Long-chain omega-3 fatty acids: EPA and DHA
There is more and more data showing that increased consumption of long-chain omega-3 fatty acids – namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) – can result in a reduced incidence of cardiovascular disease (CVD). These fatty acids are beneficial in a number of ways. Firstly, they help to reduce the risk of an irregular heart beat (arrhythmia) and improve cardiovascular efficiency. They also lower the incidence of blood clots (thrombosis) that can cause heart attacks and strokes. In addition, they reduce the levels of triglyceride in the blood. Other ways in which they benefit cardiovascular health include reducing the growth rate of atherosclerotic plaque, boosting vascular endothelial function, lowering blood pressure, and helping to ease inflammation (63)(318).
EPA and DHA (but not ALA) intake from fish or fish oil supplements has been linked with a general decrease in the incidence of death in a review of several randomized controlled trials (64). A meta-analysis of 14th RCTs including 16’338 individuals found that the treatment with omega-3 LC-PUFA (EPA, DHA) had no significant decrease in cardiovascular events but had a significant decrease in mortality from cardiac causes in particular sudden cardiac death as well as a decrease in death from all causes(65). Reviews and meta-analysis of RCT reported conflicting results on the effect of omega-3 LC-PUFA (EPA, DHA) on cardiovascular events and mortality mainly due to the heterogeneity of the selected RCT. However, overall the data indicate a beneficial effect of omega-3 LC-PUFA (EPA, DHA) on risk of CVD and cardiac mortality (319-321).
Coronary heart disease
Eating fish at least once a week can result in a lower death rate from coronary heart disease (CHD) among men(66, 67, 68), according to a number of prospective cohort studies. One of these studied 1,822 men for 30 years. The results showed that the death rate from CHD was reduced by 38% for men who ate on average at least 35 g fish per day than for men who ate no fish at all. Incidence of death from myocardial infarction was also reduced by 67% for the men that consumed fish (69). A Chinese study that followed over 18,000 men for a period of ten years demonstrated that the risk of death due to myocardial infarction was reduced by 59% among men who ate more than 200 g fish or shellfish every week compared to those who ate under 50 g per week (70).
Information on the effects of higher omega-3 fatty acid and fish consumption in women is scarcer: the Nurses’ Health Study followed over 84,000 women for a period of 16 years. The study showed that the death rate from CHD was 29–34% lower in the women who consumed fish at least once a week compared to those who consumed it less frequently than once a month (71). A prospective study following 2,445 women from Finland demonstrated that the women who ate the most fish (≥ 41 g/day; mean 70 g/day) were 41% less likely to develop CHD than those who ate the least (≤ 8 g/day; mean 4.2 g/day) (72).
Consuming more fish is associated with additional reductions in incidence of CHD, according to a large prospective study that followed 41,478 men and women from Japan. This study demonstrated that the men and women who ate fish eight times a week showed a reduction of 57% in the incidence of coronary events and a reduction 56% in the incidence of myocardial infarction compared to those who ate fish only once a week (73).
A meta-analysis of 11 prospective studies including 371’965 participants found that dietary intake as well as the blood levels of omega-3 LC-PUFA (EPA; DHA) were inversely associated with all cause of mortality (74). In a recent meta-analysis of 18 RCT (involving about 93’000 individuals) and 16 prospective cohort studies (involving about 732’000 individuals) the effects of omega-3 LC-PUFA (EPA, DHA) on the risk of CHD was evaluated (322). The meta-analysis of RCT found that EPA and DHA supplementation significantly reduced CHD risk in individuals with elevated triglycerides or LDL cholesterol levels. Moreover, the analysis of the prospective studies showed that EPA and DHA intake was associated with a 18% risk reduction of CHD (322). A review of the prospective studies estimated that eating 250 mg/day of EPA and DHA results in a 36% reduction in incidence of cardiovascular death (44).
Sudden cardiac death
Sudden cardiac death (SCD) occurs when there is an unsustainable abnormal rhythm in the lower chambers of the heart (‘ventricular arrhythmia’). Coronary heart disease (CHD) is normally the underlying cause. Epidemiological studies have pointed toward a link between eating fish regularly and a reduced incidence of sudden cardiac death(75). People who consume fish at least once a week show a 52% reduction in incidence of sudden cardiac death compared to people who eat fish less than once a month, according to a large prospective cohort study of over 20,000 men that followed them for 11 years (76, 77).
