Head: Professor David Kaye
Heart failure is a common progressive condition that may develop after a heart attack or may be the result of heart muscle weakness occurring for other reasons including hereditary causes and viral infection. Symptoms usually develop slowly and include breathlessness and increasing fatigue, although in some cases patients present for the first time with more acute illness. It is the third largest cause of death among the various forms of cardiovascular disease in Australia, and the major cause of disability in the elderly.
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 cardiac fibrosis, using experimental techniques that span from basic cellular studies through detailed clinical studies using specialised cardiac catheterisation techniques. 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. Their longstanding studies on the L-arginine:nitric oxide pathway have uncovered a series of abnormalities that contribute to the causation of heart failure, renal dysfunction and hypertension. More recently these studies have uncovered a novel role for this system in mitochondria. David and his team actively investigate new approaches to regenerating the function of the failing heart, by exploring the possibility that heart cells may be able to divide.
The Heart Failure Research Group is a leader in commercial translation of its research at the Baker Institute. Research into medical devices has generated significant intellectual property that has been commercialised by Osprey Medical Inc., which was co-founded by Professor Kaye. Components of the system have recently been successfully used in patients undergoing coronary angiography to prevent renal damage from radiographic contrast, and other components are being evaluated in diabetic patients with life-threatening infections.
- heart failure
- nitric oxide
- oxidative stress
- gene therapy
- cardiac devices
- cardiac regeneration
- cardiac fibrosis.
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.
Figure: Micrographic picture of fibrosis causing cells (fibrocytes) invading the failing heart
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.
Figure: Fat fed mice have low levels of nitric oxide; this is restored in transgenic mice with enhanced arginine uptake
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.
Figure: Stimulating the formation of new cardiac muscle cells (red) in an experimental model of heart failure
Student research opportunities
Dr Melissa Byrne
Dr Po-Yin Chu
Dr Mandar Joshi
Dr Francine Marques
Dr Tanya Medley
Dr Shane Nanayakkara
Dr Niwanthi Rajapakse
Dr Dion Stub