Plasma Extracellular Vesicle Profiles After Heart Transplantation are Associated With the Type of Allograft Rejection

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BACKGROUND: Heart transplantation (HT) remains the primary treatment for end-stage heart failure, but graft rejection-including acute cellular rejection (ACR), antibody-mediated rejection (AMR), and chronic rejection such as cardiac allograft vasculopathy (CAV)-significantly impacts long-term patient outcomes. This study investigates the role of circulating plasma extracellular vesicle profiles as potential biomarkers for distinguishing between different rejection types following HT. METHODS: We enrolled 85 HT patients with post-transplant follow-up ranging from 2 to 140 months. The cohort included patients diagnosed with AMR (n = 23), ACR (n = 11), CAV (n = 20), and those without rejection (R0, n = 31). Extracellular vesicle profiles were analyzed using the MACSPlex Exosome Kit, and associated cytokine profiles were assessed using the MILLIPLEX Human Cytokine Panel A. Statistical analysis involved the Kruskal Wallis test followed by Dunn's post-hoc test for multiple comparisons and discriminant analysis. RESULTS: Circulating plasma extracellular vesicle profiles demonstrated significant differences across post-transplantation time strata and varied according to the type of transplant rejection. During the first year post-HT, the main discriminant factors were extracellular vesicles (EVs) characterized by tetraspanins (CD9+, CD63+) and platelet markers (CD62P+, CD42a+). Five years post-transplantation, significant differences emerged in patients with AMR and ACR (both compared to each other and to the CAV/R0 groups). This difference corresponded with an increase in EV markers associated with immune cell activity (CD3+, CD4+, CD49e+, CD86+, CD20+, CD14+, CD209+, CD1c+, CD29+). Levels of prominent EV subpopulations correlated with IL‑22 in CAV patients, whereas in AMR patients, they correlated with IL‑17 and IL‑25. CONCLUSIONS: These findings support the hypothesis that extracellular vesicles may participate in both direct and indirect antigen presentation and in the regulation of immune responses leading to allograft rejection after HT. Plasma extracellular vesicle profiles hold promise as non-invasive biomarkers for monitoring and differentiating rejection types in heart transplant recipients.

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