The incidence of sudden heart death was found to be reduced by around 40–50% in people who ate on average at least 250 mg/day dietary EPA + DHA (roughly 1–2 oily fish servings per week) compared with people who ate less than 250 mg/day (52) in a prospective study that followed over 45,000 men for 14 years. No link was found between dietary EPA + DHA consumption and the incidence of non-fatal MI or total CHD events. This indicates that the cardioprotective effects of long-chain omega-3 fatty acids could be significant at normal dietary consumption levels.
In a systematic review of 8 large prospective studies the consumption of ≥250 mg/day was associated with a significant 35% reduction in the risk of SCD as compared to an intake of less than 250 mg/day which indicate a further reduction in SCD at an intake of EPA and DHA above 250 mg/day (323).
The data is inconclusive as to whether supplementation with omega-3 decreases the incidence of ventricular arrhythmias: supplementation with fish oil had no preventative effect on ventricular arrhythmias in volunteers with existing heart problems (81) in a meta-analysis of three clinical trials (78, 79, 80). Further studies must be carried out before it can be ascertained whether omega-3 fatty acid levels have an effect on the incidence of ventricular arrhythmias (82).
Stroke
Strokes occur when not enough blood reaches part of the brain. This can happen if an artery leading to the brain is obstructed by a clot (‘ischemic strokes’). When a blood vessel bursts and bleeds into the brain, this is known as a ‘hemorrhagic stroke’. Increased fish intake was found to have a beneficial effect on total stroke incidence in several prospective studies (83, 84)(324). However, other studies were unable to confirm any beneficial effect (85, 86, 87). Two large-scale prospective studies showed that consuming more fish (at least twice a week) and omega-3 fatty acid was linked to considerably reduced incidence of ischemic stroke (43%–52%), but not of hemorrhagic stroke (88,89).
The impact of long-chain omega-3 fatty acid consumption on the incidence of strokes has not been researched as thoroughly as their impact on coronary heart disease (CHD). However, a meta-analysis of the available data indicates that consuming more fish could lower the incidence of ischemic stroke, but not of hemorrhagic stroke (90). Cohort studies have led scientists to estimate that eating fish and fish oil decreases the incidence of ischemic stroke by around 30% (44). Supplementation with high doses of EPA could have a preventative effect for individuals with a history of recurring strokes (‘secondary prevention of stroke’), according to the results of a more recent study (91). High blood pressure (hypertension) is a major risk factor for stroke. A recent meta-analysis confirmed that EPA and DHA supplementation significantly reduce systolic blood pressure at dose >1 g/day and diastolic blood pressure at dose ≥2 g/day w2ith the strongest effect observed in untreated hypertensive individuals (271).
Blood serum triglycerides
High levels of blood serum triglyceride (≥ 200 mg/dl) were found to be an independent risk factor forcardiovascular disease in a meta-analysis of 17 prospective studies (92). There have been numerous randomized controlled trials that have shown that consuming more EPA and DHA reduces blood serum triglyceride levels dose dependently and linearly over a wide range of EPA and DHA intake (93) (325-327). Reductions in blood serum triglyceride levels on a clinically meaningful scale have been brought about at doses of 2 g/day EPA + DHA (2). DHA on its own also consistently lowers serum TG concentrations (272)(328).
Summary
The data from epidemiological studies and randomized controlled trials suggest that replacing saturated fatty acids (SFA) with omega-6 and 3 polyunsaturated fatty acids (PUFAs) in the diet, particularly DHA and EPA, reduces the incidence of cardiovascular disease and stroke. Lowering SFA intake while raising omega-6 and omega-3 fatty acid intake also plays a role in improving cardiovascular status. The fact that eating more omega-6 and omega-3 fatty acids has the effect of lowering serum LDL concentrations could also be a contributing factor toward better cardiovascular health.
