Tumor necrosis factor-alpha and interleukin-1 beta synergistically depresshuman myocardial function

Objective: Proinflammatory cytokines such as tumor necrosis factor (TNF)-al pha and interleukin (II)-1 beta have been implicated in the pathogenesis of myocardial dysfunction in ischemia-reperfusion injury, sepsis, chronic hea rt failure, viral myocarditis, and cardiac allograft rejection. Although ci rculating TNF-alpha and IL-1 beta are both often elevated in septic shock, it remains unknown whether TNF-alpha or IL-1 beta are the factors induced d uring sepsis that directly depress human myocardial function, and if so, wh ether the combination synergistically depresses myocardial function. Furthe rmore, the mechanism(s) by which these cytokines induce human myocardial de pression remain unknown. We hypothesized the following: a) TNF-alpha and IL -1 beta directly depress human myocardial function; b) together, TNF-alpha and IL-1 beta act synergistically to depress human myocardial function; and c) inhibition of ceramidase or nitric oxide synthase attenuates myocardial depression induced by TNF-alpha or IL-1 beta by limiting proximal cytokine signaling or production of myocardial nitric oxide (NO). Design:Prospective, randomized, controlled study. Setting: Experimental laboratory in a university hospital. Subjects: Freshly obtained human myocardial trabeculae. Interventions: Human atrial trabeculae were obtained at the time of cardiac surgery, suspended in organ baths, and field simulated at 1 Hz, and the de veloped force was recorded. After a 90-min equilibration, TNF-alpha (1.25, 12.5, 125, or 250 pg/mL for 20 mins), IL-1 beta (6.25, 12.5, 50, or 200 pg/ mL for 20 mins), or TNF-alpha (1.25 pg/mL) plus IL-1 beta (6.25 pg/mL) were added to the bath, and function was measured for the subsequent 100 mins a fter the 20-min exposure. To assess the roles of the sphingomyelin and NO p athways in TNF-alpha and IL-1 beta cross-signaling, the ceramidase inhibito r N-oleoyl ethanolamine (1 mu M) or the NO synthase inhibitor NG-monomethyl -L-arginine (10 mu M) was added before TNF-alpha (125 pg/mL) or IL-beta (50 pg/mL). Measurements and Main Results:TNF-alpha and IL-1 beta each depressed human myocardial function in a dose-dependent fashion (maximally depressing to 16 .2 + 1.9% baseline developed force for TNF-alpha and 25.7 + 6.3% baseline d eveloped force for IL-1 beta), affecting systolic relatively more than dias tolic performance teach p < .05). However, when combined, TNF-alpha and IL- 1 beta at concentrations that did not individually result in depression (p >.05 vs, control) resulted in contractile depression (p < .05 vs. control). Inhibition of myocardial sphingosine or NO release abolished the myocardia l depressive effects of either TNF-alpha or IL-1 beta. Conclusions:TNF-alpha and IL-1 beta separately and synergistically depress human myocardial function. Sphingosine likely participates in the TNF-alpha and IL-1 beta signal leading to human myocardial functional depression. Th erapeutic strategies to reduce production or signaling of either TNF-alpha or IL-1 beta may limit myocardial dysfunction in sepsis.