INTRODUCTION

Research within the Alfred hospital department of Cardiovascular Medicine and the Baker Heart Research Institutes division, Baker Clinical, continues across a wide spectrum of cardiovascular health, disease prevention and prediction and treatment. In keeping with the community burden of disease research has particularly centred on atherosclerosis and cardiac failure. The close association between the department of Cardiovascular Medicine and the Baker Heart Research Institute has been pivotal to the research output and in permitting a close integration between basic and clinical science. Of particular note in the recent period has been an expansion in catheter lab research both on the coronary and peripheral circulation and this has been particular facilitated by research-trained interventionalists. Similarly increasing activity in non-invasive imaging research particularly in MRI has also been a feature over the past year. Recent acquisition of contemporary ultrasound equipment should permit the development of comparable research in echocardiography.

CLINICAL LIPID RESEARCH

(Professor Anthony Dart)

Clinical lipid research has taken advantage of the particular and unusual groups of patients frequently referred to the Clinical Lipid Service. These namely are from the Cardiac Transplant unit and the HIV service of Infectious Diseases. They have been conduction in close collaboration with the basic biochemistry laboratory in the Baker Heart Research Institute of Dr Sviridov. HDL cholesterol is a major predictor of cardiovascular risk and can frequently be elevated (as well as being low) post cardiac transplantation. However it has not been clear till now whether this elevated HDL is functionally normal. Studies completed in the clinic have indicated that this is not the case and that elevated HDL in such patients cannot be assumed to offer the same vascular protection as in non-transplanted patient. A low HDL is a particular feature of patients with HIV infection and this is exacerbated in those on treatment, particularly protease inhibitors, by marked elevation of triglyceride in normalisation of LDL. A number of studies have been investigating the effects of drug treatment and/or infection perse on the lipid status on these patients. This is representative of fruitful collaboration between the HIV service of Infectious Disease, the Baker Institute and Cardiovascular Medicine.

THE ALFRED AND BAKER GENE BANK

The Alfred and Baker Gene Bank was initiated some years ago by Professor Garry Jennings, Associate Professor Christopher Reid and Professor Anthony Dart. The objective was to enable the collection of genetic material from a range of cardiovascular patients along with relevant clinical information. Since January 2005, the facility has been managed by Bernadette Chiodi. To date, the number of samples in the Gene Bank is close to 5000 and patient recruitment in 2005 has more than doubled from the coronary care unit and the cardiac catheter labs. Routine collection also occurs from the Baker Risk Clinic and the Heart Centre outpatient clinics. The Gene Bank is well and truly on target in accomplishing its initial goal. The research value from such an activity is increased in proportion to the number of samples collected. Several studies have been published which were conducted either in or through the gene bank and several more are currently under way.

CLINICAL PHYSIOLOGY

(A/Prof Bronwyn Kingwell)

Key Collaborators: Stephen Duffy, Tony Dart, Bruce Kemp, Greg Steinberg, Peter Blombery

Type 2 Diabetes
At least 171 million people worldwide have type 2 diabetes mellitus and this figure is likely to double by 2030. In 2005, the Clinical Physiology laboratory has continued to focus on research which may yield novel therapeutic approaches to type 2 diabetes and its antecedents including obesity.

We have recently described a novel molecular mechanism which may contribute to a unified notion of the metabolic syndrome and development of new therapeutic avenues. The metabolic syndrome is characterised by a clustering of symptoms including lipid abnormalities, obesity, insulin resistance and high triglyceride levels. However, the mechanistic basis for these associations has not been defined, and it is not clear whether the metabolic syndrome is an entity rather than a series of coexisting clinical phenomena associated by chance. Using cells obtained from human muscle biopsies we demonstrate that a pivotal metabolic enzyme may be the key which links these symptoms. Our findings offer a common molecular mechanism explaining the metabolic syndrome and provide a rationale for designing new therapies to address the metabolic syndrome, type 2 diabetes and obesity.

Other studies have been aimed at understanding how exercise improves glucose control, with a view to mimicking the effects of exercise with drugs. It is well known that exercise improves blood glucose control in patients with diabetes. Our laboratory has previously shown that the molecule nitric oxide plays a key role in glucose uptake into skeletal muscle during exercise. Increasing skeletal muscle glucose uptake is of great benefit for type 2 diabetes patients as it removes excess glucose from the blood into muscle for energy production. Current studies aim to determine whether drugs which deliver nitric oxide can increase skeletal muscle glucose uptake in patients with type 2 diabetes at rest. This work includes both clinical studies in patients with type 2 diabetes and laboratory based work using skeletal muscle cell culture models. If successful, this work could contribute to improved blood glucose control and prevention of diabetic complications through new medication.

