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Title: The role of altered calcium handling in the pathogenesis of hypertrophic cardiomyopathy
Author: Rowlands, Christina
ISNI:       0000 0004 5349 2360
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiovascular disease carrying a significant risk of sudden cardiac death (SCD) due to arrhythmias. The ACTC (cardiac actin) E99K transgenic (TG) mouse reproduces many aspects of HCM observed in humans. The most striking characteristic is the high probability of SCD at 25-45 days old. The primary effect of this mutation is increased myofilament Ca2+ sensitivity, which we hypothesise will disturb intracellular Ca2+ homeostasis. This thesis investigates the role of altered Ca2+ handling in the pathogenesis of HCM and the development of lethal arrhythmias. Cardiomyocytes from 8-12 week old TG animals showed prolonged relaxation with no differences in maximum sarcomere shortening. Fura-2AM loaded TG cells displayed smaller Ca2+ transients and SR load than their NTG littermates. Cells from 25-45 day old TG mice showed increased sarcomere shortening and faster relaxation. Ca2+ transient amplitude was greater in TG cells however there were no differences in SR load. In both age groups, cells from TG mice displayed reduced diastolic [Ca2+], slower efflux of Ca2+ via the Na+/Ca2+ exchanger and no differences in SR Ca2+-ATPase function. Frequency of spontaneous Ca2+ sparks and waves was greater in TG cells than in NTG cells. The increased diastolic Ca2+ release was not mediated by enhanced phosphorylation of RyR at serine-2808 or Ca2+ overload. To assess whole heart arrhythmogenicity, multi-electrode array and ECG recordings were made at baseline and in the presence of isoprenaline. Both genotypes displayed a low level of baseline arrhythmic activity. The ECG demonstrated increased propensity for arrhythmias during β-adrenergic stimulation in TG animals. These data show that intracellular Ca2+ handling changes with age and with stage of disease. Cardiomyocytes from young TG mice are hypercontractile with increased Ca2+ transient amplitude which, coupled with increased propensity for spontaneous Ca2+ release, could predispose the heart to arrhythmias.
Supervisor: MacLeod, Ken; Marston, Steve Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral