CARDIOVASCULAR MEDICINE SERVICES

(Director: Prof Anthony M Dart, BA, DPhil, BM, BCh, FAHA, FRCP, FRACP)

INTRODUCTION

The department participates in a large number of clinical trials and studies. These include commercially sponsored studies, collaborations with other departments within the Alfred and neighbouring institutes as well as projects initiated by departmental staff. Such projects range from those requiring outpatient visit with blood sampling or non-invasive measurements to complex studies within the cardiac catheterization laboratory.

CARDIAC MAGNETIC RESONANCE IMAGING

(Dr Andrew Taylor)

The Alfred Heart Centre, in conjunction with the Department of Radiology, runs a clinical and research CMR service, funded through a state government New Technology Grant. Approximately 500 CMR scans are performed per year, across a wide range of clinical and research indications

The CMR service has been involved in a number of international multi-centre studies, focused primarily on the measurement of changes in cardiac mass as a trial endpoint. In-house studies have utilised CMR for the evaluation of the suitability of patients with heart failure for cardiac resynchronisation therapy, diagnostic utility in arrhythmogenic right ventricular dysplasia, the detection of acute rejection in heart transplant recipients, changes in cardiac morphology in obesity with rapid weight loss, and CMR-guided left ventricular remodelling surgery. Recently, a large study investigating the non-invasive evaluation of myocardial fibrosis with CMR in heart failure, as well as its relationship with diastolic dysfunction, has been awarded a National Heart Foundation Project Grant. This study was made possible through a tripartite research agreement between the Alfred Hospital, The Baker Heart Research Institute, and General Electric Corporation (USA), enabling access to CMR sequences not yet made available for commercial use.

HEART FAILURE AND TRANSPLANT RESEARCH

(Professor David Kaye)

The Heart Failure/Transplant group in participation with Professor Kaye's Heart Failure Research Group at the Baker Heart Research Institute undertook a number of research activities. Several projects addressed the role of functional mitral regurgitation as a causal mechanism of the symptoms and progression of heart failure. In partnership with this effort Prof Stephen Duffy and Professor Kaye performed the first implant in Australia of a novel device for reducing mitral valve regurgitation. The groups' longstanding interest in endothelial function in heart failure was continued by Dr Justin Mariani, who examined the status of circulating endothelial progenitor cells in patients with heart failure. This year a several novel projects were initiated by Dr Angeline Leet, who as a part of her MD studies is examining the prevention of cardiac fibrosis in cardiac transplant recipients and is comparing the effects of various immunosuppressive protocols.

THE HUMAN NEUROTRANSMITTERS LABORATORY

(Dr Gavin Lambert)

Cardiovascular neuroscience in many guises remains the focus of our laboratory. Throughout 2007 our investigations in postural orthostasis proceeded on many fronts; we now have strong evidence that highlights the different mechanisms that come into play when people faint. Our studies examining cardiac risk in subjects with depression and panic disorder has continued and resulted in a number of significant publications. We were able to identify a subset of patients with depression in whom sympathetic nervous activity was extraordinarily high and, in panic disorder, contrary to the popular view, we documented a marked elevation in brain serotonin turnover which was normalised following therapy.

ALFRED BAKER GENE BANK

(Dr Melissa Barber)

The Alfred & Baker Gene Bank represents the most comprehensive collection of samples from patients with cardiovascular disease in Australia. Our key objective is to facilitate research into the genetic basis of heart disease. Over the last year the Gene Bank has seen significant change with development of the Risk Profiling Unit (RPU) it is now part of, and the appointment of Dr Melissa Barber as the RPU Manager. An exciting addition to the Unit is HDI (Health Data Integration); a platform that creates a centralised access point to the clinical and research databases of the Alfred Heart Centre and Baker Institute. HDI can link the Gene Bank, Echocardiography, Cardiac Catheterisation, Risk Clinic and Heart Failure databases. This 'virtual data repository' provides clinicians and researchers with access a broad range of de-identified patient information using a secure and user-friendly interface, thereby facilitating research and enhancing the utility of the Gene Bank samples.

