Plant compared with marine n3 fatty acid effects on cardiovascular

risk factors and outcomes: what is the verdict?13

Thomas AB Sanders

INTRODUCTION

The land-based food chain is dominated by an abundance of

linoleic acid (18:2n6) in seed oils, nuts, and cereals, whereas
the distribution and abundance of a-linolenic acid (ALA4;
18:3n3) are more limited. Soybean and rapeseed oils contain
w7% and 10% ALA, respectively, by weight but most of the
other major vegetable oils, such as corn, coconut, cottonseed,
sunflower, olive, and palm oil, contain ,1% (1). ALA is also
found in significant amounts in lipids of flaxseed, hempseed,
walnuts, and dark-green leafy vegetables. The fat content of
green leafy vegetables is very low but does contribute significantly to the dietary intake of herbivores. Grass-fed ruminants
produce milk with a higher content of ALA than that from animals that are stall-fed cereals (2). Because the diets of most
land-based animals contain much higher proportions of LA than
ALA, the major long-chain PUFA metabolites found in eggs,
milk, and meat are derived from the n6 series, with only small

amounts from the n3 series being present predominantly as

DHA (22:6n3) (3). Fish accumulate substantial amounts of
EPA (20:5n3), docosapentaenoic acid (22:5n3), and DHA
from marine algae (4, 5). Thus, fish consumption, especially oily
fish, can make a substantial contribution to long-chain n3
PUFA intakes. Consequently, vegan diets are usually devoid of
long-chain n3 PUFAs (6), and vegetarian diets only supply
trace amounts (,0.05 g) from eggs and dairy products (7). This
is reflected in the lower concentrations of EPA and DHA in
vegans and vegetarians compared with omnivores in several
populations (710). In a recent analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study,
the proportions of DHA in the plasma lipids of vegans and
vegetarians were 59% and 31% lower, respectively, than those in
omnivores (10).
There has been much debate as to whether ALA is efficiently
converted to DHA; however, there is clear evidence that humans
can convert ALA to DHA (11, 12). Supplementation of vegans
(13), vegetarians (14, 15), and omnivores (16) with ALA resulted
in the synthesis of EPA but did not influence the proportion of
DHA in blood lipids. Most omnivore diets contain small amounts
of DHA, typically ,0.2 g/d (1, 7, 17). In a dose-response study
(18) in which omnivore participants were advised to avoid the
consumption of oily fish, the proportion of DHA in plasma lipids
increased from 2.07 6 0.52% with placebo to 2.63 6 0.65%,
3.07 6 0.48%, and 3.84 6 0.61% with 0.18, 0.36, and 0.72 g
DHA/d, respectively, in men after 6 mo of supplementation.
Supplementing vegans with 0.2 g DHA/d derived from algae
compared with placebo (19) significantly increased the concentration of DHA in their plasma lipids from 23 6 12 mg/L to
33 6 12 mg/L, and Geppert et al (20) reported a 2.9-fold increase in the proportion of DHA in plasma phospholipids in
a randomized controlled trial of 0.94 g DHA/d compared with
1
From the Diabetes and Nutritional Sciences Division, School of Medicine, Kings College London, London, United Kingdom.
2
Presented at the symposium Sixth International Congress on Vegetarian
Nutrition held in Loma Linda, CA, 2426 February 2013.
3
Address correspondence and requests for reprints to TAB Sanders, Diabetes and Nutritional Sciences Division, School of Medicine, Kings College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1
9NH, United Kingdom. E-mail: tom.sanders@kcl.ac.uk.
4
Abbreviations used: ALA, a-linolenic acid; CHD, coronary heart disease; CVD, cardiovascular disease; PWVc-f, carotid to femoral pulse wave
velocity.
First published online June 4, 2014; doi: 10.3945/ajcn.113.071555.

Am J Clin Nutr 2014;100(suppl):453S8S. Printed in USA. 2014 American Society for Nutrition

