Polyunsaturated Fatty Acids and Cardiovascular Health

Polyunsaturated Fatty Acids and Cardiovascular Health

Kris-Etherton, Penny M

Introduction

Cardiovascular disease is the leading cause of morbidity and mortality in the US and other developed countries. Over the years, the emphasis of cardiovascular disease intervention efforts has been to lower total and lowdensity lipoprotein (LDL) cholesterol levels by reducing dietary saturated fat and cholesterol. While it is clear that polyunsaturated fat (the n-6 fatty acid class) also lowers total and LDL cholesterol, recent research has found that polyunsaturated fatty acids (PUFAs), both the n-6 and the n-3 series, affect many different cardiovascular disease risk factors in ways that are independent of total and LDL cholesterol lowering. Advances in our understanding of the biology of PUFAs relative to cardiovascular disease now positions the field to develop novel, diet-based interventions to further reduce the risk of cardiovascular disease. One challenge is to identify the optimal level of dietary PUFAs that maximally affects the greatest number of cardiovascular disease risk factors.

The objective of this paper is to review the effects of PUFAs on cardiovascular disease risk factors, with a focus on human studies. Epidemiologic and clinical trials/studies are reviewed to develop a framework that defines the extent to which PUFAs can beneficially affect multiple cardiovascular disease risk factors. In addition, we summarize the current dietary intake of PUFAs in the US, which is important in defining a context for contemporary dietary recommendations.

Epidemiologic Studies

While epidemiologic studies provide important insight into the relationship between dietary fatty acids and the prevalence of cardiovascular disease, they do not establish causal relationships. However, results of epidemiologic studies frequently provide the rationale for conducting controlled clinical studies to assess cause and effect relationships.

Caggiula and Mustad1 reviewed epidemiologic studies assessing the relationship between dietary fatty acid classes and cardiovascular disease risk. Studies that address the associations between dietary PUFAs and cardiovascular disease risk are reviewed here. Since the review published by Caggiula and Mustad, findings from several epidemiologic studies have been published that add to our understanding of the relationship between dietary PUFAs and cardiovascular disease morbidity and mortality. The effects of PUFAs on lipids and lipoproteins will be discussed in the section on controlled clinical studies/trials. Readers are referred to the review by Caggiula and Mustad1 for a summary of the epidemiologic studies that report associations between fatty acid classes and lipids and lipoproteins.

