Pathways of calcium signalling in atrial fibrillation highlighted by genomic and transcriptomic studies

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Atrial fibrillation (AF) is a common heart condition that affects many people in the United Kingdom. It often causes disabling symptoms such as palpitations and breathlessness and is associated with a fivefold increase in stroke risk. Some estimates suggest that up to 30% of strokes are AF related. Unfortunately, AF is also associated with heart failure and increased mortality. Although relatively common, the biological processes that lead to the development of AF are incompletely understood. This means we have suboptimal treatment for the condition. Improved treatments for AF are therefore needed and their development needs to be driven by a better understanding of the mechanisms that drive the arrhythmia. One strategy to develop an improved understanding of the biological processes that lead to AF is to look at common genes that are being expressed either at an increased or decreased level in people with the condition compared to those without. These genome wide association studies (GWAS) highlight gene products that are potentially important in the physiology that drives AF. One such gene that has been highlighted in multiple studies is DGK beta. This gene causes a protein to be generated in the cell that is involved in a well-documented cell signaling system known as the phospholipase C/inositol triphosphate (PLC/IP3) pathway. However, to date the role of this cell signaling cascade in AF has not been extensively investigated. Various compounds that are known to activate this pathway, such as endothelin and angiotensin, are known to promote AF in animals making this system an exciting avenue to explore. The overall aim of this project is to demonstrate that activation of this intracellular signaling pathway does indeed increase susceptibility to AF. Secondly, mechanisms by which this pathway may increase the likelihood of AF will be investigated. It is hypothesised that particular calcium currents may be activated, and we will seek to demonstrate this. The PKC/IP3 system affects internal calcium handling by the cell and we would seek to define its role in the calcium handling of heart atrial muscle cells. We will use various methods to investigate the function of this pathway including pharmacological, electrophysiological and genetic techniques. We hypothesise that when we activate the pathway using known pharmacological compounds, in single atrial cells as well as in heart atrial tissue, we will be able to induce atrial fibrillation more easily than when the system is quiescent. We will use electrophysiological and fluorescent imaging techniques to identify atrial fibrillation in atrial tissue and arrhythmia triggering events in single cells. We will complement the work using genetic techniques that allow us to manipulate the protein components of the PKC/IP3 system and in so doing demonstrate how its altered function affects the induction and maintenance of AF. In this way, we will aim to identify a novel cellular pathway that promotes AF and in so doing identify potential new drug targets for therapy. If our hypothesis is supported by experimental evidence, the work will increase our mechanistic understanding of the rhythm disturbance and inform further therapeutic strategies. It is hoped that in the future, more effective treatments to prevent or treat AF will be available for a significant majority made possible by an improved scientific understanding of the initiation and maintenance of this arrhythmia.