Cardiometabolic Disease

Lab head: Dr John O'Sullivan
Location: Charles Perkins Centre

We are utilising robustly-phenotyped patient cohorts in concert with genomic, transcriptomic, and metabolomic profiling to shed new light on gene-environment interaction in cardiovascular disease. In addition to providing new markers and predictors of disease, this approach can uncover new targets for therapy. Furthermore, it is becoming increasingly evident that a ‘one-size-fits-all’ approach to cardiovascular prevention and treatment is sub-optimal. We believe re-stratifying risk and targeting disease based on a patient’s unique profile is a far more effective strategy. We have previously identified novel markers and predictors of cardiometabolic disease, in addition to a new disease pathway linking fatty liver disease with diabetes.

We recently discovered a new pathway linking fatty liver disease and diabetes. Integrating non-targeted metabolomic profiling (which captures thousands of metabolites) with genome-wide association (GWAS), we elucidated the chemical identity of a new marker of fatty liver disease. After synthesis and purification, we developed a new assay that we used to show this same marker independently predicted diabetes over a decade in advance in the Malmo Diet and Cancer Study (a Caucasian cohort) and the Jackson Heart Study (an African-American cohort). We are now focusing on functionally interrogating this pathway in model systems, including genetically-modified mouse models.

Truly novel small molecule biomarker discovery is very challenging, and non-targeted metabolomic profiling offers this potential. However, success stories using this approach are extremely rare. We have previously identified novel disease metabolites using this approach, both in a clinical cohort and in a cell-model system. We are extending our capability and streamlining our discovery pipeline. We have unique expertise with the latest-generation mass spectrometers, chemometric software, and integrative ‘omics’. We validate findings from our wet lab and clinical cohorts in large datasets such as the Framingham Heart Study and UK Biobank. Genetic variants discovered are mechanistically interrogated in the lab using genotyped human IPSC and genetic mouse models.

Finally, we are using a combination of synthetic chemistry, antibody generation, and partnerships with industry to develop new diagnostic tools for the clinic.

Lab members: Dr Yen Chin Koay (Postdoctoral Fellow; Synthetic Chemist) Dr Jacob Cao (Medical Resident; Research Scientist) Ms Courtney Woods (Student: Talented Science Program) Ms Evie Pearson (Overseas Student, University of Bath, UK)
Funding: Sydney Medical School Chapman Fellowship; HRI Fellowship; NSW EMCR Fellowship
Research approach equipment: Clinical cohorts Large clinical datasets Functional genomics Metabolomics Bioinformatics Chemical Biology Genetic IPSC and Murine models.

  1. Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes.

John F O’Sullivan,Jordan E Morningstar, Baohui Zheng, Sarah Jeanfavre, Justin Scot, Qiong Yang, Celine Fernandez, Ramachandran S. Vasan, Michelle T. Long, Olle Melander, Thomas J. Wang, Caroline Fox, Randall T. Peterson, Clary Clish, Kathleen Corey, Robert E. Gerszten.

J Clin Invest. 2017 Dec 1;127(12):4394-4402.

PMID: 29083323.

2. Increasing proportion of ST elevation myocardial infarction patients with coronary atherosclerosis poorly explained by standard modifiable risk factors.

Stephen T Vernon, Sean Coffey, Ravinay Bhindi, Soon Yeng Soo Hoo, Gregory I Nelson, Michael R Ward, Peter S Hansen, Kaleab N Asrress, Clara K Chow, David Celermajer,John F. O’Sullivan, and Gemma A Figtree.

European Journal of Preventive Cardiology, 2017 Nov;24(17):1824-1830.

PMID: 28703626.

3. Utilising state-of-the-art “omics” technology and bioinformatics to identify new biological mechanisms and biomarkers for coronary artery disease.

Stephen T Vernon, Thomas Hansen, Jean Yang, John F. O’Sullivan, Gemma A. Figtree.

Microcirculation. 2018. Accepted

4. Metabolite Profiles and the Risk of Cardiometabolic Disease.

O’Sullivan J, Gerszten RE

Eur Heart J2014; 35; 2197–2204. (Impact Factor 15.2).

DOI: 10.1093/eurheartj/ehu270.

5. Induced Pluripotent Stem Cell Differentiation Enables Functional Validation of GWAS Variants in Metabolic Disease.

Curtis R. Warren,John F. O’Sullivan, Max Friesen, Caroline E. Becker, Xiaoling Zhang, Yoshi Wakabayashi, Jordan E. Morningstar,Xu Shi, Jihoon Choi, Fang Xia, Mary H. C. Florido, Jennifer Shay, Derek T. Peters, Kiran Musunuru, Sekar Kathiresan, Laurence Daheron, Jun Zhu, Robert E. Gerszten, Rahul Deo, Vasan Ramachandran, Christopher J. O’Donnell, and Chad A. Cowan.

