Cardiac Phenomics
In the emerging field of physiologic genomics, the goal of the ‘Cardiac Phenomics Laboratory’ is to understand the relationship between the genotype and the cardiac phenotype, as mediated by environmental influences. A particular strength of the research group is the capacity to dissect the genome-phenome relationship at the level of the intact animal, the organ, the cell and the molecule. Most recently we have focused on using unique genetic models of cardiac disease to understand the alterations in heart structure and function which occur in different forms of hypertrophic cardiomyopathy associated with hormonal disturbances (eg diabetes, renin-angiotensin system dysfunction, estrogen influences).
Cardiac Phenomics Lab Members:
Associate Professor Lea Delbridge – Head of Laboratory
Dr Claire
Curl – Post Doctoral Fellow
Ms Kate Huggins – PhD Student
Mr Enzo Porrello – PhD Student
Dr Vennetia Danes – PhD Student
Mr Andrea Domenighetti – PhD
Student
Ms Wendy Ip – Honours Student
Ms Greta Meredith - Research Assistant
Collaborators:
Professor Stephen Harrap
Department of Physiology
University of Melbourne
Dr Robert DiNicolantonio
Department of Physiology
University of Melbourne
Associate Professor Igor Wendt
Department of Physiology
Monash University
Dr Salvatore Pepe
Baker Heart Research Institute
Dr Rebecca Ritchie
Baker Heart Research Institute
Dr Walter Thomas
Baker Heart Research Institute
Professor Joe Proietto
Austin Repatriation Hospital
Dr Gordon Smyth
Walter and Eliza Hall Institute
Associate Professor Thierry Pedrazzini
University of Lausanne
Associate Professor Peter McLennan
University of Wollongong
Associate Professor Robert Widdop
Department of Pharmacology
Monash University
Professor Keith Nugent
School of Physics
University of Melbourne
Associate Professor Ann Roberts
School of Physics
University of Melbourne
Professor Peter Harris
Department of Physiology
University of Melbourne
Dr Brendan Allman
Iatia Ltd, Australia
Associate Professor Alastair Stewart
Department of Pharmacology
University of Melbourne
Professor Margaret Morris
Department of Physiology & Pharmacology
University of New South Wales
Research Projects
Omega 3 Dietary Lipids and Cardioprotection
Enlargement of the heart(hypertrophy) which precedes heart failure is accompanied by metabolic and mechanical disturbances that interfere with normal performance and reduce the heart’s capacity to withstand and recover after angina or a heart attack. The abnormal growth associated with heart enlargement may lead to changes in how the fats and proteins of heart muscle work together structurally and functionally. The overall goal of this study is to investigate whether dietary supplementation with omega-3 ‘good’ type fatty acids (commonly found in fish oil) can improve function and protect against oxygen deprivation (ie simulated heart attack) in hearts from a transgenic mouse model, which have a genetic predisposition to enlargement. Investigation of whether omega-3 diet (compared to omega-6, which is commonly found in vegetable oil) has a beneficial effect on ex vivo whole heart function during periods of myocardial stress (ischemia), metabolic status and membrane structure in normal and enlarged hearts will be undertaken. The effect of dietary modified membrane structure on expression levels of key membrane transporters involved in heart contraction (excitation-contraction coupling) is the focus of this study.
Perinatal Growth Programming of the Heart
Epidemiological studies have shown that an inverse relationship exists between birth weight and adult susceptibility to cardiovascular disease. However, relatively little is known about how the perinatal period impacts on the later capacity of the heart to undergo functional and structural adaptation. Angiotensin II (AngII), the major effector peptide of the renin-angiotensin system, is an important modulator of early cardiac growth but a detailed understanding of the physiological mechanisms involved is currently lacking. The goal of this study is to determine how angiotensin-induced modelling influences in the heart during early development may interact to limit neonatal heart growth and predispose to cardiac hypertrophy at maturity.
Estrogen, Angiotensin II and the Hypertrophic Heart
Pre-menopausal women experience significantly lower cardiovascular mortality than men of the same age. Recent clinical trials, however, have surprisingly shown that post-menopausal estrogen therapy actually exacerbates the risk of heart and other vascular diseases. In addition, evidence for a beneficial interaction between estrogen and angiotensin II (AngII) in the development of cardiac hypertrophy has been reported. This suggests that estrogen may influence how the heart responds to conditions that lead to development of cardiac hypertrophy. The goal of this project is to investigate at a cellular level, the influence exerted by estrogen on myocardial growth and function in the context of a genetic predisposition to cardiac hypertrophy.