Cross-population and within-population studies conducted to date have assessed the association between dietary fatty acids and cardiovascular disease morbidity and mortality: the specific associations for PUFAs are summarized in Table 1. A number of studies have shown an association between dietary PUFAs and reduced cardiovascular disease morbidity and mortality. Among the cross-population studies, Hegsted and Ausman2 and Artaud-Wild et al.3 found that PUFA intake was negatively associated with cardiovascular disease mortality, after adjusting for dietary saturated fat. In contrast, there was no significant association between dietary PUFAs and cardiovascular disease in the Seven Countries Study.4,5 Among the within-population studies shown in Table 1, nine reported a beneficial association of dietary PUFAs with cardiovascular disease morbidity and mortality.6-17 The Nurses’ Health Study found that for each 5% increase in energy from PUFAs the relative risk for cardiovascular disease was 0.62 (95% confidence interval, 0.46 to 0.85; P = 0.003).15 Figure 1 illustrates the favorable effect on cardiovascular disease risk when PUFAs are substituted in the diet for other fatty acids and carbohydrates. The same study found that subjects in the upper quintile for linoleic acid intake (6.4% of energy) had a 32% reduction in relative risk for cardiovascular disease events.15 In the Atherosclerosis Risk in Communities Study,13 the consumption of vegetable fat and polyunsaturated fat was shown to be inversely related to carotid artery wall thickness in men and women compared with animal fat, saturated fatty acids (SFA), cholesterol, and monounsaturated fatty acids (MUFAs) (Table 1). However, not all studies have demonstrated a beneficial association between PUFAs and cardiovascular disease morbidity and mortality, although adverse effects were not reported.10,12,17 It is important to understand that in these studies, the average PUFA content varied appreciably-between 2.1% and 10% energy. Also of note is that two studies6,7,9 reported an adverse effect on coronary end points with a diet higher in PUFAs compared with one lower in PUFAs when PUFA was expressed as a percentage of energy, not in gram quantities. A significantly lower intake of cases vs. control subjects, together with a similar gram quantity of PUFA intake, explains the significant positive association for a higher percent energy from PUFA in cases. Thus, a relationship based on percentage of calories from PUFA is confounded by the significant association reported between total calories and coronary heart disease. An adverse effect of PUFAs on coronary heart disease mortality has been reported in a summary of crosspopulation epidemiologic studies.18 The limited database used in this analysis and the lack of confirmatory evidence within a population (to control for country-specific lifestyle differences) raises questions about the implications of this summary. Because of the challenges of accurately assessing diet, adipose tissue fatty acid composition serves as a surrogate for habitual fatty acid intake. As noted by Caggiula and Mustad,1 one cross-population study reported an inverse relationship between adipose tissue linoleic acid and risk of coronary artery disease.19 In contrast, a recent study by Kark et al.17 did not find an association between linoleic acid intake and acute myocardial infarction in a Jewish population in Israel consuming high levels of PUFA (10% of energy). Furthermore, evidence from an epidemiologic analysis of the Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled trial, showed that increased consumption of PUFAs (9.7% energy) was associated with a significant increase in new artery lesion development.20 However, Kark et al.17 reported that high PUFA intakes were not associated with adverse coronary disease outcomes; 25% of the subjects in this study consumed greater than 12% energy from PUFA.

Epidemiologic evidence is not entirely consistent in demonstrating an association between PUFA intake and coronary artery disease. The variability in outcomes among studies likely reflects inherent sources of variation in these populations (including habitual PUFA intake) and other confounding variables that are difficult to control. Still, the preponderance of evidence supports the conclusion that PUFA intake within ranges typically consumed (1.4%-10.9%) is beneficially associated with coronary disease morbidity and mortality. A consideration that may be germane to the outcome of epidemiologic studies is the amount of PUFAs consumed by a population. Kark et al.17 suggest that in populations with a low PUFA intake, linoleic acid may be protective against cardiovascular disease. In populations with a high PUFA intake, it may be that increasing dietary PUFA does not confer further measurable benefits. In general, the epidemiologic studies are not supportive of high PUFA intake being associated with adverse effects on coronary disease end points.

Clinical Trials

High-PUFA Diets and Blood Cholesterol Levels

Initial studies conducted in the 1950s showed that when vegetable oils high in PUFAs replaced fats high in saturated fat, blood cholesterol concentrations were markedly decreased.21-24 Data from these and later studies provided the basis for developing equations for predicting blood cholesterol and lipoprotein cholesterol responses to changes in the fatty acid composition of the diet. The early equations of Keys et al.25 and Hegsted et al.26 have been corroborated by a number of more recent predictive equations (reviewed by Kris-Etherton et al.27). The equations demonstrate a cholesterol-lowering response of PUFA that is approximately half the cholesterol-raising response (both total and LDL cholesterol) noted for SFAs. Collectively, the equations predict that a 1% increase in PUFAs (without any corresponding changes in other fatty acid classes) would be expected to lower total cholesterol by an average of 0.024 mmol/L. Likewise, simply increasing SFAs by 1% would be expected to increase total cholesterol by an average of 0.054 mmol/L.

