Apolipoprotein E knockout (apoE^-/-) mice are commonly used models of human atherosclerosis that develop lesions in their coronaries and show evidence of infarct (Williams et al. 2002, Arterioscler Thromb Vasc Biol 22, 788–792). When fed a western type high fat diet, disease progression is accelerated. The aim of this work was to investigate whether high fat diet alters the vulnerability of diseased hearts to ischaemia and reperfusion. ApoE^-/-mice were fed on either a normal chow diet (n=15) or western-type high fat diet (n=9) for 5-6 months. At the end of this feeding period, animals were humanely killed, hearts isolated and perfused retrogradely, at constant pressure, in the Langendorff mode. Hearts were subjected to 35 minutes global, normothermic ischaemia, followed by 45 minutes reperfusion. A balloon, inserted in the left ventricle, and attached to a pressure transducer measured heart rate, left ventricular developed pressure (LVDP) and coronary flow. The % recovery of rate pressure product (RPP) at the end of 45 minutes reperfusion was 34%± 10 (mean ±SEM) for normal diet compared to 105%± 18 for apoE^-/-mice fed high fat diet. In conclusion, this work shows that acceleration in disease progression is associated with increased resistance to damage caused by ischaemia and reperfusion. This is likely to be due to differences in the extent of ischaemia-induced cardiac remodelling.