SummaryPrevious studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This depression is associated with the presence of a circulating myocardial depressant substance with physical characteristics consistent with cytokines. The present study utilized an in vitro myocardial cell assay to examine the role of various human recombinant cytokines, including tumor necrosis factor (TNF)ot and interleukin (IL)113, in depression of cardiac myocyte contractile function induced by serum from humans with septic shock. The extent and velocity of electrically paced rat cardiac myocytes in tissue culture was quantified by a closed loop video tracking system. Individually, TNF-0c and IL-113 each caused significant concentration-dependent depression of maximum extent and peak velocity of myocyte shortening in vitro. In combination, TNF-cx and IL-1[3 induced depression of myocardial cell contractility at substantially lower concentrations consistent with a synergistic effect. Using immunoabsorption, removal of both TNF-cx and IL-113 (but not either alone) from the serum of five patients with acute septic shock and marked reversible myocardial depression resulted in elimination of serum myocardial depressant activity. IL-2, -4, -6, -8, -10, and interferon ~/failed to cause significant cardiac myocyte depression over a wide range of concentrations. These data demonstrate that TNF-0t and IL-113 cause depression of myocardial cell contraction in vitro and suggest that these two cytokines act synergistically to cause sepsis-associated myocardial depression in humans. Despite therapy with appropriate antibiotics and intensive supportive care, septic shock remains a serious disorder with significant morbidity and mortality. The typical human cardiovascular response to septic shock is characterized by hypotension, decreased systemic vascular resistance, and elevated cardiac index. In addition, myocardial depression manifested by reversible biventricular dilation and reduction of ejection fraction has been shown to be common in human septic shock (1-3).A previously described in vitro model of myocardial cell performance utilizes spontaneously beating rat cardiac myocytes in culture (4-6). This system allows assessment of myocardial cell performance (i.e., contraction) independent of changes in preload, afterload, and heart rate. In this system, serum from patients with acute septic shock produced in vitro depression of cardiac myocyte contractile function (decreased maximum extent and peak velocity of shortening) that correlated quantitatively and temporally with the

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