Yuliy Chirkov

Yuliy Chirkov

Adelaide Medical School

Faculty of Health and Medical Sciences

Eligible to supervise Masters and PhD - email supervisor to discuss availability.


Dr Chirkov's current research focus is the clinical phenomenon of “clopidogrel resistance”. It appears that impairment in cyclic nucleotide signalling contributes to the pathophysiological mechanism of this condition.

Blood clots cause heart attacks and strokes. Clot formation can be prevented with special medication (e.g. clopidogrel or ticagrelor). Our research is aiming to identify a reason for the frequently occurring, less than expected response to medications designed to suppress increased blood clotting. We are focusing on platelets (little blood particles) because the starting point for blood clot formation is platelet aggregation, or platelet “clumping”. We have recently demonstrated that highly tuned regulation of platelet activity is compromised in patients with cardiovascular diseases. We are trying to work out what is going wrong with this regulation and how it could be restored. Our research will provide us with the insight into how to improve platelet regulation.

Research Projects

Yuliy’s work interfaces basic research (“bench-side”) with extensive clinical access (“bed-side”). He has been directing projects investigating the interactions between cyclic nucleotide signalling pathways and oxidative stress in cardiovascular disease states.

Together with PhD and Honours students under his supervision, he has discovered and documented the phenomena of platelet “NO resistance” (nitric oxide, NO) and impaired cAMP signalling occurring in patients with ischaemic heart disease, and associated with thrombosis.

Dr Yuliy CHIRKOV is currently a Principal Medical Scientist (MeS-4), at The Queen Elizabeth Hospital (Central Adelaide Local Health Network, SA Health), and Senior Lecturer at The University of Adelaide. He has 110 career publications and a current H-index of 25.

 

Contributions to the field of Research:

Dr Chirkov has made a number of contributions to cardiovascular disease physiology and therapeutics. He studied the interactions of nitric oxide donors (e.g. nitroglycerine, sodium nitroprusside, S-nitrosothiols, etc.) with platelet aggregation. He has provided the first description of nitrate tolerance at the level of platelet aggregation in human subjects. He has documented the phenomenon of platelet nitrate/nitric oxide resistance in patients with cardiovascular diseases (stable angina, acute coronary syndromes, vasospastic angina, aortic stenosis, diabetes mellitus and congestive heart failure), with articles published in high-impact cardiac journals. He has shown that nitric oxide resistance can be ameliorated pharmacologically, with ACE-inhibitors, perhexiline and statins.

He studied the modulatory effects of angiotensin-(1-7) and angiotensin II on platelet aggregation and platelet responsiveness to nitric oxide. He has shown that angiotensin II exacerbates platelet aggregation, while angiotensin-(1-7) potentiates the anti-aggregatory action of the NO donors, and may therefore counteract platelet NO resistance. This finding also suggested an additional mechanism for the clinical effects of ACE-inhibitor therapy.

Recent research project was aimed on the circumvention of nitric oxide resistance with alternative, nitric oxide independent, stimulators of soluble guanylate cyclase, such as nitroxyl donors and direct activators of oxidised and haem-deficient guanylate cyclase (BAY 41-2272 and BAY 58-2667).

He is currently investigating a clinical phenomenon of “clopidogrel resistance”. It appears that impairment in cyclic nucleotide signalling contributes to the pathophysiological mechanism of this condition. Because the effects of ADP receptor antagonists such as clopidogrel and ticagrelor at the level of the P2Y12 receptor are coupled with changes in activity of AC, impaired response to PGE1 might imply both increased thrombotic risk and a reduced efficacy of anti-aggregatory drugs. Accordingly, patient response to treatment with clopidogrel is determined not only by variability of clopidogrel bio-activation, but also extensively by the integrity of platelet AC signalling.

Quality of research output:

Numerous publications in top-ranked cardiology journals. Editorials and invited reviews in Circulation, Thromb Haemost, Pharmacol Ther, J Am Heart Assoc, Expert Rev Cardiovasc Ther, Am J Cardiovasc Dis, Curr Opin Cardiol.

