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What can we expect from omega-3 fatty acids?

Cleveland Clinic Journal of Medicine. 2009 April;76(4):245-251 | 10.3949/ccjm.76a.08042
April 1, 2009|Cleveland Clinic Journal of Medicine
Eric J. Chan, MD;Leslie Cho, MD
Author and Disclosure Information

Eric J. Chan, MD
Department of Internal Medicine, Cleveland Clinic

Leslie Cho, MD
Director, Women’s Cardiovascular Center, and Head, Section of Preventive Cardiology and Rehabilitation, Department of Cardiovascular Medicine, Cleveland Clinic

Address: Leslie Cho, MD, Women’s Cardiovascular Center, Jb1, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail chol@ccf.org

ABSTRACTOmega-3 fatty acids are abundant in fish oil. A high dietary intake of omega-3 fatty acids has been strongly linked to lower rates of cardiovascular disease in epidemiologic studies. Fish oil supplements lower triglyceride levels and may have other benefits such as preventing arrhythmias, reducing inflammation (although they have minimal impact on C-reactive protein), inhibiting platelet aggregation, and lowering blood pressure, all of which should reduce cardiovascular risk.

KEY POINTS

  • The American Heart Association recommends that healthy people consume fatty fish at least twice a week. The recommendation for people with coronary artery disease is 1 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day.
  • A formulation of EPA 465 mg plus DHA 375 mg is available by prescription and is approved for treating triglyceridemia in excess of 500 mg/dL. The dose is 2 to 4 capsules per day.
  • Experts generally believe that omega-3 fatty acids reduce arrhythmic events. Nevertheless, we lack clear evidence of their clinical effectiveness, and their use for such purposes is off-label.
  • Overall, omega-3 fatty acids have minimal side effects.

May prevent arrhythmias

The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Prevenzione (GISSI-Prevention) trial18 was the largest randomized trial to date of fish oil therapy as secondary prevention. In this trial, 11,323 patients who had had a myocardial infarction less than 3 months before enrollment were randomized to receive either EPA/DHA 850 mg daily, vitamin E, both, or no treatment. The primary end points were death from any cause, nonfatal myocardial infarction, and nonfatal stroke.

At 3 months, 63 (1.1%) of the patients in the EPA/DHA group had died, compared with 88 (1.6%) of those in the no-treatment group, for a relative risk of 0.59 (P = .037), and the benefit persisted for the duration of the study. However, the difference between the groups in the rates of nonfatal myocardial infarction did not reach statistical significance. Vitamin E seemed to have no effect.

EPA/DHA is thought to have prevented deaths in this study, not by reversing atherosclerosis, but rather by suppressing arrhythmias and inflammation. In support of this theory, Getz and Reardon19 noted that in GISSI the treatment showed its maximal benefit on the incidence of sudden death by 9 months, whereas statin treatment takes 1 to 2 years to reach its maximal effect. This point suggests that the role of omega-3 fatty acids in secondary prevention will be different from that of statins.

Extensive clinical studies have looked at the possibility of using omega-3 fatty acids as part of the treatment for reducing arrhythmic events. Several animal and human studies have shown that these drugs reduce the incidence of sudden death and ventricular fibrillation.20

Omega-3 fatty acids are thought to prevent arrhythmias by stabilizing the myocardial membrane through interaction with voltage-gated sodium and L-type calcium channels. During an ischemic event, the affected heart cells allow potassium ions to escape. Since potassium ions carry a positive charge, the resting membrane potential (ie, the difference in electrical charge between the inside and outside of the cell) is increased, lowering the threshold for initiating an action potential through sodium channels and increasing the risk of fatal arrhythmias. It is hypothesized that omega-3 fatty acids inhibit sodium channels by being incorporated into the membrane phospholipid bilayer, increasing its fluidity and thereby affecting the sodium channel. This reduces membrane excitability and arrhythmic potential.20

This premise was examined in three large randomized clinical trials specifically looking at ventricular arrhythmias in patients with an implanted cardioverter-defibrillator (ICD).21–23 The results were mixed.

Raitt and associates21 found that patients who recently received an ICD had higher rates of ventricular tachycardia and fibrillation if they received EPA/DHA than if they received placebo, 65% vs 59% (P = .07). In contrast, Leaf et al22 reported a lower rate of ventricular arrhythmias with EPA/DHA than with placebo, 28% vs 39%. Brouwer et al23 reported similar results, with rates of 30% vs 33% (Table 3). The difference in the results of these studies could be explained by differences in baseline fish consumption, the underlying causes of ventricular arrhythmia, and the programming thresholds of the ICDs in these studies.24

In another study, Calo and colleagues25 randomized 160 patients to receive omega-3 fatty acids 2 g per day or placebo starting at least 5 days before elective coronary artery bypass surgery and continuing until discharge. The primary end point measured was the development of atrial fibrillation after surgery. The incidence of atrial fibrillation in the omega-3 fatty acid group was 15.2%, compared with 33% in the control group (P = .013).

Despite the differences in the results of these studies, experts generally believe that these agents reduce arrhythmic events. Nevertheless, we lack clear evidence of their clinical effectiveness, and their use for such purposes is off-label.

May reduce inflammation and platelet aggregation

Arachidonic acid is an omega-6 fatty acid that is metabolized into prostaglandins, leukotrienes, and thromboxanes, which are important for cell function. Many of these by-products (eg, leukotriene B4) have inflammatory effects, and others (eg, prostaglandin I2 E2) promote arrhythmias. EPA and DHA competitively inhibit the arachidonic acid cascade, leading to different by-products that promote vasodilation and inhibit platelet aggregation, among other effects.26 The impact of this effect in clinical practice is still unclear.

The evidence still conflicts as to whether omega-3 fatty acids reduce markers of inflammation such as C-reactive protein (CRP). Balk et al,12 in their meta-analysis, looked for studies that examined the effect of these agents on CRP and cardiovascular disease (either known risk factors or coronary artery disease). They excluded studies that were less than 4 weeks in duration, did not specify the dose of fish oil, or used doses higher than 6 g/day. Four trials were found that met their criteria, with dosages of omega-3 fatty acids ranging from 1.6 g/day to 5.9 g/day and from 12 to 20 patients in each study. Although baseline CRP levels in these studies varied, the net change in CRP was minimal, ranging from −0.15 to +1.7 mg/L.

May stabilize plaque

Thies et al27 randomized 188 patients to receive fish oil supplements before carotid endarterectomy. They found that the carotid plaque of patients who received the supplements had higher levels of EPA and DHA and had thicker fibrous caps and fewer signs of inflammation (eg, macrophages) compared with a control group and a group that received sunflower oil.

These findings show that omega-3 fatty acids are readily incorporated into atheromatous plaque and can help stabilize it. An inference from this study is that fish oil could also play a role in stabilizing coronary artery plaque.

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