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Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n–3 Fatty Acids |
1 From the Massachusetts General Hospital and the Harvard Medical School, Boston, MA 02114
2 Presented at the symposium "Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n–3 Fatty Acids," held in New York, NY, June 9, 2007. 3 Address reprint requests and correspondence to A Leaf, Massachusetts General Hospital and the Harvard Medical School, Boston, MA 02114.
ABSTRACT
The first evidence that fish oil fatty acids might have a beneficial effect on coronary heart disease came from the discovery that Greenland Eskimos, who have a diet high in n–3 fatty acids, have a lower mortality from coronary heart disease than do Danes and Americans. Long-chain polyunsaturated fatty acids are essential in our diets and can be classified in 2 groups: n–6 fatty acids found in plant seeds and n–3 fatty acids found in marine vertebrates. Further evidence of n–3 benefits to human health include a 1989 study demonstrating a 29% reduction in fatal cardiac arrhythmias among subjects with a recent myocardial infarction who had been advised to consume fish oil. The GISSI-Prevenzione Trial found a significant reduction in relative reduction of death, cardiac death, nonfatal myocardial infarction, and stroke in subjects consuming n–3 fatty acids. In a recent study, subjects with implanted cardiac defibrillators (ICDs) at high risk for fatal ventricular arrhythmias were randomly assigned to four 1-g capsules of either an ethyl ester concentrate of n–3 fatty acids or olive oil daily for 12 mo. Subjects receiving n–3 who thus had significantly higher levels of eicosapentaenoic acid and docosahexaenoic acid in their red blood cell membranes showed a longer time to first ICD events and had a significantly lower relative risk of having an ICD event or probable event (P = 0.033). These studies demonstrate that fish oil fatty acids have beneficial effects on coronary heart disease.
INTRODUCTION
The first evidence that fish oil fatty acids might have beneficial effects on coronary heart disease came from a very insightful idea and observation by Danish physicians Jorn Dyerberg and Hans Olaf Bang (1, 2). They knew that at that time, in the 1970s and 1980s, the total fat in the diet of Americans, Danes, and Greenland Inuits was roughly the same, but the mortality from coronary heart disease was only about 10% among the Greenland Eskimos compared with the Danes and Americans. This they assumed to be the result of some differences in the diet among these 3 cohorts. Upon traveling to Greenland, they found the native diet was indeed quite different from that in the United States and Denmark. The Eskimos ate a diet in which the fat content was largely from whale blubber, seal fat, and some fish fat, all very high in n–3 fatty acids. To this the physicians correctly attributed the low mortality among the Eskimos from coronary heart disease. Once known, their findings stimulated investigators everywhere to commence research on these fish oil fatty acids.
There are 2 kinds of long-chain polyunsaturated fatty acids, namely the n–3 fatty acids we have mentioned and the n–6 fatty acids abundant in plant seed oils, which we consume in large amounts as our common table oils, ie, corn oil, sunflower seed, and safflower oils, all of which contain >70% n–6 fatty acids but no n–3 fatty acids. This intake is compared with the n–3 fatty acids needed for optimal health.
Both n–3 and n–6 fatty acids are essential. First, we cannot make them in our bodies, so we must obtain them from our diet. Second, they are absolutely essential for optimal growth and development of the brain, heart, and probably other organs as well. However, their functions in our bodies are quite different and, in many important instances, the 2 classes of long-chain polyunsaturated fatty acids functionally oppose one another.
