Four hours is the maximum time that a heart can survive outside of the donor’s body before the round transplant. From this period the chances are that it will not work well.
Now, researchers at the University of Michigan have used a drug, approved for the treatment of seizures, bipolar disorder and for the prevention of migraine headaches, to reprogram donor hearts by boosting the production of a beneficial enzyme that increases both how long they can be stored and transported how to improve their performance once transplanted. The results are published in “Science Translational Medicine.”
‘This technology, which induces donor hearts to mount adaptive responses to their life outside the body, could be a paradigm shift not only in prolonging the time a heart can be outside the donor during transport, but also in improve their function after transplantation,” says Paul C. Tang, lead author of the study and a heart transplant surgeon at the University of Michigan. “Being able to prolong storage of hearts by uncovering the pathways that define and modulate preservation biology is the first step toward the ultimate goal of organ storage.”
In about 10-20% of heart transplants, the transplanted hearts are unable to pump enough blood to supply the rest of the body. This disorder, known as primary graft dysfunction, is responsible for nearly 40% of premature deaths after heart transplantation and may still occur predictably despite new mechanical cardiac perfusion technology.
The investigators tried to reduce primary graft dysfunction by increasing itaconate production, an anti-inflammatory and antioxidant metabolite produced by the enzyme Irg1. Itaconate neutralizes the effects of succinate, a harmful molecule that accumulates while a heart is on ice and creates a flash of oxidative stress upon blood reperfusion causing the heart to malfunction.
“Current donor preservation techniques focus on cold storage and, more recently, technologies that maintain perfused organs during transport to minimize injury to the heart, but there are no specific molecular therapies to improve heart preservation. very precisely,” says Ienglam Lei, first author of the study.
When an organ is stored cold, succinate can build up in excess, providing more ammunition against the heart to be transplanted. In order to reprogram hearts to assimilate the heart-damaging succinate, the researchers used acid valproic, a histone deacetylase inhibitor formerly used as an anti-seizure medication. They found that it deactivated a significant amount of this cumulative stress in both human and porcine hearts by instructing the donor heart to produce antioxidant and anti-inflammatory proteins while it was stored on ice.
“Through metabolomic analysis, we found that valproic acid can reprogram the donor heart to produce beneficial itaconate during storage,” Tang explains. “We previously showed that hearts are biologically highly active while on ice, opening up the therapeutic opportunity to help protect them from metabolic stress during this time. This could not only double the time a heart spends in cold storage, but could reduce the risk of primary graft dysfunction to make transplantation even safer.”
Valproic acid is approved to treat seizures, bipolar disorder, and for the prevention of migraine headaches. Therefore, the researchers believe that the path to a clinical trial may be shorter.
This could not only double the time a heart spends in cold storage, but also reduce the risk of primary graft dysfunction.
“This discovery will buy time for a heart donor to reach patients in previously inaccessible parts of the country, which will have a major impact on the organ transplant landscape,” said study co-author Eugene Chen.
In addition, he adds, it is possible that the “general principles set forth herein apply to the preservation of other organs, such as lungs, livers, and kidneys.”