Primary prevention: With regard to primary prevention of AF (Table 1), two studies involving elderly subjects[5,6] and one focusing on patients affected by acute myocardial infarction[7] proved n-3 PUFA to be protective against AF, while other studies[8-12], showed no benefit. The influence of various diet habits, including fish consumption[8,9], can possibly explain different results, as well as different methodologies used for assessment of fish intake and for AF diagnosis. In particular, positive studies, generally included elderly individuals[5-7], suggesting benefit from antifibrotic properties of fish-oil. However, a post-hoc analysis of the randomized controlled trial GISSI-HF[13] showed no effect of long-term PUFA administration on AF development in heart failure patients, thus allowing no conclusions for the role of n-3 PUFA in AF primary prevention.

Post-operative AF: The effect of n-3 PUFA in the context of POAF, that is characterized by inflammation, electrolyte disturbances and hemodynamic instability secondary to cardiac surgery, have also been also widely investigated. An open label study[14] firstly observed a short-term n-3 PUFA administration-related decrease in POAF incidence after coronary artery bypass grafting. Two papers[15,16] also gained benefit from various fish-oil preparations and administration timings (Table 2). A recent randomized-controlled trial (RCT)[17] also observed reduction of POAF with n-3 PUFAs plus vitamins C and E administration in comparison to placebo, in 203 patients scheduled for cardiac surgery. Further studies however, failed to prove both prevention of AF[18,19] and decrease of inflammation[20] from higher serum levels of n-3 PUFA, eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA), and from higher n3-PUFA atrial content[21,22]. Recently, the multicenter double-blind RCT “OPERA”[23] showed no influence on POAF occurrence, from short-term n3-PUFA administration. The effect was unrelated to patients characteristics, kind of cardiac-surgery, antiarrhythmic drugs, fish intake and serum n-3 PUFA. In a substudy of this trial indeed[24], including 564 subjects receiving short-term PUFA or placebo before surgery, the risk of POAF was unrelated to fish oil concentrations at enrollment and day of surgery. Interestingly, PUFA increase, was characterized by significant inter-individual variableness (0.7%-7.5% after 5 d of supplementation). Finally, Metcalf et al[25], by using combined data from previous RCTs, demonstrated less incidence of POAF among subject within the fourth quintile of red blood cell n-3 DHA, thus suggesting a U-shaped relation between n-3 PUFA intake and POAF. Four recent meta-analyses of the previously presented studies showed in turn, overall protective or neutral effect on POAF from n-3 PUFA[26-29] (Table 3). Of note, none of these meta-analyses has assessed n-3 PUFA treatment duration to surgery as a covariate in a meta-regression analysis (Figure 1).

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Figure 1 Antiarrhythmic effects of n-3 poly-unsaturated fatty acids. N-3 PUFA: N-3 poly-unsaturated fatty acids; TxA2: Thromboxane A2; PLC: Phospholipase C; IP3: Inositol triphosphate; AF: Atrial fibrillation.

Dissimilarities may be explained by various study designs and populations, AF definitions, cardiac surgery, co-administration of anti-arrhythmic or anti-inflammatory drugs, dietary PUFA intake, EPA/DHA ratios and fish oil-administration modes (i.e., intravenous or through nasogastric tube) and fish-oil administration time courses. Conversely, no effects of n-3 PUFA administration on myocardial infarction and bleeding after cardiac surgery, eventually influencing POAF occurrence, have been demonstrated[27].

Interestingly, all RCTs that failed to demonstrate a beneficial effect, used a formulation containing 1.24 EPA:DHA ratio[18,20,23]. In contrast, Rodorigo et al[17] administered PUFA with an EPA:DHA ratio equal to 0.5.

Secondary prevention: Several studies have finally investigated the effect on n-3 PUFA on relapses of paroxysmal and persistent AF. Two studies[30,31], found fish oil administration (from 1 mo before, to 6 mo after cardioversion) helpful in AF prevention (Table 4). On the other hand, 4 further studies[32-35] failed to prove any effect.

A recent study[36] including 337 patients with symptomatic paroxysmal/persistent AF, randomized to receive fish oil (4 g/d) or placebo, showed no difference in time to first AF recurrence, as well as no significant decrease of inflammatory markers at 6 mo. Similarly, another RCT[37], proved no effect from n-3 PUFA on the time to AF relapses, as well as on concentrations of biomarkers of oxidative stress and inflammation and at follow-up. In particular, a large RCT[34] involving 586 patients with symptomatic paroxysmal or persistent AF, randomized to n-3 PUFA (1 g/d) vs placebo for 1 year, also proved no significant differences between the two arms, in terms of symptomatic recurrence of AF.

Contrasting outcomes between studies may be related to differences in PUFA somministration and populations characteristics. Generally, papers including subjects with more evident cardiac disease[30], more often co-administered with amiodarone[30] showed benefit. Of note, some unfavorable papers proved AF relapses to occur mostly within 3 wk, prior to an eventual effect from n-3 PUFA.