Omega-3 index in 2018/19

Abstract

The omega-3 index, the percentage of EPA plus DHA in erythrocytes (measured by standardised analysis), represents a human body's status in EPA and DHA. An omega-3 index is measured in many laboratories around the world; however, even small differences in analytical methods entail large differences in results. Nevertheless, results are frequently related to the target range of 8–11 %, defined for the original and scientifically validated method (HS-Omega-3 Index ® ), raising ethical issues, and calling for standardisation. No human subject has an omega-3 index <2 %, indicating a vital minimum. Thus, the absence of EPA and DHA cannot be tested against presence. Moreover, clinical events correlate with levels, less with the dose of EPA and DHA, and the bioavailability of EPA and DHA varies inter-individually. Therefore, the effects of EPA and DHA are difficult to demonstrate using typical drug trial methods. Recent epidemiologic data further support the relevance of the omega-3 index in the cardiovascular field, since total mortality, cardiovascular mortality, cardiovascular events such as myocardial infarction or stroke, or blood pressure all correlate inversely with the omega-3 index. The omega-3 index directly correlates with complex brain functions. Compiling recent data supports the target range for the omega-3 index of 8–11 % in pregnancy. Many other potential applications have emerged. Some, but not all health issues mentioned have already been demonstrated to be improved by increasing intake of EPA and DHA. Increasing the omega-3 index into the target range of 8–11 % with individualised doses of toxin-free sources for EPA and DHA is tolerable and safe.

Full text

The 13th European Nutrition Conference was held at the Convention Centre, Dublin on 15–18 October 2019
Conference on ‘Malnutrition in an obese world: European perspectives’
Symposium 2: Assessment and novel technologies
Omega-3 index in 2018/19
Clemens von Schacky
Omegametrix, Martinsried, Germany and Preventive Cardiology, University of Munich, Germany
The omega-3 index, the percentage of EPA plus DHA in erythrocytes (measured by standar-
dised analysis), represents a human body’s status in EPA and DHA. An omega-3 index is
measured in many laboratories around the world; however, even small differences in analyt-
ical methods entail large differences in results. Nevertheless, results are frequently related to
the target range of 8–11 %, defined for the original and scientifically validated method (HS-
Omega-3 Index
®
), raising ethical issues, and calling for standardisation. No human subject
has an omega-3 index <2 %, indicating a vital minimum. Thus, the absence of EPA and
DHA cannot be tested against presence. Moreover, clinical events correlate with levels,
less with the dose of EPA and DHA, and the bioavailability of EPA and DHA varies
inter-individually. Therefore, the effects of EPA and DHA are difficult to demonstrate
using typical drug trial methods. Recent epidemiologic data further support the relevance
of the omega-3 index in the cardiovascular field, since total mortality, cardiovascular mor-
tality, cardiovascular events such as myocardial infarction or stroke, or blood pressure all
correlate inversely with the omega-3 index. The omega-3 index directly correlates with com-
plex brain functions. Compiling recent data supports the target range for the omega-3 index
of 8–11 % in pregnancy. Many other potential applications have emerged. Some, but not all
health issues mentioned have already been demonstrated to be improved by increasing
intake of EPA and DHA. Increasing the omega-3 index into the target range of 8–11 %
with individualised doses of toxin-free sources for EPA and DHA is tolerable and safe.
n-3 Fatty acids: EPA: DHA
The omega-3 index was defined as the percentage of EPA
and DHA in a total of twenty-six specific fatty acids in ery-
throcytes in 2004
(1)
.Anintegralpartofthedefinition was
the highly standardised analytical procedure
(1,2)
. As dis-
cussed in more detail elsewhere, every step of the analytical
method impacts substantially on the result
(2)
.Moreover,
parameters such as time and vigour of shaking the sample
during lipid extraction, or time and agent used for trans-
methylation impacted on results
(2)
. Nevertheless, it was
possible to standardise the analytical method in three geo-
graphically distinct laboratories, with regular proficiency
testing demonstrating the fruitfulness of the efforts
(2)
.
Many laboratories around the world have their own
methods to analyse erythrocyte fatty acids, and some
are using these methods to produce results they call
omega-3 index. However, quantitatively, the results dif-
fer from the results obtained with the standardised
method, i.e. are either higher or lower
(2)
. This is problem-
atic if the target range of 8–11 % of the standardised
method is used as a reference. This can lead to over sup-
plementation (overshooting the target range, potential
risk of bleeding) or under supplementation (not reaching
the target value, increased risk for total mortality and
other untoward clinical events)
(3–7)
. Either way, non-
Corresponding author: Clemens von Schacky, email c.vonschacky@omegametrix.eu
Proceedings of the Nutrition Society, Page 1 of 7 doi:10.1017/S0029665120006989
© The Authors 2020. Published by Cambridge University Press on behalf of The Nutrition Society.
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-
NonCommercial-ShareAlike licence (http://creativecommons.org/licenses/by-nc-sa/4.0/), which
permits non-commercial re-use, distribution, and reproduction in any medium, provided the same
Creative Commons licence is included and the original work is properly cited. The written permission
of Cambridge University Press must be obtained for commercial re-use.
