1. Inflammatory response following heart surgery and association
with nÀ3 and nÀ6 long-chain polyunsaturated fatty acids in plasma
and red blood cell membrane lipids
L. Bjorgvinsdottir a
, O.S. Indridason b
, R. Heidarsdottir a
, K. Skogstrand c
, D.O. Arnar a,b,d
,
B. Torfason a,e
, D.M. Hougaard c
, R. Palsson a,b
, G.V. Skuladottir a,n
a
Faculty of Medicine, School of Health Sciences, University of Iceland, Vatnsmyrarvegur 16, IS-101 Reykjavik, Iceland
b
Internal Medicine Services, Landspitali—The National University Hospital of Iceland, Hringbraut, IS-101 Reykjavik, Iceland
c
Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark
d
Cardiovascular Research Center, Landspitali—The National University Hospital of Iceland, Hringbraut, IS-101 Reykjavik, Iceland
e
Landspitali—The National University Hospital of Iceland, Hringbraut, IS-101 Reykjavik, Iceland
a r t i c l e i n f o
Article history:
Received 8 April 2013
Received in revised form
12 July 2013
Accepted 26 July 2013
Keywords:
Heart surgery
Inflammatory mediators
Inflammatory response
nÀ3 long-chain polyunsaturated fatty acids
Postoperative period
Red blood cell membranes
a b s t r a c t
Background: Open heart surgery is associated with a systemic inflammatory response. The nÀ3 long-
chain polyunsaturated fatty acids (LC-PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA), and the nÀ6 LC-PUFA arachidonic acid (AA) may contribute to modulation of the inflammatory
response.
Objective: We investigated whether the preoperative levels of EPA, DHA and AA in plasma phospholipids
(PL) and red blood cell (RBC) membrane lipids in patients (n¼168) undergoing open heart surgery were
associated with changes in the plasma concentration of selected inflammatory mediators in the
immediate postoperative period.
Results and conclusions: The postoperative concentration of TNF-β was lower (Po0.05) and those
of hs-CRP, IL-6, IL-8, IL-18 and IL-10 higher (Po0.05) than the respective preoperative concentrations.
We observed that the preoperative levels of EPA and AA in plasma PL and RBC membrane lipids were
associated with changes in the concentration of pro-inflammatory and anti-inflammatory mediators,
suggesting a complex role in the postoperative inflammatory process.
& 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Heart surgery provokes a vigorous inflammatory response that
propagates within the injured tissue to initiate the healing process
[1–4]. However, excessive systemic inflammation may result in
adverse outcomes during the postoperative period [5]. The inflam-
matory response is modulated by a balance between pro-
inflammatory and anti-inflammatory mediators secreted by a vari-
ety of cell types, including activated monocytes, tissue macrophages,
lymphocytes and endothelial cells [5–7].
The nÀ3 long-chain polyunsaturated fatty acids (LC-PUFA), eico-
sapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been
shown to evoke anti-inflammatory responses [8], while the nÀ6 LC-
PUFA aracidonic acid (AA) generally induce a more pronounced
pro-inflammatory effect [9,10]. The fatty acid composition of plasma
phospholipids (PL), which are merely transporters of circulating fatty
acids, is believed to reflect short-term dietary nÀ3 LC-PUFA con-
sumption [11]. In contrast, the fatty acid composition of red blood cell
(RBC) membrane lipids is considered a good indicator of a long-term
dietary nÀ3 LC-PUFA consumption [11]. Furthermore, fatty acid
composition of RBC membrane lipids has been shown to reflect the
fatty acid composition of other cell membrane lipids, including those
of cardiac myocytes in the intraventricular septum [12], and atria [13].
