INTRODUCTION: In the heart, thermal injury activates a group of intracellular cysteine proteases known as caspases, which have been suggested to contribute to myocyte inflammation/dyshomeostasis. METHODS: In this study, Sprague Dawley rats were given either a 3° burn over 40% total body surface area (TBSA) plus conventional fluid resuscitation or sham burn injury. Experimental groups included, 1) sham burn given vehicle, 400 µl dimethyl sulfoxide, DMSO); 2) sham burn given Q-VD-OPH ( a highly specific and stable caspase inhibitor), 6 mg/kg, 24 and 1 hr pre-sham burn 3) burn given vehicle, DMSO as above; 4) burn given Q-VD-OPH, 6 mg/kg, 24 and 1 hr pre-burn. 24 hrs post burn, hearts were harvested and studied with regard to myocardial Na_i, pHi, ATP/PCr (²³Na/³¹P nuclear magnetic resonance), myocardial caspase-1, -3,and -8 expression, myocyte Na⁺ (fluorescent indicator, SBFI), myocyte secretion of TNF-, IL-1, IL-6 IL-10, and myocardial performance (Langendorff). RESULTS: Burn injury treated with vehicle alone produced increased myocardial expression of caspase-1, -3, and -8, myocyte Na⁺ loading, cytokine secretion and myocardial contractile depression; cellular pH/ATP/PCr were stable. Q-VD-OPH treatment in burn attenuated myocardial caspase expression, prevented burn-related myocardial Na⁺ loading, attenuated myocyte cytokine responses and improved myocardial contraction and relaxation. CONCLUSION: The present data suggest that signaling through myocardial caspases plays a pivotal role in burn-related myocyte sodium dyshomeostasis and myocyte inflammation, perhaps contributing to burn-related contractile dysfunction.