Researchers from King’s College London have identified a surprising new therapeutic mechanism for a type of heart failure known as heart failure with preserved ejection fraction (HFpEF)—a condition affecting nearly half of all heart failure patients that has long eluded effective treatment. The study findings were published in the journal Science Advances.
The results indicate that urolithin A—a compound produced by gut bacteria when breaking down substances found in pomegranates, walnuts, and berries—can improve heart function in mice with a condition closely mimicking human HFpEF.
HFpEF is characterized by a stiffening of the heart, making it difficult for the organ to relax and fill with blood between beats, even though its pumping function remains normal.
Unlike other forms of heart failure, this condition has proven extremely difficult to treat; large-scale clinical trials of drugs targeting nitric oxide signaling pathways have largely failed to improve patient outcomes.
“Heart failure with preserved ejection fraction accounts for nearly half of all heart failure cases and is associated with significant morbidity and mortality,” stated Joseph Burgoyne of King’s College London and his colleagues.
This common condition is difficult to treat due to its complex pathophysiology, which is primarily characterized by diastolic dysfunction.
This dysfunction impairs ventricular relaxation and filling—often worsening during physical exertion—thereby highlighting the limited cardiovascular reserve, particularly in older adults. In a new study, Burgoyne and his colleagues focused on a protein called PKGIα, which plays a central role in the relaxation of the heart and blood vessels.
Previous work by the group showed that a specific part of the protein—a cysteine residue known as Cys42—can activate the protein when chemically modified.
After testing a range of natural plant compounds, the researchers discovered that urolithin A activates PKGIα through a previously unknown mechanism: it directly modifies the Cys42 site without triggering the formation of disulfide bonds, a process observed with related compounds like quercetin.
In mice with diet- and hormone-induced heart failure with preserved ejection fraction, a one-week treatment with urolithin A improved markers of diastolic heart function, reduced cardiac enlargement and fibrosis, and increased the animals’ physical activity.
These benefits were absent in genetically modified mice lacking a functional Cys42 site, confirming that the effect relies on this specific mechanism.
Urolithin A also improved contraction and relaxation rates in heart tissue grown from human stem cells, suggesting potential applicability to patients.
“This type of heart failure remains one of the most challenging forms of heart disease to treat,” said Burgoyne. “Our findings identify a completely new therapeutic target and show that urolithin A can activate this pathway to improve heart relaxation and reduce disease severity.”
This opens up exciting prospects for developing new treatments that could improve clinical outcomes and the quality of life for people suffering from this condition. While there is insufficient evidence to claim that people should consume pomegranates to treat heart failure, these results suggest that dietary approaches boosting urolithin A production could help alleviate the condition.
“Heart failure with preserved ejection fraction accounts for approximately half of all heart failure cases in the UK, and it can be extremely debilitating,” said Professor James Leiper, Associate Medical Director at the British Heart Foundation.
This early-stage study, conducted using experimental models, suggests that urolithin A may improve the ability of heart tissue to relax and fill with blood between beats, thereby reducing the harmful changes in the heart muscle associated with heart failure with preserved ejection fraction.
Scientists emphasize that while these results are promising, the benefits have so far been observed only in animals and engineered human tissues; therefore, clinical trials involving humans are needed to determine whether this approach is effective for patients.
Eating a healthy, balanced diet remains one of the best ways to take care of your heart.
Consuming sufficient amounts of fruits and vegetables is linked to better heart health, but it is important to remember that no single food can prevent or cure cardiovascular disease.
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