Over the years, there was an assessment of how changes in individual fatty acids affected lipids and lipoproteins (reviewed by Mensink and Katan28). As shown in Figure 2, there are remarkable potency differences among the individual fatty acids with respect to their effects on total, LDL, and high-density-lipoprotein (HDL) cholesterol.27 While linoleic acid is the most potent total and LDL cholesterol-lowering fatty acid, it has little effect on the HDL cholesterol response (when replacing dietary carbohydrate). One illustration of its range in potency is exemplified by the contrast between linoleic acid and myristic acid-there is a 0.077 mmol/L differential in total cholesterol response for a 1% increase in each respective fatty acid. Moreover, linoleic acid has a greater cholesterol-lowering effect than MUFAs, a finding that is consistent with results of a study that was specifically designed to assess the cholesterolemic responses of MUFAs and PUFAs.29 With respect to the HDL cholesterol response, SFAs have the greatest raising effect (Figure 2). Thus, because of the potent LDL cholesterol-lowering effects of PUFAs concurrent with a negligible effect on HDL cholesterol, they significantly decrease the total:HDL cholesterol ratio, as well as the LDL:HDL cholesterol ratio. MUFAs have a similar effect on this ratio. In contrast, this ratio is unaffected by SFAs.30 The effects of dietary fats high in PUFAs compared with MUFAs on lipids and lipoproteins were reported in a meta-analysis of 14 studies conducted by Gardner and Kraemer.31 The results indicated similar total, LDL, and HDL cholesterol responses for diets high in MUFAs or PUFAs; however, triglyceride levels were consistently but marginally lower on the diets high in PUFAs versus MUFAs. These results, reported by Gardner and Kraemer,31 suggest a comparable blood cholesterol-lowering response when oils high in PUFAs versus MUFAs are substituted for fat sources high in SFAs. However, from a clinical perspective, PUFAs can be distinguished from MUFAs relative to their cholesterol-lowering response provided that good dietary control is achieved. In practice with free-living individuals, this level of dietary control typically is not attained, and when substituted for SFAs, PUFAs and MUFAs would be expected to have comparable effects on blood lipids and lipoproteins. This can be explained principally by the substantive decrease in SFAs, which has the biggest impact on LDL cholesterol lowering, followed by a smaller impact of changes in dietary MUFAs and PUFAs.

Compared with PUFAs, trans fat has a markedly hypercholesterolemic effect, raising both total and LDL cholesterol levels, but lowering HDL cholesterol and thereby having significant adverse affects on the total: HDL cholesterol ratio (Figures 2 and 3).27 Lichtenstein et al.32 found that diets comprised of 30% total fat containing 2/3 total fat from soybean oil or semiliquid margarine (fatty acid composition of the fats used was 41%-42% PUFAs and

The physiological mechanisms by which PUFAs favorably affect blood lipoproteins are not fully understood. It has been speculated that the changes in blood lipoproteins with increased PUFA intake may be the result of simply substituting PUFAs for hypercholesterolemic fatty acids or carbohydrates. However, linoleic acid may reduce blood cholesterol levels, in particular LDL cholesterol, by upregulating hepatic LDL receptors.33

High-PUFA Diets and Coronary Morbidity and Mortality

Studies that demonstrate effects of diet on cardiovascular disease risk factors justify conducting well-controlled clinical trials to assess treatment effects on morbidity and mortality end points. These studies are a requisite for developing evidence-based prevention and treatment intervention programs. Several studies have evaluated the effectiveness of blood cholesterol-lowering diets high in PUFAs and low in SFAs on coronary morbidity and mortality; these are summarized in Table 2.34-39 Collectively, these diet studies have shown that cholesterol-lowering diets low in SFAs (8%-9% energy) and rich in PUFAs (14%-21 % energy) reduce LDL cholesterol levels by 13%-15%, which is associated with a 25%-43% reduction in cardiovascular disease events. Moreover, although not every study reported significant positive outcomes,39 the higher intakes of PUFAs did not result in worsened morbidity or mortality.