Several pro-inflammatory and anti-inflammatory mediators, as
well as the acute-phase reactant C-reactive protein (CRP) have
been implicated in the inflammatory response early in the post-
operative course following open heart surgery [6,7,14–16]. Human
studies have demonstrated that dietary EPA and DHA may attenu-
ate postoperative concentrations of circulating pro-inflammatory
mediators [17,18]. To investigate the role of EPA, DHA and AA in
the inflammatory response following open heart surgery, we
examined the association between the preoperative levels of
EPA, DHA and AA in plasma PL and RBC membrane lipids and
the postoperative changes in plasma concentrations of 12 selected
inflammatory mediators.
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/plefa
Prostaglandins, Leukotrienes and Essential
Fatty Acids
0952-3278/$ - see front matter & 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.plefa.2013.07.007
n
Correspondence to: Department of Physiology, Faculty of Medicine, School of
Health Sciences, University of Iceland, Vatnsmyrarvegur 16, IS-101 Reykjavik,
Iceland. Tel.: +354 525 4825; fax: +354 525 4886.
E-mail address: gudrunvs@hi.is (G.V. Skuladottir).
Prostaglandins, Leukotrienes and Essential Fatty Acids 89 (2013) 189–194

2. 2. Patients and methods
2.1. Subjects
This study was based on data collected as part of a prospective,
randomized, double-blinded, placebo-controlled clinical trial on
the use of nÀ3 LC-PUFA therapy for one week prior to open heart
surgery for the prevention of postoperative atrial fibrillation. The
fatty acid analysis was pre-specified in the study protocol whereas
the measurement of the inflammatory markers other than CRP
was added post-hoc. This study was approved by the Bioethics
Committee of Landspitali—The National University Hospital of
Iceland (62/2004), and the Icelandic Data Protection Authority.
The details of the study design have been published previously
[19,20]. In brief, 168 patients scheduled for elective or semi-
emergent open heart surgery were included in this study. Patients
younger than 40 years of age, those with a history of any form of
supraventricular arrhythmias or using the antiarrhythmic medica-
tions amiodarone and/or sotalol, and patients undergoing emer-
gency surgery were excluded. Prior to surgery, all participants
answered a questionnaire on lifestyle and health-releated issues,
including consumption of fish, intake of liquid cod liver oil and
nÀ3 LC-PUFA capsules, smoking habit, height, body weight, and
medication use. All patients participating in the study gave written
informed consent. One week prior to the surgical procedure, the
patients were randomly assigned to one of two groups initiating
the study treatment and were asked to discontinue intake of liquid
cod liver oil and supplemental nÀ3 LC-PUFA capsules, but were
otherwise advised to remain on their usual diet. The nÀ3 LC-PUFA
treatment consisted of 1240 mg of EPA and 1000 mg of DHA in the
form of ethyl esters administered once daily, while the identical
placebo capsules contained 2000 mg of olive oil, also administered
once daily. The nÀ3 LC-PUFA capsules are commercially available
in Iceland (Omega-3 Forte, Lysi Inc, Reykjavík, Iceland).
2.2. Blood plasma and red blood cells
Venous blood samples were obtained from the patients before
initiating the study medication (baseline), immediately before the
surgery (preoperatively) and on the third postoperative day (post-
operatively). The blood samples were collected into disodium
EDTA tubes and the plasma separated from RBC by immediate
centrifugation at 1000g for 10 min. The RBC were washed three
times with an isotonic saline solution and the antioxidant buty-
lated hydroxytoluene (BHT), dissolved in methanol, was added to
the cells at a final concentration of 50 mg/L. The plasma and RBC
samples were frozen at À76 1C and stored until the analysis of the
inflammatory mediators and the fatty acids was carried out.
2.3. Inflammatory mediators
The plasma samples were analysed for inflammatory mediators
tumor necrosis factor-α (TNF-α), TNF-β, interleukin-1β (IL-1β), IL-6,
IL-8, IL-10, IL-12, IL-18, interferon-γ (IFN-γ), macrophage inflam-
matory protein-1α (MIP-1α) and transforming growth factor-β
(TGF-β) as previously described [21], and determined using the
Luminex 100™ platform (Luminex Corp, TX, USA). These media-
tors were selected based on their potential role in the acute
inflammatory response following major surgery (6,7,14,15,16).
