Expression of proinflammatory cytokines in the failing human heart: Comparison of recent-onset and end-stage congestive heart failure

Background: Plasma levels of proinflammatory cytokines, including tumor nec rosis factor (TNF)-alpha and interleukin (IL)-6, are elevated in patients w ith congestive heart failure (CHF). Recent studies suggest that the failing human heart is a source of proinflammatory cytokines in the end-stage fail ing heart. However, the relevance of plasma levels to those of the myocardi um remains undefined. We sought to compare cytokine expression in early and end-stage CHF, and to evaluate the correlation of tissue expression to pla sma levels. Methods: Two patient populations were studied: patients with recent-onset C HF, all with symptoms less than 6 months (n = 17, duration of symptoms 2.1 +/- 1.6 months, range of New York Heart Association (NYHA) 1 to 3), and end -stage heart-failure patients (n = 7) who underwent left-ventricular assist -device (LVAD) implantation (Duration of symptoms 47.1 +/- 28.0 months, all NYHA class 4). Plasma levels of TNF-alpha and IL-6 proteins were evaluated by an Enzyme-Linked Immuno-Sorbent Assay (ELISA), while myocardial levels of cytokine transcripts were assessed by ribonuclease (Rnase) protection as say. Results: In patients with end-stage heart failure, TNF-alpha and IL-6 were increased in the plasma-as well as in the myocardium (plasma: TNF- alpha = 7.7 +/- 2.3 pg/ml, IL-6 = 45.0 +/- 47.1 pg/ml; myocardium: TNF-alpha = 0.31 +/- 0.15% of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, IL-6 = 1.56 +/- 1.54%). In contrast, despite elevated plasma levels of TNF- alpha and IL-6, the myocardium of patients with the recent onset of symptom s demonstrated minimal expression of TNF-alpha and IL-6 messenger ribonucle ic acid (mRNA) (plasma: TNF-alpha = 4.3 +/- 1.7 pg/ml, IL-6 = 3.3 +/- 1.8 p g/ml; myocardium: TNF-alpha = 0.13 +/- 0.04%, IL-6 = 0.02 +/- 0.04%). Plasm a levels of TNF-alpha were significantly correlated with those in the myoca rdium when both populations were combined. (r = 0.69, p < 0.001) Conclusions: Cytokines are expressed in the myocardium in end-stage heart f ailure to a much greater degree than in patients with the recent-onset of s ymptoms. This suggests that induction of cytokines in the myocardium is a r elatively late event in the pathogenesis of CHF. Furthermore, plasma levels of TNF-alpha correlates with mRNA expression in the myocardium and thus ma y serve as an appropriate marker of myocardial cytokine activation. Whether the production of cytokines in the failing human heart precedes the elevation of cytokines in the plasma remains undefined. Therefore, we stud ied expression of TNF-alpha and IL-6 in the myocardium as well as in the pl asma in patients with early and end-stage CHF. The results have demonstrate d that cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent onset of symptom s. This suggests that induction of cytokines in the myocardium is a relativ ely late event in the pathogenesis of CHF.