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Journal of the American College of Nutrition, Vol. 27, No. 3, 367-378 (2008)
Published by the American College of Nutrition

REVIEW

Heterogeneity in Randomized Controlled Trials of Long Chain (Fish) Omega-3 Fatty Acids in Restenosis, Secondary Prevention and Ventricular Arrhythmias

David J.A. Jenkins, MD, PhD, Andrea R. Josse, MSc, Paul Dorian, MD, Michael L. Burr, MD, Roxanne LaBelle Trangmar, BSc, Cyril W.C. Kendall, PhD and Stephen C. Cunnane, PhD

Clinical Nutrition & Risk Factor Modification Center (D.J.A.J., A.R.J., R.L.T., C.W.C.K.)
Department of Medicine, and Divisions of Endocrinology and Metabolism (D.J.A.J.)
Cardiology (P.D.), St. Michael's Hospital
Departments of Nutritional Sciences (D.J.A.J., A.R.J., R.L.T., C.W.C.K.)
Medicine (D.J.A.J.), Faculty of Medicine, University of Toronto, Toronto
Ontario, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan (C.W.C.K.)
Research Center on Aging, Université de Sherbrooke, Québec (S.C.C.), CANADA
Department of Epidemiology, Statistics and Public Health, Cardiff University, Wales, UNITED KINGDOM (M.L.B.)

Address correspondence to David J.A. Jenkins, Clinical Nutrition and Risk Factor Modification Center, St. Michael's Hospital, 61 Queen St. East, Toronto, Ontario, CANADA, M5C 2T2. E-mail: cyril.kendall{at}utoronto.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Randomized controlled trials of marine omega-3 fatty acid supplementation in relation to coronary heart disease (CHD) have inconsistent outcomes, yet public health messages are uniformly positive. Originally, fish were seen as a low saturated fat protein source, and later as a valuable source of omega-3 fatty acids. Early trials indicated that increased fish oil consumption prevented restenosis after coronary angioplasty. Later trials demonstrated that fish oils prolonged life post myocardial infarction (MI). Currently, the potential antiarrhythmic effects of fish derived omega-3 fatty acids are seen as the primary reason for cardiac benefits, as suggested by one trial with compliant subjects with implantable cardioverter defibrillators (ICDs), and sudden death reduction in a post MI trial.

However, the earlier benefits of EPA and DHA on restenosis have only been confirmed in a subgroup in a recent meta-analysis. Newer data indicate that fish oils may increase CHD events in men with angina. Furthermore, in two of three trials in patients with ICDs and a history of ventricular arrhythmias, fish oils showed no significant benefit or even increased the risk of appropriate ICD discharge.

Certain groups of individuals may benefit from long-chain omega-3 fatty acids while others, including men with angina and some individuals with a history of ventricular arrhythmia, may not. Due to significant heterogeneity in the response to fish oils, further studies are required before making widespread recommendations for all groups to increase consumption of fish and fish oil.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Currently, advice is given to the general population and especially to those at risk for coronary heart disease (CHD) to eat more fish, specifically fatty fish including salmon, trout, and mackerel [1,2]. The Food and Drug Administration (FDA) have allowed a qualified health claim for fish oil (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) based on its effects on CHD risk reduction [3]. The emphasis has been to meet the need for long chain omega-3 polyunsaturated fatty acids found in fish, in which contemporary Western diets are considered relatively deficient [4]. Nevertheless, despite numerous examples of the cardiovascular benefits of fish oil, supported by mechanistic studies, a recent Cochrane review concluded that long-chain omega-3 fatty acids did not have a clear effect on combined cardiovascular events nor did they affect total mortality or cancer [5]. Our aim, therefore, was to trace the evolution of interest in fish, and review the risks and benefits of increased consumption of marine omega-3 fatty acids identified through randomized controlled trials (RCTs) of patients with CHD. Specifically, we have reviewed the RCT data in three areas of interest: restenosis after coronary angioplasty; secondary prevention of myocardial infarction (MI); and ventricular arrhythmias in patients with implantable cardioverter defibrillators (ICDs). There have already been recent meta-analyses on omega-3 marine oils and restenosis and MI. At present, there are only three published studies on the prevention of ventricular arrhythmias in patients with ICDs. Other issues including the significance of contaminants in fish have also been reviewed recently [6].

Improvements in CHD Risk Factors
There is general interest in fish oils as a source of benefit for many major chronic diseases including cardiovascular disease, cancer, and autoimmune inflammatory disorders [1,2,7–14]. It has been demonstrated that long chain, omega-3 fatty acids reduce serum VLDL triglyceride levels [15–18]. However, despite the reduction in triglycerides, the results on LDL particle size have been inconsistent [19–21]. These fatty acids are also considered to reduce thrombosis risk associated with their ability to decrease platelet adhesiveness [22–24] and prolong bleeding times [25–27]. It has been reasoned that long chain omega-3 fatty acids will reduce inflammation by countering the influence of the eicosanoids derived from the omega-6 polyunsaturated fatty acids. EPA in particular, competes with the omega-6 fatty acid, arachidonic acid, for prostaglandin synthase, resulting in lower levels of the more pro-inflammatory and pro-aggregatory type-2 eicosanoids and type-4 leukotrienes, and increased amounts of the less reactive omega-3 series, i.e. PGE3, PGI3 and thromboxane-A3 [22–24,27].

Fish oils have also been reported to reduce heart rate (1.6 bpm for 0.8–15 g/d fish oil) [28], blood pressure [29], systemic markers of inflammation, vasoconstrictive responses to angiotensin II and improve arteriolar wall compliance and left ventricular diastolic filling [24,30–34].

Further studies [35] have demonstrated reductions in gene expression of platelet derived growth factor (PDGF) and monocyte chemoattractant protein (MCP-1) after 4 weeks of fish oil supplementation, even though inflammatory markers, including E-selectin and sVCAM-1, increased following fish oil [36,37]. Furthermore, DHA in non-esterified fatty acids (NEFA) related positively to sVCAM-1 in elderly men supplemented for 18 months with fish oil [38]. It is therefore not surprising that fish oil supplementation has consistently been seen to have no effect on C-reactive protein (CRP) concentrations [36,39–43]. In this respect, however, it is of particular interest that genetic differences may explain some of the different responses seen to fish oil. Some individuals may benefit from fish oil supplementation dependent on polymorphisms in the endothelial nitric oxide synthase gene (eNOS) [44] and the inflammatory cytokine tumor necrosis-alpha (TNF-{alpha}) gene [45].

Clinical Evidence in High Risk Groups
1) Angioplasty
In the late 1980's and early 1990's, studies indicated that fish oil consumption would reduce the incidence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty [46,47]. A 1993 meta-analysis concluded that supplemental omega-3 fatty acids would reduce risk for restenosis by 14% [47]. However, in the mid to late 1990's, convincing evidence for a lack of effect came from two large studies, one multi-centre study by Leaf and colleagues [48], and the other, the coronary artery restenosis trial (CART) by Johansen et al.[49]. Both studies randomized approximately 500 people to receive fish oil, or an equivalent dose of control oil. Subjects were instructed to take the supplement for 6 months. Leaf et al. showed that restenosis occurred in 52% of subjects taking fish oil and in 46% of the placebo group [48]. In the CART study, restenosis occurred in 40% of patients treated with fish oil, and in 35% of patients in the control group [49].

