Extracorporeal Photopheresis in Heart Transplantation: Mechanisms, Clinical Integration, and the Experience of the Azienda Ospedaliera Universitaria Senese.

BACKGROUNDS: Extracorporeal photopheresis (ECP) is a promising immunomodulatory strategy for complex rejection in heart transplant (HTx) recipients. By combining leukapheresis, 8-methoxypsoralen photoactivation, and UVA irradiation, ECP induces leukocyte apoptosis and promotes immune tolerance through dendritic-cell modulation, regulatory T-cell expansion, and cytokine reprogramming. Clinical evidence supports its use in steroid-refractory acute cellular rejection (ACR) and selected antibody-mediated rejection (AMR). This study reviews the mechanistic rationale and clinical evidence for ECP and reports the real-world experience of the Azienda Ospedaliera Universitaria Senese (AOU Senese). METHODS: We retrospectively analyzed a single-centre cohort of 19 heart transplant recipients treated with extracorporeal photopheresis at AOU Senese between March 2010 and November 2024. Clinical, histological, immunological, echocardiographic, biomarker, immunosuppressive-treatment, and safety data were extracted at baseline and at dataset-defined 3-, 6-, 12-, and 24-month assessments. Analyses were descriptive and used variable-specific denominators because follow-up and laboratory data were incomplete at later time points. RESULTS: Biopsy data for cellular-mediated rejection (CMR) were available in 19 patients through 12 months and in 11 patients at 24 months. The proportion with ≥ 1R CMR decreased from 11/19 (57.9%) at baseline to 4/19 (21.1%) at 3 months, 3/19 (15.8%) at 6 months, 2/19 (10.5%) at 12 months, and 0/11 at 24 months. pAMR1 was present in 6/18 (33.3%) patients with available baseline AMR data, absent at 3 months, present in 1/19 (5.3%) at 6 months, and absent among patients with available biopsies at 12 and 24 months. In contrast, Class II DSA positivity did not show a consistent decline (12/19 [63.2%] at baseline and 8/10 [80.0%] at 24 months). Left ventricular systolic function remained broadly preserved among available observations, and corticosteroid dose decreased over time. Seven deaths occurred during the available overall follow-up, four of which were recorded as reasons for ECP discontinuation. CONCLUSIONS: In this small, retrospective, uncontrolled, and clinically heterogeneous cohort, ECP use was temporally associated with a lower biopsy-documented rejection burden and reduced corticosteroid exposure. The study does not establish a causal effect of ECP on rejection, antibody burden, or safety, and the antibody data do not support a uniform reduction in DSA. Prospective multicentre studies with standardized treatment protocols, assay definitions, and complete longitudinal follow-up are required.