Mechanisms of increased arrhythmogenic risk associated with acute regional ischaemia in rabbit: An optical mapping study

Roslan, Rosazra (2014) Mechanisms of increased arrhythmogenic risk associated with acute regional ischaemia in rabbit: An optical mapping study. PhD thesis, University of Glasgow.

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Acute coronary artery occlusion is the most common cause of sudden cardiac death. In some cases an acute myocardial infarction (MI) can immediately lead to lethal arrhythmias, but the factors that determine whether an MI precipitates arrhythmias are uncertain. In this thesis, I compare and contrast the detailed electrophysiology of hearts that develop arrhythmias post MI compared to those that do not using voltage sensitive fluorescent dyes in isolated rabbit hearts.
In an attempt to improve the information from voltage mapping studies, initial work involved attempts to use ratiometric imaging of the fluorescence from the dye RH237. These identified optimal filter settings to collect voltage data at two distinct wavebands that would eliminate movement artefact and permit absolute voltage measurements. But routine implementation of this technique was prevented by additional technical issues related to uneven illumination levels and alignment of the two cameras.
In initial studies the drug E-4031, a selective blocker of the delayed rectifier potassium current (IKr), was used to assess the contribution of this channel to repolarisation in rabbit ventricle, both in the steady state at a range of physiological and sub-physiological frequencies and in the transition between step frequency changes. The data suggests that IKr has a small but significant contribution to repolarisation at normal heart rates, 300ms pacing cycle length; a close to maximal concentration of E-4031 (0.03M) increased action potential duration (APD90) by 8.5 ± 1.7ms (P<0.01). This contribution is considerably larger at lower stimulation frequencies; at 1Hz E-4031 increased APD by 73.7 ± 13.7ms (P<0.05). The EC50 for E-4031 in this study was 0.01M which is similar to that reported in the literature. The recovery of the channel from inactivation appeared an important determinant of the rate of adaptation of the action potential duration.
In the main experimental section, a novel snare technique was used to produce the acute coronary artery occlusion in the apical region of the left ventricle (LV) free wall. From control experiments (n=21), 47.6% of the hearts develop ventricular fibrillation (VF) within 30 minutes of coronary artery occlusion. On average, hearts with intrinsically longer epicardial action potential duration prior to ischaemia (mean APD50 168.8 ± 5.5ms) did not develop VF, and those with shorter APD (mean APD50 141.5 ± 3.5ms) during pre-occlusion period were more prone to VF (P<0.001). However, artificially prolonging the APD with the drug E-4031 (0.03 concentration) prior to coronary artery occlusion did not significantly change the incidence of arrhythmia. Brief and transient exposure to isoprenaline (0.3Mconcentration) before the occlusion shortened the average APD prior to occlusion but still did not increase the likelihood of VF. Therefore, I concluded that shorter epicardial APD values prior to ischaemia are associated with a higher incidence of arrhythmia but are not the cause.
To investigate this further, a panoramic optical mapping technique was used to look at the electrophysiological properties across the entire ventricular surface of the hearts. The panoramic optical mapping study confirmed the correlation between shorter APD pre-occlusion and the incidence of VF during occlusion and indicated that the region of the LV exhibiting a shorter APD is confined to the apical half of the LV, and does not include basal LV or RV electrophysiology. Panoramic imaging also revealed a delayed activation time predominantly in the basal aspects of the LV. Both of these events – shorter APD in the apex and longer activation time in the base – were a feature of hearts that developed VF on ligation of the coronary artery. Future work will investigate the cellular/molecular basis for these differences in ventricular electrophysiology.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: arrhythmia, ischaemia, coronary artery occlusion, optical mapping
Subjects: Q Science > QP Physiology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences > Cardiovascular Science
Supervisor's Name: Burton, Dr. Francis and Smith, Professor Godfrey
Date of Award: 2014
Depositing User: Dr Rosazra Roslan
Unique ID: glathesis:2014-5484
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 Sep 2014 08:54
Last Modified: 23 Nov 2015 14:40

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