453S

Downloaded from ajcn.nutrition.org by guest on June 21, 2016

ABSTRACT
Plants provide a-linolenic acid [ALA; 18:3n3 (18:3v-3)], which
can be converted via eicosapentaenoic acid (EPA; 20:5n3) to docosahexaenoic acid (DHA; 22:6n3), which is required for normal
visual and cognitive function. Dietary ALA is provided mainly by
vegetable oils, especially soybean and rapeseed oils, but is destroyed by partial hydrogenation; it is also present in high amounts
in walnuts and flaxseed. Dietary EPA and DHA are provided mainly
by fish and so are absent from vegan diets and only present in trace
amounts in vegetarian diets. Vegetarians and vegans have lower
proportions of DHA in blood and tissue lipids compared with omnivores. High intakes of EPA and DHA (typically in the range of
35 g/d) but not ALA have favorable effects on several cardiovascular
disease (CVD) risk factors and have been postulated to delay arterial aging and cardiovascular mortality, but these intakes are beyond
the range of normal dietary intake. Arterial stiffness, which is a measure of arterial aging, appears to be lower in vegans than in omnivores; and risk of CVD in vegetarians and vegans is approximately
one-third that in omnivores. Prospective cohort studies showed
higher intakes of EPA+DHA, and less consistently ALA, to be
associated with a lower risk of CVD, especially fatal coronary heart
disease, but meta-analyses of randomized controlled trials of supplementation of EPA+DHA or ALA in secondary prevention of
CVD showed no clear benefit. Current evidence is insufficient to
warrant advising vegans and vegetarians to supplement their diets
with EPA or DHA for CVD prevention.
Am J Clin Nutr 2014;100
(suppl):453S8S.

454S

SANDERS

LDL-cholesterol and apolipoprotein B concentrations in normolipidemic subjects (31). A meta-analysis (32) confirmed that
LDL cholesterol is increased by algal DHA, on average, by 0.23
mmol/L but showed that HDL cholesterol increased in parallel so
that the net effect on the total:HDL-cholesterol ratio was null.
Although the total:HDL-cholesterol ratio is regarded as a more
robust indicator of cardiovascular risk than nonHDL cholesterol
or HDL cholesterol alone (33), interpreting these effects is difficult because the higher proportion of DHA in LDL lipids
renders the LDL particles more susceptible to oxidative modification (34, 35). Supplementation of vegetarian diets (20) with
algal DHA at 0.9 g/d increased LDL cholesterol by w0.28
mmol/L. It may well be that the DHA-mediated increase in LDL
cholesterol with higher intakes is counterbalanced for CVD risk
by an increase in HDL cholesterol and a decrease in dense LDL
particles (36). It needs to be emphasized, however, that the average increase in LDL cholesterol with DHA supplementation is
of a similar magnitude to that derived from increasing the intake
of SFA by 6% of energy (37) and should be considered in any
risk-benefit analysis on the merits of supplementing vegetarian
diets with DHA.

DIFFERENCES BETWEEN ALA AND LONG-CHAIN

n3 PUFAs ON CARDIOVASCULAR RISK FACTORS

Blood pressure and hemostatic and inflammatory risk

markers

Lipids
Intakes of EPA and DHA in excess of w1 g/d lower plasma
triglyceride concentrations in a dose-dependent manner (18);
ALA does not produce this effect even at high intakes (25). This
dissimilarity is likely attributable to the differences in chain
length and the fact that a high proportion of ALA is oxidized
(26) by mitochondrial b-oxidation. EPA and DHA fatty acids
are poor substrates for mitochondrial b-oxidation but are both
ligands for peroxisome proliferator receptor a, whose activation
inhibits hepatic triglyceride synthesis and promotes peroxisomal
oxidation of these fatty acids (1, 27). Pharmacologic intakes of
EPA and DHA (the dose used in prescription medications is w3
g/d) decrease VLDL synthesis and secretion (27). In addition to
lowering fasting triglyceride concentrations, this also decreases
postprandial lipemia, probably as a consequence of reduced competition for lipoprotein lipase by VLDL-triacylglycerol (1, 27).
The reduction in serum triglyceride concentration is also accompanied by altered cholesterol ester transfer protein activity, resulting in increases in the less-dense fractions of LDL and HDL,
which may be less atherogenic (28). However, some individuals
who exhibit the relatively common Fredrickson lipoprotein
IV phenotype (increased VLDL triglycerides and low HDL cholesterol) as well as the less common type V phenotype show
marked increases in LDL-cholesterol concentrations that accompany the triglyceride-lowering effect of EPA+DHA (29, 30).
This effect is believed to result from less-dense VLDL (as a result of a lower triglyceride content) being converted to LDL.
This potentially adverse effect is relevant in individuals with the
metabolic syndrome and in people with type 2 diabetes in whom
these phenotypes are more prevalent.
Low intakes of fish oil or oily fish that provide a combination
of EPA+DHA generally do not affect total cholesterol or LDL
cholesterol in normolipidemic subjects (18, 27). In contrast,
relatively low intakes of algal DHA, as little as 0.8 g/d, increase

