AMREP RESEARCH REPORT 2009
Cardiovascular Medicine

Director: Professor Anthony M Dart BA DPhil BM BCh FAHA FRCP FRACP

The department of Cardiovascular Medicine has an extensive research program covering most aspects of adult cardiovascular disease. Studies range from cardiac risk factors such as diet, hypertension and hyperlipidaemia to treatment options in late stage disease such as advanced heart failure and valvular heart disease. The majority of studies are investigator led from staff within the department or Baker IDI and in addition there are a number of clinical trials. The research conducted spans the range from exploratory and early proof of concept studies to evaluation of definitive treatments.

Research within the department is funded from a number of sources including the NHMRC, NHF and Alfred Health as well as from a number of commercial sources.

Coronary Artery Disease
Research into coronary artery disease includes continuation of our single centre study into the effect of iron chelation with deferrioxamine on the outcome after myocardial infarction and on the use of novel biomarkers including level of oxidative stress and non-invasive assessment of vascular function in predicting acute cardiac events in patients undergoing major vascular surgery. Dr Duffy has the lead role in these studies and in addition takes a prominent role in the Melbourne Intervention Group database for interventional procedures which has yielded significant research information. Other studies involving Dr Duffy and Professor Kaye have evaluated two devices developed by Professor Kaye for the treatment of mitral regurgitation and the capture of X-ray contrast dye in subjects at risk of contrast nephropathy. Professor Karl Heinz Peter continues studies on novel agents to inhibit platelets and the role of inflammation in vascular disease. Professor Dart and Professor Kingwell are working with US collaborators on new methods for predicting cardiac output from arterial wave form measurements. New research is underway by Professor Dart in relation to monocytes and the outcome of coronary disease. There are several collaborative studies underway with the department of Infectious Disease and Burnett Institute in relation to cardiovascular risk in subjects with HIV.

Heart Failure and Transplantation
A major research effort led by Professor Kaye centres around the phenomenon of symptomatic heart failure in subjects with normal systolic (contraction) left ventricular function. This is recognised as a major cause of morbidity and is little understood. A particular focus of the research group is using exercise to unmask cardiac abnormalities. Other activities in this area relates to the role of fibrosis and its detection and treatment. Whether the use of advanced imaging techniques (see below) will identify which patients will benefit from biventricular pacing.

Non-invasive Cardiac Imaging
In addition to a large echocardiography service the department is also active in cardiac MRI and cardiac CT research with an extensive program directed by Dr Andrew Taylor. As indicated there is a particular interest in fibrosis and the use of cardiac MRI in predicting response to treatment and identifying patients with anatomical substrates for significant arrhythmias. The role of cardiac CT in the intermediate risk group is also focus for research.

Metabolism and Nutrition
Nutrition studies (conducted with colleagues at Baker IDI) have focused on the ratio of n3-n6 fatty acids rather than individual components and have found significant benefits from increasing this ratio in regard to risk factors for coronary disease. Much work in the department has focussed on various effects of HDL (good) cholesterol. These have included effects on glucose and insulin as well as vascular plaque with Professor Kingwell and Dr Duffy playing a major role in this area.

Atrial Fibrillation
Associate Professor Kistler has continued a program of research into atrial fibrillation. Recent studies have demonstrated that atrial fibrillation is much less common in patients recovering a double lung transplant then single lung transplant or lobectomy confirming the importance of the pulmonary vein in the origin of atrial fibrillation. Other studies are evaluating the role of cardiac MRI in predicting which patients are likely to suffer recurrence of atrial fibrillation following isolation of the pulmonary vein as well as studying the role of hypertension in causing atrial fibrillation. In collaboration with the department of Cardiothoracic Surgery (Dr Marasco and colleagues), Professor Dart and Dr Woodcock (Baker IDI) are undertaking biochemical analyses on actual samples obtained at surgery in subjects with atrial fibrillation to study the basic biochemical bases for this important arrhythmia.

Brain-Heart Interaction
Professor Esler and his team have continued to investigate links between brain and cardiac disease and in particular the role of depression and of panic attack. In addition and in pioneering studies the team in conjunction with Dr Tony Walton have conducted the first evaluation of a new catheter base device to damage the nerves leading to the kidney and hence effect a cure for patients with severe hypertension. These preliminary findings have been published and a formal controlled clinical trial evaluating this novel form of treatment for hypertension is now underway.

