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Title: Models for assessment of arrhythmogenicity after cardiac gene transfer
Author: Lyon, Dr. Alexander
ISNI:       0000 0001 3614 491X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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The aim of this thesis is the development of models to assess ventricular arrhythmia thresholds after heterogeneous gene delivery to the left ventricle. Heterogeneous SERCA2a gene delivery has been successfully achieved in the normal rat hearts when assessed by fluorescence microscopy and immunohistochemistry. The model measures in vivo ventricular arrhythmias with implantable ECG telemetry. Baseline 24 hour recording was performed to assess spontaneous arrhythmias, and isoproterenol administration assessed arrhythmia frequency after provocation in vivo. Hearts were studied ex vivo on the Langendorff apparatus with continuous ECG recording to evaluate ventricular arrhythmia thresholds. Hearts were subjected to regional ischaemia-reperfusion via proximal coronary ligation, programmed electrical stimulation with pacing and progressive interval shortening, or isoproterenol challenges ex vivo. Initial studies applied this model to assess the arrhythmic effect of heterogeneous SERCA2a gene delivery to the normal rat heart. The model demonstrated a proarrhythmic effect of needle injection in the normal rat heart when measuring spontaneous ventricular arrhythmias in vivo, or ischaemia-reperfusion-induced ventricular fibrillation ex vivo, and SERCA2a gene transfection may have a protective effect. Conversely SERCA2a has a proarrhythmic effect upon isoproterenol-induced ventricular arrhythmias, both in vivo and ex vivo, in the normal heart. The rat post myocardial infarction heart failure model was developed. The proximal left anterior descending coronary artery was ligated in vivo, and the animals develop post myocardial infarction cardiac failure. In vivo pressure-volume assessment of myocardial contractility 16 weeks post infarction demonstrated significant left ventricular dilatation and impairment of systolic and diastolic function. Serum brain natriuretic peptide levels was elevated in rats with myocardial infarction and left ventricular impairment. Histology demonstrated chronic left ventricular infarction with scar tissue replacing 40% of left ventricular muscle mass. Rats with left ventricular impairment post chronic myocardial infarction (MI) were treated with SERCA2a gene therapy delivered using an adenoviral vector, or Ad.GFP control. SERCA2a gene therapy reduced the incidence of ventricular arrhythmias in all arms of the arrhythmia .model, both in vivo and ex vivo, suggesting a protective antiarrhythmic effect of SERCA2a transfection in the failing heart. Heterogeneous SERCA2a gene transfection has differential effects upon arrhythmia generation in the rat heart. These depend upon the arrhythmic challenge, and whether the SERCA2a is delivered to the normal myocardium resulting in supraphysiological levels of SERCA2a, or to the failing myocardium where SERCA2a protein levels are reduced, with restoration of SERCA2a levels towards normal. This model was able can be applied to other therapeutic interventions or cardiac disease phenotypes to assess arrhythmic potential.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available