Collectively the data alsoindicate that raising omega-3 LC-PUFA (EPA, DHA) consumption is linked with a considerable lowering of the incidence of cardiovascular disease as a result mechanisms other than the reduction of LDL cholesterol. Raising eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels through consumption of seafood has especially been linked with a substantial lowering of the incidence of sudden heart death, which indicates that long-chain omega-3 fatty acids possess anti-arrhythmic properties when consumed in quantities equivalent to two small servings of oily fish a week. Approximately 400–500 mg/day EPA + DHA is provided by this quantity of fish (94). In general, when diet is the source of DHA and EPA, the appropriate intake of these fatty acids would appear to be between 250 mg/day and 400–500 mg/day for primary prevention of CVD.
Omega-3 fatty acids: ALA
The link between alpha-linolenic acid (ALA) consumption and coronary heart disease (CHD) incidence has been investigated in a number of prospective cohort studies: every 1 g/day increase in ALA consumption was linked with a 16% lowering of the incidence of CHD in a group of over 45,000 American men who were followed for a period of 14 years (52). Additionally, every 1 g/day increase in ALA consumption was linked with a 47% lowering of the incidence of CHD among the men who consumed little or no seafood. Another study followed over 76,000 American women for a period of ten years. The women who consumed the most ALA (approx. 1.4 g/day) had a 45% lower incidence of death from CHD than was the case for women who consumed the least (about 0.7 g/day)(53). More specifically, those women whose ALA intake was derived from consuming oil and vinegar salad dressing 5–6 times a week showed a reduction of 54% in the incidence of CHD death compared with the women who consumed it rarely. A more limited study following over 6,000 American men showed that those who consumed the most ALA experienced a 40% reduction in the incidence of fatal CHD over the subsequent decade compared with the men who consumed the least (54).
Conversely, two European studies demonstrated no link between ALA consumption and CHD incidence (55, 56). The Nurses’ Health Study following 76,763 women for 18 years also showed no link between ALA consumption and CHD mortality or non-fatal myocardial infarction. However, it did find a link with a reduced incidence of sudden heart death (5, 6, 7). ALA consumption had no discernible lowering effect on the overall death rate, or on the incidence of sudden cardiac deaths or those resulting from strokes, as noted in a systematic review of the data(64).
The data from the majority of prospective studies indicate that increased ALA consumption (2–3 g/day) is linked with a considerable reduction in CHD incidence, particularly among people who eat very little fish (58). However, this data is not as consistent as that supporting higher consumption of long-chain omega-3 fatty acids from seafood. The protective effects of increased ALA consumption do not seem to be linked to changes in blood serum lipid profiles, unlike omega-6 fatty acid LA. Supplementation with ALA was found to have no effect on total cholesterol or LDL cholesterol levels in a meta-analysis of 14 randomized controlled trials (59). Yet a number of controlled clinical trials showed that raising ALA consumption lowered blood serum 'C-reactive protein' (CRP) levels, which are used as a marker of inflammation that is strongly linked to the incidence of myocardial infarction and strokes (60, 61, 62).
Omega-6 fatty acids: LA
Linoleic acid (LA) is an omega-6 fatty acid. It is the polyunsaturated fatty acid (PUFA) that is found most frequently in food. Data from prospective cohort studies investigating the link between PUFA consumption and the incidence of coronary heart disease (CHD) have been inconclusive (37). A few studies have shown that higher PUFA and LA consumption is linked with a considerable lowering of CHD incidence (38, 39, 40) or cardiovascular-related death (41). The Nurses’ Health Study was the largest prospective cohort study to investigate the effects of fat consumption on CHD incidence. In it, over 78,000 women were followed for a period of 20 years. The women who consumed the most PUFAs (7.4% of energy) and LA showed a 25% reduction in the incidence of CHD compared with the women who consumed the least PUFAs (5% of energy) and LA (39). While no relationship was found between saturated fatty acid (SFA) consumption and CHD incidence, a higher ratio of PUFA to SFA consumption was linked with reduced CHD incidence.
