Damn...now thats concentrated!!! I found this article, it's mostly about the bioavailability and metabolism of EPA and DHA, so i thought it was relavant.
By: Tina Sampalis, M.D., Ph.D.
Over the years, numerous animal and human studies have evaluated the effect of polyunsaturated fatty acids on cardiovascular health and have attributed these effects on their potential antiarrhythmic properties. The outcomes measured in these studies were incidence of ventricular fibrillation, ventricular tachycardia, myocardial infarction, cardiac arrest, or cardiovascular specific mortality. The materials (nutrients) investigated in these trials were long-chain omega-3 polyunsaturated fatty acids (lc-PUFAs), mainly eicosapentanoic acid (EPA) or docosahexanoic acid (DHA). However, the form of delivery of lc-PUFAs varied between trials from a simple fish or seafood meal consumption to a supplementation with pure free fatty acids or pure fatty acid esters or fish oil. Nevertheless, the effects revealed in these trials, although controversial, have all been generalized and attributed directly to omega-3 fatty acids regardless of the delivery vehicle. The question that arises here is if this generalization is scientifically valid or does the carrier of EPA and DHA play a role of its own on these benefits.
In order to respond to this question a simple review of the published literature is an essential first step. A Medline search of peer-reviewed medical journals was performed of the term "arrhythmia" related to any one of the terms "omega-3", "eicosapentanoic acid", "EPA", "docosahexanoic acid", "DHA", "fish", "seafood" or "fish oil" until the second week of June 2005. This search revealed 47 studies between the years 1985 and 2005. Of these, 4 were animal studies, 15 human trials, 2 basic research on cellular cultures and 26 literature reviews. We have excluded the 26 reviews and have focused on the 15 actual research articles.
Considering the strength of evidence of the type of study and the study design, animal and basic research studies are considered as only suggestive of potential benefits on humans. For the purpose of this review given that there are only two different study designs used for the 15 human trials, the strength of evidence is rated on a scale of 1-4, with 1 being the lowest strength and 4 being the highest. Nested case controls rank 1, prospective open-label design ranks 2, and randomized controlled trials (RCT) are rated with 4 points. Of the 15 human trials 1 was a prospective nested cases control, 6 were prospective open-label studies and 8 were RCTs.
Of the 4 animal and 2 basic research studies, 4 studies used pure free fatty acids (EPA and DHA) and 2 used fish oil. They all showed an antiarrhythmic effect suggesting a potential similar benefit on humans. Among the human studies, the nested case control trial showed a possible protective effect of fish consumption on mortality due to cardiovascular disease. Of the 6 prospective open label trials, two evaluated the effects of fish oil on indicators of arrhythmia. In one, the results were inconclusive showing an insignificant effect on heart rate variability but no effect on the length of QTc-interval and the second demonstrated a reduction of tachyarrhythmia. One study suggests a protective effect of intravenous administration of free fatty acids on ventricular tachycardia. The remaining 3 trials proved a beneficial effect of fish consumption by reducing atrial fibrillation, arrhythmia, or mortality due to cardiac death.
However the results of the 8 RCTs, which are accepted as the gold standard in clinical research, differ from the previously mentioned trials. Beneficial effects were demonstrated in 3 of the 8 trials while a negative effect was proven in the remaining five. Analytically, seafood consumption was shown to reduce the incidence of cardiac arrest, fatty acid esters reduced heart variability, and fish oil reduced the incidence of sudden deaths due to cardiovascular disease. The remaining 5 studies all showed a proarrhythmic effect of fish oil by evaluating arrhythmia, premature ventricular complex, heart rate variability, and cardiac death. It is interesting to note that 5 of the 6 (83%) randomized controlled trials that directly evaluated the effect of fish oil supplements on indicators of arrhythmia proved a proarrhythmic effect which contradicts the consistent cardioprotective or antiarrhythmic findings of free fatty acids, fatty acid esters, or consumption of seafood or fish.
