Cardioplegic ischemia or reperfusion: Which is a main trigger for tumor necrosis factor production?

Background: Tumor necrosis factor alpha (TNF-α) is a key cytokine in the pathogenesis of ischemia-reperfusion injury (I/R) that also possesses negative inotropic and direct cardiotoxic effects. We investigated whether myocardial ischemia and/or reperfusion is the trigger for TNF-α synthesis and whether TNF-α release is time dependent. Methods: Isolated rat hearts undergoing 30 min of coronary perfusion with modified Krebs-Henseleit solution followed by cardioplegic arrest for 60 min of global cardioplegic normothermic ischemia (GCI) and 30 min of reperfusion using a modified Langendorff model. Myocardial TNF-mRNA expression and TNF-α protein levels in effluent from the coronary sinus were measured at baseline and then after 15, 30, and 60 min of GCI and after 10 and 30 min of reperfusion. Results: GCI induced myocardial TNF-α mRNA expression and elevation protein TNF-α levels in a time-dependent manner after 30 min of ischemia from 78 ± 17 pg/ml to 915 ± 287 pg/ml after 60 min (p < 0.0015). Reperfusion did not cause time-dependent increase of TNF-α synthesis and release but was accompanied by progressive decrease of left ventricular (LV) function. There was a correlation between TNF-α protein levels and depression of LV function immediately after GCI but not with TNF-α protein levels at 30 min of reperfusion. Conclusion: This study demonstrated that myocardial ischemia rather than reperfusion is the main trigger for time-dependent TNF-α synthesis. Depression of LV function during reperfusion correlated significantly only with TNF-α levels at the end of GCI.