Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-α

Debora Bryant, Lisa Becker, James A Richardson, John Shelton, Fatima Franco, Ronald M Peshock, Marita Thompson, Brett Giroir

Research output: Contribution to journalArticlepeer-review

517 Scopus citations

Abstract

Background - Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine that has been detected in several human cardiac-related conditions, including congestive heart failure and septic cardiomyopathy. In these conditions, the origin of TNF-α secretion is, at least in part, cardiac myocytes. Methods and Results - To determine the consequences of TNF-α production by cardiac myocytes in vivo, we developed transgenic mice in which expression of a murine TNF-α coding sequence was driven by the murine α- myosin heavy chain promoter. Four transgenic founders developed an identical illness consisting of tachypnea, decreased activity, and hunched posture. In vivo, ECG-gated MRI of symptomatic transgenic mice documented a severe impairment of cardiac function evidenced by biventricular dilatation and depressed ejection fractions. All transgenic mice died prematurely. Pathological examination of affected animals revealed a globular dilated heart, bilateral pleural effusions, myocyte apoptosis, and transmural myocarditis in both the right and left ventricular free walls, septum, and atrial chambers. In all terminally ill animals, there was significant biventricular fibrosis and atrial thrombosis. Conclusions - This is the first report detailing the effects of tissue-specific production of TNF-α by cardiac myocytes in vivo. These findings indicate that production of TNF-α by cardiac myocytes is sufficient to cause severe cardiac disease and support a causal role for this cytokine in the pathogenesis of human cardiac disease.

Original languageEnglish (US)
Pages (from-to)1375-1381
Number of pages7
JournalCirculation
Volume97
Issue number14
DOIs
StatePublished - Apr 14 1998

Keywords

  • Apoptosis
  • Cardiomyopathy
  • Heart failure
  • Magnetic resonance imaging
  • Myocarditis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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