Bidirectional Role of Tumor Necrosis Factor-α in Coronary Microembolization

Abstract

In patients with unstable angina, plaque rupture and coronary microembolization (ME) can precede complete coronary artery occlusion and impending infarction. ME-induced microinfarcts initiate an inflammatory reaction with increased tumor necrosis factor-α (TNF-α) expression, resulting in progressive contractile dysfunction. However, TNF-α is not only a negative inotrope but can also protect the myocardium against infarction. In anesthetized pigs, we studied whether ME protects against infarction when TNF-α expression is increased. ME (group1; n=7) was induced by intracoronary infusion of microspheres (42 μm; 3000 per mL/min inflow). Controls (group 2; n=8) received saline. Groups 3 and 4 (n=4 each) were pretreated with ovine TNF-α antibodies (25 mg/kg body weight) 30 minutes before ME or placebo, respectively. Ischemia (90 minutes) was induced 6 hours after ME when TNF-α was increased (66±21 pg/g wet weight; mean±SEM) or after placebo (TNF-α, 21±10 pg/g; P <0.05). Infarct size (percentage area at risk) was determined after 2 hours of reperfusion (triphenyl tetrazolium chloride staining). ME decreased systolic wall thickening progressively over 6 hours (group 1 versus group 2, 65±4% versus 90±1%; percentage of baseline; P <0.05). TNF-α antibodies attenuated the progressive decrease in systolic wall thickening following ME (group 3, 77±5% of baseline; P <0.05 versus group 1) with no effect in controls (group 4; 90±8% of baseline). With ME, infarct size was decreased to 18±4% versus 33±4% in group 2 ( P <0.05). The infarct size reduction was abolished by TNF-α antibodies (group 3 versus group 4, 29±3% versus 35±5%). In ME, TNF-α is responsible for both progressive contractile dysfunction and delayed protection against infarction.