Role of tumor necrosis factor-α in myocardial dysfunction and apoptosis during hindlimb ischemia and reperfusion

Objective. Peripheral vascular surgery involving limb ischemia/ reperfusion is associated with tumor necrosis factor-alpha production and an increased risk of cardiac complications. The objective of this study was to investigate the role of tumor necrosis factor-alpha in myocardial apoptosis and dysfunction following hindlimb ischemia/ reperfusion. Design: Randomized perspective animal study. Setting., Research laboratory. Subjects: Adults male tumor necrosis factor-alpha(-/-) and littermate wild-type mice. Interventions. Bilateral hindlimb ischemia/reperfusion was induced in wild-type and tumor necrosis factor-alpha(-/-) mice using tourniquet occlusion. After 2 hrs of hindlimb ischemia, the tourniquets were released, allowing reperfusion for 0.5-24 hrs. Measurements and Main Results., In wild-type mice, hindlimb ischemia/reperfusion resulted in myocardial depression early during the reperfusion period (p <.05). These effects were temporally correlated with enhanced levels of myocardial and plasma tumor necrosis factor-alpha. All variables were restored to baseline levels by 24 hrs of reperfusion. Myocardial apoptosis, assessed by cell death enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling staining, and caspase-3 activity, was also significantly higher at 6 hrs of reperfusion (p <.05) but returned to baseline levels by 24 hrs. Interestingly, cardiac dysfunction and myocardial apoptosis were abolished in tumor necrosis factor-alpha(-/-) mice subjected to the same degree of hindlimb ischemia/ reperfusion as the wild-type mice. Treatment of etanercept restored cardiac function in wild-type mice. Conclusions. Tumor necrosis factor-alpha contributes significantly to myocardial dysfunction and apoptosis in hindlimb ischemia/ reperfusion. Although a causal link between myocardial apoptosis and cardiac dysfunction is not established, our study does suggest that tumor necrosis factor-alpha may be a potential therapeutic target for cardiac injury in clinical situations involving prolonged remote ischemia/reperfusion.