The impact of angiotensin II type 1 receptor antibodies on post-heart transplantation outcome in Heart Mate II bridged recipients

Urban, Marian; Slavčev, Antonij; Gazdic, T.; Ivák, Peter; Bešík, Josef; Netuka, Ivan

doi:10.1093/icvts/ivv344

Cited by 30 publications

(28 citation statements)

References 23 publications

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“…A recent study found that VAD implantation was not associated with sensitization to MICA [2]. On the other hand, patients bridged with LVAD appeared to have higher titers of anti-AT1R antibodies compared to unsupported patients [18] although this increase did not portend reduced graft survival. In the present study, VAD was associated with poorer outcomes (Table S3).…”

Section: Discussionmentioning

confidence: 99%

“…Our results support the view of a broad B cell activation rather than stimulation through exposure to distinctive antigens. We propose that the humoral response induced by VAD support is a consequence of a systemic immune activation that leads to the generation of anti-HLA and non-HLA IgG including IgG Nabs along with anti-AT1R [18], - albumin [29], -phospholipids [30] and clinically irrelevant antibodies binding to HLA-coated beads [31]. In addition, the biomaterials used in the implanted devices are known to activate endothelial, coagulation and fibrinolytic pathways [32] and could plausibly contribute to sensitization in such a non-antigen specific manner [33].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation

See

Clerkin

Kennel

et al. 2017

The Journal of Heart and Lung Transplantation

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Background Pre-transplant sensitization is a limiting factor in solid organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed the generation of Nabs following VAD implantation in pre-transplant sera and examined their contribution to the cardiac allograft outcome. Methods IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant (OHT) recipients, including 128 VAD and 78 no-VAD patients. Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by ELISA. Results No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared to no-VAD patients. This increase was likely due to presence of VAD, as revealed by lower serum IgG Nabs levels before implantation. Lastly, elevated pre-transplant IgG Nabs level was associated with the development of primary graft dysfunction in this patient series. Conclusions Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support the idea of a broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with the development of primary graft dysfunction suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation

See

Clerkin

Kennel

et al. 2017

The Journal of Heart and Lung Transplantation

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“…Non‐HLA antibodies such as antibodies against AT1R, vimentin, myosin, and other endothelial cell (EC) antigens are prevalent among ventricular assist device (VAD) patients . Anti‐AT1R antibodies are known to initiate coagulation and inflammatory responses independent of the complement cascade .…”

Section: Introductionmentioning

confidence: 99%

“…Anti‐AT1R antibodies are known to initiate coagulation and inflammatory responses independent of the complement cascade . There are conflicting reports about whether anti‐AT1R and EC antibodies play a role in cardiac allograft survival …”

Section: Introductionmentioning

confidence: 99%

Hyperacute graft dysfunction in an orthotopic heart transplant in the presence of non-HLA antibodies

Villa

Mesa

Smith

et al. 2020

American Journal of Transplantation

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Antibody‐mediated rejection (AMR) in heart transplants in the absence of anti‐HLA donor‐specific antibody (DSA) is not well studied or documented. This case reviews hyperacute fulminant graft dysfunction suspected to be mediated by non‐HLA antibodies. After cross clamp removal, the patient developed severe pulmonary edema, profound coagulopathy, and biventricular failure. The patient's presumed AMR, cardiogenic shock, and coagulopathy were treated with extracorporeal membrane oxygenation (ECMO), plasmapheresis, intravenous immunoglobulin (IVIG), multiple blood products, and prothrombin complex concentrate. The recipient was 0% panel‐reactive antibody (PRA), ABO, and crossmatch compatible. Intraoperative biopsy sample revealed a thrombotic process suggestive of a coagulation pathway activated by AMR; however, no C4d deposition was detected. Postmortem biopsies also suggested AMR. Retrospective testing of the patient's pretransplant serum revealed strong antiangiotensin II type 1 receptor (AT1R) antibodies and a strongly positive endothelial cell crossmatch. Anti‐AT1R antibodies are known to be AT1 receptor agonists and may trigger inflammation and activate the extrinsic coagulation pathway. Given the potential effects of signaling through the AT1R, the patient's preexisting anti‐AT1R antibodies and procoagulant therapy may have adversely affected the patient's clinical course.

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“…Over 60% of heart transplant candidates who were AT1R negative prior to LVAD implantation developed de novo AT1R antibodies after the procedure independent of blood product usage 57 . Development of AT1R antibodies post-LVAD did not impact incidence of rejection or transplant survival.…”

Section: Introductionmentioning

confidence: 99%

The importance of non-HLA antibodies in transplantation

2016

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The development of post-transplant antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, recent studies provide compelling experimental and clinical findings demonstrating that antibodies directed against autoantigens contribute to the process of antibody-mediated acute and chronic rejection. Important areas for investigation remain understanding the mechanisms underlying the production of autoantibodies in the setting of organ transplantation. Ischaemia-reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens in the form of soluble antigens, extracellular vesicles or apoptotic bodies that are presented in context of the transplant recipient’s antigen presenting cells to stimulate autoantibody production. Th17 cells are essential in the orchestrating autoantibody production by supporting the proliferation and maturation of autoreactive B cells within ectopic tertiary lymphoid tissue. Conversely, autoantibody-mediated graft damage can trigger alloimmunity and the development of donor-specific HLA antibodies that can act in synergy to promoteallograft rejection. Identification of the immunologic phenotypes of transplant recipients at risk of non-HLA antibody-mediated rejection and the development of targeted therapies to treat these rejections are sorely needed to improve both transplant and patient survival.

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The impact of angiotensin II type 1 receptor antibodies on post-heart transplantation outcome in Heart Mate II bridged recipients

Cited by 30 publications

References 23 publications

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation

Hyperacute graft dysfunction in an orthotopic heart transplant in the presence of non-HLA antibodies

The importance of non-HLA antibodies in transplantation

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