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The Cardiovascular Pathophysiology & Therapeutics Group reflects the combined interests of members of The Queen Elizabeth Hospital’s (TQEH) Cardiology and Clinical Pharmacology groups. This research collaboration has existed for over the past 20 years at TQEH.

We are mainly interested in developing a better understanding of the “new” cardiovascular epidemics of the 21st century, including atrial fibrillation, systolic hypertension, aortic valve disease, stress “Tako-Tsubo” cardiomyopathy and metabolic heart disease. We recognise that these conditions are responsible for impaired quality of life, as well as increased mortality rates. Therefore, we consider the development of effective treatment modalities as a major priority.

 

Researchers

Student Alumni (since 2016)

NameDegreeYear AwardedThesis titleSupervisors
Hasan ImamPhD, The University of Adelaide2018Post-receptor signalling mechanisms and platelet responsiveness to ADP receptor antagonistsHorowitz JD, Chirkov Y
Chuks AjaeroPhD, The University of Adelaide2018Interactions between Cardiac Resynchronisation Therapy and Amelioration of Peripheral Vascular Dysfunction: Impact upon Outcomes
Horowitz JD, Arstall M, Chan A, McGavigan A
Dongqing (Kelly) ChanFirst Class Honours, The University of Adelaide2018Early detection of chemotherapy-induced cardiomyopathyHorowitz JD, Liu S
Vivek NooneyPhD, University of South Australia2017Determinants of clinical responses to platelet ADP receptor antagonists
Roberts MS, Horowitz JD, Chirkov Y
Cher-Rin ChongPhD, The University of Adelaide2017A pharmacological approach towards myocardial protection: new perspectives in acute and chronic cardiac diseaseHorowitz JD, Sallustio B
Zaipul MD DomPhD, The University of Adelaide2017Mycophenolic acid pharmacokinetics and clinical outcomes in renal transplantation: Effect of ABCC2 haplotype analysis and distribution into lymphocytes and kidneySallustio BC, Somogyi AA, Coller JK
Matthew ChapmanMResearch, The University of Adelaide2016Pathogenesis of valvular and aortic degenerative changes in association with bicuspid aortic valveHorowitz JD, Nguyen TH
G MahadavanPhD, The University of Adelaide2016The pathophysiology and potential therapeutics of diastolic heart failureFrenneaux MP, Horowitz JD
N HurstPhD, The University of Adelaide2016The effect of the nitric oxide and prostacyclin pathways on platelet aggregationHorowitz JD, Chirkov Y, McRae S
Honours Project: Impaired platelet autacoidal signalling in patients with coronary vasospasm
Supervised by: Dr Y Chirkov, Dr TH Nguyen and Professor J Horowitz Angina pectoris is a common and debilitating problem in Western society, usually resulting from narrowing of coronary arteries. However, in a substantial minority of patients, spasm of the large or small coronary arteries is the cause of pain. While this condition can be treated symptomatically, there is no available cure, and many patients have poor quality of life because of frequent and recurrent episodes of pain. We are currently evaluating integrity of signalling pathways related to anti-aggregatory autacoids (e.g. nitric oxide and prostacyclin) in coronary spasm patients, with encouraging pilot results. These ongoing studies may lead to the development of better treatments for this condition.
Honours Project: The “Resilient Heart” Project: towards better understanding of anthracycline-induced cardiac injury
Supervised by: Dr S Liu and Professor J Horowitz Chemotherapy-induced cardiotoxicity is an emerging cause of heart failure that could add millions more to the healthcare budget. Currently, there are over 400,000 cancer survivors in Australia and that number is expected to continuously increase. Given that virtually all of the drugs concerned are cardiac toxic, this advance has come at the cost of increased risk of symptomatic or fatal heart failure. Doxorubicin, a member of the anthracycline family, is a well-known chemotherapeutic agent which is used in treatment of a wide variety of cancers. The successful use of doxorubicin has been hampered by toxicities such as hematopoietic suppression, nausea, vomiting, extravasation, and alopecia, yet the most feared side-effect is cardiotoxicity. The planned study will utilize technology which is already established in our laboratory to establish the determinants of extent of toxic effect of doxorubicin compared with those of other more recently developed antineoplastic drugs. The technology will utilize human myocardial cell grown in culture, and will quantitate the transition from complete cell viability through apoptosis to eventual necrosis. The results will help in the development of methods to develop cardiac-safe anticancer therapeutics.
Higher Degree Research Project: Impact of B-type natriuretic peptide (BNP) on stabilisation and function of the myocardium
Supervised by: Dr S Liu, Dr Y Chirkov and Professor J Horowitz We have recently shown that BNP exerts important anti-inflammatory effects, by stabilising white blood cells and diminishing superoxide production. We wish to determine whether this results in limitation of inflammatory change within the heart, and whether this anti-inflammatory effect of BNP is lost in acute heart failure.
Higher Degree Research Project: The heart in stress: Tako-Tsubo cardiomyopathy
Supervised by Dr TH Nguyen and Professor J Horowitz Tako-Tsubo syndrome (TS) occurs mainly in ageing women as a dysfunctional, inflammatory response of the heart to adrenaline. We have partially characterised the chemical signal transduction pathway in TS, and now seek to evaluate potential therapeutic avenues, using intact animal models, essentially to characterize the impairment in post-receptor signaling.
Higher Degree Research Project: Defects in physiological regulation of platelet aggregation: implications in the setting of potential coronary stenting
Supervised by Dr Y Chirkov and Professor J Horowitz We are studying regulation of blood clot formation in patients with different cardiac conditions. Blood clots cause heart attacks and strokes. Clot formation can be prevented with special medications (eg. clopidogrel or ticagrelor), which are used clinically to prevent thrombosis. Our research is aiming to identify a reason for the frequently occurring less-than-expected response to these medications. We are focusing on platelets because the starting point for blood clot is platelet aggregation. Autacoids, naturally occurring within the organism (e.g. nitric oxide and prostacyclin) which are supposed to control the normal function of platelets, stop working properly in patients with cardio-vascular diseases. It turns out that the platelet adenylate cyclase system is particularly important in predicting responses to clopidogrel and related drugs, implying that defective adenylate cyclase signalling may be the basis for poor patient responses to this class of drugs. We are trying to work out what is going wrong with this regulation and how it could be restored.
also refer to p95 of BHI Research Report 2017
An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease

