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Title: An analysis of ventricular arrhythmogenesis following genetic and pharmacological intervention in the isolated, perfused, mouse heart
Author: Balasubramaniam, R. N.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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I have adapted clinical techniques to look at ventricular arrythmogenesis in the genetically and pharmacologically modified mouse heart at the whole heart and cellular levels. Using programmed electrical stimulation, I have demonstrated the arrhythmogenic phenotype of murine models of LQT3 and LQT5. I have successfully applied a clinically derived analysis technique (paced electrogram fractionation analysis (PEFA)) in order to suggest a propensity to arrhythmogenesis. I have also demonstrated the efficacy of the sodium channel blocker, mexiletine and the L-type calcium blocker, nifedipine in arrhythmia suppression in murine models of LQT3 and LQT5 respectively. Following on from this, I have demonstrated the antiarrhythmic effects of the L-type calcium channel blockers, nifedipine and diltiazem, in the suppression of arrhythmias in the wild-type mouse heart rendered arrhythmogenic following the addition of the β-adrenergic agonist, isoproterenol. These effects were then correlated with those seen on parallel cellular experiments examining changes in cytosolic calcium using confocal microscopy and a calcium-sensitive dye, in which the increase in cytosolic calcium seen following the addition of isoproterenol was suppressed by either nifedipine or diltiazem. Finally, I examined the effects of caffeine and FK506, both of which are thought to increase the open probability of the cardiac ryanodine receptor, in common with what is thought to occur in heart failure. I demonstrated the arrhythmogenic effect of caffeine on the whole mouse heart and again correlated this with parallel cellular experiments where I was able to demonstrate an increase in cytosolic calcium release in high calcium solution following the addition of caffeine of FK506, an effect that was suppressed by diltiazem, but not nifedipine.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available