Publications
50 Journal Articles

Students

  1. Bertovic D: "The influence of heart rate reduction up coronary blood flow as assessed by coronary wave intensity analysis". PhD. Monash University. 2009-
  2. Chan W: "Iron and Oxidative Stress in Coronary Artery Disease". PhD. Monash University. 2008-2010. NHMRC Medical Postgraduate Scholarship
  3. Corcoran S: "Neural Mechanisms of Fainting Disorders". PhD. Monash University, 2009- . Greg Page Autonomic Insufficiency Foundation.
  4. Habersberger J: "The role of mCRP in inflammation". PhD. Monash University. 2007-2010. NHMRC Postgraduate Scholarship
  5. Haqqani H: PhD. Melbourne University. RMH
  6. Lam N: "Cardiac Niche and Cardiac Regeneration". Monash University. 2007-2010. Monash ARMI Postgraduate Scholarship
  7. Liang H: "Atrial Fibrillation and Heart Failure". Melbourne University. 2009-2011 CSANZ Scholarship.
  8. Medi C: PhD. Melbourne University.RMH
  9. Mukherjee S: "Oxidative Stress and Coronary Artery Disease" PhD. Monash University. 2005-2010. Previously on a NHMRC Medical Postgraduate Scholarship but presently unfunded.
  10. Teh A: PhD. Melbourne University.RMH
  11. Smith B: "Anti-inflammatory therapy in ACS". PhD. Monash University. 2007-2011 (part time). Monash NHMRC Postgraduate Scholarship
  12. Vadaddi G: "The Neural Pathophysiology of Postural Circulatory Control Disorders. PhD. Monash University; 2006-2009. NHMRC Medical Postgraduate Scholarship

