Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile depression following ischemia and reperfusion

J Mol Cell Cardiol. 1999 May;31(5):931-47. doi: 10.1006/jmcc.1999.0924.


Recent evidence has implicated proinflammatory mediators such as TNF- alpha in the pathophysiology of ischemia-reperfusion (I/R) injury. Clinically, serum levels of TNF-alpha are increased after myocardial infarction and after cardiopulmonary bypass. Each of these represent clinically relevant instances of cardiac I/R injury. We and others have recently reported that TNF-alpha is produced by the heart following experimental I/R in animals and that TNF-alpha directly decreases animal and human myocardial contractility in a dose dependent fashion. Thus, strategies to reduce or neutralize myocardial TNF- alpha production should conceptually decrease myocardial contractile dysfunction following I/R. The purposes of this manuscript are: 1) to explore the clinical and experimental instances of I/R injury in which TNF-alpha is elevated, 2) to review the molecular mechanisms of TNF- alpha induced contractile dysfunction, 3) to examine both experimental and clinical strategies of reducing myocardial TNF-alpha production, and 4) to determine the influence of reducing post-I/R TNF-alpha on cardiac contractile function in both animals and man.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Humans
  • Myocardial Contraction / physiology*
  • Myocardial Reperfusion Injury / physiopathology*
  • NF-kappa B / antagonists & inhibitors
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Sphingosine / biosynthesis
  • Tumor Necrosis Factor-alpha / physiology*


  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Sphingosine