Numerous epidemiological studies, case-control series, and randomized trials have demonstrated the ability of fish oil to reduce major cardiovascular (CV) events. The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione1 trial catapulted fish oil to mainstream medical therapy by demonstrating that fish oil reduces major CV events mainly by reducing the risk for sudden cardiac death (SCD) in patients following acute myocardial infarction (MI). This review focuses on how fish oil therapy has performed in primary prevention trials in patients with implantable cardioverter defibrillators (ICDs), reviews the various effects fish oil exerts on the autonomic nervous system, focuses on the use of fish oil as a novel therapy for atrial fibrillation (AF), revisits other beneficial effects of fish oil (eg, ability to lower serum triglycerides), and finishes with a review of the safety profile of fish oil.

FISH OIL FOLLOWING ACUTE MYOCARDIAL INFARCTION

The Diet and Reinfarction Trial2 examined the effects of dietary intervention in the secondary prevention of MI in 2,033 males who recovered from a recent MI and were allocated to 3 different dietary advice groups: (a) fat advice, designed to reduce fat intake to 30% of total energy and to increase the polyunsaturated-saturated ratio to 1:1; (b) fish advice, at least 2 weekly portions (200-400 g) of fatty fish (mackerel, herring, kipper, pilchard, sardine, salmon, or trout); and (c) fiber advice, increased intake of cereal fiber to 18 g daily. The subjects advised to eat fish experienced a 29% reduction in 2-year all-cause mortality in comparison with the remaining 2 groups (P < .05). However, no difference in total events for coronary heart disease (CHD) existed, as more nonfatal MIs occurred in the fish advice group. The authors suggested that fish consumption might decrease the incidence of lethal arrhythmias and therefore preferentially affect mortality after MI.

The GISSI-Prevenzione,1 the largest secondary prevention trial studying the consumption of fish oil in patients with a recent MI, randomized 11,323 patients to supplements of omega-3 polyunsaturated fatty acids (PUFAs) (one gelatin capsule containing 850-882 mg eicosapentanoic acid [EPA] and docosahexanoic acid [DHA] as ethyl esters in the average EPA/DHA ratio of 1.2:1), vitamin E (300 mg), both therapies, and no therapy. The primary combined efficacy endpoint was death, nonfatal MI, and stroke. After 3.5 years, treatment with PUFAs, but not with vitamin E, significantly lowered the primary combined endpoint by 15%. Further analysis revealed that this endpoint reduction was driven by a highly significant 45% reduction in SCD, after only 4 months of randomization.3,4

FISH OIL AND PRIMARY PREVENTION

The Japan EPA lipid intervention study (JELIS),5 a primary prevention trial, tested the hypothesis that long-term use of EPA (1800 mg/day) is effective in reduction of major CHD events in Japanese hyperlipidemic patients who are also taking statins (ie, simvastatin or pravastatin). The primary endpoint was any major CHD event, including SCD, fatal and nonfatal MI, unstable angina, angioplasty, stenting, or coronary artery bypass grafting (CABG). After randomizing 18,645 patients to statin therapy alone or statin plus EPA therapy, no significant reduction in SCD could be demonstrated among patients receiving therapy for primary prevention. More interestingly, no significant reduction in SCD could be demonstrated among patients being treated for secondary prevention. This finding seems to be at odds with the GISSI-Prevenzione trial, which reported a 45% decrease in the risk for SCD in post-MI patients. The authors of the JELIS trial reconciled this difference by stating that the Japanese population already consumes more fish than Western populations and their baseline population cardiac death rates are lower than those in the Western world. Therefore, there may be a dose beyond which additional antiarrhythmic benefit may not be demonstrable. However, among all patients, the JELIS study did find a 19% relative risk reduction in nonfatal CHD events (P = .015).

FISH OIL AND HIGH-RISK VENTRICULAR ARRHYTHMIAS

A double-blind study by Raitt et al6 examined whether omega-3 PUFAs have beneficial antiarrhythmic effects in patients with a history of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). The study randomized 200 patients with ICDs to 1.8 g of omega-3 PUFAs (756 mg EPA and 540 mg DHA) or placebo and followed them for a median of 718 days. Primary endpoint was time to the first episode of VT/VF that would lead to ICD shocks. Approximately half of the patients involved in the study experienced an MI. In addition, the group receiving omega-3 PUFAs had a higher rate of statin use than the placebo group. They found that omega-3 PUFAs supplementation did not reduce the risk of VT/VF. In the subset of 133 patients whose entry arrhythmia was VT, 79% of the patients in the fish oil group experienced VT/VF at 24 months in comparison with 65% of patients in the control group (P = .007). The authors concluded that fish oil therapy does not reduce the risk of VT/VF and may even be proarrhythmic in certain patients.

