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Title: Load-dependent electrophysiological and structural cardiac remodelling studied in ultrathin myocardial slices
Author: Alayoubi, Samha
ISNI:       0000 0004 6061 6827
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Introduction: Myocardial slices are becoming an established system to study cardiac electrophysiology and pharmacological research and development. Unlike other preparations, cardiac slices are a multicellular preparation that has an intermediate, adequate complexity required for this research. Previous studies have successfully obtained slices from human biopsies and animal models, where the electrical and structural parameters could be maintained for several hours - a process which is comparable to other preparation types. Therefore, we aimed to use left ventricular myocardial slices obtained from rat models of mechanical unloading (HAHLT) and from two models of overload (TAC and SHR), to investigate electrophysiological and structural alterations in these models. Methods: Mechanical unloading was achieved by heterotopic abdominal heart and lung transplantation (HAHLT, 8 weeks) and overload was induced by thoracic aortic constriction (TAC, 10 and 20 weeks) in male Lewis rats. Spontaneous hypertensive rats (SHR) were also used as a second model of overload and were primarily induced by hypertension (3, 12 and 20 months). Brown Norway and Wistar Kyoto rats were used as the control groups for SHR. Myocardial slices from the left ventricle (LV) free wall were cut (300-350 μm thick) tangentially to the epicardial surface using a high-precision slow-advancing Vibratome and were point-stimulated using a multi-electrode array system (MEA), therefore, acquiring field potentials (FPs). Field potential duration (FPD) and conduction velocity (CV) were analysed locally and transmurally across the LV free wall. In addition, FPD heterogeneity within each slice was calculated. For the SHR group, the same slices used for the MEA recording were preserved and used subsequently to measure Cx43, Nav1.5 protein levels and fibrosis. Results: Slices obtained from normal rat hearts that are chronically unloaded were found to develop atrophy at a whole heart level. They showed an increase in FPD and its heterogeneity with preserved conduction properties when compared to controls. In TACs, an in vivo whole heart function assessment confirmed hypertrophy with no signs of cardiac dysfunction. Slices from TAC rats showed an increase in FPD at both 10 and 20 weeks after banding. FPD heterogeneity was increased at 10 weeks but normalised at 20 weeks. Changes in CV properties were observed in this group, showing a faster CV and longitudinal conduction velocity (CVL) at 10 weeks and no change at 20 weeks. Transverse conduction velocity (CVT) was unchanged in the TAC group. In SHRs, however, hypertrophy was confirmed and signs of dysfunction in the aged group (20 months) were observed due to the decrease in EF by 18%, especially when compared to the 12 months group. FPD and its heterogeneity was unchanged in SHR when compared to controls. Disease and age-related abnormalities in CV properties were observed in SHR and these were associated with changes in Cx43, Nav1.5 protein level and fibrosis. Conclusion: Myocardial slices are a suitable multicellular preparation to study electrophysiological remodelling obtained from different rat models of cardiovascular disease. In addition, it was possible to investigate the changes in CV and FPD transmurally in rats using this type of preparation method. Thus, this study supports the use of this multicellular preparation in understanding the mechanisms of cardiac disease and the testing of new treatments and therapeutic targets.
Supervisor: Terracciano, Cesare Sponsor: King Fahad Cardiac Center ; King Saud University
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral