From rejection to vasculopathy: a review of non-invasive biomarkers in alloimmune responses in heart transplantation.

Background: Heart transplantation is the gold standard treatment for end-stage heart failure. Despite immunosuppression as the cornerstone therapy for post-transplant management, the presence of immunological complications including acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV)-remain major barriers to long-term graft survival. Graft monitoring largely remains dependent on protocolized endomyocardial biopsy (EMBx), an invasive, risky procedure. Scope: This narrative review focuses on aggregating the published evidence, summarizing key clinical complications, and presenting the available tools to date. Furthermore, we discuss key limitations which must be addressed to improve patient care, including the need for non-invasive biomarkers in cardiac allograft vasculopathy. Key findings: Significant progress in the development and promising use of non-invasive biomarkers for the detection of graft rejection has emerged over the last decade; particularly for monitoring ACR and AMR. Donor-derived cell-free DNA and gene expression profiling of circulating immune cells have both emerged as promising tools to aide post-transplant management of graft health and reduce EMBx frequency. Soluble protein biomarkers-including hs-cTn, BNP, and NT-proBNP-provide supplementary information on graft stress and injury but lack specificity. In contrast, evidence supporting non-invasive biomarker use in CAV remains sparse. Conclusions: Non-invasive biomarkers have meaningfully advanced rejection surveillance in heart transplantation and hold promise for reducing procedural burden on patients. However, their role in detecting and monitoring CAV remains underdeveloped, and represents the most critical unmet need in the field.