In contrast to the above study, Leaf et al7 performed a double-blind study that randomized 402 patients with ICDs to either a fish oil or placebo for 12 months. The primary endpoint was time to first ICD event for VT or VF or death from any cause. The patients received either four 1.0 g capsules of omega-3 PUFAs (total dose of EPA plus DHA of 2.6 g) or four 1.0 g capsules of olive oil. The noncompliance rate was high, but similar between the 2 groups. Despite this, during primary analysis, patients receiving omega-3 PUFAs supplement showed a trend toward a prolonged time to the first ICD event (VT or VF) or of death from any cause (risk reduction of 28%; P = .057). However, when the authors included probable episodes of VT/VF therapy, the risk reduction became significant at 31% (P = .033). Moreover, when multivariate analysis was performed only on subjects who were compliant for at least 11 months, the relative risk reduction improved to 48% (P = .0060). Although statistically significant, bias is introduced into the data because softer endpoints, such as probable VT/VF therapy, are included in the subgroup analysis.

The Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) trial8 was a randomized, double-blind trial that randomized 546 patients with ICDs to 2 g of fish oil (464 mg EPA and 335 mg DHA) or placebo for a median of 356 days. The primary endpoint was defined as an appropriate ICD intervention (ie, shock or antitachycardia pacing) for spontaneous VT/VF or death from any cause. No observable difference between the 2 groups could be found with respect to the primary endpoint. However, in subgroup analysis, the authors state that in patients with a prior MI (n = 342), there was a nonsignificant trend toward a longer event-free survival in the fish oil group than in the placebo group. In this trial, patients experienced an MI between 2 weeks and 25 years before entry into the study. The authors suggested that this wide time range may have obscured a possible beneficial effect of fish oil therapy on patients with MI. They further suggested that fish oil therapy may be more beneficial in preventing ventricular arrhythmia in patients with recent MI, as there is a lower amount of scar tissue in these patients.

In aggregate, 2 of the 3 ICD trials support at least a modest benefit of omega-3 PUFAs for the prevention of high-risk ventricular arrhythmias.

FISH OIL AND ION CHANNEL EFFECTS

Current research suggests that omega-3 PUFAs prevent fatal arrhythmias via their ability to inhibit fast, voltage-dependent sodium channels and L-type calcium channels.9,10 Following an MI, cardiomyocytes within the MI territory are in different stages of depolarization. In the center of the ischemic zone, cells depolarize and die. But at the periphery of the ischemic zone, cardiomyocytes may be only partially depolarized. Thus, they are hyperexcitable. The resting membrane potential of these cells has become more positive and approaches the threshold for generating action potentials, which may lead to arrhythmia initiation. The omega-3 PUFAs work by shifting the cellular membrane to a more negative or hyperpolarized state, making it more difficult for these cells to reach their action potential threshold.11 Overall, the omega-3 PUFAs make partially depolarized myocytes less excitable and thus their arrhythmic potential is prevented.

Furthermore, DHA has been demonstrated to directly inhibit the delayed-rectifier potassium channel,12 which is responsible for the repolarization phase of ventricular and atrial cardiac potentials. Although the relative antiarrhythmic effect of DHA or EPA remains uncertain, DHA's effect on atrial and ventricular repolarization raises the possibility that DHA could be providing greater protection against dysrhythmias.

AUTONOMIC TONE AND FISH OIL

Chronic imbalance of the autonomic nervous system causing sympathetic hyperactivity increases the CV workload and predisposes endothelial dysfunction, left ventricular hypertrophy, coronary spasm, and dysrhythmias.13 Any therapy that can increase sympathetic tone or decrease parasympathetic tone will raise the risk of CV events.14 This risk factor, although not widely recognized, is assessed by measures of resting and peak exercise heart rate, heart rate recovery (HRR) after exercise, heart rate variability (HRV), and baroreflex sensitivity (reflex-mediated changes in heart rate as a response to fluctuations in preload and venous return).

Studies have established an elevated resting heart rate as an independent risk factor for CV disease and mortality.15 An impaired chronotropic response to exercise, defined as a failure to achieve 85% of the age-predicted maximal heart rate, increases the mortality independent of findings on coronary angiography and stress myocardial perfusion imaging.16 Impaired HRR postexercise, defined as a failure to decrease heart rate by more than 12 beats per minute during the first minute after exercise, increases the relative risk of CV mortality by 3- to 4-fold.17,18 Abnormal HRV, defined as a failure to change heart rate by more than 10 beats per minute during 1 minute of deep breathing,19 has been associated with an increased risk of CHD and mortality,20 as well as angiographic progression of atherosclerosis21 and SCD.22

The CV benefits of omega-3 PUFAs appear to be driven primarily by a reduction in SCD. Whether this reduction is due to the antiarrhythmic or autonomic properties, or a combination of both, remains unclear. In a double-blind randomized controlled trial, Christensen et al23 found that patients with an MI and ejection fraction less than 0.40 receiving 5.2 g of omega-3 PUFAs (4.3 g EPA and DHA) for 12 weeks had a statistically significant improvement in HRV. The authors hypothesized that increased parasympathetic cardiac tone reflected by an increased HRV may decrease SCD risk by increasing VF threshold and thus guard against fatal ventricular arrhythmias.

