August 12/The Lancet -- Much evidence shows that the marine omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid have beneficial effects in various cardiac disorders, and their use is recommended in guidelines for management of patients after myocardial infarction. However, questions have been raised about their usefulness alongside optimum medical therapies with agents proven to reduce risk of cardiac events in high-risk patients. Additionally, there is some evidence for a possible pro-arrhythmic effect in subsets of cardiac patients. Some uncertainly exists about the optimum dose needed to obtain beneficial effects and the relative merit of dietary intake of omega-3 polyunsaturated fatty acids versus supplements. The following reviews evidence for the effects of omega-3 polyunsaturated fatty acids on various cardiac disorders and the risk factors for cardiac disease, while also assessing areas of uncertainty needing further research.
The marine omega-3 polyunsaturated fatty acids (n-3 PUFAs) eicosapentaenoic acid and docosahexaenoic acid are present mainly in oily fish and commercially available supplements, which are available either over the counter (as fish oils) or as concentrated pharmaceutical preparations. Such supplements are becoming increasingly popular, with several health benefits attributed to them. Substantial benefits are reported in relation to diseases of the cardiovascular system, and guidelines recommend use of these agents in some cardiac disorders.
Coronary Artery Disease
Researchers of observational studies
This hypothesis was supported by findings of the landmark DART study,
Data for the effect of n-3 PUFAs on risk of development of coronary artery disease in healthy participants are inconsistent.
Findings from initial studies
Information about the role of n-3 PUFA intake or supplementation in primary prevention of coronary artery disease is scarce, but the available evidence suggests that those with hyperlipidaemia and diabetes might benefit most. The main benefit reported for the secondary prevention relates to the reduction in occurrence of sudden cardiac death, leading to much interest in the role of n-3 PUFAs in prevention of sudden cardiac death and their anti-arrhythmic potential.
Sudden Cardiac Death and Ventricular Arrhythmias
Several observational and interventional studies reported that high intakes of n-3 PUFAs reduced risk of cardiovascular mortality and sudden cardiac death, especially in patients with previous myocardial infarction. The most convincing evidence for a protective role of n-3 PUFAs against sudden cardiac death comes from a subanalysis of the GISSI-Prevenzione study12 showing a significant reduction (p=0·048) within four months after a myocardial infarction. The presumed mechanism of such benefit would be a reduction in life-threatening ventricular arrhythmias-the most common cause of sudden cardiac death in the early stages after a myocardial infarction.
The role of n-3 PUFA in reduction of risk of sudden cardiac death in patients with non-ischaemic cardiac disease is unknown, and very little investigation has been done in this area. Investigators of a study
Anti-arrhythmic potential of n-3 PUFAs was tested in patients with an automatic implantable cardioverter defibrillator. Results of such studies have reported inconsistent results, with one study showing marginal benefit,
The two common mechanisms of initiation of life-threatening ventricular arrhythmias are triggered activity and re-entry. Of the cellular electrophysiological effects of n-3 PUFAs, shortening of action potential duration
In experimental studies, mostly done in laboratory animals, researchers have reported that n-3 PUFAs have several potential anti-arrhythmic effects
In addition to a direct anti-arrhythmic effect, other mechanisms that could explain some or all of the observed benefits from large clinical trials have been reported. These mechanisms are: beneficial modulation of the autonomic tone shown as improved heart rate variability;
However, in the OMEGA multicentre study
Atrial fibrillation is the most common cardiac arrhythmia reported in clinical practice. Drug treatments for this disorder are restricted by pro-arrhythmic effects on the ventricles, and a need exists to identify effective drugs that can be used to treat atrial arrhythmias with a minimum risk of ventricular arrhythmia. In the absence of coronary ischaemia, n-3 PUFAs are unlikely to increase risk of ventricular arrhythmias, and might have the potential to be useful in management of atrial fibrillation. However, evidence for the effect of n-3 PUFAs on the incidence of atrial fibrillation seems to be inconsistent.
