Microvascular Thrombosis and Cardiac Allograft Vasculopathy in Rat Heart Transplantation

Labarrere, Carlos A.; Ortíz, Miguel A; Ruzmetov, Nargiz; Sosa, M.J.; Campaña, Gonzalo; Terry, Colin; Baldridge, Lee Ann; Antonopoulos, Roula; DiCarlo, Hector L.

doi:10.1016/j.healun.2006.06.013

Cited by 8 publications

(5 citation statements)

References 33 publications

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“…20,21 Thrombotic AV lesions affecting microvessels 21,22 and large-caliber vessels 23 are associated with worsened long-term graft outcomes. 24 Unexpectedly, we observed that several of our vessels subjected to IRI and then transplanted into animals with circulating human T cells developed thrombosis (Fig 6d).…”

Section: Discussionmentioning

confidence: 99%

Complement C5 Inhibition Reduces T Cell–Mediated Allograft Vasculopathy Caused by Both Alloantibody and Ischemia Reperfusion Injury in Humanized Mice

Qin

Kirkiles-Smith

et al. 2016

American Journal of Transplantation

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Allograft vasculopathy (AV) is characterized by diffuse stenoses in the vasculature of solid organ transplants. Previously, we developed two humanized models showing that alloantibody and ischemia reperfusion injury (IRI) exacerbated T cell-mediated AV in human arterial xenografts in vivo. Here we examined a causal role for terminal complement activation in both settings. IRI, in contrast to alloantibody, elicited widespread membrane attack complex (MAC) assembly throughout the vessel wall. Both alloantibody and IRI caused early (24 h) and robust endothelial cell (EC) activation localized to regions of intimal MAC deposition, indicated by increases in NF-κB inducing kinase, a MAC-dependent activator of non-canonical NF-kB, VCAM-1 expression, and Gr-1+ neutrophil infiltration. Endothelial cell activation by alloantibody was inhibited by anti- mouse C5 mAb, but not by anti-C5a mAb or by control mAb, implicating MAC as the primary target of anti-C5 mAb. Anti-mouse C5 mAb significantly reduced alloantibody- and IRI-enhanced T cell infiltration and AV-like changes including neointimal hyperplasia as well as intraluminal thrombosis in a subset of IRI-treated arterial grafts. These results indicate that increased AV lesion formation in response to either alloantibody or IRI are dependent on complement C5 activation and accordingly inhibition of this pathway may attenuate AV.

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Section: Discussionmentioning

confidence: 99%

Complement C5 Inhibition Reduces T Cell–Mediated Allograft Vasculopathy Caused by Both Alloantibody and Ischemia Reperfusion Injury in Humanized Mice

Qin

Kirkiles-Smith

et al. 2016

American Journal of Transplantation

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“…Infections have become one of the most common causes of death in post-transplant follow-up ( 43 ). The microvascular deposition of fibrin and capillary antithrombin binding in the later stages of HT leads to coronary thrombosis, coronary occlusion, and coronary stenosis as well as cardiac enlargement which jointly leads the graft failure is the leading cause of late death ( 44 , 45 , 63 , 64 ). And the risk of developing new solid malignancies in 1–5 years after transplantation is up to 10% ( 46 ).…”

Section: Therapeutic Nanomaterials Applied In Htmentioning

confidence: 99%

Application of nanomaterials in heart transplantation: a narrative review

Jiang,

Zhao,

2024

J Thorac Dis

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Background and Objective Heart transplantation (HT) is a therapeutic option for end-stage heart disease. Still, it faces many challenges, especially the shortage of donor sources and the poor durability of grafts, which are the two critical issues. In this review, we generalize the application of existing nanomedicine technologies in donor management as well as prevention and diagnosis of post-transplantation complications, also including the current preclinical studies of nanomaterials in cardiac tissue engineering and gene-editing xeno-donor grafts. Finally, we discuss the remaining problems and future directions of nanomaterials in the field of HT. Methods A narrative review using current search of the most recent literature on the topic. The terms “nanomaterials”, “nano medicine’’, “Heart transplantation (HT)”, “Nano-drug delivery system (NDDS)” or their combination were searched in PubMed and Google Scholar. The specified timeframe began from 1990, and we prioritized publications mainly from the last 10 years. Key Content and Findings Nano-systems integrating therapeutic and diagnostic functions have been applied to cardiovascular diseases (CVDs) with their unique advantages in multiple fields such as drug delivery, tissue engineering, gene editing, imaging, biomarker editing, and many other aspects. In terms of transplantation, the preservation, transportation, and pretreatment of donor hearts machine perfusion (MP) provide the possibility for nano-systems with unique features, and therapeutic and diagnostic functions to be directly and passively targeted in order to improve the functional status of the transplanted organs or to increase the ability to tolerate the graft of patients. The development of nano-imaging, nanosensor, and nano biomarker technologies are also being applied to monitor the status of transplant recipients for early prevention and treatment of post-transplantation-related complications. Nanomaterials combined with cardiac tissue engineering and gene editing technologies could also expand graft sources and alleviate donor shortages. Conclusions Although the overall research on nanomaterial applications in the field of HT is in its infancy, its role in improving the prognosis of transplant recipients and breaking the current dilemma of HT is clear. However, before nanotechnologies can be translated into clinical applications in the future, they must be aimed at ensuring the drug delivery system’s safety and pose a challenge in the direction of the ability to intervene with multiple drugs in combination.