Most recently, a new meta-analysis [50] of omega-3 fatty acids on coronary restenosis identified sixteen studies which evaluated coronary angiography parameters. Assessment of the 12 RCTs showed no significant reduction in coronary artery restenosis with fish oil supplementation (RR 0.87, 95% CI: 0.73–1.05, P = 0.16). In the 5 RCTs which defined restenosis as recurrent stenosis of at least 50% in any vessel, a significant protective effect was observed (RR 0.68, 95% CI: 0.53–0.87, P = 0.002). Surprisingly, the study by Alexander Leaf [48], the second largest study undertaken on this topic, was omitted from this meta-analysis. This appears to be because the meta-analysis only included studies where the omega-3 fish oil supplement was <6 g/d. The authors of the meta-analysis commented that this cut-off was used for reasons of "practicality" since they considered it unreasonable for patients to consume more than 12 capsules a day. The Leaf study supplement was 6.8 g/d of DHA + EPA, but only 10 capsules per day [48]. Therefore, the conclusion of a weak benefit of fish oils in this meta-analysis must be questioned especially as it was only seen in a subgroup.

Of greater importance for cardiovascular disease, especially in primary prevention, is the stability of the atherosclerotic plaque. The post-balloon angioplasty restenosis model involves smooth muscle cell migration rather than lipid accumulation, plaque rupture and arterio-thrombosis; the unmodified, natural history of coronary artery occlusion. In this respect, it is of interest that 1.4 g/d of fish oil supplementation for a median of 42 days improved the histological appearance of atherosclerotic plaques, indicative of stability, in 188 patients who had their plaques removed by carotid endarterectomy [14]. Obviously, until direct means of assessing plaque stability become available, the true efficacy of fish oils on CHD prognosis will remain speculative.

Table 1 lists the RCTs that have examined the effects of DHA and EPA on restenosis since the early 1980's.


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  		Table 1. Randomized Controlled Trials Supporting (Pro) or Not Supporting (Con) the Use of Omega-3 Fatty Acids in Reducing Restenosis after Angioplasty

 
2) Secondary Prevention: The Basis for Dietary Advice
At a time when interest was high in fish oil supplementation to prevent restenosis after angioplasty, the first high impact, randomized controlled trial of fish and fish oil consumption on CHD risk reduction after myocardial infarction, the Diet and Reinfarction Trial (DART), was undertaken [51]. DART was a factorial design (which also studied the cardioprotective effects of dietary advice to reduce total fat and/or increase fruit and vegetable intakes) where approximately 1,000 men who had suffered a myocardial infarction were advised to eat fatty fish (mackerel, herring, kipper, pickerel, sardine, salmon or trout). If they chose not to consume the minimum dose of two weekly portions of fish (200 g-400 g), they were provided with and instructed to take 3 fish oil (MaxEPA) capsules providing 0.9 g of EPA + DHA daily. An equal number of men not so advised served as controls. After two years, 22% of the men were taking fish oil capsules, and total mortality in the fish and fish oil group was reduced by 29% compared with the controls (9.3% versus 12.8%). Ischemic heart disease (IHD) deaths showed a similar percentage reduction, with no change in serum cholesterol. Furthermore, the survival curves started to diverge by 100 days, reached a maximum by 200–300 days, and remained parallel for the duration of the study.

This study was followed ten years later by the second high impact randomized controlled trial, the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) trial, which supported the DART. It was an open label trial of fish oil capsules delivering a combined total of 850–882 mg EPA and DHA (1.2:1) daily [52]. Like the DART, this study also utilized a factorial design, only here, the separate and combined effects of fish oil and vitamin E (300 mg/d) was tested. The total number of patients involved was 11,324 divided into 4 groups, each of approximately 2800 individuals; all of whom had suffered a myocardial infarction (MI) in the previous 3 months. Over the following 3.5 years, by two way analysis, the primary end point of total mortality and non-fatal MI and stroke was reduced by 10% (12.6 deaths per 100 subjects versus 13.9 deaths per 100 subjects; P = 0.048). The advantage of fish oil over the control increased to 30% after 4-way analysis only if cardiovascular mortality was included. However, the greatest effect of fish oil was on sudden cardiac death for which the 4-way analysis showed a 45% reduction (P = 0.01). A non-significant increase (20%) in fatal or non-fatal stroke was also seen but the numbers were too small to draw firm conclusions. No post-treatment body weight or blood pressure data were reported. The only lipid change at 6 months was a small (6%) reduction in serum triglyceride. The GISSI data were interpreted as confirming the antiarrhythmic effects of omega-3 fatty acids as demonstrated experimentally in dogs [53], and explained mechanistically by Kang and Leaf [54], rather than the reversal of arteriosclerosis. This conclusion was further supported by the major benefit on sudden cardiac death, and was in agreement with DART where the effect was also seen too soon to be associated with significant regression of atheroma.

The conclusions of the DART and GISSI studies are in agreement with the data from most large cohort studies including the Zutphen Study [55], the MRFIT trial [56], the Honolulu Heart Program [57], the Western Electric Study [58], the US Physicians Health Study [59], and the Nurses Health Study [60], although a recent large Japanese study noted only an effect on non-fatal CHD [61].

Based on such data, in 2004, FDA recommended that, "a well balanced diet that includes a variety of fish and shellfish can contribute to a healthy heart and to healthy, well-developed children [62]. Furthermore, the American Heart Association (AHA) recommended that healthy adults eat at least two servings of preferably oily fish per week such as mackerel, lake trout, herring, sardines, albacore tuna and salmon [1]. Based on typical serving sizes (4 oz) and considering the fatty acid composition of typical oily fish, these recommendations would translate into about 33 g of fish per day providing approximately 400–500 mg of EPA + DHA. Although the AHA recognized that marine omega-3 fatty acids may help reduce the risk of CHD or its complications, they maintained that "additional studies are needed to confirm and further define the health benefits of omega-3 fatty acid supplements for both primary and secondary prevention" [1]. Therefore, there is still a perceived need for more RCTs to help establish the utility of fish and fish oil in high risk populations before general recommendations can be made.

This dietary approach has also been recommended because it would help move the typical Western diet closer to the Mediterranean diet (more specifically the Greek pattern of eating described by Trichopoulou et al. [63]), where fish intake was about 21 g/d. This eating pattern was proposed long ago by Ancel Keys [64] and more recently by others [65,66] as a model for healthy eating. However, there are many facets of the Mediterranean diet which may confer benefits on cardiovascular risk.

Secondary Prevention: Recent Data
By early 2007, the two most quoted papers which relate to fish or fish oil consumption and CHD were the DART and GISSI studies, cited 1,056 and 1,099 times, respectively. More recent and less recognized studies include a further RCT involving fish advice or MaxEPA capsules (3 g/d of fish oil) given to men with angina (DART 2) [67] with 58 citations, and the Japan EPA Lipid Intervention Study (JELIS), which was just recently published in March 2007 [68].

The less cited DART 2, published in 2003, investigated the effect of increasing omega-3 fatty acid intake from fish in patients who suffered from angina pectoris [67]. The dietary advice included; 1) to eat two portions of oily fish each week or 3 fish oil capsules daily, 2) to eat more fruit, vegetables and nuts, 3) to combine the fish and vegetable advice, or 4) no specific advice. The fish and fish oil group increased their weekly EPA intake by approximately 2.4 g, and at the 6-month visit, serum levels had risen by approximately 30% in the 2% of the population tested. Compliance with the fish advice was better than that with the fruit and vegetable advice for which compliance was considered poor. Death over 3–9 years was assessed by accessing the central records of the British National Health Service. Surprisingly, the risk of cardiac death was higher among subjects advised to take oily fish than among those not so advised. The adjusted hazard ratio was 1.26 (95% CI: 1.00, 1.58; P = 0.047) and was even greater for sudden cardiac death (1.54, 95% CI: 1.06, 2.23; P = 0.025). The excess mortality was largely seen in the sub-group given fish oil capsules at randomization (cardiac death RR 1.45, CI: 1.05, 1.99; p = 0.024; and sudden death RR 1.84, CI: 1.11, 3.05; p = 0.018). These findings were unexpected, and the authors discussed at great length possible explanations. What is particularly disconcerting about this study is that, with essentially the same intervention as the very successful DART 1 study, but using a different patient population, precisely the opposite results were obtained. Although this was a relatively small study by comparison with GISSI, the total number of deaths were substantial, with 1,017 (9%) in GISSI [52], compared to 529 (17%) in DART 2 [67].

Most recently, data from JELIS have been published [68]. In this trial, 18,645 patients were divided into two groups, those who received 1,800 mg EPA plus a statin and those who received a statin alone, with a mean follow-up of 4.6 years. Analysis was performed on the group as a whole where major coronary events (RR = 0.81; CI: 0.69–0.95) and unstable angina (RR = 0.76; CI: 0.62–0.95) were significantly different, favoring the fish oil group. Fatal MI and sudden cardiac deaths were not different between treatments. These results were not materially altered when the group was further subdivided into those for whom the treatment was primary prevention and those with known cardiovascular disease for whom the treatment was secondary prevention. The case may be made that the effects on CHD may be different in an already high omega-3 fatty acid consuming population in whom CHD events were relatively low (2.8% test and 3.5% control over 4.6 years), and the low mortality (0.1% and 0.2% respectively) may make these data more difficult to extrapolate to lower fish-eating populations. Furthermore, the dose of fish oil was high.

Table 2 provides a timeline illustrating the increased interest in fish and fish oil supplementation in the secondary prevention of CHD since the early 1980's.


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  		Table 2. Randomized Controlled Trials in Secondary Prevention of Coronary Heart Disease and Subsequent Cardiac Deaths

 
3) Cardiac Arrhythmia
Early on, positive laboratory findings by Black [69] and by McLennan [70], and later by Leaf and colleagues and others had indicated that fish oils have antiarrhythmic properties. They have since been proposed to operate via inhibition of sodium and L-type calcium channels [71], and have shown to have acute antiarrhythmic effects after coronary artery ligation in the dog [72]. Induction of coronary artery occlusion during exercise in dogs produced arrhythmias which were ~80% prevented when infusions of 2–5 g of fish oil were given [53]. Omega-3 fish oils have therefore been proposed to play a role in decreasing the occurrence of fatal cardiac arrhythmias, although studies of pig ventricular myocytes interpreted the shorter action potentials as also possibly increasing risk under certain circumstances [73].

Results from prospective cohort studies of fish intake for atrial fibrillation have been promising [55,58–60,74,75]. One population-based cohort study by Mozaffarian et al. followed 4,815 adults age ≥65 years for 12 years and showed a 28% lower risk of atrial fibrillation (AF; the most common form of arrhythmia) in subjects who consumed tuna or other broiled or baked fish 1–4 times per week [76]. Also, a protective effect of fish oil was shown in an Italian RCT, in which patients undergoing coronary artery bypass graft surgery were randomized to 1,732 mg of DHA and EPA per day or usual care beginning five days pre-operatively until discharge. The fish oil patients showed a reduced incidence of AF from 33.3% in the control group to 15.2% in the test group (P = 0.013), and a shorter hospital stay from 8.2 ± 2.6 days in the control to 7.3 ± 2.1 days in the test group (P = 0.017) [77].

Conversely, in another prospective cohort study, Frost and Vestergaard [78] followed 47,949 participants for a mean of 5.7 years and reported the development of AF in 556 participants. Hazard ratios in quintiles were calculated based on amount of fish-derived omega-3 fatty acids consumed, using the lowest quintile as a baseline (0.16 g/d). The adjusted hazard ratios in quintiles 2, 3, 4 and 5 (1.29 g/d) were 0.86, 1.08, 1.01, and 1.34 (P for trend = 0.006) respectively. Thus, the highest quintile of fish-derived omega-3 fatty acid consumption was associated with the highest risk of incident AF in this Scandinavian population [78].

Results from RCTs of fish oil for the secondary prevention of ventricular tachycardia/fibrillation (VT/VF) have been more difficult to interpret. In the first of three studies, Raitt et al. randomized 200 patients with implantable cardioverter defibrillators (ICDs) and a history of sustained ventricular tachycardia (VT) or previous ventricular fibrillation (VF) in a double-blind, placebo-controlled trial to either receive 1.8 g/d fish oil (containing 42% EPA and 30% DHA) or placebo for up to 2 years [79]. No antiarrhythmic effect of fish oil was found. Indeed, there was a significant increase in risk for an ICD discharge in patients who had a history of VT (P = 0.007) [79].

The second study was reported by Leaf and colleagues [80]. They examined the effect of fish oil in ICD patients (n = 402), 35% of whom were being treated with antiarrhythmic drugs. Patients were randomized to either fish oil (2.6 g/d of EPA and DHA) or olive oil supplements for 12 months. The primary analysis showed a risk reduction of 28% (P = 0.057) in the omega-3 group. When therapies for probable episodes of VT or VF were included, the beneficial effects of fish oil increased to 31% (P = 0.033), while for those adherent to the protocol for at least 11 months, the risk reduction was 38% (P = 0.034) [80].

Most recently, the largest study of omega-3 fatty acids in ICD patients was reported by Brouwer et al [81]. In this multicenter, multi-country study, 544 patients were randomized to either 800 mg of EPA + DHA per day or took a look-alike vegetable oil placebo and followed for about 1 year. They found no significant effect on time to first ICD discharge with omega-3 treatment (hazard ratio [HR] = 0.86, P = 0.33). In those patients with a history of myocardial infarction (62% of sample), there was a trend towards fewer events with EPA + DHA therapy (HR = 0.76, P = 0.13). There was no evidence for any adverse effects of omega-3 fatty acids in those patients with a history of VT or VF, or with those with ejection fractions below 30% in the study.

