Cardiology and Therapeutics

Professor David Kaye
Head, Heart Failure Research Group
david.kaye@bakeridi.edu.au

Laboratory Research Overview

Heart failure (www.abouthf.org) 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 stopping the deterioration of heart failure patients through a range of means - from better understanding the cellular mechanisms involved in the process of heart failure itself to developing therapeutic devices to improve the health of those living with the condition.

The scientists aim to reduce the impact of heart attack on heart muscle by investigating methods for protecting the heart from the effects of myocardial ischemia. Our longstanding studies on the L-arginine:nitric oxide pathway have identified new protective pathways involving mitochondria, that show promise as new treatments. These studies combine techniques for specifically directing genes and treatments to the mitochondria in conjunction with methodology for extracting mitochondria from cells and heart muscle tissue.

David and his team are actively investigating new approaches to regenerating the function of the failing heart, through the use of gene therapy. To support this approach they recently developed a unique cardiac catheterization system designed for use in patients with heart failure. In experimental animal studies the delivery of gene therapy directly into the failing heart substantially improved heart function. This system has been commercialized by Osprey Medical Inc (www.ospreymed.com) which was co-founded byProf. Kaye and his colleague Dr John Power. Components of the system have recently been successfully used in patients undergoing coronary angiography to prevent renal damage from radiographic contrast.

The team is also actively studying the possibility that stem cells may provide another means for regenerating the heart. This research incorporates a number of different approaches including the use of unique models of heart failure developed in zebrafish, a species in which a great capacity for cardiac repair has recently been identified. This work is being conducted in parallel with other projects including the derivation of induced pluripotent stem cells, a technique in which stem cells that have the potential to form beating heart cells can be derived from tissue biopsies including skin, muscle and fat.

Research Focus

• Heart failure
• Nitric oxide
• Oxidative stress
• Stem cells
• Gene therapy
• Cardiac devices
• Cardiac regeneration
• Cardiac fibrosis

Research Projects

Understanding mitochondrial function in heart failure and myocardial ischaemia 

Group leader: Dr Kylie Venardos
Compelling evidence indicates that the failing heart is characterized metabolically by heightened oxidative stress and altered energy metabolism, and that together these processes impact adversely on contractile function and contribute to the progressive nature of heart failure. In particular, abnormal mitochondrial function has been implicated; however, the mechanisms remain poorly understood. Our studies show that impaired mitochondrial L-arginine transport may play a key role in the pathogenesis of heart failure. As a consequence, understanding the nature of mitochondrial L-arginine transport and its role in mitochondrial biology will provide new insights into potential therapies for heart failure and other myocardial disorders.

Specific studies focus on:
1. Investigating the biochemical properties of the mitochondrial L-arginine transporter, and its role in mitochondrial nitric oxide, reactive oxygen species and energy metabolism;
2. Studying the regulation of the mitochondrial L-arginine transporter in heart failure;
3. Evaluating the signaling mechanisms contributing to the regulation of the mitochondrial L-arginine transporter;
4. Examining the biochemical and physiological effects of augmented mitochondrial L-arginine transport.

Cardiac gene and cell delivery 

Group leader: Dr Melissa Byrne
Despite pharmacologic advances in the treatment of heart failure, mortality and morbidity remain unacceptably high. Moreover, for patients with end stage heart failure therapeutic options are limited to heart transplantation and possibly long-term mechanical circulatory support. However, these options are not appropriate for many patients with advanced HF when associated with other co-morbid diseases. In this context, alternative approaches such as gene and cell therapy have attracted increased attention. While these options have shown promise, significant ongoing issues related to delivery of the therapy, including dose, efficiency and safety are areas of concern.

We have developed a non-surgical device (V-Focus) that enables isolation of the heart (and other organs/regions) from the rest of the body allowing targeted delivery of a therapeutic to the site of interest. Our ongoing studies have used this technology to deliver a range of viral vectors that encode potentially therapeutic genes in our large animal model of heart failure. The effectiveness of these treatments is investigated using detailed haemodyanmic and echocardiographic investigations.Aspects of the device are already in use within the clinic (Osprey Medical Inc) and further studies are to be completed to enable further clinical application.

