A double-blind study by Raitt et al 6 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 patients with ICDs to 1. 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. In contrast to the above study, Leaf et al 7 performed a double-blind study that randomized patients with ICDs to either a fish oil or placebo for 12 months.
The patients received either four 1. The noncompliance rate was high, but similar between the 2 groups. No observable difference between the 2 groups could be found with respect to the primary endpoint. 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.
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. 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. 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.
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. Studies have established an elevated resting heart rate as an independent risk factor for CV disease and mortality.
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 al 23 found that patients with an MI and ejection fraction less than 0. 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.
No significant change was observed with ventricular conduction time. Yet another study by Geelen et al 26 supports the finding that omega-3 PUFAs lower resting heart rate. They randomly assigned 84 patients with greater than 1, premature ventricular contractions per hour period in a previous Holter recording to receive 3. After 14 weeks of therapy, they demonstrated that the mean hour heart rate was significantly lower by 2.
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.
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. 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.
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A recent large-scale, open-label, randomized, controlled trial in 11, myocardial infarction MI survivors has shown low-dose fish oil, but not vitamin E, to reduce significantly the cumulative rate of all-cause death, nonfatal MI, and nonfatal stroke.
Neither intervention significantly reduced the other primary endpoint, the cumulate rate of cardiovascular death, nonfatal MI, and nonfatal stroke. Initial experience with animal ischemia models demonstrated that the ventricular fibrillation threshold was increased in both animals fed or infused with omega-3 FA.
In the 49 patients that were randomized to either fish oil or olive oil, Holter monitor recordings showed an increase in heart rate variability in the fish oil group. Although there are no randomized data on fish oil consumption and protection from sudden death, observational studies have linked omega-3 FA with the prevention of sudden death.
In the patients that succumbed to sudden death, baseline omega-3 FA blood levels were significantly lower than in matched controls. The investigators concluded that the reduction in CAD deaths was likely due to a reduction in sudden deaths, as there was no difference in the rate of MI when comparing high and low fish consumption.
The randomized trials assessing the efficacy of fish oil supplementation on secondary prevention of CAD lend further evidence to the findings that fish oil may protect from sudden cardiac death. This was further supported by the fact that nonfatal MIs were not reduced. Although the actual modes of death other than CAD-related deaths were not documented, it has been postulated to be secondary to a reduction in sudden death. Sudden death, however, was not a primary end point.
Rather, the reduction in fatal events was driven by a reduction in cardiovascular death, which included coronary death, cardiac death, and sudden death. Three randomized trials assessing more than patients with known malignant ventricular arrhythmia were carried out under the protection of implanted cardioverter defibrillator ICD therapy.
In the first trial of its kind, patients with ICDs were randomized to either a fish oil or an olive oil supplement. This finding was not replicated in a trial of patients who were randomized to either fish oil or a placebo and followed for a median of approximately 2 years. In the largest trial, patients were randomized to supplemental fish oil or a placebo and were followed for a mean period of 1 year.
It was concluded in a recent meta-analysis of these trials that fish oil did not have a protective effect. The effect of fish oil on incident atrial fibrillation has not been studied in large randomized trials, and observational population-based trials show mixed results. Fish, however, was consumed in similar amounts by both the Western and Mediterranean diet groups.
The higher blood level of EPA in the Mediterranean diet arm was attributed to its synthesis from alpha-linolenic acid, which was times higher than the plasma concentration of EPA.
In addition, the risk reduction that occurred in this trial could not be attributed to one particular diet intervention because as the consumption of fruits and vegetables increased, the consumption of monounsaturated fat increased, while saturated fat and cholesterol were decreased. In this open-label trial, 11, post-MI patients were followed for 3.
This decreased risk occurred despite a minimal triglyceride-lowering effect because of the relatively low dose of omega-3 FA. The GISSI-Heart Failure trial was the first blinded, randomized trial to assess the efficacy of fish oil supplements in patients with heart failure.
At an average of 3. There was also a reduction in 2 other arrhythmia-related secondary end-points: first hospitalization for ventricular arrhythmia and presumed arrhythmic death. To date, no studies have assessed mortality or nonfatal MI in diabetic patients treated with fish oil. At a mean follow-up of approximately 9 weeks, triglyceride reduction was accomplished but no significant changes were seen in total cholesterol, high-density lipoprotein-cholesterol, HgA1c levels, fasting glucose levels, fasting insulin, or in body weight.
The largest randomized trial to date assessed approximately patients with impaired glucose tolerance or insulin-dependent diabetes mel-litus, and as reflected in the larger meta-analysis, found no effect of moderate to high doses of fish oil on diabetic parameters.
Several small studies have shown that combination therapy with fish oil and HMG CoA reductase inhibitors is safe. The primary outcome of any major cardiovascular event, at a mean of 4. Both unstable angina and nonfatal MI were reduced, but no change was seen in sudden death.
There was a similar rate of increase in measures of creatine phosphokinase, but more patients had an increase in aspartate aminotransferase levels 0. The rate of bleeding was 1. Fish oil combined with fenofibrate has not been studied extensively in randomized controlled trials. Data to date, however, suggest that the combination is safe and effective.
Therapy was well-tolerated without significant adverse reactions at 8 weeks or at the end of a 2-year open label extension. Fish oil supplements containing EPA and DHA are suggested as an alternative to fatty fish consumption for secondary prevention. The myriad of dietary supplements of fish oil, including Kosher capsules, vary from comparable content to insignificant amounts, and for the most part can include other fats and cholesterols. In comparison, to achieve approximately 1 g of EPA and DHA in a meal, 12 ounces of canned light tuna, 2 to 3 ounces of sardines, 1.
The FDA action level for unacceptably high mercury content in fish is 1. The mercury level in most fish is at or below 0. Dioxins, which do not have FDA action levels, are present in the majority of marine life.
The hypotriglyceridemic effect of fish oil is well established and is related to both dose and baseline triglyceride level. The most extensive data of the effect of fish oil on lipoprotein subfractions are based on trials performed before the widespread use of statins. This data were aggregated over a decade ago in a meta-analysis of 16 randomized trials including over patients.
Although a shift toward less atherogenic, larger and more buoyant LDL particle composition has been shown, 74 this has been offset by the observation that the number of apolipoprotein B particles increases and may be more susceptible to oxidation. The FDA product label on Lovaza warns of potential bleeding complications with the coadministration of anticoagulants.
This warning is based on observational studies that suggested a prolonged bleeding time in populations ingesting high levels of fish oil 77 and on in vitro studies that demonstrated an effect on pro-thrombotic mediators such as a reduction in thromboxane A2 production 78 and platelet activation factor. At 1 year, the number of bleeding complications was not increased. The evidence that fish oil consumption should be used for primary prevention of CAD is based on observational studies. The only randomized trial for primary prevention, the JELIS trial, showed a moderate relative risk reduction and was conducted in a very specific group.
Nevertheless, to date, there has been no strong signal suggesting any serious adverse effects of having high DHA and EPA oils in the diet. We agree with the national guidelines that one should consume moderate amounts of fish oil— either in supplement or through the dietary intake of fatty fish with low mercury levels. Secondary prevention fish oil studies demonstrate a significant reduction in MI.
But unfortunately, both the observational and randomized trials were conducted in an era before the widespread use of HMG-CoA reductase inhibitors, and therefore, the incremental benefit is still unknown.
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