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Translating the effect of rate control therapy in atrial fibrillation: from cellular response to cardiac function

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  • Full or part time
    Dr Kotecha
    Dr Pavlovic
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Applications are invited for a 3-year fully-funded PhD Studentship starting in September 2016, under the guidance of Dr Dipak Kotecha, Dr Davor Pavlovic and Prof Paulus Kirchhof. The purpose of this Studentship is to uncover important mechanistic insights into the (patho)physiology of cellular responses to common cardiovascular therapies in patients with atrial fibrillation.

Project summary: The RAte control Therapy Evaluation in Atrial Fibrillation (RATE-AF) trial is a head-to-head randomised trial of digoxin and beta-blockers for heart rate control in patients with atrial fibrillation (1). The trial is supported by the National Institute for Health Research (NIHR) and the Chief Investigator is Dr Kotecha (2-4). The primary endpoints for the clinical study are quality of life and heart function on echocardiography. The study will also afford a unique opportunity to assess the biological impact of therapy on both organ and cellular function, and allow development of new biomarkers for treatment efficacy and tolerability. Specifically, we propose to examine the role of intracellular sodium/calcium and cardiotonic steroids (5) in determining cardiac function and response to treatment using novel fluorescence techniques (6, 7). Using a translational approach, the PhD Student will utilise the full capabilities of the new Institute of Cardiovascular Sciences at the University of Birmingham. The PhD Student will be fully involved in the clinical trial process, including exposure to cardiac imaging techniques. The impact of endogenous cardiotonic steroids on the two therapies will be examined by a combination of liquid chromatography-mass spectrometry, novel fluorescence bioassays and use of human induced pluripotent stem cell-derived cardiomyocytes, within the laboratories of Dr Davor Pavlovic and Professor Kirchhof at the Institute of Cardiovascular Sciences. The key outcomes of the PhD Studentship will be translating these results to clinical findings from the RATE-AF trial (with opportunities for learning transferable skills in statistical methods).

Research Environment and Learning Outcomes: Required equipment is available at the Institute of Cardiovascular Sciences, with trial support from the Birmingham Clinical Trials Unit, the NIHR/Wellcome Trust Clinical Research Facility, the Human Biomaterials Resource Centre (as the study biorepository) and the University Hospitals Birmingham NHS Trust Cardiac Imaging Department (trained and accredited to British Society of Echocardiography standards). The supervisory team provides a full translational approach, including clinical aspects, methodology and statistics (Dr Kotecha), basic science (Dr Pavlovic) and the interface between these disciplines (Professor Kirchhof).

Person Specification
Applicants should have a commitment to cardiovascular research and have an interest in translational medicine (application of basic science skills to advance clinical practice). Applicants should be keen to spend some time in the clinical environment and preferably have some experience in analytical chemistry techniques (liquid chromatography-mass spectrometry), cellular and organ level cardiovascular methods, electrophysiology and molecular biology techniques. Applicants need to be able to work as part of a multidisciplinary research team according to Good Clinical Practice (GCP) standards. Applicant should hold at least an Upper Second Class Honours Degree in a relevant field and ideally be free of criminal convictions (a Disclosure and Barring Service (DBS) check will apply).

Applications should be directed to Viktorija Ziabliceva ([email protected]). To apply, please send:
• A detailed CV, including details on nationality and country of birth
• Names and addresses of two referees
• A covering letter highlighting your research experience/capabilities and key publications

Funding Notes

British and EU nationality applicants are eligible for both the cost of tuition fees and a yearly stipend (circa £14,000.00 per annum) over the course of the PhD programme.

References

1. Centre for Cardiovascular Science; University of Birmingham. Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF). National Library of Medicine (US). 2015; NLM Identifier: NCT02391337: Available from: https://clinicaltrials.gov/ct2/show/NCT02391337.
2. Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, Lip GY, Coats AJ, Andersson B, Kirchhof P, von Lueder TG, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD, Beta-Blockers in Heart Failure Collaborative Group. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet. 2014;384:2235-2243.
3. Kotecha D, Piccini JP. Atrial fibrillation in heart failure. What should we do? Eur Heart J. 2015: http://eurheartj.oxfordjournals.org/content/early/2015/09/28/eurheartj.ehv513.
4. Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GY, Steeds RP, Townend J, Kotecha D. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ. 2015;351:h4451.
5. Pavlovic D. The role of cardiotonic steroids in the pathogenesis of cardiomyopathy in chronic kidney disease. Nephron Clin Pract. 2014;128:11-21.
6. Pavlovic D, Hall AR, Kennington EJ, Aughton K, Boguslavskyi A, Fuller W, Despa S, Bers DM, Shattock MJ. Nitric oxide regulates cardiac intracellular Na(+) and Ca(2)(+) by modulating Na/K ATPase via PKCepsilon and phospholemman-dependent mechanism. J Mol Cell Cardiol. 2013;61:164-171.
7. Boguslavskyi A, Pavlovic D, Aughton K, Fuller W and Shattock MJ (2014) Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman. Cardiovascular Research Oct 1;104(1):72-82

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