ProfessorJohn O'Sullivan

PROJECT 1
Repleting the enzymatic cofactor NAD+ in heart failure: rescuing an engine out of fuel
Recent publications: Circulation Research; JACC: Basic to Translational Science (x2); Cardiovascular Research (x2).

This program has three arms.

Two clinical trials, with Professor O’Sullivan as Lead Principal Investigator, investigating the mechanistic role and therapeutic efficacy of the NAD+ precursor nicotinamide riboside (NR). CardioNAD examines whether NR can replenish myocardial NAD+ in HFpEF myocardium, with Professor Paul Bannon, Head of Cardiothoracic Surgery at Royal Prince Alfred Hospital and Chair of Surgery at the University of Sydney, and Professor Sean Lal, Clinical-Academic Cardiologist at RPAH and the University of Sydney and Director of the Sydney Heart Bank. pEF-NAD runs under the Stiff Heart Failure Alliance across Blacktown, Concord, Westmead and Liverpool Hospitals, and with Professor David Kaye at the Alfred Hospital, Melbourne.

Testing NR-derived NAD+ repletion in model systems, human HFpEF myocardium and primary cardiomyocytes.

Measuring transcardiac gradients of the NAD+ metabolome in heart failure and their relationship to invasive exercise haemodynamics, using Professor Kaye’s phenotyping methodology. Transcardiac gradient protocols are also established in Sydney in failing and non-failing hearts with A/Prof Kim Chan at RPAH, Strathfield Private and Mater Private Hospitals.

Suitable for a PhD or Honours student with a background in metabolism, pharmacology or clinical research.

PROJECT 2
Targeting rescue ketogenesis in heart failure
Recent publications: European Heart Journal; Circulation Research; Cardiovascular Research; JACC: Basic to Translational Science.

We recently showed, for the first time, that human and mammalian hearts generate their own ketones at physiologically relevant levels, and that this process is dramatically upregulated under the combination of stresses seen in HFpEF myocardium.

Led by Dr Yen Chin Koay, National Heart Foundation Future Leader Fellow, this work uses two new conditional, cardiomyocyte-specific genetic models of HMGCS2, the canonical ketogenic enzyme: a knockdown line and a transgenic overexpressing line. We will also compare this approach with exogenously delivered ketone ester, to determine whether the provenance of ketones matters in rescuing heart failure.

Suitable for a PhD student with a background in molecular biology, physiology or biochemistry.

PROJECT 3
Targeting the citraconate-ACOD1-itaconate metainflammatory pathway in heart failure
Recent publications: European Journal of Heart Failure; Cardiovascular Research.

Led by postdoctoral fellows Dr Yann Huey Ng and Dr Abhi Sharma, this project uses ex vivo beating human myocardial tissue slices, in partnership with Professor Paul Bannon, Professor Sean Lal and the Sydney Heart Bank, the world’s largest biobank of cryopreserved human heart samples, and Professor David Kaye, Head of Cardiology at the Alfred Hospital and Group Leader of the Heart Failure Research Group at the Baker Institute.

International collaborators are Professor Luke O’Neill at Trinity College Dublin, Professor Frank Pessler at the Helmholtz Centre for Infection Research, and Professor Michael Murphy at the University of Cambridge.

With Professor Kaye we recently discovered a pathway in the hearts of patients recovering with left ventricular assist device support, connecting chronic inflammation to energetic depletion in heart failure. We are now interrogating it using preclinical genetic models, patient heart biopsies, ex vivo beating human tissue and primary human cardiac cells, paired with novel formulations of itaconate and citraconate. The statewide HFpEF clinic at RPAH and our national network provide the route to the clinic.

Suitable for a PhD or Honours student with a background in immunology, immunometabolism or cell biology.

PROJECT 4
pEF-EX: a double-blind randomised controlled trial of exercise intervention in HFpEF
Recent publications: European Journal of Heart Failure; JACC: Asia.

Led by Dr Yas Kamaladasa, this trial tests a combined endurance and resistance program in HFpEF. Outcomes are measured by cardiopulmonary exercise testing at the Charles Perkins Centre, exercise right heart catheterisation in the Department of Cardiology at RPAH, skeletal muscle biopsy for immunohistochemistry and mitochondrial respiration with Dr Mathew Parker at RPAH, exercise echocardiography at Central Sydney Cardiology, and multi-omics in the O’Sullivan laboratory.

Suitable for a PhD or Honours student with a background in exercise physiology, clinical trials or integrative physiology.

