Ischaemic and Pharmacological Preconditioning of the Uraemic Heart.

Abstract

The incidence and mortality from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) far exceeds that seen in the general population. Whilst a number of risk factors and associations have been identified in patients with CKD that may contribute to the increased risk of CVD, our understanding of the underlying pathophysiology remains poor. It has previously been reported that uraemic animals sustain larger myocardial infarcts and that this ‘reduced ischaemia tolerance’ may in part explain the excess mortality from CVD seen in CKD patients. The aim of this work was to establish an in vivo model of uraemic myocardial infarction in order to further explore the pathophysiology of uraemic CVD with particular focus on ameliorating myocardial ischaemia-reperfusion injury using ischaemic and pharmacological preconditioning. An increase in myocardial infarct size was demonstrated in the sub-total nephrectomy model of chronic uraemia, confirming previous reports in the literature. However, infarct size was not found to be increased in adenine diet induced renal failure. In addition, it was demonstrated for the first time, that the techniques of ischaemic preconditioning (IPC) and remote ischaemic preconditioning (RIPC) are both efficacious and not attenuated by chronic uraemia induced by sub-total nephrectomy or adenine diet (IPC only). Investigations were undertaken using an agent (a HIF stabiliser, FG4497) to induce pharmacological preconditioning in both animals with renal insufficiency and those without. These studies demonstrate that stabilisation of hypoxia inducible factor (HIF) may be a promising strategy to induce pharmacological preconditioning. It is hoped that this work may lay the foundations for future investigations to determine why sub-totally nephrectomised rats have larger infarcts whilst those with adenine induced renal failure, with a substantially greater degree of renal dysfunction, do not. Moreover, it is hoped that; by demonstrating that uraemia 3 does not prevent or attenuate the myocardial protection afforded by ischaemic preconditioning, the recruitment of patients with CKD will be encouraged to clinical trials of both ischaemic preconditioning and other therapies to limit myocardial infarction.