Heparin Added to Cardioplegic Solution Inhibits Tumor Necrosis Factor-α Production and Attenuates Myocardial Ischemic-Reperfusion Injury

Objectives: Tumor necrosis factor (TNF)- is known to be a proinflammatory cytokine that has a pronounced negative inotropic effect and plays an important role in ischemic-reperfusion injury. Methods: Twenty isolated rat hearts were randomly divided equally into two groups (heparin and nonheparin) and were perfused with a Krebs-Henseleit solution using a modified Langendorff model. The influence of heparin on the synthesis and release of TNF- by isolated rat hearts after 1 h of global cardioplegic ischemia and on left ventricular (LV) performances during 30 min of postischemic reperfusion was investigated. Results: Significant mean ( SEM) amounts of TNF- in myocardial tissue (1,149 33.7 pg/g) and effluent (951.8 27.3 pg/mL) from the coronary sinus were detected after global cardioplegic ischemia. The addition of heparin to the cardioplegic solution significantly improved the recovery of LV function in the postischemic heart (p < 0.0001 for all measurements). TNFprotein production in the heparin-treated hearts was below detectable levels despite a postischemic increase of TNF- messenger RNA expression in both heparin-treated hearts and nontreated hearts (0.71 0.06 and 0.8 0.12 relative optical density, respectively). Conclusion: This study shows, for the first time, that heparin causes the inhibition of TNFprotein synthesis and release from the isolated ischemic rat heart within the posttranscriptional stage, and that it prevents the depression of LV function caused by ischemic-reperfusion injury. (CHEST 2005; 128:1805–1811) Abbreviations: ANOVA analysis of variance; bp base pair; CF coronary flow; CS coronary sinus; dP/dt max first derivative of the rise of the left ventricular pressure; ELISA enzyme-linked immunosorbent assay; GAPDH glyceraldehyde-phosphate dehydrogenase; KH Krebs-Henseleit; LV left ventricle, ventricular; MAP mitogen-activated protein; PCR polymerase chain reaction; TNF tumor necrosis factor