Background Gene expression profiling (GEP) and donor‐derived cell‐free DNA (dd‐cfDNA) are useful in acute rejection (AR) surveillance in orthotopic heart transplant (OHT) patients. We report a single‐center experience of combined GEP and dd‐cfDNA testing for AR surveillance. Methods GEP and dd‐cfDNA are tested together starting at 2 months post‐OHT. After 6 months, combined testing was obtained before scheduled endomyocardial biopsy (EMB), and EMB was canceled with a negative dd‐cfDNA. This approach was compared to using a GEP‐only approach, where EMB was canceled with a negative GEP. We evaluated for frequency of EMB cancellation with dd‐cfDNA usage. Results A total of 153 OHT patients over a 13‐month period underwent 495 combined GEP/dd‐cfDNA tests. 82.2% of dd‐cfDNA tests were below threshold. Above threshold results identified high‐risk patients who developed AR. 378 combined tests ≥6 months post‐OHT resulted in cancellation of 83.9% EMBs as opposed to 71.2% with GEP surveillance alone. There were 2 acute cellular and 2 antibody‐mediated rejection episodes, and no significant AR ≥6 months. Conclusion Routine dd‐cfDNA testing alongside GEP testing yielded a significant reduction in EMB volume by re‐classifying GEP (+) patients into a lower risk group, without reduction in AR detection. The addition of dd‐cfDNA identified patients at higher risk for AR.

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