The management of acute heart failure syndromes (AHFS) focuses primarily on improving hemodynamic function and alleviating symptoms. Emerging evidence has raised the possibility that patients with AHFS may be susceptible to progressive myocardial failure because of the accelerated loss of cardiac myocytes. Although there are circumstantial data to suggest that the choice of therapeutic agent may affect long-term outcomes in such patients, the responsible mechanism is not known. Activation of mitochondrial adenosine triphosphate-dependent potassium (K(ATP)) channels in cardiac myocytes is a potent cardioprotective mechanism. We studied cardiac myocytes in culture to determine whether levosimendan can protect against apoptotic cell death in response to oxidative stress, a stimulus that appears to mediate myocyte loss in response to hemodynamic overload and beta-adrenergic stimulation, conditions commonly encountered in acute HF. Levosimendan, at concentrations below the therapeutic range in humans, protected myocytes from hydrogen peroxide-induced apoptosis. This effect was prevented by K(ATP) channel inhibitors. The demonstration that levosimendan can oppose myocyte apoptosis via the activation of mitochondrial K(ATP) channels provides a potential mechanism by which this agent might protect cardiac myocytes during episodes of acute HF. Although the alleviation of symptoms should remain an important goal of therapy in acute HF, a therapeutic approach that includes a cardioprotective strategy may be able to exert a clinically meaningful benefit on disease progression. This speculation, if proved true, would mandate a fundamental paradigm shift in the acute management of acute HF.