Serum Long-Chain n-3 Polyunsaturated Fatty Acids and Risk of Hospital Diagnosis of Atrial Fibrillation in Men

Research Institute of Public Health, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
Circulation (Impact Factor: 14.43). 11/2009; 120(23):2315-21. DOI: 10.1161/CIRCULATIONAHA.109.852657
Source: PubMed


Atrial fibrillation (AF) is a common cardiac arrhythmia. Regular fish consumption has been shown to reduce the risk of AF in some but not all studies. Long-chain n-3 polyunsaturated fatty acids (PUFAs) from fish have been suggested to account for these beneficial effects. We tested this hypothesis by studying the association between the serum long-chain n-3 PUFAs eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid and risk of AF in men.
A total of 2174 men from the prospective population-based Kuopio Ischemic Heart Disease Risk Factor Study, 42 to 60 years old and free of AF at baseline in 1984 to 1989, were studied. During the average follow-up time of 17.7 years, 240 AF events occurred. In the Cox proportional hazards model, the multivariable-adjusted hazard ratio in the highest (>5.33%) versus the lowest (<3.61%) quartile of eicosapentaenoic acid plus docosapentaenoic acid plus docosahexaenoic acid was 0.65 (95% confidence interval 0.44 to 0.96, P for trend=0.07). Evaluated individually, only serum docosahexaenoic acid was associated with the risk of AF (hazard ratio in the highest versus the lowest quartile 0.62, 95% confidence interval 0.42 to 0.92, P for trend=0.02). Exclusion of subjects (n=233) with myocardial infarction or congestive heart failure either at baseline or that preceded the AF event during follow-up slightly strengthened the associations. Serum intermediate chain-length n-3 PUFA, alpha-linolenic acid, or hair methylmercury concentration were not associated with the risk.
An increased concentration of long-chain n-3 PUFAs in serum, a marker of fish or fish oil consumption, may protect against AF. Serum docosahexaenoic acid concentration had the greatest impact.

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    • "Notably, these reciprocal effects have been implicated in recent in vivo studies [50]–[56]. DHA levels are associated with a lower risk of arterial fibrillation [52], [53]. Administration of pure EPA is associated with a reduced risk of nonfatal coronary syndromes [54]–[56]. "
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    ABSTRACT: Annexin A2 (ANXA2), a member of the annexin family of cytosolic Ca(2+)-binding proteins, plays a pivotal role in vascular biology. Small amounts of this protein and S100A10 protein are exposed on the surface of endothelial cells (ECs). They control fibrinolysis by recruiting tissue-type and urokinase-type plasminogen activators from the plasma. Nutritional studies indicate that two major long-chain polyunsaturated fatty acids (PUFAs), i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), provide benefits for EC functions. The effects of EPA and DHA on the plasminogen/plasmin system have not been characterized. Proteomic analysis of a cultured human umbilical vein EC-derived cell line, HUV-EC-C, showed that cell-associated ANXA2 decreased with EPA treatment and increased with DHA. A small fraction of ANXA2 was bound to the cell surface, which was also affected by these PUFAs following the same trends. Cell surface expression was negatively regulated by protein kinase C (PKC) α-mediated Ser-phosphorylation, which was up- and down-regulated by EPA and DHA, respectively. These PUFAs differentially affected a small fraction of caveolae/rafts-associated ANXA2. In addition to chymotrypsin-like activity in the serum, newly activated plasmin cleaved the ANXA2 on the cell surface at distinct sites in the N-terminal sequence. ANXA2 also bound to membranes released in the medium, which was similarly processed by these proteases. Both the PUFAs did not directly affect the release. These results suggest that EPA and DHA reciprocally control cell surface location of ANXA2. Moreover, cleavage of this protein by plasmin likely resulted in autodigestion of the platform for formation of this protease. In conjunction with termination of the proteolysis by rapid inactivation of plasmin by α-2-antiplasmin and other polypeptide inhibitors, this feedback mechanism may emphasize the benefits of these PUFA in regulation of the initiation of fibrinolysis on the surface of ECs.
    PLoS ONE 01/2014; 9(1):e85045. DOI:10.1371/journal.pone.0085045 · 3.23 Impact Factor
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    • "Finally, DHA and EPA seem to exert different effects at the cellular level and clinical outcomes (Virtanen et al., 2009). New clinical trials based on mechanistic effects described in experimental studies will be necessary to avoid confounding factors that appear to be present in the current clinical trials. "
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    ABSTRACT: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice with growing prevalence in developed countries. Several medical and interventional therapies, such as atrial specific drugs and pulmonary vein isolation, have demonstrated prevention of recurrences. However, their suboptimal long-term success and significant rate of secondary effects have led to intensive research in the last decade focused on novel alternative and supplemental therapies. One such candidate is polyunsaturated fatty acids (PUFAs). Because of their biological properties, safety, simplicity, and relatively cheap cost, there is a special clinical interest in omega-3 PUFAs as a possible antiarrhythmic agent. Obtained from diets rich in fish, they represent one of the current supplemental therapies. At the cellular level, an increasing body of evidence has shown that n-3 PUFAs exert a variety of effects on cardiac ion channels, membrane dynamic properties, inflammatory cascade, and other targets related to AF prevention. In this article, we review the current basic and clinical evidence pertinent to n-3 PUFAs in AF treatment and prevention. We also discuss controversial outcomes among clinical studies and propose specific subsets of AF patients who will benefit most from n-3 PUFAs.
    Frontiers in Physiology 09/2012; 3:370. DOI:10.3389/fphys.2012.00370 · 3.53 Impact Factor
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    • "Similarly, a 2008 post hoc analysis of clinical data by Macchia et al. looked at ~3,000 post-MI patients and found that those prescribed n-3 LCPUFAs within 1 year post-MI had a reduced risk of developing AF (relative risk 0.19 in n-3 LCPUFA group) [37]. Observational studies such as the above-mentioned CHS and the Kuopio Ischemic Heart Disease Risk Factor Study showed that increasing fish (or fish oil) intake was associated with a reduced risk of AF [38, 39]. The CHS reported an AF relative risk of 0.69 for those who ate fish ≥5 times/week compared to those only eating fish ≤1 time/month. "
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    ABSTRACT: Long-chain n-3-polyunsaturated fatty acids (n-3 LCPUFAs), referring particularly to marine-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to be effective in treating arrhythmias in some clinical trials and animal studies. The mechanism for this effect of n-3 LCPUFAs is not well understood. Experimental studies and clinical trials published in the 1980s and 1990s suggested that n-3 LCPUFAs may be antiarrhythmic drugs, but more recent trials have not confirmed this. In this paper, we examine evidence for, and against, the direct antiarrhythmic action of n-3 LCPUFAs and suggest that antistructural remodeling effects of n-3 LCPUFAs may be more relevant in accounting for their clinical effects.
    Cardiology Research and Practice 08/2012; 2012(1):746709. DOI:10.1155/2012/746709
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