Clinical Pearl · Heart Transplantation

Heart Transplantation: Are Routine Biopsies Becoming a Thing of the Past?

For decades, the endomyocardial biopsy has been one of the necessary burdens of heart transplantation. Two blood-based approaches—gene expression profiling and donor-derived cell-free DNA—are increasingly allowing us to move toward molecular surveillance.

For decades, the endomyocardial biopsy (EMB) has been one of the necessary burdens of heart transplantation.

For patients: repeated invasive procedures. For transplant programs: cath-lab time, pathology, scheduling, cost—and procedural risk.

But technology is changing this paradigm. Two blood-based approaches are increasingly allowing us to move toward molecular surveillance:

• Gene Expression Profiling (GEP) asks: what is the recipient's immune system doing? • Donor-derived cell-free DNA (dd-cfDNA) asks: is the transplanted heart being injured?

When donor cells are injured, fragments of donor DNA enter the recipient's circulation—essentially providing a “liquid biopsy” of the transplanted heart.

The landmark IMAGE trial demonstrated that GEP-based surveillance could dramatically reduce routine biopsies in appropriately selected patients without compromising outcomes.

Now, DEFINE-HT takes the story further. This prospective multicenter study demonstrated that elevated dd-cfDNA identifies heart-transplant recipients at significantly greater risk for rejection, graft dysfunction and other adverse graft outcomes.

The biopsy isn't disappearing. When molecular signals are abnormal, graft dysfunction develops, or rejection is clinically suspected, tissue remains invaluable.

But the philosophy is changing:

Old paradigm: routine biopsy → look for rejection. Emerging paradigm: molecular surveillance → determine who actually needs a biopsy.

After decades of routinely putting a bioptome into transplanted hearts, we are increasingly reaching a point where a blood draw may tell us when we actually need to.

That is a major win for patients—and transplant programs.

Selected references: 1. IMAGE Trial — Pham MX, et al. N Engl J Med. 2010;362:1890–1900. 2. GRAfT Study — Agbor-Enoh S, et al. Circulation. 2021;143:1184–1197. 3. DEFINE-HT — Shah P, et al. JACC: Heart Failure. 2026;14:103152.

Educational purposes only.

#HeartTransplant #TransplantCardiology #ddcfDNA #CellFreeDNA #GeneExpressionProfiling #LiquidBiopsy #EndomyocardialBiopsy #HeartFailure #Rejection #PrecisionMedicine #Cardiology

Heart Transplant Surveillance: A New Era Beyond the Biopsy. From routine invasive procedures to molecular surveillance—blood-based testing is changing how we monitor for rejection. The traditional approach: endomyocardial biopsy (EMB) has been the standard for decades—repeated invasive procedures for patients, cath-lab time, scheduling and pathology resources, added cost, and small but real procedural risks (vascular complications, arrhythmias, tricuspid valve injury, perforation). The emerging paradigm: molecular surveillance to determine who actually needs a biopsy—less invasive for patients, more efficient use of transplant resources, targeted biopsies when needed, and potential for better detection of graft injury. Two complementary blood-based tools: Gene Expression Profiling (GEP) asks what the recipient's immune system is doing, evaluating patterns of gene expression in peripheral blood associated with immune activation and cellular rejection; Donor-Derived Cell-Free DNA (dd-cfDNA) asks whether the transplanted heart is being injured—when donor myocardial cells are injured, fragments of donor DNA enter the recipient's circulation, essentially a liquid biopsy of the transplanted heart. Key evidence: IMAGE Trial (2010), gene expression profiling—3.0 biopsies per patient-year reduced to 0.5, dramatically reducing routine biopsies in selected patients without compromising clinical outcomes (Pham MX, et al. N Engl J Med. 2010;362:1890–1900). GRAfT Study (2021), donor-derived cell-free DNA—AUROC 0.92 for acute rejection, negative predictive value 99.2% at 0.25% threshold, could have avoided 81% of surveillance biopsies after day 28, and dd-cfDNA elevations also preceded biopsy diagnosis (Agbor-Enoh S, et al. Circulation. 2021;143:1184–1197). DEFINE-HT (2026), donor-derived cell-free DNA—110 heart-transplant recipients at 10 U.S. centers, only 4.6% of EMBs showed rejection, about 90% of dd-cfDNA measurements were below threshold, and 4.42 times higher risk of rejection, graft dysfunction, retransplantation or death with elevated dd-cfDNA (Shah P, et al. JACC: Heart Failure. 2026;14:103152). The bigger picture: old paradigm—routine biopsy for everyone, look for rejection; emerging paradigm—molecular surveillance to determine who actually needs a biopsy. The biopsy isn't disappearing: when molecular signals are abnormal, graft dysfunction develops, or rejection is clinically suspected, tissue remains invaluable. Educational purposes only. Not medical advice.

Important notice

This content is for educational purposes only and is not medical advice for any individual patient. Patients should discuss diagnosis and treatment decisions with their own physician, or request a clinical consultation.