In attempt to understand this discrepancy it is important to review causes of arrhythmia that may be related to fish oil supplementation versus omega-3 fatty acids alone. The main possible causes are coronary artery disease, myocardial infarction, LDL-oxidation and increased accumulation of mercury. Lipid oxidation and mercury accumulation can be avoided by selecting the transport vehicle of EPA and DHA, the source of fatty acids, the antioxidant potency, as well as the susceptibility of the omega-3 supplement to oxidation. EPA and DHA are contained in fish oil as triglycerides, which act as carriers of these fatty acids in the human digestive system and eventually the lymph and blood stream. Evidence suggests that consumption of fish oil triglycerides may increase the rate of fatty acid
oxidation primarily through up-regulation of the gene expression of peroxisomal fatty acid
oxidation enzymes. LDL oxidation is believed to increase atherosclerosis through high serum LDL levels inducing LDL particles to migrate into subendothelial space. The process by which LDL particles are oxidized begins with lipid peroxidation, followed by fragmentation to short-chain aldehydes. At the same time, lecithin is converted to lysolecithin, a selective chemotactic agent for monocytes, which become macrophages that ingest oxidized LDL. The new macrophage becomes engorged with oxidized LDL cholesteryl esters and becomes a foam cell. Groups of foam cells form a fatty streak, the earliest indication of atherosclerosis.
Contrary, when phospholipids are the transport vehicle of EPA and DHA, the possibility of oxidation is significantly reduced. The association between phospholipids and long-chain omega-3 fatty acids highly facilitates the passage of fatty acid molecules through the intestinal wall, increasing their bioavailability and ultimately improving the omega-3: 6 fatty acid ratio. A recent study demonstrated
in vivo PUFA bioavailability depends on several factors, such as the type of lipids in which they are esterified, their physical state; i.e., lipid solution or colloidal particle systems, and the presence of co-ingested lipids66.
In vivo PUFA absorption was evaluated by fatty acid analysis of thoracic lymph of duct-cannulated rats after intragastric feeding of dietary fats. Evidence has shown that oral essential fatty acid supplementation in the form of phospholipids is more effective than in the form of triglycerides in increasing concentrations of long chain polyunsaturated fatty acids in liver and brain. DHA is better absorbed when delivered by liposomes than by fish oil (relative lymphatic absorption equal to 98% and 61% after liposome and fish oil administration, respectively). The best bioavailability of DHA delivered by liposomes is revealed by an increase in DHA proportions in both lymphatic triglycerides and phospholipids, compared to fish oil diet.
Werner et al demonstrated that essential fatty acids in the form of phospholipids were superior to essential fatty acids as triglycerides in significantly decreasing the saturated fatty acid ratios of liver triglycerides and phospholipids (each P < 0.05), significantly reduces LDL-oxidation (P < 0.05), while significantly increasing the phospholipid concentrations of the long-chain polyunsaturated fatty acids (P < 0.05). The results of a human randomized controlled trial evaluating the effects of Neptune Krill Oil, a phospholipid carrier of EPA and DHA with naturally attached carotenoids, demonstrate a superior effectiveness for the management of hyperlipidemia and a significant reduction of LDL (P = 0.000).
The effect of fish oil on cardiovascular disease is tempered by the presence of methylmercury in many fish. In fact, the U.S. Food and Drug Administration has advised pregnant women and women who may become pregnant not to eat swordfish, king mackerel, tilefish, shark, or fish from locally contaminated areas. A study in Finland showed an excess risk of myocardial infarction associated with the concentration of mercury in hair and with the intake of fish, which was apparently contaminated with mercury.
The findings of this review can be summarized as follows:
A. Fish oil supplements have been evaluated at 8 of the 15 human trials:
- 2 prospective open-label studies of which one was inconclusive 1 showed a benefit
- 6 randomized controlled trials of which 6 showed a negative or proarrhythmic effect and 1 a positive beneficial effect
B. Six studies, 1 randomized control and 5 prospective open-label, evaluating fatty acid administration or fish or seafood consumption all showed a beneficial antiarrhythmic effect.
C. Potential causative factors for arrhythmia and specific to fish oil are:
- Increased LDL-oxidation
- Higher concentration of mercury than simple fish consumption
D. Possible solutions:
- Alternate transport vehicle of EPA and DHA from triglycerides to phospholipids which will:
- Increase bioavailability of EPA and DHA
- Reduce serum LDL and LDL-oxidation
- Increased awareness of mercury levels in supplements
In response to our initial question, the results of the present review suggest that we should attribute potential pro-arrhythmic properties to omega-3 fatty acids but specifically to fish oil? EPA and DHA have been proven to have cardioprotective and mainly antiarrhythmic properties as long as a safe and stable carrier is chosen. Evidence has shown that the safest and most effective carrier of EPA and DHA are phospholipids.
