PhD Partnership Program

Heart attacks and strokes are caused by the build-up of cholesterol (called a plaque) in the arteries of the heart or brain, a process named atherosclerosis, which leads to death of heart or brain tissue. Animal studies have shown that vaccination against the Pneumococcus bacterium reduces the size and number of plaques. The mechanism appears to be that the cell wall of the bacterium contains a fat that looks like the bad cholesterol that builds up in the plaque. Vaccination triggers the production of antibodies towards this cell wall fat and these antibodies cross react with the bad cholesterol, attacking and basically “clearing away” the plaque.

The obvious question has been whether pneumococcal vaccination can do the same thing in humans. Observational human studies are promising, indicating that people who receive the pneumococcal vaccine have a lower risk of heart attack and stroke than those who do not. Unfortunately, these studies are not randomised and it is possible that these results are confounded.

The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is the first and only registered study worldwide to test this hypothesis in a randomised controlled clinical trial. Funded by NHMRC ($1.8 million) in 2013, it has recruited 4725 people across six centres nationally, with half receiving the pneumococcal vaccine and half receiving placebo. It is one year into the six year follow-up needed to have sufficient power to detect a 17% reduction in heart attacks and strokes. While waiting for endpoints to develop over the next five years, we will investigate the potential mechanisms of a protective effect; this was not covered by the original grant. One thousand participants have given blood samples at baseline and one month after vaccination, and agreed to undergo measures of atherosclerosis at baseline and two and four years after vaccination. We anticipate that those who get and respond to the vaccine will show a reduction in plaque during follow-up.

If a vaccine can protect against heart attacks and strokes, it will be a major public health advance. The vaccine has a well-established safety profile but is underused. If this study is positive, coverage could be increased (currently less than a third of those eligible get the vaccine) and the target age could be reduced from 65 to 55 to cover more of the population at risk. This fits squarely with the NSW Health priority of “Keeping People Healthy”.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality globally. Our health system is largely still a medicalised and facility (hospital or clinic) based model of care. This model of care is rapidly out-stripping our ability to resource it especially as it is faced by an aging population and the increasing prevalence of complex chronic health care conditions. A greater focus on a prevention is needed. We should develop innovative approaches to maintain health and prevent deterioration of health in patients with existing or chronic health conditions. This should also include systems to enable earlier identification of those at risk and implementation of interventions to prevent catastrophic health events e.g. heart attack, stroke or premature mortality.

My research to date in CVD prevention has involved novel approaches such as using mobile and digital health interventions to support patients after a heart attack modify their health behaviours and support them to take their healthcare treatments. My program of work in the next five years will focus on innovative opportunities to strengthen CVD prevention through enhanced clinical approaches and enhanced health service delivery. This will involve integrating the digital health interventions and other new interventions we have developed into clinical pathways and the health system as well as creating new care models. The goal of my research is to cultivate a program of work that utilises innovative, practical and scalable approaches to improve CVD preventative care for patients and populations.

The ultimate goal of our research is to be able to take a sample of your blood, predict how likely you are to suffer a heart attack or stroke, decide if you need a new medication to reduce your risk, then retest your blood to see if you responded to the treatment.

Our research focuses on understanding blood platelets, tiny cells that form clots to stop us bleeding. Platelets need to be able to activate, otherwise we would bleed to death, but when they are too active, or their activity occurs in the wrong place, you can suffer a heart attack or stroke. Aspirin, one of the main drugs that reduces death from heart attack, works by inhibiting platelet function. However, despite current best anti-platelet drugs, thousands of people continue to have heart attacks and strokes every day.

Our research has shown that not all platelets are the same, that different populations within our platelets have different roles. There is one particular sub-population that stimulates the circulating blood clotting proteins to make blood clots bigger and more stable. Our research has found that these “procoagulant platelets” are made in excess in patients during heart attack or stroke, but they are less important in stopping bleeding. Until now, there was no easy way to measure these “procoagulant platelets”. We developed a blood test that can measure how many procoagulant platelets you make when your blood is exposed to the stimuli that it would experience during heart attack or stroke. We further refined this into a test that measures the balance of an individual’s platelet sub-populations with the intention to give more information about your risk of heart attack and to determine whether you need extra treatment to reduce the risk. We hope this will eventually become a diagnostic test available to people with coronary disease within in a routine diagnostic laboratory and have partnered with a company with experience making platelet function tests into test kits.

Procoagulant platelets are not affected by aspirin, so new drugs are needed. Our research also has a drug discovery arm using our novel assay and state-of-the-art drug discovery methods. We have found a potential drug that affects the interaction between the stimulant and the platelets, bringing the hyperactivity in coronary disease patients back to normal without affecting bleeding. Test-tube based experiments have been promising, and we are moving into the next phase of testing.

The purpose of this project is to develop new therapies to reduce costs associated with deaths and illnesses from large myocardial infarctions (heart attacks) and resulting heart failure. Cardiovascular disease is the largest killer of Australians and heart attacks are a large cause of this. Heart attacks affect an estimated 258.45 people per 100,000 US population (Global Data 2017), and potential for treatment costs are estimated to reach US$1,726.3 million by 2023 (Zion Market Research).

Treatment of heart attack includes immediate measures to salvage the parts of the heart muscle at risk of permanent damage (scarring). Most patients who receive sufficient treatment survive. However, as a result of their heart injury, these patients frequently progress to heart failure. The potential for treatment costs for chronic heart failure in the US is estimated to reach US$12,137 million by 2026.

Our research explores two broad themes to achieve these treatment goals: 1) use of heart muscle grafts derived from stem cells; and 2) changing how the scarring of the heart occurs after a heart attack. My previous training and my group's unique techniques will push these research themes forward. These techniques include: developing a stem cell culturing technique on a clinical scale (billions of cells), and developing the stem cells into heart muscle cells; small animal models (mouse and rat) and large animal models (sheep and pig) of heart attack and heart failure; and new, cutting-edge molecular and imaging analysis.

I am translating our most promising therapeutic methods towards clinical trials so that this research may one day lead to new therapies for patients who have had a heart attack, are in heart failure and who have heart rhythm abnormalities. A patent has already been filed and the University of Sydney is commercialising our methods.

Professor Figtree is a clinician researcher whose integrated program of research extends from fundamental discovery through to clinical trials, interventional cardiology and implementation. She coordinates a team of multi-disciplinary researchers, driven by the increasing number of heart attack patients who are asking “why me”? While it is imperative that we treat established risk factors, this approach “misses” a substantial group of patients who are not identified as “at risk”. Indeed, the proportion of patients presenting with life-threatening heart attacks to Professor Figtree’s hospital with 0 standard modifiable risk factors [SMuRFs] has increased from 13% 10 years ago to ~30% in 2014. Her driving hypothesis is that major residual mechanisms for atherosclerosis can be unravelled by comprehensive molecular characterisation of such “athero-vulnerable” and “athero-resilient” patients.

Professor Figtree has established and continues to expand a suite of biobanks that combine state-of-the-art imaging of the heart with a panel of high-technology “omics” measures and clinical data. Through novel computational bioinformatics approaches she plans to unravel new mechanisms and biomarkers of both coronary artery disease susceptibility and resilience.

Given coronary artery disease kills approximately 3x more Australians than the leading individual cancer, the expanding group with “SMuRFless” coronary artery disease has enormous public health significance. Furthermore, new mechanistic pathways will likely have broad relevance, bringing improved risk stratification and targeted preventative management to all patients at risk of atherosclerosis. She has established a collaboration with Professor Alex Brown to ensure novel markers can be tested for efficacy in the Indigenous population.

Discoveries made during the proposed program of work will guide the design of dedicated trials testing the ability of new markers to guide clinician decision making above and beyond traditional risk factor profiling, with beneficial outcomes on health. Existing intellectual property (USA14/069913), a formal research agreement with NSW Health Pathology and CDA with Abbott Diagnostics highlights Professor Figtree’s commitment to commercialisation and translation. Her position in national and international clinical leadership groups and extensive network of collaborators leading cardiovascular advances and practices will ensure rapid translation and benefit to international patient populations.

In addition to the risk identification and prognostic value of Professor Figtree’s study, her team is well positioned to discover completely novel pathophysiological pathways relevant to atherosclerosis. These will pave the way for testing new therapeutic targets. Her team are well placed to capitalise on such discoveries, with an established pipeline for drug development that progresses from preclinical disease models to humans.

Spontaneous coronary artery dissection (SCAD) is a tear in an artery that supplies blood to the heart. It is a potentially fatal problem that presents as a heart attack or sudden death, affecting relatively young (45-52 years old) women (95% of cases) with few heart disease risk factors, and is, therefore, often overlooked. The underlying defect causing SCAD is entirely unknown, however, our work and that of others suggests that it is most likely due to a gene change that enhances susceptibility to vessel rupture.

Our purpose is to better understand, treat and prevent SCAD by identifying factors that predispose the coronary artery to spontaneous tearing. Our objectives are to investigate the genetics and cell biology, as well as blood pressure and heart function responses, of our familial SCAD survivors versus controls. The proposed research brings together multi-disciplinary, internationally-competitive researchers to dissect the molecular mechanisms underlying SCAD, with the objective of identifying targets for the development of effective preventative and treatment strategies, irrespective of ethnicity. This research will thus be equally effective, impactful and applicable to the health needs of priority populations, such as the Aboriginal and Torres Strait Islander people, individuals from CALD backgrounds and socio-economically disadvantaged groups.

Scientifically, the work will change how the field views SCAD, and will pave the way for others, thus rapidly increasing progress. Technologically, the work is underpinned by powerful, contemporary methodological approaches that will allow deep interrogation of genomics and cardiac biology, as well as the elucidation of innovative approaches to SCAD risk identification and management. The latter has translational and therapeutic significance and has the potential to lead to simple, evidence-based implementable therapies, irrespective of ethnicity. The findings of the study will be disseminated in leading international journals, at major national and international meetings, and through our patient groups, media and social media to increase exposure, awareness and public engagement.

Heart attacks and strokes are among the major causes of death in Australia. While some of these events can be explained by risk factors such as high blood pressure, cholesterol diabetes, age and smoking, many are unexplained. Aboriginal Australians, patients with schizophrenia and women with preeclampsia (a disease of high blood pressure during pregnancy) are at increased risk of heart disease and stroke at a young age, for reasons we do not understand. In this study we will investigate if these people have reduced capacity to clear cholesterol from their body using new methods never before applied to these Australians. It will involve taking a small volume of their blood and specialised testing for the ability of that blood to remove cholesterol from cells and to deliver it to the liver for clearance. As part of this project we will also develop a new rapid version of one of these tests that will make these tests available to large numbers of people in the community.

Our hypothesis is that inability to clear cholesterol from the body is one of the causes of premature heart disease and stroke. Our study will investigate if this is true in three Australian populations. If this is confirmed, we will use this information to predict who is at risk of having future heart attacks and stroke, and identify future therapies by overcoming those areas where the clearance of cholesterol is slowed. Our studies are therefore directly relevant to Australian populations. We will work closely with experts in the fields of Aboriginal health, schizophrenia, and women’s health to publish our work, present it at scientific and educational meetings, and apply it to the wider Australian population.

This project will use novel and innovative approaches to answer key research questions related to the clinical and genetic basis of inherited heart diseases, such as muscle or electrical problems of the heart, and sudden cardiac death, particularly in the young. While there has been significant progress in defining the genetic causes of many of these inherited heart diseases, no cause is identified in over 50% of these inherited heart diseases. Furthermore, in those where a genetic diagnosis has been made, how these genetic faults lead to heart disease, and what factors influence how the disease develops, remain unclear. Finally, how to translate these key genetic discoveries to improved diagnostic, therapeutic and prevention approaches in families with inherited heart diseases remains unclear.

The three-year research study will focus on the identification of new disease genes in families with inherited heart disease and sudden cardiac death using state-of-the-art genetic approaches which allows us to study thousands of genes at one time, so-called whole exome and genome sequencing. This cutting-edge technology will allow us to understand how these genetic discoveries lead to human inherited heart disease, and how to apply this new knowledge in the clinical setting to assess patients and their families. The overarching purpose of this study is to be able to gain new genetic knowledge about inherited heart diseases and then translate these findings to improved diagnostic and therapeutic approaches, with the ultimate goal to improve the care of families with inherited heart diseases, including the prevention of sudden cardiac death in the young.

A key aspect of this study is to translate these findings immediately into practice, with the improved diagnosis and management of patients and their families with inherited heart diseases. The findings will lead to the development, for the first time, of evidence-based best practice guidelines for the investigation of inherited heart disease families and sudden cardiac death in the young. The findings will be disseminated to patient, clinicians and to the wider public not only within NSW, but across Australia, and internationally, such that the care of these families is improved globally.

Heart failure is a modern epidemic and carries a similar five-year mortality to many common cancers. We aim to thoroughly understand mechanisms underlying a type of “stiff” heart failure common in diabetics, where the heart doesn’t relax properly. It now accounts for over half of all cases and there is no specific therapy.

However, for the first time, there is promise on the horizon. Recently, three independent clinical trials showed that a new class of type 2 diabetes medication called “SGLT2 inhibitor” improved outcomes for this type of heart failure. We will analyse blood plasma from one of these international clinical trials, the CANVAS study.

These medications raise levels of particular nutrients in the blood that are used by the diabetic heart to provide energy.

Our initial work using human hearts revealed several classes of nutrients that are deprived in heart failure. We will now determine those that are specific to diabetic cardiomyopathy using our diabetic cardiomyopathy clinic, CANVAS trial samples, and mouse and cell models of disease.

Aboriginal Australians are affected disproportionately by this disease. We are collaborating with indigenous researchers in Redfern NSW, and with a leading Australian Aboriginal researcher, Prof Alex Brown, who now has a joint appointment at our Institute, and who will provide plasma samples and relevant imaging and clinical measures.

To determine mechanisms underlying cardiac nutrient changes in this disease, we will use a mouse model established in our lab where the mice develop stiff hearts and the same cardiac nutrient changes as humans. Furthermore, we will use a technique to trace the fate of labelled nutrients in mouse hearts with this disease. Finally, we will deliver candidate nutrients that are depleted in diabetic cardiomyopathy to the mice, and compare effects on heart function with those of SGLT2 inhibitors.

A key aspect of our clinic is patient education. We find that our patients are extremely enthusiastic to join our study, learn more about their disease, and contribute to finding a solution for all. We are launching an awareness campaign to make the public more aware of this condition, which will also help recruit patients. As our project includes pre-clinical work, alongside two clinical cohorts, and has engaged hospital and Local Health District senior administration, we are in a strong position to take forward any potential new therapies into human clinical trials, and to contribute to local policy-making regarding diagnosis and treatment of this condition.

Patients with heart failure related to a ‘stiff heart’, termed heart failure with preserved ejection fraction (HFpEF), often have a poor quality of life, shortness of breath and repeat admissions to hospital. Other conditions like high blood pressure and obesity can make this condition worse. Currently, there are no treatments to make these patients feel better or prevent them from becoming unwell and needing to go to hospital. This study aims to find a new treatment for these patients, which will help them feel better, lose weight and reduce hospitalisations. The treatment combination is: sodium glucose co-transporter inhibitors (SGLT2i), and glucagon like peptide 1 receptor agonists (GLP1-RA).

This research program has two key components which are outlined below.
1. Project one will look at cardiac, kidney and safety outcomes in patients on this combination therapy using data from two large studies we have conducted at the George Institute for Global Health, the CANVAS Program and the CREDENCE Trial.
2. Project two is a new study, in patients with HFpEF that will be done across Australia, the USA and Singapore. Patients will receive either SGLT2i/GLP1-RA combination or placebo and we will look at effects on quality of life, blood pressure, body weight, kidney function and need to be hospitalised.

This will be the first study of this treatment combination in HFpEF and has the potential to identify the first proven therapy to improve outcomes in these patients. A positive result would have direct implications for the quality of life of millions of patients worldwide. The study will involve patients throughout the research process, seeking advice on design and conduct using focus groups, surveys and interviews as well as incorporating plans for consumer-led dissemination of study findings.

The research team is led by Dr Clare Arnott but includes international heart failure and clinical trial experts with specific expertise in using research to inform international guidelines and clinical care pathways.

The key potential outcomes and benefits of this project are:
1. identifying the first proven therapy for HFpEF resulting in improved quality of life for patients
2. the integration of this new treatment into national and international guidelines
3. education of patients and physicians on HFpEF, risk factors and best medical management.

Diabetes has become one of the major healthcare challenges of the 21st century and a leading cause of clotting diseases such as heart attack and stroke worldwide in which blood flows are obstructed. Unfortunately, the existing anti-clotting drugs are not ideal, with less than 1 in 6 patients with diabetes taking these therapies avoiding a fatal thrombotic event.

This research aims to identify more effective approaches. It will elucidate a novel biomechanical mechanism that associates with mechanical force generated by dynamic blood flow and leads to enhanced blood clotting in diabetes. This field of work is called ‘mechanobiology’ and involves the application of engineering principles at the molecular and cellular scale.

Dr Ju has established the innovative 4Ms approach: Mechanics, Microscopy, Microfabrication & Mouse mode. This approach brings together the fields of biomechanical engineering, imaging, microfluidics and molecular biology. In particular, Dr Ju has developed a state-of-the-art pico-force (10-12 Newton) nanotool called Biomembrane Force Probe (BFP) which is the first of its kind in Australia, capable of correlating the mechanical stimulation profile with real-time cellular responses of a single blood clotting cell, or platelet.

The expected outcome will explain the reduced efficacy of current anti-clotting drugs in individuals with diabetes, which does not take the ‘haemodynamic force factors’ into account. Moreover, it will provide an innovative therapeutic strategy to reduce the sticky blood clots of diabetes.

This project will take place in USYD’s newly launched research hub for diabetes and cardiovascular diseases. Dr Ju’s team brings together clinicians and scientists from the School of Biomedical Engineering (BME), the Heart Research Institute (HRI), and Charles Perkins Centre (CPC) at the University of Sydney.

