Overexpression of tumor necrosis factor (TNF),α and TNFα receptor I in human viral myocariditis: Clinicopathologic correlations

Fiorella Calabrese, Elisa Carturan, Cristina Chimenti, Maurizio Pieroni, Carlo Agostini, Annalisa Angelini, Martino Crosato, Marialuisa Valente, Giovanni M. Boffa, Andrea Frustaci, Gaetano Thiene

Research output: Contribution to journalArticlepeer-review


Proinflammatory cytokines, including tumor necrosis factor (TNF)α, have been recognized as important physiopathogenetic factors in the inflammatory initiation and continuation of inflammatory cardiomyopathies. Experimental and preliminary human studies have demonstrated that TNFα plays a crucial role in enteroviral-induced myocarditis. In this study, we investigated the expression of TNFα and both its receptors (TNFRI and TNFRII) in both viral and nonviral myocarditis. Myocardial expression of TNFα was then correlated with different clinical and pathologic findings. TNFα expression was investigated in endomyocardial biopsies obtained from 38 patients with myocarditis and from eight control subjects by using reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry. Viral etiology was diagnosed by PCR in 20 cases: enterovirus in seven, Epstein-Barr virus in four, hepatitis C virus in three, adenovirus in two, influenza virus in two, cytomegalovirus in one, and double infection adenovirus and enterovirus in one. Immunohistochemistry was also used to analyze both TNFα receptors (RI and RII). A semiquantitative analysis was employed (score 0-3) for necrosis, inflammation, fibrosis and immunohistochemical findings. TNFα mRNA and TNFα protein were significantly more present in viral myocarditis than in nonviral myocarditis (16/20 vs 3/18, P = 0.001). Remarkable immunostaining was observed for both receptors, particularly TNFRI. Histological analysis revealed that myocardial necrosis (mean score 1.89 vs 1.15, P = 0.01) and cellular infiltration (mean score 2.26 vs 1.78, P = 0.05) were more prominent in TNFα-positive cases. Among TNFα-positive cases, the greater TNFα mRNAs, the more impaired was cardiac function. Our findings suggest that the expression of TNFα may play an important role in the pathogenesis of viral myocarditis of any etiology and may influence the severity of cardiac dysfunction. Cytokine effects are more strictly linked to overexpression of TNFRI.

Original languageEnglish
Pages (from-to)1108-1118
Number of pages11
JournalModern Pathology
Issue number9
Publication statusPublished - Sep 2004


  • TNFα
  • TNFα receptors
  • Viral myocarditis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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