Researchers have found a combination of biomarkers related to blood vessel and tissue injury that, when measured together, could signal when a transplanted heart is becoming damaged to the point of failure, a process that is often undetected. The markers would give doctors an opportunity to intervene and save a recipient's heart, and also provide a starting point for identifying long-term rejection biomarkers for several kinds of organ transplants.
The research team—led by Kevin P. Daly and David M. Briscoe, both at the Harvard Medical School department of pediatrics at Boston Children’s Hospital, and S. Ananth Karumanchi, Harvard Medical School associate professor of medicine at Beth Israel Deaconess Medical Center—published their findings online Dec. 26 in the Journal of Heart and Lung Transplantation.
The study, which was partly funded by the Harvard Catalyst | The Harvard Clinical and Translational Science Center, reflects a shift in the field of organ transplantation from short- to long-term rejection concerns, and from invasive to noninvasive methods for detecting chronic rejection early. In the 45 years since the first successful human heart transplant, concerns about short-term or acute organ rejection have largely been addressed by drugs like cyclosporine. However, long-term or chronic rejection—characterized by the loss of function in a transplanted organ over time—is becoming a larger issue, especially since transplant recipients are living longer now than ever before.
"All transplant patients eventually progress to chronic rejection," according to Briscoe, director of the hospital’s Transplant Research Program and a nephrologist with a long-standing interest in molecular monitoring for transplant rejection. "It's a slow process that evolves over years."
Cardiac allograft vasculopathy (CAV) is one of the main forms of chronic rejection in heart transplant patients. CAV results from continual injury to the transplanted organ's blood vessels by the recipient's immune system over time.
While both adult and pediatric heart transplant patients are monitored for signs of long-term rejection, the current test for CAV—annual screening via coronary angiography—is both invasive and risky. And by the time arterial damage is apparent on an angiograph, a patient may already be experiencing heart attacks without knowing it.
"Silent heart attacks are a major concern in long-term heart transplant recipients," Daly, a cardiologist in Boston Children's Heart Center, noted. "The transplanted heart doesn't develop new nerve connections, so the pain that would normally accompany a heart attack is absent in these patients. We want to be able to screen more frequently and intervene earlier, but to do that we need a less invasive test."
Briscoe and his colleagues took a translational approach to identifying biomarkers associated with CAV, 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.
The discovery, if validated in a larger population of patients, could be a boon for transplant recipients by allowing their care team to address rejection-related problems before the risk of graft loss becomes too high. "There are a number of medications available and in the pipeline to treat CAV and other forms of chronic rejection," said Briscoe. "The problem has been detecting disease early, when these drugs would be most effective."
The team also hopes to expand the findings beyond adult populations and heart transplant recipients. "We would like to see whether these markers or other markers could be useful in detecting chronic rejection in children, or in patients who have received other kinds of organs," Briscoe commented.
"At this time children who have had heart transplants are screened for rejection via biopsy," Daly added. "We need better, less invasive ways to monitor ongoing injury in transplanted children, and this is where studies like this could have the greatest benefit."
The study was supported by Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH grant UL1RR025758), the National Institute of Allergy and Infectious Diseases (grants 5U01AI063623, 5U01AI063594 and 3R01AI046756-10S1), the National Heart, Lung and Blood Institute (grant T32HL07572), the Eunice Kennedy Shriver National Institute of Child Health and Development (grant K12HD052896-06), the National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007726), the Boston Children’s Hospital Cardiac Transplant and Education Fund and the Howard Hughes Medical Institute.
Adapted from Boston Children's Hospital news release.