PROJECT 5
The role of maternal diet in cardiac development in utero

Led by Dr Yen Chin Koay, National Heart Foundation Future Leader Fellow, in collaboration with Professor Fatima Crispi at the University of Barcelona. We have shown that maternal diets high in sucrose produce male offspring with larger hearts, and identified the transcriptional regulator in one-carbon metabolism responsible.

Professor Crispi’s group has demonstrated that Mediterranean dietary intervention from 20 weeks gestation prevents intrauterine growth restriction. We are now determining which maternal dietary components are harmful and which protective for fetal cardiac development, and the molecular mechanisms involved.

Suitable for a PhD student with a background in developmental biology, nutrition science or metabolism.

PROJECT 6
Access, adherence, polypharmacy and precision therapy in elderly and remote heart failure populations
Recent publications: Pharmaceuticals; Pathology.

Led by Dr Xiao Suo Wang, this project is developing a point-of-care assay for patients who face barriers to specialist access, difficulty with medication adherence, or the complications of polypharmacy. The assay is being engineered with Professor Hala Zreiqat, Professor of Biomedical Engineering, and Professor Steve Wise, Professor of Cardiovascular Bioengineering, both at the University of Sydney.

In parallel, with RPA Virtual Health, Professors Asad Patanwala and Parisa Aslani in Pharmacy at Sydney, and Professor Richard Sinnott in Computing and Information Systems at the University of Melbourne, we are building a Heart Failure Medication Dashboard enabling live tracking of patients’ heart failure medications and their active drug metabolites.

Suitable for a PhD or Honours student with a background in pharmacy, bioengineering or health informatics. Honours student Carolina Barbero Garcia is currently working on the assay engineering component.

PROJECT 7
Microbiome, metabolome and cardiovascular disease
Recent publications: American Journal of Clinical Nutrition; iScience. Collaborator: Professor Francine Marques, Monash University and Victor Chang Cardiac Research Institute.

Diets high in fibre and microbiome-accessible carbohydrate carry substantial cardiometabolic benefit, but the mediators are poorly defined. We found that resistant starch feeding alters a wide range of circulating metabolites, most strikingly producing a large increase in the gut microbiome-derived tryptophan metabolite indole-3-propionate, which tracked with the abundance of several specific bacterial taxa.

We are now testing whether indole-3-propionate and related indoles are the principal mediators of the cardiometabolic benefits of high-fibre diets, and more broadly how diet, microbiome and metabolome interact to shape cardiovascular risk.

Suitable for a PhD or Honours student with a background in microbiome science, nutrition or metabolomics.

PROJECT 8
Machine learning for the detection of HFpEF from echocardiographic images

With Dr Gianni and Nicholas Chan, this project applies deep learning directly to raw echocardiographic image data to detect HFpEF, including in patients who fall into the diagnostic grey zone of the HFA-PEFF and H₂FPEF scores. The work draws on large, deeply phenotyped imaging datasets linked to invasive haemodynamics and multi-omics, allowing model outputs to be anchored to mechanism rather than to label alone.

Suitable for a PhD or Honours student with a background in computer science, biomedical engineering or data science, or a clinician with strong computational skills.

PROJECT 9
Cardiac magnetic resonance radiomics and genomics in UK Biobank

With Dr Yas Kamaladasa, Dr Gianni and Nicholas Chan, this project applies radiomic analysis to cardiac magnetic resonance imaging in UK Biobank, with a focus on the left atrium, and links imaging phenotypes to genetic data to identify determinants of cardiac remodelling at population scale.

Suitable for a PhD or Honours student with a background in imaging analysis, statistical genetics or data science.

PROJECT 10
Bioengineered platforms for small human myocardial biopsies

An emerging collaboration with Professor Wenlong Cheng in bioengineering and Dr Charles Cox at the Victor Chang Cardiac Research Institute, developing a miniaturised soft bioelectronic platform tailored to human cardiac biopsy tissue. The aim is continuous readout of electrophysiological and mechanical function from living human myocardium, with extension to biochemical sensing, bringing mechanics, electrophysiology and biochemistry together on the same piece of tissue.

Suitable for a PhD student with a background in bioengineering, materials science or cardiac electrophysiology.

Supervision and enquiries

The group has a record of developing independent investigators. Dr Yen Chin Koay joined as its first postdoctoral fellow and now holds a National Heart Foundation Future Leader Fellowship, leading two of the projects listed above.

Enquiries are welcome from medical students, Honours candidates and prospective higher degree students. Please email a CV and a short note on which project interests you and why to john.osullivan@sydney.edu.au.