High-PUFA Diets and Postprandial Lipemia

The postprandial state includes the 4 to 8 hours following a meal. Since most individuals ingest 3 or more meals per day, they are in the postprandial state for the majority of the day. Postprandial hypertriglyceridemia has been established as a significant and independent risk factor for cardiovascular disease, and may be a better predictor of risk than fasting triglyceride levels alone because of variations in postprandial triglyceride responses, even in individuals with normal fasting triglyceride levels.40 The atherogenicity of postprandial hypertriglyceridemia is associated with the presence of higher levels of triglyceride-rich lipoproteins, which includes triglycerides, very-low-density-lipoprotein triglycerides, chylomicrons and their smaller, denser remnants, and small, dense LDL cholesterol formations.41 Both triglyceride-rich lipoproteins and small, dense LDL cholesterol are prone to delayed clearance from circulation, are more susceptible to oxidative modification, and more apt to penetrate the arterial wall.40

The optimal type and amount of fat consumption to reduce postprandial lipemia remains unclear and studies are limited. In the absence of a controlled background diet, Thomsen et al.42 showed that a high-fat test meal containing an energy-free soup, 50 g of carbohydrate as white bread and 80 g of olive oil (74% MUFAs) induced a lower postprandial triglyceride level compared with the same meal with 100 g of butter (72% SFAs) in healthy individuals. However, Higashi et al.43 reported that a single fat load (40 g fat/m^sup 2^ body surface area) of olive oil produced significantly greater postprandial peak triglyceride and triglyceride-rich lipoproteins remnant responses than either a milk fat load (69% SFAs) or a safflower oil load (74% linoleic acid) in eight healthy men. Bergeron and Havel44 reported that chylomicron clearance was not affected by a high n-6 PUFA challenge meal versus a high-SFA meal; however, postprandial hepatic triglyceride-rich lipoprotein levels were reduced in subjects who consumed an n-6 PUFA-rich diet for 30 days compared with a high-SFA diet. Another study showed that 9 days on a linoleic acid-rich diet (37% total fat, 27% SFAs, 24% MUFAs, 49% PUFAs) resulted in significantly lower (43%) postprandial serum concentrations of chylomicron and chylomicron remnants via greater removal (from circulation) rates versus a diet enriched in butter fat (36% total fat, 58% SFAs, 33% MUFAs, 8% PUFAs) in 12 normolipemic volunteers.45 Weintraub et al.46 found that after 25 days of dietary intervention, n-3- and n-6-PUFA-rich diets attenuated postprandial lipemic responses following fat loads similar in composition to the background diets but also when the challenge fat load was enriched in SFA. Even greater reductions in postprandial lipemia have been reported with long-chain n-3 PUFAs compared with n-6 PUFAs and SFAs in both acute and chronic feeding trials.46,47

All of these studies demonstrate that postprandial lipid metabolism can be modulated by acute and chronic dietary changes, but that maximal reductions in postprandial lipemia can only be achieved in the presence of chronic dietary intervention. Although the studies are limited in number and differing in methodologies and clinical end points, collectively they would suggest that PUFAs (especially n-3 PUFAs and to a lesser extent n-6 PUFAs) have more favorable effects on postprandial triglyceride and triglyceride-rich lipoprotein metabolism than either MUFAs or SFAs, particularly when consumed on a habitual basis. However, more research is needed to confirm this hypothesis.

Interactive Effects of PUFAs with Other Fatty Acids

Many controlled clinical studies have shown that saturated fatty acids, trans fats, and dietary cholesterol increase total and LDL cholesterol levels, whereas PUFAs decrease them and MUFAs may have a neutral cholesterolemic effect. The Keys Equation has been used to show that changes in blood cholesterol levels in the US population between the National Health and Nutrition Examination Survey (NHANES) I and NHANES III surveys could be predicted on the basis of decreases in saturated fat and cholesterol and increases in polyunsaturated fat.48 Specifically, between 1971-1975 (NHANES I) and 1988-1991 (NHANES III), SFA intake decreased from 13.2% to 11.7% and PUFA intake increased from 4.3% to 7.1 % of total energy. Total cholesterol and LDL cholesterol both decreased 0.21 mmol/L over this time. Therefore, PUFAs and SFAs play a key role in regulating plasma total and LDL cholesterol levels at the population level.

