THE CORONARY HEART DISEASE RISK REDUCING EFFECTS OF N-3 FATTY ACIDS
William E. Connor, MD
The Division of Endocrinology, Diabetes and Clinical Nutrition, Department of
Medicine, Oregon Health & Science University , Portland , Oregon 97239-3098
June 18, 2003
The early observations of Arctic explorers that the Eskimos, despite a very high fat diet, rarely had coronary heart disease was buttressed by Dyerberg and Bang, two Danish scientists who explored the prevalence of heart disease in Greenland Eskimos (1,2). They found that the Greenland Eskimos had a much lower rate of coronary heart disease than Danes living side by side with them in Greenland . The Danes, of course, ate the Western diet, high in cholesterol and saturated fat, and had a high incidence of coronary heart disease, whereas the Eskimos ate their traditional diet from the sea: fish, whale and seal. Dyerberg and Bang pointed to the difference in the kind of fat which the Eskimos ate compared to the Danes. The Eskimos were consuming the n-3 fatty acids with high concentrations of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). These fatty acids are very long chain and highly polyunsaturated, quite different from the saturated fat found in the Danish diet. Later, the Eskimos were found to have high blood levels of EPA and DHA. These fatty acids seemed to produce an anti-blood clotting effect as well.
There then followed many epidemiological observations, indicating that in the United States and other Western countries coronary heart disease was much less prevalent, perhaps only 50% of the usual heart attack rate, in Americans who ate more fish compared to those who ate very little fish. Again, the Americans who ate more fish had higher levels of EPA and DHA in their blood. In particular, coronary deaths were prevented because there were fewer episodes of irregular heartbeats known as ventricular fibrillation or ventricular tachycardia. When this condition occurs, individuals may die suddenly. Thus, the scientific opinion developed that fish oil containing EPA and DHA would prevent cardiac arrhythmias and sudden death which claims 300,000 lives each year.
That scientific opinion has only been strengthened in recent times. Since 2000, eight prospective randomized clinical trials, eight epidemiological studies, and two animal studies provide substantial and conclusive scientific evidence that omega-3 fatty acids (DHA and EPA) reduce the risks of coronary heart disease. As explained below, the evidence is very strong and warrants approval of the following claim by the FDA without need for a disclaimer or qualification: Omega-3 fatty acids (DHA and EPA) may reduce the risk of coronary heart disease.
The safety of fish and fish consumption and the use of fish oil in humans dates back to the dawn of civilization. People have eaten fish and other seafood for hundreds of thousands of years. The use of fishhooks is certainly prehistoric. Whole cultures have existed on mainly whale, seal and fish and have flourished; this is one measure of safety. A second measure of safety is the recent epidemiological and clinical trial studies. Fish oil has certainly been safe to use. So safe, that the FDA has established fish oil as a member of the GRAS group, which means generally regarded as safe. Furthermore, the American Heart Association in their review confirms the safety of fish oil. Used in reasonable doses, there have been no safety considerations. According to the Physician's Desk Reference for Dietary Supplements, "there have been no reports of serious adverse events in those taking fish oil supplements, even up to 15 grams daily for prolonged periods of time." (Exhibit 1).
In fish, both EPA and DHA are present in varying amounts, usually in a ratio of 3/2 EPA/DHA. The effects demonstrated in the perspective studies and the clinical trials are dependant upon the presence of both EPA and DHA. Each has slightly different effects, with EPA operating more specifically as a prostaglandin precursor and DHA being inserted in the membranes of the heart as detailed in one of the experimental studies described in this report. Both have been shown to have antiarrhythmic effects. Their interconvertibility is of interest also. EPA may be synthesized into DHA, both being a part of the n-3 fatty acid family. In a different modality of action DHA may be retroconverted to EPA. The present state of knowledge would indicate that both EPA and DHA must be present to achieve the effects described in this review. The methods used to measure n-3 fatty acids are well standardized (3). The methodology is by gas liquid chromatography.
