Introduction of Upstream Treatment of Atrial Fibrillation with n-3 Polyunsaturated Fatty Acids: Myth or Reality?

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Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and confers increased risk of death,1 thromboembolism and impaired quality of life.2 Current pharmacological antiarrhythmic drugs provide limited protection against AF recurrence and have poor safety profiles, while invasive ablation treatments are associated with significant risks and limited long-term success rates. Moreover, neither of these treatments has been documented to reduce adverse outcomes associated with AF.3,4 Several pathophysiological processes have been proved to be involved in AF, such as inflammation, oxidative stress, endothelial dysfunction, initiating triggers (often from pulmonary veins), changes in autonomic tone in addition to fibrosis and ischaemia. Prevention of AF with interventions that modify these substrates or target specific mechanisms for AF has emerged as a result of recent experimental studies suggesting the use of upstream therapies. Non-antiarrhythmic drugs that have been tested in prevention of AF include angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, statins and long chain-3 polyunsaturated fatty acids (n-3 PUFA). n-3 PUFA have multiple effects on cardiac electrophysiology,5–10 such as membrane stabilisation in the myocardial cell by prolonged inactivation of the fast sodium outward channel, resulting in a longer refractory time and provide protection from ventricular arrhythmias and sudden death,11–13 but also have antifibrotic, anti-inflammatory and antioxidant characteristics that might influence the mechanisms involved in the initiation and maintenance of AF.14

In several experimental animal models, pre-treatment with n-3 PUFA decreased the development and progression of atrial fibrosis, reduced the abundance of collagen in atrial appendage and the duration of induced episodes of AF.15,16 They also prevented, in this kind of model, significant shortening of the atrial effective refractory period associated with AF, reduced inducibility of AF and sustainability of induced AF and attenuated structural changes in the atrial myocardium.16

Results of epidemiological studies have been controversial: In the Cardiovascular Health Study, the consumption of boiled or baked fish one to four times per week was associated with a 30 % lower risk of incident AF at 12 years compared with fish consumption less than once a week.17 However, in other population-based studies no association was found between n-3 PUFA intake and incident AF. Both the Danish Study and the Physicians’ Health Study showed that the patients with higher fish intake were more likely to develop AF: in the Danish study adjusting hazard ratios (HRs) for incident AF at 5.7 years, in quintiles 2–5, were 0.86, 1.08, 1.01 and 1.34 (p for trend = 0.006) compared with the lowest quintile and in the Physicians’ Health Study patients with the highest fish intake (≥5 meals per week) were more likely to develop AF compared with those eating fish <1 time per month (RR 1.46; 95 % CI 0.94–2.28).18,19

Finally, no association between development of AF at 3 years and fish intake was found in the Women’s Health Initiative study, which was carried out in more than 45,000 women.20 All these studies were based on food frequency questionnaires to assess fish intake and none provided data on serum n-3 PUFA content and its relationship with development of AF. In the Kuopio Ischaemic Heart Disease Risk Factors Study, designed to investigate risk factors for cardiovascular diseases, atherosclerosis and related outcomes in middle-aged men from eastern Finland, the serum concentration of n-3 PUFA was measured in 2,174 men. Only high docosahexanaeoic (DHA) acid but not eicosapentaenoic (EPA) acid content was associated with reduced risk of incident AF (HR 0.62; 95 % CI 0.42–0.92; p=0.02) suggesting that the preventive effect may depend on the use of a specific acid.21 These results are consistent with other studies in which DHA has been shown to be able to inhibit cardiac arrhythmias in rats and to have a beneficial effect on heart rate variability in humans.22,23

In this context, the focus of several randomised clinical trials in n-3 PUFA has been on two AF populations: patient for whom the objective was to maintain normal sinus rhythm after cardioversion or spontaneous restoration of sinus rhythm and patients in whom the objective was to prevent AF after cardiac surgery. The aim of this paper is to give an up-to-date review of the results of these trials and of recently published meta-analyses on this topic, trying to explain the conflicting results that have emerged by focusing on methodological aspects and on possible pathophysiological mechanisms, such as the role of inflammation and oxidative stress, as suggested by more recent studies and from biohumoral subanalysis of these trials.

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