Project Background: Rheumatoid arthritis (RA) patients do not die from arthritis but from complications associated with this devastating chronic disease, with cardiovascular events causing around half of all deaths in these patients [1]. Compared to the general population, RA patients are over twice as likely to develop heart problems. They are particularly susceptible to a type of heart failure with preserved ejection fraction/contractility (HFpEF) [1]; it is accompanied by diastolic dysfunction, whereby the heart fails to relax and refill fully after each heartbeat. What causes this dysfunction in RA patients is unknown and current medicines do not reduce these heart problems. We have developed an experimental animal model of arthritis, which mirrors the specific heart dysfunction of RA patients [2] and plan to use to it to uncover novel therapies.
The aim of this studentship is to i) further our understanding of cellular alterations in the blood as well as the heart in concomitance with the heart dysfunction over time; ii) determine the impact of novel and current anti-inflammatory strategies on heart dysfunction and joint disease.
Training/techniques to be provided: The student will gain a home office personal license and will be trained in models of arthritis as well as assessment of cardiac function by echocardiography. The project will also involve a significant component of flow cytometry, RT-PCR and ELISAs, for which full training will be given.
In this project, using a mouse model of arthritis, we can select specific times when i) mice have arthritis but no heart problems, ii) when heart problems begin and iii) when heart problems are fully evident. We can monitor these events over time and establish whether certain white blood cells [3] contribute to heart inflammation and development of the diastolic dysfunction. Heart dysfunction will be monitored by state-of-the-art small animal echocardiography, and white blood cells will be assessed by flow cytometry [2]. Molecular changes will be analysed by RT-PCR for the heart, and by selected ELISAs for plasma samples.
A novel inhibitor that limits the movement of inflammatory cells from the blood to the heart [3] will be tested. We will also treat mice with an anti-interleukin 1β medicine (an existing therapy for RA patients). The therapeutic effects of these molecules on heart function and joint symptoms will be assessed.
Benefits for patients: i) As we will study the association between white blood cells in the bloodstream and development of heart problems in RA patients, we hope to identify markers predictive of heart dysfunction to guide early cardiovascular intervention, as well as identify novel therapeutic targets; ii) Elucidation of therapeutic targeting of inflammation may ultimately impact decision making for preventing development of heart failure in RA patients and/or a tailored treatment for patients who have already developed heart problems; iii) Successful reduction/halting of heart dysfunction in RA patients will not only reduce death but will also improve their quality of life.
Benefits for the wider scientific and clinical community: Both human and murine studies indicate existence of a link between diseases associated with inflammation (obesity, diabetes mellitus, chronic kidney disease and inflammatory arthritis) and development of HFpEF; unfortunately the long-term prognosis for HFpEF patients remains bleak. Findings from this project will increase our knowledge on mechanisms of the experimental disease and may offer therapeutic avenues for controlling it.
Applications should be sent directly to QMUL admissions via this link (choosing the category: PhD Full-time William Harvey Research Institute (non-clinical) Semester 3):
https://www.qmul.ac.uk/postgraduate/research/subjects/medicine-william-harvey-research-institute.html
Informal inquiries should be addressed to [Email Address Removed]
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