The diabetic heart - early cellular disturbances
Type 2 diabetes comprises 85-90% of all cases of diabetes, and represents an
escalating and major public health challenge. Diabetes is associated with
a significantly greater risk of cardiovascular morbidity and mortality. This
cardiovascular demise involves not only vascular dysfunction, but can also
be attributed to cardiac muscle tissue structural and functional deficits.
There is good evidence that the myocardium in particular may be especially
vulnerable to the pre-diabetic damage assocoiated with insulin resistance,
and excess production of oxygen free radicals. Our research focuses on investigating
how the myocardium is impacted by the metabolic shifts associated with insulin
resistance, and evaluating how substrate and hormonal interventions may ameliorate
cardiomyocyte dysfunction associated with diabetic cardiomyopathy. These
studies involve experimental dietary interventions and anti-oxidant treatments.
Facilities & Techniques
- Mouse and rat single cardiac cell isolation
- Ex vivo perfused Langendorff heart apparatus
- Cardiac Myocyte Contractility
- Quantitative Phase Microscopy
- Confocal Microscopy
- Epifluorescence Microscopy including indo-1 and snarf
- Electrophysiology including patch clamping
- Real-time PCR
- Cell culture
- Blood Pressure measurement
- Surgical intervention to simulate disease and hormonal disturbances
- Microarray gene profiling
- Genotyping
Publications
Refereed Papers
- Ritchie RH, Delbridge LMD. Cardiac hypertrophy, substrate utilization and metabolic remodeling: cause or effect? Clin Exp Physiol Pharmacol, 2005 In Press.
- Domenighetti AA, Wang Q, Egger M, Richards SM, Pedrazzini T, Delbridge LMD. Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure. Hypertension. 2005 Aug;46(2):426-32..
- Curl CL, Bellair CJ, Harris T, Allman BE, Harris PJ, Stewart AG, Roberts A, Nugent KA & Delbridge LMD. Refractive index measurement in viable cells using quantitative phase-amplitude microscopy and confocal microscopy. Cytometry 65A:88-92, 2005.
- Porrello E, Huggins C, Curl CL, Domenighetti, AA, Pedrazzini T, Delbridge LMD, Morgan TO. Elevated dietary sodium intake exacerbates myocardial hypertrophy associated with cardiac-specific overproduction of angiotensin II. J Renin Ang Aldo System 5 (4):169-175, 2004.
- Curl CL, Bellair CJ, Allman BE, Harris PJ, Roberts A, Nugent KA & Delbridge LMD. Quantitative Phase microscopy – a new way to interrogate the structure and function of unstained viable cells. Clin Exp Physiol Pharmacol, 31:896-901, 2004.
- Delbridge LMD & Curl CL Putting the heart through its paces – cellular insights from frequency phenomena. Heart Lung and Circulation, 13:361-362, 2004.
- Morris MJ, Tortelli CF, Hart DP & Delbridge LMD. Vascular and brain neuropeptide Y in banded and spontaneously hypertensive rats. Peptides, 25:1313-1319, 2004.
- Lax CJ, Domenighetti AA, Pavia JM, Di Nicolantonio R,Curl CL, Morris MJ & Delbridge LMD. Transitory reduction in angiotensin AT2 receptor expression level in post-infarct remodelling in rat myocardium. Clin. Exp. Physiol. Pharmacol, 31:512-517, 2004.
- Tobin JM, Delbridge LMD, Di Nicolantonio R & Bhathal P. Development of colorectal sensitization is associated with increased eosinophils and mast cells in dextran sulphate sodium-treated rats. Digestive Diseases and Sciences, 49:1302-1310, 2004.
- Curl, C.L., Harris T., Harris P.J., Allman B.E., Stewart A.G.,Delbridge L.M.D. Quantitative phase microscopy: a new tool for measurement of cell culture growth and confluency in situ. Pflugers Archiv – Eur J Physiol, 448:462-468, 2004.
- Bellair C.J.,Curl C.L., Allman B.E., Harris P.J., Roberts A., Delbridge L.M.D., Nugent K.A. Quantitative phase-amplitude microscopy IV: imaging thick specimens. Journal of Microscopy, 214:62-70, 2004.
- Trongtorsak P., Morgan T.O., Delbridge L.M.D. Combined renin-angiotensin system blockade and dietary sodium restriction impairs cardiomyocyte contractility. J Renin-Angiotensin-Aldosterone System, 4:213-219, 2003.
- Van den Brink O.W.V, Delbridge L.M.D, Rosenfeldt F.L., Penny D., Esmore D.S., Quick D., Kaye D.M., Pepe S. Endogenous cardiac opiods: enkephalins in adaptation and protection in the heart. Heart, Lung and Circulation. 12:178-187, 2003
- Kaczmarczyk S.J., Andrikopoulos S., Favaloro J., Domenighetti A.A., Dunn A., Ernst M., Grail D., Fodero-Tavoletti M., Huggins C.E., Delbridge L.M.D., Zajac J.D., Proietto J. Threshold effects of glut4 deficiency on cardiac glucose uptake and development of hypertrophy. J Mol Endocrinol. 3:449-459, 2003.
- Huggins C.E., Domenighetti A.A., Pedrazzini T., Pepe S., Delbridge L.M.D. Elevated intracardiac angiotensin II leads to cardiac hypertrophy and mechanical dysfunction in normotensive mice. J Renin-Angiotensin-Aldosterone System, 4:186-190, 2003.
- Curl, C.L., Wendt, I.R., Canny, B.J, Kotsanas G. Effects of ovariectomy and 17b-estradiol replacement on [Ca2+]i in female rat cardiac myocytes. Clinical and Experimental Pharmacology and Physiology 30, 489-494, 2003.
Conference Presentations
- Porrello ER, D’Amore A, Curl CL, Harrap SB, Thomas WG, Delbridge LMD (2005) The Angiotensin Type 2 receptor prevents cell death in neonatal cardiomyoctyes of the hypertrophic heart rat. Australian Physiological Society, Canberra, September 27-30.
- Huggins CE, Favaloro J, Proietto J, Pepe S, Delbridge LMD (2005) Salutary effects of pyruvate are more evident in female than male glut4-deficient mouse hearts. Australian Physiological Society, Canberra, September 27-30.
- Curl CL, Caldwell AM, Harrap SB, Delbridge LMD (2005) Enhanced inotropic responses of cardiomyocytes from the hypertrophic heart rat: a model of normotensive cardiac hypertrophy. International Society for Heart Research, Perth, August 5-8.
- Porrello ER, D’Amore A, Huggins CE, Curl CL, Harrap SB, Thomas WG, Delbridge LMD (2005) Evidence suggestive of an angiotensin II-dependent cardiomyocyte cull in neonatal hypertrophic heart rat. International Society for Heart Research, Perth, August 5-8.
- Huggins CE, Proietto J, Pepe S, Delbridge LMD. (2005) Eevidence of sex-specific cardiac contractile dysfunction in glut4-deficient mice. International Society for Heart Research, Perth, August 5-8.
- Curl CL, Canny BJ, Delbridge LMD, Wendt IR (2004) Gonadectomy and testosterone replacement influence intracellular calcium in male rat cardiac myocytes. International Society for Heart Research. Brisbane August 7 – 11. Journal of Molecular and Cellular Cardiology.
- Porrello ER, Huggins CE, Curl CL, Harrap SB, Thomas WG, Delbridge LMD. (2004) Increased angiotensin AT2 receptor expression is associated with neonatal cardiac growth restriction in a genetic model of adult cardiac hypertrophy. Poster presented at the Australian Physiological Society (AuPS) meeting, Australian Health and Medical Research Congress (AHMRC), Sydney.
- Porrello E, Morgan TO, Huggins C, Domenighetti A, Pedrazzini T, Delbridge L. (2004) Effect of different sodium intakes on cardiac size in mice producing angiotensin II locally in the heart. Oral presentation by Prof Trefor Morgan at the International Society of Hypertension (ISH) meeting, Sao Paulo.
