TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-1-BETA ARE RESPONSIBLE FOR IN-VITRO MYOCARDIAL-CELL DEPRESSION INDUCED BY HUMAN SEPTIC SHOCK SERUM

Previous studies have demonstrated the presence of myocardial depressi on in clinical and experimental septic shock. This depression is assoc iated with the presence of a circulating myocardial depressant substan ce with physical characteristics consistent with cytokines. The presen t study utilized an in vitro myocardial cell assay to examine the role of various human recombinant cytokines, including tumor necrosis fact or (TNF)alpha and interleukin (IL)1 beta, in depression of cardiac myo cyte contractile function induced by serum from humans with septic sho ck. The extent and velocity of electrically paced rat cardiac myocytes in tissue culture was quantified by a dosed loop video tracking syste m. Individually, TNF-alpha and IL-1 beta each caused significant conce ntration-dependent depression of maximum extent and peak velocity of m yocyte shortening in vitro. In combination, TNF-alpha and IL-1 beta in duced depression of myocardial cell contractility at substantially low er concentrations consistent with a synergistic effect. Using immunoab sorption, removal of both TNF-alpha and IL-1 beta (but not either alon e) from the serum of five patients with acute septic shock and marked reversible myocardial depression resulted in elimination of serum myoc ardial depressant activity. IL-2, -4, -6, -8, -10, and interferon gamm a failed to cause significant cardiac myocyte depression over a wide r ange of concentrations. These data demonstrate that TNF-alpha. and IL- 1 beta cause depression of myocardial cell contraction in vitro and su ggest that these two cytokines act synergistically to cause sepsis-ass ociated myocardial depression in humans.