High intakes of EPA+DHA (normally .3 g/d), but not ALA

(37), lowered blood pressure (38). However, intakes in the range
of a normal diet had no effect on blood pressure (18, 39). The
effects of pharmacologic intakes of EPA and DHA on other
CVD risk factors have been reviewed elsewhere (1, 40). Generally, in addition to their documented effects on blood pressure
and fasting and postprandial lipids, they have no influence on
clotting factors or fibrinolysis but decrease the production of
thromboxane A2, leukotriene B4, IL-6, and TNF-a, and thus
have an anti-inflammatory effect.
Effects on arterial aging
Because it has not been possible to discern effects on blood
lipids, blood pressure, and inflammation within the range of
intakes normally encountered in Western diets, other mechanisms
have been proposed to explain how low intakes of long-chain n3
PUFAs may influence CVD risk. These include altered susceptibility to cardiac arrhythmias that contribute to sudden cardiac
death (41) and reduced arterial stiffness. The latter is emerging
as a significant predictor of cardiovascular death in older individuals, independent of blood pressure (42), and is a robust
index of arterial aging and correlated with increased carotid
intimal media thickness. A prospective study (43) and a metaanalysis (44) suggested that EPA+DHA are associated with
decreased arterial stiffness. If this were the case then vegetarians
and vegans, in particular, might have stiffer arteries.
To test this hypothesis, we extracted data previously collected
in our laboratory from 2 studies (17, 45) conducted over the same
time period (20002003) in 159 healthy vegan and 164 healthy
omnivore men (aged 2070 y) who had no clinical history of
CVD; smoking prevalence was low in both groups (6%). Liver
function tests and full blood counts and a medical history were
obtained to exclude participants with chronic health problems.
Fasting blood samples were collected from all participants.

Downloaded from ajcn.nutrition.org by guest on June 21, 2016

placebo in German vegetarians. Thus, although there is a basal

rate of DHA synthesis from ALA in humans, the proportions in
blood lipids are greatly augmented by dietary DHA.
High intakes of EPA, n3 docosapentaenoic acid, and DHA
(314 g/d) plausibly explained the low incidence of acute
myocardial infarction in Inuit groups consuming their traditional
diets because of the pharmacologic effects on eicosanoid synthesis (21); however, more recent studies (22, 23) have not found
cardiovascular disease (CVD) prevalence to be lower among Inuit
people, possibly because their traditional lifestyle has changed.
Nevertheless, there is a large body of evidence showing that high
intakes of EPA and DHA have antithrombotic and anti-inflammatory
effects (1). However, low intakes of fish (24), providing ,1 g
long-chain n3 PUFAs/d, were also associated with a lower risk
of CVD, with as little as 1 serving/wk showing a 16% reduction
in risk of death from coronary heart disease (CHD). Consequently, important questions are whether ALA and long-chain
n3 PUFAs have comparable effects on cardiovascular risk
factors and whether ALA and long-chain n3 PUFAs differ with
regard to risk using clinical endpoints (ie, CVD incidence and
mortality).

455S

n3 FATTY ACIDS AND CVD OUTCOMES

BMI-adjusted difference of 0.42 m/s would be predicted to be

associated with an w4% lower risk of CVD mortality (42). It
may well be that the consequences of lacking EPA and DHA are
mitigated by their more favorable CVD risk factor profile.

Height, weight, and waist circumference were measured. After

15 min supine rest, blood pressure was measured by using an
automated sphygmomanometer (Omron 70CP; Omron Health
Care, Inc), and arterial stiffness was estimated by measuring
carotid to femoral pulse wave velocity (PWVc-f) with the use of
the SphygmoCor PVW apparatus with SphygmoCor version
7.01 analysis software (AtCor Medical Pty). PWVc-f was computed from the time delay between the upstroke of the arterial
pressure wave at the carotid and femoral arteries and the anatomic distance between the sternal notch and femoral pulse at
the point of applanation. Plasma total fatty acid composition and
serum lipid profile were measured by using identical methods
(17) in the same laboratories on fasting samples collected at the
same time as the PWVc-f measurement. Statistical analysis was
conducted by using SPSS/PC version 20:0 (IBM SPSS Statistics), and comparisons between vegans and omnivores were
performed by using ANOVA variance adjusted for age and BMI.
Automatic linear regression analysis was also conducted to explore sources of variation in PWVc-f. As expected, plasma EPA
and DHA concentrations were markedly lower in vegans compared with omnivores, but arterial stiffness adjusted for age and
BMI was 0.42 m/s lower in vegan men (Table 1).
The results of regression analysis on PWVc-f in all of the
subjects, which explained 53% of the variance, are shown in
Figure 1; the main determinants were age and systolic blood
pressure with smaller contributions from BMI and total:HDL
cholesterol. Furthermore, supplementation of a subgroup of
these vegan men (n = 39) with 0.2 g DHA/d for 3 mo compared
with placebo (n = 29) had no effect on arterial stiffness (mean
difference for treatment compared with placebo: 20.05 m/s;
95% CI: 20.35, 0.26 m/s), systolic blood pressure (mean difference: 22.0 mm Hg; 95% CI: 27.0, 2.9 mm Hg), or serum
LDL cholesterol (mean difference: 20.07 mmol/L; 95% CI:
20.27, 0.15 mmol/L) (46).
These observations refute the hypothesis that arterial stiffness
is increased by a lack of fish and other sources of EPA and DHA
in the vegan diet. Indeed, there was tentative evidence to suggest
that arterial aging may be slower in vegans, and the age- and

