Community Research and Development Information Service - CORDIS

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

The scientific objective of this CIG project was to determine the mechanisms underlying cardiac arrhythmia. Currently 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. Currently, 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.

Initial results from the CARDIOCLUSTER project suggested alterations in Calcium release in atrial myocytes A model of myocardial infarction available in Glasgow was used to explore if this mechanism also occurred in the ventricle. To this end, new tools were developed, establishing the dSTORM super resolution microscopy method in Glasgow. This allowed 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 assessed the subcellular morphology of ryanodine receptor clusters in cardiac myocytes and how this is altered after remodelling in ischaemic heart disease. This will have functional ramifications, leading to a dysregulation of subcellular Ca2+ processes.

Further progress was made on how alterations in cellular calcium release feedback on electrophysiology were explored using optical and patch clamp methodologies to record cellular voltage. This showed a major role of calcium dependant processes to alter the time course of the electrical activity of single heart cells. It is hoped this will lead to the development of future antiarrhythmic therapies.

The CIG funding was critical for initiating new technologies in Dr Macquaide’s laboratory and has attracted new students from the BHF funded 4-year PhD scheme. Collaborative visits to
Belgium and Norway have allowed the development of new collaborations. Dr Macquaide has also contributed to the Masters course in Bio Imaging and senior undergraduate Pharmacology course. Further funding was acquired through a BHF project grant to explore the activation of phosphodiesterases in cardiac muscle responsible for controlling calcium release and contractility in patients with cardiac disease. It is hoped this work will develop a new cardiac therapy.

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United Kingdom


Life Sciences
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