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

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Abstract
Tumor necrosis factor-α (TNF-α) likely plays a role in the pathophysiology of myocardial depression observed in septic shock. To evaluate the hemodynamic effects of TNF-α 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-α (rhTNF-α, 40 μg/kg for 1 hour). Plasma was analyzed for epinephrine and norepinephrine. Between 1 and 7 hours of exposure, rhTNF-α induced significant increases in circulating catecholamines. Norepinephrine rose from 268.6±47.2 to 426.2±87.0 pg/mL (P<.05) at 1 hour and peaked at 921.2±156.8 pg/mL (P<.001) at 4 hours after initiating rhTNF-α treatment. Similarly, epinephrine increased from 130.2±30.9 to 884.5±210.2 pg/mL (P<.05) at 1 hour and peaked at 3195.3±476 pg/mL (P<.001) at 4 hours. Before the surge of circulating catecholamines and despite complete β-adrenergic blockade, rhTNF-α induced a 7% to 40% increase in LV contractile performance during the 60-minute infusion. After this initial positive inotropic effect, rhTNF-α 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-α affects LV systolic function in a time-dependent biphasic manner. Increases in circulating catecholamines after rhTNF-α infusion cannot account for the early improvement in LV systolic performance.