In another study by O'Keefe et al,24 consumption of omega-3 PUFAs (585 mg DHA and 225 mg EPA) for 4 months decreased heart rate from 73 +/- 13 beats per minute to 68 +/- 13 beats per minute (P < .0001), improved 1-minute HRR postexercise (-27 +/- 10 beats per minute to -32 +/- 12 beats per minute, P < .01), and improved HRV in the high-frequency band (P < .02) but not overall. These observed changes support omega-3 PUFAs ability to improve vagal tone and may partly explain the observed decrease in SCD in numerous trials.

In a large population-based study of 5,096 men and women, Mozaffarian et al25 investigated the associations between dietary fish intake and electrocardiographic measures of heart rate, atrioventricular conduction (PR interval), ventricular repolarization (QT interval), and ventricular conduction (QRS interval). They found that consumption of tuna or other broiled/baked fish was associated with a lower heart rate (-3.2 beats per minute, P < .001), slower atrioventricular conduction (PR interval +7.2 millisecond, P = .03), and substantially lower likelihood of prolonged QT interval (relative risk reduction 50%, P = .03). No significant change was observed with ventricular conduction time.

Yet another study by Geelen et al26 supports the finding that omega-3 PUFAs lower resting heart rate. They randomly assigned 84 patients with greater than 1,440 premature ventricular contractions per 24-hour period in a previous Holter recording to receive 3.5 g/day of either omega-3 PUFAs (700 mg EPA and 560 mg DHA) or placebo. After 14 weeks of therapy, they demonstrated that the mean 24-hour heart rate was significantly lower by 2.1 beats per minute in the fish oil group in comparison with the placebo group.

In aggregate, these studies support a substantial benefit of omega-3 fatty acids, both dietary fish consumption and, particularly, fish oil supplementation for aiding in augmentation of autonomic tone, which should decrease the risk of serious ventricular tachyarrhythmias and, especially, the risk of SCD.27

FISH OIL AND ATRIAL FIBRILLATION

In addition to the effects on ventricular arrhythmias and autonomic tone, much research has elucidated a positive role for omega-3 PUFAs in the management of AF. In a study by Mozaffarian et al.28 consumption of tuna or other broiled/baked fish was associated with a 30% lower risk of incident AF over a 12-year follow-up period. Although this association does not prove causality, after correcting for variables such as age, gender, education, smoking, CHD history, diabetes, heart failure, and MI, the relationship between increased fish consumption and lowered incidence of AF persisted.

The Rotterdam study,29 a prospective population-based trial examining dietary intake of fish and its association with AF incidence, found no correlation. The authors of the Rotterdam study list several reasons why they did not observe a correlation, as observed by Mozaffarian et al. Their study participants were younger with a mean age of 67 years, whereas the population of Mozaffarian et al. consisted of somewhat older patients (mean age 73 years). It was also difficult to control for dietary changes during the follow-up period and the possible adverse effects of fried fish consumption.

In a study performed by Calo et al,30 they investigated the efficacy of preoperative and postoperative treatment with omega-3 PUFAs in preventing the occurrence of AF after CABG. A total of 160 patients with no prior history of AF were prospectively randomized to a control group or to the PUFA group receiving 2 gelatin capsules containing 850 to 882 mg EPA and DHA in the average EPA/DHA ratio of 1:2. No significant baseline differences or difference in surgical technique existed between the 2 groups. The primary endpoint was the development of AF in the postoperative period. Postoperative AF developed in 33.3% of the control group and in 15.2% of the PUFA group (P = .013). After CABG, the PUFA patients were hospitalized for significantly fewer days than controls (7.3 +/- 2.1 days vs 8.2 +/- 2.6 days, P = .017). When AF did occur among patients, treatment group did not demonstrate a difference with regard to arrhythmia duration, rate of spontaneous conversion to sinus rhythm, or response to pharmacologic/electrical cardioversion.

In comparison with [beta]-blockers, sotalol (Betapace) and amiodarone (Cordarone), omega-3 PUFAs are as efficacious in prophylaxis against AF post-CABG.31 The use of PUFAs affected an 18.1% absolute risk reduction and 54.4% relative risk reduction for the occurrence of AF post-CABG. The consequent number of patients needed to treat was 5.51 (95% CI, 3.43-20.40).30 More importantly, PUFAs could be used to prevent AF post-CABG in patients with contraindications to [beta]-blockers or sotalol (ie, bradycardia or severe chronic obstructive lung disease).

