title: Inducible cardiac ischaemia is related to a decrease in the whole-blood Toll-like receptor 2 and 4 response.
abstract: TLR (Toll-like receptor) activation-induced inflammatory responses are important in the progression of atherosclerosis. We previously showed that TLR-dependent leucocyte responsiveness is acutely attenuated following percutaneous coronary intervention or vascular surgery. Furthermore, cytokine release following whole-blood TLR-2 and TLR-4 stimulation is negatively correlated with fractional flow reserve, suggesting that chronic ischaemia can elicit an enhanced inflammatory response. In the present study, we assessed the association between leucocyte TLR-2 and TLR-4 responsiveness and pre-existent and inducible ischaemia in patients undergoing SPECT (single-photon emission computed tomography)-MPI (myocardial perfusion imaging). TLR-2, TLR-4 and CD11b expression on monocytes were measured in blood samples that were obtained from 100 patients with suspected coronary artery disease before and after myocardial stress testing for SPECT-MPI. IL-8 (interleukin-8) levels were determined after whole-blood stimulation with Pam3Cys (TLR-2) and LPS (lipopolysaccharide; TLR-4). On the basis of SPECT-MPI, patients were categorized into three groups: reversible defect, irreversible defect and no defect. Myocardial stress induced a reduction in TLR-4 expression (2.46±0.21 compared with 2.17±0.16 arbitrary units, P=0.001) and CD11b expression (83.2±1.73 compared with 76.0±1.89 arbitrary units, P<0.001). TLR-induced IL-8 production before myocardial stress induction was not associated with the results of SPECT-MPI. However, a significant decrease in IL-8 production following TLR stimulation was observed after stress, which was more pronounced in patients with a reversible defect. In conclusion, inducible ischaemia is associated with a decrease in whole-blood TLR-2 and TLR-4 response. These results point to a regulating role of TLRs in order to prevent excessive inflammatory events known to occur during acute ischaemia.
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Ellen H A M
authors.initials: EH
authors.lastname: Elsenberg
authors.forename: Dik
authors.initials: D
authors.lastname: Versteeg
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Sels
authors.forename: Pieter-Jan J
authors.initials: PJ
authors.lastname: Vlaar
authors.forename: Monique G G
authors.initials: MG
authors.lastname: Hobbelink
authors.forename: Maarten-Jan M
authors.initials: MJ
authors.lastname: Cramer
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
authors.forename: René A
authors.initials: RA
authors.lastname: Tio
authors.forename: Bart J G L
authors.initials: BJ
authors.lastname: de Smet
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
mesh_terms: D000328:Adult; D025401:Echocardiography, Stress; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood* / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000097:blood* / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000097:blood* / Q000502:physiology; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D016209:Interleukin-8; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4