The Physicians' Health Study and the Nurses' Health Study have long been sources of important information about nutrition and chronic disease, especially coronary heart disease. In the same week last year came two reports about the effects of long-chain n-3 fatty acid or omega-3 fatty acid intake and the risk of sudden death and coronary heart disease. These are both prospective, controlled studies in apparently healthy individuals who were followed for many years. In the Physicians' Health Study healthy men were followed for up to 17 years (3). The fatty acid composition of previously collected baseline blood was analyzed for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched for age and smoking status. Again, as in many other prospective studies, baseline blood levels of long-chain n-3 fatty acids were inversely related to the risk of sudden death (p=0.007). The risk of sudden death was significantly lower among the men with levels in the third and the fourth quartiles of blood levels of long-chain n-3 fatty acids. This report stressed a reduced risk of sudden death in men who had higher blood levels of n-3 fatty acids (EPA and DHA) found in fish.
In the Nurses' Health Study data was taken from 84,688 female nurses, age 34-39, and free from coronary heart disease (CHD) when enrolled at baseline in 1980 (4). At 16 years of follow-up there were 1,513 cases of cardiovascular disease. After adjustment for other risk factors, the multivariate relative risks of CHD were 0.79 for fish consumption 1-3 times per month, 0.71 for fish consumed once per week. 0.69 for fish eaten 2-4 times per week and 0.66 for fish consumption five or more times per week (p=0.001), all compared to no fish consumption. Similar findings occurred across quintiles of omega-3 fatty acid intakes. The higher the intake of omega-3 fatty acids from fish, lower the risk of CHD and especially for CHD Deaths.
Clinical trials and further associations to prove this hypothesis then occurred. The first clinical trial was carried out in Wales by Burr and colleagues (5). They conducted a randomized controlled trial in 2,033 men who had survived a myocardial infarction. The trial was based on dietary advice on fat, fish and fiber, to find out which one would be protective in preventing further episodes of heart disease. Only benefits from fish or fish oil consumption resulted, however. At the end of two years there was a 29% decrease in the mortality of the men who had received advice to eat fish or take fish oil, compared to the men who had not received fish advice. The 29% reduction in deaths from heart disease in those who ate fish or took fish oil was considered a reduction in deaths from cardiac arrhythmias, since the total number of cardiac episodes was not decreased. Men who developed heart disease survived because they did not have the serious and fatal arrhythmic disturbances.
In 1997 there came a report from India by Singh and co-workers (6). In this study 360 patients with suspected myocardial infarction were randomized to placebo, fish oil
(2 g of EPA plus DHA per day), or mustard seed oil. The number of episodes of sudden deaths was 11.2% in the fish oil group, versus 22.0% in the placebo group. This study also suggested an effect of fish oil fatty acids on the prevention of sudden death.
The next important clinical trial was the GISSI-PREVENZIONE trial, a very large randomized clinical trial of 11, 334 patients who had had a myocardial infarction (7). There were four intervention groups: one group received EPA plus DHA as a fish oil capsule (850 mg), another group received vitamin E, a third group received fish oil plus vitamin E and a fourth group received only placebo. The vitamin E supplement had no effect. The fish oil supplement reduced the deaths from heart disease by 10-15%, depending upon the analysis, the relative risk of death was reduced by 14-20% and the risk of cardiovascular deaths by 17-30%. There was a 45% reduction in sudden deaths. This 1999 study was re-analyzed in 2002 (8). It was shown that the risk of sudden death was significantly prevented by only three months of treatment with fish oil and there was a 67% reduction in the overall deaths. This benefit continued for 312 years to the end of the study. It is important to recognize that the benefit from fish oil occurred early. Instead of dying from the onset of a myocardial infarction, fish oil treated men survived.
Another earlier case controlled study occurred in the Physicians Health Study (9). Healthy men were followed up to 17 years and the incidence of sudden deaths was monitored in the study. There was also analysis of the composition of blood to determine the levels of EPA and DHA at baseline. The levels of EPA plus DHA in the blood predicted the outcome. The highest EPA plus DHA concentrations in the blood led to a 72% and 81% risk reductions in the incidence of sudden death. These data stress the importance of fish and fish oil consumption in the prevention of coronary heart disease.
