Objective: Altered myocardial Ca²⁺ and Na⁺ handling in congestive heart failure (CHF) may be expected to decrease the tolerance to ischemia by augmenting reperfusion Ca²⁺ overload. The aim of the present study was to investigate tolerance to hypoxia-reoxygenation by measuring enzyme release, cell death, ATP level and cell Ca²⁺ and Na⁺ in cardiomyocytes from failing rat hearts. Methods: CHF was induced in Wistar rats by ligation of the left coronary artery during isoflurane anesthesia, after which cardiac failure developed within 6 weeks. Isolated cardiomyocytes were cultured for 24 hours and subsequently exposed to 4 hours of hypoxia and 2 hours of reoxygenation. Cell damage was measured as lactate dehydrogenase (LD) release, cell death as propidium iodide uptake, and ATP by firely luciferase. Cell Ca²⁺ and Na⁺ were determined with radioactive isotopes, and free intracellular Ca²⁺ ([Ca²⁺]_i) with fluo-3 AM. Results: CHF cells showed less increase in LD release and cell death after hypoxia-reoxygenation and had less relative reduction in ATP level after hypoxia than SHAM cells. CHF cells accumulated less Na⁺ than SHAM cells during hypoxia (117 vs. 267 nmol/mg protein). CHF cells maintained much lower [Ca²⁺]_i than SHAM cells during hypoxia (423 vs. 1766 arbitrary units at 4 hour hypoxia) and exchangeable Ca²⁺ increased much less in CHF than in SHAM cells (1.4 vs 6.7 nmol/mg protein) after 120 minutes of reoxygenation. Ranolazine, an inhibitor of late Na⁺ current, significantly attenuated both the increase in exchangeable Ca²⁺ and increase in LD release in SHAM cells after reoxygenation. This supports that differences in Na⁺ accumulation during hypoxia caused the observed differences in Ca²⁺ accumulation during reoxygenation. Conclusion: Tolerance to hypoxia and reoxygenation surprisingly was higher in CHF than in SHAM cardiomyocytes, probably explained by lower hypoxia-mediated Na⁺ accumulation and subsequent lower Ca²⁺ accumulation in CHF after reoxygenation.