How the failing heart recovers energy supply after mechanical support
A world-first study in end-stage heart failure patients reveals how mechanical support helps the failing heart restore energy use. This breakthrough offers clues to better treatments for advanced heart failure. The team of collaborative researchers includes experts from the University of Sydney, Royal Prince Alfred Hospital and Baker Heart and Diabetes Institute.
The study听听published in the provides new insights into the energy metabolism of the heart under mechanical unloading and identifies a novel inflammation-linked pathway that could open new doors for therapeutic intervention.听
Using tissue from the , the world鈥檚 largest biobank of cryopreserved human heart tissue and 鈥檚 transcardiac sampling program, the team examined myocardial and plasma-gradient samples from heart failure patients before and after support with a left ventricular assist device (LVAD), a mechanical pump used in end-stage heart failure to take over the pumping function of the heart.
鈥淥ur study revealed that in failing hearts, several metabolic pathways 鈥� particularly those related to glucose uptake and mitochondrial energy generation 鈥� were significantly suppressed,鈥� said lead author John O鈥橲ullivan, Professor of Cardiometabolic Medicine, The University of Sydney, cardiologist at Royal Prince Alfred Hospital and Charles Perkins Centre member.
鈥淗owever, after mechanical unloading with LVAD support, many of these pathways showed signs of recovery, including restored glucose metabolism.
鈥淐rucially, our researchers identified a novel molecular pathway, the ACOD1鈥揷itraconate pathway, which appears to link inflammation and energy production in the recovering heart. Succinate accumulation is a metabolic hallmark of heart failure, and our data suggests the citraconate pathway underpins this longstanding observation. This citraconate-mediated mechanism may be a key factor influencing the capacity of the failing heart to recover metabolic function.
Citraconate rescues TCA cycle and reduces succinate accumulation, a hallmark of heart failure
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鈥淪ome patients supported with an LVAD regain heart function, while others don鈥檛. Until now, we haven鈥檛 fully understood why. Our study offers a first window into the bioenergetic changes that occur during mechanical unloading, and the metabolic signatures associated with recovery,鈥� said Professor O鈥橲ullivan.
While LVADs are typically used as a 鈥榖ridge to transplant鈥�, this work contributes to a growing body of evidence suggesting a potential recovery of the heart with LVAD, and crucially the underlying mechanisms by which this occurs.
Professor John O'Sullivan
The newly-identified citraconate pathway represents a promising therapeutic target. As an intermediary at the crossroads of inflammatory signalling and metabolic regulation, modulating this pathway could support metabolic recovery and ultimately improve outcomes in patients with advanced heart failure, especially following myocardial infarction or other cardiac injury.
鈥淭his reframes our understanding of human heart energy recovery. It also helps resolve a long-standing clinical question: how do inflammation and impaired energy production interact in the failing heart?鈥� said Professor O鈥橲ullivan.
The work provides foundational insights with potential implications for precision therapies that target metabolic and inflammatory pathways in heart failure. While further investigation is needed, the findings mark an important step toward personalised recovery strategies and metabolic support in advanced cardiac care.
, published in the 4 June 2025听
The research team comprises:
Professor | Baker Heart and Diabetes Institute
Dr | Heart Research Institute
Dr Yen Chin Koay | University of Sydney
| Walter and Eliza Hall Institute of Medical Research
Bailey McIntosh | University of Sydney
Yann Huey Ng | University of Sydney
Michael Rahman | University of Sydney
Yiyang Cao | University of Sydney
Francine Z Marques | Baker Heart and Diabetes Institute
Cassandra Malecki | University of Sydney
Dr Shane Nanayakkara | Baker Heart and Diabetes Institute
Associate Professor Justin Mariani | Baker Heart and Diabetes Institute
Associate Professor | Baker Heart and Diabetes Institute
Associate Professor Sean Lal | University of Sydney
Giovanni Guglielmi | University of Sydney
Professor John O'Sullivan | University of Sydney