In large epidemiological studies
Data for the role of therapeutic supplementation of n-3 PUFAs in management of atrial fibrillation are restricted to few studies with relatively small sample sizes that were undertaken in patients undergoing cardiac surgery. Of these, one study
Atrial fibrillation is a heterogeneous disease that affects various age groups. Often young patients (35 years) have lone atrial fibrillation in the absence of structural heart disease, whereas older individuals (typically 65 years) have underlying cardiovascular disorders that result in structural remodelling of the atrium, predisposing to atrial fibrillation. Therefore, on the basis of available evidence, we can postulate that n-3 PUFAs might have a beneficial effect on the structural remodelling of the atrium but a lessened effect on electrical remodelling, underpinning maintenance of atrial fibrillation in lone atrial fibrillation. This view is supported by the observation that n-3 PUFAs do not have a great effect on the atrial electrical properties in an atrially paced model of atrial fibrillation, whereas they have substantial benefits in a ventricular-paced (heart failure) model of this disorder.
Findings from epidemiological studies
Atherosclerosis and Stroke
Researchers for observational studies
Researchers for a randomized, double blind, placebo-controlled clinical trial
Dyslipidaemia, Diabetes and Hypertension
A consistent effect of n-3 PUFAs is a lowering of plasma triglyceride concentrations.
In the past, concerns have been raised that n-3 PUFAs in high doses might lead to deterioration of diabetic control, but a systematic review
Hypertension is another important risk factor for cardiac disease, and several studies have indicated that sufficiently high doses of n-3 PUFAs are associated with modest reductions in systemic blood pressure.
Anti-inflammatory and Immunomodulatory Effects
Increased consumption of marine n-3 PUFAs results in their dose-dependent incorporation into cell phospholipids,
Thus, it seems that n-3 PUFAs exert an anti-inflammatory or immunomodulatory action through several mechanisms. A combination of all these effects might be beneficial in various clinical cardiac disorders in which inflammation (eg, acute coronary syndrome) and excessive immune activation (eg, post-cardiac transplant allograft rejection) account for poor outcomes. No clinical trial evidence is yet available to support use of n-3 PUFAs as an immunomodulator after cardiac transplant, but studies in laboratory animals have shown encouraging results.
Adverse Effects and Drug Interactions
n-3 PUFAs have been reported to reduce synthesis of the platelet agonist thromboxane A298 and might also affect platelet reactivity by other mechanisms.
Dietary Intake versus Therapeutic Supplements
Dietary intake of fish is the most desirable way to increase marine n-3 PUFA intake, but 1g per day of a n-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) supplement is equivalent to the fish oil present in about 55-85g of fresh tuna, sardines, salmon, or trout, and 652g of Atlantic cod fish
A new approach suggested by Harris and von Schacky
Guidelines and Further Recommendations
The joint American College of Cardiology and American Heart Assoication statement on n-3 PUFA use recommends an intake of at least two fish meals per week in patients with coronary artery disease, and supplemental therapy for one year with 1g per day of n-3 PUFA ethyl esters for those who have had a myocardial infarction.
In patients with high triglyceride concentrations, present guidelines recommend n-3 PUFA supplementation at a dose approaching 4g per day. Although clinical studies
Marine n-3 PUFAs act as pleiotropic agents on the cardiovascular system with a diverse range of effects, most of which are beneficial. So far, the most important effect seems to be related to reduction in mortality after a myocardial infarction. Although findings from several studies have suggested a mechanistic possibility of an anti-arrhythmic effect, those from clinical studies have not convincingly supported this mode of action. The overall effect of n-3 PUFAs in patients with coronary ischaemia without previous myocardial infarction is not established, with a potential benefit in the reduction of ischaemic coronary events set against an ongoing controversy over a possible rise in the risk of arrhythmic events. The anti-inflammatory, anti-atherosclerotic, and anti-immunomodulatory effects have not yet been proven to translate into clinical benefits, and further focused studies are needed to explore these properties. Assessment of effectiveness of these agents in the setting of optimum conventional drug therapy and elucidation of the mechanisms of the perceived benefits also need to be established.
Contact Dr Palaniappan Saravanan, Cardiovascular Research Group, 3rd floor, Core Technology Facility, 46 Grafton Street, University of Manchester, Manchester M13 9NT, United Kingdom.
From the August 30, 2010, Prepared Foods E-dition