inflammatory activation with increased serum cytokine levels has been described by several authors as an important factor in the progression of the syndrome of chronic heart failure ( chf ) [ 13 ] . in multifactorial analyses , elevated levels of tumour necrosis factor-(tnf- ) alpha and interleukin-(il- ) 6 have been identified as prognostic heart failure markers [ 46 ] . cytokines act as catabolic factors involved in the pathogenesis of muscle wasting and cardiac cachexia [ 3 , 7 ] , and increased levels of serum tnf - alpha have been identified in patients with reduced skeletal muscle cross - sectional area and peripheral muscle strength . there also exists a statistical significant association between elevated serum cytokine levels ( especially tnf - alpha ) and new york heart association ( nyha ) functional class as well as exercise intolerance . inflammatory cytokines may alter skeletal muscle histology and have a negative impact on left ventricular remodelling and cardiac contractility [ 2 , 3 , 8 ] . the inflammatory response is also associated with progression of atherosclerosis , oxidative stress , no impairment , vasoconstriction , endothelial cell apoptosis , and adverse vascular remodelling . exercise training has been documented to improve the inflammatory profile in chf by inhibition of cytokine - chemokine production , regulation of monocyte activation and adhesion , inhibition of inflammatory cell - growth signals and growth factor production , reduction of soluble apoptosis signalling molecules , and attenuation of monocyte - endothelial cell adhesive interaction . a study of 277 patients with coronary artery disease reported a significant 41% reduction in high - sensitivity c - reactive protein following exercise training . a recent study of four - month duration , utilizing combined endurance / resistance training demonstrated reduced tnf - alpha receptor levels ( tnfr1 and tnfr2 ) and a significant ( 7.5% ) increase in peak vo2  in patients with ischemic cardiomyopathy , although changes in il-6 and tnf - alpha were not apparent . this effect on circulating levels of tnf - alpha receptors , there were no alterations in il-6 , c - reactive protein ( crp ) , or tnf - alpha . in addition , electrical muscle stimulation provided no changes in any of the aforementioned cytokines . larsen et al .   reported an 11% increase in peak vo2 following 3 months of endurance training ; tnf - alpha was significantly reduced , and this decrease was significantly correlated to the increase in peak vo2 . adamopoulos   reported a 13% increase in functional capacity with a 12-week cycle ergometry training program , which correlated with lower levels of soluble adhesion molecules . the authors later reported a strong and highly significant correlation between improvements in peak vo2 ( 15% ) and reduction in tnf - alpha , soluble tnfr-1 and -2 , and il-6 . plasma tnf - alpha   is also documented to decrease after twice daily 6-minute walk tests in nyha ii / iii heart failure patients . a recently published study reported absent von willebrand factor ( vwf ) release upon exercise testing in heart failure patients ; this normalised following 6 months of exercise training ; other plasma endothelial markers were unaltered . changes in skeletal muscle , but not systemic expression of tnf - alpha , il-1-beta , and il-6 have been reported in heart failure patients undertaking a regimen of 10 minutes cycling , 46 times daily for 6 months . this exercise program resulted in large changes in functional capacity ( 29% ) , nearly twice the mean expected increment ( 17% ) shown from our review of 81 heart failure exercise training studies . this study suggested the existence of a cytokine cascade where levels may be changed at altered rates in different tissues . as heart failure exercise training studies are often small , we sought by pooling data from four studies to establish whether exercise training programs were able to modulate systemic cytokine levels . a second aim was to establish if differences in ext regimens are related to the degree of change in cytokines and peak vo2 . we searched pubmed and medline for exercise training studies in heart failure patients that had measured one or more of the proinflammatory cytokines . the focus of this work was interleukin-6 and tnf - alpha as these cytokines were measured in 10 exercise training studies , the correspondence authors of which were contacted for their cooperation in collaboration . authors were requested to provide individual patient data from their study ; four centres provided data ( table 2 ) . sufficient data were not available to analyse changes in other cytokines . in 3 studies , plasma or serum samples were obtained by venipuncture ( arterial cannula used in larsen 's study ) and stored on ice . in all studies , venipuncture collections were taken between 0900 , and 1200 , at least 24 hours and not more than 5 days after the last exercise session , thus negating the effects of the intervention . within one hour , samples were centrifuged at 4c , 15002000  rpm for 10 minutes , and then separated into aliquots and stored at between 75c and 80c . concentrations of il-6 or tnf - alpha were measured by commercially available enzyme - linked immunosorbent assays ( elisas ) ( r&d systems minneapolis , minnesota ) in all 4 studies . the intra- and interassay coefficients of variation were < 10% for all assays . in one study , 16 healthy , male volunteers of approximately the same age ( 62    5 years ) served as controls   although this data was not included in our analyses . all four collaborating investigators completed baseline and posttraining metabolic exercise tests to establish functional capacity . larsen  and smart used cycle ergometers with a 15  w and 10  w per min stepped protocol , respectively ; lemaitre and ferraz used a modified bruce treadmill protocol . two studies used supervised cycle ergometry as the primary mode of exercise training [ 21 , 22 ] , and one study used both home - based and neuromuscular stimulation of the legs . baseline and posttraining cytokine levels , peak vo2 , left ventricular ejection fraction ( lvef ) , clinical , demographic , and pharmacological characteristics of patients are shown in table 2 . paired student t - tests were used to analyse baseline and postintervention changes in cytokines and peak vo2 . anova ( 2  4 ) was used to analyse differences between the four datasets . univariate and multivariate regression analysis with change in tnf - alpha as the dependent variable were used to determine factors leading to cytokine change . the four collaborating authors provided data on 106 patients ( 98 male , age 