- Huggins CE, Pedrazzini T, McLennan PL, Pepe S, Delbridge LMD. (2004) Dietary fatty acids alter phospholipid composition in a murine model of AngII induced cardiac growth. Proc. I.S.H.R. World Congress, Brisbane, Australia. August 7-11 2004 J.Mol.Cell.Cardiol. (in press).
- Huggins CE, Khalil N, Proietto J, Pepe S, Delbridge LMD.(2004) Pyruvate supplementation ameliorates ex vivo cardiac dysfunction in glut4 deficient mice. Proc. I.S.H.R. World Congress, Brisbane, Australia. August 7-11 J.Mol.Cell.Cardiol. (in press).
- Harris T, Curl CL, Allman BE, Harris PJ, Delbridge LMD, Stewart AG (2003). Measurement of area changes in human cultured airway smooth muscle cells using quantitative phase microscopy. Thoracic Society of Australia and New Zealand. Adelaide, April, 2003.
- Curl CL, Bellair CJ, Allman BE, Roberts A, Nugent KA, Harris PJ, Delbridge LMD (2003) Measurement of erythrocyte volume changes in response to osmotic stimuli using quantitative phase microscopy. Experimental Biology, San Diego, April 2003.
- Harris T, Curl CL, Chuo TN, Allman BE, Harris PJ, Delbridge LMD, Stewart AG (2003). Measurement of area changes in human cultured airway smooth muscle cells using quantitative phase microscopy. American Thoracic Society, Seattle, May 2003.
- Bellair CJ, Curl CL, Allman BE, Harris PJ, Roberts A, Delbridge LMD, Nugent KA (2003) Quantitative phase amplitude microscopy of three dimensional objects. 2nd International Workshop on Phase Retrieval, Cairns, June 29 – July 2.
- Curl CL. (2003) Gender, Sex Hormone Status and Calcium in the Heart. Invited Symposium Speaker. ISHR, Melbourne, August 7 -9.
- Curl CL & Delbridge LMD. (2003). Quantitative Phase Microscopy – A new way to interrogate the structure and function of unstained viable cells. Invited Symposium Speaker. Australian Physiological and Pharmacological Society. 33:106P.
- Curl CL, Bellair CJ, Harris T, Allman BE, Roberts A, Nugent KA, Harris PJ, Stewart AG, Delbridge LMD (2003) Measurement of culture confluency and volume of human airway smooth muscle cells using quantitative phase microscopy. Proceedings of Australian Physiological and Pharmacological Society. 33:75P.
- Bellair CJ, Curl CL, Allman BE, Roberts A, Delbridge LMD, Nugent KA (2003) Quantitative phase amplitude microscopy imaging of thick objects. ACOLS, Melbourne, Dec 1-Dec 4.
- Porrello E, Morgan TO, Huggins C, Domenighetti A, Pedrazzini T, Delbridge LMD. (2003) Sodium, angiotensin II and cardiac hypertrophy. Poster presented at the High Blood Pressure Research Council of Australia (HBPRCA) meeting, Melbourne.
- Porrello E, Huggins C, Domenighetti A, Pedrazzini T, Morgan T, Delbridge L. (2003) High dietary Na selectively exacerbates hypertrophy in cardiac AngII-overexpressing mice. Poster presented at the International Society for Heart Research (ISHR) meeting, Melbourne.
- Huggins CE, Domenighetti AA, Pedrazzini T, Pepe S, Delbridge LMD.(2003) Chronic overexpression of cardiac angiotensin suppresses basal ex vivo heart function and cardiomyocyte contractility in hypertrophic transgenic mice. European Soc Cardiol Congress, Vienna, Aug 30-Sept 3,. Abs 22548.
- Huggins CE, Domenighetti AA, Pedrazzini T, Pepe S, Delbridge LMD.(2003) Effects of elevated cardiac AngII on ventricular function in mice. Proc. I.S.H.R., Melbourne, Australia. August 7-9 J.Mol.Cell.Cardiol. (in press).
Current Grants
NHMRC:
Enkephalin metabolism in cardiac ischemia, heart failure and cardiac surgery.
NHMRC:
Statistical issues in microarray data analysis.
NHMRC:
Estrogen, Angiotensin II and the hypertrophic heart – cellular mechanisms of estrogenic cardioprotection
National Heart Foundation:
Omega 3 Dietary Lipids and Cardioprotection
Wenkart Foundation:
Neonatal Hormones and Heart Growth