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(Circulation Research. 2007;100:140.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Bidirectional Role of Tumor Necrosis Factor- in Coronary Microembolization

Progressive Contractile Dysfunction Versus Delayed Protection Against Infarction

Andreas Skyschally, Petra Gres, Simone Hoffmann, Michael Haude, Raimund Erbel, Rainer Schulz, Gerd Heusch

From the Institute of Pathophysiology (A.S., P.G., S.H., R.S., G.H.) and Department of Cardiology (R.E.), Center of Internal Medicine, University of Essen Medical School; and Lukaskrankenhaus (M.H.), Neuss, Germany.

Correspondence to Prof Dr Gerd Heusch, Institut für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Germany. E-mail gerd.heusch{at}uk-essen.de

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- (TNF-) expression, resulting in progressive contractile dysfunction. However, TNF- 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- 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- antibodies (25 mg/kg body weight) 30 minutes before ME or placebo, respectively. Ischemia (90 minutes) was induced 6 hours after ME when TNF- was increased (66±21 pg/g wet weight; mean±SEM) or after placebo (TNF-, 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- 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- antibodies (group 3 versus group 4, 29±3% versus 35±5%). In ME, TNF- is responsible for both progressive contractile dysfunction and delayed protection against infarction.

Key Words: microembolization • inflammation • myocardial infarction • TNF-

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