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• Research program
• Research support (2008/09)

Research program

Kids Heart Research was established in 2005 and is a NSW based organisation that performs research relevant to the diagnosis and treatment of children affected by heart disease, a condition that currently affects 1 in 100 children. Our facilities are based at The Children's Hospital at Westmead, which is the principle site for diagnosis and treatment of children with heart disease in NSW.

We are a multi-disciplinary team comprising of scientists, researchers, cardiologists and surgeons. A two-way interaction between doctors and researchers fosters an ideal environment to develop, test and implement new treatments as well as understand disease processes to prevent disease or discover cures.

• Therapeutic testing in a model of cardiopulmonary bypass
• Impact of ischaemia/reperfusion injury on cardiomyocyte membranes and function
• Cardiomyocyte membrane maintenance and mechanisms of repair
• Genetic causes of congenital heart disease

Therapeutic testing in a model of cardiopulmonary bypass

Many of the babies born with congenital heart disease need surgery to repair their heart defects. Our service alone performs approximately 350 cardiac repair surgeries each year. While the operations typically proceed well and the children recover rapidly, around 1 in 5 patients suffer a severe drop in heart function during the recovery from surgery that is termed a low cardiac output state (LCOS). This condition is life threatening and patients require vigilant clinical care until the heart can recover.

The causes of LCOS are poorly understood. Swelling is a common complication and is aggressively treated as a potential contributor. Our recent research in this area has shown that swelling is not a major player in the development of poor heart function in patients. In contrast, ischemia/reperfusion injury, which is a necessary part of open heart surgery, does prevent the heart from functioning normally. We are now exploring ways to minimise the effects of ischemia/reperfusion injury and therefore reduce the severity of LCOS in children recovering from heart surgery.

Our team of clinicians and scientists are developing a large animal surgical model to probe the causes of LCOS and evaluate treatments. This comprehensive investigation includes precise modelling of the human surgical setting together with invasive monitoring of cardiac function and other haemodynamic indices.

Impact of ischaemia/reperfusion injury on cardiomyocyte membranes and function

The most important feature of cardiac surgery is the need to stop the heart beating so that surgeons can perform the necessary repair. This causes a form of injury to the heart known as ischaemia/reperfusion injury. The result is damage to the membranes that surround heart muscle cells. Cell membranes form a critical physical and functional link between the inside of cells and their external environment and damage can affect cell function both immediately and over the long term. Membrane damage and the subsequent course of events may be the cause of LCOS after cardiac surgery.

We are exploring ways to minimise the effects of ischemia/reperfusion injury and reduce the severity of LCOS in children recovering from heart surgery. To do this, we must probe the effect of ischemia/reperfusion injury at a molecular level to understand what happens within individual heart muscle cells. We have developed a Cardiac Function Laboratory with world-class equipment and technology to ask and answer important clinical questions such as this. Using these models, we will determine the effect of ischemia/reperfusion injury at a molecular level to understand what happens within individual heart muscle cells. With a focus on membrane integrity, we are examining the impact of ischaemic injury on cardiomyocyte homeostasis and function.

Cardiomyocyte membrane maintenance and mechanisms of repair

We are exploring the molecular pathways by which cells repair their membranes to develop treatments for LCOS in paediatric surgery. A small number of proteins are known to be critical for membrane resealing after injury but it is not yet clear how these proteins work as their molecular partners are not known. We will identify other functional players in the repair process by determining which proteins interact with the known repair proteins. This is achieved with technology that allows us to use the known proteins as 'bait' to identify interacting 'prey' from a library of all proteins expressed in the heart.

As we identify proteins important to heart muscle membrane repair, we are characterising these in animal models. This is critical to understand how all of the proteins work in concert to perform their roles. Our group has commonly used strains of mice available to us for this purpose, as well as strains that we imported from a leading laboratory in the USA and have exclusive access to in Australia.

Genetic causes of congenital heart disease

Our current understanding of genetic causes of congenital heart disease are derived largely from study of rare, dominantly inherited forms caused by mutations in single genes. However, this does not explain "common" congenital heart disease, seen in over 70% of children who have no family history of disease.

We are investigating genetic causes of common congenital heart disease in a number of complementary research projects. This is made possible by our extensive Kids Heart Research DNA bank - the only such resource for congenital heart disease in Australia and one of few worldwide. Detailed information on cardiac phenotype is collected using an internationally recognized clinical coding system. This is matched with highly secure and de-identified information on sequencing results, family history and ethnicity that are stored in a purpose built web-based platform.

Using this unique resource, we are discovering the detailed molecular pathways and genes involved in common congenital heart disease. Our research will allow us to model inheritance, gene/gene and gene/environment interactions. One focus is to identify common changes seen in DNA, known as single nucleotide polymorphisms (SNPs), to investigate how allelic variation may contribute to heart malformation. These novel approaches to genetic investigation will in time provide better counselling for the 1 in 100 affected children and their parents regarding risk of inheritance. With a better understanding of the genetic control of heart development our research will also help us develop future therapies.

Research support (2008/09)

NHMRC

National Heart Foundation

March of Dimes

HeartKids