Professor Michael Feneley, MD FRACP FACCHead, Cardiac Physiology and Transplantation DivisionDirector, Cardiology, St Vincent's Hospital Professor, Department of Medicine, UNSW
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Research Focus:
The Cardiovascular Mechanics Program has three major elements: (i) a large animal research facility, (ii) a small animal physiology core laboratory, and (iii) a clinical research program.
In a collaborative research project led by A/Prof Peter Macdonald and the Cardiac Transplantation Team at St. Vincent's Hospital, the large animal laboratory has focused on determining whether the contractility of the donor heart can be improved in a porcine model of cardiac transplantation by pharmacological preconditioning and sodium/hydrogen exchange inhibition, providing the basis for clinical trials of improved myocardial preservation strategies in human cardiac transplantation.
The establishment of a new small animal physiology laboratory and isolated myocyte laboratory over the last four years has provided core facilities that have produced a range of collaborative projects with other members of the VCCRI. Major recent research highlights include:
(i) the invention of a method of determining cardiac contractility independent of loading conditions from a single cardiac beat
(ii) demonstration that calcineurin activation plays a role in the induction of left ventricular hypertrophy in response to increased afterload only when the systemic renin-angiotensin system is activated
(iii) delineation of the role of the gene Nkx 2-5 in the genesis of atrial septal defects and patent foramen ovale in a mouse gene knockout model in a collaboration led by Professor Richard Harvey's laboratory
(iv) the demonstration of the very limited role of the gene Nkx 2-5 in the causation of familial and spontaneous human atrial septal defects and patent foramen ovale in collaboration with Richard Harvey and Dr Diane Fatkin
(v) demonstration of enhanced left ventricular contractility but no hypertrophy in transgenic mice with cardiac-targeted overexpression of the a1A-adrenergic receptor in collaboration with Professor Robert Graham's laboratory
(vi) with Diane Fatkin on a collaborative NHMRC grant (2002-2004), isolated myocyte studies and detailed echocardiographic and pressure-volume loop analyses of left ventricular systolic and diastolic function in LMNA gene knockout mice, in which the dilated cardiomyopathy phenotype is the result of a genetic defect in non-contractile, nuclear structural proteins (lamins A and C)
(vii) with Diane Fatkin and Robert Graham, examining the structural and functional consequences of left ventricular hypertrophy regression in a novel transgenic mouse model
(viii) with Ahsan Husain and Robert Graham, demonstration that mast cells are the source of the vascular ACE-independent (chymase) pathway to angiotensin II generation and that the anti-hypertensive benefit of combining ACE inhibitor and AT1 receptor antagonist therapy is most likely due to the negation of this pathway.
Most recently, we have been awarded a National Stem Cell Centre grant (with Richard Harvey, Robert Graham and Diane Fatkin) for studies ranging from isolated cells to applications in animal models of cardiac disease and a human cardiac stem cell trial.
Other clinical studies involve the non-invasive clinical application of our new single-beat contractility method (see above) with Dr Christopher Hayward and a range of coronary interventional clinical trials headed by A/Prof David Muller.
Co-Investigators:
Chris Blair, PhD
Yun Dai, BSc
Scott Kesteven, BSc Grad Dip BiomedE
Dominic Nguyen
Wendy Saad, BSc
Jane Yu, MBBS, PhD
Xiao-Hui Xiao, PhD
Collaborators:
Richard Harvey, PhD; VCCRI, Sydney, Austraila
Diane Fatkin, PhD; VCCRI, Sydney, Australia
Robert Graham, FAA, MD, FRACP, FACP, FAHA; VCCRI, Sydney, Australia
Ahsan Husain PhD; Centre for Heart Failure Research, Alabama, USA
Serjan Nikolicic, PhD; Stanford University, USA
Selected Publications:
Karunanithi MK and Feneley MP. Single-beat determination of preload recruitable stroke work relationship: derivation and evaluation in conscious dogs. J Am Coll Cardiol 2000; 35:502-513
Biben C, Weber R, Kesteven S, Stanley E, McDonald C, Elliott DA, Barnett L, Koentgen F, Robb L, Feneley M, Harvey RP: Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx 2-5. Circ Res 87: 888-895, 2000. [see also accompanying Editorial: Epstein JA: Developmental cardiology comes of age] Circ Res 2000; 87:833-834
Lin F, Owens AW, Chen S, Stevens ME, Kesteven S, Arthur JF, Woodcock EA, Feneley MP, Graham RM. Targeted a1A-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy. Circ Res 2001; 89:343-350
Elliott DA, Kirk E, Yeoh T, Chandar S, McKenzie F, Taylor P, Grossfeld P, Fatkin D, Jones O, Hayes P, Feneley M, Harvey RP: Cardiac homeobox gene Nkx2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Card 2003; 41:2072-2076
Ryan J, Hicks M, Cropper J, Garlick S, Kesteven S, Feneley M, Macdonald P: Sodium-hydrogen exchanger inhibition, pharmacological preconditioning or both for extended cardiac allograft preservation. Transplantation 2003; 76:766-771
Nikolova V, Leimena C, McMahon AC, Tan JC, Chandar S, Jogia D, Kesteven SH, Michalicek J, Otway R, Verheyen F, Rainer S, Stewart CL, Martin D, Feneley MP, Fatkin D. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J Clin Invest 2004; 113:357-69
Li M, Liu K, Michalicek J, Angus JA, Hunt JE, Dell'Italia LJ, Feneley MP, Graham RM, Husain A. Involvement of chymase-mediated angiotensin II generation in blood pressure regulation. J Clin Invest 2004; 114:112-20.
Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro ML, Butler TL, Hyun C, Guo G, Otway R, Mackay JP, Waddell LB, Cole AD, Hayward C, Keogh A, Macdonald P, Griffiths L, Fatkin D, Sholler GF, Zorn AM, Feneley MP, Winlaw DS, Harvey RP. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet. 2007;81:280-291.
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