Abstract—To investigate if spontaneous ischemic events in mice with severe multi-organ atherosclerosis could adapt to ischemia, apolipoprotein E/LDL receptor knockout mice were fed an atherogenic diet for 7 to 9 months. Signs of spontaneous ischemia occurred. One to two days later, hearts were excised, Langendorff-perfused with induced global ischemia, and compared with mice without signs of disease. In vivo heart or brain infarctions were verified by heart histology and/or increased serum levels of cardiac troponin T and S100B. Hearts of mice with spontaneous ischemic events had improved function and reduced Langendorff-induced infarctions. To investigate the remote preconditioning effect of brain ischemia, bilateral ligation of the internal carotid arteries was performed in C57BL6 mice. Twenty-four hours later, their isolated hearts were protected against induced global ischemia. A possible role of inducible NO synthase (iNOS) was studied in iNOS knock out mice, who were not preconditioned by induced brain ischemia. Cardiac iNOS was unchanged 24 hours after preconditioning, suggesting that NO is a trigger rather than a mediator of protection. These findings suggest that spontaneous ischemic events in the brain and heart adapt the heart to ischemia. This can be mimicked by induced brain ischemia, with iNOS as a key factor of protection.