Acute Coronary Syndromes
Accurate identification of patients at risk for unstable coronary syndromes is still not possible. Worldwide, more than 19 million people experience a sudden cardiac event annually. A large proportion of these individuals have no prior symptom. This fact emphasises that prevention of sudden cardiac events is essential to further reduce coronary artery disease-related morbidity and mortality. Better predictors of individual vulnerability (or risk) are required. This is driving the search for new biomarkers of susceptibility to coronary plaque rupture or surface erosion, the most frequent precipitating events.

Arterial remodeling plays an important role in plaque vulnerability. Positive or expansile remodeling in response to atheroma was initially described as a compensatory phenomenon, that preserves the lumen and delays the point at which a given volume of atheroma in the vessel wall becomes flow-limiting. However, more recently, positive remodeling has been associated with adverse characteristics including more inflammation and unstable clinical presentation. The matrix metalloproteinases (MMPs) play an integral role in both remodeling and plaque rupture/erosion making them attractive candidates as biomarkers for unstable coronary syndromes. Collectively MMPs are capable of degrading all components of the extracellular matrix and have been implicated in both positive remodeling and plaque instability. Due to the complex biology of coronary atherosclerotic plaques, a causal role for MMPs in coronary plaque instability remains to be unequivocally established. We sought to provide mechanistic insight into the role of MMPs in unstable coronary disease by comprehensive examination of the relationships between common functional genetic polymorphisms in MMPs, their plasma concentrations, coronary plaque and remodeling characteristics assessed using intravascular ultrasound (IVUS). Four MMPs implicated in coronary plaque remodeling were studied, MMPs-1, -2, -3 and -9. MMP-3 (stromelysin-1) may be particularly significant to plaque stability and coronary remodeling owing to its broad substrate spectrum and its role in activation of other MMPs including, interstitial collagenase (MMP-1) and gelatinase B (MMP-9). The relationships between common promoter polymorphisms in these MMPs, stable versus unstable clinical presentation and plaque morphology have not previously been examined.

Our work has established a plausible mechanistic link between a common genetic MMP-3 variant and unstable coronary syndromes in a predominantly Caucasian population. The mechanism appears to include elevation of MMP-3 expression, positive coronary remodeling, greater plaque burden and increased susceptibility to plaque instability. The high frequency of the 6A variant increases the importance of this finding for risk assessment in Caucasian populations. MMP-3 genotype can be assessed prior to clinical presentation and may be a useful component of a risk prediction model for unstable coronary disease.

Peripheral Arterial Disease
Peripheral arterial disease (PAD) is a common disorder, with 12% of adults over 50 having an ankle-brachial index (ABI) diagnostic of PAD (<0.9). Approximately one third of these patients experience intermittent claudication during walking, limiting normal activities. Medical treatments to improve walking distance are limited. The angiotensin converting enzyme (ACE) inhibitor, ramipril, reduced cardiovascular morbidity and mortality compared to placebo in patients with established atherosclerotic disease, including PAD, in the Heart Outcomes Prevention Evaluation (HOPE) study. This effect appeared to be independent of blood pressure reduction and may relate to the known benefits of ACE inhibitors on both coronary and brachial endothelial function. No previous controlled studies have investigated the effect of ACE inhibitors on symptoms of intermittent claudication. Given the positive effects of ramipril in the HOPE trial and its convenient once daily dosing formulation, we hypothesised that therapy with ramipril would improve intermittent claudication symptoms. The aim of the current study was to examine the effect of six months therapy with ramipril on walking distance and claudication pain in a defined group of patients with claudication due to infrainguinal PAD, using a double-blind, randomised, placebo-controlled design.

Our study demonstrated that treatment of patients with PAD with an ACE inhibitor, ramipril, markedly improves walking ability. Ramipril therapy increased mean treadmill-assessed maximum walking time by over 200% (~ 7 mins or 400m). This change would impact appreciably on daily functional capacity. The magnitude of this effect is significantly greater than that reported for conventional medical therapies and provides worthwhile clinical benefit.

While ACE inhibitor therapy reduces vascular events in patients with PAD, it is not currently specifically indicated for relief of clinical symptoms. Our data demonstrate that ramipril may have benefits beyond reduction in vascular events in this high risk population, and provide substantial improvement in clinical symptoms and quality of life.