The timing of this capacity building grant aligns well with the development of Dr Ju’s independent lab space at the new Engineering & Technology Precinct of the University of Sydney. The funding will enable Dr Ju to build his own bioengineering team to apply the 4Ms approach to make ground-breaking cardiovascular discoveries that could revolutionise anti-thrombotic strategies.

Atrial Fibrillation and Ventricular Tachycardia occur when aberrant signals disrupt and override the natural electrical rhythm of the heart. For a majority of the >300,000 Australian’s with atrial fibrillation and ventricular tachycardia, treatment options are available and include catheter ablation to scar tissue and prevent aberrant signals. Unfortunately, survival rates are very low for patients that have exhausted all treatment options and are not good candidates for surgical ablation (e.g. failed catheter ablation or co-morbidities).

Radiation is a non-invasive way of causing ablative scarring that blocks these aberrant electrical signals. The potential for radiation-ablation has been demonstrated through a recent trial at Washington University, where improvements for 18 out of 19 ventricular tachycardia patients following radiation-ablation were shown to reduce the median number of ventricular tachycardia events from 119 to three. Due to the stunning results from this trial, radiation-ablation is receiving global attention due to the potential to treat patients with limited options remaining.

Directly irradiating the heart remains a very high-risk procedure with two of the 19 patients in the Washington University trial experiencing serious adverse events due to the radiation-ablation treatment alone, indicating that further improvements are urgently needed. A/Professor O'Brien’s research is pioneering new techniques to make radiation-based treatment for atrial fibrillation and ventricular tachycardia safer. He aims to do this by performing research into better targeting the ablation site with radiation while steering radiation away from healthy structures in the heart. His initial focus is on the cohort of patients with very poor survival rates with the results from this initial cohort informing treatment decisions for the more general atrial fibrillation and ventricular tachycardia patient cohort.

Heart failure affects more than one million Australians, a third of whom live in NSW. It is a syndrome caused by structural or functional abnormalities of the heart which results in tiredness, fatigue, shortness of breath and swelling, which are chronic, worsen over time and result in poor quality of life.

Up to half of all heart failure patients have normal contraction, but impaired relaxation. This condition, known as “Heart Failure with preserved Ejection Fraction” or “HFpEF”, has a poor prognosis and causes a significant number of potentially avoidable admissions to NSW hospitals. There are currently no effective therapies for HFpEF and we lack a clear understanding of how it develops. Common risk factors include high blood pressure, obesity, diabetes, increasing age and obstructive sleep apnoea.

The goal of this project is to better understand the biological basis of HFpEF, in particular the role of tissue hypoxia (low oxygen) as well as sleep apnoea, and develop new targeted therapies. The role of a key signalling protein, known as Hypoxia Inducible Factor (HIF) will be studied. HIF is likely to play an important role in heart failure. Cardiac injury, heart muscle hypoxia and intermittent hypoxia from sleep apnoea cause changes in HIF, which may alter metabolism and growth of the heart muscle, leading to HFpEF.

We anticipate that an understanding of the biological basis of HFpEF will lead to new drugs to be trialled in human heart failure. Early effective intervention is paramount in order to reduce the considerable human cost and impact of HFpEF on the community.

Cardiovascular (or circulatory) diseases comprise all diseases of the heart and blood vessels. Among these diseases, the four types responsible for the most deaths in NSW are: coronary heart disease, stroke, heart failure, and peripheral vascular disease. Circulatory diseases cause more than 15,000 deaths and 150,000 hospitalisations of NSW residents in each year. Cardiovascular diseases accounted for 14% of the total disease burden in Australia in 2015, second only to cancers.

The cause of coronary heart disease and stroke is the formation of clots within the blood vessels. This process is called thrombosis. The thrombotic event causes impaired blood flow through the vessel and myocardial infarctions and strokes are the outcome.

Given the importance of preventing thrombosis and therefore diseases such as cardiovascular disease and stroke, Dr Coleman’s project aims to identify novel proteins which can be targeted to stop the clot from starting to develop. To do this the project will study the Von Willebrand factor (VWF). In the circulation, VWF unfolds from an inactive conformation into an active string-like form that allows platelets and inflammatory cells such as neutrophils to anchor with blood vessels and a clot begins to develop. Failure of the blood vessels to control the size and amount of VWF leads to increased amounts of long strands that promote excessive platelet adhesion and clot formation leading to thrombosis. There is increasing epidemiological and clinical evidence indicating that the incidence of thrombotic diseases, including heart attack and stroke, highly correlates with increased levels of vascular VWF and increased binding to platelets and neutrophils.

Dr Coleman’s study will be a collaboration between the Centenary Institute and Heart Research Institute. Utilising the resources of both Institutes, they hope to develop new ways to prevent cardiovascular diseases.

Dr Francois is an early career researcher who is passionate about lifestyle therapy, namely physical activity and nutrition. Her research focuses on testing and implementing simple and feasible lifestyle strategies to improve metabolic and cardiovascular health. With the support received from NSW Health, her team will investigate and compare two lifestyle strategies that target the lowering post meal glucose spikes in order to improve blood vessel health.

The team will test the independent and combined effects of restricting carbohydrates and post-meal physical activity, to see which approach (importantly when integrated into current standard-care) can best improve cardiovascular health in patients with and at risk for diabetes.

Spontaneous coronary artery dissection (SCAD) is an emergency condition that occurs when a tear forms in one of the blood vessels in the heart. If not diagnosed and treated quickly, it can cause heart attack or sudden death. SCAD predominantly affects young healthy women with no obvious risk factors, often when they have been in a vulnerable condition such as during pregnancy, postpartum or after physical or emotional stress. To date, no obvious cause of this acute disease has been identified. As a result, patients do not currently receive optimal disease diagnosis and management.

However, increased awareness and recent advances in the screening of SCAD have facilitated the identification of multiple SCAD occurrences within families. This indicates that genetics may have a more significant role in the pathogenesis of SCAD than previously thought.

Associate /Professor Giannoulatou’s team of researchers and clinicians is currently leading the discovery of the genetic causes of SCAD by using the latest technologies to study the genetic code of SCAD patients and their families. They have shown that SCAD genetics is complex, and the disease cannot be attributed to the disruption of the same genes across different families. The teams’ goal is limited by the current methodologies used to analyse such large genetic datasets to identify pathogenic mutations.

In this project, it’s propose to develop new quantitative and analytical approaches to improve their ability to identify mutations that are the cause of SCAD in every patient. To achieve a deeper understanding of the genetic architecture of SCAD, data sharing via international collaborations is essential. The team is building a network of SCAD cohorts globally and will leverage this data to validate and replicate their findings. This will allow them to make novel discoveries about the genetic aetiology of SCAD.

This research has immediate clinical benefit for the SCAD patients that have been recruited. Facilitating the genetic diagnosis of SCAD will help patients not only within NSW and across Australia, but also internationally, to receive an accurate diagnosis, personalised management and treatment, and genetic counselling concerning the disease risk in their family.

Identifying the genetic causes of SCAD has benefits not only for the patient and the family but also for the community. Currently, efforts to identify causes of disease are costly and can include multiple medical screens and procedures. The team expects that systematic adoption of genetic testing in clinical practice will improve the financial sustainability of the health system.

Heart disease causes nearly 20% of deaths around the world. Unfortunately, the ongoing care for secondary prevention that people receive after they leave hospital has not kept up with related medical advances. To fix this, the team of researchers and software developers will unite to develop and test a new system for providing support and motivation to patients attending cardiac rehabilitation. The team will build an electronic peer support system that patients with coronary heart disease can access to help motivate each other reduce their risk. The system will be meaningful and usable for patients with heart disease and could be easily distributed and expanded to other health areas. The project has the potential to be scalable and influence health service delivery and close current evidence-practice gaps relating to secondary prevention of heart disease.

Atherosclerosis is a chronic condition involving the hardening and narrowing of arteries, due to a build-up of fatty plaque on the arterial wall. It remains the most common cause of cardiovascular disease-related death worldwide. Reducing blood cholesterol was considered a universal solution for preventing and treating atherosclerosis. However, a large number of individuals receive little cardiovascular benefit from cholesterol-lowering therapies. The old problem needs a new solution.

How atherosclerosis develops is far more complicated than initially thought. In addition to cholesterol and other risk factors in the blood, how blood vessels respond to the deleterious environment may also determine the outcome of the disease. The injury of blood vessels is considered one of the first step of atherosclerosis.

This injury induces chronic inflammatory phenotypes in the endothelium, the interior lining of blood vessels, and subsequently results in the inappropriate accumulation of inflammatory cells underneath the endothelium within the vessel walls. Prevention and reversal of vascular injury have great promise in treating atherosclerosis.

Dr Qi’s cutting-edge research has identified a critical regulator of both fat movement and storage within cells. His work has implicated this deleterious factor in vascular cell health, since it serves as a ""catapult"", hurling unhealthy fat products within vascular cells and predisposing to a higher risk of vascular injury. Dr Qi’s research is to explore how this fat regulator functions to control fat movement and storage, specifically in the endothelial cell lining of blood vessels, to uncover the mechanistic links between intracellular fat and vascular injury, and thus generate new understanding of the initiation and progression of atherosclerosis. Further, he will test a new intervention targeting this deleterious factor in animal models, which will lay the foundation for the development of novel treatment options in combating atherosclerosis.

Genes are made of DNA which is the code or blueprint for proteins that make our bodies grow and work. Small changes in the DNA code or the way genes are expressed can have major effects on our health. These changes can be inherited or acquired as we age. In the event that a gene change causes disease then gene therapy may be able to help. Gene therapy is the introduction of genetic material into the cells of a patient to treat a specific disease. The transferred genetic material changes how a protein is produced by the cell. This new genetic material is delivered into the cell using a vector.

Typically, viruses are used as vectors because they have evolved to be very good at making their way into cells during infection. In gene therapy however, their purpose is to insert the new genetic material into the cell. Some types of viruses being used are typically not known to cause disease, such as the one in this proposal. In gene therapy, we often use adeno-associated viruses (AAV) as vectors. AAV is a small virus that isn’t known to cause disease, significantly reducing the chance of a negative side effect.

Gene therapy has had success in the treatment for patients with inherited disorders such as haemophilia and acquired disease such as cancer. Progress in gene therapy for patients with heart disease has been limited despite strong predictions of success from experimental models. Much of this lack of clinical benefit is due to the unexpectedly poor performance of the AAV vector in human hearts. To overcome this barrier this project will use cutting-edge molecular biology technology and Darwinian-like evolutionary principles to create AAV vectors selected for their ability to efficiently deliver genetic material to human hearts. Success with this project will overcome the major barrier for gene therapy as a treatment modality for patients with all forms of heart disease.

The research team (clinicians and scientists) have access to NSW based technology for vector development and a heart biobank that will make this research internationally unique and competitive. This research strategically aligns with other NSW Health supported initiatives for the development of novel biological therapies for human disease. To accelerate the clinical use of promising vectors, protected findings will be disseminated via academic channels and vectors will be made available to other clinician/researchers world-wide to ensure maximum knowledge translation.

Ventricular tachycardia (VT) is a life-threatening heart rhythm disorder that leads to sudden cardiac death (SCD)/cardiac arrest. Approximately 15,000 Australians die of SCD each year. Cardiac arrest survivors receive a specialised pacemaker implanted under the skin called a defibrillator. If a patient experiences VT again, the defibrillator will internally shock the patient and prevent a cardiac arrest. There are an increasing number of cardiac arrest survivors in Australia who are recipients of a defibrillator.

Whilst a defibrillator will stop VT when it occurs, thus avoiding a cardiac arrest, up to 40% of defibrillator recipients will experience a highly malignant condition called VT Storm. This is when ≥3 episodes of VT occur within 24 hours. Storm results in an 18-fold increase risk of death, and major psychological trauma from recurrent painful shocks. Hospitalisation and medical costs dramatically escalate after an episode of storm. Currently, storm is treated with powerful doses of medications called anti-arrhythmic drugs (AADs). AADs tend to have potent side effects, and a delayed onset of action resulting in prolonged hospitalisation (for two or more weeks) and are limited in their effectiveness in controlling storm.

An alternate option is to perform a cardiac keyhole procedure called ablation. Ablation involves navigating electrical wires up through the veins to the heart, to identify, cauterise and destroy the abnormal heart muscle tissue causing VT. Observational studies show that ablation has the potential to cure storm in 95% of patients, and leads to early discharge from hospital (within a few days), with a potential reduction in health care costs. However, ablation carries a risk of 1-5% risk of complications.

No prior study has directly compared the effectiveness of the two treatment approaches (AAD vs. cardiac ablation) for VT storm. The Code STORM study is a randomised controlled trial of ablation compared to the traditional approach of AAD for the treatment of storm. The primary outcomes will compare if one strategy is superior to the other in abolishing storm, preventing future recurrence of VT, survival, quality of life and medical costs. We hypothesise that ablation will result in reduction in recurrence of VT, complications related to hospitalisation and use of AADs, improved survival, improved quality of life and a cost advantage relative to AADs.

This world first, innovative clinical trial will provide robust evidence for a clear pathway for VT storm management that will be adopted in treatment guidelines, policy and clinical practice.

Heart procedures are changing. Valve replacement used to be done with open heart surgery and bypass. More and more, heart valves are being replaced by a small wire or catheter inserted from the arteries and veins at the top of the leg. These minimally invasive catheter procedures can be safe, allow faster recovery, and reduce costs to the health system.

The mitral valve is the most commonly diseased heart valve, but currently there is a problem with catheter-based procedures to replace it. Because the cardiologist can’t see the valve and is operating via X-ray and a wire, the valve has to be perfectly sized before the operation, and placed to fit each patient individually. The valve can also block the flow of blood out of the heart, resulting in a catastrophic loss of blood pressure. Because of this potential complication, up to 60% of patients referred for a catheter mitral valve replacement are refused the procedure.

The team has developed a method to create an exact 3D model of a patient’s heart from a CT scan. Using computer simulation, the team can practice heart surgery using different valve sizes, positions and techniques. They can also use the computer to predict exactly how blood will flow around the new valve in the beating heart.

These computer simulations can make valve procedures safer and more predictable. They can help patients and doctors decide which is the best procedure for them. They can help doctors learn about new catheter-based techniques more quickly and more safely. The computer simulations can also help patients avoid long stays in hospital and reduce the surgery costs to the health system.

NSW was one of the first places in the world to introduce catheter based mitral valve replacement, and NSW continues to lead the way coordinating the largest trials in this new procedure. This project will reinforce the leading role of NSW in health research in this area. It will also give NSW patients access to the very best possible technology for planning and performing their heart procedures.

Inflammation plays a critical role in rupture (or bursting) of atherosclerotic plaques in the wall of blood vessels supplying heart muscle, leading to cessation of blood flow and resulting in a heart attack, the leading cause of death in Australia. Despite current guideline-directed treatments, approximately 20% of patients who have had a heart attack remain at high risk of future heart attacks, predominantly because current therapies do not specifically target the inflammatory component of atherosclerosis.

Colchicine is a commonly used and well tolerated anti-inflammatory agent, used to treat a variety of non-cardiovascular diseases (for example gout). This project aims, for the first time, to investigate whether colchicine can specifically inhibit the inflammation that drives atherosclerotic plaque rupture leading to a heart attack. This outcome will be assessed by utilisation of cutting edge imaging techniques of the heart and large arteries of the neck (which commonly develop atherosclerosis).

The team will also follow these patients for up to three years to determine whether colchicine therapy reduces future heart events. This study has the potential to (1) increase our understanding of the role of inflammation in patients that have had a heart attack and are at risk of future heart attacks, and (2) demonstrate that colchicine, an inexpensive and well tolerated currently available drug, decreases future heart attacks in this high risk population, in a cost-effective fashion. In turn, the team expect their findings will change heart attack management to include colchicine in current guidelines.

Overweight and obesity affects over 25% of adolescents (aged 13-18 years) living in NSW. Weight gain in adolescents is related to heart disease in later life. NSW Health offers state-based obesity prevention programs for children <13-years-old and adults >18-years-old. Currently, there are no adolescent-focused NSW-wide obesity prevention programs, which is inequitable. Lifestyle risk factors namely, suboptimal diet, physical inactivity, and overweight and obesity are well established during adolescence, making this second decade of life (10-19 years) a critical period for the development of lifelong health trajectories.

In Australia, over 90% of adolescents own a mobile phone. Text message based healthy lifestyle programs can improve lifestyle behaviours in adults. However, there is limited long-term, high-quality evidence for the role of text messages in prevention of obesity in adolescents.

To address this evidence gap, Dr Partridge has codesigned an interactive text message program for adolescents, targeting key weight-related lifestyle behaviours namely, physical activity, healthy eating, and mental wellbeing. In the text message development phase, she has already engaged key stakeholders, including adolescents, adolescent health experts, and public health and research professionals. Specifically, her research aims to:
1. test the effectiveness of a text message healthy lifestyle program compared to usual care in improving BMI z-scores and key lifestyle behaviours
2. explore the acceptability, utility and feasibility of the program to inform implementation and integration into existing services.

This research will generate much needed evidence on text message programs to improve BMI, diet, physical activity and mental wellbeing in adolescents, as well as evidence to incorporate the program within the NSW health system. Above all, this program could ultimately help reduce the burden of obesity and heart disease in adolescents in NSW and potentially across Australia.

More information:
www.textbitesstudy.com
https://www.sydney.edu.au/medicine-health/about/our-people/academic-staff/stephanie-partridge.html

Approximately one in five adult Australians have metabolic syndrome, a condition characterised by a combination of increased weight, high blood sugar, cholesterol and blood pressure in the same person that triples their risk of heart attack and stroke. Heart attack and strokes result from the presence of “sticky” platelets that build up clots in the blood stream. Common drugs such as aspirin are not very effective in preventing “sticky” blood in metabolic syndrome; there is a pressing need to understand mechanisms causing this to develop new drugs to prevent clots.

