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Toll-like receptor 2 signaling triggers fatal arrhythmias upon myocardial ischemiareperfusion*

Mersmann, Jan MD; Koch, Alexander MD; Tran, Nguyen PhD; Zimmermann, René PhD; Granja, Tiago F. BSc; Larmann, Jan MD; Herzog, Christine PhD; Theilmeier, Gregor MD; Bornstein, Stefan R. MD; Kirschning, Carsten J. PhD; Zacharowski, Kai MD, PhD, FRCA

Critical Care Medicine:
doi: 10.1097/CCM.0b013e3181ef455b
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Abstract

Objective: Restoration of myocardial blood flow after ischemia triggers an inflammatory response involving toll-like receptors. Toll-like receptor 2 deficiency is associated with a reduced infarct size after myocardial ischemia and reperfusion. Because a marked mortality was observed in C3HeN wild-type mice, which was absent in TLR2−/− mice, we tested whether cardiac arrhythmias are the underlying pathology and aimed to elucidate how toll-like receptor 2 ligation might prevent lethal arrhythmias.

Design: Experimental animal model.

Setting: University hospital research laboratory.

Subjects: Male C3HeN mice.

Interventions: Myocardial ischemia and reperfusion was surgically induced by ligation of the left anterior descending coronary artery for 20 mins followed by 24 hrs of reperfusion. Electrocardiography was continuously recorded during the observation period through an implantable telemetry transmitter to detect cardiac arrhythmias during reperfusion.

Measurements and Main Results: Toll-like receptor 2 expression was associated with a 51% mortality rate (23 of 45 mice died) after myocardial ischemia and reperfusion. Absence of toll-like receptor 2 improved survival toward 100% (17 of 17 mice survived). Electrocardiography diagnostics in conscious animals and histologic analysis revealed that absence of toll-like receptor 2 signaling prevented the formation of pathologic heart rate turbulence after myocardial ischemia and reperfusion and modulated the density of connexin 43-positive gap junctions in the ischemic area compared with wild-type hearts, indicating arrhythmia as the cause underlying the observed mortality.

Conclusions: The results presented here indicate toll-like receptor 2 as a novel target for the prevention of lethal arrhythmic complications after myocardial ischemia and reperfusion.

Author Information

From the Clinic of Anaesthesiology (JM, AK, NT, RZ, TFG, KZ), Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany; the Department of Anaesthesia (JM), Heinrich Heine University, Düsseldorf Germany; the Department for Anesthesiology (JL, CH, GT), Medizinische Hochschule Hannover, Hannover, Germany; the Department of Medicine III (SRB), University of Dresden, Dresden, Germany; and the Institute of Medical Microbiology (CJK), University of Duisburg-Essen, Essen, Germany.

This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 815/A17) to KZ and (TH667/6-1) to GT.

Dr. Zacharowski received a grant from Delphi Financial Group.

All other authors have no potential conflicts of interest to disclose.

Drs. Mersmann and Koch contributed equally to this work.

For information regarding this article, E-mail: zacharowski@med.uni-frankfurt.de

© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins