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Valproic acid, an old seizure drug, sees new potential in preserving donor hearts

Surgeons have about four hours from the moment a heart is removed from the donor to transplanting the heart into a patient. After that, the chances that the heart will be fully functional begin to fall. This is why it’s not yet feasible to move donor hearts across a wide geographic area, as there’s too great of a risk that they won’t get to the patient in time. Organ donors are by definition already deceased.

In a study published Feb. 8 in Science Translational Medicine, a research team from the University of Michigan described how infusing valproic acid into human, mouse and pig hearts protected the tissue from metabolic processes that, in real-world scenarios, would otherwise have rendered them unfit for transplant. If replicated, the findings could help more patients survive heart failure by extending the viability of donor heart tissue.

“This is the first time it’s been shown that we can actually intervene on a key process in preservation biology,” Paul Tang, M.D., Ph.D., a heart transplant surgeon and senior author of the study, told Fierce Biotech Research in an interview.

Hearts for transplant have been preserved in basically the same way for the past 40 years. When a heart is removed from a donor, it’s put to “sleep” to prevent it from contracting. The transplant team packs it in a solution made up of electrolytes, glucose, antioxidants and buffer to maintain the pH, then puts on ice so it stays around 4 degrees Celsius until it’s time for surgery.

But though the heart may not beat, it’s still metabolically active. The cold and lack of oxygen can lead to the accumulation of the compound succinate, Tang explained, which has received attention in recent years for its potential to damage the heart. When the heart is implanted into the patient and blood flow is restored—a process called reperfusion—built-up succinate is oxidized to cause what Tang described as a “flash of oxidative stress”.

The longer the heart is stored, the more succinate builds up, and the bigger that flash will be. This can cause reperfusion injury or damage to the heart cells. “That really causes the heart to malfunction,” Tang said

To understand the mechanisms behind succinate accumulation, Tang’s team analyzed the metabolites present in the hearts of pigs, mice and humans, comparing “fresh” tissue to tissue that had been preserved the same way donor hearts would. They saw that succinate production was linked to the reduction of itaconate, an antioxidant that under normal conditions inhibits the enzyme responsible for succinate creation. In a cold environment without oxygen, the DNA winds up too tightly for the RNA transcriptional machinery to get in and express the gene that codes for the enzyme that produces itaconate, so levels fall. With nothing to stop the production of succinate, it builds up unchecked.

“We found that as succinate goes up, this protective compound itaconate actually goes down at the same time,” Tang explained.  One consequence of reperfusion injury is primary graft dysfunction, or PGD, a condition where the weakened heart can’t pump well enough to support a patient’s circulation. PGD happens in somewhere between 10 and 20 percent of heart transplant recipients and is the most common cause of death in the first few months after the procedure, according to the Mayo Clinic.

While the risk-benefit tradeoff is acceptable for patients who choose to undergo heart transplants, Tang’s team wanted to find a way to reduce the risk of PGD—and to preserve donor hearts for longer. To do that, researchers turned to valproic acid. First synthesized in 1882, it wasn’t until 1967 that France gave the drug the go-ahead to stop seizures and FDA followed in 1978.

Tang lab has now found that the drug loosened up the tightly-wound DNA in the preserved heart tissue, making room for transcription molecules to express the gene and protein that makes itaconate. With sufficient itaconate to disrupt succinate production, oxidative stress levels were reduced. This kept the hearts closer to their “fresh” state for longer.

Administering valproic acid to donor hearts requires no additional procedure, Tang said—the drug could simply be added to the reperfusion solution. His team is now filing a clinical trial application with the FDA. “We want this to be in clinical practice to help patients,” Tang said. “So that will be the next step.”

Meanwhile, the team is also planning more studies to learn how different heart cell types are affected by reperfusion injury and primary graft dysfunction. They’d also like to apply their findings to lungs, kidneys and more to improve the supply of those organs too.

“Our findings probably have a lot of implications for those organs as well as nontransplant heart surgery, like where we have to stop the heart to replace or repair a valve or perform bypass,” Tang said.

Ultimately, this research could be the first step towards more ambitious efforts to make transplant organs widely available, like organ banking, Tang added. It could even lay the foundation of developments that will someday enable humans to preserve themselves for journeys well beyond our home planet. “Maybe this is the basis for future cryostasis technology that allows us to travel astonishing distances in space, the kind of thing you see in sci-fi movies,” Tang said. “We’ve got to start somewhere.”