Cardiovascular Research Capacity Program

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 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.

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.

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.

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”.

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.

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 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.

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).

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.

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.

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.

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.

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.

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.

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.

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.