Researchers at King’s College London have identified a surprising new therapeutic mechanism for a type of heart failure called heart failure with preserved ejection fraction (HFpEF), a condition that affects nearly half of all heart failure patients and has long resisted effective treatment. Their results show that urolithin A — a compound produced when gut bacteria break down substances found in pomegranates, walnuts, and berries — can improve heart function in mice with a condition designed to closely mimic human HFpEF.
Urolithin A is a metabolite compound produced when gut bacteria break down ellagitannins and ellagic acid, which are found in foods like pomegranates, berries, and walnuts. Image credit: Albrecht Fietz.
HFpEF is marked by a stiffened heart that struggles to relax and fill with blood between beats, even though its pumping strength remains normal.
Unlike other forms of heart failure, it has proven notoriously difficult to treat: major clinical trials of drugs targeting nitric oxide signaling pathways have largely failed to improve patient outcomes.
“HFpEF accounts for nearly half of all heart failure cases and is associated with substantial morbidity and mortality,” said Dr. Joseph Burgoyne of King’s College London and colleagues.
“This prevalent condition is challenging to treat due to its complex pathophysiology, which is predominantly characterized by diastolic dysfunction.”
“This dysfunction impairs ventricular relaxation and filling, often exacerbated during physical exertion, highlighting a limited cardiovascular reserve capacity, particularly in older individuals.”
In a new study, Dr. Burgoyne and co-authors focused on a protein called PKGIα, which plays a central role in heart and blood vessel relaxation.
Previous work by the group had shown that a specific site on the protein, a cysteine molecule called Cys42, can activate the protein when chemically modified.
Testing a panel of natural plant compounds, the researchers found that urolithin A activated PKGIα through a previously unrecognized mechanism, directly modifying the Cys42 site without triggering the disulfide bonding seen with related compounds like quercetin.
In mice with diet- and hormone-induced HFpEF, a week of urolithin A treatment improved measures of diastolic heart function, reduced heart enlargement and fibrosis, and increased the animals’ running activity.
These benefits disappeared in genetically modified mice lacking a functional Cys42 site, confirming the effect depended on this specific mechanism.
Urolithin A also improved contraction and relaxation speed in heart tissue grown from human stem cells, suggesting possible relevance to human patients.
“This type of heart failure remains one of the most challenging forms of heart disease to treat,” Dr. Burgoyne said.
“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.”