Tumor Necrosis Factor-alpha Induces a Biphasic Effect on Myocardial Contractility in Conscious Dogs

Tumor necrosis factor-alpha (TNF-alpha) likely plays a role in the pathophysiology of myocardial depression observed in septic shock. To evaluate the hemodynamic effects of TNF-alpha in vivo while eliminating the influence of altered sympathetic tone, eight conscious chronically instrumented dogs were studied after pretreatment with propranolol (2 mg/kg) and atropine (2 mg). Using three sets of piezoelectric crystals to measure left ventricular (LV) volume and LV manometers to measure pressure, we determined load-independent parameters of LV systolic performance before, during, and after infusion of recombinant human TNF-alpha (rhTNF-alpha, 40 mu g/kg for 1 hour). Plasma was analyzed for epinephrine and norepinephrine. Between 1 and 7 hours of exposure, rhTNF-alpha induced significant increases in circulating catecholamines. Norepinephrine rose from 268.6 plus minus 47.2 to 426.2 plus minus 87.0 pg/mL (P less than .05) at 1 hour and peaked at 921.2 plus minus 156.8 pg/mL (P less than .001) at 4 hours after initiating rhTNF-alpha treatment. Similarly, epinephrine increased from 130.2 plus minus 30.9 to 884.5 plus minus 210.2 pg/mL (P less than .05) at 1 hour and peaked at 3195.3 plus minus 476 pg/mL (P less than .001) at 4 hours. Before the surge of circulating catecholamines and despite complete beta-adrenergic blockade, rhTNF-alpha induced a 7% to 40% increase in LV contractile performance during the 60-minute infusion. After this initial positive inotropic effect, rhTNF-alpha treatment led to precipitous systolic dysfunction between 2 and 7 hours of exposure; this myocardial depressant effect persisted at 25 hours. LV systolic performance declined to 19% to 35% of baseline values, depending on the specific contractile parameter evaluated. We conclude that rhTNF-alpha affects LV systolic function in a time-dependent biphasic manner. Increases in circulating catecholamines after rhTNF-alpha infusion cannot account for the early improvement in LV systolic performance.(Circ Res. 1996;78:154-160.)