Proceedings of the Nutrition Society
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665120006989
Downloaded from https://www.cambridge.org/core. IP address: 178.171.17.215, on 11 May 2020 at 17:10:52, subject to the Cambridge Core terms of use, available at

standardised measurements create serious ethical issues;
standardising the omega-3 index methodology is needed.
Currently, the standardised analytical method can be
identified by the trademark HS-Omega-3 Index
®
.As
with all other laboratory parameters, standardisation of
the omega-3 index is one of the prerequisites for this par-
ameter entering clinical medicine.
The present review of scientific publications highlights
developments in the past two years.
Omega-3 index and human life
Using the standardised method to analyse erythrocytes,
and more than 20 000 samples from Omegametrix clin-
ical routine determinations, no sample was found with
an omega-3 index <2 % (Fig. 1). The same was true for
tens of thousands of samples from the Omegametrix
two sister laboratories called Omegaquant in Sioux
Falls, SD, USA and Seoul, South Korea (data not
shown). Thus, human life without a defined minimum
of EPA and DHA in erythrocytes remains to be found,
i.e. minimum levels of EPA and DHA seem to be needed
for human life. This puts the discussion, as to whether
EPA and DHA can be considered drugs, to rest. Life
without drugs is possible, whereas life without EPA
and DHA is not.
How the human body maintains these minimum levels
is unclear. Individuals, such as vegans or vegetarians,
ingest minimal amounts EPA and DHA (e.g. in one
study the mean was 1⋅5(
SD 3⋅5) mg/d EPA and 2⋅8
(SD 10⋅1) mg DHA/d according to dietary recall), yet in
these individuals, the mean omega-3 index found was
3⋅7(
SD 1⋅0) %
(8)
. In vegans or vegetarians, the omega-3
index did not correlate with the intake of α-linolenic
acid
(8)
, which was also true for omnivores in a country,
such as Canada, with high intake of α-linolenic contain-
ing flaxseed
(9)
. As a general rule, no level is solely con-
trolled by the influx, i.e. amounts going into the pool,
but also by other factors, such as distribution volume
(pool size), and efflux, i.e. amounts leaving the pool.
The pool size for EPA and DHA in human subjects
has not been determined, and what factors regulate the
catabolism of EPA and DHA have not yet been well
defined in quantitative terms. It is not yet clear whether
small amounts of α-linolenic acid are metabolised to
EPA or DHA, or whether catabolism of EPA and
DHA is shut off to maintain a minimum omega-3
index
(10,11)
. Correspondingly, EPA and DHA might be
essential because life without a minimum omega-3
index is not possible. Alternatively, this may not be the
case if a minimum omega-3 index arises from α-linoleic
acid metabolism to EPA and/or DHA. The question of
essentiality cannot be resolved by simply analysing the
levels of fatty acids, but only by detailed metabolic stud-
ies in appropriate populations.
Issues in trial design
Frequently, clinical research organisations are hired to
conduct a multi-centre trial. By default, clinical research
organisations ask trial participants to ingest their trial
medication in the morning, which was also the case in
many, but not all large trials with clinical endpoints in
the omega-3 field
(12,13)
. Trial medication in such trials
frequently was one capsule containing 1 g fat containing
860 mg EPA and DHA
(12,13)
. In many countries, break-
fast is a low-fat meal, if eaten at all. Bioavailability of
EPA and DHA is minimal with a low-fat meal, since
fat absorption requires a number of steps that are acti-
vated by a high-fat, but not by a low-fat meal
(14,15)
.In
other words, the bioavailability of EPA and DHA was
minimised by asking participants to ingest EPA and
DHA in the morning.
Moreover, in all trials so far, participants were
recruited irrespective of their baseline omega-3
index
(12,13)
. Patients with congestive heart failure with
reduced ejection fraction or major depression are charac-
terised by a low omega-3 index, but in many other health
issues, such as coronary artery disease, this is not neces-
sarily the case
(12,13,16,17)
. In addition, uptake of EPA and
DHA has high inter-individual variability, e.g. by a fac-
tor 13 in one trial
(18)
. The consequence of both inhomo-
geneous baseline levels and high inter-individual
variability of uptake was that on-trial levels of EPA
and DHA largely overlapped among placebo and
verum groups
(19)
. Since clinical events correlate with
the levels rather than with the intake of omega-3s, this
made it impossible to discern an effect of the intervention
with EPA and DHA
(12,13)
. The issues mentioned here are
discussed in more detail elsewhere
(12,13)
. In the future,
recruitment of trial participants will have to depend on
a low baseline omega-3 index (room for improvement
needed), and doses of EPA and DHA will have to be
individualised, in order to separate the levels in the pla-
cebo and verum groups. Positive trial results in popula-
tions characterised by a low omega-3 index, such as
patients with major depression or congestive heart failure
with reduced ejection fraction, support this approach,
although the dose was not individualised in the pertinent
trials
(20,21)
. Individualising the dose is likely to increase
the effect, and thus reduce the sample size, as well as
reduce the untoward effects
(12)
. The latter is supported
by the results of trials using high doses of EPA and/or
DHA, as in the JELIS or REDUCE-It trials
(6,7)
.In
both cases, the cost of a positive trial result was a small
increase in bleeding episodes (0⋅1 %/year)
(6,7)
.