Cell Stem Cell2017 Apr 6;20(4):547-557. (Impact Factor 23.6).

PMID: 28388431.

6. Metabolite Profiling Identifies Anandamide as a Biomarker of Nonalcoholic Steatohepatitis.

W. Taylor Kimberly,John O’Sullivan, Anjali Nath, Michelle Keyes, Qiong Yang, Martin G. Larson, Vasan Ramachandran, Randall T. Peterson, Thomas J. Wang, Kathleen Corey, and Robert E. Gerszten.

J Clin Invest. Insight2017 May 4;2(9).

PMID: 28469090.

7. HELZ2 is an IFN Effector Mediating Suppression of Dengue Virus.

Dahlene Fusco, Henry Pratt, Wenyu Lin, D. Alex Cronkite, Kate Jeffrey, Joshua Pondick, Alan Mullen, Anthony Anselmo, Ruslan Sadreyev,John O’Sullivan, Robert Gerszten, Tetsurou Satoh, Raymond T. Chung.

Frontiers in MicrobiologyFront Microbiol. 2017 Feb 20;8:240.

PMID: 28265266.

8. Aptamer-based proteomic profiling reveals novel candidate biomarkers of cardiovascular disease.

Debby Ngo, Sumita Sinha, Dongxiao Shen, Eric Kuhn, Michelle Keyes, Xu Shi, Mark Benson,John F O’ Sullivan, HasmikKeshishian, Laurie Farrell, Michael A. Fifer, Ramachandran S. Vasan, Marc Sabatine, Martin G. Larson, Steven A. Carr,Thomas J. Wang, Robert E. Gerszten.

Circulation2016; 134:270-285. (Impact Factor 14.4).

PMID: 27444932.

9. miR-93-5p and other miRNAs as Predictors of Stable Coronary Artery Disease and STEMI.

JF O’Sullivan, A Neylon, C McGorrian, G Blake.

International Journal of CardiologyDec 2016, Vol 24, 310-316. (Impact Factor 4.0).

PMID: 27665403.

10. Integrative analysis of iPS cell models of PRKAG2 cardiomyopathy identifies AMPK as a regulator of cardiomyocyte survival, contractility and fibrosis in microtissues.

J. Travis Hinson, Anant Chopra, Calvin C. Sheng, Rajat M. Gupta, Rajarajan Kuppusamy, John F.O’Sullivan, Glenn Rowe, Joshua Gorham, Kiran Musunuru, Robert E. Gerszten, Sean M. Wu, Christopher Chen, Jonathan E. Seidman, Christine E. Seidman.

Cell Reports2016 Dec 20;17(12):3292-3304.PMID: 28009297. (Impact Factor 7.9).

11. Rapid and efficient generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells.

Christoph Patsch, Ludivine Challet-Meylan, Eva Christina Thoma, Eduard Urich, Tobias Heckel,John F O’Sullivan, Stephanie J Grainger, Friedrich G Karpp, Lin Sun, Klaus Christensen, Yulei Xia, Marie Florido, Wei He, Wei Pan, Michael Prummer, Curtis Warren, Oliver Wernet, Roland Jakob-Roetne, Ulrich Certa, Ravi Jagasia, Per-Ola Freskgård, Isaac Adatto, Dorothee Kling, Paul Huang, Leonard I Zon, Elliot Chaikof, Robert E. Gerzsten, Martin Graf, Roberto Iacone and Chad A. Cowan.

Nature Cell Biology2015 Aug;17(8):994-1003. (Impact Factor 18.7).

PMID: 26214132.

12. Increases in Myocardial Workload Induced by Rapid Atrial Pacing Trigger Alterations in Global Metabolism.

Turer AT, Lewis GD, O'Sullivan JF, Elmariah S, Mega JL, Addo TA, Sabatine MS, de Lemos JA, Gerszten RE.PLoS One.2014 Jun 16;9(6):e99058. (Impact Factor 3.2).

PMID: 24932507.

13. β-Aminoisobutyric Acid Increases Browning of White Fat and Hepatic β-Oxidation and is Inversely Correlated with Cardiometabolic Risk Factors in Humans.

Lee D. Roberts, Pontus Boström,John F. O'Sullivan, Robert T. Schinzel, Gregory D. Lewis, Youn-Kyoung Lee, Melinda J. Palma, Sondra Calhoun, Ming-Huei Chen, Vasan S. Ramachandran, Martin G. Larson, Claude Bouchard, Tuomo Rankinen, Amanda L. Souza, Clary B. Clish, Thomas J. Wang, Alexander A. Soukas, Chad A. Cowan, Bruce M. Spiegelman, Robert E. Gerszten.