The samples were measured in duplicate and standard curves
were fitted with a five parameter logistic equation (Logistic-5PL)
using BioPlex™ Manager 5.0 (Bio-Rad Laboratories, CA, USA).
Plasma CRP concentration was determined using a commer-
cially available high sensitivity (hs)-CRP latex-enhanced immuno-
turbidimetric assay (Roche Diagnostics, Mannheim, Germany) and
Hitachi 911 analyser. The lower detection limit of the assay is
0.1 mg/L. The total coefficient of variation for hs-CRP measure-
ments of internal controls was 1.1% at a concentration of 3.73 mg/L
and 1.9% at a concentration of 0.68 mg/L.
2.4. Fatty acid composition of plasma phospholipids and RBC
membranes lipids
Total lipids were extracted from plasma using the Folch method
[22], and the phospholipid (PL) fraction isolated using thin layer
chromatography. The lipid fraction was extracted from RBC mem-
brane lipids using a method described by Bligh and Dyer [23]
except that isopropanol was used instead of methanol (isopropa-
nol/chloroform 2:1, v/v). BHT (50 mg/L) was added to the extrac-
tion medium. Fatty acid methyl esters (FAME) of plasma PL and
RBC membrane lipids were formed using 14% boron trifluoride/
methanol (Sigma Chemical Co., St. Louis, MO, USA) at 110 1C for
45 min. The FAME of plasma PL were analysed by gas–liquid
chromatography as previously described [19], but those of the
RBC membrane lipids were analysed by gas chromatography
(Agilent 6890N, Agilent, Palo Alto, CA, USA) using a Chrompack
CP-SIL 8CB column (25 m  250 mm i.d.  0.12 mm film thickness).
The oven was programmed to provide an initial temperature of
150 1C for 4 min, then increasing temperature by 4 1C/min to
230 1C and then by 20 1C/min to 280 1C, and finally the oven was
held isothermal for 4 min. The injector and detector temperatures
were maintained at 280 1C and 300 1C, respectively. Hydrogen was
used as the carrier gas. The FAME peaks were identified and
calibrated against commercial standards (Sigma Chemical Co.; Nu-
Chek-Prep, Elysian, MN, USA). Fatty acid values in plasma PL and
RBC membrane lipids are presented as % weight of total fatty acids
with chain length from C14 to C24. Instrumental control and data
handling was performed using HP 3365 Chemstation, Version
A.02.12. (Hewlett Packard Co., Palo Alto, CA, USA).
2.5. Statistical analysis
The main objective was to examine the relationship between
fatty acid levels in plasma PL and RBC membrane lipids preopera-
tively and the changes in concentrations of inflammatory media-
tors from immediately prior to surgery to the third postoperative
day. Independent samples t-test was used to compare groups with
respect to the levels of EPA, DHA and AA in plasma PL and RBC
membrane lipids at baseline and preoperatively, and paired t-test
to examine the significance of changes between time points within
groups. Due to non-normal distribution, Wilcoxon signed rank test
was used to compare the difference in median concentrations of
inflammatory mediators between time points. Spearman's corre-
lation coefficient was employed to examine the relationship
between continuous variables. Multivariable linear regression
was used to assess the relationship between preoperative levels
of fatty acids in plasma PL and RBC membrane lipids and changes
in the concentrations of inflammatory mediators following sur-
gery, adjusting for age, body mass index (BMI) and smoking, as
these variables were a priori assumed to have a potential con-
founding effect on the relationship.
Data are presented as median and range, percentages or mean7
standard error of the mean (SEM). A two-sided P valueo0.05 was
considered statistically significant. All statistical analyses were carried
out using SPSS software (version 17.0, IBM Corporation, Somers,
NY, USA).
