Novel cardioprotective strategies for the uraemic heart.
Abstract
Cardiovascular disease is the leading cause of death in patients with underlying chronic
kidney disease (CKD). Up to one third of patients presenting with an acute coronary
syndrome have CKD stage 3-5. Outcomes following acute myocardial infarction in
patients with underlying CKD remain poor. CKD patients are routinely excluded from
clinical trials in novel cardioprotective strategies resulting in a paucity of prospective
data on which to base guidelines for clinical practice.
The aims of this work were to:
• Establish and characterise two models of chronic uraemia in rodents: the
subtotal nephrectomy model and the adenine diet model.
• Determine the effects of underlying chronic uraemia on myocardial ischaemia
tolerance.
• Examine pharmacological cardioprotective strategies in the context of
underlying uraemia using a PARP inhibitor
• Investigate the cardioprotective effects of ischaemic conditioning in the
context of uraemia. Ischaemic preconditioning and postconditioning protocols
were used in both uraemic and non-uraemic animals in a model of acute
myocardial infarction.
• Preliminary work, using standard molecular biological techniques, was carried
out in order to confirm the putative survival pathways responsible for the
effect of preconditioning.
• Investigate the effect of combining early and late remote ischaemic
preconditioning to identify whether summation of these strategies could
provide additional tissue protection in a model of acute kidney injury.
The results demonstrate that both models develop a uraemic phenotype. Subtotal
nephrectomy animals exhibit reduced ischaemia tolerance. PARP inhibition as a
pharmacological post conditioning agent was shown to be ineffective at conferring
tissue protection, whereas both ischaemic preconditioning and postconditioning were
effective cytoprotective strategies in both non-uraemic and uraemic animals.
Furthermore, additional benefit was seen when early and late remote preconditioning
were summated in a rodent model of acute kidney injury.This work provides a basis for future clinical trials in cardioprotection in the context of
underlying CKD.
Authors
McCafferty, KieranCollections
- Theses [3600]