One difference among these studies was the nature of the patient population studied. Although the average ejection fraction was similar in all studies (about 35%), around 60% of the patients in the Raitt study had New York Heart Association (NYHA) functional class III/IV heart failure, whereas only 15% of such patients were included in the Leaf study, and fewer than 3% were in the Brouwer study. In addition, none of the patients in the Raitt study were taking anti-arrhythmic drugs, whereas about 30% were doing so in the other two ICD studies. Thus, the worse outcome was seen in the trial with the most compromised patients according to the NYHA classification and only medically untreated patients. On the other hand, patients with lower ejection fractions did not fare worse than those with higher fractions. The other difference among these studies was in the dose of EPA + DHA. Intakes were about 800 mg in Brouwer, 1,300 mg in Raitt and 2,600 mg in Leaf. Since patients on omega-3 fatty acid supplements tended to do better in the studies with the lowest and the highest dose, it seems unlikely that differences in dose were responsible for the reported effects. The extent to which differences in patient populations played a role in the divergent results between these three studies remains an unresolved question.

Table 3 summarizes the data on the antiarrhythmic effect of fish and fish oil.


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  		Table 3. Randomized Controlled Trials in Fatal Cardiac Arrhythmia and Ventricular Tachycardia (VT) or Fibrillation (VF), Reduced (Pro) or Not Reduced (Con) When Treated with Fish Oil

 
4) Proposed Mechanism of Action of Fish Oil and Potential Adverse Events
Leaf suggested that fish oils will eliminate partially depolarized heart cells from functioning, and that after an acute myocardial infarction, elimination of these cells at the junction between ischemic and normally perfused myocardium will reduce the risk of fatal arrhythmias [82]. In this hypothesis, if the heart shows widespread ischemic changes (as may have been the case in the DART 2 angina study [67]), remaining cardiac action is carried out by partially depolarized myocytes [82], and fish oils will tend to eliminate these remaining active cardiomyocytes resulting in increased mortality [82]. This hypothesis has prompted Leaf to warn that patients with an advanced state of impaired cardiac function should not be given advice to take fish oil supplements or increase fish intake [82].

Contrary to this hypothesis, in two ICD studies [79,80], and the post-hoc analysis of the GISSI study [83], subjects with worse left ventricular function appeared to derive the greatest benefit from fish oils in terms of arrhythmia control and sudden death. In addition to the physiological state of the heart, potential DHA/EPA-drug/nutrient interactions may also be important. Of the three studies of patients with ICDs [79–81], the one study which showed a benefit for fish oil [80], and the one showing no adverse effects in patients with a history of MI [81] were the ones in which approximately 30% of patients were taking the antiarrhythmic drugs sotalol and amiodarone. In the latter study, there was no difference in outcomes for those not taking these drugs compared to the group as a whole [81], and no subgroup analyses were reported by Leaf et al [80]. Hence, we have only suggestive evidence for a possible fish oil-drug interaction. Further evidence for a potential interaction comes from the DART 2 [84] where it was noted that β-blockers and calcium channel blockers (nifedipine) appeared to protect against the adverse effects of fish.

Given the differences in outcomes in the clinical trials, and the unanswered questions, it is clear that not all "cardiac" patients should be advised to increase their omega-3 intake. Although the AHA recommended an increase in marine omega-3 intake for patients with coronary heart disease, caution was expressed that more studies were required [1]. Patients with rhythm problems warranting the implantation of an ICD may not have CHD, but may have other cardiac diseases, such as dilated non-coronary cardiomyopathy or genetic anomalies, in which fish oils have been little studied [85]. The challenge remains to determine precisely which patients will and will not benefit from long-chain omega-3 fatty acid supplementation, and additional studies designed specifically to address this question will be required. There are currently trials on-going that hopefully will provide some answers. For example, the GISSI Heart Failure trial [86], grew out of the post-hoc observation in the GISSI-Prevenzione trial [52], that the greatest sudden death benefit was seen among those patients with left ventricular dysfunction [83]. The GISSI heart failure trial is therefore randomizing such patients to either fish oil (1 g/d) or placebo using a double blind, event-driven design, aiming for a 15% reduction in all-cause mortality as the primary endpoint [86]. Whether the heart failure patients will follow the pattern of those with a lower ejection fraction in receiving benefit from fish oils, as seen with the ICD trials [79–81], or possibly harm, as in the angina study [67], remains an open question.

5) DHA, Depression and Coronary Syndromes
A potentially important area which has received little discussion is the impact of fish oils on depressive symptoms in CHD patients, which may in part, mediate a better prognosis. There has been much debate over the effect of DHA supplementation in brain development and cognition in neonates and infants, but the effect of long-chain omega-3 fatty acids on adult mental function is only now becoming of interest. Depression is associated with a worse prognosis in patients with CHD [87,88] including post-MI [89,90], unstable angina [91], post-bypass [92] and congestive heart failure [93]. Furthermore, those with a preceding history of depression are significantly more likely to develop cardiovascular conditions ranging from acute MI to heart failure [94–96]. It is therefore of interest that studies are now emerging which assess the effects of serum long-chain omega-3 fatty acids in depression and acute coronary syndromes. As yet, the ability of DHA to reduce depression has not been linked to prognosis. Nevertheless, it has been suggested that the lower the omega-3 fatty acid concentrations and the higher the omega-6 to omega-3 ratio in patients with acute coronary syndromes, the greater the likelihood of depression [87,97]. An additional aspect of the relation of omega-3 fatty acids and hear disease may therefore involve central nervous system (CNS) linkages.

6) Dose
Although no dose response studies have been undertaken, a recent analysis of prospective cohort and RCT studies of fish and fish oil and relative risk of CHD death indicated an apparent dose response with a maximum effect at 250 mg/d of EPA and DHA [6]. Successful RCTs of fish oils reviewed here have used doses ranging from 0.85 g/d [52] to 5.4 g/d [98]. The corresponding range for trials which did not show benefit was from 1.3 g/d (EPA + DHA) [79] to 6.9 g/d (EPA + DHA) [48]. Most cohort studies have shown significant inverse associations between fish/fish oil intake and CHD [99]. However, one large Danish cohort study demonstrated a positive association between fish oil intake and atrial fibrillation [78] while a Greek study showed a J-shaped association for fish intake and the odds of developing acute coronary syndromes [100].

It is possible that the earlier successes of RCTs using fish oils to prevent restenosis after angioplasty were due to the lower fish oil intakes used [46,47], compared to later studies (8 g/d [48]; 5 g/d [49]). However, dose does not explain the discrepancy in the effects on VF/VT in the ICD studies as noted above.

Current data suggest that no additional benefit is obtained above 250 mg/d of fish oil supplementation [6]. No data exist to determine whether the dose is different for different individuals, or whether there is an effective or safe upper level.