Since PUFAs have an independent LDL cholesterol lowering effect, Hayes et al.49 reasoned that increasing dietary PUFAs could attenuate the cholesterol-raising effects (and reduced LDL cholesterol clearance) due to saturated fat. For example, in monkeys when C18:2 is low (

Other studies have demonstrated the importance of PUFAs in maintaining lower total and LDL cholesterol levels in subjects following a low saturated fat and cholesterol diet, where decreasing PUFAs and increasing MUFAs without changing SFAs and cholesterol led to expected increases in total and LDL cholesterol levels. Lichtenstein et al.52 fed subjects diets high in canola, corn, or olive oil for 32 days each. The composition of the oil diets were as follows: Canola oil: 29.5% total fat, 5.4% SFAs, 14.5% MUFAs, and 6.7% PUFAs; corn oil: 29.4% total fat, 6.9% SFAs, 9.0% MUFAs, 11.2% PUFAs; olive oil: 30.0% total fat, 6.9% SFAs, 17.0% MUFAs, 3.9% PUFAs. All of the oil diets resulted in reductions in total and LDL cholesterol compared with the baseline diet. However, the reduction in total cholesterol was significantly greater for the canola and corn oil diets (12% and 13%, respectively) than for the olive oil diet (7%), which could be explained by the lower level of dietary PUFAs in the olive oil diet. Reductions in LDL cholesterol were greater for the canola (16%) and corn (17%) oil diets compared with the olive oil diet (13%); however, these reductions were not significantly different. HDL cholesterol levels were lower on all of the test diets, but these declines were only significant for the canola (7%) and corn (9%) oil diets, which likely explains the greater reduction in total cholesterol for those diets.

Another example of the importance of PUFAs in a cholesterol-lowering diet is a controlled feeding study conducted by Binkoski et al.53 in which moderately hypercholesterolemic subjects (n = 31) were fed diets high in olive oil or NuSun(TM) sunflower oil as well as an average American control diet (34% total fat, 11.2% SFAs, 14.9% MUFAs, 7.8% PUFAs) for 4 weeks each. NuSun(TM) sunflower oil was developed by standard hybrid breeding of sunflowers, and contains 57.3% MUFAs, 32.3% PUFAs, and 9.6% SFAs. Olive oil or NuSun(TM) sunflower oil provided one-half of the total fat in the experimental diets. Both diets contained 30% total fat (8.3% vs. 7.9% SFA, 17.2% vs. 14.2% MUFA, and 4.3% vs. 7.7% PUFA for olive oil and NuSun(TM) sunflower oil, respectively). The NuSun(TM) sunflower oil diet decreased both total and LDL cholesterol compared with the average American diet (4.7% and 5.8%, respectively) and the olive oil diet (3.5% and 4.8%, respectively). However, total and LDL cholesterol were not reduced on the olive oil diet compared with the average American diet. There also was no effect of the experimental diets on HDL cholesterol or triglycerides. It was concluded that despite similar amounts of SFAs in the olive oil and NuSun(TM) sunflower diets, the greater total and LDL cholesterol lowering effect of the NuSun(TM) sunflower oil diet was due to its higher PUFA content compared with the olive oil diet.

With regard to trans fat and its deleterious effects on cardiovascular disease risk, Zock and Katan54 reported that compared with a diet rich in linoleic acid (12% energy PUFAs, 11% SFAs, 16% MUFAs, 0.1% trans fat), diets rich in stearic acid (4.3% PUFAs, 20% SFAs, 17% MUFAs, 0.3% trans fat) and trans fat (4.2% PUFAs, 10% SFAs, 23% MUFAs, 7.7% trans fat) produced higher serum total cholesterol concentrations by 0.15 mmol/L and 0.16 mmol/L and LDL cholesterol by 0.17 mmol/L and 0.24 mmol/L on the stearic acid and trans fat diets, respectively, in normolipemic subjects. HDL cholesterol levels were lower by 0.06 mmol/L and 0.10 mmol/L on the stearic acid and trans fat diets, respectively, compared with the linoleic-rich diet. Additionally, the stearic acid and trans fat diets produced increases in atherogenic apolipoprotein B levels relative to the linoleic acid diet. Overall, the much lower concentrations of linoleic acid on the stearic acid and trans fat diets were not adequate to prevent unfavorable changes in blood lipids compared with the diet containing approximately three-fold more linoleic acid. Additionally, a report by the US Food and Drug Administration estimated that replacing trans fat with PUFAs (1% energy) would reduce the risk of cardiovascular disease by 2.96% when taking into account changes in both LDL and HDL cholesterol.55