HUMAN VASCULAR BIOLOGY LABORATORY

(Dr Stephen J Duffy)

Research Projects for 2005

Relationship of Iron Status to Oxidative Stress in vivo, Nitric Oxide Bioactivity and Coronary Artery Disease Activity
Patients with high total-body iron levels may be at higher risk for the development of atherosclerosis and coronary artery disease. In animal models of atherosclerosis, iron has been shown to contribute to the progression of disease development. Endothelial-derived nitric oxide (EDNO) is an important anti-atherosclerotic molecule, and its activity is decreased in patients with coronary artery disease. Reactive oxygen species have been implicated in the pathogenesis of both endothelial dysfunction and atherosclerosis. Redox-active iron increases production of reactive oxygen species (via Fenton chemistry) and causes lipid peroxidation. F2-isoprostanes are a reliable method for assessment of oxidant stress in vivo. We recently demonstrated that iron chelation with desferrioxamine reversed endothelial dysfunction in patients with coronary artery disease (CAD).

In our first study we aimed to determine whether acutely increasing iron would result in oxidative stress in vivo and produce endothelial dysfunction. In healthy controls and patients with CAD we demonstrated that acute iron infusion induces oxidative stress in vivo (increased production of F2-isoprostanes), without affecting nitric oxide-mediated vascular reactivity. Given our previous evidence, this suggests that chronic iron overload is necessary to affect endothelial function, and by inference, atherosclerosis.

In our second study we hypothesised that aortic and coronary trans-lesional ferritin levels, a marker of iron stores, would relate to coronary plaque characteristics on intravascular ultrasound and clinical presentation as stable versus unstable angina. We have demonstrated that markers of iron stores and oxidative stress are increased in coronary atherosclerotic plaque, and are released with plaque disruption. Redox-active iron appears to contribute to higher coronary plaque burden, positive remodelling and unstable presentation.

Coronary Plaque Stability
Better predictors of unstable coronary syndromes are needed to reduce the incidence of sudden cardiac death and unheralded myocardial infarction. Matrix metalloproteinases are plausible candidates for susceptibilility to acute coronary syndrome, due to their role in arterial remodeling and potential to promote plaque disruption. This is a collaborative project with A/Prof. Kingwell and Professors Dart and Jennings. Results of a recently completed study are discussed elsewhere in this report by A/Prof. Kingwell.

The Role of Non-prostanoid, Non-nitric oxide, Endothelium Derived Factors in Patients with Cardiovascular Disease
We have previously demonstrated that endothelium-derived vasodilators such as nitric oxide and prostacyclin contribute to metabolic vasodilation in skeletal muscle and coronary artery vasculature. In vascular smooth muscle cells, efflux of K+ through large-conductance Ca-sensitive K+-channels and ATP-sensitive K+-channels results in hyperpolarization, relaxation and consequent vasodilation. In recently completed studies, we have shown that the forearm vasodilator response to the endothelium-dependent vasodilator acetylcholine was impaired in patients with CAD compared to that of healthy volunteers. Administration of tetraethylammonium (TEA), a compound that selectively blocks Ca-sensitive K+-channels, decreased resting blood flow in healthy volunteers but not in patients with CAD. Interestingly, TEA had no effect on blood flow after exercise (metabolic vasodilation) in either group, despite adjustment for changes in baseline. TEA did not attenuate the vasodilator response to acetylcholine in either healthy controls or patients with CAD. Combined inhibition of nitric oxide and prostacyclin attenuated the response to acetylcholine in healthy controls, but co-infusion of TEA did not further reduce the response to acetylcholine. Additionally, TEA alone did not attenuate the vasodilator response to another endothelium-dependent vasodilator, namely bradykinin. These data suggest that tonic activation of Ca-dependent K+-channels contributes to resting blood flow in skeletal muscle vasculature in health, but not in patients with CAD. Furthermore, activation of Ca-dependent-K+-channels does not contribute to agonist-induced vasodilation in the skeletal muscle vasculature of humans.

Contraction-mediated Glucose Uptake as a Therapeutic Target in Type 2 Diabetes Mellitus
In this NHMRC funded (Project Grant) study we are testing the hypothesis that a separate pathway to insulin-mediated glucose uptake can be utilised in patients with type 2 diabetes mellitus to improve glycaemic control. In type 2 diabetics there is insulin resistance, but contraction- (or exercise-) mediated glucose uptake appears to be of increased importance. This is a collaborative project with A/Prof. Kingwell. Results of a recently completed study are discussed elsewhere in this report by A/Prof. Kingwell.