Cardiomyocytes derived from induced pluripotent stem cells - making heart cells from fat, skin and muscle 

Group leader: Dr Tanya Medley
It has recently been discovered that adult cells can be ‘de-aged' by a process termed genetic reprogramming. When fully reprogrammed they are essentially similar to stem cells from the embryo. Named ‘induced pluripotent stem: iPS cells', they have they ability to make any cell type in the human body. Using this method it may be feasible to generate cells from individual patients to potentially treat themselves, thereby avoiding the issues of immune rejection and the ethical challenges associated with using human embryos.

Our study aims to determine the type of tissue that is best suited to being reprogrammed into new heart cells in the laboratory. Specifically, we will compare the ability of cells from skin, fat and muscle to be reprogrammed. Heart failure patients and age-matched controls will undergo a muscle, skin and/or fat biopsy. This tissue will be used to isolate primary cell lines of muscle, skin and or fat cells in the laboratory. Each cell line will then be reprogrammed and tested for their ability to make the best heart cells in the laboratory. Identifying the tissue that can be reprogrammed to make the best heart cells in the laboratory will pave the way for future studies looking to use reprogrammed cells to develop new treatments.
Findings from this study will assist in determining whether patients with heart failure can use their own tissue to generate new heart cells. Findings are also likely to provide critical information about how these cells might be used in future studies to assist people suffering from heart attack and heart failure.

Investigating the cause, effects and treatment of cardiac fibrosis 

Group leader: Professor David Kaye
Cardiac fibrosis is a key adverse response to a wide range of common cardiovascular disorders including hypertension, 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.

Lab Head Profile

David trained as a Cardiologist at the Alfred Hospital. On completion of his clinical training undertook a PhD at the Baker Institute, working on aspects of the physiology of heart failure and heart transplantation. He subsequently went to the Brigham and Women's Hospital/Harvard Medical School as a postdoctoral Fellow before returning to Baker IDI and the Alfred Hospital.

Achievements/Awards

• Eric Sussman Prize for Research Excellence (College of Physicians), 2003
• RT Hall Prize (Cardiac Society of Australia and New Zealands), 2007
• Co-founder, Cardiac Dimensions Inc, USA
• Co-founder, Osprey Medical, USA

Publication Highlights

• Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic nervous activity in the failing human heart.  J AM Coll Cardiol 1995;26:1257-1263.
• Yang Z, Venardos K, Jones E, Morris BJ, Chin-Dusting J, Kaye DM. Identification of a novel polymorphism in the 3'UTR of the L-arginine transporter gene, SLC7A1: contribution to hypertension and endothelial dysfunction. Circulation 2007;115:1269-74.
• Kaye DM, Preovolos A, Marshall T, Byrne M, Hoshijima M, Hajjar R, Mariani JA, Pepe S, Chien KR, Power JM. Percutaneous cardiac recirculation mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals. J Am Coll Cardiol 2007;50(3):253-60.
• Kaye DM, Krum H. Drug discovery for congestive heart failure: new era of pharmacological therapies or end of the pipeline? Nature Reviews: Drug Discovery 2007;6:127-39.
• Schofer J, Siminiak T, Haude M, Herrman J, Vainer J, Wu, J, Levy W, Mauri L, Feldman T, Kwong R, Kaye D, Duffy S, Tubler T, Degen H, Brandt M, Van Bibber R, Goldberg S, Reuter D, Hoppe U. Percutaneous mitral annuloplasty for function mitral regurgitation: results of the CARILLON mitral annuloplasty device European Union study. Circulation 2009;120:326-33.

Key Staff

Contact

Direct: +613 9076 8044

Email: david.kaye@bakeridi.edu.au