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Title: Cardiac arrhythmogenesis in Scn36 knockout mice
Author: Hakim, P.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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The initial series of experiments investigated the ventricles of Scn3b-/- hearts. These mice showed increased expression levels of Scn1b and Scn5a mRNA compared to those shown in the wild-type (WT) hearts. The application of a programmed electrical stimulation protocol in Langendorff-perfused Scn3b-/- hearts elicited ventricular tachycardias and demonstrated abnormal conduction properties, as well as shorter ventricular effective refractory periods (VERPs), compared to those shown in WT hearts. Scn3b-/- hearts also demonstrated shorter action potential durations (APDs) relative to those shown in WT hearts. These electrophysiological features of Scn3b-/- hearts were similar to those shown in Scn5a-/- hearts. Reduced peak Na+ currents and a negative shift in their steady-state inactivation in isolated Scn3b-/- myocytes were corrected with the changes in the whole heart electrophysiology. These studies were then extended to examine the effects of quinidine and flecainide in ventricular electrophysiology of Scn3b-/- mice. Both agents exerted anti-arrhythmic effects in Scn3b-/- hearts. These effects were associated with prolonged VERPs. The monophasic action potential waveforms and their corresponding APDs were significantly shorter in these harts compared to those shown in untreated hearts, resulting in negative critical intervals. The effects of both flecainide and quinidine in Scn3b-/- hearts are in contrast to their differing effects in Scn5a+/- and Scn5a+/ΔKPQ hearts. The final series of experiments investigated atrial activity and cardiac conduction properties of Scn3b-/- mice. The expression levels of Scn1b and Scn5a mRNA were similar in the atrial appendages of Scn3b-/- and WT hearts. The expression of β3 subunits was demonstrated in the transverse tubules of WT myocytes. Such subunits were absent from Scn3b-/- myocytes. Surface electrocardiographic recordings from intact anaesthetised Scn3b-/- mice showed prolonged P wave durations and PR intervals. BEG recordings from spontaneously-beating Scn3b-/- hearts demonstrated episodes of spontaneous atrial tachycardia and complete heart block. Additionally, burst pace protocols applied to Scn3b-/- hearts induced atrial tachycadias and fibrillation, as well as prolonged sinus node recovery times. Taken together, these findings suggest that β1 subunits may affect Na+ channel expression and function. Deletion of Scn3b results in arrhythmogenicity, abnormal action potential properties and cardiac conduction defects.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available