Atrial fibrillation (AF) is prevalent in 4% of the general population and on the rise due to ageing population and lifestyle factors. For every unit increase in body mass index, there is a parallel 3-3.5% increase in AF risk. There is clear evidence that obesity itself drives cardiac tissue remodelling, via alterations in ion channel expression, fatty tissue deposition and fibrosis. Our pilot data indeed demonstrates that obesity alters atrial electrical function in high fat diet fed mice (Fig 1, panel A). Patients with AF receive one of a number of anti-arrhythmic drugs (AADs) in order to return to sinus rhythm. However, 5-year recurrence of AF is high, over 60- 80%. Recent clinical trial suggests that obesity can negatively affect the response to a standard cardiovascular drug spironolactone. Mechanisms driving the altered response are unclear.
Aims:
In this project we will utilise our obesity animal models, patient data (acquired during ablation) and cellular models to examine whether and how obesity alters cardiac electrophysiology and antiarrhythmic drug responses.
Experimental Methods and Research Plan:
The project will provide training opportunities in state-of-the-art methodologies and be implemented in several stages, providing a number of intermediate goals and allowing for several independent deliverables, see Gannt chart in Figure 1D.
Proposal is divided into three programmes of study:
- Programme 1 - Adipocyte-Cardiomyocyte co-culture
- Programme 2 - Mouse model of obesity
- Programme 3 - Patient electrophysiology data
Expected outcomes and impact:
Our translational approach will robustly characterise the effects of cardiomyocyte- adipocytes coupling on electrical activity in hPSC-CM lines and shed light on the effects of obesity on responses to standard anti-arrhythmic drugs.
The project is run as part of the MIBTP doctoral training programme.
Links to the relevant MIBTP pages are below.
https://warwick.ac.uk/mibtp/
https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx
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