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Effects of pentoxifylline on cytokine profiles and left ventricular performance in patients with decompensated congestive heart failure secondary to idiopathic dilated cardiomyopathy☆

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Abstract

Patients with severe heart failure have plasma cytokine concentrations that are more than twofold greater than those in patients with moderate heart failure. Although pentoxifylline, an immunomodulatory agent that inhibits tumour necrosis factor-α (TNF-α) production, improves pump function in mild-to-moderate heart failure, its effects on advanced heart failure have not been determined. In a prospective, randomized, double-blind, placebo-controlled study we compared the effects of 1-month therapy with pentoxifylline (400 mg 3 times daily) (n = 9) and placebo (n = 9) on left ventricular systolic function and dimensions as well as on plasma TNF-α (picograms per milliliter), interleukin-10 (IL-10), and the apoptosis-signaling receptor Fas/Apo-1 in patients with idiopathic dilated cardiomyopathy and advanced heart failure. All patients had New York Heart Association functional class IV heart failure, required intravenous inotropic agents for >72 hours at the beginning of the study, and received diuretics, digoxin, and an angiotensin-converting enzyme inhibitor for the duration of the study. Marked increases in TNF-α and Fas/Apo-1 concentrations were noted in the 18 patients compared with patients with functional class II to III heart failure and controls (p <0.001). Baseline characteristics were the same between the pentoxifylline and placebo groups. Pentoxifylline administration resulted in reduced TNF-α and Fas/Apo-1 concentrations, and an increase in ejection fraction at 1 month (p <0.05 compared with baseline and with placebo), effects that were not observed in the placebo-treated group. These data suggest that pentoxifylline may be a useful adjunct to conventional therapy in patients with severe heart failure.

Section snippets

Study design and patient enrollment:

This study was approved by the Committee for Research on Human Subjects of the University of the Witwatersrand. Eighteen consecutive newly diagnosed, untreated black patients with idiopathic dilated cardiomyopathy were recruited for this single-center, prospective, double-blind, randomized, placebo-controlled study. All patients were ≥18 years of age, had class IV heart failure, a left ventricular ejection fraction ≤40% as determined by radionuclide ventriculography, a left ventricular

Baseline characteristics:

There were no differences in the baseline characteristics between study groups (Table 1). Moreover, the mean dose and duration of administration of quinapril, furosemide, digoxin, and dobutamine did not differ between the groups (data not shown).

Side effects:

Administration of pentoxifylline was well tolerated. No side effects were noted.

assessment of the degree of cytokine activation:

Compared with patients with class II to III heart failure and with normal subjects, plasma cytokine and Fas/Apo-1 concentrations were markedly elevated in the patients with

Discussion

This is the first study of the administration of a cytokine-modulating agent in patients with severe, decompensated heart failure. The main finding of the present study is that in association with alterations in the proinflammatory cytokine, TNF-α, and the apoptosis-signaling receptor, Fas/Apo-1, pentoxifylline administration resulted in an improved left ventricular pump function in patients with advanced heart failure.

In accordance with the findings of other studies, we found markedly

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☆

This study was supported by the H.E. Griffin Charitable Trust and the University of the Witwatesrand Research Council, Johannesburg, South Africa.

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