EVIDENCE FROM PROSPECTIVE COHORT STUDIES

RESULTS FROM RANDOMIZED CONTROLLED TRIALS

WITH CLINICAL ENDPOINTS

Several large randomized controlled trials of n3 PUFA

supplementation in the secondary prevention of CVD have been
conducted. The Mediterranean diet study by de Lorgeril et al
(52) is often cited as evidence to show that an increased intake

TABLE 1
Indexes of PUFA intake, cardiovascular risk factors, and arterial stiffness measured as carotid to femoral pulse wave
velocity in vegan and omnivore men aged 2070 y1
Vegans2
Plasma PUFAs (wt%)
18:2n6
18:3n3
20:5n3
22:6n3
BMI (kg/m2)
TC:HDL cholesterol4
SBP4 (mm Hg)
DBP4 (mm Hg)
PWVc-f4 (m/s)

36.0
0.82
0.46
0.98
23.9
3.62
123
73
8.20

(35.1, 36.9)
(0.74, 0.91)
(0.34, 0.58)
(0.83,1.13)
(23.3, 24.4)
(3.44, 3.80)
(120, 126)
(71, 74)
(7.98, 8.42)

Omnivores3
26.2
0.65
1.31
2.66
26.3
4.01
125
76
8.62

(25.4, 27.1)
(0.57, 0.72)
(1.20, 1.42)
(2.52, 2.79)
(25.7, 26.8)
(3.84, 4.18)
(123, 128)
(75, 78)
(8.37, 8.82)

Difference
9.8
0.18
20.85
21.67
22.4
20.39
21.96
23.58
20.42

(8.4, 11.2)
(0.05, 0.30)
(21.04, 20.67)
(21.91, 21.44)
(23.2, 21.7)
(20.66, 20.11)
(26.07, 2.16)
(25.92, 21.23)
(20.71, 20.05)

P
,0.001
,0.001
,0.001
,0.001
,0.001
0.005
0.35
0.002
0.03

1
Values are means; 95% CIs in parentheses. Unpublished data from 2 previously published studies (17, 45). P values
were derived by using ANOVA adjusted for age and BMI. Data for PWVc-f were log-transformed before analysis. DBP,
diastolic blood pressure (supine); PWVc-f, carotid to femoral pulse wave velocity; SBP, systolic blood pressure (supine);
TC, total cholesterol; wt%, percentage by weight.
2
n = 159 and n = 124 for plasma fatty acids.
3
n = 165 and n = 141 for plasma fatty acids.
4
Values were adjusted for age and BMI.

Downloaded from ajcn.nutrition.org by guest on June 21, 2016

Many prospective cohort studies indicate a lower risk of CVD

with higher intakes long-chain n3 PUFAs by fish (1, 47) and
indicate a greater effect on fatal CVD than nonfatal CVD.
However, it is difficult to gauge the specific contribution to risk
reduction made by long-chain n3 PUFAs from other nutrients/
compounds present in fish (47). The estimation of ALA intake
from food-frequency tables is fraught with many problems, especially because ALA is often a target for reduction by partial
hydrogenation of soybean and rapeseed oils to increase food
product stability. A meta-analysis (48) that used dietary intake
of ALA suggested that higher intakes reduced risk of CVD
mortality by 10%, and with the use of biomarkers the reduction
was greater (by14%), which is comparable to the risk reductions
reported for long-chain n3 PUFAs provided by fish (24). This
ratio seemed to be stronger for fatal, especially sudden, cardiac
death (49) than nonfatal CHD, which is similar to the relation
for long-chain n3 PUFAs. It also appears that there was
a threshold effect. For example, in the Nurses Health Study, risk
was greatest with intakes of ,1 g/d in women (50). However,
a recent nested case-control study from the EPIC-Norfolk cohort
(51) found neither the proportion of ALA nor EPA+DHA in
plasma phospholipids, which are good biomarkers of intake of
the latter, were associated with risk of incident CHD.