List of Current Projects

  • Hs-CRP and its association with vascular events in HIV positive patients. (Dart)
  • Oral sirolimus for the prevention of restenosis after coronary artery stenting. (Duffy)
  • Preventive use of Probiotics in chronic liver disease with portal hypertension, effect on circulatory changes. (Chin-Dusting)
  • Cyclosporin-a bioavailability study: Neork verses cyclosporin in stable heart transplant recipients. (Kaye, Mulhmann)
  • Cardiovascular disease and its genetic correlation with pseudoxanthoma elasticum. (Dart)
  • Research study using the cardiac dimensions, inc (CDI) percutaneous mitral annuloplasty device for the temporary plication of the mitral annulus in a dilated cardiomyopathy patient population Protocol CVP –0894-01. (Kaye)
  • Clinical utility of Amlodipine/Atorvastatin to improve concomitant cardiovascular risk factors of hypertension. (Jennings)
  • Metabolic regulation of ABCA1 expression in patients with type 2 diabetes and athletes (Kingwell)
  • Effect of the isoflavone metabolite trans-tetrahydrodaidzein on cardiovascular risk factors in middle-aged subjects. (Nestel)
  • An investigation in to the ability of the body to re-innervate the heterotopic cardiac graft (Kaye)
  • The use and misuse of aspirin-An audit of the use of Aspirin in Hypertension. (Reid)
  • In vivo microdialysis studies of metabolite and neurotransmitter overflow from the adipose tissue and skeletal. (Esler)
  • Variations in augmentation index between left and right carotid arteries and a comparison PWV and FMD (Dart)
  • Clinical follow up of Patients undergoing percutaneous revascularization at Melbourne hospitals. (Duffy)
  • The association between the newly identified CRP receptor polymorphism and cardiovascular disease (Chin-Dusting)
  • Does systemic arterial compliance predict blood pressure responses in patients undergoing percutaneous renal intervention. (Shaw)
  • Telmisartan effectiveness on left ventricular mass reduction as assessed by MRI, in patients with hypertension.(Taylor)
  • Phase 3 multi-centre, double-blind, randomized, parallel group evaluation of the fixed combination torcetrapib/atorvastatin, administered alone, on the occurrence of major cardiovascular events in subjects with coronary heart disease or risk equivalents. (Dart)
  • A survey of Eating-behaviour and school-community based Nutrition-Health Promotion, programs and policies (Reid)
  • Effect of fitness on chronic low-grade activation of the immune system and insulin sensitivity in physically fit and healthy sedentary individuals (Kingwell)
  • Effects of polymorphisms in antioxidant genes on the clinical presentation (stable versus unstable coronary syndrome) in a group of patients undergoing coronary angiography. (Duffy)
  • Evaluation of the VentrAssistTM left Ventricular Assist System as a Bridge to Cardiac Transplantation" Trial Number: CP023001 (Kaye)
  • Evaluation of the VentrAssistTM left Ventricular Assist System as Destination Therapy" Trial Number: CP024001 (Kaye)
  • A novel mechanism mediating anti-atherosclerotic and metabolic actions of HDL cholesterol. (Kingwell)
  • Efficacy and mechanisms of exercise training in diastolic heart failure (Kaye)
  • Effects of ivabradine on cardiovascular events in patients with stable CAD and LV systolic dysfunction. A 3 yr randomised DB placebo controlled study. (Kaye)
  • A Study to Evaluate the Efficacy and Safety of Ezetimibe/Simvastatin and Fenofibrate Co-administration (Dart)
  • A Randomised Dose Ranging Study of Hexadecasaccharide including Active Control, in Patients with Unstable Angina or Non-ST-segment elevation Myocardial Infarction Scheduled to Undergo Percutaneous coronary Intervention (SHINE). (Shaw)
  • Mechanisms of Atherosclerotic Plaque Development and Rupture (White)
  • Sex dimorphism in MMP activity in peripheral white blood cells from healthy controls and patients with acute myocardial infarction. (Dart)
  • The effect of anti-inflammatory treatment on insulin sensitivity and insulin secretion in obese non-diabetic (De Courten)
  • MacrofluxTM hBNP Tolerability and Bioavailability Study In Healthy Subjects (Kaye)
  • Growth factor secretion by the normal and failing human heart (Kaye)
  • Utility of cardiac magnetic resonance imaging to detect cardiac transplant rejection (Taylor)
  • Identifying predictors of progressive mitral regurgitation in heart failure (Kaye/Mariani)
  • Impact of Type 2 Diabetes on Reverse Cholesterol Transport (Sviridov)
  • Randomized Evaluation of Long term anticoagulant therapy comparing the efficacy and safety of two blinded (Dart)
  • Role of sP-selectin in Patients with peripheral occlusive arterial disease (Chin-Dusting)
  • VERITAS™ Study: A Safety and Efficacy Study of the Carillon™ Mitral Contour System™ for the Treatment (Duffy)
  • Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (Dart)
  • Heart Transplant Myocardial fibrosis Study: Effect of Spironolactone on Myocardial fibrosis and myocardial function in patients with left ventricular diastolic dysfunction after heart transplantation (Leet)
  • Role of Endothelial progenitor cells in peripheral occlusive vascular disease (Dart)
  • A Study to Characterise the Pharmacokinetics and Pharmacodynamics and to Assess the Safety and Tolerability of MacrofluxTMhBNP In Healthy Male Subjects (Kaye)
  • A clinical trial comparing cangrelor to clopidogrel in subjects who require percutaneous coronary intervention (Duffy)
  • A Randomised, Double-blind, Parallel Group, Phase 3, Efficacy and Safety Study of AZD6140 Compared with Clopidogrel for Prevention of Vascular Events in Patients with Non-ST or ST Elevation Acute Coronary Syndromes (ACS) PLATO – A Study of PLATelet inhibition and patient outcomes. (Dart)
  • Mechanisms of the disorders of circulatory control which may cause syncope: Pure Autonomic Failure, multiple systems atrophy and Parkinson's disease with autonomic failure (Esler)
  • IMPROVE IT. A Multicenter, Double-Blind, Randomised Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) (Shaw)
  • The role of cardiac biomarkers in Reverse Remodelling and comparison of Cardiac magnetic resonance imaging to echocardiography in the prediction of response following cardiac Resynchronisation therapy (The "CMR-Triple R" study) (Butler)
  • Mechanisms of the disorders of circulatory control which may cause syncope: Neurocardiogenic Syncope and Carotid Sinus Hypersensitivity (Esler)
  • Mechanisms of the disorders of circulatory control which may cause syncope: Chronic Low Blood Pressure (Esler)
  • Role of Endothelial progenitor cells in metabolic syndrome and weight loss. (Dart)
  • VYTUL - VYtorin Treating Uncontrolled Lipids A multi-centre, randomised, open-label parallel groups study comparing the effectiveness and safety of treatment with VYTORIN® 10/40 (Ezetimibe 10 mg and Simvastatin 40 mg) versus Lipitor (Atorvastatin) 80 (Dart)
  • Do High Dose Tirofiban and Reopro have Similar Effects on Platelet Function and Recovery of LV function in Patients With Acute Myocardial Infarction? (Shaw)
  • Sympathetic function in the heart, brain and kidney of patients with postural orthostatic tachycardia syndrome (Esler)
  • Novel vascular treatments for angina and heart failure (Andrews)
  • ACE Inhibition; A Potential New Therapy for Peripheral Arterial Disease (Kingwell)
  • Novel therapies for the treatment of Type 2 Diabetes (Kingwell)
  • The use of single chain antibodies for the detection of monocyte activation in patients with stable and acute coronary syndromes (Karlheinz)
  • Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care: The WHICH? Study (Stewart)
  • The effects of insulin on L-arginine transport in the human forearm (Kaye)
  • Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LY2405319 after Multiple Subcutaneous Injections in Subjects with Type 2 Diabetes (Shaw)
  • Lipid profiling: early detection, monitoring and pathogenesis of atherosclerotic heart disease (Meikle)
  • The Atrial Electrical and Structural Effects of Systemic and Pulmonary Hypertension in Humans (Kistler)
  • Characterization of electrophysiological and radiological substrates in ischemic and dilated cardiomyopathy patients with and without ventricular tachycardia using three-dimensional electroanatomic mapping and magnetic resonance imaging (Kaye)
  • Randomised controlled pilot trial of n-acetylcysteine in the management of chronic heart failure with coexistent chronic renal failure (Kaye)
  • A randomised crossover trial to assess the impact of the dietary n-6:n-3 polyunsaturated fatty acid ratio on markers of cardiovascular health in patients with dyslipidaemia (Chin-Dusting)
  • The influence of heart rate reduction upon central arterial pressure in younger and older healthy individuals (Kingwell)
  • Characterization of electrophysiological, radiological and histological substrates for ventricular tachycardia in patients undergoing cardiac transplantation for ischemic and non-ischemic cardiomyopathy. (Kaye)
  • The influence of heart rate reduction upon coronary blood flow as assessed by coronary wave intensity analysis. (Dart)
  • An Observational Safety Follow-up Trial of the Occurrence of Major Cardiovascular Events and All-cause Mortality in subjects Who Participated in Selected Torcetrapib/Atorvastatin Clinical Trials (Dart)
  • Determination of central arterial pressure and left ventricular ejection fraction in humans by analysis of peripheral arterial pressure waveforms. (Dart)
  • A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Tolerability of E5555, and its Effects on Markers of Intravascular Inflammation in Subjects with Coronary Artery Disease. Study Number: E5555-G000-201 (Dart)
  • Cardiac magnetic resonance imaging in the evaluation of myocardial fibrosis in advanced heart failure (Iles)
  • Reversibility of chronic atrial remodeling late after curative atrial flutter ablation (Kistler)
  • A randomised study of a Nurse-led Intervention for Less Chronic Heart Failure: The NIL-CHF Study (Stewart)
  • A multicentre, randomised, double-blind, placebo-controlled study to evaluate the safety and efficacy of SCH 530348 in addition to standard of care in subjects with acute coronary syndrome (Duffy)
  • The role of the Renin Angiotensin Aldosterone system activation in myocardial fibrosis, diastolic function and its link to liver fibrosis in morbid obesity (Wong)
  • A Single Center Pilot Study Evaluating the Use of the Osprey Medical CIN SystemTM (Duffy)
  • Noradrenaline transporter (NET) dysfunction in neural circulatory disorders (Schlaich)
  • The Baker Risk Clinic (Stewart)
  • Understanding the acute effects of prolonged sedentary behaviour (sitting) on post-meal glucose and lipids – A pilot study (Kingwell)
  • Cardiac and Liver Fibrosis in Patients with the Metabolic Syndrome as detected by Magnetic Resonance T1 mapping (Butler)