The parent fatty acid of the n–6 class, linoleic acid (C18:2n–6; LA) has 18 carbons in its acyl chain, and the first 2 C
In the chloroplast of green plants, algae, and phytoplankton, LA can be further desaturated in the n–3 position to yield 
-linolenic acid (C18:3n–3; ALA), the 18-carbon parent fatty acid of the n–3 class. ALA can be further elongated and desaturated by the same enzymes that convert n–6 LA to AA to form the 20-carbon n–3 analog of AA for the same cyclooxygenase, lipoxygenase, and epoxygenase to form a different class of eicosanoids, which in several important instances can oppose and counteract the actions of the n–6 eicosanoids. The final elongation-desaturation product is docosahexaenoic acid (C22:6n–3; DHA), the longest and most unsaturated fatty acid normally encountered in our diets. Eicosapentaenoic acid (EPA) and DHA are physiologically the most important members of the n–3 class. Their source is largely from marine vertebrates, and they are accumulated in the phospholipids in our cell membranes, especially in the brain and heart. By contrast, the source of the n–6 fatty acids is from plant seeds, which we use abundantly as the common table oils, corn oil, safflower seed oil, and soy oil, all of which contain about 70% n–6 LA and no n–3 fatty acids.
Evidence that n–3 Fish Oil Fatty Acids are Beneficial to the Health of Humans
Several clinical trials indicate the beneficial effects of the n–3 fatty acids on the cardiovascular system. The first was published in 1989 by Burr et al (3), who advised a group of 1015 men, who had just had a myocardial infarction, to ingest oily fish 2 times a week. Another group of 1018 men were not advised to do the same. At the end of 2 y there was a 29% reduction in fatal arrhythmias in the men advised to eat oily fish compared with the men who had not been so advised. There was no significant difference in the group that ingested oily fish compared with the group that did not as more nonfatal infarcts occurred in the fish oil advice group. Today, we interpret this difference as resulting from the fish oil advice group having fewer fatal cardiac arrhythmias than the no-fish oil advice group.
More recently, another clinical trial, "Dietary supplementation with n–3 polyunsaturated fatty acids and vitamin E after a myocardial infarction: results of the GISSI-Prevenzione Trial" (4), was reported. This was a large, prospective, randomized clinical trial of 11 324 patients who had a recent myocardial infarction. They were randomly assigned to 4 equal groups to test a daily dose of one capsule of 850 mg EPA+DHA, 300 mg vitamin E or n–3 fish oil plus vitamin E, and a control group received neither. This combination was adopted on optimal pharmacology and lifestyle advice.
The primary efficacy endpoint was death, nonfatal myocardial infarction, and stroke. At the end of 3.5 y there was no significant benefit from the vitamin E. The n–3 fish oil supplement significantly reduced the primary endpoint by 10% (2-way analysis) and 15% (4-way analysis). Treatment lowered the relative risk of death by 14% or 20% (2-way or 4-way analysis, respectively) and cardiovascular death by 17% or 30%. Although not a stated primary endpoint, there was a 45% reduction in sudden cardiac death (4-way analysis).
These encouraging reports led me to hypothesize that these long-chain n–3 fatty acids may prevent fatal arrhythmias in high-risk patients. To test this hypothesis, 402 patients with implanted cardioverter defibrillators (ICDs) who were at high risk for ventricular arrhythmias were enrolled into our Fish Oil Anti-arrhythmia Trial (5) at 18 collaborating centers.
Subjects were included who had an ICD implanted because of history of cardiac arrest, sustained ventricular tachycardia I (VT), or syncope with inducible ventricular tachycardia/ventricular fibrillation (VT/VF) during electrophysiologic studies. The qualifying ICD must have been implanted within 12 mo before entry into the study or the patient had at least one spontaneous ICD event for VT/VF in the preceding 12 mo.
Enrollees were randomized in a double-blinded controlled fashion either to 4 one-gram gelatin capsules of an ethyl ester concentrate of n–3 fish oil fatty acids (total dose of 2.6 g) or to 4 one-gram capsules of olive oil of identical appearance for 12 mo.
At baseline, clinical data and blood samples were collected, and subjects were told not to eat >2 fish meals in a month and to use olive oil rather than common plant seed oils for dressing for salads and other such uses. The recommendation to use olive oil was emphasized, and 87% of enrollees indicated that they had adhered to our advised diet for the duration of the trial. Substituting olive oil, which contains no n–6 fatty acid, made the study diet similar to the Mediterranean diet, which reduces the n–6:n–3 ratio and favors the action of whatever amount of n–3 fatty acids are contained in the diet.
