2015 AMREP Research Report

1. Department Details

Name of Department Cardiovascular Medicine
Name of Department Head Professor Anthony M Dart
Title of Department Head Director
Dregrees of Department Head BA DPhil BM BCh FRCP FRACP

 

2. Brief description of Department and main areas of research

The department of Cardiovascular Medicine provides a full range of clinical investigation and therapies for all forms of adult cardiac disease, from risk factor management to cardiac transplantation and mechanical cardiac support.  Its staffing comprises staff with full or part time Alfred appointment or a joint appointment with Baker IDI Heart and Diabetes Institute and Monash University.  A majority of the senior medical staff have completed higher research degree.  The department hosts a number of clinical PhD students as well as post FRACP fellows.  There are extensive research collaborations with other Alfred Departments as well as with Baker IDI and Burnet Institute.  Research is supported by grants from NHMRC, NHF, NIH and commercial entities.

Research is undertaken widely throughout the department.  In addition to fully equipped catheter labs and imaging suites the Department also has a number of procedural and investigations room dedicated to research.  Research within the cardiac catheter lab is performed in relation to electrophysiology, particularly atrial fibrillation, coronary disease, renal denervation and structural heart disease.  The majority of these studies are investigator led and there are additional company sponsored trials particularly of new devices.  There is also a particularly focus on heart failure found in patients with normal systolic function.  Many of the later study require combined exercise and haemodynamic measurements.  The use of exercise haemodynamic studies is not generally available.  The other major area of focus for the department is on cardiac imaging particularly in relation to cardiac MRI.

3. RESEARCH HIGHLIGHTS AND ACHIEVEMENTS

A) Brief description of major findings or outcomes from research projects conducted during 2015.

Previous studies led by Professor Dart have demonstrated that the inflammatory cytokine macrophage migration inhibitory factor (MIF) is released very early following myocardial infarction.  Experimental studies by Prof Dart and Dr Du established that MIF release also occurred in the absence of infarction during the course of the ischaemia.  Further studies conducted in collaboration with the department of Nuclear Medicine (Dr T Barbar) have now examined whether such release could also be

found in clinical settings.  This was examined by obtaining blood samples before and after diagnostic stress testing.  In subjects with no evidence for ischaemia there was no change in the MIF level post exercise.  The same study found that exercise induced ischaemia was not associated with any change in the circulatory level of troponin at CRP.  In contrast those with object evidence of the ischaemic did show an elevation in their plasma MIF levels.  This finding suggests that the mechanism of MIF release differs from that of other well-known cardiac biomarkers such as the Troponin, which require irreversible myocyte damage.  Furthermore it raises the possibility that measurement of this biomarker might assist in the evaluation of exercise test.  Further studies are required to demonstrate whether this biomarker will also indicate the extent of the associated ischaemia.  In related studies the group is also testing the predictive potential of plasma microRNAs released during exercise.

The role of vitamin D in the pathophysiology of coronary artery disease is controversial.  There are epidemiological studies suggesting that a low vitamin D level increases patients risk of cardiac disease.  This is an important issue as low vitamin D levels are common and can be treated easily with oral replacement therapy.  We prospectively studied patients presenting for coronary angiography and measured their vitamin D level at the time of angiography.  The main findings of the study were that patients with angiographic coronary artery disease had a significantly lower vitamin D level than those without disease furthermore the levels were lower in patients with more significant disease, those patients with triple vessel coronary artery disease had lower levels than those with single vessel disease.  When the data was analysed to look for predictors of the presence and extent of coronary artery disease, including traditional risk factors, vitamin D was the most powerful predictor.
In related studies the relation between vitamin D levels and the rate of progression of aortic stenosis has been examined.  

These data support the hypothesis that vitamin D is important in the pathophysiology underlying coronary artery disease and further studies are required to assess whether vitamin D supplementation reduces patients risk of developing coronary artery disease or reduces their risk of Cardiovascular events.  In contrast to the positive associations found with coronary disease in vitamin D levels there was no difference between those whose aortic valve disease progressed rapidly or slowly.  Further studies are underway to try to identify biomarkers which do discriminate between rapid and slow progresses in this rapidly increasing patient cohort.

Studies by Associate Professor Andrew Taylor and his team have further established the role of cardiac MRI in detecting and quantifying both diffuse and localized cardiac fibrosis.  A/Prof Taylor and his collaborators have been leaders in the establishment of specific methods for the detection of diffuse interstitial fibrosis which is a feature of many myocardial diseases including hypertrophic cardiomyopathy.  Now that an accepted and quantifiable assessment of fibrosis can be made noninvasively, the team is able to undertake clinical trials of both existing (eg eplerenone) and novel agents as potentially able to reverse this pathology.  The demonstration of effective therapies for cardiac fibrosis would have widespread clinical benefit in a number of cardiac conditions.

