title: Toll-like receptor 2 signaling triggers fatal arrhythmias upon myocardial ischemia-reperfusion.
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.
  
  
  METHODS
  Experimental animal model.
  
  
  METHODS
  University hospital research laboratory.
  
  
  METHODS
  Male C3HeN mice.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Clinic of Anaesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mersmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Nguyen
authors.initials: N
authors.lastname: Tran
authors.forename: René
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Granja
authors.forename: Jan
authors.initials: J
authors.lastname: Larmann
authors.forename: Christine
authors.initials: C
authors.lastname: Herzog
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000401:mortality / Q000503:physiopathology*; D018031:Connexin 43 / Q000032:analysis / Q000502:physiology; D004195:Disease Models, Animal; D004562:Electrocardiography; D017629:Gap Junctions / Q000737:chemistry / Q000502:physiology; D006339:Heart Rate / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion / Q000401:mortality; D009206:Myocardium / Q000737:chemistry; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D020107:Troponin T / Q000097:blood
chemical_list: D018031:Connexin 43; D051195:Toll-Like Receptor 2; D020107:Troponin T