Replacing SFA with PUFA consistently reduces blood serum total and LDL cholesterol levels (42) in controlled dietary trials. Moreover, it has been demonstrated that LA is the most powerful fatty acid for reducing blood serum total and LDL cholesterol when replacing SFA (43). The effects of diets containing large quantities of SFA (18–19% of energy) and diets low in SFA (8–9% of energy) and high in PUFA (14–21% of energy) on illness (‘morbidity’) have been compared in several dietary intervention trials to assess death rates from CHD (37). Even though most of the increase in PUFA from food was provided by LA, ALA consumption was also raised in these trials (44).
Replacing SFAs from food with PUFAs was shown to lower morbidity or mortality from CHD in further dietary intervention trials in men (45, 46, 47, 48). However, two comparable dietary intervention trials in women showed no discernible lowering of morbidity or mortality from CHD (49, 50). Receiving 5–10% of one’s total energy from omega-6 PUFAs is linked with a lower incidence of CHD, according to the conclusions of the American Heart Association (51). In adults accustomed to a Western diet, raising LA consumption over recommended levels does not seem to raise AA levels (270).
Breast cancer
The balance between omega-3 and omega-6 fatty acids appears to play an important role in the development and growth of breast cancer. Higher intake of omega-3 LC-PUFA is associated with a reduced risk of breast cancer (329). Researchers speculate that omega-3 fatty acids in combination with other nutrients, such as vitamin C, vitamin E, beta-carotene, selenium, and coenzyme Q10 may be of particular value in the prevention and treatment of breast cancer (95).
Further research is still needed to understand the effect that omega-3 fatty acids may have on prevention or treatment of breast cancer
Colon cancer
Significant dietary intake of omega-3 fatty acids may reduce the risk of colorectal cancer. Certain populations such as the Inuit, who have high-fat diets, but also consume significant quantities of fish rich in omega-3 fatty acids, have surprisingly low rates of colorectal cancer. However, the available evidence supporting the link between omega-3 PUFA and a reduced risk of colon cancer is limited (329).
Animal studies have shown that the intake of omega-3 fatty acids can prevent the progression of colon cancer, while high levels of omega-6 fatty acids can actually promote the growth of those tumors (96).
Some studies have shown the slowing or reversing of the progression of colon cancer with daily consumption of DHA and EPA (97).
A recent meta-analysis suggested that omega-3 intake improves immune function and reduce the inflammation response in patients undergoing surgery for gastrointestinal malignancy (98).
Prostate cancer
As with breast cancer, the balance of omega-3 to omega-6 fatty acids may play a role, while as with colon cancer studies, alpha-linolenic acid (ALA) has actually been seen in higher levels of individuals with prostate cancer in a study of 67 men with the condition (100).
However, more recent studies that were specifically designed to look for prostate cancer risk factors in humans as well as one systematic review found no such link (101). Two recent cohort studies of prostate cancer by the same investigators report conflicting results with respect to the consumption of fish oil (DHA+EPA) and the risk of prostate cancer. One study suggested an increased risk of having a high-grade tumor with higher DHA+EPA levels, while the second study showed no increased risk for developing prostate cancer with fish oil consumption (273).
Epidemiological studies provide inconsistent results suggesting that higher intake of omega-3 fatty acids are associated with a reduced risk of prostate cancer and mortality but the results are inconsistent. further research is needed to clarify the link between omega-3 fatty acids and the incidence and progression of prostate cancer (99)(329).
A questionnaire administered to more than 3,000 people over the age of 49 found that those who consumed more fish in their diet were less likely to have age-related macular degeneration, a serious eye condition that can progress to blindness, in comparison to those who consumed less fish (102).
Similarly, a clinical study comparing 350 people with macular degeneration to 500 people without the eye disease found that those with a healthy dietary balance of omega-3 and omega-6 fatty acids and higher intake of fish in their diets were less likely to have this particular eye disorder (103).
Another larger epidemiological study confirms that consuming EPA and DHA from fish four or more times per week may reduce the risk of developing macular degeneration. Notably, however, this same study suggests that ALA may actually increase the risk of this eye condition (104).
A recent prospective cohort study showed that higher intake of EPA and DHA reduced the risk of developing intermediate stage AMD but no significant effect was found on the development of advanced stage AMD (331).