Unfortunately, perception of the effectiveness of EPA
and DHA in clinical medicine is frequently shaped by the
results of pertinent Cochrane-Analyses. Cochrane-Analyses
include trials based on standardised Cochrane-criteria
designed for drug trials. In areas in which EPA and
DHA have been tested in randomised controlled trials,
Cochrane-Analyses tend to demonstrate no or only small
effects
(22)
. This is because Cochrane-criteria do not allow
trials with the design issues just discussed to be excluded.
Cardiovascular effects
The magnitude of the potential effects of EPA and DHA
can be estimated by considering the results of
C. von Schacky2
Proceedings of the Nutrition Society
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665120006989
Downloaded from https://www.cambridge.org/core. IP address: 178.171.17.215, on 11 May 2020 at 17:10:52, subject to the Cambridge Core terms of use, available at

epidemiologic studies, e.g. the Framingham study, using
the original omega-3 index. With an omega-3 index >6⋅8
%, total mortality was 65 % of total mortality with an
omega-3 index <4⋅2%
(3)
,reflecting very similar results
from earlier studies
(4,5)
. The respective numbers for
total CVD (63 %), total CHD (59 %) and total stroke
(47 %) were similar
(3)
. Interestingly, simultaneously mea-
sured cholesterol levels were no risk for any of the events
mentioned
(3)
. The risk for peripheral artery disease was
also substantially lower with a higher omega-3 index
than with a lower omega-3 index
(23)
. When dietary intake
was assessed, associations with the health issues men-
tioned were substantially smaller
(24,25,26)
. Together with
the positive results from large intervention trials, the
numbers mentioned support the use of the omega-3
index to maximise the benefit and minimise the risk of
EPA and DHA in the prevention of mortality and
CVD. In keeping, the American Heart Association has
issued scientific advisories recommending EPA and
DHA for the secondary prevention of CVD but refrained
from mentioning a dose
(27,28)
.
Low levels of EPA and DHA precede the development
of congestive heart failure, and a low omega-3 index can
be found in these patients
(16,29,30)
. A large intervention
trial with approximately 860 mg EPA and DHA daily
in patients with congestive heart failure with reduced
ejection fraction increased the omega-3 index in the
verum group from 4⋅75 (SD 1⋅68) to 6⋅73 (SD 1⋅93) %
after 3 months, whereas it remained constant about
4⋅77 (SD 1⋅60) in the placebo group
(30)
. The target range
was not reached, but, since omega-3 index levels in the
verum group were somewhat separated from omega-3
index levels in the placebo group, the primary endpoint,
a combination of total mortality and hospitalisations,
was significantly reduced in the verum group
(21)
.
An association between the intake of fish and blood
pressure was not found
(31)
. However, the circulating
levels of EPA and DHA were inversely related to blood
pressure
(31)
. In a representative assessment of the entire
population of Liechtenstein, the omega-3 index corre-
lated inversely with blood pressure (both systolic and
diastolic), whether assessed over 24 h, during daytime
or night, or conventionally in the office. The inverse cor-
relation was independent of age and sex and other con-
founders such as BMI, smoking status, glycated
haemoglobin A1c, educational status, fruit and vegetable
consumption, physical activity and others
(32)
.
Endothelial function improved in intervention trials,
also depending on the omega-3 index
(33,34)
.
Meta-analyses of intervention trials demonstrated that
EPA and DHA lower blood pressure
(35)
.
Brain and the omega-3 index
As mentioned, in the Framingham study, an omega-3
index of 6⋅8 % was associated with a 53 % lower risk
for total stroke than an omega-3 index of 4⋅2%
(3)
.In
the Reduce-It trial, in the verum group, stroke occurred
in ninety-eight patients, whereas it occurred in 134
patients in the placebo group, a 28 % reduction (hazard
ratio 0⋅72, 95 % CI 55, 0⋅93, P=0⋅01)
(7)
. Therefore, n-3
fatty acids must be considered a powerful possibility
for preventing the stroke, a catastrophic event for brain
structure and thus brain function.
In an epidemiologic study in children with a mean age
of 4, the omega-3 index correlated with complex brain
functions, such as executive function, in this case assessed
as the dimensional change card sort task
(36)
, extending
similar findings from study populations aged 31, 67
and 78 years
(37–40)
. Recent intervention trials confirmed
that improvements in complex brain functions correlate
with omega-3 index, when measured
(41,42)
.
Pregnancy and lactation
Premature birth before week 34 of pregnancy is more likely
with low levels than with high levels of EPA and DHA in
plasma or erythrocytes, with the risk for preterm birth cor-
relating inversely with those levels
(43,44)
. Another publica-
tion found post-partum depression to strongly depend on
Fig. 1. Omega-3 index (y-axis) in 23 615 erythrocyte samples from Europe (x-axis), as
determined in the clinical routine of Omegametrix
(66)
.
Omega‐3 index in 2018/19 3
Proceedings of the Nutrition Society
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665120006989
Downloaded from https://www.cambridge.org/core. IP address: 178.171.17.215, on 11 May 2020 at 17:10:52, subject to the Cambridge Core terms of use, available at

the omega-3 index, i.e. with a higher omega-3 index, post-
partum depression was much less likely than with a lower
omega-3 index
(45)
. Unfortunately, however, the findings
are not directly comparable to the results obtained with
the original omega-3 index, since different analytical proce-
dures were used
(44,45)
.
In 2018, a large Cochrane Meta-Analysis clearly found
premature birth to be reduced both before weeks 34 and
37, gestational age to be prolonged by 1⋅67 days (95 % CI
0⋅95, 2⋅39), based on forty-one randomised controlled
trials in 12 517 pregnant women, a lower incidence of
low birth weight 15⋅6v. 14 %; relative risk 0⋅90 (95 %
CI 0⋅82, 0⋅99), based on fifteen randomised controlled
trials in 8 449 pregnant women, and relative risk for peri-
natal death of the child to be 0⋅75 (95 % CI 0⋅54, 1⋅03),
based on ten randomised controlled trials in 7 416 preg-
nant women, and more benefits for mother and child
(all comparisons relative to placebo or control)
(46)
.In
the practical conclusion, the authors mentioned: A uni-
versal supplementation can make sense, although, with
better knowledge, it should be aimed for women benefi-
tting the most
(46)
.
Already in 2016, the omega-3 index had been assessed
in an almost representative manner in pregnant and lactat-
ing women in Germany and was found to be between 2⋅49
and 11⋅10 % regardless of timepoint (pregnancy v. lacta-
tion) and whether the woman supplemented EPA and
DHA
(47)
. Taken together, in this author’s opinion, the
data to date make it necessary to determine the omega-3
index before or early in pregnancy, later in pregnancy
and in lactation to make a targeted supplementation feas-
ible, with a target range of 8–11 % for the omega-3 index.
Omega-3 index in sports medicine
In 2014, we had observed that 106 German world class
athletes had a mean omega-3 index of 4⋅97 (SD 1⋅19) %,
with only one athlete in the target range
(48)
. More recently,
similar data were found in 404 US national division I col-
lege football athletes with a mean omega-3 index of 4⋅4(
SD
0⋅8) %, again only one athlete in the target range
(49)
.
Interestingly, the more energy was burned throughout
the season, the lower the omega-3 index became
(50)
.This
has important implications for athletes, since a low
omega-3 index predisposes to delayed-onset muscle sore-
ness, and increasing the omega-3 index results in less creat-
inekinasereleasefrommuscle,lessinflammatory reaction
(measured as muscle swelling and pro-inflammatory cyto-
kines in plasma) and less loss of function
(51,52)
. Joint pain
was reduced with a higher omega-3 index, at least in
dogs
(53)
. Joint stability, e.g. in the case of the shoulder rota-
tor cuff, was higher with a higher omega-3 index
(54)
.Inan
intervention trial, it had been demonstrated that brain
damage, assessed as neurofilament light (the pertinent bio-
marker), can be reduced with high doses of EPA and DHA
in professional players of American football
(55)
. Jointly,
these findings point towards higher membrane stability
with a higher omega-3 index. Together with the aspects
of cognition that have been improved by EPA and DHA
in intervention trials in athletes, such as reaction time
and efficiency
(56)
, current data indicate that an omega-3
index in the target range may be an important asset for
the athlete. This is supported by the fact that athletes are
at an increased risk for major depression, suicide and sud-
den cardiac death, all in keeping with a low omega-3 index,
and all seriously impacting on an athlete’s life
(48)
.
Other recent findings
Conventionally, SFA are considered as a homogenous
group with an ominous effect on life expectancy. With
the determination of the original omega-3 index comes
the measurement of six individual SFA in erythrocytes
(1)
.
It was thus determined that palmitic acid (C16:0) was
associated with increased total mortality in a 10-year epi-
demiologic study of 3259 participants, while the other
erythrocyte SFA investigated (C14:0, C18:0, C20:0,
C22:0, C24:0) had no association with total mortality
(57)
.
In a meta-analysis, higher levels of palmitic acid were
associated with a higher risk for developing type 2 dia-
betes
(58)
. In a single study, this was also true for gesta-
tional diabetes
(59)
. Cell membrane levels of palmitic acid
are partly derived from ingested palmitic acid, and partly
produced endogenously, e.g. in reaction to energetic sur-
plus
(60)
. Together with other findings of individual struc-
ture, metabolism, biologic effects and impacts on life
expectancy, our findings question the conventional group-
wise nomenclature of fatty acids (e.g. SFA, PUFA and
others), as well as the conventional recommendation to
avoid all SFA. Whether high levels of palmitic acid
might be a biomarker for metabolically untoward body
fat, such as excess hepatic fat, remains to be investigated,
which is also true for the potential effects of actively redu-
cing levels of palmitic acid.
