title: Coronary microembolization: the role of TNF-alpha in contractile dysfunction.
abstract: Coronary microembolization is a frequent complication of atherosclerotic plaque rupture in acute coronary syndromes and during coronary interventions. Experimental coronary microembolization results in progressive contractile dysfunction associated with a local inflammation. We studied the causal role of tumor necrosis factor-alpha (TNF-alpha) in the progressive contractile dysfunction resulting from coronary microembolization. Anesthetized dogs were subjected to either coronary microembolization with infusion of 3.000 microspheres (42 microm diameter) per ml coronary inflow into the left circumflex coronary artery (n=9), or to intracoronary infusion of recombinant human TNF-alpha without microembolization (n=4), or to treatment with anti-murine TNF-alpha sheep antibodies prior to microembolization (n=4). Posterior systolic wall thickening (PWT; sonomicrometry) decreased from 21.1+/-5.3% (s.d.) at baseline to 5.5+/-2.2% (P<0.05) at 8 h after microembolization. Infarct size (1.8+/-1.9%; TTC and histology) and the amount of apoptosis (<0.1%; TUNEL and DNA-laddering) were small. TNF-alpha at the protein level (WEHI cytolytic assay) was increased and localized to leukocytes (immunostaining), which were increased in number (quantitative histology). In situ hybridization for TNF-alpha mRNA identified viable cardiomyocytes surrounding the microinfarcts as the major source of TNF-alpha. Supporting the role of TNF-alpha, infusion of TNF-alpha without microembolization decreased PWT from 27.3+/-6.9% at baseline to 10.1+/-4.9% after 8 h (P<0.05); in contrast, in the presence of TNF-alpha antibodies, microembolization no longer reduced PWT (19.3+/-7.0% at baseline v 16.9+/-5.0% at 8 h). In conclusion, TNF-alpha is the mediator responsible for the profound contractile dysfunction following coronary microembolization.
authors.affiliation: Abteilungen für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany.
authors.forename: Hilmar
authors.initials: H
authors.lastname: Dörge
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.forename: Sergej
authors.initials: S
authors.lastname: Belosjorow
authors.forename: Heiner
authors.initials: H
authors.lastname: Post
authors.forename: Anita
authors.initials: A
authors.lastname: van de Sand
authors.forename: Ina
authors.initials: I
authors.lastname: Konietzka
authors.forename: Stilla
authors.initials: S
authors.lastname: Frede
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.forename: Jakob
authors.initials: J
authors.lastname: Vinten-Johansen
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Raimund
authors.initials: R
authors.lastname: Erbel
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
mesh_terms: D000818:Animals; D017209:Apoptosis; D001161:Arteriosclerosis / Q000503:physiopathology*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007962:Leukocytes / Q000378:metabolism; D008833:Microcirculation / Q000502:physiology; D008856:Microscopy, Fluorescence; D009200:Myocardial Contraction / Q000502:physiology*; D009203:Myocardial Infarction; D009336:Necrosis; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha