ProfessorJohn O'Sullivan

Professor O’Sullivan’s work centres on heart failure with preserved ejection fraction (HFpEF), and on the principle that it is not a single disease but a set of mechanism-defined endotypes, each with its own biology and its own therapeutic lever.

Clinical phenotyping and management

• Deep phenotyping of heart failure, particularly HFpEF, and the classification of patients by mechanism rather than by syndrome
• Invasive and exercise haemodynamics, and their integration with molecular profiling
• The diagnostic grey zone of the HFA-PEFF and H₂FPEF scores, and how to resolve it
• Exercise as both a diagnostic stressor and a therapeutic hormetic intervention in HFpEF

Mechanism

• Cardiac metabolism in heart failure, including NAD+ biology and the sirtuin axis
• Endogenous cardiac ketogenesis and the HMGCS2 pathway, and whether the provenance of ketones matters therapeutically
• Immunometabolism in the failing heart, particularly the citraconate-ACOD1-itaconate axis linking chronic inflammation to energetic depletion
• Living human myocardium as an experimental system, including tissue slices, wedge preparations and biopsy-derived models
• Developmental programming of the heart, and the influence of maternal diet on cardiac development in utero
• Diet, the gut microbiome and the circulating metabolome as determinants of cardiovascular risk

Platforms and methods

• Translational multi-omics, with an emphasis on mass spectrometry-based metabolomics and lipidomics
• Drug and active metabolite monitoring, and its application to adherence, polypharmacy and precision dosing
• Machine learning applied to cardiac imaging, including detection of HFpEF from raw echocardiographic data
• Advanced cardiac imaging and imaging-genomics, including cardiac MRI radiomics at population scale

Translation

• • Investigator-initiated clinical trials arising directly from laboratory discovery
  • Biomarker and diagnostic assay development, and the regulatory pathway through the US Food and Drug Administration, the Therapeutic Goods Administration and the European Medicines Agency
  • Cardiometabolic risk stratification and prevention, including the role of novel biomarkers in population risk assessment