The research summarized underscores the importance of the relative amounts of individual fatty acids that have opposing effects on blood cholesterol levels. It is evident that the changes in the proportion of each result in interactive effects that enhance or attenuate the blood cholesterol response. The fatty acid profiles of different diets can be changed in a myriad of ways, with potentially different effects on blood cholesterol levels.

Proposed Adverse Cardiovascular Effects of High-PUFA Diets

While both epidemiologic and clinical studies have shown beneficial effects of PUFAs, there is some evidence to suggest that linoleic acid may adversely affect certain cardiovascular disease risk factors.

Endothelial Function, Adhesion Molecules, Cytokines, and Oxidative Stress

Endothelial activation refers to the modifications that occur to the vascular endothelium after encountering inflammatory stimuli, including cytokines and oxidized LDL. Linoleic acid has been reported to stimulate endothelial activation, which results in the up-regulation of adhesion molecules by inducible transcription factor nuclear factor-κB, causing monocytes to adhere the endothelium.56 Toborek et al.57 showed that among individual unsaturated fatty acids, treatment of cells with linoleic acid resulted in the most marked increase in the activation of both nuclear factor-κB and activator protein. Both animal and human in vitro models have shown increased cellular oxidative stress and increased production of proinflammatory cytokines (interleukins 1, 6, and 8) and cellular adhesion molecules (intracellular adhesion molecule-1 and vascular cell adhesion molecule-1) subsequent to treatment with linoleic acid.58-60

Contrary to these findings, De Caterina et al.61 found that as the number of double bonds present in a particular fatty acid increase, there is a successive increase in the inhibitory activity on adhesion molecule expression. Thus, endothelial cells would be less responsive to cytokine stimulation with the incorporation of n-6 fatty acids than of MUFAs or SFAs.

In contrast, PUFAs tend to be positively associated with measures of oxidative stress due to their high degree of unsaturation. One study62 showed that compared with a high-MUFA diet, a high-linoleic acid diet significantly increased urinary excretion of isoprostanes (8-iso-PGF2α) and decreased urinary concentration of nitric oxide metabolites in healthy subjects, though plasma sICAM-1 was unchanged in both groups. Furthermore, exposure of endothelial cells to linoleic acid can amplify the TNF-α-mediated induction of oxidative stress as well as endothelial dysfunction.63 However, a recent study by Binkoski et al.53 showed no adverse effects of a diet rich in PUFAs consumed for 4 weeks duration. LDL oxidation lag time was the longest following a MUFA-rich olive oil diet and shortest following a PUFA-rich NuSun(TM) sunflower oil diet (diet compositions are described above). However, no significant changes were observed for rate of oxidation, total dienes, lipid hydroperoxides, or alpha-tocopherol. Therefore, while the increase in PUFAs in the NuSun(TM) sunflower oil diet may explain the reduction in LDL oxidation lag time observed, no differences in the resulting oxidation products (total dienes and lipid hydroperoxides) were observed, suggesting no adverse effects of the NuSun(TM) oil diet on LDL oxidation. Due to the small number of studies, differing methodologies for measuring oxidative stress, and inconstencies in study results, conclusive inferences on the putative adverse effects of PUFAs on non-lipid risk factors cannot yet be made. Other potentially adverse affects of n-6 PUFAs (i.e., tumor growth, inflammation) have been mainly observed in vitro and in animal models, and will require more study.64 Additionally, a review of the safety considerations of PUFAs concluded that little evidence exists to support health risks with PUFA intake up to 10% of energy.65

