Discussion
To the best of our knowledge, this clinical study is the first to investigate the effect of n-3 PUFAs on AF in patients with chronic HF. In a large, representative population of patients with optimized pharmacological treatment, we found that: (i) high circulating n-3 PUFA levels, an objective estimate of exposure to PUFAs, were inversely and independently associated with prevalent AF, but did not predict its new occurrence in patients with HF without AF on the baseline ECG; (ii) fish consumption, the main dietary source of n-3 PUFAs, was not independently associated with the prevalence or incidence of AF; and (iii) 1 g daily supplementation of n-3 PUFAs did not reduce the incidence of AF compared with placebo in 5835 patients without AF on the baseline ECG.
n-3 Polyunsaturated Fatty Acid Supplementation and Development of Atrial Fibrillation
In animal models, n-3 PUFA supplementation has favourable effects on electric and structural atrial remodelling, consequently reducing the incidence of AF. In an ovine model of chronic HF induced by intracoronary infusion of doxorubicin, supplementation with n-3 PUFAs, starting before and continued after the last dose of the drug, prevented adverse left atrial enlargement, fibrosis, and conduction abnormalities. Similarly, n-3 PUFA pre-treatment attenuated HF-induced left atrial structural remodelling and AF promotion in a model of canine ventricular tachypacing.
In the present clinical study, we did not find any protective effect of n-3 PUFA supplementation on AF in this large population of patients with chronic HF. An increase in risk of incident AF with n-3 PUFAs was apparent after exclusion of patients with a history of AF and those with pacemaker rhythm, which by itself could hamper the diagnosis of AF. The overall effect in primary prevention is hard to define and may depend on underlying cardiac diseases or conditions. Epidemiological studies indicate that in older adults, free of AF or HF, higher circulating total n-3 PUFA levels are associated with a lower risk of incident AF. However, several randomized clinical trials have reported controversial effects of n-3 PUFA supplementation in the prevention of AF after cardiac surgery or on recurrent AF in patients with a history of paroxysmal or persistent AF. Recent meta-analyses have also reported conflicting evidence. He et al. concluded that n-3 PUFA supplementation could significantly reduce the incidence of AF after heart surgery, but had no significant effect on its recurrence, while others did not observe any favourable effect. The lack of effect of n-3 PUFA supplementation on post-operative AF has been recently confirmed by the OPERA trial in 1516 patients. The possibility of long-term treatment with n-3 PUFAs in elderly subjects for primary prevention of incident AF may be worth an ad-hoc large-scale trial. The use of higher doses of n-3 PUFAs and/or different EPA/DHA ratios may also be studied in patients with HF.
Fish Intake, Circulating Levels of n-3 Polyunsaturated Fatty Acids, and Atrial Fibrillation
Baseline n-3 PUFA levels in our patients were significantly associated with a lower prevalence of AF (Figure 1), but not independently with incident AF during the follow-up. In a prospective cohort study, a higher circulating concentration of total long-chain n-3 PUFAs was associated with a reduced risk of AF, and it was suggested that the effect might be ascribable to the DHA concentration. However, the association was strongest in subjects without HF or myocardial infarction. Therefore, the pathophysiology of AF may differ according to the presence of underlying cardiac disease and its severity. The influence of n-3 PUFAs on the development of AF in chronic HF may be limited by the dominant roles of the adrenergic and renin–angiotensin systems in facilitating arrhythmogenic atrial remodelling
In our study, which enrolled mainly patients on a Mediterranean diet, fish consumption was not independently associated with either prevalent or incident AF. Some epidemiological studies also found no real association between dietary fish intake and reduced AF incidence.
Study Limitations
The current study has several limitations. First, it was not specifically designed to test the effects of n-3 PUFAs on AF and no specific search for AF episodes was planned (Holter or trans-telephonic monitoring). Most cases of asymptomatic AF could not be detected. Therefore, the definition of AF used in our analysis has limited sensitivity. The characteristics of the different types of AF were not available (paroxysmal, persistent, permanent, etc). As the trial was not designed to assess the effect of n-3 PUFAs on AF, our ancillary analysis may have been underpowered. Moreover, dietary information was collected in a self-administered questionnaire.