International standing:

  • International research collaboration: Since 1998, Dr Chirkov participated in a cooperative research project with Prof M.P. Frenneaux in UK (University of Wales Medical Centre, Cardiff; University of Birmingham; University of Aberdeen) related to investigation of endothelial-platelet dysfunction in heart failure and diabetes. Also, the investigation of the “Tako-tsubo” syndrome and effects of nitrite on blood vessels and platelets in cardiac patients.
  • International conferences: Since 1991, a total of 73 papers were presented at major international cardiac congresses held by World Heart Federation, American Heart Association and European Society of Cardiology. 18 papers were presented in the last 5 years

Publications

Over the past 5 years, Dr Chirkov had 17 publications in peer-reviewed journals.

Top 5 publications in the last 5 years:

  • Liu S et al. Suppression of neutrophil superoxide generation by BNP is attenuated in acute heart failure: a case for 'BNP resistance'. Eur J Heart Fail. 2015 Feb 11.  This publication provided the first evidence of diminished responsiveness to the anti-inflammatory effects of BNP in patients with acute heart failure, which may account for the failure of nesiritide in the ASCEND-HF trial to reduce the rate of death and re-hospitalization.
  • Nooney VB et al. Post receptor determinants of acute platelet response to clopidogrel in patients with symptomatic myocardial ischemia. Vascul Pharmacol. 2015;65-66:17-22. Since adenylate cyclase (AC) and sGC pathways are variably impaired in ischaemic heart disease, we tested the relevance of these determinants to platelet response to clopidogrel. While genetically impaired bio-activation markedly limited acute clopidogrel  response, impaired AC signalling provided an additional cause for clopidogrel resistance.
  • Hurst NL et al. Determinants of subacute response to clopidogrel: relative impact of CYP2C19 genotype and PGE1/adenylate cyclase signalling. Thromb Res. 2015;136(2):308-14. A potential basis for clopidogrel resistance extends beyond impaired bioactivation. Pre-clopidogrel PGE1 platelet response predicted clopidogrel response at 7 days. This was a stronger multivariate associate of response than bio-activator genotype.
  • Procter NE et al. New Developments in Platelet Cyclic Nucleotide Signalling: Therapeutic Implications. Cardiovasc Drugs Ther. 2016;30(5):505-513. Because the effects of ADP receptor antagonists such as clopidogrel and ticagrelor at the level of the P2Y12 receptor are coupled with changes in activity of AC, impaired response to PGE1 might imply both increased thrombotic risk and a reduced efficacy of anti-aggregatory drugs. Accordingly, patient response to treatment with clopidogrel is determined not only by variability of clopidogrel bio-activation, but also extensively by the integrity of platelet AC signalling.
  • Liu S., Chirkov Y.Y, Horowitz J.D. Neutrophil-initiated myocardial inflammation and its modulation by B-type natriuretic peptide: a potential therapeutic target. Internat J Molec Sci. 2018 Dec 31;20(1). pii: E129. Activation of neutrophils is a critically important component of the innate immune response to bacterial and chemical stimuli, and culminates in the "neutrophil burst", which facilitates neutrophil phagocytosis via the release of superoxide anion radical (O-) from NADPH oxidase. We have demonstrated that B-type natriuretic peptide (BNP), acting via inhibition of activation of neutrophil NADPH oxidase, is an important negative modulator of the "neutrophil burst", though its effectiveness in limiting tissue injury is partially lost in acute heart failure. The potential therapeutic implications of these findings are discussed.
 
Grants and Funding
Date Funding Body Funding Title
2017-2019 NHMRC "Therapeutic approaches to circumvent nitric oxide resistance in the type II diabeticheart and vasculature: Myocardial relaxation in response to NO donors"
2009-2014 The Queen Elizabeth Hospital TQEH vascular disease and therapeutics research group: towards improved outcomes for vascular disease
2007-2008 National Heart Foundation of Australia Modulation of myocardial metabolism in heart failure: implications regarding inflammation, vascular, platelet and myocardial function
2004-2005
National Heart Foundation of Australia
Mechanisms of therapeutic effect of perhexiline in severe myocardial ischaemia
2002-2002 NHMRC
Berthold Model LB953 Autolumat Plus tube luminometer

Dr Chirkov was responsible for training of both undergraduate and postgraduate students, a total of 29, in the role of lecturer and research supervisor. In the last 5 years, he supervised 7 PhD students.