7) Genetic Differences
The situation is clearly complex, probably involving dose, the condition of the heart (ischemic, scarred, or heart failure), and genetic makeup. Genetic differences may include polymorphisms which influence the rate of conversion of short to long chain omega-3 fatty acids. Although specific polymorphisms favoring conversion of short to long-chain omega-3 fatty acids have not yet been identified, increased short chain omega-3 fatty acid intakes (alpha-linolenic acid) have been associated with reduced risk for CHD in some RCTs and cohort studies [101,102]. In relation to blood lipids, the apoE4 genotype has been associated with raising LDL-C on fish oil supplementation [19]. Furthermore, as already alluded to earlier, polymorphisms in the TNF-{alpha} gene and the eNOS gene may determine whether benefit is derived by fish oil [44,45]. These data explain why only 6 out of 11 studies of fish oil supplementation reported a suppressive effect of fish oil on TNF-{alpha} production by peripheral blood mononuclear cells [45]. Although genetic differences cannot be used to explain differences in the present studies, emerging data on the influence of genes on the metabolism of nutrients and food components in relation to CHD is making this line of research increasingly relevant [103].

8) Source of EPA and DHA
At the same time as fish consumption is being recommended as a means of reducing the risk for CHD, concerns have arisen over the contamination of fish with mercury and polychlorinated biphenols (PCBs) [1,6,104]. Furthermore, fish supplies in the wild have been greatly reduced [105], and there is also concern over the ecological effects of large scale captive breeding for food [106]. However, demand may be met from phytoplankton and monocellular organisms as currently used to produce DHA for infant formula [107]. Pure supplies of DHA and EPA will allow the necessary standardization of therapeutic interventions with precise dosage monitored by serum and red blood cell DHA and EPA concentration using metrics such as the omega-3 index [108].


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSION
ACKNOWLEDGMENTS
 REFERENCES
 
Fish oils have complex and pleiotropic effects on myocardial function. Divergent results have been reported from trials with different patient populations with differing pathophysiologies and therapeutic regimens. Randomized controlled trials have indicated that DHA and EPA supplementation can reduce cardiac events. However, current data suggest that caution must be exercised in certain subgroups, notably patients with ICD's who have a history of VT, heart failure and are not taking anti-arrhythmic medications. Caution may also be needed in men with stable angina. Further studies are essential in order to establish the extent to which long-chain omega-3 fatty acids can be used in the treatment of cardiovascular disease.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSION
 ACKNOWLEDGMENTS
REFERENCES
 
The authors wish to acknowledge the valuable insights and helpful criticism of Dr. Dariush Mozaffarian and Dr. Eric Rimm. S.C.C. was supported by the Canadian Research Chairs, CFI, CIHR and NSERC.

Received February 19, 2007. Accepted May 25, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 


  1. Kris-Etherton PM, Harris WS, Appel LJ: Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation106 :2747 –2757,2002 .[Free Full Text]

  2. Bucher HC, Hengstler P, Schindler C, Meier G: N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med112 :298 –304,2002 .[Medline]

  3. FDA: FDA Announces Qualified Health Claims for Omega-3 Fatty Acids. Available at: http://www.fda.gov/bbs/topics/news/2004/NEW01115.html

  4. Crawford MA, Bloom M, Broadhurst CL, Schmidt WF, Cunnane SC, Galli C, Gehbremeskel K, Linseisen F, Lloyd-Smith J, Parkington J: Evidence for the unique function of docosahexaenoic acid during the evolution of the modern hominid brain. Lipids34 (Suppl):S39 –S47,1999 .[Medline]

  5. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA, Ebrahim SB, Davey Smith G: Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ332 :752 –760,2006 .[Abstract/Free Full Text]

  6. Mozaffarian D, Rimm EB: Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA296 :1885 –1899,2006 .[Abstract/Free Full Text]

  7. Simopoulos AP: Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr21 :495 –505,2002 .[Abstract/Free Full Text]

  8. Kris-Etherton PM, Harris WS, Appel LJ: Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vase Biol23 :E20 –E30,2003 .

  9. Shahidi F, Miraliakbari H: Omega-3 (n-3) fatty acids in health and disease: Part 1--cardiovascular disease and cancer. J Med Food7 :387 –401,2004 .[Medline]

  10. Mozaffarian D, Ascherio A, Hu FB, Stampfer MJ, Willett WC, Siscovick DS, Rimm EB: Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation111 :157 –164,2005 .[Abstract/Free Full Text]

  11. von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H: The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med130 :554 –562,1999 .[Abstract/Free Full Text]

  12. Yokoyama M, Origasa H: Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J146 :613 –620,2003 .[Medline]

  13. Schrepf R, Limmert T, Claus Weber P, Theisen K, Sellmayer A: Immediate effects of n-3 fatty acid infusion on the induction of sustained ventricular tachycardia. Lancet363 :1441 –1442,2004 .[Medline]

  14. Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP, Gallagher PJ, Calder PC, Grimble RF: Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet361 :477 –485,2003 .[Medline]

  15. Phillipson BE, Rothrock DW, Connor WE, Harris WS, Illingworth DR: Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia. N Engl J Med312 :1210 –1216,1985 .[Abstract]

  16. Lu G, Windsor SL, Harris WS: Omega-3 fatty acids alter lipoprotein subfraction distributions and the in vitro conversion of very low density lipoproteins to low density lipoproteins. J Nutr Biochem10 :151 –158,1999 .[Medline]

  17. Harris WS, Windsor SL, Dujovne CA: Effects of four doses of n-3 fatty acids given to hyperlipidemic patients for six months. J Am Coll Nutr10 :220 –227,1991 .[Abstract]

  18. Harris WS, Connor WE, McMurry MP: The comparative reductions of the plasma lipids and lipoproteins by dietary polyunsaturated fats: salmon oil versus vegetable oils. Metabolism32 :179 –184,1983 .[Medline]

  19. Minihane AM, Khan S, Leigh-Firbank EC, Talmud P, Wright JW, Murphy MC, Griffin BA, Williams CM: ApoE polymorphism and fish oil supplementation in subjects with an atherogenic lipoprotein phenotype. Arterioscler Thromb Vasc Biol20 :1990 –1997,2000 .[Abstract/Free Full Text]

  20. Li Z, Lamon-Fava S, Otvos J, Lichtenstein AH, Velez-Carrasco W, McNamara JR, Ordovas JM, Schaefer EJ: Fish consumption shifts lipoprotein subfractions to a less atherogenic pattern in humans. J Nutr134 :1724 –1728,2004 .[Abstract/Free Full Text]

  21. Rivellese AA, Maffettone A, Vessby B, Uusitupa M, Hermansen K, Berglund L, Louheranta A, Meyer BJ, Riccardi G: Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects. Atherosclerosis167 :149 –158,2003 .[Medline]

  22. Holub BJ: Dietary fish oils containing eicosapentaenoic acid and the prevention of atherosclerosis and thrombosis. CMAJ139 :377 –381,1988 .[Abstract]

  23. Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ: The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr63 :116 –122,1996 .[Abstract/Free Full Text]

  24. James MJ, Gibson RA, Cleland LG: Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr71 :343S –348S,2000 .[Abstract/Free Full Text]

  25. Dyerberg J, Bang HO: Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet2 :433 –435,1979 .[Medline]

  26. Bang HO, Dyerberg J, Sinclair HM: The composition of the Eskimo food in north western Greenland. Am J Clin Nutr33 :2657 –2661,1980 .[Abstract/Free Full Text]

