The impact of erythropoietin on uraemic cardiomyopathy

Smith, Katie

Biological sciences
December 2009

Thesis or dissertation

© 2009 Katie Smith. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). The uraemic heart is characterised by cellular and structural remodelling, including left ventricular hypertrophy LVH), which contribute to heart failure. Erythropoietin (EPO) has evolutionised the treatment of the anaemia associated with CKD. The discovery that the EPO receptor is also expressed on cardiomyocytes highlights a role of EPO beyond haematopoiesis. However, little is known on the cellular impact of EPO on the uraemic heart. The aim of this study was to determine the effect of EPO administration on uraemic cardiomyopathy.Uraemia was induced surgically in male Sprague-Dawley rats via a subtotal nephrectomy and animals retained for 3, 6, 9 or 12 weeks post-surgery. EPO was administered subcutaneously twice a week for 2 weeks prior to sacrifice at a dose of 30 μg/Kg. Cardiac function was assessed in vitro in the perfused heart and in vivo using an arterial pressure catheter. Cardiac metabolism was analysed using 13C NMR along with the activity and protein expression of key metabolic enzymes. In a separate set of experiments, mitochondrial function was determined in vitro using an oxygen electrode. To determine the extent of cardiac fibrosis, collagen was stained using picro-sirius red in frozen sections.Kidney dysfunction was observed from 3 weeks post-surgery as evident by significantly raised serum creatinine and urea, and development of anaemia. LVH was present at 6 and 12 weeks post-induction of uraemia, however in vitro and in vivo cardiac function was preserved,highlighting a compensatory phase. EPO did not impact on renal function, however, EPO significantly improved haematocrit and induced regression of LVH in uraemic animals at 12 weeks. In addition to preserved cardiac function, myocardial mitochondrial respiration was not modified by uraemia and unaffected by EPO administration. There was a decrease in palmitate utilisation in uraemic hearts compared to controls at 6 weeks post-surgery despite the unchanged activities of key metabolic enzymes including citrate synthase, medium chain acyl-CoA dehydrogenase and pyruvate dehydrogenase activity. Furthermore, the protein expression of CD36 and PPARα was the same in uraemic and control hearts. At 12 weeks post-surgery, uraemic animals exhibited significantly increased collagen within the heart compared to controls, highlighting cardiac fibrosis.In summary, by 12 weeks post-induction of uraemia, animals exhibited impaired kidney dysfunction, LVH, metabolic remodelling and cardiac fibrosis with preserved cardiac and mitochondrial function. Further work is required to determine whether the structural and metabolic remodelling which accompany uraemic cardiomyopathy would lead to a deterioration in cardiac function with prolonged uraemia.

Biological Sciences, The University of Hull
Seymour, Anne-Marie; Bhandari, Sunil
Sponsor (Organisation)
British Heart Foundation
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