Cardiovascular & Hormonal Research Laboratory

Lab head: Dr Anastasia Susie Mihailidou
Location: Lvl 13, Kolling Building, Royal North Shore Hospital

The Cardiovascular & Hormonal Research (CHR) Laboratory's research focus is the cardiac actions of corticosteroids in the heart, in particular regulation of mineralocorticoid receptors and diabetes. The laboratory is equipped with both physiological and electrophysiological equipment to investigate cellular mechanisms and how these translate to functional regulation. The relocation of the laboratory to the Research & Education (Kolling) building at Royal North Shore Hospital has encouraged collaboration, sharing technologies and equipment.
Heart disease is the leading cause of death in Australia, with ischemic heart disease a major cause of morbidity and mortality. Although thrombolytic therapy and percutaneous coronary interventions reduce mortality from acute myocardial infarction (MI), additional therapeutic strategies are needed. Clinical trials have shown low doses of mineralocorticoid receptor blockade administered to patients with heart failure decreased morbidity and mortality versus standard care alone, despite starting levels of plasma aldosterone in the low/normal range, raising the question of exactly what is the mechanism for the cardioprotective action of MR antagonists. The CHR Laboratory have provided important advances into defining the mechanism(s) involved in regulation of mineralocorticoid receptors in the heart. The knowledge generated by our research studies has radically changed assumptions that mineralocorticoid receptors are uniquely an aldosterone receptor, and that any instance of activation of these receptors necessarily involves aldosterone.
Diabetes is the fastest growing disease worldwide, with increased mortality and morbidity resulting from the cardiovascular complications. Hyperglycemia has been shown to correlate closely with poor outcomes following acute myocardial infarction (AMI). The relationship between aldosterone and glucose metabolism is poorly explored. The group is currently investigating the mechanisms involved.
The Cardiovascular & Hormonal Research Laboratory is recognised internationally for its contribution to understanding the mechanisms involved in regulation of mineralocorticoid receptors in the heart. . Dr Mihailidou experience in ambulatory blood pressure monitoring is recognised nationally. A research collaborative was initiated to determine the relationship between ambulatory and clinic blood pressure: defining diagnostic and treatment targets for Australian population. All States contributed data and it is the first study to provide reference Ambulatory Blood Pressure Monitoring equivalents for hypertension management targets and not only diagnosis.  Our strong partnership with a multidisciplinary team to investigate the mechanism for increased risk of cardiovascular events during bereavement with a view to cardiovascular protection also continues. A new collaboration has started with Professor Peter Cistulli, Dept of Respiratory Medicine & Centre for Sleep Health & Research., RNSH, Dr Craig Phillips and colleagues of the Sleep & Circadian Group, Woolcock Institute of Medical Research comparing CPAP and Oral Appliance Therapy in the treatment of sleep disordered breathing.

Lab members: Ms Loan Le Dr Mahidu Mardini Dr Vincent Wong Mr Harris Mihailidis
Funding: National Heart Foundation & North Shore Heart Research Foundation
Research approach equipment: We will use established techniques in our laboratories recently relocated to the Kolling Building. These include Langendorff apparatus for the ischaemia-reperfusion studies, electrophysiology workstations for patch-clamping heart cells and access to equipment to measure molecular changes.

Buckley T, Mihailidou AS, Bartrop R, McKinley S, Ward C, Morel-Kopp M-C, Spinaze M, Hocking B, Tofler G. Increased blood pressure and heart rate during early bereavement: Potential mechanism of increased cardiovascular risk (submitted Heart Lung & Circulation 2010)

 Buckley T, Morel-Kopp M-C, Ward C, Bartrop R, McKinley S, Mihailidou AS, Spinaze M, Chen W, Tofler G. Inflammatory and Thrombotic Changes in Early Bereavement: a Prospective Evaluation (submitted European Heart Journal 2010)

 Wong V, Mardini M, Cheung W, Mihailidou AS. High dose insulin in experimental myocardial infarction in rabbits: protection against effects of hyperglycaemia.(In Press, Journal of Diabetes and Its Complications, 4 March2010)

 Head G, MihailidouAS, Duggan K, Beilin LJ, BerryN, Brown MA, Bune A, Cowley D, Chalmers JP, Howe PRC, Hodgson J, Ludbrook J, Mangoni AA, McGrath BP, Morley CM, Nelson MR, Sharman JE, Stowasser M. Relationship between ambulatory and Clinic Blood Pressure: Defining diagnostic and treatment targets. (British Medical Journal, Online April  2010)                                 

 Mihailidou AS, Le TYL, Mardini M, Funder JW (2009). Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension 54:1306-1312.

 Funder JW, Mihailidou AS (2009). Aldosterone and mineralocorticoid receptors: Clinical studies and basic biology. Mol Cell Endocrinol  301: 2-6.

 Buckley T, Bartrop R, McKinley S, Ward C, Bramwell M, Roche D, Mihailidou AS, Morel-Kopp M-C, Spinaze M, Hocking B, Goldston K, Tennant C, Tofler G. (2009). A Prospective study of early bereavement on psychological and behavioural cardiac risk factors. Internal Med J 39: 370-378.

 Mihailidou AS (2006). Nongenomic actions of aldosterone: Physiological or pathophysiological role? Steroids 71: 277-280. 

Mihailidou AS, Funder JW (2005). Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system. Steroids 70: 347-351.

Mihailidou AS (2005). Review: Nongenomic cardiovascular actions of aldosterone: a receptor for all seasons? Endocrinology 146: 971-972.

Mihailidou AS, Mardini M and Funder JW (2004). Rapid, non-genomic effects of aldosterone in the heart medicated by ePKC. Endocrinology 145: 773-780.

Regulation of aldosterone/mineralocorticoid receptors in the heart

Primary supervisor: Susie Mihailidou

Ischemic heart disease remains the leading cause of death worldwide. Following the ischemic event, reperfusion triggers generation of reactive oxygen species and impairs myocardial antioxidant defences, leading to further cardiac damage. High plasma aldosterone levels during percutaneous coronary intervention double the risk of mortality. Inappropriately elevated levels of aldosterone produce cardiac and vascular inflammation and fibrosis, via activation of mineralocorticoid receptors. Clinical trials show that low doses of mineralocorticoid receptor antagonists added to standard treatment increase survival and decrease hospitalization. Since free circulating levels of cortisol are 100-fold higher than aldosterone levels, mineralocorticoid receptors bind both aldosterone and cortisol with equal affinity. Our recent studies show that during myocardial ischemia-reperfusion, cardiac damage is aggravated by activation of mineralocorticoid receptors by both aldosterone and cortisol. We have recently identified that blockade of these receptors prevents cardiac damage and this project will determine the mechanisms involved. The studies will involve both functional studies and molecular techniques (immunohistochemistry, western blot analysis). 

Discipline: Pathology
Co-supervisors: Anthony Ashton
Keywords: Redox biochemistry, Molecular biology, Cardiovascular diseases