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  • Current Higher Degree by Research Supervision (University of Adelaide)

    Date Role Research Topic Program Degree Type Student Load Student Name
    2015 Co-Supervisor Receptor and Postreceptor Determinants of Platelet Responses to Ticagrelor Doctor of Philosophy Doctorate Part Time Mr Gao Jing Ong
  • Past Higher Degree by Research Supervision (University of Adelaide)

    Date Role Research Topic Program Degree Type Student Load Student Name
    2015 - 2018 Co-Supervisor Inter-Individual Variability in Platelet Adenylate and Soluble Guanylate Cyclase Signaling: Therapeutic Perspectives Doctor of Philosophy Doctorate Full Time Mr Md Hasan Imam
    2014 - 2019 Co-Supervisor Nitrosative Stress and the Pathogenesis of Takotsubo Syndrome: Insights from a Novel Female Rat Model Doctor of Philosophy Doctorate Full Time Sven Yuri Surikow
    2012 - 2015 Co-Supervisor Natural History and Pathogenesis of Takotsubo Cardiomyopathy Doctor of Philosophy Doctorate Full Time Dr Kuljit Singh
    2011 - 2015 Co-Supervisor Effects of Nitrite and Nitroxyl on Human Vascular and Platelet Function Doctor of Philosophy Doctorate Full Time Dr Rustem Dautov
    2011 - 2016 Co-Supervisor Post-P2Y 12-Receptor Signalling Mechanisms and Platelet Responses to Clopidogrel Doctor of Philosophy Doctorate Full Time Dr Nicola Hurst
    2010 - 2015 Co-Supervisor Variability of Nitric Oxide Signalling in Atrial Fibrillation: Potential Modulation Doctor of Philosophy Doctorate Part Time Mr Nathan Edward Kevin Procter
    2010 - 2015 Co-Supervisor Impaired Tissue Responsiveness to B-Type Natriuretic Peptide in Heart Failure: Biochemical Bases Doctor of Philosophy Doctorate Full Time Dr Saifei Liu
    2009 - 2012 Co-Supervisor Pathogenesis of Aortic Stenosis: Implications Regarding Impairment of Nitric Oxide Signalling Doctor of Philosophy Doctorate Full Time Dr Aaron Sverdlov
    2009 - 2013 Co-Supervisor Cardiovascular Risk Assessment in Women: Impact of Ageing, Polycystic Ovarian Syndrome and Menopause on Nitric Oxide Signalling Doctor of Philosophy Doctorate Full Time Dr Alicia Chan
    2005 - 2009 Co-Supervisor Platelet and Endothelial Function: Polycystic Ovary Syndrome and the Renin-Angiotensin System Doctor of Philosophy Doctorate Full Time Dr Sharmalar Rajendran
    1998 - 2003 Co-Supervisor Pathophysiological and platelet anti-aggregatory effects of nitric oxide Doctor of Philosophy Doctorate Full Time Dr Andrew Holmes
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  • Committee Memberships

    Date Role Committee Institution Country
    2009 - ongoing Member QEH Research Day Conference Organising Committee Queen Elizabeth Hospital Australia
  • Review, Assessment, Editorial and Advice

    Date Title Type Institution Country
    2003 - ongoing Assessor Grant Assessment National Health and Medical Research Council Australia
    2003 - ongoing Peer reviewer in the area of cardiovascular research (physiology and biochemistry) Journal Review "Heart, Lung and Circulation", "Cardiovascular Research", "Cardiovascular Drugs and Therapy", "Nitric Oxide" and "Clinical and Experimental Pharmacology and Physiology"

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