Bidirectional role of tumor necrosis factor-α in coronary microembolization -: Progressive contractile dysfunction versus delayed protection against infarction

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-alpha (TNF-alpha) expression, resulting in progressive contractile dysfunction. However, TNF-alpha 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-alpha expression is increased. ME (group1; n = 7) was induced by intracoronary infusion of microspheres (42 mu m; 3000 per mL/min inflow). Controls (group 2; n = 8) received saline. Groups 3 and 4 (n = 4 each) were pretreated with ovine TNF-alpha antibodies (25 mg/kg body weight) 30 minutes before ME or placebo, respectively. Ischemia ( 90 minutes) was induced 6 hours after ME when TNF-alpha was increased (66 +/- 21 pg/g wet weight; mean +/- SEM) or after placebo (TNF-alpha, 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-alpha 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-alpha antibodies (group 3 versus group 4, 29 +/- 3% versus 35 +/- 5%). In ME, TNF-alpha is responsible for both progressive contractile dysfunction and delayed protection against infarction.