Prevention of the No-reflow Phenomenon in Myocardial Infarction
Defined angiographically, the "no-reflow" phenomenon manifests as an acute reduction in coronary blood flow in the absence of epicardial vessel obstruction. No-reflow (or slow-flow) occurs in up to 2% of all percutaneous interventions (PCI) and in 30-40% of interventions in acute myocardial infarction (MI) when defined by myocardial perfusion techniques. If persistent, no/slow-reflow may result in MI, or extension of MI, and is associated with a poor prognosis. Verapamil and adenosine are commonly used treatments, however, recent experimental studies and small case-series reports have suggested that sodium nitroprusside (SNP) is an effective alternative therapy for no-reflow. However, few patients reported were being treated for MI. Recent retrospective data presented by us at a national conference suggest that SNP is as effective and safe a treatment for no/slow-reflow as verapamil in the setting of PCI for MI. However, prospective, randomised studies will be required before this therapy can be recommended generally. The aim of our proposed prospective, randomised study is to determine whether the vasodilators sodium nitroprusside (SNP) and verapamil will improve coronary blood flow, coronary flow reserve and reduce myocardial infarct size in patients with myocardial infarction.

Melbourne Interventional Group
This is a co-operative database of percutaneous revascularization procedures that includes seven of the Victorian public hospitals that perform coronary interventions. Our ultimate aim is to obtain short- & long-term outcomes of coronary interventions for all patients in the state. Currently more than 2,700 patients have been entered into this database, and 30-day and 12-month follow-up is available for more than 2,200 and 600 patients at these respective time points. An additional aim is to provide a framework to complete interventional/clinical trials.

LABORATORY OF CARDIOVASCULAR NUTRITION

(Professor Paul Nestel)

Two clinical projects have been completed.
A clinical trial of oral trans-tetrahydrodaidzein (a synthetic isoflavone) on pulse wave velocity and plasma lipids.

The objective was to test whether metabolites of ingested isoflavones were inactivated or retained bioactivity. 25 overweight men and women received the metabolite orally over 5 weeks in a double-blind randomised, placebo controlled cross-over study.

Pulse wave velocity (across aorta-femoral artery) decreased significantly, indicating reduced central arterial stiffness. Blood pressures (systolic and diastolic also decreased significantly but the changes in pulse wave velocity were independent of the blood pressure changes. Plasma lipids did not change. Absorption of the metabolite was at least 85% far better than that of the parent isoflavones.

Sympathetic nervous activity and insulin sensitivity in subjects with the metabolic syndrome. With Nora Straznicki and the Esler-Lambert Laboratories.

This study showed that subjects with the metabolic syndrome who had lost body weight and abdominal fat showed significant improvement in plasma lipids, in glucose and insulin sensitivity, and in parameters of sympathetic nerve activity (turnover of noradrenaline and microneurography). The study is continuing as a factorial study of the effects of weight reduction and increased physical activity.

Outside Collaborations
With collaborators in the LIPID Trial the stored plasmas from the 9000 participants are being systematically assayed for biomarkers that may indicate increased risk for cardiovascular events. The LIPID Trial was one of the largest trials of the effects of statin therapy on recurrent cardiovascular events. To date, in a pilot study of 500 subjects the two best independent predictors of future events were the tissue inhibitor of metalloproteinase-1 that is involved in plaque stabilisation and remodelling of damaged artery and myocardium, and BNP that is also involved in remodelling of damaged myocardium.

With collaborators in Singapore and Dmitri Sviridov, the effects of polymorphisms in lipid regulatory genes, specifically cholesterol ester transfer protein and hepatic lipase are being evaluated in the 3 ethnic populations of Singapore. The Baker involvement relates to the putative effects of the polymorphisms that influence the activities of CETP and HL on HDL structure and function.

VASCULAR PHARMACOLOY LABORATORY

(Dr Jaye Chin-Dusting)

Raised soluble p-selectin enhances neutrophil adhesion in patients with peripheral arterial occlusive disease. K Woollard (1), S Jackson (2), D Kling (3), S Kulkarni (2), A Dart (1) and J Chin-Dusting (1). 1.Alfred Baker Medical Unit, Wynn Domain, Baker Heart Research Institute, Melbourne; 2. Australian Centre of Blood Diseases, Burnet Tower, Monash University, Melbourne; 3. F-Hoffman La Roche, Basel, Switzerland.