The findings just discussed were mirrored in an epide-
miologic study in children with a median age of 11 years,
with palmitic acid correlating positively with waist cir-
cumference, TAG, fasting insulin and fatty liver index,
against the background of a low omega-3 index (4⋅7
(SD 0⋅8) %)
(61)
. Interestingly, the levels of arachidonic
acid correlated inversely with the parameters men-
tioned
(61)
. According to a recent meta-analysis, high
levels of EPA and DHA in plasma or erythrocytes
were associated with a low risk for the metabolic syn-
drome
(62)
. Thus, the omega-3 index makes it possible to
investigate the relations between metabolism and
non-n-3 fatty acids in more detail.
In patients with chronic fatigue syndrome/myalgic
encephalomyelitis, a low mean omega-3 index was
found
(63)
. Chronic fatigue syndrome/myalgic encephalo-
myelitis is a debilitating chronic medical condition with-
out a known aetiology, no clinically established
diagnostic test and no effective pharmacologic treat-
ment
(63)
. Our findings add chronic fatigue syndrome/
myalgic encephalomyelitis to the list of chronic inflam-
matory diseases where EPA and DHA should be tested
in intervention trials for potential therapeutic value
(63)
.
Some recent intervention trials with EPA and DHA
had neutral results. In one trial, it became clear by meas-
uring the omega-3 index that this was due to participants’
C. von Schacky4
Proceedings of the Nutrition Society
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665120006989
Downloaded from https://www.cambridge.org/core. IP address: 178.171.17.215, on 11 May 2020 at 17:10:52, subject to the Cambridge Core terms of use, available at

non-compliance
(64)
. In another trial, effects on cognitive
parameters were smaller than expected within the
16-week trial period, demonstrating the difficulties of
such trials
(65)
.
Conclusion
In the years 2018 and 2019, a perspective on EPA and
DHA levels has proven useful to generate new knowl-
edge on fatty acids, such as there is no human life with
an omega-3 index ≤2 % in erythrocytes. Deficits in
EPA and DHA, i.e. an omega-3 index below the target
range of 8–11 %, have been found in many countries
and populations. A deficit in EPA and DHA is asso-
ciated with increased total mortality, fatal and non-fatal
cardiovascular events, stroke, impaired cognition, pre-
mature birth, perinatal mortality and other health
issues
(3–5,8,9,16,17,30,32,37–39,45,47,48,54,63,64)
.Adeficit in
EPA and DHA in the population studied is required
for positive results of a randomised controlled interven-
tion trial. Reducing a deficit in EPA and DHA prolongs
life, and reduces fatal and non-fatal cardiovascular
events, strokes, premature birth, perinatal mortality and
other health issues. In a trial, this can only be detected if
the levels in the verum group differ sufficiently from the
levels in the placebo or control group. Increasing the
omega-3 index into the target range of 8–11 % with indi-
vidualised doses of toxin-free sources for EPA and DHA
is tolerable and safe.
Financial Support
The present work was not supported by any funding
agency or by industry.
Conflict of Interest
C. v. S. operates Omegametrix, a laboratory for fatty
acid analyses. In the past 3 years, C. v. S. received hon-
oraria for speaking and consulting from BASF/Pronova,
EPAX, Huntsworth Medical, Abbott, DSM, Marine
Ingredients and Norsan.
Authorship
The author had sole responsibility for all aspects of
preparation of this paper.
References
1. Harris WS & von Schacky C (2004) The omega-3 index: a
new risk factor for death from CHD? Prev Med 39,212–220.
2. Harris WS, von Schacky C & Park Y (2013) Standardizing
methods for assessing omega-3 fatty acid biostatus. In The
Omega-3 Fatty Acid Deficiency Syndrome, pp. 385–398.
[McNamara RK, editor]. Hauppauge, NY: Nova Science
Publishers.
3. Harris WS, Tintle NL, Etherton MR et al. (2018)
Erythrocyte long-chain omega-3 fatty acid levels are
inversely associated with mortality and with incident car-
diovascular disease: the Framingham Heart Study. J Clin
Lipidol 12, 718–727.
4. Kleber ME, Delgado GE, Lorkowski S et al. (2016)
Omega-3 fatty acids and mortality in patients referred for
coronary angiography –the Ludwigshafen risk and cardio-
vascular health study. Atherosclerosis 252, 157–181.
5. Harris WS, Luo J, Pottala JV et al. (2017) Red blood cell
polyunsaturated fatty acids and mortality in the womens’
health initiative study. J Clin Lipidol 11, 250–259.
6. Yokoyama M, Origasa H, Matsuzaki M et al. (2007) Japan
EPA lipid intervention study (JELIS) Investigators (2007)
Effects of eicosapentaenoic acid on major coronary events
in hypercholesterolaemic patients (JELIS): a randomised
open-label, blinded endpoint analysis. Lancet 369, 1090–1098.
