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(Circulation. 2005;112:691-698.)
© 2005 American Heart Association, Inc.

Heart Failure

Mechanisms of Cardiac Depression Caused by Lipoteichoic Acids From Staphylococcus aureus in Isolated Rat Hearts

Ulrich Grandel, MD; Michael Hopf, MD; Michael Buerke, MD; Katja Hattar, MD; Martina Heep; Ludger Fink, MD; Rainer M. Bohle, MD; Siegfried Morath, PhD; Thomas Hartung, MD, PhD; Soni Pullamsetti; Ralph T. Schermuly, PhD; Werner Seeger, MD; Friedrich Grimminger, MD, PhD; Ulf Sibelius, MD

From the Departments of Internal Medicine (U.G., M. Hopf, K.H., M. Heep, S.P., R.T.S., W.S., F.G., U.S.) and Pathology (L.F., R.M.B.), Justus Liebig University, Giessen; Department of Internal Medicine, Martin Luther University, Halle-Wittenberg (M.B.); and Department of Biochemical Pharmacology, University of Konstanz, Konstanz (S.M., T.H.), Germany.

Correspondence to Ulf Sibelius, MD, Department of Internal Medicine, Klinikstrasse 36, D-35392 Giessen, Germany. E-mail ulf.sibelius{at}innere.med.uni-giessen.de

Received September 13, 2004; revision received April 19, 2005; accepted April 22, 2005.

Background— Lipoteichoic acid (LTA) represents a major virulence factor in gram-positive sepsis.

Methods and Results— In the present study we perfused isolated rat hearts for 180 minutes with highly purified LTA from Staphylococcus aureus. A progressive decline of left ventricular contractile function paralleled by the expression of myocardial tumor necrosis factor- (TNF-) mRNA and protein as well as the release of TNF- into the perfusate was observed in LTA-perfused hearts. Employment of an anti–TNF- antibody completely prevented the loss in contractile function. When CD14, a prominent pathogen recognition receptor, was blocked by a specific antibody, induction of TNF- mRNA and protein release as well as the associated cardiodepression was diminished in response to LTA. Synthesis of TNF- protein was located to interstitial cells of LTA-challenged hearts as detected by immunohistochemistry. Besides progressive cardiodepression, coronary perfusion pressure (CPP) was moderately increased in LTA-perfused hearts. This was accompanied by the release of thromboxane A₂ (TXA₂) into the perfusate and the induction of cyclooxygenase (Cox)-2 mRNA and protein in the myocardium. Blocking of TXA₂ by the nonspecific Cox inhibitor indomethacin, the thromboxane receptor antagonist daltroban, or the selective Cox-2 inhibitor NS-398 prevented the increase in CPP.

Conclusions— LTA causes cardiac depression by activating myocardial TNF- synthesis via CD14 and induces coronary vascular disturbances by activating Cox-2–dependent TXA₂ synthesis. These phenomena may contribute to cardiac depression in gram-positive sepsis.

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