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Heart failure is the commonest chronic, progressive cardiovascular condition. It is accompanied by severe symptoms, frequent hospitalisation and reduced life expectancy. The features of heart failure relate to the presence of impaired heart muscle pumping (systole) or an inability of the heart to fill adequately (diastole). The condition is particularly common in older people and may develop after a heart attack or may result from many other triggers such as high blood pressure, diabetes, chronic kidney disease, heart rhythm disturbances (such as atrial fibrillation) and chemotherapy or radiotherapy. Symptoms usually develop slowly and include breathlessness and increasing fatigue, although in some cases patients present for the first time with more acute illness.

Research in Professor Kaye's laboratory is directed at improving the prognosis and quality of life for heart failure patients by finding ways of improving the function of the heart and blood vessels. Professor Kaye and his colleagues investigate several of the fundamental abnormalities the cause the symptoms of heart failure. David and his team investigate the causes of heart failure, using experimental techniques that span from basic cellular studies on cardiac muscle cells and cardiac fibroblasts through detailed studies in heart failure patients using specialised cardiac catheterisation techniques. The team are interested in the processes that cause diffuse cardiac fibrosis and they have recently identified a major link between changes in the gut microbiome and cardiac fibrosis. Research in the laboratory is focussed upon the close interaction between the heart and kidney, with a particular focus on the cardiorenal syndrome. Abnormalities of heart rhythm are commonly found in patients with heart failure, frequently causing the condition to worsen. The team investigates the mechanism by which atrial fibrillation accelerates heart failure. The group also has a longstanding interest in the mechanism and role of altered endothelial function as a cause of cardiovascular disease including heart failure.

The Heart Failure Research Group is an internationally recognised leader in the commercial translation of its research at Baker Institute. Research conducted by Prof Kaye and his team has generated a large body of intellectual property leading to the development of medical devices and drug therapies. Companies including Cardiac Dimensions Incorporated (based in Seattle), Osprey Medical (based in Minneapolis and listed on the Australian Stock Exchange: OSP) and Cardiora (based in Melbourne) were all founded on the basis of the group’s research.

Research focus

  • Heart failure.
  • Hemodynamics and cardiovascular physiology.
  • Cardiac fibrosis.
  • Nitric Oxide.
  • Oxidative stress.
  • Microbiome and CVD.
  • Cardiac devices.

Projects

Investigating the cause, effects and treatment of cardiac fibrosis 

Leader: Professor David Kaye

Cardiac fibrosis is a key adverse response to a wide range of common cardiovascular disorders including hypertension and heart failure. The development of interstitial fibrosis has several major pathophysiologic sequelae including a contribution towards increase ventricular stiffness and heightened susceptibility to the development of arrhythmias. Our group is undertaking a series of studies directed towards understanding how cardiac fibrosis develops and subsequently how it may be reversed.

In small in-animal models of heart failure, hypertension and diabetes we are investigating the contribution of various homing signals that appear drive the recruitment of bone marrow derived fibrocytes to the heart. Using novel intervention we have recently shown that the use of drugs that block certain cytokines can markedly block the development of fibrosis.

Our studies are underpinned by invasive clinical studies in which the production of cytokines and collagen by the heart are evaluated by performing arterial and coronary sinus blood sampling. These biochemical findings are directly correlated with measures of cardiac function.

- Kaye - Fibrocytes
Figure: Micrographic picture of fibrosis causing cells (fibrocytes) invading the failing heart

- Kaye - Stiffness
Figure: Measuring the stiffness of the heart in a heart transplant recipient, using cardiac catheterisation

Understanding mitochondrial function in heart failure 

Leader: Dr Mandar Joshi 

The cardiovascular complications including heart attack, stroke and poor circulation in the legs are the most disabling and life-threatening problems for patients living with both Type 1 and Type 2 diabetes. Whilst various risk factors for the development of vascular disease are known, including poor disease control, hypertension and smoking, the mechanism(s) responsible for the development of vascular disease are not well known.

Our laboratory has shown that the function of cardiac and vascular cells is abnormal in a range of patients with cardiovascular disease and diabetes. Recently we have identified new defects in the function of mitochondria (the energy powerhouse of cells). We are developing new approaches to target these defects.

Cardiac gene and cell delivery 

Group Leader: Dr Melissa Byrne

The association between heart failure and heart rhythm disturbances are well known and frequently accompanied by adverse outcomes. For example, atrial fibrillation, which causes an irregular heart rhythm is known to exacerbate heart failure and worsen outcome. Melissa is expert in the use of large animal models to study the causes of heart failure. Our studies have identified key changes in heart proteins, which develop early in atrial fibrillation that lead to reduced pumping capacity. These findings form the basis of new clinical studies aimed at improving outcome in heart failure.

L-arginine transport in cardiovascular disease

Group Leader: Dr Niwanthi Rajapakse

The prevalence of obesity is rising at an alarming rate world-wide and estimated 65% and 75% of hypertension in women and men is directly attributed to obesity. We recently made the startling discovery that the reduced availability of endothelial nitric oxide (NO) is a critical factor in the pathogenesis of obesity hypertension. By increasing NO bioavailability with over expression of the L-arginine transporter in mice, obesity hypertension was abolished. Our evidence also suggests that the mechanism involved a reduction in the sympathetic contribution to the hypertension. The interaction of sympathetic nerve activity, NO and also the renin-angiotensin-aldosterone system (RAAS) most likely occurs within the kidney. Understanding these interactions is the main focus of our current work. The importance of this discovery is that it offers a very specific and novel approach to treating obesity related hypertension. We use an integrated approach from biochemistry, physiology, pharmacology through to clinical work to address our research aims.

- Kaye - Arginine
Figure: Fat fed mice have low levels of nitric oxide; this is restored in transgenic mice with enhanced arginine uptake

Cardiac regeneration

The reduced pumping capacity of the failing heart represents the combined effects of a loss of heart cells, and a reduction in the strength of the remaining cells. Over the past decade, developments in the stem cell field provided hope that it may be possible to re-build the heart by replacing lost cells. Recently we and other teams have shown that heart cells have a capacity to divide, thereby potentially replacing lost cells. Our group is investigating the way in which cells may be encouraged to divide, in order to provide a possible method of cardiac repair.

- Kaye - Cardiac regeneration
Figure: Stimulating the formation of new cardiac muscle cells (red) in an experimental model of heart failure

Student research opportunities

The role of the microRNA miR-181a in blood pressure

The role of Gpr43 in the dietary prevention of cardiovascular disease

Staff

Scientific staff
Dr Melissa Byrne
Dr Po-Yin Chu
Duncan Horlock
Dr Mandar Joshi
Ouda Khammy
Melissa Knight
Vivian Mak
Dr Francine Marques
Dr Tanya Medley
Dr Shane Nanayakkara
Dr Niwanthi Rajapakse
David Williams

Students
Steven Fernandez
Nicholas Lam
Dr Dion Stub

Support us

With the rising number of Australians affected by diabetes, heart disease and stroke, the need for research is more critical than ever.

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