Cardiodepression by tumor necrosis factor-alpha.
Cardiodepressant effects of tumor necrosis factor-alpha (TNF-alpha have been documented in numerous experimental settings in vivo and in vitro. In vivo administration of TNF-alpha mimicks the cardiovascular pattern of sepsis including septic cardiomyopathy. Serum levels of TNF-alpha were found to be elevated both in sepsis and in numerous non-septic heart disorders. Although an involvement of TNF-alpha in the pathogenesis of septic cardiomyopathy seems likely, presently no definite conclusion can be drawn with regard to the role of TNF-alpha in chronic heart failure. The origin and trigger mechanisms for the release of TNF-alpha in heart failure are a matter of debate, endotoxin (LPS) from intestinal translocation in venous congestion being one possible player. The negative inotropic impact of TNF-alpha is frequently ascribed to the induction of inducible nitric oxide (NO) synthase (iNOS). Results from in vitro studies rather suggest a complex interaction of TNF-alpha with the heart, with pleiotropic effects on cardiomyocyte performance, including an induction of iNOS at higher TNF-alpha concentrations, but NO-independent cardiodepression at low, pathophysiologically more relevant concentrations. TNF-alpha effects on the heart also vary with regard to the kinetics of the process: rapidly occuring cardiodepressant effects include a release of sphingosine and a suppression of the calcium transient, while chronic administration of TNF-alpha was shown to depress the synthesis of precursors for the phosphoinositide pathway and inhibit pyruvate dehydrogenase activity and mitochondrial function. Whether secondary cytokines induced by TNF-alpha in cardiomyocytes contribute to cardiodepression or whether apoptotic signals activated by TNF-alpha are involved in the cardiodepressive pathways is presently unknown.
Müller-Werdan
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Department of Medicine III, Martin-Luther University Halle-Wittenberg, Ernst-Grube-Strasse 40, D-06097 Halle, Germany. Tel: (+49) 345 557 4545, Fax: (+49) 345 557 4546, e-mail: ursula.mueller-werdan@medizin.un
Engelmann
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Werdan
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D000818:Animals; D003864:Depression, Chemical; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006331:Heart Diseases / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha