Toll-like receptor 2 signaling triggers fatal arrhythmias upon myocardial ischemia-reperfusion.
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.
Mersmann
Jan
J
Clinic of Anaesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany.
Koch
Alexander
A
Tran
Nguyen
N
Zimmermann
René
R
Granja
Tiago F
TF
Larmann
Jan
J
Herzog
Christine
C
Theilmeier
Gregor
G
Bornstein
Stefan R
SR
Kirschning
Carsten J
CJ
Zacharowski
Kai
K
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
D018031:Connexin 43; D051195:Toll-Like Receptor 2; D020107:Troponin T