Coronary microembolization: The role of TNF-α in contractile dysfunction

Hilmar Dörge, Rainer Schulz, Sergej Belosjorow, Heiner Post, Anita Van De Sand, Ina Konietzka, Stilla Frede, Thomas Hartung, Jakob Vinten-Johansen, Keith A. Youker, Mark L. Entman, Raimund Erbel, Gerd Heusch

Research output: Contribution to journalArticle

158 Scopus citations

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-α) in the progressive contractile dysfunction resulting from coronary microembolization. Anesthetized dogs were subjected to either coronary microembolization with infusion of 3.000 microspheres (42 μm diameter) per ml coronary inflow into the left circumflex coronary artery (n = 9), or to intracoronary infusion of recombinant human TNF-α without microembolization (n = 4), or to treatment with anti-murine TNF-α 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-α 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-α mRNA identified viable cardiomyocytes surrounding the microinfarcts as the major source of TNF-α. Supporting the role of TNF-α, infusion of TNF-α 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-α antibodies, microembolization no longer reduced PWT (19.3±7.0% at baseline v 7 16.9±5.0% at 8 h). In conclusion, TNF-α is the mediator responsible for the profound contractile dysfunction following coronary microembolization.

Original languageEnglish (US)
Pages (from-to)51-62
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume34
Issue number1
DOIs
StatePublished - 2002

Keywords

  • Inflammation
  • Ischemia
  • Microcirculation
  • Microspheres

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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