In this meta-analysis, we summarized evidence from 7 published intervention trials that investigated the effects of fish oil supplementation on circulating markers of inflammation in patients with CHF. The results showed that fish oil reduced the circulating levels of TNF-α, IL-1 and IL-6 in patients with CHF, although the levels of hsCRP, sICAM-1 and sVCAM-1 were not significantly affected. Results of meta-regression and subgroup analysis suggested that supplementation with higher dose of fish or for a longer follow-up duration might associate with more remarkable reduction of TNF-α and IL-6 levels. These results suggested that anti-inflammation may be a mechanism underlying the potential benefits of fish oil for patients with CHF.
Results of a few epidemiologic studies demonstrated that fish consumption or fish oil intake was inversely associated with incidence of CHF in general population
[30–32]. Furthermore, recently published GISSI-HF trial
 showed that in patients with CHF on evidence-based therapy, long term treatment with fish oil reduced combined endpoint of mortality or hospitalizations for cardiovascular reasons. Besides, our recently published meta-analysis also indicated that fish oil supplementation can favorably affect the cardiac function and functional capacity in CHF patients
. However, the exact mechanisms of these beneficial effects of fish oil to patients with CHF are not fully understood
Accumulating evidence from animal experiments and clinical investigations have revealed that CHF may at least partially be an inflammatory disease, where various cytokines and adhesion molecules are involved in CHF pathogenesis and progression via contribution to endothelial dysfunction, cardiomyocyte apoptosis, cardiac remodeling and left ventricular dysfunction
[10, 34–36]. These inflammatory markers, including hsCRP, TNF-α, IL-1, IL-6, ICAM-1 and sVCAM-1 et al., were found to be elevated in patients with CHF
[37–42], and were associated with the severity of the disease and the prognosis of the patients
[11–13]. Moreover, experimental evidence suggested that inflammation may also be a treatment target for CHF, and suppression of the above inflammatory factors or inhibition their adverse biological effects in CHF may be of great potential therapeutic significance
It has been suggested that fish oil supplementation may exert anti-inflammation effects by decreasing the production of inflammatory cytokines and adhesion molecules in some of the inflammation associated diseases, such as rheumatoid arthritis, inflammatory bowels diseases and asthma, but there were also studies didn’t support this concept
[43, 44]. Furthermore, a recent systematic review in healthy subjects, subjects with cardiovascular risk and established cardiovascular disease indicated that intervention studies with fish oil in these population demonstrated rather different results on inflammatory markers, although the reasons for above controversy were unknown
. Since anti-inflammation was suggested to be involved in the therapeutic mechanisms of fish oil to cardiovascular disorders, we systematically evaluated the effects of additional fish oil supplementation on the circulating levels of inflammatory markers in CHF patients. The results of our meta-analysis indicated the suppressive effects of fish oil on circulating TNF-α, IL-1 and IL-6, suggesting the potential role of fish oil supplementation in blunting the inflammatory response associated with CHF and modifying the outcomes of these patients. Previous studies indicated that the potential mechanisms of fish oil on these inflammatory markers may involve its ability to modulation the nuclear transcription factor (NF-ΚB)
[46, 47], which subsequently inhibited transcription of above inflammatory markers in CHF. Besides, recent evidence suggested that fish oil may transcriptionally up-regulate adiponectin, a potential anti-inflammatory factor, thereby suppressing above inflammatory cytokines
Considering the significant heterogeneity that existed in the pooled analysis of TNF-α and IL-6, we performed meta-regression and predefined subgroup analysis to explore the potential sources. The results suggested that the dose and follow-up duration of fish oil supplementation might influence the effects of fish oil on circulating levels of TNF-α and IL-6 in patients with CHF, and a higher dose of fish oil or a longer follow-up duration seem to be associated with a more remarkable reduction of circulating levels of TNF-α and IL-6. Notably, for the studies included in meta-analysis of IL-1
[18, 23], the doses of fish oil are over 1000 mg/day and the follow-up durations are 6 to 12 months, which made the pooled result a reduction of IL-1 by fish oil supplementation.
High sensitivity C reactive protein is considered to be of prognostic value in many cardiovascular diseases
[50, 51], including CHF
. However, the pooled results of our meta-analysis failed to demonstrate a significant effect of fish oil supplementation on circulating level of hsCRP in patients with CHF. These results are supposed to be robust, because none of the included studies in meta-analysis of hsCRP showed a significant influence of fish oil supplementation on circulating hsCRP levels, and the heterogeneity among these studies was very little. The nonsignificant efficacy of fish oil supplementation on circulating hsCRP levels in the included CHF patients of this meta-analysis may be explained by the following two reasons. First, the patients of the included studies were in stable clinical and hemodynamical conditions receiving treatment of the optimal medications (including neurohormonal inhibitors in all studies and statins in some studies) according to the current guidelines. Therefore, the mean baseline circulating levels of hsCRP for the participants of included studies were relatively low (1.3 to 5.6 μg/ml, Table
2) and additional supplementation of fish oil had little effect on it. Second, the low number of included studies (4 studies) and the small size of the included population (285 patients) may make the analysis underpowered to show significant effect.
Our meta-analysis also failed to show a significant efficacy of fish oil supplementation on the levels of sICAM-1 and sVCAM-1 in CHF. These results, from our point of view, may also be attributed to the low number of included studies (2 studies) and the small size of the included population (213 patients).
Several potential limitations should be addressed regarding the present meta-analysis. First, the numbers of studies and patients included in this meta-analysis were small, so results of some of estimations, such as for the effects of fish oil supplementation on IL-1, sICAM-1 and sVCAM-1, should be interpreted with caution. Second, because baseline data of statins using in half of the included study arms were unavailable, we were unable to estimate the effects of statins using on the pooled analysis of the inflammatory markers. This may be an important source of heterogeneity. Third, as for the subgroup analysis, the number of included studies and patients in each stratum is relatively small. Besides, we did not have access to individual patient data. Some subgroup analysis of CHF patients might show a difference with fish oil supplementation if larger numbers of patients were included or individual patient data were available (e.g. fish oil supplementation on circulating IL-6 in ischemic and non-ischemic CHF patients). Fourth, this meta-analysis included one study
[21, 22] in which the data were imputed from median and IQRs for some outcomes. Although inclusion of the imputed data may add to the potential bias, sensitivity analysis by excluding this study showed generally consistent results with which all the studies were included. Furthermore, we considered this as the best possible approach to not exclude valuable data from related studies.