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 Mechanical unloading is accompanied by reverse metabolic remodelling in the failing heart: Identification of a novel citraconate-mediated pathway published in the European Journal of Heart Failure 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. 

Using tissue from the Sydney Heart Bank, the world’s largest biobank of cryopreserved human heart tissue and The Alfred’s 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.

“Our study revealed that in failing hearts, several metabolic pathways – particularly those related to glucose uptake and mitochondrial energy generation – were significantly suppressed,” said lead author John O’Sullivan, Professor of Cardiometabolic Medicine, The University of Sydney, cardiologist at Royal Prince Alfred Hospital and Charles Perkins Centre member.

“However, after mechanical unloading with LVAD support, many of these pathways showed signs of recovery, including restored glucose metabolism.

“Crucially, our researchers identified a novel molecular pathway, the ACOD1–citraconate 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.

“Some patients supported with an LVAD regain heart function, while others don’t. Until now, we haven’t 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,” said Professor O’Sullivan.

While LVADs are typically used as a ‘bridge to transplant’, 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.

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.

“This 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?” said Professor O’Sullivan.

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.

Mechanical unloading is accompanied by reverse metabolic remodelling in the failing heart: Identification of a novel citraconate-mediated pathway, published in the European Journal of Heart Failure 4 June 2025 https://doi.org/10.1002/ejhf.3704

The research team comprises:

Professor David Kaye | Baker Heart and Diabetes Institute

Dr Xiao Suo Wang | Heart Research Institute

Dr Yen Chin Koay | University of Sydney

Mengbo Li | 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 Bing Wang | Baker Heart and Diabetes Institute

Associate Professor Sean Lal | University of Sydney

Giovanni Guglielmi | University of Sydney

Professor John O'Sullivan | University of Sydney