  27. Knapp HR: Dietary fatty acids in human thrombosis and hemostasis. Am J Clin Nutr65 :1687S –1698S,1997 .[Medline]

  28. Mozaffarian D, Geelen A, Brouwer IA, Geleijnse JM, Zock PL, Katan MB: Effect of fish oil on heart rate in humans: a meta-analysis of randomized controlled trials. Circulation112 :1945 –1952,2005 .[Abstract/Free Full Text]

  29. Morris MC, Sacks F, Rosner B: Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation88 :523 –533,1993 .[Abstract/Free Full Text]

  30. Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ: Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens20 :1493 –1499,2002 .[Medline]

  31. Chin JP, Gust AP, Nestel PJ, Dart AM: Marine oils dose-dependently inhibit vasoconstriction of forearm resistance vessels in humans. Hypertension21 :22 –28,1993 .[Abstract/Free Full Text]

  32. Kenny D, Warltier DC, Pleuss JA, Hoffmann RG, Goodfriend TL, Egan BM: Effect of omega-3 fatty acids on the vascular response to angiotensin in normotensive men. Am J Cardiol70 :1347 –1352,1992 .[Medline]

  33. McVeigh GE, Brennan GM, Cohn JN, Finkelstein SM, Hayes RJ, Johnston GD: Fish oil improves arterial compliance in non-insulin-dependent diabetes mellitus. Arterioscler Thromb14 :1425 –1429,1994 .[Abstract/Free Full Text]

  34. Grimsgaard S, Bonaa KH, Hansen JB, Myhre ES: Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemodynamics in humans. Am J Clin Nutr68 :52 –59,1998 .[Abstract]

  35. Baumann KH, Hessel F, Larass I, Muller T, Angerer P, Kiefl R, von Schacky C: Dietary omega-3, omega-6, and omega-9 unsaturated fatty acids and growth factor and cytokine gene expression in unstimulated and stimulated monocytes. A randomized volunteer study. Arterioscler Thromb Vase Biol19 :59 –66,1999 .

  36. Grundt H, Nilsen DW, Mansoor MA, Hetland O, Nordoy A: Reduction in homocysteine by n-3 polyunsaturated fatty acids after 1 year in a randomised double-blind study following an acute myocardial infarction: no effect on endothelial adhesion properties. Pathophysiol Haemost Thromb33 :88 –95,2003 .[Medline]

  37. Johansen O, Seljeflot I, Hostmark AT, Arnesen H: The effect of supplementation with omega-3 fatty acids on soluble markers of endothelial function in patients with coronary heart disease. Arterioscler Thromb Vase Biol19 :1681 –1686,1999 .

  38. Berstad P, Seljeflot I, Veierod MB, Hjerkinn EM, Arnesen H, Pedersen JI: Supplementation with fish oil affects the association between very long-chain n-3 polyunsaturated fatty acids in serum non-esterified fatty acids and soluble vascular cell adhesion molecule-1. Clin Sci (Lond)105 :13 –20,2003 .[Medline]

  39. Seierstad SL, Seljeflot I, Johansen O, Hansen R, Haugen M, Rosenlund G, Froyland L, Arnesen H: Dietary intake of differently fed salmon; the influence on markers of human atherosclerosis. Eur J Clin Invest35 :52 –59,2005 .[Medline]

  40. Geelen A, Brouwer IA, Schouten EG, Kluft C, Katan MB, Zock PL: Intake of n-3 fatty acids from fish does not lower serum concentrations of C-reactive protein in healthy subjects. Eur J Clin Nutr58 :1440 –1442,2004 .[Medline]

  41. Vega-Lopez S, Kaul N, Devaraj S, Cai RY, German B, Jialal I: Supplementation with omega3 polyunsaturated fatty acids and all-rac alpha-tocopherol alone and in combination failed to exert an anti-inflammatory effect in human volunteers. Metabolism53 :236 –240,2004 .[Medline]

  42. Chan DC, Watts GF, Barrett PH, Beilin LJ, Mori TA: Effect of atorvastatin and fish oil on plasma high-sensitivity C-reactive protein concentrations in individuals with visceral obesity. Clin Chem48 :877 –883,2002 .[Abstract/Free Full Text]

  43. Basu A, Devaraj S, Jialal I: Dietary Factors That Promote or Retard Inflammation. Arterioscler Thromb Vase Biol26 :995 –1001,2006 .

  44. Leeson CP, Hingorani AD, Mullen MJ, Jeerooburkhan N, Kattenhorn M, Cole TJ, Muller DP, Lucas A, Humphries SE, Deanfield JE: Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function. Circ Res90 :1153 –1158,2002 .[Abstract/Free Full Text]

  45. Grimble RF, Howell WM, O'Reilly G, Turner SJ, Markovic O, Hirrell S, East JM, Calder PC: The ability of fish oil to suppress tumor necrosis factor alpha production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor alpha production. Am J Clin Nutr76 :454 –459,2002 .[Abstract/Free Full Text]

  46. O'Connor GT, Malenka DJ, Olmstead EM, Johnson PS, Hennekens CH: A meta-analysis of randomized trials of fish oil in prevention of restenosis following coronary angioplasty. Am J Prev Med8 :186 –192,1992 .[Medline]

  47. Gapinski JP, VanRuiswyk JV, Heudebert GR, Schectman GS: Preventing restenosis with fish oils following coronary angioplasty. A meta-analysis. Arch Intern Med153 :1595 –1601,1993 .[Abstract/Free Full Text]

  48. Leaf A, Jorgensen MB, Jacobs AK, Cote G, Schoenfeld DA, Scheer J, Weiner BH, Slack JD, Kellett MA, Raizner AE, et al.: Do fish oils prevent restenosis after coronary angioplasty? Circulation90 :2248 –2257,1994 .[Abstract/Free Full Text]

  49. Johansen O, Brekke M, Seljeflot I, Abdelnoor M, Arnesen H: N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial. J Am Coll Cardiol33 :1619 –1626,1999 .[Abstract/Free Full Text]

  50. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J: Effects of omega-3 fatty acids on coronary restenosis, intima-media thickness, and exercise tolerance: a systematic review. Atherosclerosis184 ,2006 .