Cell MetabolismVolume 19, Issue 1, 96-108, 7 January 2014. (Impact Factor 17.6).

PMID: 24411942.

14. Bone marrow-derived mesenchymal stem cells have innate procoagulant activity and cause microvascular obstruction following intracoronary delivery: amelioration by anti-thrombin therapy.

Birgitta M Gleeson,Kenneth Martin, Arun HS Kumar DVM, Mohammed T Ali, M Gopala-Krishnan Pillai,John F O’Sullivan, Derek Whelan, Frank P Barry, Timothy O’Brien, Noel M Caplice.

Stem Cells.2015 Sep;33(9):2726-37.(Impact Factor 7.8).

PMID: 25969127.

15. 2-aminoadipic acid is a novel biomarker of diabetes risk and modulates glucose homeostasis

Wang TJ, Ngo D, Psychogios N, Dejam A, Larson MG, Vasan RS, Ghorbani A,O'Sullivan J, Cheng S, Rhee EP, Sinha S, McCabe E, Fox CS, O'Donnell CJ, Ho JE, Florez JC, Magnusson M, Pierce KA, Souza AL, Yu Y, Carter C, Light PE, Melander O, Clish CB, Gerszten RE.

J Clin Invest. 2013 Oct 1;123(10):4309-4317. (Impact Factor 12.6). PMID: 24091325.

16. Multi Detector Computed Tomography Accurately Defines Infarct Size, but not Microvascular Obstruction After Myocardial Infarction (MI).

John F O’Sullivan, MD, PhD, Anne-Laure Leblond, PhD, John O’Dea, MD, Ivalina Hristova, BS, Sujith Kumar, DMRIT, Noel M Caplice, MD, PhD.

J Am Coll Cardiol. 2013;61(2):208-210. (Impact Factor 17.8).

PMID: 23177294.

17. Association of bicuspid aortic valve with an abnormally elongated rudimentary chordae tendininae protruding into the left ventricular outflow tract.

Abid Hussaini, John F. O'Sullivan, Nazima Hussaini, Brendan Meany.

Int J Cardiol01/2012; 159(3):45-6. (Impact Factor 4.0).

PMID: 22217483.

18. Potent Long-term Cardioprotective Effects of Single Low Dose Insulin-like Growth Factor-1 (LD-IGF-1) Treatment Post Myocardial Infarction.

John F O’Sullivan, Anne-Laure Leblond, Geraldine Kelly, Arun HS Kumar, Pat Metharom, Ivalina Hristova, Niki Alizadeh-Vikali, Brian G Hynes, Rosemary O’Connor, Noel M Caplice.

Circulation: Cardiovascular Interventions2011;4:327-335. (Impact Factor 7.0).

PMID: 21712526

19. Potent EPC conditioned media induced anti-apoptotic, cardiotrophic and proangiogenic effects post myocardial infarction are mediated by IGF1.

Brian Hynes, Arun HS Kumar,John O’Sullivan, Anne-Laure Leblond, Sharon Weiss, Jeffrey Schmeckpeper, Kenneth Martin, Noel M Caplice.

Eur Heart J2011 Dec 15. (Impact Factor 15.2).

PMID: 22173909

20. Microribonucleic acids for Prevention of Plaque Rupture and Instent Restenosis: “A Finger in the Dam”.

John F O’Sullivan, Kenneth Martin, Noel M Caplice.

State of the Art Paper.J Am Coll Cardiol2011 Jan 25;57(4):383-9. (Impact Factor 17.8).

PMID: 21251577

21. New therapeutic potential of microRNA treatment to target vulnerable atherosclerotic lesions and plaque rupture.

Kenneth Martin,John F O’Sullivan, Noel M Caplice.

Current Opinion in Cardiology2011 Sep 13. (Impact Factor 2.7).

PMID: 21918434

22. MicroRNA Expression in Coronary Artery Disease.

John F O’Sullivan, Antoinette Neylon, Catherine McGorrian, Gavin J Blake

MicroRNAVolume 2, Issue 3, 2013. (Impact Factor 3.8).

PMID: 25069444.

23. Thrombin Stimulates Smooth Muscle Cell Differentiation From Peripheral Blood Mononuclear Cells via Protease-Activated Receptor-1, RhoA, and Myocardin.

Kenneth Martin, Sharon Weiss, Pat Metharom, Jeffrey S Schmeckpeper, Brian G

Hynes,John F O’Sullivan, Noel M Caplice.