456S

SANDERS

studies indicate that higher intakes of EPA/DHA, and less

consistently ALA, are associated with a lower risk of fatal CVD,
but data from randomized controlled trials showed no clear
benefit of additional ALA or EPA/DHA in secondary prevention
of CVD. DHA concentrations in plasma and erythrocyte lipids
are lower in vegetarians than in omnivores primarily attributable
to the absence of DHA from the diet. Yet, despite the lack of
EPA and DHA in their diets, vegetarians are at lower risk of
CVD compared with omnivores. In conclusion, current evidence
does not justify advising vegan and vegetarians to supplement
their diet diets with EPA or DHA for CVD prevention.
FIGURE 1. Predictors of importance in the variance in arterial stiffness
measured as PWVc-f on the basis of analysis of data from 159 vegan and 165
omnivore men aged 2070 y of age. Data were analyzed by linear regression
modeling on log-transformed data for PWVc-f. The results show the proportion
of the total variance (53%) that could be explained by differences in age
(60%), systolic BP (36%), BMI (2%), and TC:HDL-C (2%). Unpublished data
from 2 previously published studies (17, 45). BP, blood pressure; PWVc-f,
carotid to femoral pulse wave velocity; TC:HDL-C, total:HDL cholesterol.

CONCLUSIONS

DHA and EPA have pharmacologic effects different from ALA

on CVD risk factors, but these effects are only seen at high
intakes (.3 g/d), well above the amounts likely to be consumed
in most human diets (typically ,0.5 g/d). Prospective cohort

REFERENCES
1. WHO/FAO. Fats and fatty acids in human nutrition. Report of an expert
consultation. Rome, Italy: FAO, 2010. Available from: http://www.fao.
org/docrep/013/i1953e/i1953e00.pdf (cited 15 May 2014).
2. Larsen MK, Nielsen JH, Butler G, Leifert C, Slots T, Kristiansen GH,
Gustafsson AH. Milk quality as affected by feeding regimens in
a country with climatic variation. J Dairy Sci 2010;93:286373.
3. Tinoco J. Dietary requirements and functions of alpha-linolenic acid in
animals. Prog Lipid Res 1982;21:145.
4. Metz JG, Roessler P, Facciotti D, Levering C, Dittrich F, Lassner M,
Valentine R, Lardizabal K, Domerque F, Yamada A, et al. Production
of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes. Science 2001;293:2903.
5. Uttaro AD. Biosynthesis of polyunsaturated fatty acids in lower eukaryotes. IUBMB Life 2006;58:56371.
6. Roshanai F, Sanders TA. Assessment of fatty acid intakes in vegans and
omnivores. Hum Nutr Appl Nutr 1984;38:34554.
7. Welch AA, Shakya-Shrestha S, Lentjes MA, Wareham NJ, Khaw KT.
Dietary intake and status of n-3 polyunsaturated fatty acids in a population of fish-eating and non-fish-eating meat-eaters, vegetarians, and
vegans and the product-precursor ratio of a-linolenic acid to long-chain
n3 polyunsaturated fatty acids: results from the EPIC-Norfolk cohort.
Am J Clin Nutr 2010;92:104051.
8. Sanders TA, Ellis FR, Dickerson JW. Studies of vegans: the fatty acid
composition of plasma choline phosphoglycerides, erythrocytes, adipose tissue, and breast milk, and some indicators of susceptibility to
ischemic heart disease in vegans and omnivore controls. Am J Clin
Nutr 1978;31:80513.
9. Sanders TA, Reddy S. The influence of a vegetarian diet on the fatty
acid composition of human milk and the essential fatty acid status of
the infant. J Pediatr 1992;120:S717.
10. Rosell MS, Lloyd-Wright Z, Appleby PN, Sanders TA, Allen NE, Key
TJ. Long-chain n-3 polyunsaturated fatty acids in plasma in British
meat-eating, vegetarian, and vegan men. Am J Clin Nutr 2005;82:327
34.
11. Jensen CL, Prager TC, Fraley JK, Chen H, Anderson RE, Heird WC.
Effect of dietary linoleic/alpha-linolenic acid ratio on growth and visual function of term infants. J Pediatr 1997;131:2009.
12. Makrides M, Neumann MA, Jeffrey B, Lien EL, Gibson RA. A randomized trial of different ratios of linoleic to alpha-linolenic acid in the
diet of term infants: effects on visual function and growth. Am J Clin
Nutr 2000;71:1209.
13. Sanders TA, Younger KM. The effect of dietary supplements of omega
3 polyunsaturated fatty acids on the fatty acid composition of platelets
and plasma choline phosphoglycerides. Br J Nutr 1981;45:6136.
14. Li D, Sinclair A, Wilson A, Nakkote S, Kelly F, Abedin L, Mann N,
Turner A. Effect of dietary alpha-linolenic acid on thrombotic risk
factors in vegetarian men. Am J Clin Nutr 1999;69:87282.
15. Wien M, Rajaram S, Oda K, Sabate J. Decreasing the linoleic acid to
alpha-linolenic acid diet ratio increases eicosapentaenoic acid in
erythrocytes in adults. Lipids 2010;45:68392.
16. Valsta LM, Salminen I, Aro A, Mutanen M. Alpha-linolenic acid in
rapeseed oil partly compensates for the effect of fish restriction on
plasma long chain n-3 fatty acids. Eur J Clin Nutr 1996;50:22935.
17. Sanders TA, Lewis F, Slaughter S, Griffin BA, Giffin M, Davies I,
Millward DJ, Cooper JA, Miller GJ. Effect of varying the ratio of n-6 to

