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Title: Arrhythmogenic sarcoplasmic reticulum calcium leak in isolated ventricular cardiomyocytes : changes in heart failure and mechanisms of pharmacological modulation
Author: Sikkel, Markus
ISNI:       0000 0004 6348 0654
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Cardiomyocyte contraction involves sarcolemmal depolarization causing a small influx of Ca2+ which is then amplified via a larger release from the sarcoplasmic reticulum (SR). Under certain conditions SR Ca2+ is released in the absence of depolarization - so called SR Ca2+ leak. This is thought to be a key cause of arrhythmogenesis in heart failure (HF). The aims of this thesis were to assess how SR leak changes in a rat model of HF induced by chronic myocardial infarction (MI) and the mechanism of modulation using INa blockers. Several novel methodologies were developed to do this including the use of hierarchical statistical analysis which reduced the chance of type I errors in comparison to standard techniques. Detailed assessment of the HF model showed that there was fluid retention and eccentric hypertrophic remodelling of an impaired left ventricle by 16 weeks post MI which were more marked compared with earlier timepoints. Although under basal conditions Ca2+ leak was similar in HF and control cells, leak enhancement in response to isoprenaline was more marked in HF cells and there were significant heterogeneities in leak when comparing the borderzone to remote regions. At an earlier stage (8 weeks post MI) we found more frequent Ca2+ waves even under basal conditions. Analysis of Ca2+ leak in 3-D for the first time using a novel microscopy technique showed that arrhythmogenic waves originate from regions of preserved t-tubules. Finally we explored the use of flecainide to inhibit SR leak and showed that it acts via reduction of INa, which enhances Ca2+ efflux via the Na+/Ca2+ exchanger. In conclusion this thesis has drawn on several novel methodologies to gain a deeper understanding of SR leak, both in terms of how it changes in HF and by exploring a novel mechanism by which it can be reduced.
Supervisor: MacLeod, Kenneth ; Lyon, Alexander ; Harding, Sian Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral