Key points:
- Primary draft dysfunction causes nearly 40% of early deaths after heart transplant.
- Researchers used valproic acid, an anti-seizure medication, to reprogram donor hearts to reduce the likelihood of primary draft dysfunction.
- The treatment strategy could allow a donor heart to reach patients in parts of the country not previously accessible.
Using a drug previously used to treat seizures, researchers have found a way to reprogram donor hearts to boost the production of a beneficial enzyme that both increases the amount of time they can be stored and transported, as well as improves their function after they are transplanted.
In around 10-20% of heart transplants, transplanted hearts cannot pump sufficient blood to supply to the rest of the body. The condition, known as primary graft dysfunction, is responsible for nearly 40% of early deaths after heart transplant. The longer it takes for a heart transplant to be transported to the recipient, the higher the chance of failure.
For the study, published in Science Translational Medicine, researchers focused on reducing primary graft dysfunction by increasing the production of itaconate, 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 following blood reperfusion that causes the heart to malfunction.
When an organ is in cold storage, succinate is free to build up in excess—the longer the storage, the more buildup to cause stress on the soon-to-be-transplanted heart.
To reprogram donated hearts to take on the heart-damaging succinate, the researchers used valproic acid, a histone deacetylase inhibitor previously used as an anti-seizure medication. Results showed that it defused the cumulative stress in human and pig hearts by instructing the donor heart to produce antioxidants and anti-inflammatory proteins while preserved on ice.
“We showed previously that hearts are biologically very active while stored on ice, which opens up the therapeutic opportunity to help it protect itself from metabolic stress during this time. Not only could this possibly double the time a heart could spend in cold storage, but it could reduce the risk of primary graft dysfunction to make transplant even safer,” said Paul Tang, M.D., senior author of the study and a heart transplant surgeon at University of Michigan Health.
Additionally, since valproic acid is already approved by the FDA to treat seizures, bipolar disorder and migraine headaches, the road to a future clinical trial may be easier and/or shorter.
“This discovery will buy time to allow a donor heart to reach patients in parts of the country not previously accessible—greatly impacting the landscape of organ transplant in America,” said Y. Eugene Chen, M.D., co-author of the study and professor of cardiovascular medicine at U-M Medical School.
The researchers believe the study findings should apply to the preservation of other organs as well, including lungs, livers and kidneys. The treatment strategy may also be relevant for other conditions where blood supply is disrupted, such as heart attack or stroke.