Re-tuning the heart's furnace to rescue heart failure

Professor John O'Sullivan, University of Sydney

Future Leader Fellowship

Years funded: 2026 - 2029

Heart Failure with preserved Ejection Fraction (HFpEF), a type of heart failure where the heart can still contract but is too stiff to relax properly, is now the most common form of heart failure. 1 in 10 people aged 40 will develop this disease in their lifetime; it has a 5-year mortality of 75%, an average survival after diagnosis of 2.1 years, similar to many cancers. Cardiometabolic HFpEF is an aggressive, recalcitrant subtype that presents at a younger age with worse outcomes. It is driven by obesity and metabolic disease (high blood pressure, abnormal glucose, deranged lipids), with an urgent need for effective therapies. Here, "cardiometabolic" refers to fuel generation and consumption in the heart. Metabolites are fuel molecules. In heart failure, these metabolites can miscue and cause inflammation ("meta-inflammation"). It has become apparent that meta-inflammation is the key mechanistic process in cardiometabolic HFpEF that leads to a series of changes that stiffens the heart. However, the key targets to reverse this process remain elusive. Excitingly, we have recently discovered three distinct, yet related, metainflammatory pathways in cardiometabolic HFpEF. All three pathways involve fuel molecules that miscue and provoke inflammation, ultimately starting a cascade that stiffens the heart. In this program of research, we will use heart tissue and cells from patients with cardiometabolic HFpEF, along with our clinically-representative models. We will modify genes, test candidate fuel molecules, and analyse proprietary drugs. Crucially, our pathways enable EARLY modification of the cascade before irreversible stiffening occurs. Each pathway is a separate, yet related, project in our program of work. The first, I have translated as Lead PI to two first-in-man clinical trials: CardioNAD and pEFNAD. The second involves an enzyme at the nexus of fat and ketone metabolism, which we modified to increase energy, and prevent toxic fat accumulation, in the heart. The third involves a molecule released from inflammatory cells invading the heart. This program will have major impact – HFpEF is the greatest unmet need in cardiovascular medicine. We have established a national clinical trial network in HFpEF. We will work with our international HFpEF networks, international guideline developers, policymakers, pharma partners, patients, and consumers to maximise impact and disseminate findings. We have established a national Heart Failure Alliance of specialists, patients, advocates, and consumers. We have longstanding partnerships with Heart Support Australia and hearts4heart with whom we co-design our projects and further disseminate our findings.