Coronary artery disease with resultant myocardial ischaemia is responsible for major clinical complications including acute myocardial infarction, cardiac arrhythmias, and can lead to sudden cardiac death. The burden of ischaemic heart disease on the health service is on the increase as a result of an ageing population and an increase in survival rate after cardiovascular events (e.g. myocardial infarction). A number of clinical interventions (e.g. thrombolysis, percutaneous coronary angioplasty and coronary bypass surgery) are used to reperfuse the acutely or chronically ischemic myocardium. Reperfusion of the ischaemically diseased heart can induce myocardial injury which can be further compounded when coronary revascularization involves cardio-pulmonary bypass surgery and cardioplegic ischaemic arrest. Therefore myocardial protection strategies are continuously being designed, tested but with relatively low success rate. It has been suggested that the "use of animal models that do not adequately approximate the clinical setting" is one major barrier to translation into clinical therapy.

We have recently demonstrated that our validated apolipoprotein E knockout (apoE^-/-) mouse model of atherosclerosis and plaque rupture is also a relevant model of coronary artery disease and sudden death. Hearts of apoE^-/- mice fed high-fat diet for 24 weeks are ischaemic, show extensive coronary disease and infarcts in complete contrast to their littermates, apoE^-/- mice fed normal diet. In some animals the lesions caused significant occlusion of the lumen of the vessel and there was evidence of myocardial infarction primarily at the apex of the heart. In contrast, none of the sections from hearts of apoE^-/- mice fed normal diet for the same duration showed any sign of occlusive coronary artery disease or myocardial infarction. ApoE^-/- diseased hearts had increased pro-survival signalling (a higher ratio of phospho-Akt/total Akt) and were more resistant to cardiac insults than those from normal apoE^-/- mice. Differences cannot be due simply to high cholesterol as both control apoE^-/- and diseased apoE^-/- mice are grossly hypercholesterolaemic. The possibility that the increased resistance of diseased apoE^-/- hearts to ischaemia and reperfusion could be simply due to high-fat diet feeding has been excluded using wild-type mice. Our results show the opposite; hearts from wild-type mice fed a high-fat diet had increased vulnerability to ischaemia and reperfusion injury.

Progression of coronary disease in apoE^-/- mice or high-fat feeding of wild type mice induce significant changes in myocardial calcium cycling which may explain some of the differences observed and can be used in the design of suitable myocardial protection strategies.