  • Do coronary plaque biomechanical differences between diabetic and non diabetic subjects relate to differences in plaque morphology and measures of neovascularisation (Shaw)
  • A 76-Week, Worldwide, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Tolerability and Efficacy of Anacetrapib When Added to Ongoing Therapy With a Statin in Patients With Hypercholesterolemia or Mixed Hyperlipidemia (Nestel)
  • Exertional dyspnea in patients with echocardiographic signs of diastolic dysfunction: are symptoms really caused by impaired left ventricular filling? – A prospective case-control study (Kaye)
  • Effects of Peri-procedural Iron Chelation on Myocardial Infarct Size and Oxidative Stress In ST-elevation Myocardial Infarction (Duffy)
  • Does tricuspid regurgitation contribute to renal dysfunction in patients with heart failure? (Kaye)
  • Utilisation of coronary CT angiography (CCTA) in cardiac risk stratification (Taylor)
  • INTERNATIONAL ReValving™ REGISTRY (Walton)
  • Do fermented dairy foods confer benefits over and above Non-fermented foods? Effects of fats on circulating inflammatory biomarkers (Nestel)
  • Cardiac and liver fibrosis in patients with viral hepatitis as detected by Magnetic Resonance T1 mapping (Taylor)
  • The association between carotid extra-media thickness and cardiovascular risk factors (Dart)
  • Anaemia and myocardial iron in heart failure (Kaye)
  • Applying Novel Biomarkers to Assess Cardiac Risk in Patients Undergoing Major Vascular Surgery: Defining Iron, Oxidative Stress, Inflammation, Matrix Metalloproteinases, Coagulation Factors, Lipidomics, Endothelial Dysfunction, and Other Relevant Risk Mar (Duffy)
  • Correlation of cardiac magnetic resonance imaging (CMR) findings with subsequent ventricular arrhythmias in subjects with heart failure (Taylor)
  • A Quality Improvement Initiative on the Discharge Management of Acute Coronary Syndromes (DMACS) (Dart)
  • The role of cardiac magnetic resonance imaging and serum biomarkers in the identification and monitoring of myocardial involvement in patients with established non-cardiac sarcoidosis. (Habersberger)
  • Effects of a 10 or 15 mg single intravenous bolus of ivabradine versus placebo on heart rate control during a multislice computed tomography coronary angiography for the evaluation of coronary artery disease. A randomised, double-blind, international mul (Taylor)
  • A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Withdrawal-Design Study to Assess the Clinical Effect of Droxidopa in Subjects With Primary Autonomic Failure, Dopamine Beta Hydroxylase Deficiency or Non-Diabetic, Neuropathy and Symptomatic Neurogenic Orthostatic Hypotension. (Esler)
  • An 8 week, double-blind, randomized, parallel group, active-controlled study to evaluate the efficacy and safety of the combination of aliskiren /amlodipine / HCTZ in patients with moderate to severe hypertension (Schlaich)
  • A randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Effects of Intravenous BG9928 on Body Weight in Subjects with Acute Decompensated Heart Failure and Renal Insufficiency ("The Trident-1 Study"). (Krum)
  • Study on mechanisms and interventions for dysfunction of endothelial progenitor cells in coronary artery disease (Dart)
  • Atrial Fibrillation and Lung Transplantation (Kistler)
  • A Multi-Centre, Open-Label Study, with a Two Week Randomized, Placebo-Controlled, Withdrawal Period, to Assess the Long-Term Safety and Clinical Benefit of Droxidopa in Subjects with Primary Autonomic Failure, Dopamine Beta Hydroxylase Deficiency or Non-D (Esler)
  • Heart Rate in Relation to Beta-Blocker Dosing for Patients with Heart Failure (Krum)
  • Non-invasive assessment of Liver Stiffness/Fibrosis by Transient Elastography (FibroScan) in Patients with Left and/or Right Sided Heart Failure (Porapakkham)
  • A Clinical Outcomes Study of Darapladip versus Placebo in Subjects with Chronic Coronary Heart Disease to Compare the Incidence of Major Adverse Cardiovascular Events (MACE) (Krum)
  • Does Warfarin affect left ventricular diastolic function? (Kaye)
  • Exploring the oxidative burden in heart failure and atherosclerosis for the development of a novel patient tailored therapy (Peter)
  • Atrial Fibrillation & Heart Failure: The chicken or the egg? (Kistler)
  • Identification of genes contributing to atrial fibrillation (Kistler)
  • A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of both aliskiren monotherapy and aliskiren/enalapril combination therapy compared to enalapril monotherapy, on morbidity and mortality in (Krum)
  • Cardiac Magnetic Resonance Imaging to detect Regional patterns of fibrosis Post Myocardial Infarct (Taylor)
  • Analysis of reverse atrial remodelling following ablation of atrial fibrillation (Kistler)
  • Reducing Patient Harm from Blood Transfusion: An Investigation of 'Wrong Blood In Tube' (WBIT) Events (Jeffcott)
  • Cancer Biomarkers (Rice)
  • Can Heberden's nodes be diagnosed from hand photocopies? (Cicuttini)
  • Retrospective correlation for the role of natural killer cells in the rejection of human heart transplants. (Leet)
  • Australian Cardiac Procedures Registry (ACPR) (Reid)
  • A longitudinal assessment of the effect of substantial and sustained weight loss on blood pressure and target organ damage in obese subjects (Dixon)
  • Impact of changes in heart rate and blood pressure on outcomes in patients with heart failure and normal left ventricular ejection fraction (Kaye)

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