The structural heart program, headed by Associate Professor Walton, has participated in a wide range of both multicenter and investigator initiated studies.  These have included novel devices for the treatment of both aortic and mitral valve disease.  The department played a large role in earlier studies with renal denervation for persistent hypertension and although a subsequent trial failed to show benefit, there are a number of important questions which still need to be addressed.  These include the evaluation of the newer generation of denervation catheters and these will be important studies to decide whether this form of therapy has a future role for this patient group.  Evaluation of percutaneous treatments for valvular heart disease have immediate implications for the management of patients with valve disease enabling patients to be treated without the need for open heart procedures.

The Heart Failure team in partnership with the Heart Failure Research Group at Baker IDI continue to investigate the causes of heart failure and to develop new treatments for patients with heart failure.

Many patients with advanced heart failure are frequently admitted to hospital and have a poor quality of life.  Unfortunately, in some cases it is not possible to offer heart transplant or artificial heart device surgery because of concomitant illnesses.  Professor Kaye has continued to investigate a novel oral formulation of milrinone, with over 20 patients treated.  Early evidence of improvements in symptoms and end-organ function is emerging.  In parallel studies the potential utility of the drug is being investigated in other forms of heart failure.

The basis of the symptoms in heart failure is complex, and current drug therapies do not necessarily adequately target the main defects.  In these situations, medical devices are increasingly used.  For example, Profs Walton and Kaye have been key investigators in a mutlicentre, international trial of a device designed to reduce elevated intra-cardiac pressures in patients with heart failure due increased cardiac stiffness (so called “HFPEF”).  This device (below) is placed into the heart without surgery.  A recent study of over 60 patients was recently published in The Lancet.

2015 amrep research report 1

The relationship between atrial fibrillation, heart failure and cardiac imaging is the ongoing focus of research in the Electrophysiology department headed by Professor P Kistler.  A large multicentre international study (MINIMAX) led from the Alfred, investigated optimal techniques for catheter ablation in atrial fibrillation.  This study involved sites in Australia, UK and New Zealand and compared two commonly performed ablation strategies to complete pulmonary vein isolation for patients with paroxysmal atrial fibrillation.  It demonstrated an increase in success if the pulmonary veins can be isolated as a pair and that routine individual isolation does not confer any additional advantage, which is a significant advance in refining this increasingly used therapeutic approach.


B) Important research-related achievements by staff members of the Department (e.g. awards, prizes, major grants)

  • Alexis, J: completion of honours year medical student thesis with first class honours through the University of Notre Dame (sole supervisor A/Prof A Taylor).
  • Hopper I: NHMRC Early Career fellowship.
  • Hopper I: RACP Vincent Fairfax Family Research establishment fellowship.
  • Hopper I: completed PhD under supervision of Prof Henry Krum, “Polypharmacy in heart failure: are all the prescribed medications required?”
  • Kingwell BA, Duffy SJ, Siebel, A NHMRC Project Grant. “HDL Elevation and Glucose Metabolism: A Mechanistic Proof-of-Concept Intervention Trial in Pre-Diabetes” $490,468. (2014-2016).
  • Kistler P: Practitioner Fellow of the NHMRC.
  • La Gerche A:  NHMRC Career Development Fellowship (2015 – 2018).
  • La Gerche A: NHF Future Leaders Fellowship (2015 – 2018).
  • Reid C, Krum H, Cullen L, Chew D, Briffa T, Brieger D, Smith J, Duffy SJ, Macdonald P, Liew D. NHMRC. Centre of Research Excellence in Cardiovascular Outcomes Improvement” $2,500,000. (2016-2020).
  • McLellan A: European training fellowship from European Heart Rhythm Society 2015.
  • McLellan A:  The Australian Government Endeavour Research Fellowship starting 2016.
  • Stub D: Early Career Fellowship NHMRC.
  • Stub D: RACP Foundation project grant.
  • Stub D: NRMRC project grant for EXACT trial (Australia wide randomized trial of oxygen in cardiac arrest).
  • Taylor A: Chief investigator NHMRC funded ($250,000) randomised controlled trial evaluating the antifibrotic effects of eplerenone in hypertrophic cardiomyopathy.
  • Taylor A: Chief investigator of industry funded (N-Gene, USA - $800,000) randomised controlled trial evaluating the antifibrotic effects of the investigational compound BGP-15 in non-ischaemic cardiomyopathy.


4. PHOTOGRAPHS

Dr Dion StubDr Dion Stub received an NHMRC/NHF Early Career fellowship and an RACP Foundation project grant.  PI on an NHMRC project grant (EXACT trial) an Australia wide randomized trial of oxygen in cardiac arrest.

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