The team discovered a group of enzymes in blood, named thiol isomerases, which control blood clot formation. These are overactive in metabolic syndrome, making platelets stickier. Importantly, they found that these enzymes are particularly overactive under conditions of disturbed blood flow, as occurs when blood vessels are narrowed by cholesterol build up. Using new technology, the team has developed a biochip to measure effects of thiol enzymes, coupled with disturbed flow, and are evaluating this as a new blood test to detect sticky blood. They envision that their flow chips will become a useful tool to detect prothrombotic tendency in patient samples and that inhibitors of thiol isomerases will prove to be an effective and safe treatment for individuals with metabolic syndrome.

With collaborators at Harvard University, the team identified a drug, isoquercetin, that inhibits thiol isomerase activity and can prevent vein clots in cancer patients. They will evaluate this in mice with metabolic syndrome to determine its ability to prevent thrombosis. If effective, they will perform a clinical study using isoquercetin treatment to decrease sticky blood in people with the metabolic syndrome.

Dr Freda Passam is a haematologist in the Royal Prince Alfred Hospital, Sydney, with a special interest in thrombosis and haemostasis. She leads the Haematology Research Group of the Heart Research Institute/University of Sydney in the Charles Perkins Centre focused on new mechanisms of clot formation that can lead to the development of efficient and safer antithrombotic drugs. She has a keen interest in the application of microfluidic devices for the detection of thrombotic tendency in patient samples.

This project aims to improve survival and quality of life in people with obesity, by allowing for recognition of currently undiagnosed heart disease.

In 2014-15, 11.2 million (2/3 Australians) were overweight or obese. Obesity directly impacts heart function and in the long-term leads to various cardiac problems including: heart attacks, heart failure and irregular heart rhythms. The tools available to detect the impact of obesity on the heart are limited and often miss early disease. Current guidelines and recommendations for both our diagnosis and treatment of heart disease often ignore patients with obesity.

The team will use recent advances in how images of the heart are taken (cardiac imaging) to detect very early signs of heart disease. Dr Pathan’s team will use tools including recent advances in ultrasound and magnetic resonance imaging of the heart to pick up early heart disease, allowing them to treat patients and their family members before it is too late.

This research will focus on impact of obesity in the fetal stage (unborn baby) to adult life and comprehensively provide a life span view of obesity on the developing and adult heart.

The questions we are looking to answer are:
1.) how does maternal obesity and diabetes impact the heart of the fetus?
2.) is there evidence of early heart disease in adolescents and adults who are obese?
3.) what is the impact of obesity on the hearts of adults and can they be reversed with weight loss surgery?

The areas serviced by Nepean Hospital face significant socio-economic disadvantage and a disproportionately higher burden of obesity. This is necessary local research which will first and foremost benefit the local community, as well as having an impact worldwide.

Hypertension is a disease affecting over one billion people worldwide. It is the strongest modifiable risk factor for cardiovascular diseases, which is the leading cause of death worldwide. Despite multiple medications, up to one in eight patients fail to achieve blood pressure control. Overly active kidney nerves are a driver for hypertension.

Using a minimally invasive procedure where catheters are placed into the kidney artery, it is possible to ablate (inactivate with heat) these nerves as they course around the artery. This is called Renal Denervation (RDN). Currently available RDN devices use radiofrequency energy that burns the inside of the artery and do not penetrate deep enough to reach all the nerves; resulting in incomplete denervation and inconsistent therapeutic efficacy. Furthermore, no clinically feasible method has been available to assess kidney nerve function during the procedure to determine denervation.

Dr Qian is a Cardiologist and with his team at Westmead Hospital and the University of Sydney, have created the Mu Catheter, an RDN device that uses microwave energy to ablate kidney nerves. They have showed that the prototype Mu Catheter can effectively destroy the vast majority of kidney nerves without injury to the artery. They also discovered a useful method to test kidney nerve function. A ganglion called the aorticorenal ganglion (ARG) sends nerves to the kidney. Using a catheter, they can electrically stimulate this ganglion and make the kidney artery constrict. The absence of this response can show that the kidney has been denervated. This is a simple test that can be used during a RDN procedure to confirm treatment effect.

This grant will fund a project examining the safety and efficacy of an industrially designed preclinical version of the Mu Catheter and the use of ARG stimulation in guiding renal denervation to treat hypertension. The teams findings may have important implications in reducing the risk of cardiovascular disease for patients who have difficulty controlling blood pressure or prefer to be on fewer blood pressure medications.

Sepsis is a life-threatening syndrome caused by a dysregulated immune response to infection and characterised by cardiovascular and organ dysfunction. Conservative estimates indicate sepsis to be the leading cause of mortality in critically ill patients worldwide. Mortality rates dramatically increase in patients suffering from septic shock, a severe form of sepsis characterised by low blood pressure. Each year 18,000 Australians suffer from sepsis or septic shock, with an associated mortality rate of >25%. In-hospital costs for treating patients with sepsis amount to AUD$846 million, with the annual all cost economic burden estimated at $1.5 billion. Due to the heavy financial burden and high fatality rate, treatment of sepsis is a state and national priority.

The clinical management of sepsis relies on treatment of the underlying infection (administration of antibiotics), resuscitation (administration of oxygen and fluid), and supportive care (lung ventilation, kidney replacement therapy, sedatives and nutrition). Alarmingly however, there is still no specific treatment available to treat the cause of, or clinically manage the loss of blood pressure control seen in septic shock. Current treatment (administration of vasoconstrictors) non-specifically increase blood pressure but do not improve the ability of the small blood vessels to sufficiently perfuse essential organs such as the brain, heart and kidneys, and can also be associated with detrimental side effects.

The team have recently discovered a completely novel mechanism of blood pressure control in an experimental model of sepsis. Preliminary studies suggest that this pathway may also be operative in humans suffering from sepsis. The newly discovered pathway is predominantly active in the small blood vessels that regulate blood pressure and is dependent on the formation of a novel molecule. Dr Stanley now wishes to obtain proof-of-principle that the novel pathway and molecule are also relevant in human sepsis. In doing so, he will define new treatment options for the restoration of normal blood pressure in experimental sepsis, thus laying the foundations for translation into human sepsis.

Advances in anti-cancer treatment have led to improved survival of patients with cancer but have also increased morbidity and mortality due to treatment side effects. Cardiovascular diseases are one of the most frequent of these side effects, leading to premature morbidity and death among cancer survivors, affecting up to a third of people living with and beyond cancer.

The number of cancer patients and especially survivors is growing exponentially and thus there is a growing need for ‘cardio-oncology’ specialists to manage the rapidly growing number of patients with cancer and co-morbid cardiovascular disease.

One of the key issues in management of these patients is the lack of proven cardioprotective strategies. While cardiotoxicity of chemotherapy has been known since 1960s, to date, there are no cardioprotective agents in routine clinical use.

A/Professor Aaron Sverdlov in partnership with A/Professor Doan Ngo have established and co-lead a unique “Cancer and the Heart” Cardio-Oncology Program. Their mission is to improve acute and long-term cardiovascular outcomes in patients with cancer via an integrative multidisciplinary collaboration between cardiology, oncology, haematology, radiation oncology, pharmacy and pharmacology, leading to better understanding, detection, monitoring and treatment of cardiovascular complications arising from cancer therapies.

The purpose of this specific project is to initiate and lead a discovery research as part of our overall Cardio-oncology Program that is focused on repurposing drugs that could provide dual cardio-protective as well as anti-cancer roles. The team will screen a number of medications, some already available on the market and some in final stages of development, for their ability to protect cardiovascular system from damage caused by chemotherapy.

The overall goal is to enable and lead a NSW-initiated direct translation of world-class Australian biomedical research, into lifesaving medicines for a rapidly rising number of patients with concomitant cancer and cardiovascular diseases worldwide.

This capacity building scheme recognises the leading role cardiovascular disease plays in illness and death for the people of NSW and Australia. Surgery or device implantation is increasingly the approach for many patients, though we continue to rely on materials and implants developed using old technology.

Implants are typically made from metal alloys (e.g. stainless steel) or hydrophobic plastics we use every day in our homes such as Gore-Tex (rain jackets) or PET (drink bottles). These materials are chosen for their durability and ease of mass manufacture, though they promote blood clots and interact poorly with vascular cells, driving chronic inflammation. Accordingly, bypass grafts made from these materials uniformly fail in small diameter applications such as the coronaries or in the legs. Metal stents have serious shortcomings when deployed in the legs. The lack of effective and biocompatible devices means that improved alternatives are urgently needed. Development of new biomaterials with appropriate mechanical and biological properties would revolutionise the treatment of cardiovascular disease.

A/Professor Wise’s group is developing new materials and devices to better treat cardiovascular disease, including grafts, stents and valves. The multi-disciplinary team consists of bioengineers, biologists, physicists and surgeons working together to find solutions for the most pressing unmet needs in cardiovascular medicine. To evaluate and drive them toward translation, the team have developed a suite of lab-based assays, complimented by small and medium animal models and comprehensive histopathology. At present, large animal models required before first-in-human evaluation are commonly outsourced interstate or overseas, a resource and cost intensive approach yielding poor quality results.

This project aims to establish a Centre for Pre-clinical Evaluation of Cardiovascular Devices in NSW, aiming to bridge the divide between the lab bench and first-in-human trials. With important components of these pathways already in place, the funding will close the current gaps, leveraging existing support and expertise from Sydney Local Health District, and access to world-class facilities.

A/Professor Wolfenden is a NHMRC Career Development Fellow / National Heart Foundation Future Leaders Fellow and Health Promotion Program Manager at the Hunter New England Local Health District. He is also the Director of the NHMCR Centre for Research Excellence in Implementation for Community Chronic Disease Prevention and serves as a Co-Director for the WHO Collaborating Centre for NCD Program Implementation. His research seeks to reduce the burden of chronic diseases including cardiovascular disease in the community through undertaking research to trial interventions to reduce modifiable cardiovascular disease risks, and trialling implementation strategies to increase their adoption in clinical and community settings. He has a particular interest in identifying low cost interventions that can rapidly be delivered at scale to reduce population levels cardiovascular disease risks.

As part of the NSW Cardiovascular Research Capacity Program funding, he will seek to test the impact of a simple intervention to improve physical activity and cardio-respiratory fitness among primary schools students, and in particular girls. To reduce the burden of cardiovascular disease on the community, it is recommended that governments invest in promoting physical activity in schools.

The aim of this study is to assess the effectiveness of an ‘activity supporting’ school uniform in reducing cardiovascular risks in children attending NSW primary schools. The study will recruit NSW primary schools who will either introduce an activity supporting school uniform, or to maintain their current traditional school uniform. In each group the team will assess student cardio-respiratory fitness, physical activity levels, and weight status. These measures will be assessed at baseline, six months and twelve month follow-up.

This research tests an intervention that has been purposefully selected on the basis that it is amenable to rapid spread (highly scalable). If effective, the intervention may represent a priority candidate for adoption across the Hunter New England Local Health District, and other jurisdictions to reduce cardiovascular disease risks. The research has been developed to address a specific need identified by local health services and will be undertaken in partnership with end-users.

Vascular calcification is the pathological hardening of blood vessels. The presence of calcium minerals in blood vessels compromises vessel elasticity, leading to vessel stiffness, rupture, and premature death. It is a frequent and deadly complication of many cardiovascular disorders including coronary artery disease and atherosclerosis, and is significantly exacerbated with ageing, and in individuals with diabetes mellitus and chronic kidney diseases.

The change in the function of vascular smooth muscle cells, the main cell type found in blood vessel walls, from the contractile state to a bone-forming cell type, is a key initiating cause of vessel calcification. The main Aim of this Research Grant is to develop new methods to revert calcified vascular smooth muscle cells back to their physiological cellular state.

Through this research the team will (1) uncover novel genes and pathways that are involved in vascular calcification, and (2) identify clinically approved compounds that may be repurposed as novel treatments to reduce/reverse vascular calcification. Through clinical collaborators and the availability of a large repertoire of human samples, the teams’ data may lead to better recognition of at-risk individuals, and lead to earlier initiation of life-saving therapies. The project brings together researchers, clinicians, surgeons, and pathologists from Australia, China and USA with expertise in vascular biology, epigenetics, human genetics, and bioinformatics.

In Australia, 6% of adults have diabetes mellitus (DM), which is associated with a doubled risk of heart attack, precipitated by atherosclerotic cardiovascular disease. In the past 25 years, the prevalence of DM in Australia has more than tripled and projected to rise.

An estimated one-third of young adults will develop DM during their lifetime, translating to increased risk of cardiovascular (CV) events.

Despite the high CVD burden associated with DM, the pathways responsible for elevated risk are incompletely understood. CV risk factors often seen in conjunction with DM include
hyperglycaemia, atherogenic dyslipidemia, insulin resistance and low-grade systemic inflammation - all of which may contribute to platelet and myeloid hyperactivity. Platelet hyperactivity is independently associated with long-term mortality and CV events. Notably platelets from DM subjects are more hyperreactive and less responsive to current antiplatelet, antithrombotic-based therapies.

Dr Barrett has recently found that platelets primarily associate with macrophages in atherogenesis, the inflammatory hallmark of lesions, and directly mediate myeloid inflammatory responses accelerating atherogenesis [12, 13]. Moreover, Dr Barrett has found myeloid cells and platelets to be hyper-inflammatory in DM indicating these interactions are exacerbated in DM.

Dr Barrett’s research proposes that an unbiased approach to assess DM platelet hyperactivity will provide insight into the mechanisms by which they contribute to unresolved inflammation, an increasingly appreciated risk factor for CVD. Additionally, this approach is likely to facilitate the development of a new class of therapeutics to suppress platelet inflammatory potential (i.e. distinct from therapies that curtail their thrombotic actions, aspirin & P2Y12 inhibitors) translating to reduced platelet-mediated inflammation in CVD, especially in those with DM.

Heart Disease in Women has been universally described as “under recognised, under treated and under researched.” Australian and international evidence demonstrates poorer outcomes for women with heart disease as well as an extreme paucity of data on female-predominant heart conditions.

Dr Zaman will build a nationally leading and internationally recognised program of research that improves outcomes for women with heart disease. This program of work will be most successful by gaining the mentorship from experienced clinical researchers within the Westmead Applied Research Centre (WARC) of The University of Sydney and, by locating it within a population of need in the Western Sydney Local Health District; a socioeconomically disadvantaged area with a culturally and linguistically diverse population.

Dr Zaman’s two research flagships are (i) atherosclerotic heart disease in women and (ii) improving care of Female-Predominant Cardiac Conditions. The potential impact will be discovering new interventions for women’s heart disease including the development of innovative models of care. Ultimately, these findings will be translated to clinical guidelines and address the large burden of cardiac disease in women.

Professor Jason Kovacic is among the world’s leading authorities on PHACTR1, with his studies demonstrating the key role of this gene in multiple vascular diseases including fibromuscular dysplasia (FMD), spontaneous coronary artery dissection (SCAD) and coronary artery disease (CAD). Due to its profound complexity, prior research efforts spanning almost a decade have struggled to understand this critical gene. In response, Prof. Kovacic has set about to systematically understand PHACTR1 and wishes to establish a cutting-edge program of research in NSW to finally understand its causative mechanisms.

To do so, he has created unique mouse models where the entire PHACTR1 gene is deleted. Partnering with an Australian mouse engineering company (Ozgene), this important resource is now validated ready for immediate transfer to NSW and the VCCRI to facilitate these studies. The vital importance of these studies is underscored by the multiple vascular diseases where a role for PHACTR1 has been shown, including FMD, SCAD, CAD, migraine, cervical artery dissection and hypertension. Thus, the patient populations that stand to benefit from his proposed studies are substantial. PHACTR1 is a causative gene in multiple vascular diseases that afflict a broad spectrum of our population. Due to higher rates of obesity and smoking, CAD, a focus area of this proposal, disproportionately affects socioeconomically disadvantaged groups. Furthermore, PHACTR1 is also involved in the pathobiology of FMD and SCAD – both being diseases that affect women at about a 10:1 ratio over males. Thus, the proposed studies are of major relevance for priority population groups in NSW.

The sympathetic nervous system (SNS) is a key regulator of cardiovascular (CV) and metabolic function. Targeting the SNS to inhibit its activation therefore has great potential to improve both CV and metabolic health. A pioneer in exploring potential therapeutic targets to inhibit SNS activation, Professor Schlaich currently leads a first-in-human study to assess the BP lowering effect of transluminal ablation of the carotid body (CB) and is involved in a first-in-human study of catheter-based hepatic denervation to improve glucose metabolism in patients with T2DM. Mechanistically, he has demonstrated a link between SNS activation and other drivers of CV and metabolic disease such as the immune system14,15. This work provides the foundation for the proposed highly innovative research program. Prof Schlaich will utilize the University of Sydney’s resources to perform further studies and translate these novel therapeutic approaches and technologies into clinical practice. The program’s 5 projects are highly likely to result in significant knowledge gain and changes in clinical practice within 5 years.

The heart is innervated by a network of nerves (intrinsic cardiac ganglion neurons) that modulates heart rhythm and force of contraction. This network interposes between the brain and the heart, influencing the reciprocal signalling between both organs. There is compelling evidence that this network of nerves can trigger serious arrhythmias and affect survival in a range of cardiac diseases from coronary heart disease through to single gene disorders. At present, we have a limited understanding of how these nerves communicate with each other and with the heart, and we only have crude methods (e.g. nerve ablation) to deal with malfunction of intrinsic cardiac nerves. This project will study ion channels and receptors, membrane proteins that are responsible for the molecular mechanisms by which nerves communicate, to help design better treatments.

Over 400 distinct ion channels and receptors have been identified to date, and changes in their expression and function can lead to the manifestation of various diseases including in the cardiovascular system. Thus, modification of pathological cardiac function through ion channels expressed in the intrinsic cardiac nervous system is a plausible therapeutic strategy demanding development.