62    10  yrs , body weight 79    14  kg ) . mls / kg / min ) , with moderate lv systolic dysfunction ( ef 30 seventy eight % ( 83 ) had an ischaemic cardiomyopathy ( table 2 ) . adherence data relating to training regimes were 87.2    1.9%   and 85    12%   and were unavailable for the other 2 studies . regimes varied between 3 and 5 exercise sessions per week , at an intensity of 5880% of peak vo2 . program durations were between 6 and 24 weeks , 90150 minutes per week , and total program hours varied between 15 and 54 hours ( table 3 ) . after training , peak vo2 increased by 1.4    3.4  ml / kg / min or 9% ( p < .001 ) from 16.9    4.4 to 18.4    4.5 , serum tnf - alpha decreased from a baseline value of 13    15.2  pg / ml by 1.9    8.6  pg / ml ( p = .02 ) , and il-6 increased slightly from a baseline value of 7.8    11.4  pg / ml by 0.5    5.4  pg / ml ( p = .32 ) . none of the clinical , demographic , or pharmacologic variables were correlated with changes in circulating il-6 or tnf - alpha following training . the correlations between change in posttraining peak vo2 and changes in tnf - alpha ( r = 0.023 , p = .82 ) and il-6 ( r = 0.12 , p = .21 ) were not significant . change in tnf - alpha was correlated with exercise session duration and anerobic threshold ( both r = 0.21 , p = .31 ) , univariate but not multivariate analysis identified that previous myocardial infarction , longer exercise session duration , and higher body mass index predicted change in tnf - alpha ( r = 0.18 , p = .001 ) . a total exercise program duration of 54 hours appeared to be superior than 15 or 18 hours in effecting change in peak vo2 ( p < .001 ) ; however , no difference was seen for change in cytokine levels . the longest program duration resulted in a greater increment in peak vo2 compared to 12 weeks ( p = .003 ) and 6 weeks ( p = .001 ) , while peak vo2 or 6-minute walk distance was unchanged in the ext programs of 6 and 12 weeks duration . pooled data from four studies demonstrated that alterations in levels of the cytokines il-6 and tnf - alpha are not necessarily uniform . increments in peak vo2 following exercise training are widely accepted ; however , they may be unrelated to changes in cytokine levels . . one can not be sure about the variable effects of the different program parameters and exercise adherence rates ; nevertheless , the mean change in functional capacity from the four studies was 8% , suggesting that cumulatively the four exercise programs provided stimulus for a possible favourable change in cytokine expression . interpretation of this pooled data is limited by the fact that several other centres did not supply data . table 2 suggests that study participants showed heterogeneity for age , peak , vo2 and beta - blocker use . moderate endurance activity in frail , elderly , but otherwise healthy persons has previously been reported to influence circulating cytokine levels . as our patients had mild to moderate heart failure , it is not surprising to observe that levels of systemic tnf - alpha were decreased after training , thereby initiating anti - inflammatory effects . however , one study has suggested that il-6 produced by exercising muscle is thought to exert an anti - inflammatory effect . these data suggest that production and removal of tnf - alpha and il-6 may be , at least partially , from independent mechanisms and may have opposing effects ( inflammatory versus anti - inflammatory ) . recent clinical trials have not shown benefit from treatments that target tnf - alpha . a clinical trial of etanercept ( a tnf - alpha antagonist ) therapy has cast doubt on the role of cytokines in the pathogenesis of heart failure . there are then implications for health professionals or researchers in the process of designing an exercise program for heart failure patients . primary end points of chf exercise programs should perhaps not include lowering cytokine levels as they may represent surrogate markers of efficacy ; this may be particularly true in patients with milder degrees of chf . in this population , program design may be better focussed on the parameters such as program frequency ( sessions / week ) , duration ( number of weeks ) , and intensity that may have a greater effect on peak vo2 changes . peak vo2 improvement from exercise training may be linked to attenuated levels of oxidative stress which in turn may attenuate cytokine expression . previous work in healthy older adults   and heart failure patients   has shown intermittent exercise programs to be at least more effective in improving peak vo2 than a continuous regime that would produce greater cumulative oxidative stress . in our work , peak vo2 was not significantly changed in patients who exercised despite utilizing a reasonable volume of exercise to elicit functional capacity changes .   in heart failure , the effect of inflammation , which may be due partly to inactivity , may manifest in the terminal disease phase . the study by adamopoulos et al .   may provide the best evidence to date linking change in peak vo2 and cytokines in heart failure patients . the small cytokine change shown in our studies may be due to the fact that our patients exhibited mild to moderate heart failure symptoms . the participants in the study of adamopoulos et al .   exhibited moderate to severe symptoms . in addition , our participants had higher left ventricular ejection fractions ( 30% versus 24% ) than those of adamopoulos et al . . exercise training has been shown to significantly reduce the local muscle expression of tnf - alpha , il-1-beta , il-6 , and inos in the skeletal muscle of chf patients . in turn , physical exercise has been shown to improve both basal endothelial nitric oxide ( no ) formation and agonist - mediated endothelium - dependent vasodilation of the skeletal muscle vasculature in patients with chf . these local anti - inflammatory and systemic effects of exercise may attenuate the catabolic wasting process associated with chf progression . in addition to an overall beneficial effect on exercise capacity , combined endurance / resistance exercise training has an anti - inflammatory effect in patients with heart disease . these skeletal muscle and anti - inflammatory changes may explain why alterations in tnf - alpha levels are most likely to be observed in patients with moderate or severe heart failure . however , across a heterogenic patient group , change in peak vo2 was not correlated with alterations in cytokine levels . while greater exercise volume ( number of hours ) was superior in improving peak vo2 , no particular characteristic of ext regimes appeared superior in effecting change in serum cytokines .