ECHOCARDIOGRAPHY SERVICES

(Dr Jack Federman)

The echocardiography laboratories have participated in a number of departmental, hospital and international studies.
Ventricular and Structural Heart Disease: These have included evaluation of a novel device for reducing mitral regurgitation secondary to poor left ventricular function (VERITAS), closure of patent foremen ovale in patients at risk of stroke and evaluation of bioprosthetic aortic valves.
Left Ventricular Systolic Function: These have included drug therapy trials in heart failure (CIBIS) as well as evaluating the value of resynchronization therapy (Triple R study). Other studies have evaluated the effect of vapour ablation therapy in emphysema, cytotoxin drugs in leukaemia (TIDEL II) and evaluating optimal timing of renal dialysis (IDEAL).
Left Ventricular Mass/Hypertrophy: Evaluation of antihypertensive treatment in reducing left ventricular hypertrophy (DORADO).
Left Ventricular Diastolic Function: Studies with diastolic function as the primary end point are being conducted in patients post cardiac transplantation and in subjects treated for marked obesity.

CLINICAL PHYSIOLOGY

(Associate Professor Bronwyn Kingwell)

New Therapy for Marfan Syndrome
Although Marfan syndrome is a relatively rare genetic disorder, affecting around 7,000 Australians, it has life-threatening consequences for those afflicted. The underlying pathology is of the connective tissue which increases aortic fragility leading to rupture and death. Therapy aims to reduce the rate of aortic dilatation, but current approaches do not address the underlying pathology. A/Prof Kingwell and Dr Ahimastos with collaborators from the Royal Melbourne Hospital and the Murdoch Children's Research Institute has shown that the blood pressure lowering drug, perindopril reduces aortic diameter by between 3 and 7 mm in this population after only 6 months of therapy. This finding is highly clinically significant and likely to delay the need for surgery and reduce the risk of aortic rupture. After publication in the high impact general medical journal, Journal of the American Medical Association in 2007, this work has created substantial international interest including direct patient and physician enquiries and translation into other clinical journals including Nature Clinical Practice. This work will be extended to determine whether perindopril therapy may have more general application in the treatment of aortic aneurysms unrelated to Marfan syndrome.

VASCULAR PHARMACOLOGY

(Dr Jaye Chin-Dusting)

The Vascular Pharmacology Group, together with Dr Dmitri Sviridov's Lipoprotein Lab at the Baker Heart research Institute demonstrated that the anti-inflammatory effects of high density lipoprotein (HDL) on human monocytes were dependent on apolipoprotein A-1 (apoA-I) and cholesterol efflux via the ABCA1 receptor. This was definitively confirmed using monocytes derived from a Tangier disease patient which lacks ABCA1 receptors. As well the group showed that arginase II plays a role in the in vitro development of nitrate tolerance where increased arginase II stimulation, led to a decrease in intracellular L-arginine levels, uncoupling of eNOS and an increase in ROS production. As such, arginase inhibition may prove useful as adjunct therapy for the prevention of nitrate tolerance. Finally, in collaboration with A/Prof Kingwell and Dr Moe's group in the Singapore General Hospital, the TT genotype of C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was shown to be significantly associated with acute ischemic stroke, particularly in young, male and ethnic Chinese Singaporeans.

ALFRED MINIMALLY INVASIVE VASCULAR DIVISION

(Dr James Shaw)

Studies on the non coronary arterial circulation have included assessment of the acute effects of infused reconstituted HDL on atheroma plaque composition and studies on the intima-medial thickness (IMT) of the carotid artery as a surrogate of atherosclerosis.

The effects of HDL infusion were examined in subjects with symptomatic peripheral arterial disease undergoing angioplasty and atherectomy. Infusion as HDL several days before plaque excision were shown to favourably affect a number of plaque characteristics including lipid content, cellular accumulation and oxidation.

Studies on IMT have been examining the role of HIV infection and its treatment on this surrogate measure of atherosclerosis. Other studies are examining the effect of profound weight loss, induced by laparoscopic gastric banding in the severely overweight.