The intra-cardiac neuronal network is linked to various cardiac diseases, including heart attack, angina, nerve damage caused by diabetes and the infectious Chagas disease. In the context of heart attack, changes to intra-cardiac nerves during healing of the heart can often produce fatal arrhythmias. Professor Adams’ laboratory has developed techniques that allow an innovative approach to understanding the abnormal electrical behaviour of these nerves, including the ability to prepare and study whole mammalian intrinsic cardiac ganglion. These techniques can precisely guide the development of novel therapies or repurposing currently available drugs for novel therapeutic interventions.

The proposed research seeks to better understand intrinsic cardiac neurotransmission as a prerequisite to the development of new therapeutic approaches for treating common, serious life-threatening cardiovascular conditions. This research will help build capacity in cardiovascular disease research in NSW with emphasis on those conditions associated with atrial fibrillation and cardiac arrhythmias.

Professor David Celermajer leads a multidisciplinary clinical and research team caring for young adults with congenital heart disease (CHD), an important and growing sector of the community, at the Adult Congenital Heart Centre. With major advances in treatments for children with heart disease since the 1970s, an increasing number of survivors with complex heart problems have now reached adult life and require ongoing expert care.

The comprehensive Adult Congenital Heart Centre at Royal Prince Alfred Hospital is the biggest in the Southern Hemisphere and looks after several thousand young adults with complicated and often difficult ongoing heart problems. These young adults need expert care for their medical needs but also their psychosocial and mental health needs also.

The team involves nurse specialists, psychologists, exercise physiologists, dieticians and of course cardiologists, cardiac surgeons and other medical specialists. The current project aims to conduct the first comprehensive survey of the “life experience” of adolescents and young adults with congenital heart disease”. The eventual aim is to develop the best and most effective strategy for delivering the best wholistic, clinical care.

The research program aims to profile the health and social outcomes for CHD patients and their parents and to determine their healthcare utilisation through data linkage with important health databases across Australia. Consumer engagement is an important issue in determining the best way to provide optimal CHD care, throughout an individual’s life.

The project involves assessing the psychosocial, mental health, neurocognitive and quality of life outcomes for young adults with congenital heart disease, as well as physical assessments such as body composition and fitness. The project will account for their educational level and employment history, and will study their health services utilisation. It will also look at financial impacts and employment disruption.

This research aims to give the best picture yet, internationally, of the burden of disease on young adults with congenital heart problems, across the life course.

Professor Beng Chong is a haematologist who is renowned internationally for his research in clotting and bleeding disorders. Clotting of arteries causes heart attacks and stroke. The current concept of clotting is rapidly changing away from the traditional view that clot comprises only platelets and fibrin.

New research shows white cells and a network of DNA acting as a scaffold for clot formation is essential for clotting. Professor Chong’s research will produce new knowledge of clotting mechanisms and will provide ideas for new research resulting in discovery of new drugs that are more efficacious and safer as they will cause less bleeding. These drugs will undergo clinical trials to test their efficacy and safety. If successful, treatments with these new drugs will improve patient outcomes.

The team will collaborate with other clinicians, policy-makers, patient-advocacy groups, industry and the media, to facilitate translation of the new treatment into practice and policy.

Dilated cardiomyopathy (DCM) is a costly and often deadly heart muscle disease. It can strike at any age and is a major cause of heart failure in the young and in pregnant women. Consequently, its medical, psychosocial, and productivity costs are substantial. New ways to treat and prevent DCM are urgently required. This is an enormous challenge for patients with genetic causes of DCM, since interventions to change the inevitable effects of underlying gene mutations have not been possible.

Mutations in the TTN gene that result in an abnormally short titin protein (called “TTNtv”) are present in one in every five families and are the most common genetic cause of DCM. By studying hundreds of families, the team has found that some TTNtv-positive relatives experience heart failure in their teens or early twenties, while others have relatively normal heart function until late in life. This marked variability suggests that factors in addition to the TTNtv may be involved.

In this study, the team are investigating the hypothesis that unique combinations of genetic background, other illnesses and lifestyle factors can increase (or reduce) the severity of disease in individual TTNtv carriers.

The first aim is to find out what some of these “modifier” factors might be. This will be done by gathering information about health and lifestyle in a large group of families who have TTNtv-related DCM. The team will also undertake genetic analyses to see if there are any other genetic variants present that might have deleterious effects. The second aim is to get evidence that suspected modifying factors do in fact alter heart function in the setting of TTNtv. The team will use a unique zebrafish laboratory generated model generated that spontaneously develops DCM during adult life, similar to human TTNtv-related DCM. The team will look to see whether these effects of TTNtv are magnified (or attenuated) in the presence of additional genetic and/or environmental insults. These cutting-edge studies are only now possible following development of new miniaturised tools for undertaking serial assessment of cardiac function in living fish.

It’s expected that incorporation of risk factor management will emerge as an important component of personally-tailored clinical care. The ability to shift DCM onset potentially by decades and/or reduce disease severity, would have substantial benefits for patients and their families, as well as reducing healthcare costs.

By the time cardiovascular disease has become life threatening it is often very difficult to make sense of the complex changes that have occurred in the heart secondary to disease. Better, earlier descriptions of disease are vital. The lack of detailed phenotype information of common heart diseases limits the potential of powerful and fast evolving fields like genomics, pharmacogenomics and molecular biology.

The Cardiovascular iBank will establish a powerful imaging databank designed to describe and measure common cardiovascular diseases using imaging and other techniques. Our approach will use advanced imaging and analysis to obtain “Deep Phenotypes” of common diseases as they evolve from the healthy state to symptomatic disease.

Accurate measurements of diseases such as atherosclerosis, hypertension, heart failure and structural heart issues like aortic stenosis will permit researchers to target interventions before diseases are irreversible. These “phenotype” signals will enable earlier detection, allowing intervention before diseases declare themselves via hospitalisation or death. The iBank will enhance work in other non-imaging areas like genomics by providing a more complete picture of the whole patient, aiding cardiovascular “precision medicine” to become a reality.

Proteins are responsible for all of life’s processes and are the most sophisticated molecules made in nature. Professor Phillip Hogg’s research has changed our concept of how proteins work, discovering that several proteins involved in cardiovascular disease exist and function not as a single form but as a multitude of different forms. This has significant implications for how these proteins function generally and for drug resistance and drug development in cardiovascular disease. For example, if a drug binds preferentially to one or more forms of a protein, then events that reduce the incidence of these forms in individuals would result in drug resistance. Similarly, if drugs are developed against some forms of a protein but not others, this will inevitably result in drug resistance in some individuals. This project will focus on the importance of this discovery for the formation of blood clots.

Blood clots in heart blood vessels both accelerate the development of heart disease as well as trigger heart attacks. Many individuals have a heightened tendency to form blood clots for usually unknown reasons, so it has been difficult to reduce their lifetime risk of cardiovascular disease. In addition, preventing clots forming in diseased heart blood vessels and on implanted blood vessel stents is an ongoing challenge, as the current anti-clotting drugs are ineffective in up to half of patients for often unknown reasons. The discovery that proteins involved in blood clotting exist in many different forms represents an entirely novel aspect of how and why blood clots form. This finding may underlie why some individuals have increased tendency to form blood clots and why they are often resistant to anti-clotting drugs.

Professor Hogg will investigate these questions in patients with coronary artery disease, heart failure and type II diabetes. These three cardiovascular diseases are strongly associated with blood clot formation. A better understanding of why blood clots form and why patients can be resistant to anti-clotting drugs will enable personalised anti-clotting therapy and development of more effective anti-clotting drugs. The long-term aim is to develop new anti-clotting drugs that overcome the resistance to the current drugs.

Described as the epidemic of the 21st century, diabetes represents a serious healthcare problem globally, and the biggest challenge confronting the Australian health system. A large proportion of deaths (70%) associated with diabetes can be attributed to the development of blood clots in the circulation of the heart and brain (heart attack/stroke). Both conditions are typically caused by clots that block the supply of blood to the heart or brain. Blood thinners are commonly used to prevent clots with millions of people worldwide taking them daily to keep strokes and heart attacks at bay.

However, in individuals with diabetes, not only is the blood clotting mechanism ‘hyperactive’ for reasons that are unclear, the benefits of standard blood thinning therapies like aspirin and Plavix are also limited. Diabetic individuals don’t respond as well to standard blood thinning drugs like aspirin and Plavix that are used as standard therapy for treating blood clots. With 1.2 million people with diabetes in Australia, there is urgency to understand why these patients are at greater risk of developing blood clots and dying from cardiovascular disease.

Professor Jackson’s research team has studied the blood of people with diabetes and unexpectedly discovered a new pathway responsible for triggering the formation of blood clots, demonstrating that disturbances in blood flow (biomechanical forces) can activate blood clotting cells, leading to growth of bigger clots. While this process occurs in all individuals, the clotting cells of patients with diabetes are exquisitely more sensitive to these mechanical forces, triggering larger blood clots. How blood clotting cells can sense disturbances in blood flow, and why this process is altered in diabetic individuals to cause the formation of dangerous blood clots that cause cardiovascular disease is an important area of study which will be addressed in this proposal.

Professor Shaun Jackson is an NHMRC Senior Principal Research Fellow, faculty member at the prestigious Scripps Research Institute in La Jolla, San Diego (CA, USA), and recently appointed to the title of Honorary Visiting fellow at the University Cambridge, School of Clinical Medicine, within the Department of Haematology.

Professor Jackson established his independent research laboratory in the Monash Department of Medicine at Box Hill Hospital in Victoria (1998–2003). In 2004 he moved to the Alfred Medical Research and Education Precinct, where he co-founded and became Research Director of the Australian Centre for Blood Diseases. He is a founder of Kinacia, an Australian biotechnology company developing novel diagnostic and therapeutic products aimed at preventing blood clotting. In 2013, he was appointed the inaugural Director of Cardiovascular Research, HRI & Charles Perkins Centre, The University of Sydney, where he remains to this day.

Professor Jackson’s research interests are focused in the area of atherothrombosis and cardiovascular disease.

Heart attack and heart failure claim the lives of 30 Australians daily. For patients suffering a heart attack, emergency transfer to hospital and urgent opening of the blocked coronary artery is the most effective treatment. However, delays in the recognition of the problem and in transferring patients to hospital—the latter compounded in rural and remote areas—reduce the amount of heart muscle that can be salvaged. For a person suffering a heart attack, “time is muscle” and every minute counts.

Heart transplantation (HTx) is the most effective treatment for advanced heart failure but is limited by donor availability. Deceased organ donation can proceed by one of two pathways – donation after brain death (DBD) or donation after circulatory death (DCD). While each pathway provides unique stresses on the donor heart, both pathways deprive the donor heart of its normal blood supply – during withdrawal of life support in the case of DCD and during transport of the heart in the case of DBD.

Recently, a peptide extracted from a funnel web spider venom was found by Professor Macdonald’s colleague, Professor Glenn King, to dramatically reduce the size of a stroke in an experimental mouse model, even when administered up to eight hours after the onset of the stroke!

There is now preliminary evidence for a similarly dramatic protective effect of this peptide, called Hi1a, in the heart in an experimental model of donor heart preservation. The team has also found that a new diabetes drug, empagliflozin, also provides potent protection of the heart in the same model. The team believes that Hi1a and empagliflozin exert their protective effect on the heart by blocking different cellular channels in the heart and that administering them in combination will provide additional protection to the heart.

In this project, the team will test the effectiveness of combining Hi1a and empagliflozin in experimental models of heart attack and of HTx. It’s believed that timely administration of these drugs may reduce the size of a heart attack by as much as 50%, even when given hours after the onset of the attack. This will result in fewer deaths caused by heart attack and fewer survivors developing heart failure. Improved preservation of the donor heart for transplantation by Hi1a and empagliflozin will result in an increase in the number and quality of donor hearts that are suitable for HTx.

There are some very common events in pregnancy that unmask a women’s future cardiovascular profile. The amount and severity of high blood pressure in any given pregnancy are directly related to both pregnancy (and baby) outcomes and provide an insight into the risk of future cardiovascular disease for the woman. If a woman has hypertension in pregnancy, her risk is two-fold for developing future cardiovascular disease. This risk is equivalent to the risk of smoking for future heart attack and stroke.

While we can do something in public health terms to prevent smoking, the way to predict and manage the events of pregnancy are yet to be fully explored for women. If we can prevent or control high blood pressure in pregnancy, then the favourable impact to women’s cardiovascular risk would be equivalent to that of stopping smoking.

The strategy within the teams’ grasp is to provide novel treatment that has been trailed in the lab, to treat those in the throes of preeclampsia (the most severe form of high blood pressure in pregnancy). This builds on the teams’ work in establishing a clear diagnosis of preeclampsia, and in developing a prediction model for high risk women.

Sodium glucose 2 transporter (SGLT2) inhibitors are a highly effective treatment for diabetes. Large trials of SGLT2 inhibitors show that these drugs reduce the risk of death, heart attack, heart failure and kidney failure in high risk patients with diabetes. The team in Sydney has led two of the five large studies completed to date and are world experts in the field. Professor Neal will lead a team of NSW researchers that will leverage this existing global leadership position in the field, to design, fund and implement new, large-scale international collaborative trials of SGLT2 inhibitors.

An example of a study already in advanced stages of development is a trial designed to test the effects of SGLT2 inhibitors when used early in diabetes. There is a strong likelihood that the benefits of SGLT2 inhibition will be greater if started early but all trials to date have been in individuals with long-term diabetes. With colleagues in Sweden, the team have designed an international collaborative study of 4400 individuals that will compare the effects of using the SGLT2 inhibitor dapagliflozin as an alternative to current guideline recommended first-line treatment, metformin.

Professor Neal will also work to grow research capacity in NSW with the specific goal of putting the State at the forefront of clinical trials in Australia. This will help patients in NSW to access world first treatments sooner, as well as bringing significant new commercial opportunities to the State. A key component of this work is the development and testing of a Health Research Register. The ‘Count Me In’ register will seek to embed research within the NSW health system and increase community participation in trials by tailoring a model developed in the United Kingdom.

Positive results from Professor Neal’s program of research will lead to new treatments for large numbers of patients in Australia and overseas. By working closely with industry and academic partners the team have already secured drug supply for several and partial funding for others. Development of the ‘Count Me In’ Register is underway and some development funding has been secured from the University New South Wales to use the register to meet COVID-19 research objectives. Our partners will use the data we generate to seek expanded labelling indications for drugs, broader inclusion of patients in reimbursement schemes and drive major beneficial health impacts through the application of their research discoveries.

Simone Schoenwaelder is an Associate Professor at the Heart Research Institute, where her research focus is investigating the biology of platelets – blood clotting cells with a critical role in health and disease. A major part of this focus is to translate discoveries in order to develop innovative therapies for the treatment of cardiovascular diseases including stroke.

A/Professor Schoenwaelder completed her undergraduate Bachelor of Science degree in 1992, receiving first class honours at Monash University in Victoria. Following completion of doctoral studies at Monash University (1996), she spent several postdoctoral years at the University of North Carolina, Chapel Hill (USA) as a National Health and Medical Research Council (NHMRC) CJ Martin Fellow in the Department of Cell Biology and Anatomy, in the laboratory of Professor Keith Burridge.

Returning to Australia in 1999 as an NHMRC RD Wright and Monash University Logan Research Fellow, she joined the Australian Centre for Blood Diseases. In 2015, Simone relocated to her current position at HRI and The University of Sydney. Here, her roles include Associate Director of Research Management and Education at HRI, with a conjoint research title of Associate Professor at Charles Perkins Centre, The University of Sydney (Discipline of Physiology), and honorary visiting scholar at the University of Technology Sydney.

Acute Ischaemic Stroke (AIS) is the third most-common cause of death and a leading cause of disability worldwide. The vast majority (>80%) of strokes are caused by blood clots that block blood flow to the brain. The delivery of treatment for stroke is exquisitely time-sensitive – and only rapid removal of obstructive clot(s) and restoration of blood flow to the brain can prevent permanent brain damage and death.

Drugs that degrade the scaffold of the blood clot (fibrin) are currently used to remove dangerous clots and reopen blood vessels. This type of therapy - referred to as intravenous “Thrombolytic therapy” (IVT) - involves the delivery of an artificial (recombinant) version of the protein tissue plasminogen activator (rtPA). Despite being the only approved drug option since 1996, rtPA has significant limitations which undermine its effectiveness, and cause significant risk of life-threatening bleeding in the brain. t-PA remains the mainstay of stroke treatment globally, and yet is only administered to 10-13% of all stroke patients, less than half of these achieving a good therapeutic outcome.

The identification of safer drugs that can improve the clot-busting potential of rtPA would represent a major advance in the treatment of stroke. The team have found that a naturally occurring anticlotting protein which demonstrates promising anticlotting properties with minimal bleeding. Their studies will determine whether this protein is a safe anticlotting drug that can be used with rtPA to increase the removal of blood clots using a novel preclinical stroke model. These studies have the potential to not only improve the quality of stroke treatment in general, but also to allow access to safer stroke therapies for those in regional and remote areas.

Stroke caused by blockage of a brain artery is a leading cause of death and disability. This project builds on the teams’ recent discoveries in the laboratory and patient imaging. Professor Spratt’s laboratory team discovered a rise in pressure within the skull (intracranial pressure - ICP) 24 hours after minor experimental stroke. We showed that such a pressure rise reduces blood flow further to those areas of brain most at risk of dying from reduced blood flow due to the stroke. This may worsen stroke outcome. The team showed that this occurs by a new mechanism, triggered by a molecule released into the fluid around the brain after stroke.

Additionally, the clinical team have used a new technique to measure pressure within the skull of patients, and shown that this normally remains very stable in people, but rises significantly 24 hours after minor stroke. This is quite a surprise, since previously it was assumed that pressure only increased because of brain swelling.

