Seizure drug offers hope of expanding the pool of donor hearts

The moment a donor heart is cut off from its blood supply, transplant teams are on a race against the clock to remove it, transport it, and sew it into the recipient, all within four hours. A new way of reprogramming donor hearts could give them more time.

A study published Wednesday in Science Translational Medicine finds that when valproic acid, a medication to treat seizures, is infused in donor hearts, it could significantly extend — potentially double — the safe storage time of the organs.

If the findings are confirmed in further studies, this new method could expand the number of available donor hearts. Currently, the four-hour cap limits the geographic region from which a recipient can obtain a heart. Less than a third of potential donors are typically accepted for transplant.

The method could also improve outcomes for recipients. When a donor heart stays outside the body for a prolonged time, there’s an increased risk of primary graft dysfunction in the recipient, in which the heart can’t pump enough blood to the rest of the body. This condition accounts for nearly 40% of early deaths after heart transplants.

Looking at mouse, pig, and human hearts, the researchers found that valproic acid promotes the activity of a gene called IRG1, which produces a substance called itaconate that has anti-inflammatory and antioxidant effects. Itaconate also neutralizes the effects of succinate, a harmful molecule that accumulates on the heart while it’s in storage and creates a shock to the heart when it’s reconnected to a blood supply, according to the study.

Traditionally during heart transplants, “it’s been cold storage and just keeping the heart still,” said Paul Tang, senior author of the study and a heart transplant surgeon at University of Michigan Health. “This is the first time that we can understand preservation biology and be able to identify a specific pathway that we can intervene on.”

When looking at human hearts that were in storage for eight hours, the researchers found that the ones that received valproic acid had lower levels of succinate, the harmful molecule, as well as higher levels of itaconate, which neutralizes succinate.

The pig hearts infused with the medication had about 25% better function compared with control at four hours of storage and then 100% better function at 10 hours.

The researchers have filed a provisional patent and expect to ask the Food and Drug Administration for approval to run a clinical trial, Tang said.

Pedro Catarino, a heart transplant surgeon at Cedars-Sinai Medical Center unaffiliated with the study, said prolonging the storage time means transplant teams could not only travel farther to get donor hearts, but also loosen some standards for determining which hearts are acceptable for transplant. Currently, medical teams want hearts from younger people with fewer health problems because of the tight, four-hour cap, but if there’s a method to better preserve donor hearts, teams could consider hearts from older people.

More broadly, the findings could also have applications for other instances in which the heart is cut off from blood supply, such as during other types of heart surgery or when a patient experiences a heart attack, Catarino said. “Potentially, it’s really profound.”

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