P-selectin supports adhesion of leukocytes to activated platelets present in thrombi or to activated endothelial cells. The soluble version of its membrane bound form has been reported as a useful biomarker of vascular disease. However soluble P-selectin (sP-selectin) may, in its own right, be active, as it possesses the lectin and epidermal growth factor domains required to bind the P-selectin receptor, PSGL-1, expressed by leukocytes. In this study we have examined a potential role for plasma sP-selectin in regulating neutrophil adhesion in patients with peripheral arterial occlusive disease (PAOD). Patients with PAOD had significantly higher levels of sP-selectin. To examine whether the raised sP-selectin levels can influence leucocyte adhesion, isolated neutrophils were incubated with plasma from PAOD patients before and after immunodepletion of sP-selectin with a P-selectin antibody. Neutrophil adhesion to fibrinogen increased 2-fold following incubation with PAOD plasma, which was abrogated upon sP-selectin immunodepletion. We subsequently demonstrated that recombinant sP-selectin dose-dependently (75-250ng/ml) increased neutrophil adhesion to fibrinogen and platelet monolayers. This increase was PSGL-1 and Src kinase-dependent and correlated with an increase in sP-selectin-mediated Mac-1 activation. sP-selectin-stimulated neutrophil adhesion to platelet monolayers was inversely correlated with shear. These studies suggest a potentially important role for soluble P-selectin in modulating neutrophil adhesion in patients with PAOD, particularly at sites of low shear. While it remains to be established whether such effects enhance leukocyte recruitment to vascular injury and promote disease progression in experimental models, they nonetheless raise the interesting possibility that pharmacological targeting of sP-selectin may represent a novel therapeutic approach to reduce inflammatory infiltration in diseased vessels.

Arginase Inhibition Prevents Nitrate Tolerance by Conserving L-arginine Levels (Chin-Dusting JPF, Huynh NN)

Nitrate tolerance, where the therapeutic efficacy of nitrates rapidly diminishes with continuous application is a limiting phenomenon well described in its clinical use as an anti-anginal, anti-ischemic agent. There are many postulates explaining the phenomenon of nitrate tolerance, the most prevalent ones being that it is caused by increased vascular superoxide production and a hypersensitivity to vasoconstrictors secondary to a tonic activation of protein kinase C. We explored whether arginase inhibition could prevent nitrate tolerance by conserving intracellular L-arginine levels. Rat isolated aortic rings and mesenteric arteries were set-up for isometric recording. Responses to repeated applications of sodium nitroprusside and acetylcholine were obtained in the absence and presence of L-arginine or the arginase inhibitors L-NOHA (NG- Hydroxy-L-arginine) and BEC ((S)-(2-boronethyl-L-cysteine). Repeated application of both acetylcholine (ACh) and sodium nitroprusside (SNP) resulted in either a significant rightward shift or a dampening of the maximal dilatation. These decreased responses were no longer observed in the presence of L-arginine or the arginase inhibitors. We hypothesise that arginase inhibition prevents nitrate tolerance by conserving L-arginine stores, possibly reducing uncoupled eNOS and superoxide production.

Responses to neither exogenous nor endogenous endothelin-1 are altered in patients with hypercholesterolemia. (Chin-Dusting, Boak, Duffy, Dart)

There is some controversy regarding whether vascular responses to endothelin are altered in hypercholesterolemia. Studies performed to date have been compromised by the use of endothelin antagonists at inappropriate concentrations. In the current study, we examine the role of endothelin-1 in hypercholesterolemic patients using lower, more selective doses of specific endothelin antagonists. Twenty-two patients with hypercholesterolemia (total plasma cholesterol > 6.0 mmol/l) and 17 healthy controls were recruited. Forearm vascular responses to endothelin-1 (5 pmol/min), the endothelin A antagonist BQ-123 (10 nmol/min), and the endothelin B antagonist BQ-788 (1 mmol/min) were obtained. Endothelin-1 caused a significant vasoconstriction in both hypercholesterolemic and control subjects, an effect that was not significantly different between the two groups. BQ-123 caused a significant vasodilatation that was not significantly different between the two groups. Similarly, responses to BQ-788 and mean plasma endothelin-1 levels were not different. Responses to neither exogenous nor endogenous endothelin are influenced by plasma cholesterol levels in humans. It is thus unlikely that the endothelin system contributes to early vascular disease pathology in patients with hypercholesterolemia.

INTERNATIONAL COLLABORATIVE TRIALS

(Chief Investigator: Professor Anthony Dart. Research Co-ordinators: Sally Kay and Kaye Carter)

TNT Trial: This study was completed in 2004 and the results were published on the 7th April 2005.
The results showed that Atorvastatin 80mg per day in patients with stable coronary heart disease provides significant benefit and reduction in major cardiovascular events than treatment with Atorvastatin 10mg per day.

IllUMINATE Trial: This trial is a five-year trial studying the effects of a new drug that increases HDL ('good') cholesterol and is being tested on patients with coronary disease. At this site 52 patients have been recruited.