The teams’ results indicate that there is another, previously unrecognised, cause of pressure rise. Preventing this has the potential to save brain tissue and reduce disability after stroke. The team has discovered a way to do this, using body cooling (hypothermia). Again, disruptive thinking comes to the fore – hypothermia has previously been used in stroke and after cardiac arrest, but typically for 24-48 hours or longer, which may result in complications such as pneumonia. Studies show that a very short duration of cooling is all that is needed to prevent the rise in intracranial pressure, and reduce the stroke size.

Professor Spratt and his team are excited to be awarded this senior researcher grant, which builds on a program of work that started with new discoveries in the laboratory, has been confirmed in studies in patients, and is now nearing the stage of being ready for testing as a very promising treatment to improve the outcome of stroke patients.

Professor Kerry-Anne Rye (BSc (Hons), PhD, FAHA) is Head of Research at the School of Medical Sciences, University of New South Wales. She is recognised internationally for her work on high density lipoprotein (HDL), or “good cholesterol” structure and function, and was the first to report that HDL apolipoproteins have anti-diabetic and anti-inflammatory properties. Her research is concerned with understanding the roles of HDL apolipoproteins in preventing heart disease, which is increasingly recognised as a pro-inflammatory and pro-oxidant disease, and preventing diabetes, a disease that is driven by loss of insulin-producing cells in the pancreas. Professor Rye is actively involved in the development of new therapies for both disorders.

This project will evaluate the capacity of a new peptide called C-II-a that mimics the cardioprotective properties of the main HDL apolipoprotein, apoA-I, to reduce heart disease in people with diabetes. Professor Rye has already shown that C-II-a (i) inhibits inflammation in cells involved in heart disease and (ii) regenerates cells in the pancreas. This is a potential game changer for patients with diabetes, who are at high risk of developing heart disease.

The first part of the project asks whether with C-II-a, when used with an inhibitor of the pro-oxidant, pro-inflammatory enzyme myeloperoxidase (MPO), stops heart disease from developing and reverses established heart disease in established mouse models of diabetes. Heart disease will be induced in the animals with cutting-edge anti-sense oligonucleotide technology.

Existing, innovative, patent-protected technology for generating a form of C-II-a/MPO inhibitor that can be taken by mouth, rather than by injection, will also be developed further.

The final part of the project will identify the optimal timing for C-II-a/MPO inhibitor combination therapy in heart attack patients with and without diabetes.

Collectively, these studies will set the scene for the translation and commercialisation of combination C-II-a/MPO inhibitor therapy into a highly innovative and transformative treatment option for patients with diabetes and heart disease.

Inherited heart diseases are a collection of heart muscle diseases and abnormal heart rhythm disorders. They can affect people of any age and may lead to heart failure or even sudden death. The inherited heart diseases are caused by variants (faults) in DNA sequence. If a person is diagnosed with an inherited heart disease they can undergo genetic testing to look for the disease-causing DNA variant. Finding the genetic cause of disease enables screening of immediate family members who may also have inherited the variant and are at risk of developing the disease. Family members who have inherited the variant and can be clinically monitored more closely whereas those family members who have not inherited the variant are released from life-long clinical surveillance.

Genetic testing for the inherited heart diseases can be improved. Commercial genetic testing currently focuses on screening the protein coding regions of genes, which represents only 1% of our DNA. The purpose of this research project is to develop new and improved approaches to find disease-causing variants in non-coding DNA. This project will develop new methods to find disease causing variants in non-coding regions of our genome, and new assays to confirm that the variants are responsible for disease development.

The project will translate to new genetic testing approaches for the inherited heart diseases with higher diagnostic yield. This will result in earlier identification of at-risk family members, thereby allowing earlier initiation of clinical management with the potential to prevent sudden cardiac death. The new genetic testing approaches will be integrated into clinical practice by our multidisciplinary team, who are recognised internationally in the field of inherited heart disease and sudden cardiac death.

During the course of this research project we will provide free state-of-the-art genetic testing to a large NSW-based patient population, including people who would otherwise not be able to afford to pay for genetic testing. The ultimate beneficiaries of this research project will be NSW-based families with potentially lethal inherited heart disease.

Ischaemic stroke is caused by blockage of an artery supplying a portion of the brain. In most cases, this blockage is caused by a blood clot. Successful treatment of stroke depends on removal of this blood clot, which can be accomplished mechanically with a catheter inserted into the brain artery, or using a drug commonly known as a ‘clot buster’, which can be injected into a vein in the arm. Although catheter-based therapy has been shown to be effective up to 24 hours after onset in carefully selected patients, clot busters are approved for use only within 4.5 hours of onset. Unfortunately, many patients present with blood clots that are in small arteries that cannot be reached with a catheter. If these patients present more than 4.5 hours after their stroke began, they cannot be treated at all. We plan to use the same selection techniques that were used to prove catheter- based treatment can be effective for up to 24 hours after onset to select patients for clot buster therapy.

Clot busters can be used in many more hospitals than catheter-based methods, which require specialised equipment and personnel to perform the operation. This means we can treat many more patients living in rural and small urban centres far from specialised hospitals found in only two cities in NSW.

We will use an advanced form of brain imaging, known as ‘CT Perfusion’. This allows us to measure the blood flow to different parts of the brain. Brain blood flow measurements can be used to predict who will respond to therapy, even when they present late (more than 4.5 hours after onset) and who will not. We will use CT Perfusion to select patients for treatment. They will be randomly (like the flip of a coin) assigned to receive a clot buster known as tenecteplase (‘TNK’) or the standard treatment, which is a baby aspirin. We will then re-image the patients at 24 hours and measure their clinical symptoms for the next three months.

We believe that patients treated with TNK will have better outcomes than those given aspirin. Our research will be the first to show that clot busters can be used safely and effectively in patients presenting to hospital more than 4.5 hours after onset. This will allow treatment of a group of stroke patients who currently have no options available to them, including many who live in rural areas. This study has the potential to change guidelines and treatment approaches almost immediately.

Congenital heart disease (CHD) is the most common human congenital defect, occurring in just under 1% of live-births. CHD is the biggest single cause of child mortality and hospitalisation, excluding communicable diseases. Despite this, only a minority of CHD cases are genetically diagnosed, partly because about 90% of families are not offered the opportunity of having a genetic diagnostic test through the Australian healthcare system. Thus, families are denied the real and the potential benefits enabled by such a genetic diagnosis. Moreover, they are unaware of the impact that CHD will have on their child, and on their lives, as the broad impact has not been studied.

A genetic diagnosis brings immediate benefits to families as they receive information concerning the chance of CHD occurring in subsequent pregnancies. In Australia, with the growing adult CHD population (64,000 living with CHD, half now adults) such family-specific information to manage reproduction is becoming increasingly relevant. Moreover, a genetic diagnosis can in some cases inform a child’s clinical care or predict complications and risk factors for surgery or treatment.

The purpose of this research is to improve the lives of patients and families with congenital heart disease. We will tackle this by: 1) providing families with a genetic diagnosis, 2) improving the rate of genetic diagnosis, and 3) studying the health and education outcomes of CHD patients.


The project makes use of cutting-edge technologies. For example, whole-genome sequencing will determine the sequence of each of 6 billion base pairs of DNA in each patient and their parents so that we can find the genetic mutation that caused their CHD. Likewise, CRISPR technology will improve the rate of genetic diagnosis by helping us rapidly test gene function (in a mouse model) not previously known to cause CHD.

Once we find mutations that cause CHD in each family, this genetic diagnosis will be given to the families’ clinician so that they can be counselled concerning the ramifications of the diagnosis. We will also study aspects of the journey and outcomes associated with the life of a child with CHD in the hope of identifying key points where various activities might improve their lives long-term. In these ways, this research aims to benefit the health of NSW society by improving the quality of life of people with CHD and their families.

Age is the greatest risk factor for disease, particularly heart disease, diabetes and dementia. One in three deaths in Australia are from cardiovascular disease. With the ageing population, and the obesity epidemic, it is imperative that new strategies are developed that can be used to limit the morbidity of age.

These cardiovascular diseases show early changes in the blood vessels and in particular in the structure and function of a highly specialised cell type called endothelial cells. Endothelial cells line the blood vessels and act as a selective barrier between the blood and the tissues. Changes in the endothelial cells result in the loss of the protective barrier function resulting in leaky blood vessels and in a chronic inflammatory state. Such changes have been shown to contribute to the initiation and progression of age-associated disease.

Our ultimate goal is to develop new therapeutics directed towards the age-damaged endothelium, in order to alleviate the scourge of age-associated diseases. To this end, we are defining the molecular changes in endothelial cells as they undergo cellular ageing. Using sophisticated biological analysis and state-of-the-art computer-generated learning technologies in collaboration with national and international experts, we will determine new targets in the ‘aged endothelial cells’ that may be amenable to manipulation. This will be the initial step in development of new drugs that specifically target, for removal, the ‘aged’ endothelium.

Our research findings will be presented in international peer reviewed journals to give maximum exposure to the international scientific field. The scientists involved in the program will also attend relevant national and international meetings where poster or oral presentations of the work will be expected. The Centenary Institute has an active publicity group and any major discoveries will be advertised to the public through this forum. In addition, through symposia organised by Gamble, the work will be disseminated to focussed NSW and Australian researchers.

Before new drugs come to market, we need to ensure that they not only work, but they are safe. It is well known that drugs that unintentionally block the hERG ion channel in the heart can cause fatal cardiac rhythm disorders. This is a major problem for development of new therapeutics since it is estimated up to 70% of all compounds can bind to hERG channels. Consequently, testing for block of hERG as well as prolongation of action potential duration is a mandatory part of preclinical development. This approach has been effective in that no new dangerous drugs have come to market since they have been in place. However, there is widespread agreement that this measure is not specific, resulting in false positive results that have led to premature termination of potentially valuable therapeutics that could prolong or enhance the quality of patient’s lives. The economic implications are also huge, with around $5 billion per annum spent on these screens.

The shortcomings of current methods are that they rely on measures that are poor surrogates for risk that are not mechanistically linked to arrhythmias. We propose that rather than analysis of the duration of repolarisation, that the shape of the cardiac action potential is a much richer source of information about underlying electrophysiology, and that subtle changes in this shape precede the emergence of the irregular activity that triggers arrhythmias. In this study we will test the hypothesis that parameters extracted from quantitative analysis of the shape of action potentials recorded from stem cell derived cardiomyocytes can more accurately predict drug-induced arrhythmia than changes in repolarisation duration. We will build and validate a screening workflow and accompanying software that can be incorporated into preclinical safety screening pipelines that will permit more accurate allocation of cardiovascular safety liabilities and increase the output of new drugs to benefit patients.

The project will leverage the technology infrastructure in the Victor Chang Innovation Centre, which was recently established with a $25 million investment from NSW Health. As part of the iPSC phenotyping core facility we have installed robotic, automated platforms for culture and differentiation of iPSC and functional characterisation of iPSC derived cardiomyocytes. We are the only facility in Australia with access to these combined enabling technologies that will be built on to develop drug screening infrastructure and establish NSW as an internationally recognised centre for safety pharmacology.

The overarching aim of this study is to understand the cellular, molecular and genetic causes of hypoplastic left heart (HLH), a condition that is among the most severe of heart defects occurring in babies at birth. HLH babies are born with a small cardiac left ventricle, the main pumping chamber of the heart. While HLH fetuses are viable after birth without treatment, HLH is inevitably lethal. Therapy involves three surgeries, during which the heart is radically reconstructed. Even though HLH is relatively infrequent (4-8% of all heart defects) and advances in surgery have brought survival to 76% at 25 years, there are many possible complications, sometimes necessitating heart transplantation. There is also a massive cost to the health care system, and a life-long economic and emotional burden on families.

Researchers can now create a type of super stem cell (induced pluripotent stem cells) from any tissue such as skin, from any individual. Stem cells of this sort can be grown in a dish and directed with chemicals to form virtually any mature cell type in the body, including heart muscle cells. This has brought the exciting possibility of studying human disease using (previously inaccessible) patient-specific human tissue. Developments in stem cell culture now allow the formation of cardiac mini-organs (called 3D organoids) containing muscle, vessels and other heart cells, enabling analysis of disease at a whole organ level.

Our team of researchers and clinicians are studying the causation of HLH using super stem cells. We have made stem cells from 10 HLH patients and their parents, who serve as genetically well-matched healthy controls. Researchers previously thought that HLH arose from altered blood flow and pressure secondary to the valve and vessel defects seen in HLH hearts. However, our preliminary studies show that HLH cardiac muscle has underlying growth and functional defects, and reduced expression of genes associated with both heart and brain development, potentially connecting heart structural defects with the poor learning outcomes seen in HLH babies after birth. Our aims here are to delve more deeply into the molecular causes of HLH using 3D beating cardiac stem cell organoids, and to identify and test individual causative genes for this disease. We will also use the organoid model to screen for drugs that overcome muscle growth and functional defects seen in HLH, which could be further developed into therapies that support the post-surgical HLH heart throughout life.

The heart is a companion we must rely on 24/7 all our life. It cannot rest and keeps our blood flow going. This incredible organ stoically transforms electrical into chemical and finally, mechanical signals, ultimately cycling between filling and pumping sequences, like a piston pump. It has to react to changes in load and blood demand, e.g. in exercise and heavy work. Thus, the workload must also be sensed in terms of sensing the mechanical strain on the heart walls and each heart cell reacts with signal modulations. Some of these cellular mechanical biosensors comprise mechanosensitive ion channels (MSC) on the surface membrane of cardiomyocytes (CMs) that are supposed to open in response to wall strain to allow Ca2+ influx into CMs, to not only modulate electrical activity and chemical signalling, but also to support growth and cell anchorage during our life. Under disease conditions, in particular with the very common condition of cardiac hypertrophy and heart failure in Australia, the heart is exposed to reduced pumping force, resulting in increased residual filling pressure and thus, aberrant activation of MSC and downstream signalling. Thus, to control the MSC activity in disease would represent a new tool to control heart failure. Development of the MultiStretcher platform in this project presents a significant step in this direction.

In our project, we will study responses of cardiac model cells to define strains pulling individual cells in multiple directions applying a novel biomechatronics ‘stretch rack’ systems technology that will be re-engineered for high throughput/content application to NSW cardiac research. This international Australian-German partnership will contribute to NSW’s capacity building for better understanding the underlying causes of CVD and their prevention/treatment in the future that, in particular, will benefit adult males and females living in the lowest socioeconomic areas. We will determine the crucial involvement of a specific type of MSC, called Piezo1, in driving aberrant heart signals in response to overstretch of heart cells and will employ pharmacological agents to control this mechanical biosensor.

We expect our fundamental research, which combines cardiac research, biophysics and biotechnology, will be applied to clinical settings using human cells as a validation after completion of our project, resulting in translation of pharmacology insights into drug development pipelines. We will disseminate our research findings though publications in high-impact international scientific journals and presentations at national and international meetings.

Cardiovascular disease (CVD) affects 22% (4.2 million) of Australians. It is expected that in 2019, some 80,000 Australians will be admitted to hospital with acute coronary syndrome (ACS), with more than 55,500 suffering a heart attack. The major cause of heart attacks is atherosclerosis, a progressive disease of large arteries that culminates in the rupture of unstable (or ‘soft’) atherosclerotic plaque, which can lead to a blood clot, the abrupt blocking of the artery and acute, life-threatening heart attack (or stroke).

While death from CVD in Australia has declined over the last decades, the rate of heart attacks has paradoxically increased, and in NSW, the population-adjusted number of heart attacks has remained above the nation’s average. The annual cost of ACS to the Australian Government is around two billion dollars, of which ~75% is due to hospitalisation. To reduce these costs and save lives, it is important to prevent avoidable hospital admission and improve patient outcomes by targeting those most at risk and by improving the diagnosis and treatment of high-risk people.

Currently, the assessment of coronary plaque relies on information obtained from the physical contour of the arterial lumen (coronary angiography) and plaque burden (computed tomography coronary angiography). While these methods have significantly improved the treatment and management of heart disease, they cannot detect ‘soft’ plaques, the rupture of which is thought to cause up to half of all fatal heart attacks. Therefore, identifying and treating ‘soft’ plaque and subjects at high risk of developing an acute event remain major unresolved problems in clinical cardiology and could save the lives of 30-50% of those experiencing a heart attack.

This proposal addresses these important contemporary issues in clinical cardiology, by using novel non-invasive imaging methods to selectively detect ‘soft’ plaque, based on measuring inflammatory activity in arteries; and specific drug-induced inhibition of this arterial activity to prevent plaque rupture and associated thrombosis.

To facilitate translation of the research findings from bench-to-bedside, the investigating team includes clinicians and scientists to provide relevant expertise and practical advice in pre-clinical models (development of novel methods and tools); clinical cardiology (current clinical needs, alignment and improvement of methods to be developed with current practice in ACS diagnosis and patient treatment stratification); cardiovascular imaging (development of probes and specialised imaging sequences for coronary arteries, e.g., for motion correction); thrombosis (assessment of clinically relevant parameters); and industry (economical and intellectual property considerations).

Heart failure is a very common and costly disease that is defined as the inability to pump adequate amounts of blood to meet the body’s needs. A particularly large group of heart failure patients that are difficult to both diagnose and treat, is heart failure due to high blood pressure, diabetes, and/or obesity. This large category of heart failure is particularly associated with three problems, (I) inefficient filling of the heart, (II) thick walls of the heart, and (III) a reduction in blood flow to the smallest vessels of the heart. These three problems are more common with increasing age, are more common in women and indigenous populations, and have been shown to be associated with hospital admission and death.

The purpose of this research is to develop and use state-of-the-art magnetic resonance imaging (MRI) to better understand, diagnose, and evaluate a new treatment heart failure. Specifically, the research focuses on the challenges related to identifying and treating inefficient filling, thick walls, and small vessel disease.