7. Bhatt DL, Steg PG, Miller M et al. (2019) Cardiovascular
risk reduction with icosapent ethyl for hypertriglyceride-
mia. N Engl J Med 380,11–22.
8. Sarter B, Kelsey KS, Schwartz TA et al. (2015) Blood doc-
osahexaenoic acid and eicosapentaenoic acid in vegans:
associations with age and gender and effects of an algal-
derived omega-3 fatty acid supplement. Clin Nutr 34,
212–218.
9. Langlois K & Ratnayake WMN (2015) Omega-3 index of
Canadian adults. Statistics Canada, Catalogue No. 82–
003-X. Health Rep 26,3–11.
10. Plourde M & Cunnane SC (2007) Extremely limited syn-
thesis of long chain polyunsaturates in adults: implications
for their dietary essentiality and use as supplements. Appl
Physiol Nutr Metab 32, 619–634.
11. Metherel AH & Bazinet RP (2019) Updates to the n-3
polyunsaturated fatty acid biosynthesis pathway: DHA
synthesis rates, tetracosahexaenoic acid and (minimal) ret-
roconversion. Prog Lipid Res 76, 101008.
12. von Schacky C (2015) Omega-3 fatty acids in cardiovascu-
lar disease –an uphill battle. Prostaglandins Leukot Essent
Fatty Acids 92,41–47.
13. Rice HB, Bernasconi A, Maki KC et al. (2016) Conducting
omega-3 clinical trials with cardiovascular outcomes: pro-
ceedings of a workshop held at ISSFAL 2014.
Prostaglandins Leukot Essent Fatty Acids 107,30–42.
14. Davidson MH, Johnson J, Rooney MW et al. (2012) A
novel omega-3 free fatty acid formulation has dramatically
improved bioavailability during a low-fat diet compared
with omega-3-acid ethyl esters: the ECLIPSE (Epanova
(®) compared to Lovaza(®) in a pharmacokinetic single-
dose evaluation) study. J Clin Lipidol 6, 573–584.
15. Schuchardt JP & Hahn A (2013) Bioavailability of long-
chain omega-3 fatty acids. Prostaglandins Leukot Essent
Fatty Acids 89,1–8.
16. Berliner D, Mattern S, Wellige M et al. (2019) The
omega-3 index in patients with heart failure: a prospective
cohort study. Prostaglandins Leukot Essent Fatty Acids
140,34–41.
17. Baghai TC, Varallo-Bedarida G, Born C et al. (2011)
Major depression is associated with cardiovascular risk fac-
tors and low omega-3 index. J Clin Psychiat 72, 1242–1247.
18. Köhler A, Bittner D, Löw A et al. (2014) Effects of a con-
venience drink fortified with n-3 fatty acids on the n-3
index. Br J Nutr 104, 729–736.
19. Muhlhausler BS, Gibson RA, Yelland LN et al. (2014)
Heterogeneity in cord blood DHA concentration: towards
an explanation. Prostaglandins Leukot Essent Fatty Acids
91, 135–140.
Omega‐3 index in 2018/19 5
Proceedings of the Nutrition Society
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665120006989
Downloaded from https://www.cambridge.org/core. IP address: 178.171.17.215, on 11 May 2020 at 17:10:52, subject to the Cambridge Core terms of use, available at

20. Grosso G, Pajak A, Marventano S et al. (2014) Role of
omega-3 fatty acids in the treatment of depressive disor-
ders: a comprehensive meta-analysis of randomized clinical
trials. PLoS ONE 9, e96905.
21. Tavazzi L, Maggioni AP, Marchioli R et al. (2008) Effect
of n-3 polyunsaturated fatty acids in patients with chronic
heart failure (the GISSI-HF trial): a randomised, double-
blind, placebo-controlled trial. Lancet 372, 1223–1230.
22. Abdelhamid AS, Brown TJ, Brainard JS et al. (2018)
Omega-3 fatty acids for the primary and secondary preven-
tion of cardiovascular disease. Cochrane Database Syst Rev
11, CD003177.
23. Ramirez JL, Zahner GJ, Spaulding KA et al. (2019)
Peripheral artery disease is associated with a deficiency of
erythrocyte membrane n-3 polyunsaturated fatty acids.
Lipids 54, 211–229.
24. Micha R, Peñalvo JL, Cudhea F et al. (2017) Association
between dietary factors and mortality from heart disease,
stroke, and type 2 diabetes in the United States. JAMA
317, 912–924.
25. Chowdhury R, Warnakula S, Kunutsor S et al. (2014)
Association of dietary, circulating, and supplement fatty
acids with coronary risk: a systematic review and
meta-analysis. Ann Intern Med 160, 398–406.
26. Chowdhury R, Stevens S, Gorman D et al. (2012)
Association between fish consumption, long chain omega
3 fatty acids, and risk of cerebrovascular disease: systematic
review and meta-analysis. Br Med J 345, e6698.