EZJ Trial: This was a twelve-week treatment program comparing the effectiveness of a combination of cholesterol lowering medications currently available for the treatment of high cholesterol levels in people with both high LDL ('bad') cholesterol and high triglyceride levels and who were otherwise healthy. The results showed that the use of a combination of two and three medications was more effective in lowering the bad cholesterol and triglyceride levels compared to single or monotherapy in this group of patients.

CARDIOVASCULAR NEUROSCIENCE

(Dr Gavin Lambert)

Cardiovascular neuroscience, in several guises, remains the continuing focus of the laboratory. The notion that stress can cause cardiovascular disease, an idea in the past often banished to the realm of medical folklore and mythology, now has strong supporting scientific evidence. Our own method has been to study patients with high blood pressure, in whom chronic stress may be a causative factor for the hypertension, and panic disorder and depression sufferers, in whom there is epidemiological evidence of increased cardiac risk.

The neurobiology of essential hypertension
Our comprehensive examination of the neurobiology of hypertension has continued through 2005. Available evidence indicates that in a substantial proportion of patients essential hypertension is neurogenic, with documentation of high rates of spillover of noradrenaline from the heart and kidneys and increased firing of muscle (vasoconstrictor) sympathetic nerves. Although this increased cardiac and renal spillover of noradrenaline is attributable at least in part to increased sympathetic nerve firing rates, our recent data indicates that there may be some impairment of neuronal noradrenaline reuptake after its release from sympathetic nerves. In addition, using hand vein biopsies obtained from volunteers, we are examining the hypothesis that there might be an increase in the density of sympathetic innervation in human hypertension. Facilitation of neuronal noradrenaline release by adrenaline released from sympathetic nerves as a cotransmitter, and impairment of neuronal noradrenaline reuptake after its release from sympathetic nerves are also possibilities under investigation in this project.

Obesity and obesity-related hypertension
Given the worldwide epidemic of obesity, and the pivotal importance of obesity as a cause of hypertension, it is surprising that knowledge of the mechanisms by which blood pressure is elevated by obesity is so rudimentary. It is now becoming clear from our own observations and those of others that the link between obesity and hypertension involves sympathetic nerves. The impetus for investigating sympathetic activity in obesity stems from the putative role played by the sympathetic nervous system both in the genesis of obesity and the cardiovascular complications associated with obesity. The sympathetic nervous system is important in virtually all of the components of daily energy expenditure, including resting metabolic rate, energy expenditure associated with physical activity, the thermic effect of food, cold-induced thermogenesis, and thermogenesis related to daily stimulants including caffeine and nicotine. Indeed, it is well known that increased sympathetic nerve activity, if sustained, contributes to the development of hypertension. Our research plans in obesity are driven by these facts, and in their content draw on the new biology of leptin, a 167 amino acid protein product of the ob gene produced by adipose tissue that has been identified as a blood borne factor regulating appetite. Also unclear are the predisposing factors, genetic or otherwise, which dictate that obesity leads to hypertension; perhaps 50% of the obese do not have hypertension. We are investigating these matters further.

The neurobiology of panic disorder
Until recently panic disorder was considered distressing and disabling but not a risk to life. However, it is now clear that there is a 3-6 fold increased risk of myocardial infarction and sudden death in patients with panic disorder. The cause is not known, but cardiac sympathetic activation during a panic attack, which can induce ventricular tachyarrhythmias, and activation of platelets by high plasma catecholamine concentrations leading to thrombogenesis, are candidates. Our observations also incriminate coronary artery spasm and pathological release of adrenaline from the heart as a sympathetic cotransmitter. Delineating the CNS neurochemical mechanisms underlying panic disorder (our recent finding is that activation of CNS serotonergic systems is the neurochemical "signature" of panic disorder), quantifying the cardiac sympathetic outflow during panic attacks, examining the cardiac and sympathetic baroreflex and establishing whether platelet activation is present, will indicate which pharmacological measures for prophylaxis of sudden death should be considered. We are continuing to build on our extensive studies of the neurobiology of panic disorder in this way, and in addition comparing the effects of therapeutic intervention with selective serotonin reuptake blockers and cognitive behavioural therapy.

Depressive illness and the heart
Recent reports demonstrate that patients with depressive illness are at an increased risk of developing coronary heart disease. This increase is independent of conventional risk factors, and is so marked that advisory bodies have concluded that depressive illness is a proven cause of coronary heart disease, ranking with established risk factors (high blood pressure, cigarette smoking and lipid disorders) in terms of its impact. The mechanism of increased cardiac risk in depressive illness is uncertain, but activation of the peripheral nervous system is likely to be of prime importance. It is likely that related neural mechanisms are of importance in determining the depression and the development of increased cardiac disease in patients with depressive illness. Clearly, identifying the underlying mechanisms responsible and testing whether therapeutic interventions can reduce cardiac risk will be an important step forward in alleviating the burden of depressive illness on the community.

