title: Inhibition of tumor necrosis factor-alpha improves postischemic recovery of hypertrophied hearts.
abstract: BACKGROUND
  Tumor necrosis factor (TNF)-alpha has been implicated in the pathogenesis of heart failure and ischemia-reperfusion injury. Effects of TNF-alpha are initiated by membrane receptors coupled to sphingomyelinase signaling and include altered metabolism and calcium cycling, contractile dysfunction, and cell death. We postulate that pressure-overload hypertrophy results in increased myocardial TNF-alpha expression and that it contributes to decreased contractility in hypertrophied infant hearts subjected to ischemia-reperfusion.
  
  
  RESULTS
  Neonatal rabbits underwent aortic banding to induce LV hypertrophy. Myocardial TNF-alpha protein expression increased progressively with LV hypertrophy. Serum TNF-alpha was detected only after the onset of heart failure. Before onset of ventricular dilatation and heart failure (determined by serial echocardiograms), hearts from aortic banded and age-matched control rabbits were perfused in the Langendorff mode and subjected to 45 minutes of ischemia and 30 minutes of reperfusion. Postischemic recovery was impaired in hypertrophied hearts, but addition of neutralizing anti-rabbit TNF-alpha antibody to cardioplegia and perfusate solutions restored postischemic function. This effect was mimicked by treatment with the ceramidase inhibitor N-oleoyl ethanolamine. TNF-alpha inhibition also was associated with faster postischemic recovery of phosphocreatine, ATP, and pH as assessed by (31)P nuclear magnetic resonance spectroscopy. Intracellular calcium handling, measured by Rhod 2 spectrofluorometry, demonstrated lower diastolic calcium levels and higher systolic calcium transients in anti-TNF-alpha treated hearts.
  
  
  CONCLUSIONS
  TNF-alpha is expressed in myocardium during compensated pressure-overload hypertrophy and contributes to postischemic myocardial dysfunction. Inhibition of TNF-alpha signaling significantly improves postischemic contractile function, myocardial energetics, and intracellular calcium handling.
authors.affiliation: Children's Hospital Boston, Department of Anesthesia, Harvard Medical School, 300 Longwood Ave, Boston, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Stamm
authors.forename: I
authors.initials: I
authors.lastname: Friehs
authors.forename: D B
authors.initials: DB
authors.lastname: Cowan
authors.forename: A M
authors.initials: AM
authors.lastname: Moran
authors.forename: H
authors.initials: H
authors.lastname: Cao-Danh
authors.forename: L F
authors.initials: LF
authors.lastname: Duebener
authors.forename: P J
authors.initials: PJ
authors.lastname: del Nido
authors.forename: F X
authors.initials: FX
authors.lastname: McGowan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003971:Diastole; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D006321:Heart / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring; D006863:Hydrogen-Ion Concentration; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000503:physiopathology*; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010725:Phosphocreatine / Q000378:metabolism; D011817:Rabbits; D013599:Systole; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D006575:Heterocyclic Compounds, 3-Ring; D014409:Tumor Necrosis Factor-alpha; D010725:Phosphocreatine; C068483:rhod-2; D000255:Adenosine Triphosphate; D002118:Calcium