopathies/therapy ; Heart Failure/etiology ; Heart Failure/therapy ; Heart Transplantation ; Heart-Assist Devices ; Humans ; Neoplasms/drug therapy ; Registries
    Chemical Substances Adrenergic beta-Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Antineoplastic Agents
    Language English
    Publishing date 2016-06
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1281194-4
    ISSN 1532-8414 ; 1071-9164
    ISSN (online) 1532-8414
    ISSN 1071-9164
    DOI 10.1016/j.cardfail.2016.04.009
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  9. Article ; Online: Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients.

    Zhang, Qiuheng / Hickey, Michelle / Drogalis-Kim, Diana / Zheng, Ying / Gjertson, David / Cadeiras, Martin / Khuu, Tam / Baas, Arnold S / Depasquale, Eugene C / Halnon, Nancy J / Perens, Gregory / Alejos, Juan / Cruz, Daniel / Ali, Nsair / Shemin, Richard / Kwon, Murray / Fishbein, Michael C / Ardehali, Abbas / Deng, Mario /
    Reed, Elaine F

    Transplantation

    2018  Volume 102, Issue 10, Page(s) e431–e438

    Abstract: Background: Donor-specific HLA antibodies (DSA) are associated with increased rates of rejection and of graft failure in cardiac transplantation. The goal of this study was to determine the association of preformed and posttransplant development of ... ...

    Abstract Background: Donor-specific HLA antibodies (DSA) are associated with increased rates of rejection and of graft failure in cardiac transplantation. The goal of this study was to determine the association of preformed and posttransplant development of newly detected DSA (ndDSA) with antibody-mediated rejection (AMR) and characterize the clinical relevance of complement-activating DSA in heart allograft recipients.
    Methods: The study included 128 adult and 48 pediatric heart transplant patients transplanted between 2010 and 2013. Routine posttransplant HLA antibody testing was performed by IgG single-antigen bead test. The C3d single-antigen bead assay was used to identify complement-activating antibodies. Rejection was diagnosed using International Society for Heart and Lung Transplantation criteria.
    Results: In this study, 22 patients were transplanted with preexisting DSA, and 43 patients developed ndDSA posttransplant. Pretransplant (P < 0.05) and posttransplant (P < 0.001) ndDSA were associated with higher incidence of AMR. Patients with C3d + DSA had significantly higher incidence of AMR compared with patients with no DSA (P < 0.001) or patients with C3d-DSA (P = 0.02). Nine (36%) of 25 patients with AMR developed transplant coronary artery disease compared with 17 (15.9%) of 107 patients without AMR (P < 0.05). Among the 47 patients who received ventricular assistant device (VAD), 7 of 9 VAD+ patients with preformed DSA experienced AMR compared with 7 of 38 VAD+ patients without preformed DSA, indicating presensitization to donor HLA significantly increased the risk of AMR (P < 0.01).
    Conclusions: Preformed and posttransplant ndDSA were associated with AMR. C3d + DSA correlates with complement deposition on the graft and higher risk of AMR which may permit the application of personalized immunotherapy targeting the complement pathway.
    MeSH term(s) Adolescent ; Adult ; Child ; Child, Preschool ; Complement Activation/immunology ; Complement C3d/analysis ; Complement C3d/immunology ; Female ; Graft Rejection/blood ; Graft Rejection/epidemiology ; Graft Rejection/immunology ; Graft Rejection/prevention & control ; Graft Survival/immunology ; HLA Antigens/immunology ; Heart Diseases/mortality ; Heart Diseases/surgery ; Heart Transplantation/adverse effects ; Heart-Assist Devices ; Histocompatibility Testing/methods ; Humans ; Incidence ; Infant ; Isoantibodies/blood ; Isoantibodies/immunology ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Tissue Donors ; Treatment Outcome ; Young Adult
    Chemical Substances HLA Antigens ; Isoantibodies ; Complement C3d (80295-45-0)
    Language English
    Publishing date 2018-06-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 208424-7
    ISSN 1534-6080 ; 0041-1337
    ISSN (online) 1534-6080
    ISSN 0041-1337
    DOI 10.1097/TP.0000000000002333
    Database MEDical Literature Analysis and Retrieval System OnLINE

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