Our observations indicate that in unmedicated patients with depression the nervous activity of the heart and blood vessels follows a bimodal pattern ie. in some patients the values are very high and in others very low – very few are "normal". Understanding the reason why this difference occurs presents us an exciting challenge. Interestingly, pharmacological treatment of depression is associated with a reduction in sympathetic nervous activity. Moreover, the regulation of blood pressure and heart rate in patients with depressive illness is significantly modified by therapy. Impaired regulation of blood pressure and heart rate has been directly linked to incidence rates for acute cardiac events in conditions such as hypertension, diabetes and myocardial infarction. These insights into the mechanisms responsible for generating cardiac risk may pave the way for novel therapeutic strategies to be administered in order to modify cardiac risk.

Postural Orthostatic Tachycardia Syndrome
The postural orthostatic tachycardia syndrome (POTS) is a condition in which heart rate increases abnormally when the patient assumes an upright position. This is a disabling condition characterised by light-headedness, fatigue, palpitations and recurrent episodes of fainting with standing. The cause of POTS remains unknown.

Poorly defined diagnostic criteria and the likelihood of multiple causes have made it difficult to clarify the underlying pathophysiology of POTS. Our recent results suggest that NET gene inactivation from hypermethylation of the NET gene promoter region possibly underlies the impairment of NET function phenotype described in POTS. Through causing persistence of the sympathetic neurotransmitter in the synaptic space, and consequently augmenting the sympathetic neural signal, such an abnormality could be an important causal factor in the disorder.

WYNN DEPARTMENT OF METABOLIC CARDIOLOGY

(Head, Professor David Kaye and Dr Rebbecca Ritchie, Head, Molecular Pharmacology Lab)

The Wynn department acknowledges the generous support of Professor Victor Wynn.

Particular areas of research include:

The Nitric Oxide: L-arginine Transport System

  • Development of an endothelial specific CAT1 transgenic mouse
  • Protein kinase C and regulation of CAT1 activity or function
  • Mitochondrial L-arginine transport
  • Arginine transporter polymorphisms in hypertension
  • The effects of peroxynitrite and protein nitration on arginine metabolism.
  • Oxidised LDL and arginine transport
  • Effects of ischemia reperfusion on arginine transport, NO production and ROS production

Myocardium and Heart Failure

  • Molecular regulation of BNP in the myocardium
  • Overexpression of the Noradrenaline Transporter as an Anti-Hypertrophic Strategy
  • New targets for preventing cardiac hypertrophy
  • Influence of sex hormones on cardiac hypertrophy
  • Role of reactive oxygen species in diabetic cardiac disease
  • Role of reactive oxygen species in insulin-resistant cardiac disease
  • Gene Therapy for Congestive Heart Failure
  • Homing factors in heart failure
  • Novel mechanisms for cardiac fibrosis
  • Cellular and molecular mechanisms of atrial fibrillation and its effects on the failing heart

CARDIAC MAGNETIC RESONANCE IMAGING

(Dr Andrew J Taylor)

Cardiac magnetic resonance imaging (CMR) has become an integrated part of non-invasive imaging at the Heart Centre, with particular utility in the evaluation of heart failure and transplant patients. Around 200 CMR scans are performed per year for a variety of clinical and research indications.

In-house human CMR research projects currently in progress aim to identify those patients with severe heart failure who will respond to cardiac resynchronisation therapy, aid in the diagnosis of arrhythmogenic right ventricular dysplasia, document changes in cardiac morphology following gastric banding for obesity, and non-invasively detect acute heart transplant rejection. The last project has been awarded a Cellcept Australia Research Grant for the Alfred Hospital. In addition, animal studies will investigate the utility of CMR in the non-invasive evaluation of diffuse myocardial fibrosis in heart failure.

The Alfred Hospital CMR service also is an active participant in a number of international multicentre clinical trials, including the OnTarget/Transend sub-studies, as well as the ADDUCE study, which evaluates the effect of a new drug therapy on left ventricular mass. With the Baker Heart Research Institute, the Alfred Hospital has formed one of only two Australian CMR Investigator Sites for General Electric Corporation, allowing access to specialised CMR sequences and software not yet available commercially.