Consumption of Linoleic Acid over Time

Results from NHANES I (1971-1974), NHANES II (1976-1980), and NHANES III (phase 1, 1988-1991) showed that PUFA intake increased over this time. In 1972 (the midpoint of the survey), PUFA intake for all persons was 4.3% of energy; in 1978 it was 5.7% of energy; and in 1991 it was 7.1% of energy.48 Thus, between 1972 and 1990, energy intake from PUFAs increased 2.8 percentage points. More recent data from NHANES III (1988-1994) indicate that PUFA intake is 6.9% of energy for the total population. Within the different gender and age groups, the range of median PUFA intake is from 5.4% to 7.3% of energy. The higher end of the range is for women ages 40-49 years. PUFAs contribute approximately 19% to 22% of energy from fat in the diets of adults.66

Current Recommendations for PUFAs

Linoleic acid is an essential nutrient in the diet, and Figure 4 shows some of its primary dietary sources. The acceptable macronutrient distribution range for n-6 PUFAs, set forth by the Dietary Reference Intakes report of the National Academies, is 5%-10% of energy67, which is in agreement with the 2005 Dietary Guidelines recommendations.68 The adequate intake for linoleic acid was set at 17 g/day for young men and 12 g/day for young women. Both the National Cholesterol Education Program and the American Diabetes Association recommend that polyunsaturated fat intake should be about 10% of energy intake to reduce LDL cholesterol levels and for the treatment and prevention of diabetes and related complications.69,70 Globally, the European Commission has recommended 4%-8% of energy from n-6 PUFAs, and the WHO recommends 5%-8% of energy from n-6 PUFAs.71,72 While the n-6 PUFA recommendations in North America and Europe are comparable, the Japan Society for Lipid Nutrition recommends that linoleic acid intake be reduced to 3%-4% of energy,73 and the International Society for the Study of Fatty Acids and Lipids (ISSFAL) also recommends a low level of linoleic acid intake (2% of energy and an upper limit of 3% of calories).74 The rationale for the Japanese recommendation was based on an association between an increase in death rates from cerebral infarction and ischemic heart disease in Japan and an associated increase in linoleic acid intake (in grams/day). The ISSFAL recommendation was based principally on the goal of reducing excess arachidonic acid and its eicosanoid products, which can occur as the result of high levels of linoleic acid and arachidonic acid, and accompanying low levels of alpha-linolenic acid. Although some studies have shown beneficial effects of diets much higher in PUFAs (between 14% and 21% of calories),34-39 the ideal level of PUFAs to both maximally reduce cardiovascular disease and favorably affect other health outcomes remains to be determined.

Research Needed

Research is needed to identify the portfolio of cardiovascular disease risk factors affected by PUFAs, and to establish the optimal level of dietary PUFAs to maximally and beneficially affect the greatest number of these risk factors. This research must be done in a way that resolves how other dietary constituents impact the biological effects mediated by dietary PUFAs. The issue of the ratio of omega-6 to omega-3 fatty acids has recently been of interest to many researchers. However, similar ratios between these two fatty acids may be observed at very high as well as very low intake levels. Furthermore, even with a recommended healthy ratio of 4:1, saturated fat, trans fat, and cholesterol intakes could exceed recommended levels. Therefore, the ratio could misrepresent the overall quality of the diet. Consequently, it may be more important to focus on recommended levels rather than the ratio. The ratio can be considered/reported but should not the primary basis for any conclusion on dietary effects of PUFAs without considering the diet in its entirety.75 Research is also needed to determine the amount of linoleic acid in the diet necessary to achieve maximal benefits on certain end points such as lipids and lipoproteins, but still remain at a level that does not result in detrimental effects on emerging risk factors such as oxidative stress and adhesion molecules.

Acknowledgment

This work was supported in part by an educational grant from Frito-Lay, Inc.

Copyright International Life Sciences Institute and Nutrition Foundation Nov 2004

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