With regards to evaluating inefficient filling, this requires accurate measurement of the speed of movement of the heart during filling, and blood pressure in different chambers of the heart. We have developed pioneering new MRI methods to measure these movements and pressures, and will be evaluating these new non-invasive MRI measures compared to reference measurements in patients. Furthermore, we have found that surgical reduction in the size of the left atrium of the heart may improve the efficiency of filling. Thus, we will evaluate the ability of this new surgical treatment to improve filling efficiency in patients undergoing open-heart surgery.

With regards to evaluating thick walls of the heart, we have developed new methods to better diagnose thick walls by both MRI and the electrical activity of the heart using electrocardiography (ECG). The accuracy and utility of these new methods will be evaluated in patients. Also, the accuracy of a new ECG method to diagnose small vessel disease, as shown by MRI, will be evaluated.

The development and evaluation of these new diagnostic methods and treatment will establish their utility for use in every day care in patients with heart failure who otherwise currently may be incorrectly diagnosed and lack treatment options.

The spectacular developments in sequencing the human genome have led many to speculate that we will soon enter an era of personalised genome guided precision medicine. However, the speed with which we can now “read” the human genome far exceeds our capacity to interpret how gene mutations affect protein function and clinical outcomes. We urgently need to dramatically improve our skills at characterising how mutations affect gene outputs, i.e. functional genomics.

Mutations in the KCNH2 gene are a well-established cause of sudden cardiac death, caused by disturbed electrical signalling, in otherwise healthy young people. Yet, we now appreciate that the majority of variants identified in the KCNH2 gene do not change its function. The planned global efforts to sequence millions of genomes in the next few years will result in thousands of variants being identified in the KCNH2 gene; some of these will identify patients at increased risk of sudden death but most of these variants will be benign.

To cope with this deluge of variants of unknown significance we will develop a high throughput functional assay to assess how every possible mutation in KCNH2 affects the electrical function of heart cells. To achieve this, we will utilise state-of-the art robotic platforms to first help generate thousands of mutations in KCNH2 and then to assess the electrical consequences of these mutated genes. This data will be made available to geneticists, treating physicians and their patients through publicly accessible databases, such as ClinVar, so that all patients (both in NSW and throughout the world) who have their genome sequenced can access this data. Successful completion of this project would pave the way for using a similar approach to tackle other genes associated with sudden cardiac death and ultimately any cardiac disorder where it is possible to develop a high throughput assay to quantify altered function. It will also help to establish the Victor Chang Cardiac Research Institute and NSW as a world centre for functional genomics for inherited heart diseases.

Gene therapy, or the use of genes as medicine, has immense therapeutic potential in the treatment of many genetic diseases and cancers that are currently difficult or impossible to treat. While progress in the development of the underpinning gene transfer technology (vectors) has been hard won, we are finally witnessing astounding successes in human clinical trials in both children and adults.

This in turn has led to a global upsurge in clinical trial activity for a vast number of troubling diseases, and unprecedented demand for gene transfer vectors prepared to the exacting GMP manufacturing standards required for human clinical use. This demand has dramatically out-stripped supply and has created a clinical trial log-jam that threatens to slow the realisation of therapeutic benefit to the many potential beneficiaries of gene therapy.

This project will develop CAR T cells to target a broad range of paediatric tumours, and CAR T cells to protect kidney transplants from chronic allograft nephropathy, as well as gene viral vectors to target blinding eye disease and to treat childhood kidney disease. This will allow us to quickly initiate desperately needed paediatric trials for cancer, eye and kidney disease.

Bone marrow transplants (also known as blood stem cell or stem cell transplants) are the only way to cure the worst types of leukaemia and lymphoma in adults and children.

Patients undergoing bone marrow transplant often die of infection rather than the disease for which the transplant was performed because for a year or more after the transplant, the patient’s new immune system is immature and does not function properly.

Cell therapy involves growing infection and malignancy fighting cells called T-cells in the laboratory, training them to recognize infection and disease, and then giving them to patients soon after the transplant. The idea is to make the patient’s immune system functional and strong soon after transplant and to avoid the period when the patient is most vulnerable to dying.

The proposed clinical trial will test the theory that adding cell therapy to standard antibiotic treatment for infection in patients after bone marrow transplant will improve the immune system leading to better control of serious infections, less serious illness and fewer deaths.

In Australia chronic pain is estimated to cost over $30 billion per year to the overall economy, and current therapies do not adequately address pain for most patients.

The primary aim of this proposal is to generate GMP-grade clinic ready transplant material and then test the safety and efficacy of this material in rodents and large mammals. By moving these new technologies to the pain clinic, we can start to provide some relief to the millions of people currently living with untreatable and devastating chronic pain.

We have developed a long-lasting stem cell therapy that can reverse neuropathic pain, and here we will develop this technology for human use.

The adeno-associated virus (AAV) is gaining widespread use in gene therapy due to its ability to safely and efficiently deliver a genetic payload into a broad range of tissues.

In the clinic, AAV has successfully been used to treat patients with the bleeding disorder haemophilia by delivering a good copy of the Factor IX gene to replace a faulty copy in patient livers. Limitations of previous studies have included a failure to achieve a sustained therapeutic dose and recognition of the AAV particle by the host immune system.

While these problems have been addressed by designing custom AAVs, a tremendous opportunity still remains to further boost therapeutic efficacy by identifying the specific cell entry mechanism or receptor used by AAV’s. We will identify the specific receptors that allow entry of two liver-specific AAVs, one which is already in clinical use, using biochemical and genetic approaches.

We will identify genetic variants that may affect receptor expression and enable us to screen patients for those who will be better responders. We will then screen a ‘library’ of clinically-approved drugs to boost receptor expression and AAV uptake in liver cells in mice. This study will identify new avenues to enhance therapeutic efficacy in patients undergoing gene therapy.

The top causes of disease burden among Australians (15–44yrs) are dominated by mental health and substance use disorders. Of particular concern is the common co-occurrence (i.e. comorbidity) of disorders, with up to 50 per cent of people presenting to services with more than one disorder. Despite increased awareness and public concern leading to a major government initiative (National Comorbidity Initiative), comorbid mental health and substance use remains a major cause of disability, poor quality of life, early mortality and poses a significant challenge for the Australian health system.

Evidence suggests that integration of substance use and mental health treatment is ideal for optimal patient outcomes and to avoid patients falling through the gaps. Individuals with comorbidity however, continue to receive disparate care targeting either the mental health or substance use disorder. NSW Health is well placed to be the leader in responding to this crisis by translating high quality comorbidity research evidence to practice. The improved clinical management of comorbidity is a priority for NSW Health and is consistent with the NSW State Health Plan: Towards 2021 which aims to deliver truly integrated care by providing right care in the right place at the right time.

The purpose of this project is to directly address this priority by implementing effective models of translation to increase the capacity for NSW treatment services to respond to comorbidity. The specific objectives are to:
1. Employ standardised US toolkits for assessing comorbidity competency (DDCAT and DDCMHT) and adapt them for adolescent and adult treatment services in NSW and Australia
2. Implement these adapted toolkits and evidence-based recommendations in NSW treatment services to examine utility in assessing comorbidity competency and enhancing capacity to respond to comorbidity.

Genomic technologies, including targeted sequencing, and more recently, whole genome sequencing (WGS) have generated unprecedented insights into the molecular basis of disease. The application of WGS to patients with rare Monogenic Disorders is now identifying a molecular diagnosis in approximately 50 per cent of patients. The ability for WGS to characterise structural variants (SV) has redefined the genomic landscape of many cancers, providing treatment insights that were not possible from targeted sequencing approaches alone. One of the greatest challenges for precision medicine is the translation of bioinformatic methods developed in the research setting, often to study cohorts, into the clinic. Methods must be accurate, fast, comprehensive, interpretable by a multidisciplinary team, and must apply to the n-of-1 patient-centred situation.

The purpose of this proposal is to improve the clinical management of patients with inherited genetic disease, through increasing the diagnostic yield in rare disease, or improved tumour characterisation. The objectives of the proposal are to continue to develop a suite of bioinformatic approaches to uncover different aspects of genome biology and assess how these influence disease, and ultimately to translate these methodologies into clinically accredited tests. Many of these aspects of genome biology can only be uncovered by WGS. As we have already developed Australia’s first clinically accredited^ WGS-based diagnostic test for investigating single nucleotide variants (SNVs) and small insertions and deletions, we are uniquely positioned to achieve these objectives.

This proposal will develop critical bioinformatic and translational capability to improve patient care in NSW, and beyond.

Mitochondrial diseases are the commonest group of inherited metabolic disorders. Children often present with severe disease that is fatal in two thirds of patients before the age of 16. Adults tend to endure chronic and progressive disease that is often be severely debilitating and precludes them from employment. Mitochondrial diseases are notoriously difficult to diagnose due to the diversity of genetic causes (>300 mutations in mitochondrial DNA and >150 known nuclear disease genes), the extreme variability in clinical presentation (the same mutation in a family can manifest very differently) and a lack of comprehensive and definitive diagnostic tools.

The current diagnostic pathway involves invasive, expensive and inaccurate testing that often results in patients going undiagnosed or being misdiagnosed and spending years trying to access appropriate healthcare. This project will evaluate two new diagnostic tools, metabolomic biomarker profiling and genomic sequencing, in order to define a rapid, cost-effective, comprehensive and accurate diagnostic pathway that will improve the diagnosis of mitochondrial diseases.

Accurate diagnosis enables specialist clinicians to encourage disease modifying lifestyle changes, to administer appropriate treatments, identify and avoid contraindicated pharmacological agents (e.g. the common antiepileptic sodium valproate can cause death in mitochondrial disease patients presenting with seizures) and to provide informed family planning. The accurate diagnosis of mitochondrial diseases would also have a significant impact on the cost to NSW Health associated with undiagnosed or misdiagnosed patients, would enable treatment development through better understanding of disease pathophysiology in defined disease-specific cohorts, would define patient cohorts for genotype-specific clinical trials and enable appropriate treatment administration to those who will benefit most.

As genomic sequencing and bioinformatic analysis costs are still considerable, the first objective of this project is to develop metabolite signatures (combinations of small molecules that can be used to define a disease discriminatory test) of the mitochondrial disease group and individual mitochondrial diseases. This frontline indication of disease will inform clinical decision-making on whether to progress to other diagnostic testing, including comprehensive genomic sequencing.

As a result of recent technological advances, it is now possible to simultaneously and comprehensively sequence both mitochondrial and nuclear genomes. However, the very recent introduction of this technique means that objective research evidence for its applicability to genomic healthcare and how best to integrate it into clinical practice is lacking. Therefore, the second objective of this project is to develop a robust bioinformatic approach for the identification of causative mitochondrial disease mutations.

PIDs result from monogenic mutations in genes crucial to the functioning of an intact immune system. Currently, mutations in ~290 genes have been identified that cause PID. However, there are many more cases where the genetic lesion is unknown. This project will perform WGS on these PIDs to reveal the underlying gene mutation.

This “from bedside to bench and back” approach incorporating genomics and bioinformatics will identify novel gene mutations in PID patients and provide an explanation for disease pathogenesis. While PIDs are rare, they have played an instrumental role in pinpointing the essential and non-redundant roles of genes in the development and function of immune cells. Furthermore, some of the complications affecting PID patients are prevalent in the healthy population; for example, the incidence of thrush due to chronic fungal infections. In addition to having direct affects on clinical policy/practice ie treatment regimens for affected patients, results will be disseminated via the publication of manuscripts, presentations at national/international conferences and via media outlets through the work of the Garvan Research Foundation.

Burn injury can be a traumatic event for both the child and their carer, requiring extensive, specialised care and protracted hospitalisations. For paediatric burn injuries, optimal outcomes are associated with good multidisciplinary care, consistent follow-up with high quality burns units, functioning family units, and early return to pre-burns activities. In Australia, Aboriginal and Torres Strait Islander children are over-represented in burn-related hospitalisations yet, no research until now has examined the outcomes of these children nor their access to care either immediately after the burn injury or following discharge from hospital.

In addition to being more likely to be hospitalised following a burn injury, unpublished data suggest Aboriginal and Torres Strait Islander children are less likely to be treated in a specialist tertiary burn service.(Moller, unpublished). The NSW ACI Statewide Burn Injury Service, NSW Burn Transfer Guidelines provides clear guidelines for paediatric burn referral to tertiary burn services. However, there is evidence to suggest these guidelines are inconsistently applied. The proportion of Aboriginal and Torres Strait Islander children treated at specialist tertiary burn services in NSW is lower than population expectations. Further, numbers treated in regional centres appear to be higher, suggesting children are not referred as per the guidelines.

This project will:
(i) identify the processes for referral and treatment of children who present to an emergency department in NSW with a burn injury,
(ii) describe awareness and understanding of the referral guidelines and
(iii) develop processes to facilitate more widespread, equitable and systematic referral processes leading to integrated care of the child
(iv) develop a new Model of Care for an Aboriginal or Torres Strait Islander child who presents with a burn injury.

Further, with a focus on core components of Integrated Care, the outcomes of this research will lead to better understanding and management of care for an Aboriginal or Torres Strait Islander child with a burn injury.

A transient Ischemic Attack (TIA) is a major warning sign for stroke. There is a 15 per cent risk of stroke ≤ 90 days following initial event and the risk of cardiovascular events remains high 10-15 years post-TIA. It is best practice for TIA patients to receive secondary medical care to determine TIA cause and to commence preventative pharmacological therapy early post-event.

Behaviour change programs which include education and group exercise (ie. advice and support to address modifiable cardiovascular disease risk factors including hypertension, inactivity, poor diet etc) significantly reduce the odds of further cardiovascular events. These programs significantly increase the time TIA patients spend in moderately vigorous physical activity (ie. brisk walking) (5). The latter extremely important as increasing physical activity independently contributes to significant reductions in cardiovascular risk, with an inverse relationship between time spent in moderately vigorous physical activity and risk of cardiovascular events and all-cause mortality.

This project aims to :
1. Develop and implement a new service- a behaviour change program for people who have had a recent TIA (Study 1: Implementation Study)
2. Increase the minutes/week people who have had a recent TIA spend in moderately vigorous physical activity (Study 2: Outcomes Study).

This screening and secondary prevention project could help reduce the burden of stroke worldwide by introducing a novel, scalable, cost-effective technology to screen for post-operative atrial fibrillation (POAF) following cardiac surgery discharge. This project could influence policy and AF management guidelines to include routine monitoring for POAF recurrence.

POAF occurs in 25-40 per cent of cardiac surgery patients, and is associated with increased mortality and stroke risk. POAF is thought to be transient and self-correcting, thus patients discharged in stable sinus rhythm are rarely followed up. POAF recurrence is often missed as it is largely asymptomatic or has non-specific symptoms. Additionally, patient knowledge of the extent of AF symptoms is poor despite inpatient education. In my systematic review (n=6 studies) active monitoring post-discharge identified POAF recurrence in 33 per cent of patients with transient in-hospital POAF, and late-onset POAF in ~4 per cent with no prior POAF. I have shown self-monitoring for POAF recurrence is feasible using a smartphone handheld ECG (iECG).

The outcomes from this study will assist development of a risk score to better identify patients at highest risk of devastating complications, such as stroke, allowing clinicians to better target effective preventative therapy. The project aims to:
1. Determine the incidence and predictors, and explore the prognostic significance of recurrent POAF and late-onset POAF
2. Determine if education using a 'graphic app' improves patient knowledge, particularly awareness of POAF symptoms
3. Determine scalability of self-monitoring using an iECG.

Increasing life expectancy has resulted in a higher proportion of older individuals (≥65 years) in the population compared to a decade ago. As the population ages, demand will increase for hospital and aged care services, including permanent residential aged care (RAC), respite RAC, and transitional care (TC). The number of injury-related hospitalisations for older individuals are growing, accounting for 27 per cent of hospitalised injury.

Following an injury, older individuals may require assistance to perform activities of daily living (ADL), either transitionally as they return to their prior ability, or on a more permanent basis. Prior research has identified that age, functional ability, cognitive impairment, depression, multimorbidity and falls are commonly associated with aged care placements. However, individual and psychosocial characteristics associated with admission/return to RAC have not been examined following a hospitalised injury at a population-level, nor have factors associated with entry into supplementary care programs, such as TC or respite RAC, been identified. For older individuals, there is limited information available regarding their care transitions between the home, hospital, RAC, respite RAC and TC following a hospitalised injury in NSW. Suboptimal care transitions may result in diminished ADL and increased costs, including through re-hospitalisation.

This research will examine factors that influence older individuals transitioning between services and will advance the understanding of the influence of individual and psychosocial characteristics on post-acute care placement of individuals who are hospitalised following an injury. Ultimately, this information will be invaluable in influencing policy, driving change, and informing planning of the post-acute phase healthcare for older individuals in NSW and to identify future priority areas for research.

Mental and substance use disorders account for more years of life lost due to disability than any other disorders and are second only to cardiovascular disease and cancer as leading causes of disease burden. Comorbidity of mental and substance use disorders pose a significant challenge for the Australian health system. The silo structure of the healthcare system has historically treated clients in parallel by different treatment providers. Typically, treatment is incomplete and outcomes are poor.

The NHMRC Centre of Research Excellence in Mental Health and Substance Use (CREMS) leads the way in new research examining innovative treatments for comorbidity. NSW health services provide a unique context into which new approaches to comorbidity treatment can be embedded. Our research has demonstrated that an integrated, stepped care (ISC) approach is ideal for optimal client outcomes and to avoid clients falling through the gaps.

Integrated care involves both substance use and the mental health condition being addressed by the same provider. This can be facilitated by a stepped approach where additional care is provided for a mental health diagnosis after stabilisation from substance use, enabling the distinction between substance-related mental health symptoms versus symptoms remaining or emerging once use has resolved.