  51. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM: Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet2 :757 –761,1989 .[Medline]

  52. GISSI-Prevenzione: Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'lnfarto miocardico. Lancet354 :447 –455,1999 .[Medline]

  53. Billman GE, Kang JX, Leaf A: Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation99 :2452 –2457,1999 .[Abstract/Free Full Text]

  54. Kang JX, Leaf A: Antiarrhythmic effects of polyunsaturated fatty acids. Recent studies. Circulation94 :1774 –1780,1996 .[Free Full Text]

  55. Kromhout D, Bosschieter EB, de Lezenne Coulander C: The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med312 :1205 –1209,1985 .[Abstract]

  56. Dolecek TA: Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial. Proc Soc Exp Biol Med200 :177 –182,1992 .[Medline]

  57. Rodriguez BL, Sharp DS, Abbott RD, Burchfiel CM, Masaki K, Chyou PH, Huang B, Yano K, Curb JD: Fish intake may limit the increase in risk of coronary heart disease morbidity and mortality among heavy smokers. The Honolulu Heart Program. Circulation94 :952 –956,1996 .[Abstract/Free Full Text]

  58. Daviglus ML, Stamler J, Orencia AJ, Dyer AR, Liu K, Greenland P, Walsh MK, Morris D, Shekelle RB: Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med336 :1046 –1053,1997 .[Abstract/Free Full Text]

  59. Albert CM, Hennekens CH, O'Donnell CJ, Ajani UA, Carey VJ, Willett WC, Ruskin JN, Manson JE: Fish consumption and risk of sudden cardiac death. JAMA279 :23 –28,1998 .[Abstract/Free Full Text]

  60. Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, Albert CM, Hunter D, Manson JE: Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA287 :1815 –1821,2002 .[Abstract/Free Full Text]

  61. Iso H, Kobayashi M, Ishihara J, Sasaki S, Okada K, Kita Y, Kokubo Y, Tsugane S: Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I. Circulation113 :195 –202,2006 .[Abstract/Free Full Text]

  62. FDA: FDA, EPA Revised Guidelines on Mercury in Fish,2004 .

  63. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D: Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med348 :2599 –2608,2003 .[Abstract/Free Full Text]

  64. Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, Djordjevic BS, Dontas AS, Fidanza F, Keys MH, et al.: The diet and 15-year death rate in the seven countries study. Am J Epidemiol124 :903 –915,1986 .[Abstract/Free Full Text]

  65. Willett WC, Sacks F, Trichopoulou A, Drescher G, Ferro-Luzzi A, Helsing E, Trichopoulos D: Mediterranean diet pyramid: a cultural model for healthy eating. Am J Clin Nutr61 :1402S –1406S,1995 .[Medline]

  66. Renaud S, de Lorgeril M, Delaye J, Guidollet J, Jacquard F, Mamelle N, Martin JL, Monjaud I, Salen P, Toubol P: Cretan Mediterranean diet for prevention of coronary heart disease. Am J Clin Nutr61 :1360S –1367S,1995 .

  67. Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, Zotos PC, Haboubi NA, Elwood PC: Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr57 :193 –200,2003 .[Medline]

  68. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K: Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet369 :1090 –1098,2007 .[Medline]

  69. Black KL, Culp B, Madison D, Randall OS, Lands WE: The protective effects of dietary fish oil on focal cerebral infarction. Prostaglandins Med3 :257 –268,1979 .[Medline]

  70. McLennan PL, Abeywardena MY, Charnock JS: Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and reperfusion. Am Heart J116 :709 –717,1988 .[Medline]

  71. Leaf A, Kang JX, Xiao YF, Billman GE, Voskuyl RA: Experimental studies on antiarrhythmic and antiseizure effects of polyunsaturated fatty acids in excitable tissues. J Nutr Biochem10 :440 –448,1999 .[Medline]

  72. Kang JX, Leaf A: Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids. Am J Clin Nutr71 .202S –207S,2000 .[Abstract/Free Full Text]

  73. Verkerk AO, van Ginneken AC, Berecki G, den Ruijter HM, Schumacher CA, Veldkamp MW, Baartscheer A, Casini S, Opthof T, Hovenier R, Fiolet JW, Zock PL, Coronel R: Incorporated sarcolemmal fish oil fatty acids shorten pig ventricular action potentials. Cardiovasc Res70 :509 –520,2006 .[Abstract/Free Full Text]

  74. Albert CM CH, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J: Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med346 :1113 –1118,2002 .[Abstract/Free Full Text]

  75. Mozaffarian D, Lemaitre RN, Kuller LH, Burke GL, Tracy RP, Siscovick DS: Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study. Circulation107 :1372 –1377,2003 .[Abstract/Free Full Text]

  76. Mozaffarian D, Psaty BM, Rimm EB, Lemaitre RN, Burke GL, Lyles MF, Lefkowitz D, Siscovick DS: Fish intake and risk of incident atrial fibrillation. Circulation110 :368 –373,2004 .[Abstract/Free Full Text]

  77. Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E, Meo A, Pandozi C, Staibano M, Santini M: N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol45 :1723 –1728,2005 .[Abstract/Free Full Text]

  78. Frost L, Vestergaard P: n-3 Fatty acids consumed from fish and risk of atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study. Am J Clin Nutr81 :50 –54,2005 .[Abstract/Free Full Text]

  79. Raitt MH, Connor WE, Morris C, Kron J, Halperin B, Chugh SS, McClelland J, Cook J, MacMurdy K, Swenson R, Connor SL, Gerhard G, Kraemer DF, Oseran D, Marchant C, Calhoun D, Shnider R, McAnulty J: Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. Jama293 :2884 –2891,2005 .[Abstract/Free Full Text]

  80. Leaf A, Albert CM, Josephson M, Steinhaus D, Kluger J, Kang JX, Cox B, Zhang H, Schoenfeld D: Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation112 :2762 –2768,2005 .[Abstract/Free Full Text]

  81. Brouwer IA, Zock PL, Camm AJ, Bocker D, Hauer RN, Wever EF, Dullemeijer C, Ronden JE, Katan MB, Lubinski A, Buschler H, Schouten EG: Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA295 :2613 –2619,2006 .[Abstract/Free Full Text]

  82. Leaf A: Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids. Fundam Clin Pharmacol20 :525 –538,2006 .[Medline]

  83. Macchia A, Levantesi G, Franzosi MG, Geraci E, Maggioni AP, Marfisi R, Nicolosi GL, Schweiger C, Tavazzi L, Tognoni G, Valagussa F, Marchioli R: Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids, Eur J Heart Fail7 :904 –909,2005 .[Abstract/Free Full Text]

  84. Burr ML, Dunstan FD, George CH: Is fish oil good or bad for heart disease? Two trials with apparently conflicting results. J Membr Biol206 :155 –163,2005 .[Medline]

  85. Connolly SJ, Hallstrom AP, Cappato R, Schron EB, Kuck KH, Zipes DP, Greene HL, Boczor S, Domanski M, Follmann D, Gent M, Roberts RS: Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. Eur Heart J21 :2071 –2078,2000 .[Abstract/Free Full Text]

  86. Tavazzi L, Tognoni G, Franzosi MG, Latini R, Maggioni AP, Marchioli R, Nicolosi GL, Porcu M: Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail6 :635 –641,2004 .[Abstract/Free Full Text]

  87. Frasure-Smith N, Lesperance F, Julien P: Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biol Psychiatry55 :891 –896,2004 .[Medline]

  88. Rozanski A, Blumenthal JA, Kaplan J: Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation99 :2192 –2217,1999 .[Abstract/Free Full Text]

  89. Frasure-Smith N, Lesperance F, Talajic M: Depression following myocardial infarction. Impact on 6-month survival. JAMA270 :1819 –1825,1993 .[Abstract/Free Full Text]

  90. Frasure-Smith N, Lesperance F, Talajic M: Depression and 18-month prognosis after myocardial infarction. Circulation91 :999 –1005,1995 .[Abstract/Free Full Text]

