# Noninvasive Biomarkers for Cardiac Allograft Rejection Monitoring: Advances, Challenges, and Future Directions

## TL;DR

This paper reviews noninvasive blood-based biomarkers for detecting heart transplant rejection, highlighting molecular tools like ddcfDNA and GEP.

## Contribution

The paper synthesizes current evidence and challenges of molecular biomarkers for cardiac allograft rejection monitoring.

## Key findings

- Donor-derived cell-free DNA and gene expression profiling are effective for detecting acute rejection.
- MicroRNAs and extracellular vesicles show promise but require further validation.
- Traditional biomarkers like BNP and troponins lack specificity for rejection.

## Abstract

Cardiac transplantation remains an important therapy for end-stage heart failure, although allograft rejection continues to pose significant clinical challenges. This review evaluates both established and emerging blood-based biomarkers for noninvasive monitoring of rejection in heart transplant recipients. Donor-derived cell-free DNA (ddcfDNA) and gene expression profiling (GEP) represent well-validated, commercially available molecular tools that demonstrate strong discriminative capacity for acute rejection episodes. Additionally, microRNAs (miRs) and extracellular vesicles (EVs) show considerable potential as novel biomarkers, although further validation is required. In contrast, conventional biomarkers such as B-type natriuretic peptide (BNP), cardiac troponins, and creatine kinase-MB (CK-MB) offer limited specificity in the context of rejection. This review synthesizes current evidence on the clinical utility, methodological challenges, and integration strategies of these biomarkers, highlighting a shift toward molecular-based approaches for improving post-transplant surveillance and patient outcomes.