This project aims to:
i) Evaluate the impact of a Multi-modal Translation Intervention Package (MTP) to (a) increase ISC proficiency and uptake; (b) enhance clinician knowledge and attitudes; (c) improve substance use and mental health outcomes.
ii) Examine barriers and facilitators of ISC implementation using the MTP.
iii) Deliver MTP resources and sustainability recommendations to NSW Health for future rollout.
Promote identification, assessment and clinical management of comorbidity within the drug and alcohol services of NSW local health districts.

Delirium, a transient confusional state, is an increasing problem for Australia’s ageing inpatient demographic. Incidence rates from international studies range between 3-29 per cent for patients over 65 years, equivalent to 116,731 – 1,128,400 inpatients using Australian 2013-14 admissions data.

Higher rates of 47-63 per cent have been observed in surgical patients over 65 years, and critically ill patients with delirium have substantially higher prevalence rates (up to 70 per cent) and longer hospital stays (by 6.5 days). Delirium has a significant health impact as inpatients developing delirium are 2.6 times more likely to die during admission, and have a higher risk of developing dementia (adjusted relative risk of 5.7, CI 1.3-24.0). The presence of pre-existing dementia increases the risk of developing delirium two to five times.

A key factor for this research is that delirium is largely preventable, using evidence based guidelines for implementing pharmaceutical, physical, and care delivery changes to inpatient care. The Australian Commission for Safety and Quality in Health Care is releasing a new Delirium Clinical Care Standard (Standard) in 2016 which incorporates this multi-component approach. This is therefore a critical time to investigate and evaluate the impact and effect size of implementing the new Standard, whether the Standard is being implemented as planned, and whether the Standard is effectively addressing the need to identify, prevent and treat delirium.

This study will provide critical data for assessing the benefits to patients and cost-savings gained through preventing and treating delirium in a rapidly ageing population, using a novel combination of applied health economic and implementation science principles. Delirium incidence rates in study hospitals will be measured before, and after, the implementation of the multi-component intervention that forms the basis of the Standard. In addition to standardised clinical outcomes, the study will assess barriers and enablers to the implementation and provide vital feedback to policy makers to understand and improve translation of the evidence based guidelines into practice. Despite existing research on the design of the multi-component interventions, the financial impact of delirium to the health system, and effectiveness of interventions for clinical outcomes, the unique contribution of this study is in determining the cost-effectiveness of these multi-component interventions in Australian acute care and the factors that ensure success.

Inflammation is central to the pathogenesis of atherosclerotic plaque progression and athero-thrombotic vascular events with systemic inflammatory markers correlating strongly with prognosis in acute coronary syndrome (ACS) patients. Indeed, these patients are particularly vulnerable to recurrent ischaemic events in the early post-ACS period, likely driven by pan-coronary inflammation, resulting in a higher prevalence of vulnerable non-culprit plaque.

Moreover, percutaneous coronary intervention (PCI) to treat culprit coronary stenoses in the setting of ACS, is strongly associated with a relatively high rate of peri-procedural myocardial infarction and adverse cardiovascular outcomes, due in part, to distal embolisation of inflamed plaque fragments with microvascular obstruction. Therefore, suppression of atherosclerosis-associated inflammation is of critical importance to stabilise vulnerable plaque (AIM 1); to decrease inflammatory mediator release after PCI of vulnerable lesions (AIM 2); and to reduce plaque progression/instability, which itself is strongly linked with adverse cardiovascular outcomes (AIM 3).

The principle aim of this project is to investigate a new, innovative, and cost-effective approach to reduce the deleterious effects of atherosclerosis-associated inflammation, based on our discovery that oral colchicine, a safe and well established drug, widely used in non-vascular inflammatory disorders, has marked anti-inflammatory properties in ACS patients. Notably, SP’s recent published studies have elucidated that colchicine, within hours of ingestion, markedly reduces (1) secretion of the pro-inflammatory cytokine IL-1β by circulating monocytes and (2) local coronary levels of the inflammatory cytokines IL-1β and IL-18, together with downstream IL-6, a cytokine strongly linked with future coronary events.

Based on these findings, colchicine’s acute effects on plaque stability will be studied, as well as its more long term effects on plaque volume/inflammatory content. Such studies have enormous clinical relevance as they have the potential to directly improve outcomes in patients presenting with unstable coronary syndromes, particular in the context of PCI, as well as ‘stable” patients with established atherosclerosis. Moreover, as colchicine is safe, readily available and cost-effective, it can be rapidly included as part of the standard therapy for both ACS and stable coronary disease patients.

Antibodies are the effector molecules of the immune system and are responsible for neutralising pathogens with remarkable specificity and memory. However, 5 per cent of Australians suffer from autoimmune diseases, such that their antibodies recognise their own cells, tissues and organs (autoantibodies). Autoantibody-mediated disorders account for a large burden of chronic disease and can be difficult to diagnose and treat due to heterogeneous symptoms ranging from arthritis, dry eyes/mouth to kidney failure and giving birth to a child with cardiac abnormalities. The unpredictability of disease outcomes reduces patient quality-of-life, while posing significant costs to healthcare systems for ongoing monitoring and treating symptoms as they occur. Treatment options are limited to non-specific steroids and expensive biologics that are only effective in a subset of patients.

The objective of this research is to use cutting-edge genomic technology to characterise human autoantibodies to improve diagnosis and monitoring of disease. This approach traces the cellular source of autoantibodies revealing novel and specific therapeutic targets.

There are two ways to characterise an antibody: i) antigen specificity - what the antibody interacts with; ii) the genes that form the antigen binding site on the antibody (variable (V), diversity (D) and joining (J) genes). For the last 40 years, the former method has been employed by clinical diagnostics to detect autoantibodies but has limited value for predicting disease outcome. For example, maternal autoantibodies binding the Ro self-antigens are associated with foetal cardiac abnormalities such that weekly echocardiograms from 12-22 weeks gestation are recommended for all Ro autoantibody-positive pregnancies. However only 2 per cent of these pregnancies result in this disease. A more specific biomarker would identify patients at highest risk, allowing for early intervention and improved disease management.

Advances in genomic technologies for sequencing antibody genes now make it possible to evaluate VDJ-genes for diagnostic purposes. Specific VDJ-genes have become useful diagnostic and prognostic indicators of lymphoma. Extending this approach to autoimmunity creates the exciting possibility of stratifying autoantibodies according to VDJ-gene usage and clinical symptoms. Previous research by others and myself has revealed distinct subsets of Ro autoantibodies that cause disease pathology. These “pathogenic” Ro autoantibodies cannot be distinguished from “quiescent” Ro autoantibodies by routine diagnostic assays. Genetic analysis of Ro autoantibodies is limited but has revealed biases in VDJ-gene usage across multiple patients. This research will extend these promising preliminary studies to evaluate the diagnostic utility of sequencing VDJ-genes and reveal where autoantibodies come from.

The promise of e-health interventions as a solution to overcome current healthcare challenges such as accessibility and cost have been hampered by poor translation into the community. Despite major advances in the availability of evidence-based mental health programs there is a serious shortfall in the delivery of such programs in practice, with an estimated 17-year delay between the identification of an effective program and its integration into practice and policy domains (IOM, 2001; Westfall, 2007). A significant contributor to this problem is the lack of available skills and knowledge to conduct rigorous interdisciplinary implementation science research.

The goal of this project is to inform the implementation of an evidence-based e-health intervention to prevent the onset of depression in youth. The intervention, SPARX, is a six-session online ‘serious game’, based on the principles of Cognitive Behaviour Therapy, which we have adapted into a prevention program (SPARX-R) for adolescents. In an randomised-controlled trial conducted across 10 Sydney high schools we showed that SPARX-R prevents the onset of depression, with gains maintained at 6-month follow up (Perry et al., 2005; the trial is ongoing and 18-month outcomes are expected in August 2016). SPARX-R does not require extensive training to support its delivery, making ideal for the school context.

Cardiovascular disease is the leading cause of premature death among Aboriginal Australians and there is increasing disparity in rates of cardiovascular-related deaths between Aboriginal and non-Aboriginal Australians. From 2008-2012, non-communicable diseases, such as cardiovascular disease and diabetes, accounted for 81 per cent of the gap in mortality rates. Obesity (16 per cent) and physical inactivity (12 per cent) are leading risk factors in the development of chronic disease and the overall health gap in Aboriginal Australians.

Obesity is responsible for 1-3yrs of the 10-yr gap in life expectancy. Higher levels of these modifiable risk factors that contribute to this health disparity among Aboriginal adults are already present in Aboriginal children. Compared with their non-Aboriginal peers, Aboriginal children are 1.4 times more likely to be overweight or obese, 1.8 times more likely to exceed screen time guidelines and 1.6 times more likely to have unhealthy eating habits. The risk of type 2 diabetes in Aboriginal children is 8 times higher than in their non-Aboriginal counterparts.

As cardiovascular disease is one of the leading contributors to the life expectancy gap, there is a need to better understand the key modifiable behaviours of cardiovascular disease, such as physical activity (PA) and sedentary behaviour (SB), and better understand culturally acceptable ways to promote healthy levels of these behaviours among Aboriginal children. This evidence is currently lacking for Aboriginal children and is critical to improving cardiovascular health behaviours in Aboriginal Australians.

Conducting research with Aboriginal communities is a long-term commitment, requiring respectful negotiations within the research partnership, which can only occur through continuous and consistent relationship building. This fellowship will build on a 2-year partnership with three Aboriginal communities in NSW. A priority identified by these communities is to raise healthy children and provide their children with opportunities to connect with Country and culture. This fellowship will use a behavioural epidemiology framework to understand PA and SB behaviours among Aboriginal children and how these health behaviours relate to cultural connectedness.

Specifically, this project aims to:
1. Determine the prevalence and patterns of PA and SB and their associations with cardiovascular health.
2. Identify the cultural determinants of PA and SB;
3. Design, implement and evaluate an afterschool Aboriginal cultural program to promote healthy lifestyle behaviours; and
4. Translate the evidence into dissemination strategies of Australia’s Physical Activity Guidelines to 5-12 year-old Aboriginal children.

This project will address an internationally-important healthcare problem in hospital emergency departments: with a surging demand for services, how can we ensure a safe environment for patients while still maintaining throughput?

In the first quarter of 2016 there were 672,483 presentations to NSW emergency departments (EDs) – a 9 per cent increase in triage Category 1 patients, and a 4 per cent increase in presentations overall compared with 2015. Despite introduction of National Emergency Access Targets across Australia in 2010, 25 per cent of patients were not ‘seen on time’ in accordance with Australasian Triage Scale standards, and 26 per cent of visits were not concluded within 4 hours. Increasing numbers of patient presentations, coupled with limited in-patient bed capacity, can result in long waiting times and prolonged lengths of stay in the ED. Overcrowding is becoming more prevalent, and has been associated with an increase in medical errors and poor patient outcomes, including death.

When EDs get overloaded, things are more likely to go wrong (e.g diagnostic errors, medication errors, delayed treatment). The processes we put in place to prevent errors from occurring often add to workload in the ED, paradoxically making it even more likely that things will go wrong. A new way to solve this dilemma is to shift our focus from preventing things going wrong, to increasing the number of things that go right. We call this ‘productive safety’. The purpose of this project is to design and implement ED processes to improve productive safety in NSW public hospitals. This project will seek to identify key quantitative and qualitative measures that are predictive of productive safety in response to unexpected events and periods of peak patient demand in the ED. Based on these measures, processes will be developed for assessing and improving productive safety. By doing so, we will assist ED leaders and clinicians to evaluate their organisation, and implement action to improve the number of things that go right when faced with challenging or unanticipated conditions. Such a proactive effort is likely to strengthen ED responses to threats and crises, and thereby save money and lives.

The project aims are to:
1. establish baseline measurement of productive safety in EDs in NSW public hospitals
2. refine productive safety processes, following an in-depth study of two NSW ED cases
3. develop a suite of context-dependent and generic tools to support re-design of processes to improve productive safety in EDs in NSW public hospitals.

A better approach to bridging the gap between ‘what we know’ and ‘what we do’ in health could make a substantial contribution to improving health outcomes and efficiencies. Increasingly it has been recognised that research to bridge this gap (implementation research) requires the expertise of researchers, policy makers and practitioners to be combined; implementation projects require both a deep understanding of the real world and how it operates, along with the often sophisticated research skills necessary for complex research designs. This is commonly referred to as partnership or co-production research.

Co-production, where researchers and research users work together throughout the research process from question formation through to interpretation and dissemination of findings, appears likely to be the most effective model for partnership. Such partnerships are a relatively recent phenomenon, however, and there is much to be learnt about how best to bring the diffuse skills, needs and priorities of these groups together to drive more effective implementation research and reduce research wastage. In Australia, the promise of co-produced research has led to the creation of funding schemes designed to foster collaboration (e.g. NHMRC partnership grant, NSW Health Translational Grant Scheme) but it is unknown how effective these partnerships are or how they operate in practice.

The specific aims are to:
1. Understand how research/end user partnerships are currently enacted in New South Wales, what works and what does not: and
2. Evaluate, for the first time internationally, a suite of tools to strengthen coproduction in implementation research:
a. A training course for early career researchers to build their capacity to develop and sustain effective research partnerships with policy agencies;
b. A tool for research users to help them navigate the process of working with researchers, from the initial agreement to partner through to dissemination.

This project is a joint collaboration between the Northern Sydney Primary Health Network (PHN), Healthdirect Australia, Hornsby General Practice (GP) Unit (a NSW Health entity), Macquarie University Health Services, and the Australian Institute of Health Innovation. It is designed specifically to realise the vision of “a digitally enabled and integrated health system delivering patient-centred health experiences and quality health outcomes”, set by NSW Health in its recently released eHealth Strategy (2016-2026).

General Practitioners (GPs) tend to refer patients to the Emergency Department (ED) in order to ensure their patients receive affordable specialist care without extensive delays. They may not be aware of outpatient services available at their local hospital. This contributes to unnecessary ED access block and increased waiting times. Patients are frustrated by months of waiting for outpatient appointments, and they lack skills in self-management in the interim.

To address this, health pathways (a collaborative initiative between primary and secondary health providers to improve the referral and management of patients) have aimed to build capacity in general practice to help patients navigate the health system. Supported by the NSW Agency of Clinical Innovation (ACI), health pathways are implemented and evaluated across NSW.

This research will make use of the unique opportunity at the NHMRC Centre of Research Excellence in eHealth which is co-located within the Northern Sydney PHN. The PHN will develop its first 20 local health pathways over the next six months. We will work closely with the PHN to select two high-priority health pathways and conduct studies to 1) understand the pain points experienced by consumers in their journey through the current service landscape (e.g. inability to get timely access to specialist care; lack of self-management skills due to limited health literacy); 2) co-design a consumer portal to address these challenges with input from consumers, GPs, clinicians and health service practitioners; and 3) evaluate the acceptance of the portal from consumer, GP and health service practitioner perspectives.

Heart failure rates are increasing exponentially in Australia and worldwide. One in two people diagnosed with severe heart failure will die within one year of diagnosis. This burden of heart failure is underpinned by the heart’s limited capacity for self-repair after injury. This limitation could be overcome by stimulating newly discovered stem cell populations residing within the adult heart itself. We recently discovered a cardiac colony-forming stem cell population and have found that the molecule Platelet Derived Growth Factor (PDGF) can improve the heart function of mice and pigs after induced heart attack. PDGF does this by activating and rejuvenating resident heart stem and stromal cells. Before this promising therapy can be considered for clinical trials in humans, further testing to validate its safety is required.

This project will build on over a decade of preliminary work in mice and pigs, validating our results in a preclinical large animal model. In the second phase of this work, new materials such as nanoparticles will be used to more selectively deliver PDGF therapy to the heart. Outcomes of this project include expedited progression of this promising therapy, from the laboratory into the clinic, where thousands of heart failure patients could one day benefit.

Note: This project received project funding only. This project did not received full Fellowship funding.

The proposed projects will study new mechanisms that may be involved in a disease that results in increase in blood pressure in the lungs, which is called pulmonary hypertension. This disease is very deadly and despite the progress made, the survival rates within five years of diagnosis remain unacceptably low (up to 50 per cent of patients may die or require heart-lung transplantation). Therefore, research in this area is of high priority.

We will study two different drugs both in the basic science lab, and if these studies support our theories; and as suggested by the safety of the target drugs that are already in use in patients for other diseases; we believe that the second part of the project where we will test these drugs in patients is practically feasible, promising to add two new drugs for treatment of pulmonary hypertension.

I have studied new intricate methods in my post-doctoral studies In the United States which I am excited to establish back in my lab in Australia. This has also provided the team with the opportunity for collaboration with centers of excellence internationally, which will be key in conducting a multi-center clinical study. The proposed team consist of clinician-scientist who can lead both the basic science project and the human trial.

Heart defects are the most common form of birth defects, occurring in ~1 per cent of live born babies. In 80 per cent of families it is not known why they occur. We use the latest technologies to study the genetic code of families with children that are born with heart defects. We aim to identify mutations, i.e. changes in the genetic code that are the cause of these defects.

The genetic code of each individual is stored in large datasets. Our goal is limited by the current methodologies to analyse such large datasets to identify causal mutations. Currently, a large percentage (~70 per cent) of families we study cannot receive a personalised genetic diagnosis. We propose to develop new quantitative and analytical approaches to improve our ability to identify mutations that are the cause of heart defects in every family.

Our research has specific and immediate clinical benefit for the families affected with heart defects that have been recruited. Increasing the genetic diagnosis of heart defects will help more families receive an accurate genetic diagnosis, personalised advice concerning the disease in their family and a better estimate of the risk of having a subsequent child with a heart defect.

Identifying the genetic causes of heart defects not only has benefits for the patient and the family but also for the community. Currently, efforts to identify causes of disease require large costs, and it can include multiple medical screens and procedures. We expect that systematic adoption of genetic testing in clinical practice will improve the financial sustainability of the health system.

Note: This project received project funding only. This project did not received full Fellowship funding.