Although it could not be directly proven, the authors suggest that the antiarrhythmic properties of PUFAs may contribute to the decreased incidence of AF post-CABG. In addition, experts have intimated a role for inflammation in the pathophysiology of AF after bypass.32,33 Calo et al.30 agree that the anti-inflammatory properties of PUFAs could play a role in the prevention of AF after cardiothoracic surgery.

OTHER CARDIOVASCULAR EFFECTS OF FISH OILS

There are numerous other potential CV and general medical benefits of fish oils. Probably, the most studied and proven effect is the ability of moderate and large doses of EPA/DHA (generally 3-5 g/day) to produce a 30% to 50% reduction in plasma triglycerides (although small, but statistically significant, reductions have been reported with a dose less than 1 g/day). We previously reported statistically significant improvement in blood pressure and diastolic ventricular function among recipients of heart transplants,34 and recently reported marked benefits of this therapy to produce anti-inflammatory effects and improve body composition in patients with advanced heart failure, which could prove beneficial particularly for the cardiac cachexia noted with this disease.35 In addition, increased consumption of fish oils has been associated with other potential benefits, including decreased risk of prostate cancer, depression, inflammatory bowel disease, and other medical disorders.36

FISH OIL AND SAFETY RECOMMENDATIONS

The US Food and Drug Administration performed a comprehensive review of the safety of fish oil in 1997. After reviewing more than 2,600 articles, it was concluded that dietary intakes of up to 3 g/day of EPA plus DHA were "generally recognized as safe." A "fishy burp" is the most common side effect reported by individuals taking these supplements. Omega-3 fish oil supplementation may modestly increase low-density lipoprotein level (usually less than 5%), but this is counteracted by its ability to reduce triglyceride levels by 30% to 50%. Although doses of omega-3 PUFAs greater than 20 g/day have been noted to prolong bleeding time, this has not been noted with lower doses.37 Moreover, no increase in bleeding complications have been reported when fish oil therapy was combined with aspirin or warfarin (Coumadin).38 In addition, no bleeding complications were noticed with a 7 g/day dose of omega-3 PUFAs in a large restenosis study.39

With increasing pollution of the world's oceans, mercury content in the water and thus the marine animals that live in the ocean has been rising. Since mercury is water-soluble and not lipid-soluble, this is contained in the muscles of certain fish (especially sardines, swordfish, mackerel, shark, tuna, and other deep-sea fish), but significant mercury should not be present in the oil (such as fish oil supplements). Therefore, clinicians may consider recommending fish oil supplements to avoid consuming additional mercury, as well as for most of the patients who do not consume significant quantities of fatty fish.

Although there are numerous nonprescription fish oil supplements available containing wide ranges of EPA and DHA, in the United States, a concentrated prescription fish oil preparation similar to that used in the GISSI study has been available since 2005 (Reliant pharmaceuticals). However, the indications sought and received by Reliant pharmaceuticals were only for reduction of marked triglyceride elevations. Therefore, a low dose of the prescription fish oil (normally prescribed as 2 pills twice daily for triglycerides, whereas only 1 pill daily would provide the doses of EPA/DHA used for cardiac arrhythmias/survival benefits) would be off-label at the present time.40 Over-the-counter preparations of fish oil can also be given at various doses depending on concentrations of EPA/DHA to provide the doses of EPA and DHA in the combined 800 to 1000 mg/day range to provide antiarrhythmic effects.

RECOMMENDATIONS

We believe that the current data support considering supplementation with omega-3 PUFAs for patients with documented CHD and those with risk factors for SCD, such as left ventricular dysfunction, left ventricular hypertrophy, prior MI, or high-grade ventricular dysrhythmias. The American Heart Association recommends four 3-ounce servings of oily fish weekly. For those who cannot eat fish, do not have access to fish, or who would prefer not to eat fish regularly, capsules of omega-3 PUFAs are readily available. We recommend a dose of combined EPA and DHA of 800 to 1000 mg daily for primary and secondary prevention.

CONCLUSIONS

In summary, among other CV benefits, omega-3 PUFAs have been associated with a reduction in the risk for SCD, a reduction in the incidence of AF post-CABG, and improvement in overall autonomic tone. No clinically significant adverse events or significant pharmacologic interactions between other CV medications have been documented with these supplements. Omega-3 PUFAs are readily available through dietary sources or from purified oil capsules. After nearly 3 decades of research, we can recommend omega-3 PUFAs supplementation to many patients for the primary and secondary prevention of CV diseases.

References