Is Tumor Necrosis Factor-α Friend or Foe for Chronic Heart Failure?
Dilated Cardiomyopathy in Transgenic Mice With
Cardiac-Specific Overexpression of Tumor Necrosis Factor-α
Kubota et al
Circ Res. 1997;81:627–635.
Although detrimental effects of tumor necrosis factor-α (TNF-α) have been reported in failing myocardium, clinical trials using TNF-α antagonists did not show the benefit of TNF-α inhibition in patients with chronic heart failure (CHF). The double-edged effects of TNF-α/Toll-like receptors (TLRs)–related proinflammatory cytokines and downstream signal transduction, nuclear factor (NF)-κB activation on failing myocardium are discussed.
It is well known that neurohormonal activation in heart failure plays a key role in deterioration of myocardial failure, accelerating the vicious cycle in pathophysiology of heart failure. Proinflammatory cytokines are also increased in patients with heart failure. Since the first report by Levine et al1 that serum TNF-α is increased in patients with severe heart failure, other cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and their soluble receptors, have been reported to increase in heart failure.2 Several reports indicated that plasma levels of these proinflammatory cytokines are correlated with severity of heart failure, New York Heart Association functional class.3 The question was whether these proinflammatory cytokines deteriorate the failing myocardium as a cause of detrimental mechanism or merely secondary phenomenon in heart failure.
To answer this question, Kubota et al4 established a murine transgenic line of TNF-α in which expression was driven by the murine α-myosin heavy chain promoter. The transgenic heart with chronic overexpression of TNF-α showed (1) ventricular hypertrophy, (2) ventricular dilatation, (3) interstitial infiltrates, (4) interstitial fibrosis, (5) rare myocyte apoptosis, (6) a diminished ejection fraction, (7) attenuation of β1-adrenergic responsiveness, and (8) expression of atrial natriuretic factor in the ventricle. Moreover, mice overexpressing the TNF-α transgene had a marked increase in mortality, suggesting that they died of congestive heart failure because most of the mice presented an increase in lung weight and pleural effusion. In their earlier study, they demonstrated that robust overexpression of TNF-α …