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“…An animal experiment showed that the presence of fibrin or antithrombin reactivity in the coronary capillary was more pronounced in CAV. 6 Similarly, a study investigating coronary morphology by serial intravascular ultrasounds in 132 heart transplantation recipients suggested that frequent thrombosis in coronary arteries may lead to the progression of CAV. 12 Recently, emerging evidence illustrated that antiplatelet therapy might reduce the risk of CAV or attenuate its progression.…”

Section: Pathway Enrichment Analysismentioning

confidence: 99%

“…4 Although various risk factors, such as inflammation, thrombosis, endothelial dysfunction, and fibrosis have been demonstrated to be associated with CAV, the pathogenesis remains incompletely understood. [5][6][7][8][9][10][11][12] To date, the routine surveillance of CAV is via invasive diagnostic techniques. Non-invasive diagnostic biomarkers are scarce in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

The novel proteomic signature for cardiac allograft vasculopathy

Wei

Trenson

Keer³

et al. 2022

ESC Heart Failure

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Aims Cardiac allograft vasculopathy (CAV) is the major long-term complication after heart transplantation, leading to mortality and re-transplantation. As available non-invasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV. Methods and resultsWe measured urinary proteome by capillary electrophoresis coupled with mass spectrometry in 217 heart transplantation recipients (mean age: 55.0 ± 14.4 years; women: 23.5%), including 76 (35.0%) patients with CAV diagnosed by coronary angiography. We randomly and evenly grouped participants into the derivation cohort (n = 108, mean age: 56.4 ± 13.8 years; women: 22.2%; CAV: n = 38) and the validation cohort (n = 109, mean age: 56.4 ± 13.8 years; women: 24.8%, CAV: n = 38), stratified by CAV. Using the decision tree-based machine learning methods (extreme gradient boost), we constructed a proteomic signature for CAV discrimination in the derivation cohort and verified its performance in the validation cohort. The proteomic signature that consisted of 27 peptides yielded areas under the curve of 0.83 [95% confidence interval (CI): 0.75-0.91, P < 0.001] and 0.71 (95% CI: 0.60-0.81, P = 0.001) for CAV discrimination in the derivation and validation cohort, respectively. With the optimized threshold of 0.484, the sensitivity, specificity, and accuracy for CAV differentiation in the validation cohort were 68.4%, 73.2%, and 71.6%, respectively. With adjustment of potential clinical confounders, the signature was significantly associated with CAV [adjusted odds ratio: 1.31 (95% CI: 1.07-1.64) for per 0.1% increment in the predicted probability, P = 0.012]. Diagnostic accuracy significantly improved by adding the signature to the logistic model that already included multiple clinical risk factors, suggested by the integrated discrimination improvement of 9.1% (95% CI: 2.5-15.3, P = 0.005) and net reclassification improvement of 83.3% (95% CI: 46.7-119.5, P < 0.001). Of the 27 peptides, the majority were the fragments of collagen I (44.4%), collagen III (18.5%), collagen II (3.7%), collagen XI (3.7%), mucin-1 (3.7%), xylosyltransferase 1 (3.7%), and protocadherin-12 (3.7%). Pathway analysis performed in Reactome Pathway Database revealed that the multiple pathways involved by the signature were related to the pathogenesis of CAV, such as collagen turnover, platelet aggregation and coagulation, cell adhesion, and motility. Conclusions This pilot study identified and validated a urinary proteomic signature that provided a potential approach for the surveillance of CAV. These proteins might provide insights into CAV pathological processes and call for further investigation into personalized treatment targets.

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Microvascular Thrombosis and Cardiac Allograft Vasculopathy in Rat Heart Transplantation

Cited by 8 publications

References 33 publications

Complement C5 Inhibition Reduces T Cell–Mediated Allograft Vasculopathy Caused by Both Alloantibody and Ischemia Reperfusion Injury in Humanized Mice

Complement C5 Inhibition Reduces T Cell–Mediated Allograft Vasculopathy Caused by Both Alloantibody and Ischemia Reperfusion Injury in Humanized Mice

Application of nanomaterials in heart transplantation: a narrative review

The novel proteomic signature for cardiac allograft vasculopathy

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