Downloaded from ajcn.nutrition.org by guest on June 21, 2016

of ALA reduces CVD mortality, but this was a multifactorial

intervention. The Indo-Mediterranean diet also claimed a beneficial effect of ALA, but it emerged that this was fraudulent and
so its findings should be ignored (53). Only one sufficiently
powered study (the Alpha-Omega Trial) compared EPA+DHA
with ALA supplementation in secondary prevention, and this
showed no difference in the primary or secondary outcomes
(54). The UK Diet and Reinfarction Trial (DART) study (55)
showed that dietary advice to eat 2 portions of oily fish/wk
decreased total mortality over the following 2 y by 29%.
However, a second study (DART-2) by the same group (56),
which used fish-oil supplements instead of fish in patients with
stable angina, found no benefit and a trend for a less favorable
outcome in the supplemented group. Two Italian studies (41, 57)
by the Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto Miocardico (GISSI) investigators reported a benefit in
reduced cardiovascular mortality with a purified fish-oil triglyceride concentrate providing w0.8 g EPA+DHA. Another
open-label study conducted in Japan, which used 1.8 g ethyl
EPA in addition to a statin compared with a statin alone, found
a 19% reduction in incident CHD in a mainly female population
(58). However, more recent larger double-blind controlled trials
of EPA+DHA supplementation showed no benefit on CVD incidence or mortality (54, 59, 60). Furthermore, supplementation
with EPA+DHA failed to produce the hoped-for clinical benefit
in patients with implantable cardioverter defibrillators (61) or in
those with atrial fibrillation (62). Meta-analyses (63, 64) of these
intervention trials concluded that there was no evidence of
a reduction in total mortality or CVD events with n3 supplementation, although there was a trend for risk of cardiac death to
be 9% lower (95% CI: 85, 98). However, it is to be emphasized
that, in the more recent trials, blood pressure and lipids were
well controlled by medication and this may have obscured any
dietary effect.

The author declared that he had no conflicts of interest.

n3 FATTY ACIDS AND CVD OUTCOMES

18.

19.
20.
21.
22.

23.

24.

26.
27.
28.

29.
30.
31.
32.

33.

34.

35.

36.
37.