Kikuchi R, Nakamura K, MacLauchlan S, Ngo DT, Shimizu I, Fuster JJ, Katanasaka Y, Yoshida S, Qiu Y, Yamaguchi TP, Matsushita T, Murohara T, Gokce N, Bates DO, Hamburg NM, Walsh K. An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. Nat Med; 2014. 20(12): 1464-71. 

Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity

Ngo DT, Farb MG, Kikuchi R, Karki S, Tiwari S, Bigornia SJ, Bates DO, LaValley MP, Hamburg NM, Vita JA, Hess DT, Walsh K, Gokce N. Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity. Circulation; 2014. 130(13): 1072-80.

Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload

Elezaby A, Sverdlov AL, Tu VH, Soni K, Luptak I, Qin F, Liesa M, Shirihai OS, Rimer J, Schaffer JE, Wilson S C, Edward J M. Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload. J Mol Cell Cardiol; 2015. 79: 275-83.

Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI)

Siddiqi N, Neil C, Bruce M, MacLennan G, Cotton S, Papadopoulou S, Feelisch M, Bunce N, Lim PO, Hildick-Smith D, Horowitz J, Madhani M, Boon N, Dawson D, Kaski JC, Frenneaux M; NIAMI investigators. Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI). Eur Heart J; 2014. 35(19): 1255-62. 

Determinants of aortic sclerosis progression: implications regarding impairment of nitric oxide signalling and potential therapeutics

Sverdlov AL, Ngo DT, Chan WP, Chirkov YY, Gersh BJ, McNeil JJ, Horowitz JD. Determinants of aortic sclerosis progression: implications regarding impairment of nitric oxide signalling and potential therapeutics. Eur Heart J; 2012. 33(19): 2419-25.

Patent

Nitrosative stress and diagnosis/treatment of stress cardiomyopathy.

