Administration of a tumor necrosis factor inhibitor at the time of myocardial infarction attenuates subsequent ventricular remodeling

Mark F. Berry, Y. Joseph Woo, Timothy J. Pirolli, Lawrence T. Bish, Mireille A. Moise, Jeffrey W. Burdick, Kevin J. Morine, Vasant Jayasankar, Timothy J. Gardner, H. Lee Sweeney

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31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1061-1068
Number of pages8
JournalJournal of Heart and Lung Transplantation
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2004

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ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Berry, M. F., Woo, Y. J., Pirolli, T. J., Bish, L. T., Moise, M. A., Burdick, J. W., Morine, K. J., Jayasankar, V., Gardner, T. J., & Sweeney, H. L. (2004). Administration of a tumor necrosis factor inhibitor at the time of myocardial infarction attenuates subsequent ventricular remodeling. Journal of Heart and Lung Transplantation, 23(9), 1061-1068. https://doi.org/10.1016/j.healun.2004.06.021