27. Siscovick DS, Barringer TA, Fretts AM et al. (2017)
Omega-3 polyunsaturated fatty acid (fish oil) supplementa-
tion and the prevention of clinical cardiovascular disease: a
science advisory from the American heart association.
Circulation 135, e867–e884.
28. Rimm EB, Appel LJ, Chiuve SE et al. (2018) Seafood long-
chain n-3 polyunsaturated fatty acids and cardiovascular
disease: a science advisory from the American Heart
Association. Circulation 138, e35–e47.
29. Mozaffarian D, Lemaitre RN, King IB et al. (2011)
Circulating long-chain ω-3 fatty acids and incidence of con-
gestive heart failure in older adults: the cardiovascular
health study: a cohort study. Ann Intern Med 155, 160–170.
30. Harris WS, Masson S, Barlera S et al. (2016) Red blood
cell oleic acid levels reflect olive oil intake while omega-3
levels reflect fish intake and the use of omega-3 acid ethyl
esters: the Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto Miocardico –Heart Failure
trial. Nutr Res 36, 989–994.
31. Yang B, Shi MQ, Li ZH et al. (2016) Fish, long-chain n-3
PUFA and incidence of elevated blood pressure: a
meta-analysis of prospective cohort studies. Nutrients 8,
pii: E58.
32. Filipovic MG, Aeschbacher S, Reiner MF et al. (2018)
Whole blood omega-3 fatty acid concentrations are
inversely associated with blood pressure in young, healthy
adults. J Hypertens 36, 1548–1554.
33. Skulas-Ray AC, Kris-Etherton PM, Harris WS et al.
(2011) Dose response effects of omega-3 fatty acids on tri-
glycerides, inflammation, and endothelial function in
healthy people with moderate hypertriglyceridemia. Am J
Clin Nutr 93, 243–252.
34. Wang Q, Liang X, Wang L et al. (2012) Effect of omega-3
fatty acids supplementation on endothelial function: a
meta-analysis of randomized controlled trials.
Atherosclerosis 221, 536–543.
35. Miller PE, Van Elswyk M & Alexander DD (2014)
Long-chain omega-3 fatty acids eicosapentaenoic acid
and docosahexaenoic acid and blood pressure: a
meta-analysis of randomized controlled trials. Am J
Hypertens 27, 885–896.
36. Adjepong M, Yakah W, Harris WS et al. (2018) Whole
blood n-3 fatty acids are associated with executive function
in 2–6-year-old Northern Ghanaian children. J Nutr
Biochem 57, 287–293.
37. Dretsch MN, Johnston D, Bradley RS et al. (2014) Effects
of omega-3 fatty acid supplementation on neurocognitive
functioning and mood in deployed U.S. Soldiers: a pilot
study. Mil Med 179, 396–403.
38. Tan ZS, Harris WS, Beiser AS et al. (2012) Red blood cell
omega-3 fatty acid levels and markers of accelerated brain
aging. Neurology 78, 658–664.
39. Lukaschek K, von Schacky C, Kruse J et al. (2016)
Cognitive impairment is associated with low omega-3
Index in the elderly. Results from the KORA-Age study.
Dementia Geriatr Cogn Dis 42, 236–245.
40. Bigornia SJ, Scott TM, Harris WS et al. (2018) Prospective
associations of erythrocyte composition and dietary intake
of n-3 and n-6 PUFA with measures of cognitive function.
Nutrients 10, 1253.
41. Witte AV, Kerti L, Hermannstädter HM et al. (2014)
Long-chain omega-3 fatty acids improve brain function
and structure in older adults. Cereb Cortex 24, 3059–3068.
42. Külzow N, Witte AV, Kerti L et al. (2016) Impact of
omega-3 fatty acid supplementation on memory functions
in healthy older adults. J Alzheimers Dis 51, 713–725.
43. Olsen SF, Halldorsson TI, Thorne-Lyman AL et al. (2018)
Plasma concentrations of long chain N-3 fatty acids in
early and mid-pregnancy and risk of early preterm birth.
EBioMedicine 35, 325–333, Correction in Olsen SF,
Halldorsson TI, Thorne-Lyman AL et al. (2020)
Corrigendum to ’Plasma concentrations of long chain
N-3 fatty acids in early and mid-pregnancy and risk of
early preterm birth. EBioMedicine. 51 102619.
44. Hoge A, Donneau AF, Dardenne N et al. (2020) Impact of
erythrocyte long-chain omega-3 polyunsaturated fatty acid
levels in early pregnancy on birth outcomes: findings from
a Belgian cohort study. J Perinatol 40, 488–496.
45. Hoge A, Tabar V, Donneau AF et al. (2019) Imbalance
between omega-6 and omega-3 polyunsaturated fatty
acids in early pregnancy is predictive of postpartum depres-
sion in a Belgian cohort. Nutrients 11, pii: E876.
46. Middleton P, Gomersall JC, Gould JF et al. (2018)
Omega-3 fatty acid addition during pregnancy. Cochrane
Database Syst Rev 11, CD003402.
