Protamine-induced cardiotoxicity is prevented by Anti-TNF-alpha antibodiesand heparin

Background: We Investigated the role of tumor necrosis factor alpha (TNF-al pha) in protamine-induced cardiotoxicity and the possibility of preventing or decreasing this effect by anti TNF-alpha antibodies and heparin. Methods: Isolated rat hearts were perfused for 60 min with Krebs-Henseleit solution (KIT). The control group was perfused with KIT alone, the KIT > pr otamine > KIT group was treated from the 20th to the 40th minute with prota mine, and the KIT + anti-TNF > protamine + ainti-TNF > KH + anti-TNF group was treated the same as the KH > protamine > KIT group but with anti-TNF-al pha antibodies added throughout perfusion. The KIT + heparin > protamine heparin > KIT + heparin group was treated the same as the KH > protamine > KH group but with heparin added to KH throughout perfusion. The KIT > prota mine > KIT + heparin was perfused the same as the KH > protamine > KIT grou p but with heparin added to KIT for the last 20 min. Left ventricular (LV) function and coronary flow were measured every 10 min. TNF-alpha was measur ed in the coronary sinus effluent. Left ventricular TNF messenger RNA was d etermined in the control and KIT > protamine > KIT groups at baseline and a fter the 40-min perfusion. Results: Protamine caused a significant decrease of peak systolic pressure and dP/dt (to 25% of baseline). Significant amounts of TNF-alpha in the eff luent in the KIT > protamine > KIT group (102.3 +/- 15.5 pg/min) and TNF me ssenger RNA expression in left ventricular samples were detected. TNF-alpha was below detectable concentrations in the control, KIT + anti-TNF > prota mine + anti-TNF > KIT + anti-TNF, and KIT + heparin > protamine + heparin > KH + heparin groups. TNF-alpha concentrations correlated with depression o f LV peak systolic pressure (r = 0.984; P = 0.01) and first derivate of the increase of LV pressure (r = 0.976; P = 0.001). Heparin Improved LV recove ry and decreased protamine-induced TNF-alpha release (KIT > protamine > KIT + heparin group). Conclusions: Anti-TNF-alpha antibodies and heparin prevent protamine-induce d TNF-alpha release and depression of LV function. Heparin Improves protami ne-induced depression of cardiac function.