L. Bjorgvinsdottir et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 89 (2013) 189–194190

3. 3. Results
3.1. Characteristics of the patients
The median plasma concentrations of the inflammatory med-
iators did not differ between the groups of patients receiving nÀ3
LC-PUFA or placebo (P40.05; data not shown). Thus, all patients
were combined for analysis of the association between preopera-
tive levels of fatty acids in plasma PL and RBC membrane lipids
and postoperative changes in plasma concentrations of inflamma-
tory mediators. Baseline and surgical characteristics of the patients
(n¼168) are outlined in Table 1. The median age of the patients
was 67 (range, 43–82) years, 79.2% were men, and their median
BMI was 27.4 (range, 17.2–41.3) kg/m2
. Seventy-two percent of the
patients consumed fish once or more each week, 55% used cod
liver oil and one-quarter nÀ3 LC-PUFA capsules as daily
supplements.
3.2. EPA, DHA and AA levels of plasma PL and RBC membrane lipids
As shown in Table 2, our patients had relatively high baseline
levels of EPA and DHA in plasma PL and RBC membrane lipids.
Table 2 also demonstrates how the one-week nÀ3 LC-PUFA or
placebo treatment affected the levels of EPA, DHA and AA in
plasma PL and RBC membrane lipids of our patients, i.e. the
preoperative levels.
3.3. Preoperative and postoperative plasma concentrations of
inflammatory mediators
Fig. 1 shows the plasma concentrations of the inflammatory
mediators in the patients preoperatively and on postoperative day
three. The postoperative concentration of the pro-inflammatory
cytokine TNF-β was significantly lower (Po0.05), and those of
the pro-inflammatory mediators hs-CRP, IL-6, IL-8 and IL-18 and
the anti-inflammatory cytokine IL-10 were significantly higher
(Po0.05) than the preoperative concentrations. No changes were
observed in the concentrations of the pro-inflammatory mediators
TNF-α, IL-1β, IL-12, IFN-γ, MIP-1α, and the anti-inflammatory
cytokine TGF-β.
3.4. Relationship between preoperative levels of EPA, DHA, and AA in
plasma PL and RBC membrane lipids and postoperative changes in
inflammatory mediators
A separate multivariable linear regression model was used to
assess the relationship between the preoperative levels of AA, EPA
and DHA in plasma PL and RBC membrane lipids and the intra-
individual change in the plasma concentration of each inflamma-
tory mediator, observed on the third postoperative day. The
changes in the plasma concentrations of TNF-β, IL-1β, IL-10,
IFN-γ and TGF-β were significantly (Po0.05) associated with the
levels of one or more of the fatty acids in plasma PL and/or in RBC
membrane lipids when adjusted for age, BMI and smoking
(Table 3). A more conspicuous decrease in the concentration of
TNF-β was associated with a higher AA level (β¼ À0.240), and a
smaller decrease with a higher ratios of DHA/AA and EPA+DHA/AA
(β¼0.196 and 0.170, respectively) in RBC membrane lipids. A more
pronounced increase in the IL-1β concentration was associated
with higher ratios of DHA/AA and EPA+DHA/AA in plasma PL
(β¼0.221 and 0.191, respectively), and with a higher level of EPA,
as well as with higher ratios of EPA/AA, DHA/AA and EPA+DHA/AA
in RBC membrane lipids. A greater increase in IL-10 was associated
with a higher AA level, a lower EPA level and lower ratios of EPA/
AA and EPA+DHA/AA in plasma PL. A greater increase in IFN-γ was
associated with a higher EPA level, and with a higher ratio of EPA/
AA in RBC membrane lipids. A smaller increase in TGF-β was
associated with a higher level of AA, and a greater increase was
associated with higher ratios of DHA/AA and EPA+DHA/AA in
plasma PL. Furthermore, a smaller increase in TGF-β was asso-
ciated with a higher AA level, and a greater increase with higher
EPA and DHA levels, and higher ratios of EPA/AA, DHA/AA and EPA
+DHA/AA in RBC membrane lipids. The relationship between post-
operative changes in the plasma concentrations of hs-CRP, IL-6, IL-8,
Table 1
Baseline and surgical characteristics of the patients.