HUMAN VASCULAR BIOLOGY LABORATORY

(Dr Stephen J Duffy)

A series of studies on the effects of iron and oxidative stress on vascular function and clinical presentation of coronary artery disease have been completed. We have shown in a study of 66 patients who underwent intra-coronary ultrasound, trans-coronary blood sampling and percutaneous coronary intervention that markers of iron stores and oxidative stress are increased in coronary atherosclerotic plaque, and are released with plaque disruption. Redox-active iron stores appear to contribute to plaque composition, positive remodelling and unstable clinical presentation. In another study of 179 patients with coronary artery disease and 125 healthy controls we have shown that an iron regulatory/antioxidant enzyme heme oxygenase-1 is upregulated in response to stressful stimuli in vivo, as evidenced by higher heme oxygenase-1, bilirubin and ferritin levels. While it has been shown that heme oxygenase-1 expression and higher level of heme degradation products are protective in terms of progression of atherosclerosis, this study shows in humans that heme oxygenase-1 is induced in unstable coronary artery disease as an adaptive response, and the levels correlate to clinical markers such as hsCRP and troponin.

We have also continued our active participation in the Melbourne Interventional Group (MIG), which is a cooperative registry of percutaneous revascularization procedures that includes 8 Victorian public hospitals that perform coronary interventions. Currently more than 8,500 patient procedures have been entered into this database, with inpatient, 30-day and 12-month follow data available in eligible patients. Besides providing quality assurance data, we have published several manuscripts with results from MIG in the medical literature.

OTHER PRIZES INCLUDE

Ahimastos A: CSANZ Travel Fellowship to American Heart Association
Ahimastos A: National Heart Foundation Travel Grant
Ahimastos A: Baker Heart Research Institute Prize for Cardiovascular Research
Ahimastos A: Baker Institute Publication of the Month
Esler M: Order of Australia award - for his services to medical research
Murphy A: National Heart Foundation of Australia: Travel award.
Murphy A: Baker Heart Research Institute – Foundation: Travel award.
Murphy A: Winner Rod Andrew Prize – 2nd and 3rd year Baker Heart PhD student poster prize
Murphy A: Winner Paul Kroner Medal – Most outstanding 3rd year PhD student at the Baker Heart Research Institute
Murphy A: Runner-up Oral Young Investigator Award– Frontiers of Vascular Medicine

POSTGRADUATE STUDENTS

Anderson J. Examining cognition function in patients with the orthostatic intolerance. DPsych, Monash University.
Bails, R. Examination of the noradrenaline transporter in major depressive disorder: delineating mechanisms of cardiac risk. PhD, Deakin University
Ballinger M. Role of tyrosine kinases in controlling glycosaminoglycan length of vascular proteoglycans. PhD, Monash University.
Bertovic D. The arterial biomechanical and hemodynamic factors contributing to unstable coronary disease. PhD, Monash University.
Connelly N. Mechanisms of vascular changes in hepatic cirrhosis. PhD, University of Melbourne.
Dawood T. Affective disorders and their association with the cardiovascular system. PhD, Monash University.
Drew B. The role of HDL and dyslipidaemia in NO medicated glucose uptake in Type 2 diabetes. PhD, Monash University.
Henstridge D. Contraction mediated glucose uptake as a therapeutic target in Type 2 diabetes. PhD, Monash University.
Huynh N. The role of endothelin and nitric oxide in hypercholesterolaemia. PhD, Monash University.
Iles L. Myocardial fibrosis and heart failure. PhD, Monash University.
Khong S. PhD, Monash University
Lee S. PhD, Monash University.
Mariani J. Gene therapy in hear failure. PhD, Monash University.
Medi C. Atrial remodelling in pulmonary and systemic hypertension. PhD, University of Melbourne.
Mukherjee S. Nitric Oxide and oxidative stress in human hypertension. PhD, Monash University.
Murphy A. The role of C-reactive protein in leukocyte mediated vascular inflammation. PhD, Monash University.
Nair R. Neovascularisation in the pathogenesis of atherosclerosis. PhD, Monash University.
Rose, H. Impact of HIV infection and its treatment on cholesterol metabolism. PhD, Monash University.
Vaddadi G. Genetic and epigenetic mechanisms of the disorders of circulatory control which cause postural syncope. PhD, Monash University.
White A. Large artery stiffness as a risk marker and therapeutic target: Structural and genetic aspects. PhD, Monash University.

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