38. Kestin M, Clifton P, Belling GB, Nestel PJ. n-3 Fatty acids of marine
origin lower systolic blood pressure and triglycerides but raise LDL
cholesterol compared with n-3 and n-6 fatty acids from plants. Am J
Clin Nutr 1990;51:102834.
39. Appel LJ, Miller ER III, Seidler AJ, Whelton PK. Does supplementation of diet with fish oil reduce blood pressure? A meta-analysis of
controlled clinical trials. Arch Intern Med 1993;153:142938.
40. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J.
Effects of omega-3 fatty acids on serum markers of cardiovascular
disease risk: a systematic review. Atherosclerosis 2006;189:1930.
41. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio
R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, et al. Early
protection against sudden death by n-3 polyunsaturated fatty acids after
myocardial infarction: time-course analysis of the results of the Gruppo
Italiano per lo Studio della Sopravvivenza nellInfarto Miocardico
(GISSI)-Prevenzione. Circulation 2002;105:1897903.
42. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010;55:
131827.
43. Anderson SG, Sanders TA, Cruickshank JK. Plasma fatty acid composition as a predictor of arterial stiffness and mortality. Hypertension
2009;53:83945.
44. Pase MP, Grima NA, Sarris J. Do long-chain n-3 fatty acids reduce
arterial stiffness? A meta-analysis of randomised controlled trials. Br J
Nutr 2011;106:97480.
45. Lloyd-Wright Z, Hvas AM, Moller J, Sanders TA, Nexo E. Holotranscobalamin as an indicator of dietary vitamin B12 deficiency. Clin
Chem 2003;49:20768.
46. Lloyd-Wright Z. The nutritonal status of vegan men in the United
Kingdom with particular reference to vitamin B12. PhD dissertation,
Kings College London, University of London, London, United
Kingdom, 2005.
47. Chowdhury R, Stevens S, Gorman D, Pan A, Warnakula S, Chowdhury
S, Ward H, Johnson L, Crowe F, Hu FB, et al. Association between fish
consumption, long chain omega 3 fatty acids, and risk of cerebrovascular
disease: systematic review and meta-analysis. BMJ 2012;345:e6698.
48. Pan A, Chen M, Chowdhury R, Wu JH, Sun Q, Campos H, Mozaffarian
D, Hu FB. a-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis. Am J Clin Nutr 2012;96:126273.
49. Albert CM, Oh K, Whang W, Manson JE, Chae CU, Stampfer MJ,
Willett WC, Hu FB. Dietary alpha-linolenic acid intake and risk of
sudden cardiac death and coronary heart disease. Circulation 2005;112:
32328.
50. Hu FB, Stampfer MJ, Manson JE, Rimm EB, Wolk A, Colditz GA,
Hennekens CH, Willett WC. Dietary intake of a-linolenic acid and risk
of fatal ischemic heart disease among women. Am J Clin Nutr 1999;69:
8907.
51. Khaw KT, Friesen MD, Riboli E, Luben R, Wareham N. Plasma
phospholipid fatty acid concentration and incident coronary heart
disease in men and women: the EPIC-Norfolk prospective study. PLoS
Med 2012;9:e1001255.
52. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N.
Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon
Diet Heart Study. Circulation 1999;99:77985.
53. Horton R. Expression of concern: Indo-Mediterranean Diet Heart
Study. Lancet 2005;366:3546.
54. Kromhout D, Giltay EJ, Geleijnse JM. n-3 Fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010;363:
201526.
55. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam
PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, and
fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 1989;2:75761.
56. Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton
T, Zotos PC, Haboubi NA, Elwood PC. Lack of benefit of dietary
advice to men with angina: results of a controlled trial. Eur J Clin Nutr
2003;57:193200.
57. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini
R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSIHF trial): a randomised, double-blind, placebo-controlled trial. Lancet
2008;372:122330.

Downloaded from ajcn.nutrition.org by guest on June 21, 2016

25.