Alzheimer's disease, the most common cause of dementia in older adults, results in memory loss and confusion that worsens over time (105). Many epidemiological studies have associated high intake of fish or high DHA intake or plasma levels with decreased risk of impaired cognitive function (274), dementia (107, 113, 275)(332), and Alzheimer's disease (107, 108, 111, 112)(332). Docosahexaenoic acid (DHA), the major omega-3 fatty acid in the brain, may be protective against some sub-populations of Alzheimer's disease patients (276)(333) and those with mild cognitive impairment (277) (333) and age-related cognitive decline (278) (334).
In the Framingham Heart Study, men and women with the highest concentration of blood plasma DHA and consumed an average of three servings of fish weekly (0.18 g/day DHA), had a 47% decreased risk of developing all-cause dementia and a 39% decreased risk of developing Alzheimer's disease when compared to those with lower concentrations (113). Thus, low DHA status may be a risk factor for Alzheimer's disease, other types of dementia, and age-related cognitive impairment.
A trial of 204 mild to moderate Alzheimer's disease patients showed no delay in rate of decline on the Alzheimer Disease Assessment Scale-Cognitive Examination (ADAS-Cog) with DHA+EPA (2-3 g/day) administration (276). However, in a sub-group of individuals with very mild Alzheimer's disease Mini-Mental State Examination (MMSE scores >27), there was a significant decrease in the MMSE rate of decline after supplementation for periods of six and 12 months. Similarly, a recent randomized controlled trial of 402 mild to moderate Alzheimer's disease patients supplemented with 2 g/day DHA or a placebo for 18 months demonstrated no decrease in the rate of cognitive or functional decline overall (279). However, a sub-group analysis by ApoE e4 allele (a significant risk factor for Alzheimer's disease) showed significantly less decline on the both the ADAS-Cog and MMSE score in ApoE4 negative individuals supplemented with DHA. The ApoE e4 allele appears to modulate the response of DHA supplementation on cognitive status (335, 336). The findings suggest that sub-populations of Alzheimer's disease patients, based on genotype and severity of disease, may benefit from DHA supplementation in the early stage of the Alzheimer’s disease and that further clinical trials within these groups are needed.
DHA has also recently been shown as a beneficial supplement that supports cognitive health in older adults with mild memory complaints (278). A large, randomized, controlled trial of 485 healthy adults with age-related cognitive decline found that 900mg/day of DHA significantly improved visuospatial learning and memory skills after six months of supplementation. Improvements in verbal recognition memory were also demonstrated with DHA supplementation and the changes in memory scores were correlated with increases in plasma DHA levels. Additionally, DHA treatment over six months showed a significant decrease in heart rate in this older age group, demonstrating a cardiovascular benefit. In another RCT omega-3 LC-PUFA (DHA, EPA) supplementation for 26 weeks significantly increased executive functions and improved brain functions in healthy older adults (50-75 years) (337). A recent RCT showed that omega-3 LC-PUFA treatment improved memory functions in cognitively healthy individuals aged 50 to 75 years (338). Other studies conducted on healthy elderly people have not demonstrated cognitive benefits of fish oil supplementation (280, 281). A recent systematic review and meta-analysis of RCT found that DHA/EPA improved memory function in healthy older adults (334). Differences in study designs, especially the selection of the study population, baseline cognitive variability, baseline dietary omega-3 fatty acid intake, DHA dose, and sensitivity of cognitive measures, most likely explain the inconsistent results between some of these studies. Collectively, the data show that individuals with mild memory and/or cognitive impairment would benefit from a higher intake of omega-3 LC-PUFA (332-338). The long-term effects of DHA on cognitive decline rates or conversion rates to MCI have not been studied and remain a target for further clinical research.
In summary, the results of recent trials in Alzheimer's disease and cognitive decline indicate that treatments such as DHA may be most beneficial for cognitive aging and prevention of cognitive decline. Early detection of impairment, enabling early intervention in the early stage of the disease process, is critical. Clinical data suggest that sub-populations of Alzheimer's disease patients may benefit from DHA supplementation. However, more research is needed to better define the sub-populations of Alzheimer's disease patients that would benefit most from omega-3 LC-PUFA supplementation.
Authored by Dr. Peter Engel in 2010 and revised by Dr. D. Raederstorff on 24.05.17
