Deletion of the gene for apolipoprotein E (ApoE^-/-) results in severe atherosclerosis in mice, with the formation of lesions strikingly similar to those found in humans (Breslow 1996; Johnson & Jackson 2001). ApoE^-/- mice fed on high fat diet show lesions in the coronaries and evidence of myocardial infarction (Williams et al. 2002). Nothing is known about the vulnerability of the myocytes in these diseased hearts to cardiac insults. The aim of this work was to isolate myocytes from ApoE^-/- mice (fed on high fat diet) and their strain-matched, age-matched wild-type (fed normal chow diet) and to compare their morphological and contractile properties during metabolic inhibition. ApoE^-/- mice (7-8 months old) fed on high fat diet for 5-6 months and their matched wild-type were humanely killed, and the hearts were removed and perfused in the Langendorff mode. Myocytes were enzymatically isolated as described previously (Williams H. et al. 2001). Isolated myocytes were perfused with normal Tyrode solution and field stimulated at 0.2 Hz at 37^oC. For metabolic inhibition, myocytes were exposed to glucose-free solution containing 2.5mmol/L sodium cyanide. Myocytes were monitored for their changes in shape and contractile activity. All results are expressed as mean ±S.E.M. and analysed using an unpaired t test. Following exposure to glucose-free cyanide containing Tyrode solution, myocytes gradually cease beating and enter a state of rigor. These changes occurred at a significantly (p<0.05, n=32 myocytes) faster rate in myocytes from ApoE^-/- in comparison to wild-type (16.1±0.8 vs. 25.4±1.0 min for cessation of contractile activity and 19.3±0.9 vs. 29.6±1.1 min for rigor contracture). Upon reperfusion with normal Tyrode, the extent of contractile recovery was dependent on the duration of time in rigor. After long duration in rigor (30-40 min) none of the ApoE^-/- myocytes recovered whereas 80% of wild-type myocytes displayed contractile recovery. In order to assess the viability of the myocytes, the dye trypan blue was used. Preliminary data showed that more wild-type myocytes were able to exclude the dye following long periods of cyanide exposure than ApoE^-/- myocytes. In conclusion, this work shows that myocytes of ischaemically diseased hearts are more vulnerable to metabolic inhibition than wild-type myocytes. Differences in metabolism and ionic mobilization may explain these observations. Whether these observations occur in myocytes of ApoE^-/- mice fed on normal chow diet requires further investigation.