n-3 fatty acids by increasing the dietary intake of alpha-linolenic acid,

eicosapentaenoic and docosahexaenoic acid, or both on fibrinogen and
clotting factors VII and XII in persons aged 45-70 y: the OPTILIP
study. Am J Clin Nutr 2006;84:51322.
Sanders TA, Hall WL, Maniou Z, Lewis F, Seed PT, Chowienczyk PJ.
Effect of low doses of long-chain n3 PUFAs on endothelial function
and arterial stiffness: a randomized controlled trial. Am J Clin Nutr
2011;94:97380.
Sanders TA. DHA status of vegetarians. Prostaglandins Leukot Essent
Fatty Acids 2009;81:13741.
Geppert J, Kraft V, Demmelmair H, Koletzko B. Microalgal docosahexaenoic acid decreases plasma triacylglycerol in normolipidaemic
vegetarians: a randomised trial. Br J Nutr 2006;95:77986.
Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis?
Lancet 1978;2:1179.
Cutchins A, Roman MJ, Devereux RB, Ebbesson SO, Umans JG, Zhu
J, Weissman NJ, Howard BV. Prevalence and correlates of subclinical
atherosclerosis in Alaska Eskimos: the GOCADAN study. Stroke 2008;
39:307982.
Kjaergaard M, Andersen S, Holten M, Mulvad G, Kjaergaard JJ. Low
occurrence of ischemic heart disease among Inuit around 1963 suggested from ECG among 1851 East Greenland Inuit. Atherosclerosis
2009;203:599603.
Zheng J, Huang T, Yu Y, Hu X, Yang B, Li D. Fish consumption and
CHD mortality: an updated meta-analysis of seventeen cohort studies.
Public Health Nutr 2012;15:72537.
Pan A, Yu D, Demark-Wahnefried W, Franco OH, Lin X. Meta-analysis
of the effects of flaxseed interventions on blood lipids. Am J Clin Nutr
2009;90:28897.
Burdge GC, Wootton SA. Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young
women. Br J Nutr 2002;88:41120.
Harris WS. n-3 Fatty acids and serum lipoproteins: human studies. Am
J Clin Nutr 1997;65(suppl):1645S54S.
Griffin MD, Sanders TA, Davies IG, Morgan LM, Millward DJ, Lewis
F, Slaughter S, Cooper JA, Miller GJ, Griffin BA. Effects of altering the
ratio of dietary n-6 to n-3 fatty acids on insulin sensitivity, lipoprotein
size, and postprandial lipemia in men and postmenopausal women aged
45-70 y: the OPTILIP Study. Am J Clin Nutr 2006;84:12908.
Sullivan DR, Sanders TA, Trayner IM, Thompson GR. Paradoxical
elevation of LDL apoprotein B levels in hypertriglyceridaemic patients
and normal subjects ingesting fish oil. Atherosclerosis 1986;61:12934.
Sanders TA. Influence of omega 3 fatty acids on blood lipids. World
Rev Nutr Diet 1991;66:35866.
Theobald HE, Chowienczyk PJ, Whittall R, Humphries SE, Sanders
TA. LDL cholesterol-raising effect of low-dose docosahexaenoic acid
in middle-aged men and women. Am J Clin Nutr 2004;79:55863.
Bernstein AM, Ding EL, Willett WC, Rimm EB. A meta-analysis
shows that docosahexaenoic acid from algal oil reduces serum triglycerides and increases HDL-cholesterol and LDL-cholesterol in
persons without coronary heart disease. J Nutr 2012;142:99104.
Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J,
Qizillbash N, Peto R, Collins R. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual
data from 61 prospective studies with 55,000 vascular deaths. Lancet
2007;370:182939.
Finnegan YE, Minihane AM, Leigh-Firbank EC, Kew S, Meijer GW,
Muggli R, Calder PC, Williams CM. Plant- and marine-derived n-3
polyunsaturated fatty acids have differential effects on fasting and
postprandial blood lipid concentrations and on the susceptibility of
LDL to oxidative modification in moderately hyperlipidemic subjects.
Am J Clin Nutr 2003;77:78395.
Pedersen H, Petersen M, Major-Pedersen A, Jensen T, Nielseen NS,
Lauridsen ST, Marckmann P. Influence of fish oil supplementation on
in vivo and in vitro oxidation resistance of low-density lipoprotein in
type 2 diabetes. Eur J Clin Nutr 2003;57:71320.
Kelley DS, Siegel D, Vemuri M, Mackey BE. Docosahexaenoic acid
supplementation improves fasting and postprandial lipid profiles in
hypertriglyceridemic men. Am J Clin Nutr 2007;86:32433.
Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty
acids and carbohydrates on the ratio of serum total to HDL cholesterol
and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003;77:114655.

457S

458S

SANDERS

58. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa

Y, Oikawa S, Sasaki J, Hishida H, Itakura H, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet
2007;369:10908.
59. Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, Gottwik M,
Steinbeck G, Del Castillo U, Sack R, et al; OMEGA Study Group.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly
purified omega-3 fatty acids on top of modern guideline-adjusted therapy
after myocardial infarction. Circulation 2010;122:21529.
60. Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, Maggiono
AP, Probstfield J, Rmachandran A, Riddle MC, et al. n-3 Fatty acids and
cardiovascular outcomes in patients with dysglycemia. N Engl J Med
2012;367:30918.
61. Brouwer IA, Raitt MH, Dullemeijer C, Kraemer DF, Zock PL, Morris
C, Katan MB, Connor WE, Camm JA, Schouten EG, et al. Effect of

fish oil on ventricular tachyarrhythmia in three studies in patients

with implantable cardioverter defibrillators. Eur Heart J 2009;30:
8206.
62. Mozaffarian D, Marchioli R, Macchia A, Silletta MG, Ferrazzi P,
Gardner TJ, Latini R, Libby P, Lombardi F, OGara PT, et al. Fish oil
and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized
trial. JAMA 2012;308:200111.
63. Hooper L, Summerbell CD, Thompson R, Sills D, Roberts FG,
Moore HJ, Davey Smith G. Reduced or modified dietary fat for
preventing cardiovascular disease. Cochrane Database Syst Rev
2012;5:CD002137.
64. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association
between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.
JAMA 2012;308:102433.

Downloaded from ajcn.nutrition.org by guest on June 21, 2016