  91. Lesperance F, Frasure-Smith N, Juneau M, Theroux P: Depression and 1-year prognosis in unstable angina. Arch Intern Med160 :1354 –1360,2000 .[Abstract/Free Full Text]

  92. Pignay-Demaria V, Lesperance F, Demaria RG, Frasure-Smith N, Perrault LP: Depression and anxiety and outcomes of coronary artery bypass surgery. Ann Thorac Surg75 :314 –321,2003 .[Abstract/Free Full Text]

  93. Lesperance F, Frasure-Smith N, Laliberte MA, White M, Lafontaine S, Calderone A, Talajic M, Rouleau JL: An open-label study of nefazodone treatment of major depression in patients with congestive heart failure. Can J Psychiatry48 :695 –701,2003 .[Medline]

  94. Lesperance F, Frasure-Smith N, Talajic M: Major depression before and after myocardial infarction: its nature and consequences. Psychosom Med58 :99 –110,1996 .[Abstract/Free Full Text]

  95. Ariyo AA, Haan M, Tangen CM, Rutledge JC, Cushman M, Dobs A, Furberg CD: Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group. Circulation102 :1773 –1779,2000 .[Abstract/Free Full Text]

  96. Abramson J, Berger A, Krumholz HM, Vaccarino V: Depression and risk of heart failure among older persons with isolated systolic hypertension. Arch Intern Med161 :1725 –1730,2001 .[Abstract/Free Full Text]

  97. Parker GB, Heruc GA, Hilton TM, Olley A, Brotchie H, Hadzi-Pavlovic D, Friend C, Walsh WF, Stocker R: Low levels of docosahexaenoic acid identified in acute coronary syndrome patients with depression. Psychiatry Res141 :279 –286,2006 .[Medline]

  98. Dehmer GJ, Popma JJ, van den Berg EK, Eichhorn EJ, Prewitt JB, Campbell WB, Jennings L, Willerson JT, Schmitz JM: Reduction in the rate of early restenosis after coronary angioplasty by a diet supplemented with n-3 fatty acids. N Engl J Med319 :733 –740,1988 .[Abstract]

  99. He K, Song Y, Daviglus ML, Liu K, Van Horn L, Dyer AR, Greenland P: Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation109 :2705 –2711,2004 .[Abstract/Free Full Text]

  100. Panagiotakos DB, Pitsavos C, Zampelas A, Chrysohoou C, Stefanadis C: The relationship between fish consumption and the risk of developing acute coronary syndromes among smokers: the CARDIO2000 case-control study. Nutr Metab Cardiovasc Dis15 :402 –409,2005 .[Medline]

  101. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, Guidollet J, Touboul P, Delaye J: Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet343 :1454 –1459,1994 .[Medline]

  102. Mozaffarian D: Does alpha-linolenic acid intake reduce the risk of coronary heart disease? A review of the evidence. Altern Ther Health Med11 :24 –30; quiz 31, 79,2005 .[Medline]

  103. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H: Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA295 :1135 –1141,2006 .[Abstract/Free Full Text]

  104. Hites RA, Foran JA, Carpenter DO, Hamilton MC, Knuth BA, Schwager SJ: Global assessment of organic contaminants in farmed salmon. Science303 :226 –229,2004 .[Abstract/Free Full Text]

  105. Brunner E: Oily fish and omega 3 fat supplements. BMJ332 :739 –740,2006 .[Free Full Text]

  106. Naylor RL, Goldburg RJ, Primavera JH, Kautsky N, Beveridge MC, Clay J, Folke C, Lubchenco J, Mooney H, Troell M: Effect of aquaculture on world fish supplies. Nature405 :1017 –1024,2000 .[Medline]

  107. Fleith M, Clandinin MT: Dietary PUFA for preterm and term infants: review of clinical studies. Crit Rev Food Sci Nutr45 :205 –229,2005 .[Medline]

  108. Harris WS, Von Schacky C: The Omega-3 Index: a new risk factor for death from coronary heart disease? Prev Med39 :212 –220,2004 .[Medline]

  109. Milner MR, Gallino RA, Leffingwell A, Pichard AD, Brooks-Robinson S, Rosenberg J, Little T, Lindsay J, Jr.: Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol64 :294 –299,1989 .[Medline]

  110. Nye ER, Ablett MB, Robertson MC, Ilsley CD, Sutherland WH: Effect of eicosapentaenoic acid on restenosis rate, clinical course and blood lipids in patients after percutaneous transluminal coronary angioplasty. Aust N Z J Med20 :549 –552,1990 .[Medline]

  111. Grigg LE, Kay TW, Valentine PA, Larkins R, Flower DJ, Manolas EG, O'Dea K, Sinclair AJ, Hopper JL, Hunt D: Determinants of restenosis and lack of effect of dietary supplementation with eicosapentaenoic acid on the incidence of coronary artery restenosis after angioplasty. J Am Coll Cardiol13 :665 –672,1989 .[Abstract]

  112. Reis GJ, Boucher TM, Sipperly ME, Silverman DI, McCabe CH, Bairn DS, Sacks FM, Grossman W, Pasternak RC: Randomised trial of fish oil for prevention of restenosis after coronary angioplasty. Lancet2 :177 –181,1989 .[Medline]

  113. Bairati I RL, Meyer F: Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary angioplasty. Circulation85 :950 –956,1992 .[Abstract/Free Full Text]

  114. Kaul U, Sanghvi S, Bahl VK, Dev V, Wasir HS: Fish oil supplements for prevention of restenosis after coronary angioplasty. Int J Cardiol35 :87 –93,1992 .[Medline]

  115. Bellamy CM, Schofield PM, Faragher EB, Ramsdale DR: Can supplementation of diet with omega-3 polyunsaturated fatty acids reduce coronary angioplasty restenosis rate? Eur Heart J13 :1626 –1631,1992 .[Abstract/Free Full Text]

  116. Franzen D, Schannwell M, Oette K, Hopp HW: A prospective, randomized, and double-blind trial on the effect of fish oil on the incidence of restenosis following PTCA. Cathet Cardiovasc Diagn28 :301 –310,1993 .[Medline]

  117. Cairns JA, Gill J, Morton B, Roberts R, Gent M, Hirsh J, Holder D, Finnie K, Marquis JF, Naqvi S, Cohen E: Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty. The EMPAR Study. Circulation94 :1553 –1560,1996 .[Abstract/Free Full Text]

  118. Maresta A, Balduccelli M, Varani E, Marzilli M, Galli C, Heiman F, Lavezzari M, Stragliotto E, De Caterina R: Prevention of postcoronary angioplasty restenosis by omega-3 fatty acids: main results of the Esapent for Prevention of Restenosis ITalian Study (ESPRIT). Am Heart J143 :E5 ,2002 .[Medline]

  119. Singer P, Wirth M: Can n-3 PUFA reduce cardiac arrhythmias? Results of a clinical trial. Prostaglandins Leukot Essent Fatty Acids71 :153 –159,2004 .[Medline]



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A. Rosengren, J. Perk, and J. Dallongeville
CHAPTER 12 Prevention of Cardiovascular Disease
ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter.
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