PERIPHERAL INTERVENTIONAL PROGRAM

(Dr James Shaw)

The Alfred Minimally Invasive Vascular Centre (AMVIC) works as a collaboration between the cardiology and radiology departments. This group has a specific interest in the management of non-coronary vascular disease with an emphasis on novel endovascular therapies. This year we commenced a clinical vascular ultrasound program which greatly helps in the management of patients with peripheral vascular disease. To date 70 scans have been performed with this number expected to grow significantly.

Current research projects include looking at predictors of blood pressure improvement following renal artery stenting. This study will provide valuable information regarding which patients with HT and renal artery stenosis will benefit from renal revascularisation. To date 25 patients have been recruited and the plan is to recruit a total of 50 patients. We are currently in the process of becoming an Australian site for the international CORAL trial which will compare medical therapy with renal artery stenting in patients with renovascular disease. The endpoints in this study will include progression to renal failure, blood pressure control and all cause mortality. Other studies in progress include the effects of HDL on atherosclerotic plaque composition and we have plans to examine patients neuropsychological status pre and post carotid stenting.

SECONDARY PREVENTION - The COACH Program

(Sarah Ballis, Cardiac Coach)

The COACH Program is a disease management program in which patients with coronary heart disease are 'coached' to achieve the National Heart Foundation of Australia target levels for their biomedical coronary risk factors as well as to take recommended cardiovascular medications. The original coach study, a multi-centre randomised controlled trial, conducted at six hospitals including The Alfred, demonstrated that coaching via telephone coaching sessions and mail outs was significantly better than usual care in reducing risk factors in patients with coronary heart disease.

The Alfred has had over 480 patients enrolled to date, since implementation of the program in December 2003 under the supervision of Prof Anthony Dart. 33 patients have now 'graduated' from the program, 127 patients have been transferred to a maintenance coach for 6 monthly reviews and 15% have been lost to follow-up. There are currently 240 patients enrolled and being intensively coached.

Recent analysis has shown that patients coached at The Alfred greatly improve coronary risk factor status and adherence to recommended medications. At 6 months follow-up three quarters of patients had total cholesterol of less than 4.5 mmol/L, two-thirds had blood pressure at target, the majority were doing regular physical activity and 20% of patients who were smokers when recruited had quit smoking. Almost all patients were taking antiplatelet medication/s, three-quarters were taking a beta-blocker, three-quarters were taking an ACE inhibitor or AII-Blocker, and 93% were taking a statin.

Four-year follow up of The COACH Program has shown that the program can reduce hospital readmissions and bed-days by 16% and 20% respectively. The Victorian Department of Human Services is mainstreaming The COACH Program with funding via the Hospital Admissions Risk Program (HARP). With further support from governments, The COACH Program will be rolled out throughout Victoria and throughout Australia.

MAJOR GRANTS

Jennings G, Dart A, Esler M, Kaye D, Chin-Dusting J, Kingwell B, Reid C. The ABMU Centre for Clinical Cardiovascular Research. NHMRC CCRE Grant 2003-2007: $2,000,000; 2005: $400,000.00

Jennings G, Bobik A, Dart A, Esler M, Kaye D. Heart failure and its antecedents: Pathophysiology, prevention and treatment NHMRC Program grant 2003-2007. $8,875,000.00; 2005: $1,775,000.00.

Duffy SJ. Nitric oxide and oxidant stress in hypertension. NHMRC Project Grant 2003-2005: $240,000; 2005: $80,000.

Kingwell B, Duffy S. A novel mechanism for manipulation of peripheral glucose utilization in patients with type 2 diabetes mellitus NHMRC Project Grant. 2004-2006: $279,750; 2005: $93,250.

Duffy SJ. The relationship of iron status to oxidative stress in vivo, nitric oxide bioactivity and coronary artery disease activity. NHMRC Career Development Award. 2002-2006: $450,000; 2005: $90,000.

Sviridov D, Hoy J, Dart A, Bukrinksy M. Impact of HIV infection and treatment of AIDS patients with highly active retroviral therapy on reverse cholesterol transport. NHMRC Project Grant. 2005-2007: $334,500; 2005: $111,500.

Kingwell BA, Duffy SJ "A novel mechanism by which HDL cholesterol may modulate glucose and fat metabolism". Diabetes Australia Research Grant. 2005-2006: $90,0000; 2005: $45,000.

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Ahimastos A (PhD)
Connelly N (PhD)
Drew B (PhD)
Gould P (PhD)
Henstridge D (PhD)
Huynh N (PhD)
Mariani J (PhD)
Mukherjee S (PhD)
Murphy A (PhD)
Nair R (PhD)
Ng JF
White A ( PhD)
Ballinger, M (PhD)

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