47. Gellert S, Schuchardt JP & Hahn A (2016) Higher omega-3
index and DHA status in pregnant women compared to
lactating women –results from a German nation-wide
cross-sectional study. Prostaglandins Leukot Essent Fatty
Acids 109,22–28.
48. von Schacky C, Haslbauer R, Kemper M et al. (2014) Low
omega-3 index in 106 German elite winter endurance ath-
letes –a pilot study. Int J Sport Nutr Exerc Metab 24,
559–564.
49. Anzalone A, Carbuhn A, Jones L et al. (2019) The
omega-3 index in national collegiate athletic association
division I collegiate football athletes. JAthlTrain54,
7–11.
50. Davinelli S, Corbi G, Righetti S et al. (2019) Relationship
between distance run per week, omega-3 index, and arachi-
donic acid (AA)/eicosapentaenoic acid (EPA) ratio: an
observational retrospective study in non-elite runners.
Front Physiol 10, 487.
51. Kim J & Lee J (2014) A review of nutritional intervention
on delayed onset muscle soreness. Part I. J Exerc Rehabil
10, 349–356.
C. von Schacky6
Proceedings of the Nutrition Society
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665120006989
Downloaded from https://www.cambridge.org/core. IP address: 178.171.17.215, on 11 May 2020 at 17:10:52, subject to the Cambridge Core terms of use, available at

52. Ochi E & Tsuchiya Y (2018) Eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA) in muscle damage and
function. Nutrients 10, pii: E552.
53. Burri L, Wyse C, Gray SR et al. (2018) Effects of dietary
supplementation with krill meal on serum
pro-inflammatory markers after the Iditarod sled dog
race. Res Vet Sci 121,18–22.
54. Hudek R, von Schacky C, Passow A et al. (2019)
Degenerative rotator cuff tears are associated with a low
omega-3 index. Prostaglandins Leukot Essent Fatty Acids
148,35–40.
55. Oliver JM, Jones MT, Kirk KM et al. (2016) Effect of doc-
osahexaenoic acid on a biomarker of head trauma in
American football. Med Sci Sports Exerc 48, 974–982.
56. Guzmán JF, Esteve H, Pablos C et al. (2011) DHA- rich
fish oil improves complex reaction time in female elite soc-
cer players. J Sports Sci Med 10, 301–335.
57. Kleber ME, Delgado GE, Dawczynski C et al.
(2016) Saturated fatty acids and mortality in patients
referred for coronary angiography –the Ludwigshafen risk
and cardiovascular health study. J Clin Lipidol 12,455–463.
58. Huang L, Lin JS, Aris IM et al. (2019) Circulating satu-
rated fatty acids and incident type 2 diabetes: a systematic
review and meta-analysis. Nutrients 11,5.
59. Zhu Y, Tsai MY, Sun Q et al. (2018) A prospective and
longitudinal study of plasma phospholipid saturated fatty
acid profile in relation to cardiometabolic biomarkers and
the risk of gestational diabetes. Am J Clin Nutr 107,
1017–1026.
60. Carta G, Murru E, Banni S et al. (2017) Palmitic acid:
physiological role, metabolism and nutritional implica-
tions. Front Physiol 8, 902.
61. Bonafini S, Tagetti A, Gaudino R et al. (2019) Individual
fatty acids in erythrocyte membranes are associated with
several features of the metabolic syndrome in obese chil-
dren. Eur J Nutr 58, 731–742.
62. Jang H & Park K (2020) Omega-3 and omega-6 polyunsat-
urated fatty acids and metabolic syndrome: a systematic
review and meta-analysis. Clin Nutr 39, 767–773.
63. Castro-Marreroa J, Zaragozáa MC, Domingo JC et al.
(2018) Low omega-3 index and polyunsaturated fatty acid
status in patients with chronic fatigue syndrome/myalgic
encephalomyelitis: myth or reality? Prostaglandins Leukot
Essent Fatty Acids 139,20–24.
64. van der Wurff I, von Schacky C, Bergeland T et al. (2019)
Effect of 1 year krill oil supplementation on cognitive
achievement of Dutch adolescents: a double-blind rando-
mized controlled trial. Nutrients 11, pii: E1230.
65. Schättin A, Baier C, Mai D et al. (2019) Effects of exer-
game training combined with omega-3 fatty acids on the
elderly brain: a randomized double-blind placebo-
controlled trial. BMC Geriatr 19, 81.
66. von Schacky C (2019) Verwirrung um die Wirkung von
omega-3 Fettsäuren. Betrachtung von Studiendaten unter
Berücksichtigung des omega-3 index. [Confusion about
the effects of omega-3 fatty acids: contemplation of study
data taking the omega-3 Index into consideration].
Internist (Berl) 60, 1319–1327.
Omega‐3 index in 2018/19 7
Proceedings of the Nutrition Society
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665120006989
Downloaded from https://www.cambridge.org/core. IP address: 178.171.17.215, on 11 May 2020 at 17:10:52, subject to the Cambridge Core terms of use, available at