Circulation Research2009;105:214-218. (Impact Factor 11.0).

PMID: 19574550

24. Enhancing Back-up Support During Difficult Coronary Stent Delivery: Single Center Case Series of Experience with the Heartrail II Catheter.

Brian Hynes, Grainne Murphy, James Dollard,John O’Sullivan, Nicholas Ruggerio, Ronan Margey, Thomas J. Kiernan, Eugene McFadden

J Invasive Cardiol2011;23(3):E43-6. (Impact Factor 1.1).

PMID: 21364247

25. Bone marrow mononuclear stem cells: potential in the treatment of myocardial infarction.

Anne-Laure Leblond,John O’Sullivan, Noel Caplice.

Stem Cells and Cloning: Advances and Applications, December 2009, Volume 2009:2 Pages 11 – 19. (Impact Factor 2.7).

PMID: 24198506

26. Ostial left main stenosis in a frequent flyer.

O’Sullivan JF, McFadden E

Int J Cardiol2008 Mar 28. (Impact Factor 4.0).

PMID: 18378023

27. Soft tissue neoplasm invading the heart with associated thrombus in a 74 year old man.

John O'Sullivan, David Kerins, Peter McEneaney, Carl Vaughan

Eur J Echocardiogr. 2007 Jul 30. (Impact Factor 4.3).

PMID: 17669689

28. Massive thrombus in the aortic arch: A 59-year-old lady with an unknown familial predisposition to vascular thrombosis.

O’Sullivan J, Kerins D, Vaughan C.

Eur J Echocardiogr. 2007 Sep 19. (Impact Factor 4.3).

PMID: 17888744

29. Distinct Effects of High-Glucose Conditions on Endothelial Cells of Macrovascular and Microvascular Origins.

A. Duffy, A. Liew,J. O’Sullivan, G. Avalos, A. Samali, T. O’ Brien

Endothelium.2006 Jan-Feb;13(1):9-16. (Impact Factor 5.5).

PMID: 16885062

30. Survival of ruptured abdominal aortic aneurysms in the west of Ireland; do prognostic indicators of outcome exist?

Sultan S, Maneshka R,O’ Sullivan J, Hynes N, Quill D, Courtney D.

Vasc Endovasc Surg, 2004, Jan-Feb; 38(1):43-9. (Impact Factor 0.9).

PMID: 14760476

31. Aortic Surgery: Do preoperative Cardio-selective β-blockers improve clinical outcome.

Sultan S,O’Sullivan J, Manecksha R, Ishak L, Sharman A, Quill D, Courtney D

Irish Journal of Medical Science01/2002; 171(3):S2:20. (Impact Factor 1.12).

32. Ruptured abdominal aortic aneurysms: prognostic indicators for outcome.

Sultan S, Manecksha R,O’Sullivan J, Ishak L, Sharman A, Quill D, Courtney D

Irish Journal of Medical Science01/2002; 171(3):S2:22. (Impact Factor 1.12).

A Key Metabolic Switch in Cardiometabolic Disease

Primary supervisor: John O'Sullivan

Non-alcoholic fatty liver disease (NAFLD) is now the commonest form of liver disease in the Western world, affecting one in three people in the general population, 90% of obese patients with T2D, and 5.5 of 6 million Australians with liver disease – accounting for much of the $51 billion annual cost to our healthcare system. Liver fat is increasingly considered a primary driver of T2D, although exact mechanisms remain unclear, and is an independent risk factor for atherosclerosis. Further - and most clinically challenging - it is unknown which patients with liver fat will progress to metabolic complications.

We recently discovered a new plasma biomarker (dimethylguanidino valeric acid [DMGV]) of liver fat that independently predicted diabetes up to 12.8 years before diagnosis in three distinct human cohorts of different ethnicity (O’Sullivan et al., J Clin Invest, 2017). We have subsequently shown that DMGV is elevated in a human cohort of hepatic insulin resistance, and that the gene producing DMGV is upregulated in fatty liver disease. Intriguingly, in dietary models of NAFLD, we found sucrose (fructose + glucose) caused the most dramatic dysregulation of this pathway, consistent with recent reports showing fructose to have dramatic effects on hepatic insulin resistance in humans and mice. Together, these data suggest this pathway is most activated in lipogenesis leading to hepatic insulin resistance. We have put together a comprehensive plan to test our proposed hypothesis, including dietary models and genetically modified murine models in addition to liver biopsy and plasma samples from carefully characterized human cohorts.

Discipline: Pathology
Co-supervisors: Yen Chin Koay, Andrew Hoy
Keywords: Diabetes, Liver Disease, Metabolic/bariatric