A team of researchers in the Department of Pediatrics at Boston Children’s Hospital and Beth Israel Deaconess Medical Center have discovered a set of biomarkers that could detect early signs of chronic heart transplant rejection — a process that is often undetectable until function of the heart has been irreversibly compromised. The team, led by Kevin P. Daly, MD, and David M. Briscoe, MD, of the Transplant Research Program (TRP) at Boston Children’s Hospital, and S. Ananth Karumanchi, MD, of Beth Israel Deaconess Medical Center, published their findings online in the Journal of Heart and Lung Transplantation.
The discovery of such short-term markers provides an opportunity to intervene upon a recipient’s transplanted heart before failure occurs. Short-term rejection has largely been ameliorated over the past 45 years, since the first heart transplant, due to the advent of immunosuppressants such as cyclosporine. However, long-term, chronic rejection is the major form of rejection nowadays as patients are living longer. What is key about this discovery is that short-term biomarkers may indicate early chronic rejection. Furthermore, it may lead to discoveries of long-term biomarkers to detect chronic rejection. According to Briscoe, director of the TRP and a nephrologist, “All transplant patients eventually progress to chronic rejection…It’s a slow process that evolves over years.”
According to the press release:
Briscoe and his colleagues took a translational approach to identifying biomarkers associated with CAV [Cardiac allograft vasculopathy, one of the main forms of chronic rejection in heart transplant patients], building on work by Karumanchi to profile the molecular ways in which blood vessels respond to injury. “As the damage to the transplant’s blood vessels increases, the endothelial cells lining those vessels release factors associated with vascular injury and repair,” Briscoe explained. “We thought that trends in the levels of those factors could serve as a way of detecting graft injury at the earliest possible stage in disease initiation.” To find out, the team measured the levels of 55 angiogenic proteins—factors that promote the growth and repair of blood vessels—in 33 adult heart transplant recipients, 17 with documented CAV and 16 without. All the patients were, on average, 12 years out from their transplant. Of the 55 proteins, three stood out as good candidate biomarkers for CAV: two forms of vascular endothelial growth factor (VEGF), which directly signal for blood vessel growth; and platelet factor 4 (PL4), which promotes clotting and is associated with wound repair. When measured together, levels of these three proteins were 98 percent accurate at differentiating patients with CAV from those without. For patients with mild CAV, only the two VEGF forms were required for accurate detection.
This study is further applicable in that if chronic rejection is detected early enough, medications could be used to prevent it, and the graft may not need to be removed or lost. Hence, these biomarkers may serve an important preventative as well as diagnostic purpose. This is certainly a revolutionary discovery that may have applications for both children and adults in the future. We are anxious to see how it is applied in clinical practice.
Original article in Journal of Heart and Lung Transplantation: VEGF-C, VEGF-A and related angiogenesis factors as biomarkers of allograft vasculopathy in cardiac transplant recipients
Boston Children’s Hospital’s press release: Biomarkers could give early warning of late heart transplant rejection