JD Horowitz/Y Chirkov. University of Adelaide

Funding since 2010

Chief InvestigatorsGranting BodyProject TitleTotal Grant AmountFunding Period
Chong CRNational Health & Medical Research Council (NHMRC) Peter Doherty Biomedical ECR Fellowship (#1162356)Novel strategy to prevent cardiovascular complications in diabetes: the role of poly(ADP-ribose) polymerase-1 inhibition$327,1932019 - 2022
Sallustio B, Evdokiou A, Horowitz JDNational Health & Medical Research Council (NHMRC) Project Grant (#1145776)Prevention of heart damage during Anthracycline cancer chemotherapy$327,2142018 - 2020
Ritchie R, Horowitz J, Kemp-Harper B, Du XJ, Chirkov YNational Health & Medical Research Council (NHMRC) Project Grant (#1120895)Therapeutic approaches to circumvent NO• resistance in the Type 2 diabetic heart and vasculature$564, 0002017 - 2019
Frenneaux M, Horowitz JDMedical Research Council, UK Therapeutic aspects of nitrite supplementation$3,500,0002014 - 2019
Sallustio BC, Evdokiou A, Horowitz JDThe Hospital Research Foundation/The University of AdelaideEquipment: Vivid Iq Premium, Rodent Echocardiography System$77,6002018
Stewart S, Horowitz JD, Carrington M, Scuffham P, Wong C, Newton P, Rischbieth A National Health & Medical Research Council (NHMRC) Which Heart failure Intervention is most Cost effective in reducing Hospital care (WHICH? II) Trial: A multicentre, randomised trial of standard versus intensified management of metropolitan and regional-dwelling patients with heart failure$1,817,8252013 - 2018
Ngo DThe Hospital Research Foundation (THRF) Mid Career FellowshipModulation of the anti-angiogenic VEGF-A165b in adipose tissue: novel approach to combat obesity$360,0002015 - 2017
Sverdlov A National Health & Medical Research Council (NHMRC) CJ Martin Biomedical Fellowship (#1037603)Lipotoxicity, mitochondrial dysfunction
and the pathogenesis of heart failure
$364,8842012 - 2017
Sverdlov AThe University of Adelaide Start Up GrantAre mitochondrial reactive oxygen species key mediators of metabolic syndrome induced heart disease$10,0002017
Frenneaux M, Feelisch M, Horowitz JD et al. Medical Research Council, UK Effect of Inorganic Nitrite on cardiac and skeletal muscle: Physiology, Pharmacology and therapeutic potential£2.3 million
2011 - 2016
Dawson D, Neil CJ, Horowitz JD, Frenneaux MPTenovus Scotland Grant, UK G13/10 Stress induced Heart Disease £9,990 2013 - 2014

Sallustio B, Horowitz JD, Kennedy JA, Frenneaux MPNational Heart FoundationUtility of (+)- and (-) perhexiline as model compounds for the development of new myocardial metabolic agents$130,000 2012 - 2013

Sorich M, Horowitz JD National Heart Foundation Assessing of the value of the confirmatory studies required for the widespread uptake of personalised cardiovascular medicine $64,602 2012
Horowitz JD, Selvanayagam J, Semsarian C, Atherton J National Heart Foundation
Multiparametric Cardiovascular Magnetic Resonance Assessment of Hypertrophic cardiomyopathy$130,000 2010 - 2011

InstitutionCityCountry
SAHMRIAdelaideAustralia
Baker Heart and Diabetes InstituteMelbourneAustralia
Department of Epidemiology and Preventative Medicine, Monash UniversityMelbourneAustralia
Department of Pharmacology, Monash UniversityMelbourneAustralia
Australian Catholic UniversityMelbourneAustralia
Westmead HospitalSydneyAustralia
The University of NewcastleNewcastleAustralia
Cardiology Department, University of AberdeenAberdeenScotland, UK
University of East AngliaNorwichEngland, UK
University of OxfordOxfordEngland, UK
Department of Biochemistry, University of HannoverHannoverGermany
Department of Medicine, Boston UniversityBostonUSA
Department of Medicine, University of PittsburghPittsburghUSA
d'Annunzio UniversityChieti-PescaraItaly