Inhibition of Tumor Necrosis Factor-α Improves Postischemic Recovery of Hypertrophied Hearts

Background Tumor necrosis factor (TNF)-α has been implicated in the pathogenesis of heart failure and ischemia-reperfusion injury. Effects of TNF-α 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-α expression and that it contributes to decreased contractility in hypertrophied infant hearts subjected to ischemia-reperfusion. Methods and Results Neonatal rabbits underwent aortic banding to induce LV hypertrophy. Myocardial TNF-α protein expression increased progressively with LV hypertrophy. Serum TNF-α 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-α antibody to cardioplegia and perfusate solutions restored postischemic function. This effect was mimicked by treatment with the ceramidase inhibitor N -oleoyl ethanolamine. TNF-α 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-α treated hearts. Conclusions TNF-α is expressed in myocardium during compensated pressure-overload hypertrophy and contributes to postischemic myocardial dysfunction. Inhibition of TNF-α signaling significantly improves postischemic contractile function, myocardial energetics, and intracellular calcium handling.