Bidirectional role of tumor necrosis factor-alpha 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 microm; 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.
Skyschally
Andreas
A
Institute of Pathophysiology, Center of Internal Medicine, University of Essen Medical School, Germany.
Gres
Petra
P
Hoffmann
Simone
S
Haude
Michael
M
Erbel
Raimund
R
Schulz
Rainer
R
Heusch
Gerd
G
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism*; D003327:Coronary Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D004617:Embolism / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008863:Microspheres; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D013552:Swine; D013556:Swine, Miniature; D013599:Systole; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D002316:Cardiotonic Agents; D014409:Tumor Necrosis Factor-alpha