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CLINICAL STUDY: HEART FAILURE

Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fasligand system in patients with chronic heart failure

Stamatis Adamopoulos, MD^*,*, John Parissis, MD^*, Dimitrios Karatzas, MD^*, Christos Kroupis, MS^*, Michael Georgiadis, MD^*, George Karavolias, MD^*, John Paraskevaidis, MD^*, Katerina Koniavitou, MD^*, Andrew J. S. Coats, MD and Dimitrios Th Kremastinos, MD^*

^* Second Department of Cardiovascular Medicine, Onassis Cardiac Surgery Center, Athens, Greece
Royal Brompton National Heart and Lung Institute, London, United Kingdom

Manuscript received December 28, 2000; revised manuscript received October 31, 2001, accepted November 28, 2001.

^* Reprint requests and correspondence: Dr. Stamatis Adamopoulos, Zinonos 9, Halandri, 15234 Athens, Greece.
sadamo{at}bigfoot.com

OBJECTIVES: We sought to investigate the effects of physical training on circulating proinflammatory cytokines and the soluble apoptosis mediators Fas (sFas) and Fas ligand (sFasL) in patients with chronic heart failure (CHF).

BACKGROUND: Recent investigations have shown an overexpression of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with CHF, which may be related to their exercise intolerance and clinical deterioration.

METHODS: Plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors I and II (sTNF-RI and sTNF-RII, respectively), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sFas and sFasL were measured in 24 patients with stable CHF (New York Heart Association functional class II/III; left ventricular ejection fraction 23.2 ± 1.3%) and in 20 normal control subjects before and after a 12-week program of physical training in a randomized, crossover design. Functional status of patients with CHF was evaluated by using a cardiorespiratory exercise test to measure peak oxygen consumption (VO₂max).

RESULTS: Physical training produced a significant reduction in plasma levels of TNF-alpha (7.5 ± 1.0 pg/ml vs. 4.6 ± 0.7 pg/ml, p < 0.001), sTNF-RI (3.3 ± 0.2 ng/ml vs. 2.7 ± 0.2 ng/ml, p < 0.005), sTNF-RII (2.6 ± 0.2 ng/ml vs. 2.3 ± 0.2 ng/ml, p = 0.06), IL-6 (8.3 ± 1.2 pg/ml vs. 5.9 ± 0.8 pg/ml, p < 0.005), sIL-6R (34.0 ± 3.0 ng/ml vs. 29.2 ± 3.0 ng/ml, p < 0.01), sFas (5.5 ± 0.7 ng/ml vs. 4.5 ± 0.8 ng/ml, p = 0.05) and sFasL (34.9 ± 5.0 pg/ml vs. 25.2 ± 4.0 pg/ml, p < 0.05), as well as a significant increase in VO₂max (16.3 ± 0.7 ml/kg per min vs. 18.7 ± 0.8 ml/kg per min, p < 0.001). Good correlations were found between a training-induced increase in VO₂max and a training-induced reduction in levels of the proinflammatory cytokine TNF-alpha (r = –0.54, p < 0.01) and the apoptosis inducer sFasL (r = –0.57, p < 0.005) in patients with CHF. In contrast, no significant difference in circulating cytokines and apoptotic markers was found with physical training in normal subjects.

CONCLUSIONS: Physical training reduces plasma levels of proinflammatory cytokines and the sFas/sFasL system in patients with CHF. These immunomodulatory effects may be related to the training-induced improvement in functional status of patients with CHF.

Abbreviations and Acronyms   sTNF-RI   ANOVA   analysis of variance   CHF   chronic heart failure   ELISA   enzyme-linked immunosorbent assay   IL-6   interleukin-6   iNOS   (inducible) nitric oxide synthase   NO   nitric oxide   sFas   soluble Fas   sFasL   soluble Fas ligand   sIL-6R   soluble intrerleukin-6 receptor   sTNF-RI   soluble tumor necrosis factor receptor type I   sTNF-RII   soluble tumor necrosis factor receptor type II   TNF   tumor necrosis factor   VO2max   peak oxygen consumption

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