Probing cardiac metabolism in uraemic cardiomyopathy

Atkinson, Robert

Biological sciences
April 2017

Thesis or dissertation


Rights
© 2017 Robert Atkinson. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
Abstract

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Uraemic cardiomyopathy (UCM) is characterised by structural and cellular remodelling including left ventricular hypertrophy (LVH), metabolic remodelling and mitochondrial dysfunction. Although ex vivo studies have highlighted evidence of enhanced glucose utilisation in the hypertrophied heart, cardiac glucose metabolism in uraemia has yet to be established in vivo. In addition, little is known about mitochondrial morphology or the impact of iron therapy on cardiac mitochondrial function in CKD. The aims of this study were to (I) investigate cardiac glucose metabolism in vivo using ¹⁸F-flurodeoxyglucose positron emission tomography (¹⁸F-FDG PET) during the development of UCM and (II) characterise mitochondrial morphology and the impact of iron therapy on cardiac mitochondrial function in uraemia.

Experimental uraemia was induced surgically in male Sprague-Dawley rats via a subtotal nephrectomy. Dynamic PET/CT scans were acquired at 5, 9 and 13 weeks post-surgery using ¹⁸F-FDG PET. The rate and distribution of ¹⁸F-FDG uptake were determined using Patlak and polar map analysis. In a separate series of experiments the iron complex, ferumoxytol, was administered 6 weeks post-surgery and mitochondrial respiratory rates and enzyme activities determined following sacrifice 6 weeks later. Cardiac mitochondrial morphology was characterised by probing the expression of key mitochondrial fusion and fission proteins and evaluating mitochondrial size and structure in left ventricular tissue and isolated mitochondria.

Renal dysfunction was prominent in uraemic animals by 12 weeks as evidenced by elevated serum creatinine, urea and the presence of anaemia. LVH was associated with moderately increased ¹⁸F-FDG uptake in the uraemic heart at 5, 9 and 13 weeks. This was paralleled at the cellular level by altered mitochondrial morphology, characterised by a more sparsely packed cristae, and increased mitochondrial state 4 respiration, indicative of reduced efficiency. However, ferumoxytol treatment did not impact on cardiac mitochondrial function at this stage of uraemia. Collectively these data suggest there is evidence of enhanced glucose utilisation in the uraemic heart in vivo and these changes are associated with altered mitochondrial structure and bioenergetics.

Publisher
School of Biological, Biomedical and Environmental Sciences, The University of Hull
Supervisor
Seymour, Anne-Marie; Bhandari, Sunil; Cawthorne, Chris; Archibald, Stephen J.
Sponsor (Organisation)
University of Hull
Qualification level
Doctoral
Qualification name
PhD
Language
English
Extent
7 MB
Identifier
hull:16521
QR Code