Community Research and Development Information Service - CORDIS


Cardiocluster Report Summary

Project ID: 632066
Funded under: FP7-PEOPLE
Country: United Kingdom

Periodic Report Summary 1 - CARDIOCLUSTER (The role of ryanodine cluster morphology in arrhythmogenic calcium release after myocardial infarction)

State-of-the-art: Patients with heart failure have a poor prognosis, with five year mortality rates around 50%. Around 40% of patients with heart failure die from a lethal electrical irregularity or arrhythmia termed ventricular fibrillation (VF). Preventative drug treatments are currently very limited. The risk of VF is increased as the disease progresses, especially with further ischaemic events or in the presence of catecholamine stimulation, as is common in heart failure patients. Effective treatment is hindered by a lack of understanding of the cellular mechanisms that initiate these arrhythmias. The development of new experimental methods has allowed new insight both into nano-structure of the cellular environment and how this can affect cellular function. The CARDIOCLUSTER project aims to harness these new tools to gain further insight into the arrangement of proteins called ryanodine receptors within the cardiac muscle cell and how this can
alter the release of calcium. This calcium release process ultimately controls cardiac contraction but may increase the likelihood of arrhythmias. The project will assess the subcellular morphology of ryanodine receptor clusters in cardiac myocytes and how this is altered after remodelling in ischaemic heart disease. It is proposed this will have functional ramifications, leading to a dysregulation of subcellular Ca2+ processes.

Progress: In the first half of the study, we have successfully installed the advanced imaging system, allowing correlative super resolution and confocal microscopy. This system has allowed the mapping of RyR cluster morphology in both mouse and rabbit heart muscle cells with <20 nm accuracy. Measurements have been taken from cohorts with and without ischaemic heart disease. Heart muscle cells from the diseased groups RyR clusters were found to be remodelled. This led to RyR clusters which were smaller, with a more fragmented morphology. The fellow has also developed an in-vitro model which mimics the changes observed in ischaemic heart disease. Using this has yielded a similar phenotype to the disease model, validating its use for future studies of the remodelling process. It is hoped this will provide further insight into the underlying cause of remodelling as observed in MI.

Functional measurements have discovered pronounced slowing of the kinetics of spontaneous calcium release events, called calcium sparks. These alterations can be explained by the nanoscale remodelling of RyR clusters. The observed functional phenotype could produce cell-wide propagating events which are known to be proarrhythmic.

The large datasets collected from the structural and functional measurements have required the construction of complex computer analysis workflows. These have now been created and validated, allowing quantification of the all experimental data collected. New methods have been devised allowing the first measurements of calcium sparks in beating heart cells. This has provides important insight into this dynamic process in a more physiological context. It is hoped this information will allow a further understanding of the processes which underlie the generation of arrhythmia in ischaemic heart disease.

Career Integration: The fellow has initiated new collaborations with the Baillie and Workman groups in Glasgow, as well as the groups in Bristol, UK, Oslo, Norway and Maastricht, Netherlands. Furthermore, the fellow has accepted several postgraduate students, as well as taking several lectures at senior honours level. It is hoped the work which was carried out with the CIG fellowship will help the long term security and continued productivity of the fellow working in the UK.


Joe Galloway, (Research Support Manager (EU & International))
Tel.: +44 1413303884


Life Sciences
Record Number: 187660 / Last updated on: 2016-08-22