Cardiovascular diseases, including heart attack and stroke, are a leading cause of disease and death. In patients who have experienced a cardiovascular event such as a heart attack, smoking increases the risk of future events and death. Programs supporting cardiac patients to quit smoking improve survival and quality of life, and reduce the burden on the hospital system. However, smoking remains undertreated in cardiac patients. Prescribed medicines, including Zyban, Champix and Nicotine Replacement Therapy, are the most effective strategies available to help smokers quit, but there have been highly publicised concerns regarding their safety among cardiac patients, contributing to reluctance to prescribe and use these treatments.

This project will examine whether these safety concerns are supported by Australian data. It will also determine which of the three medicines is most likely to have the greatest long term benefit for cardiac patients, and the extent to which each of these medicines are currently used by cardiac patients after discharge from NSW hospitals. It will achieve this by linking records of filled prescriptions with other data from health services in NSW. This will be the largest study of the safety and effectiveness of prescribed medicines for smoking cessation conducted to date, and the first conducted in Australia. It will use sophisticated statistical techniques that allow data to be analysed in a way that closely replicates the characteristics of a clinical trial.

This project will provide clinically useful information about the risks and benefits of prescribed quit aids when used by cardiac patients. This will allow cardiac patients and health care providers to make informed decisions about whether a smoking cessation medicine and which one(s), should be used. This evidence, together with statistics on how many patients receive these quit aids after they leave hospital, will indicate whether efforts to promote or discourage use of any of these treatments among cardiac patients are needed. The research team will communicate the findings to staff of NSW Health services, cardiology units in particular, so that protocols and guidelines for the discharge of cardiac patients can be updated. Likewise, the findings will be shared with general practitioners to guide the in-community prescribing of smoking cessation aids to patients with cardiovascular disease. By informing changes to the care of cardiac patients who smoke, this project has the potential to improve the survival of patients with cardiovascular disease and reduce healthcare costs.

Hypertrophic cardiomyopathy (HCM) is a clinically variable disease, ranging from asymptomatic diagnoses, to heart failure and sudden cardiac death. It occurs in 1 in 200-500 of the general population, and given it is an inherited disease close family members are recommended to undergo lifetime clinical surveillance. Due to the wide variability in disease presentation and features, there is little ability to predict who will develop the worst outcomes, despite decades of research.

Recent advances in genetic technologies have allowed an opportunity to better understand the underlying genetic causes of HCM, but have also challenged the prevailing view that HCM is primarily an inherited disease. My recent paper in Circulation: Cardiovascular Genetics proposed for the first time that a non-familial sub-group of HCM exists and that it occurs in approximately 40 per cent of cases. Non-familial HCM patients have a less severe disease and while current clinical guidelines recommend lifetime clinical screening of their first-degree relatives, our finding suggests this is not necessary.

No study to date has focused exclusively on the familial HCM sub-group. Reassessment of risk algorithms in a more homogeneous patient population will allow development of accurate risk prediction scores. Until now, risk scores have been developed in populations including both nonfamilial and sarcomere positive HCM and not surprisingly show poor predictive ability. To date, no scores have incorporated genetic variables, and based on my recent work there is a strong likelihood that genotype can impact outcomes.

For the first time, genetic testing could offer a clearer way to understand the disease, allowing us to make more precise recommendations for family screening and better predict those more likely to have poor outcomes. This will reduce uncertainty, but also minimise unnecessary health care resources from clinical screening family members who are not at increased risk of disease.

Note: This project received project funding only. This project did not received full Fellowship funding.

Chest pain is one of the most common presentations to adult emergency departments. Its management requires specialist assessment and tests, which places a significant burden on hospital resources and patients. To address this, Royal North Shore Hospital has implemented a rapid access Chest Pain Clinic (CPC) – a new model of care, for which I am director. As part of this, there is the need for cardiac investigations that are feasible, diagnostic, and cost-effective. Two advanced cardiac diagnostic techniques have untapped potential in this setting in Australia – cardiovascular magnetic resonance (CMR) and advanced electrocardiography (A-ECG). This fellowship seeks to develop new insights into health service of acute chest pain by the application and development of these state-of-the-art investigations to create a paradigm shift in chest pain management and improve healthcare costs.

CMR is the future of non-invasive cardiology, and is utilised widely in clinical practice and research worldwide but less so in Australia because of slow adoption and restrictions with Medicare rebate. In European and UK healthcare models, CMR with stress testing (‘stress CMR’) has been shown to be cost-effective in the management of suspected coronary disease with high diagnostic and prognostic performance. There is a lack of evidence of stress CMR in the Australian healthcare setting. Part 1 of this study will assess the cost-effectiveness of stress CMR in the CPC, in order to optimise its use in Australia.

The traditional ECG is a fundamental cardiac test. Standard analysis depends on visual assessment. Novel methods for computerised ECG measurement permit the application of advanced digital analysis techniques collectively known as A-ECG, which have dramatically higher diagnostic accuracy for detecting disease. Currently, A-ECG is only available in a handful of international centres outside Australia. Part 2 of this study will assess A-ECG in the CPC to show its diagnostic performance, ability to influence downstream tests, and power to predict cardiovascular outcomes. A-ECG could be the much needed paradigm shift in chest pain management – to allow patients to be managed safely as outpatients, thus avoiding hospital admission and unnecessary tests, and improving healthcare costs.

The overarching goals are aligned with Sydney Health Partners’ Cardiovascular Stream and the Northern Sydney Local Health District. Collaboration with international centres of excellence will support the science and the technology. Translation of findings and implementation into clinical practice will be led by the research team, which includes engagement with key stakeholders and hospital administration.

Sudden death or cardiac arrest occurs when the heart goes into a fatal heart rhythm called ventricular tachycardia (VT). These fatal rhythms almost invariable occur due to underlying scar tissue in the heart from a variety of heart diseases. Cardiac arrest survivors receive a specialised form of pacemaker, called an implanted cardiac defibrillator (ICD) placed under the skin that automatically delivers an internal shock if VT recurs, thereby aborting otherwise inevitable sudden death. However, ICDs do not prevent VT from occurring in the first place, they only treat VT when it occurs. Cardiac arrest survivors will experience recurrent VT at an annual rate of 30-50 per cent/year. Recurrent shocks are painful, cause tremendous psychological trauma and lead to increased risk of death. They also lead to frequent hospital visits, and exponential health care utilisation.

Recurrent VT can be treated with strong doses of anti-arrhythmic (AAD) medications but these tend to be minimally effective, and with potent side effects. An alternative is to perform a cardiac ablation (CA) procedure that entails electrical wires navigated up through the veins to the heart, to identify, cauterise and thus destroy the electrical short circuits causing VT. Some studies have shown that CA is highly effective in curing VT, reducing VT burden and improving quality of life in patients with scar tissue due to coronary heart disease (blocked arteries). It is unknown if CA is just as effective for a large population of patients who have scar related to genetic (familial) disease, or infection or inflammation of the heart (termed non-ischemic cardiomyopathy). This group is important as the incidence of non-ischemic cardiomyopathy is rising; such patients tend to be young (30-60 years), and are very likely to experience toxic side effects from AAD and thus stand to gain the most benefit from CA. This research proposal is for a randomised trial that will examine if CA is superior to AAD in the treatment of VT in patients with non-ischemic cardiomyopathy.

Results of this study will be disseminated through clinicians at scientific meetings/publication in journals (and via their social media channels), and by engagement of Sydney Health Partners, NSW Agency for Clinical Innovation and major national/international cardiac societies. Findings will lead to major practice and policy change nationally and globally. Engagement with patients and the general public will be via novel e-health social media channels such as Facebook and Twitter, as well as involvement of charitable foundations.

Blood clots blocking the blood supply to the heart and the brain, known as arterial thrombosis, cause heart attack and stroke – the leading cause of death and disability in the Australia. Platelets are the cells that form these blood clot, thus drugs targeting platelets such as aspirin are the mainstay of heart attack and stroke prevention. Yet current treatment has limited effectiveness with optimal therapy – up to 30 per cent of patients will have a recurrent event within three years, and more effective therapies often lead to bleeding side effects.

Our work has identified a particular sub-set of platelets within people with cardiovascular disease that increase blood clots, but are not turned-off by aspirin. These are called procoagulant platelets. Measurement of procoagulant platelets in patients has initially been very difficult due to the lack of sensitive and specific tests. We have recently developed a way to measure procoagulant platelets in people at risk of heart attack and stroke, and have shown that more procoagulant platelets are indeed formed during stroke and heart attacks. It is therefore this sub-set of platelets in people with cardiovascular disease that we would like to target more specifically when designing new drugs, in order to increase the beneficial effect and at the same time reduce the bleeding side effect when treating patients.

Interestingly, a simple non-invasive process called remote ischaemic preconditioning (RIPC), which is performed by inflating and deflating a blood pressure cuff three times, was able to reduce procoagulant platelets in people with heart disease when aspirin and other anti-platelet drugs could not. Others have previously shown that RIPC can protect the heart muscle and brain from damage during heart attack and stroke, but the mechanism by which it does this is unknown.

My studies indicate that RIPC affects procoagulant platelets by affecting the platelet mitochondria. Mitochondria are organelles inside the platelet that converts glucose to energy. My project investigates the link between procoagulant platelets, platelet mitochondrial function and cardiovascular disease. In addition to providing the rationale for RIPC, these studies aim to identify platelet mitochondrial pathways as a novel target for cardiovascular disease that will work in addition to existing cardiovascular drugs without causing bleeding. Ultimately, our work would be able to provide more tailored therapies for patients, reduce our patients’ waiting time, pain and risk of receiving treatments, improve their disease outcome, and reduce medical cost for the NSW health system.

Atherosclerosis and related complications are a major cause of death and disability in NSW. This project will use see-through zebrafish to literally shed new light on what happens in atherosclerotic plaques using microscopy of the disease inside living zebrafish. We will be able to ask fundamental questions about how plaques form, mature, and harm us by observing the course of disease in zebrafish embryos.

To find new cures of atherosclerosis and it’s complications, the project will take two arms. The first arm will investigate a treatment that may prevent the blood vessel damage necessary for atherosclerosis to get a foothold in our blood vessels while a second arm of the project will set up a zebrafish system to discover new drugs to prevent or reverse the build up of bad fats in atherosclerotic plaques.

Death and disability from stroke is a massive burden on the healthcare system and society. In Australia, it is estimated that one million people will be living with the effects of stroke by 2050 - more than double the number of strokes in 2017. Ischaemic stroke is caused by a blocked artery, leading to a lack of blood flow and oxygen supply to a specific region of the brain supplied by that artery, resulting in brain cell death (infarction). Up to 38 per cent of ischaemic stroke patients present to hospital with mild or rapidly improving symptoms, yet final outcomes are poor, >50 per cent require assistance with self-care at three months post stroke. This delayed progression of stroke due to early neurological deterioration (END) within the first 24hrs post-stroke remains a clinically significant, yet unresolved problem - the number of patients totalling more than the annual number of new cases of multiple sclerosis, Huntington’s disease and motor neuron disease combined. However, its cause and the underlying mechanisms are poorly understood. Currently there are no guidelines or diagnostic tests that can predict the outcome of these patients. Understanding the true pathophysiology and recognising those at risk are key first steps.

Dr Patabendige and her team will use advanced medical imaging analysis and a novel non-invasive method to measure the pressure within the skull, intracranial pressure (ICP) to provide definitive evidence to confirm that ICP elevation causes infarct expansion, and that it is associated with neurological deterioration. In addition, their previous studies confirm that oedema (swelling of the brain) was not the primary cause for this ICP rise. Therefore, Dr Patabendige will investigate whether cerebrospinal fluid (CSF, the fluid that bathes the brain and spinal cord) volume increase is responsible, and if confirmed, show that short-duration hypothermia reverses this.

These findings will provide evidence to confirm the cause for END, and provide for the first time a clear pathological explanation for why these patients, who seem to be improving when initially presenting to the hospital progress to neurological deterioration.

Expected key outcomes:
1. Provide significant fundamental knowledge about a highly clinically relevant, yet unresolved problem of END
2. Help future diagnosis, prevention and management of stroke patients that are at risk of developing END, thereby making a significant reduction in stroke morbidity in the longer term
3. Prove the effectiveness of a potential treatment that is safe, easy to apply and generalizable .

The purpose of this research project is to develop and validate a blood test that can be widely used, e.g. hospital outpatients, and general practitioner offices, to detect a new molecule in blood that we discovered. It will indicate whether a patient has liver fat and whether they are at risk of developing diabetes, which frequently leads to heart disease and stroke.

We are facing a global epidemic of obesity and related diseases. Almost three-quarters of Australians are now overweight or obese, and childhood obesity is at an all-time high. Overweight and obese people have a high risk of developing fatty liver disease and/or type 2 diabetes. Fatty liver disease is often the first stage leading to type 2 diabetes, and puts patients at increased risk of fat deposits in their blood vessels that may cause heart attacks and strokes, which are the most common causes of death in these patients.

We are failing to prevent the catastrophic obesity epidemic. It is a global challenge. The numbers are far greater in developing countries. In China, for example, 114 million people have type 2 diabetes and half a BILLION have prediabetes. These staggering numbers underscore the enormity of this healthcare challenge globally.Although obese people with diabetes most commonly die from heart attacks and strokes, the rate at which this occurs is highly variable, and until now, we cannot predict who is most at risk and who will have an event.

Our results indicate that the new blood molecule discovered by us can predict, more than a decade in advance, who will develop diabetes. This is tremendously important, as it will allow us to target those most at risk with interventions to prevent them from developing diabetes, thereby reducing complications such as heart attacks and strokes. It has been repeatedly shown that the best way to prevent diabetes and its complications is early intervention – by the time of diagnosis a lot of damage has been done, most of it irrevocably.

The way we currently measure this molecule is not widely accessible, limiting its availability to populations that need it most. In this project, we aim to develop a test that can be used everywhere -- even at the bedside, outpatients, general practitioner offices -- and will be fast, precise, and reliable. We will ensure that the public, patients, and clinicians are fully aware of all aspects of this assay.

Note: This project received project funding only. This project did not received full Fellowship funding.

Atrial fibrillation (AF), the most common abnormal heart rhythm (arrhythmia), is a major risk factor for both stroke and heart failure. With an ageing population tackling the problem of arrhythmias, in particular AF, will be a major challenge for healthcare in the coming decades. At present, we lack good drugs to treat AF. As a result there is a pressing need for new strategies to study and better understand the molecular basis of these arrhythmias. This is the best way to identify and develop novel therapeutic avenues.

While clinically we accept that altered mechanical load in the chambers of the heart leads to structural and electrical changes, the molecular mechanisms of how these mechanical forces underpin arrhythmias are not understood. This project aims to identify novel mechanical pathways that underlie arrhythmias in conditions like AF.

This project will identify these new cellular pathways underlying arrhythmia generation by evaluating how mechanical stress affects the cells that line the chambers of the heart. We have access to a unique cell type mimicking the single cell layer that lines the inner wall of the heart chambers. Using state-of-the-art technology to simulate blood flow this project will assess how these cells may provide mechanically-regulated signals to the underlying heart muscle cells and assess how this may contribute to arrhythmias. This crucially acknowledges the inseparable function of the specialized cells that line the heart chambers and the muscle cells in the overall performance of the heart. Understanding these molecular pathways and their effect on the underlying heart muscle will likely identify novel therapeutic targets for prevention but also for management of arrhythmias.

Aside from unearthing targets for therapy, these pathways are also likely to contain candidate genes for genetic studies in patients with inherited heart arrhythmias and atrial fibrillation. Thus data generated in this study will be used to look for disease causing gene variants in studies already ongoing such as a NSW Health funded project aimed at sequencing the genomes of a large cohort of patients with cardiomyopathies, many of whom will develop AF and associated arrhythmias. As a result this project is likely to provide tangible outcomes for patient and family management and counselling.

Cancer and heart disease are the two most common disease conditions and the leading causes of death. Chemotherapy is more effective than ever at treating cancer, but has a price. There are over 400,000 cancer survivors in Australia and this figure is expected to increase due to a continuous decline in cancer death rates: there is a 70 per cent chance of survival from cancer in Australia. However, up to 25 per cent of these cancer survivors die from chemotherapy-induced cardiotoxicity (CIC) within 7 years, making it the leading cause of death in cancer survivors.

Cardio-oncology, an under-recognised area in Australia, is the intersection of heart conditions in cancer patients, an emerging field with immense potential to improve quality of life and cardiovascular burden in a growing number of cancer survivors.

The main reason for long-term cardiovascular and healthcare burden is delay in early detection of CIC due to imperfect diagnostic techniques. This is a major limitation, as early detection and treatment of CIC can lead to prevention of heart failure, and recovery of heart function. In addition, lack of an integrated, patient centred approach in Australia results in the fact that most cancer patients are still largely unaware of this adverse drug reaction and tend to neglect care for risk factors that may precipitate cardiotoxicity.

Thus, our program aims to address poor outcomes for the many cancer survivors who go on to develop CIC by discovering simple blood test(s) that could detect early onset of CIC as well as providing better education and facilitating self-care and empowerment for cancer patients/survivors.

Specifically, I will utilise state-of-the-art high through-put techniques that can gather a large amount of data to identify:
1) proteins in blood that change with early onset of CIC
2) genetic markers
3) chemotherapy-induced changes in genetic dispositions (epigenetics).

This data will be combined with latest imaging modalities to develop an individualised risk prediction tool for our patients. As risk assessment and early detection are cornerstones of early treatment and improved outcomes, this could in future lead to change in clinical practice/guidelines and translate in earlier discontinuation/change in chemotherapeutic regimen and initiation of cardioprotective therapy. I will also establish and facilitate a dedicated cardio-oncology nurse-led program of patient education and empowerment. This would achieve both improved interdisciplinary communication related to the diagnosis, monitoring and therapy of cancer treatment related cardiovascular complications and improved patients’ journey and outcomes through improved and dedicated cardiovascular care.