In the Cardiovascular Health Study of Seattle, Washington, a population-based prospective cohort study, the usual fish consumption was determined in 3,910 adults (10). The consumption of tuna and other broiled or baked fish correlated well with the plasma phospholipid long chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches did not. The participants were followed for 9.5 years. Those consuming tuna and other broiled or baked fish had a lower risk of total ischemic heart disease deaths (p=0.001) and arrhythmic deaths (p=0.001) but not for non-fatal myocardial infarctions. There was a 49% lower risk of IHD deaths and a 48% lower risk of arrhythmic deaths among persons consuming tuna/other fish three or more times per week compared to those consuming less than once per month. There was no benefit from the consumption of fried fish or fish sandwiches, which probably had a lower content of n-3 PUFA.
Hu and colleagues examined prospectively any associations between the intake of fish and the risk of heart disease and death among 5,103 female nurses with type II diabetes (11). The higher consumption of fish, particularly from 2-5 times or more per week, was significantly correlated with less coronary heart disease and lower total mortality. There was also an inverse correlation between the consumption of long chain n-3 fatty acids with a trend to lower coronary disease as the intake of n-3 fatty acids increased to five or more times per week (for trend p=0.02). These data were taken from a subset of the Nurses Health Study.
The review by Kris-Etherton and Harris published in 2003 thoroughly dealt with all of the issues concerning fish oil and fish consumption and their benefits in coronary heart disease (12). After a thorough review of the benefits and any untoward effects, as well as safety, the authors, speaking for the Nutrition Committee of the American Heart Association, had three recommendations:
1. Patients without coronary heart disease should eat a variety of preferably oily fish at least twice per week and include foods rich in alpha linolenic acid as well.
2. For patients with documented coronary heart disease, the recommendation was stronger that they should consume 1 gm of EPA plus DHA per day, preferably from oily fish or could use supplements in consultation with a physician.
3. The recommendation for patients who needed plasma triglyceride lowering was 2-4 gm of EPA plus DHA per day provided as fish oil capsules under a physician's care.
This well-written and authoritative review was published by the American Heart Association Science Advisory and Coordinating Committee on May 28, 2002 (12).
In the Cardiovascular Health Study, Siskovick and colleagues investigated the association of the plasma phospholipid concentrations of EPA, DHA and alpha linolenic acid as biomarkers of n-3 PUFA intake with the risk of fatal ischemic heart disease and non-fatal myocardial infarction in older adults (13). A higher plasma phospholipid concentration of EPA plus DHA was associated with a lower risk of fatal ischemic heart disease, after adjustment for all other risk factors, (p=0.01). As in other studies, EPA plus DHA was not associated with less non-fatal myocardial infarction. The data were consistent with a possible anti-arrhythmic effect of these fatty acids.
A review from France by de Lorgeril on the dietary prevention of sudden death by n-3 fatty acids surveyed the experimental animal data as well as clinical studies (14). The animal experiments clearly indicated that a diet rich in saturated fatty acids is associated with a high incidence of ischemia and reperfusion-induced ventricular arrhythmias, and polyunsaturated fatty acids of the n-3 family reduced that risk. The epidemiological studies showed that high intakes of n-3 polyunsaturated fatty acids, along with oleic acid (Mediterranean diet pattern), was the best option to prevent sudden death and the occurrence of non-fatal myocardial enhanced infarction. The authors stressed that high saturated fat diets were associated with enhanced myocardial infarction and sudden death.
The most important recent experimental animal study of the cardiac effects of three different dietary fat sources was performed in Australia . Rats were fed EPA plus DHA, a saturated fat diet, and an n-6 fatty acid enriched diet for sixteen weeks (15). Previously, it had been demonstrated that dietary EPA and DHA were incorporated into the myocardial phospholipids. The question was now raised, would such incorporation change myocardial function, coronary blood flow and oxygen uptake of such hearts. Hearts from animals so fed were studied in vitro in a Landerdorf preparation. The authors found conclusively that n-3 PUFA improved ventricular function by reducing the oxygen required to produce a given work output, compared to either saturated fat or n-3 PUFA. In fact, saturated fat fed rats had the worst outcomes generally. The benefit was evident even at high workloads when the increased n-3 PUFA incorporation made the myocardium less susceptible to ischemic injury and aided post ischemic recovery. This was an illustration of an effect of n-3 PUFA upon the myocardium and in heart disease in general.