Subjects were asked to report at 3-mo intervals to their respective medical centers to have their ICD reports collected and have blood samples drawn. The ICD reports were sent to a Core Electrophysiology Laboratory to have their ICD interpreted by 2 or more cardiac electrophysiologists blinded to the patients’ treatment. The blood samples were separated into plasma and packed cells, kept frozen at –70 ° to –80 °C, and mailed to the Massachusetts General Hospital, where red cells were analyzed for their phospholipid content of fatty acids. Compliance was ascertained by pill count and by analysis of the red cells for their content of EPA+DHA.
The Core EP Laboratory was responsible for endpoint confirmation. All reports showing arrhythmias and a random selection of negative reports were viewed by at least 2 electrophysiologists. Wherever disagreement occurred, the reports were interpreted by a third. Each made an interpretation blinded to the supplement and to the interpretation by the other electrophysiologists. The agreement between 2 of the interpretations was the accepted interpretation. Confirmed events were defined as spontaneous episodes of VT and/or VF causing ICD discharges for which intracardiac ventricular grams were available. Probable events included ICD events for which no electrocardiograms were available, but other data recorded by the ICD supported the diagnosis of VT/VF. Such data included successful termination by antitachycardiac pacing, a ventricular rate exceeding the atrial rate in dual chamber defibrillators, and/or episodes of VT/VF with similar cycle lengths where electrograms were available.
All randomized patients were included in the intention to treat analysis. The primary analysis, based on confirmed events, was an intention-to-treat analysis of the survival, free of appropriate ICD events for VT/VF and/or death from any cause. Secondary analyses were preformed, including probable events as defined. The intention-to-treat analysis included all confirmed ICD events during the 12-mo period after the first dose of the study drug was taken, irrespective of the duration of treatment. Two on-treatment analyses were done. The first included all ICD reports that occurred no later than 2 mo after the treatment was stopped. The second on-treatment analysis was limited to those who were compliant for the duration of the trial.
One hundred forty subjects (35% of enrollees) discontinued their prescribed treatment before completing their year in the trial. Time to discontinuation did not differ significantly between the 2 arms of the study. In our intent-to-treat analysis, all those individuals who discontinued their supplements are included. Among patients who had their blood analyzed at their last visit, the 110 randomized to fish oil had a significantly higher content of EPA+DHA as percent of the total fatty acids in the phospholipids of red blood cells compared with the 119 receiving olive oil (
± SEM = 7.6 compared with 3.5; P < 0.001), whereas, at the baseline, there was no difference in the means 3.4 and 3.5, respectively. There were 25 deaths during the study, 13 in the group assigned to fish oil and 12 in those assigned to olive oil. No deaths and no serious adverse events in either cohort were attributable to the prescribed supplements.
Table 1
summarizes the relative risk of ICD events in the following discussion. In the primary analysis, according to intention-to-treat, there was a trend to a longer time to the first ICD event for VT/VF confirmed by electrograms or death from any cause among patients randomized to fish oil compared with those randomized to olive oil, but the difference was not significant (P = 0.057). When probable events were added to the endpoint, the reduction in risk became significant (P = 0.033).
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In the second on-treatment analysis, limited only to subjects compliant for the full duration of the study, reduction in risk was significant (P = 0.034). Finally, when the results of this analysis were adjusted for multivariate analysis, the relative risk became 0.52 with a 95% CI of 0.32–0.83 (P = 0.0060).
In conclusion, based on the study by Barr (3), the GISSI- Prevenzione (4), and the Fish Oil Anti-arrhythmia Trial (5), it is reasonable to conclude that fish oil fatty acids have beneficial effects on coronary heart disease.
ACKNOWLEDGMENTS
I thank Mandy Bischel for her assistance in editing this manuscript. The author has no personal or financial conflicts of interest.
REFERENCES
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