Coronary Microembolization: the Role of TNF- α 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- 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 μ m 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 16.9±5.0% at 8 h). In conclusion, TNF- α is the mediator responsible for the profound contractile dysfunction following coronary microembolization.