A recent meta-analysis of randomized trials of n-3 polyunsaturated fatty acids in coronary heart disease identified eleven trials between 1966 and 1999, which included 7,951 patients in the intervention and 7,855 in the controlled groups (16). The risk ratio of myocardial infarction of patients who were consuming an n-3 polyunsaturated enriched diet compared to controlled diets was 0.8 or a p value of 0.01. The risk of fatal myocardial infarction in this meta-analysis was 0.7, p less than 0.001. In five trials, sudden death was associated with the risk ratio of 0.7, p less than 0.01. Overall mortality was less as well. The conclusion of the authors from this meta-analysis indicated that dietary and non-dietary intakes of n-3 PUFA reduced overall mortality from myocardium infarction and sudden death in patients with coronary heart disease.
The Kuopio ischemic heart disease risk factor study is a prospective population study in Eastern Finland (16). Healthy men were followed to investigate the association between the levels of serum n-3 fatty acids, (EPA, DPA, and DHA) and the risk of acute coronary events. There were 194 men with a fatal or non-fatal acute coronary event during the follow-up period. Patients who had statistically high values of serum DHA plus DPA (the upper quantities) had a 44% reduced risk (p=0.014) of acute coronary events compared to the men in the lowest quintile of serum DHA + DPA. There was no association between n-3 PUFA and the risk of acute coronary events. This study also evaluated the effects of dietary mercury and found that the men in the highest fifth of serum DHA + DPA who had a low red blood cell content of mercury had a 67% reduced risk of acute coronary events compared to the men in the lowest fifth who had a high red blood cell content of mercury. The authors concluded that a high mercury content in fish could attenuate the protective effect of the DHA plus DPA.
A Swedish study evaluated the markers of a high fish intake and their associations with decreased risk of a first myocardial infarction (18). Biomarkers for a high fish intake include: blood levels of n-3 PUFA and also the amount of mercury in erythrocytes. The major source of mercury in the human body is from fish consumption and the result of mercury contamination of the waters. The authors measured n-3 PUFA (EPA and DHA) and erythrocyte mercury.
In this prospective, case controlled study a high level of erythrocyte mercury was associated with a reduced risk of a first myocardial infarction. This is contrary to other studies in Finland , which showed a direct correlation between higher mercury content and the risk of coronary heart disease. Likewise, in this study the blood concentrations of EPA plus DHA were found to be inversely related to the risk of a first myocardium infarction. Both of these indices are measures of a high fish consumption and so could be used statistically to relate these concentrations to the first myocardial infarction in this Swedish study.
The progression of atherosclerosis was measured by carotid ultrasound after dietary supplementation with n-3 fatty acids in 171 patients (20). The mean maximum intima-media thickness of the carotid arteries increased similarly in both fish oil and placebo groups. The conclusion was that in this two-year study on the effects of n-3 PUFA were that there was no effect on slowing of the progression of atherosclerosis in the carotid arteries as measured by ultrasound. In this population there were no hemorrhagic strokes noted. This is thus a negative study, which had probably the defect of a small number of patients and a short follow-up period (two years).
There was an important experimental study on the effects of n-3 polyunsaturated fatty acids on the cardiac sarcolemma Na + /H + exchange (21). Note, the sarcolemma is the plasma membrane of a muscle fiber, in this instance the myocardium or heart muscle. Cardiac membranes highly enriched in sarcolemma vesicles were exposed to eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). H + - dependent Na + uptake was inhibited by 30-50% after treatment with physiological amounts of EPA and DHA. This was a specific effect of these n-3 PUFA because similar amounts of linoleic or linolenic acid had no significant effect on Na + /H + exchange. These results provided insights into the cardio-protective actions of EPA and DHA in ischemia reperfusion experiments. Since it is already known that myocardial phospholipids will be enriched with EPA and DHA, especially DHA, after feeding animals diets high in these fatty acids from fish oil, these experiments have important relevance to answer the question of why EPA and DHA are cardio protective.
A special review in June, 2003 issue of Circulation, summarized the clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and the mechanism of prevention of arrhythmia by n-3 fish oils (21). The clinical and animal studies
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