Die aktuelle Studie untersucht die pathophysiologischen Mechanismen, die hinter der zweithäufigsten Form des akuten Koronarsyndroms - Plaque Erosion stehen. Dabei ist der Fokus auf der Aktivierung der neutrophilen Granulozyten über den Toll-like Rezeptor 2 Signalweg gelegt.
Background: Endothelial cell desquamation (ECD) due to inflammatory activation is one of the main pathophysiological features of acute coronary syndrome with intact fibrous cap (IFC-ACS, plaque erosion) (2, 5). The neutrophil granulocytes are the first immune cells to arrive at the coronary culprit lesion after ACS. Therefore, the current subanalysis of the OPTICO-ACS study aims to provide a better understanding of their molecular acti-vation patterns. Methods: Using optical coherence tomography (OCT) of the ACS-causing culprit lesion two groups (IFC-ACS vs. RFC-ACS) were generated, each consisting of thirty-two pa-tients matched by age, gender and diabetes mellitus type II. Local and systemic blood samples were collected from the site of the ACS-causing culprit lesion (LOC) and from the arterial sheath (SYS). Quantification of neutrophil counts and expression of activation markers was carried out by flow cytometry. MMP9 activity was assessed by fluorescence-based zymography. The combined effect of MMP9 and disturbed flow conditions were studied in an Ibidi flow chamber imitating coronary bifurcations. The direct cytotoxic ef-fects of TLR2 pre-activated neutrophils was examined in a co-culture with endothelial cells. Immunohistological staining of thrombus specimens characterized the expression of hyaluronidase 2 (HYAL2), an enzyme known to produce pro-inflammatory low molec-ular weight hyaluronan as one of the endogenous TLR2-ligands (9, 10). Results: Neutrophils of IFC-ACS patients show significantly higher expression of the toll-like receptor 2 (TLR2) in comparison to RFC-ACS-derived neutrophils, despite an equal cell count. Furthermore, the MMP9 plasma activity is significantly higher in local samples from IFC-ACS patients, indicating secretion and proteolytic activation of the enzyme dur-ing ACS. Local IFC-ACS- derived neutrophils increased their secretion and activity rates of MMP9 in response to TLR2-stimulation using Pam3CSK4, which was reversible after TLR2 blockade by a monoclonal neutralizing antibody. However, the combination of MMP9 and turbulent flow conditions leads to significant ECD. Furthermore, the TLR2-activation increases the survival of local IFC-ACS derived neutrophils, which induce higher rates of endothelial cell death in co-culture, independently of TLR2. Last but not least, IFC-ACS derived thrombi show higher expression of HYAL2 with subsequent higher local plasma concentration of hyaluronic acid as one of the main endogenous TLR2-ligands. Conclusion: By revealing novel local TLR2-dependant neutrophil activation patterns in IFC-ACS patients the current study provides new insights into the mechanism of plaque erosion. Moreover, the data suggest a crucial role of the hyaluronan metabolism in the endogenous activation of the TLR2 pathway in IFC-ACS. Further research is needed to assess the beneficial effects of a temporary TLR2-blockade in IFC-ACS and the possible application in secondary prevention.
