In 2021, more than 3,000 patients received a heart transplant in the United States and an additional 3,500 patients were awaiting transplantation. Expansion of the donor pool from a variety of factors has led to an increase in the number of heart transplants today compared to a decade ago. However, acute rejection, including acute cellular and antibody-mediated, continues to be a major source of morbidity and death among heart transplant recipients.
Donor-derived cell-free DNA (dd-cfDNA) is an approved and effective noninvasive biomarker for renal allograft injury, but it has not gained widespread acceptance in heart transplantation for rejection surveillance. In this patient population, endomyocardial biopsy remains the gold standard for rejection monitoring. However, early data from single center studies showed that elevated dd-cfDNA levels could detect acute rejection after heart transplantation prior to detection by endomyocardial biopsy.
Timothy Gong, MD, FACC, Assistant Medical Director, Advanced Heart Failure Outreach, Baylor University Medical Center (Baylor Dallas), part of Baylor Scott & White Health, and Amit Alam, MD, advanced heart failure cardiologist on the medical staff at Baylor Dallas, have received grants from the American Society of Transplantation for studies to further understanding of the use and accuracy of dd-cfDNA as a rejection surveillance method.
Variability of dd-cfDNA after heart transplant
The first study will investigate the variability of dd-cfDNA after heart transplantation and the relationship with cardiac allograft vasculopathy. To achieve this, the research team will evaluate a simple blood test that uses a proprietary dd-cfDNA technology. The favorable results that this test has achieved in the kidney transplant arena appear to hold promise for cardiac transplant as well.
To establish this test as a surveillance tool in heart transplant, clinical performance in terms of specificity and sensitivity will be determined by the data obtained from the study. In addition, comparing the test results not only in the context of biopsy results but also intravascular ultrasound, will provide valuable insight in the potential of this test in the setting of cardiac allograft vasculopathy.
“We hypothesize that this test, which utilizes a single nucleotide polymorphism-based massively multiplexed PCR methodology to estimate dd-cfDNA fraction, could transform cardiac transplant management, enabling a simpler, less invasive, and less variable method for detection of cardiac transplant rejection,” Dr. Gong says. “This would present a key strategy in improving heart transplant management and clinical outcomes.”
Impact of virus infection on dd-cfDNA after heart transplant
Multiple trials have shown that elevated levels of dd-cfDNA almost always indicate rejection of the heart allograft. Based on how high the values are, the acuity of the rejection can be categorized as mild, moderate or severe. However, some patients show elevated dd-cfDNA without clinical evidence of rejection. The second study conducted by the Baylor Scott & White research team will investigate the impact of viral infection on dd-cfDNA levels after heart transplantation.
“While elevated levels of donor-derived, cell-free DNA are a strong indicator of acute rejection, there are other disease phenomena that can produce these same elevated levels,” Dr. Alam says. “The reason for our study is that there are data from trials and the transplant literature that indicates cell-free DNA may be elevated as a result of viral infection, such as influenza or SARS-CoV-2. However, there are no studies to date that correlate elevated dd-cfDNA with viral infections. The results of this study could help determine treatment of viral infections in heart transplant recipients without assuming the need to move to the next step of an invasive biopsy.”