Tumor necrosis factor (TNF) causes myocardial extracellular matrix remodeling and fibrosis in myocardial infarction and chronic heart failure models. Pre-clinical and clinical trials of TNF inhibition in chronic heart failure have shown conflicting results. This study examined the effects of the administration of a TNF inhibitor immediately after myocardial infarction on the development of heart failure. Lewis rats underwent coronary artery ligation and then received either intravenous etanercept (n = 14), a soluble dimerized TNF receptor that inhibits TNF, or saline as control (n = 13). Leukocyte infiltration into the infarct borderzone was evaluated 4 days post-ligation in 7 animals (etanercept = 4, control = 3). After 6 weeks, the following parameters were evaluated in the remaining animals: cardiac function with a pressure-volume conductance catheter, left ventricular (LV) geometry, and borderzone collagenase activity. Etanercept rats had significantly less borderzone leukocyte infiltration 4 days post-infarction than controls (10.7 ± 0.5 vs 18.0, ±2.0 cells/high power field; p < 0.05). At 6 weeks, TNF inhibition resulted in significantly reduced borderzone collagenase activity (110 ± 30 vs 470 ± 140 activity units; p < 0.05) and increased LV wall thickness (2.1 ± 0.1 vs 1.8 ± 0.1 mm, p < 0.05). Etanercept rats had better systolic function as measured by maximum LV pressure (84 ± 3 mm Hg vs 68 ± 5 mm Hg, p < 0.05) and the maximum change in left ventricular pressure over time (maximum dP/dt) (3,110 ± 230 vs 2,260 ± 190 mm Hg/sec, p < 0.05), and better diastolic function as measured by minimum dP/dt (-3,060 ± 240 vs -1,860 ± 230 mm Hg/sec; p < 0.05) and the relaxation time constant (14.6 ± 0.6 vs 17.9 ± 1.2 msec; p < 0.05). TNF inhibition after infarction reduced leukocyte infiltration and extracellular matrix turnover and preserved cardiac function.
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Cardiology and Cardiovascular Medicine