AbstractThe inflammatory response of sepsis results in organ dysfunction, including myocardial dysfunction. Myocardial dysfunction is particularly important in patients with severe septic shock who progress to a hypodynamic pre-terminal phase. Multiple aspects of this septic inflammatory response contribute to the pathogenesis of decreased ventricular contractility. Inflammatory cytokines released by inflammatory cells contribute as does nitric oxide released by vascular endothelium and by cardiomyocytes. Endotoxins and other pathogen molecules induce an intramyocardial inflammatory response by binding Toll-like receptors on cardiomyocytes that then signal via NF-κB. These processes alter cardiomyocyte depolarization and, therefore, contractility. The particular role of the cardiomyocyte sodium current has not been characterized. Now new information suggests that the septic inflammatory response impairs normal depolarization by altering the cardiomyocyte sodium current. This results in decreased ventricular contractility. This is important because new targets for therapeutic intervention can be considered and new approaches to evaluation of this problem can be contemplated.