Characteristic Value (n¼168)
Age (years) 67 (43–82)
Gender (% men) 79.2
BMI (kg/m2
) 27.4 (17.2–41.3)
Diabetes (%) 14.9
Smoking (%) 19.0
Fish intake (%, 4once a week) 72.0
Liquid cod liver oil (%) 54.8
nÀ3 LC-PUFA capsules (%) 26.8
Use of statins (%) 80.4
ECC time (min) 96 (0–261)
On-pump surgery (%) 88.1
Aortic cross-clamp time (min) 48 (0–208)
Blood volume in drains (mL) 765 (96–4980)
Data are presented as median (range) or percentage. BMI,
body mass index; LC-PUFA, long-chain polyunsaturated
fatty acids; ECC, extracorporeal circulation.
Table 2
Fatty acid levels (% of total fatty acids) in plasma PL and RBC membrane lipids at
baseline and preoperatively after one week of placebo or nÀ3 LC-PUFA treatment.
Fatty acids Placebo (n¼79) nÀ3 LC-PUFA (n¼80)
Plasma PL
EPA (20:5nÀ3)
Baseline 2.7570.20 2.5470.15
Preoperative 2.3470.12a
4.4370.16a,b
DHA (22:6nÀ3)
Baseline 6.0670.16 6.1770.16
Preoperative 5.9870.14 6.9870.13 a,b
AA (20:4nÀ6)
Baseline 8.8570.26 8.6070.25
Preoperative 9.0770.25 a
8.9370.24 a
RBC membrane lipids
EPA (20:5nÀ3)
Baseline 1.9670.09 1.9270.10
Preoperative 1.8870.08 a
2.3270.09 a,b
DHA (22:6nÀ3)
Baseline 7.3170.13 7.4870.14
Preoperative 7.3570.13 7.5870.14 a,b
AA (20:4nÀ6)
Baseline 12.2270.19 12.0770.20
Preoperative 12.1670.18 12.0870.20
Data are expressed as mean7SEM. PL, phospholipids; RBC, red blood cell;
LC-PUFA, long-chain polyunsaturated fatty acids; EPA, eicosapentaenoic acid;
DHA, docosahexaenoic acid; AA, arachidonic acid.
a
Po0.05, compared with the baseline levels within groups. Paired t-test.
b
Po0.05, compared with the placebo group at the same time period.
Independent samples t-test.
L. Bjorgvinsdottir et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 89 (2013) 189–194 191

4. IL-12, IL-18, TNF-α and MIP-1α and the preoperative levels of AA, EPA
and DHA in plasma PL or RBC membrane lipids was not statistically
significant.
4. Discussion and conclusions
In this study we observed a vigorous systemic inflammatory
response following open heart surgery. More importantly, we
found this response to be related to the preoperative fatty acid
composition of plasma PL and/or RBC membrane lipids.
During cardiac surgery, tissue injury and other factors induce a
robust systemic inflammatory reaction [5]. Animal and human
studies have demonstrated that the inflammatory response can be
modulated through changes in dietary intake of nÀ3 LC-PUFA,
which predominantly have anti-inflammatory properties [8].
Moreover, it has been demonstrated that patients undergoing
major non-cardiac surgery who received fish oil parenterally for
7 days postoperatively, had lower serum concentrations of the
pro-inflammatory mediators IL-1β, IL-8 and IFN-γ on postoperative
day 4 compared with patients receiving soybean oil-based lipid
emulsion, which is rich in the AA precursor linoleic acid [17].
In the present study, we observed marked postoperative changes
in the concentrations of several pro-inflammatory and anti-
inflammatory mediators, consistent with previous reports
[14,24], although no difference was observed between the nÀ3
LC-PUFA- and placebo-treated patients. The relatively high base-
line levels of EPA and DHA in plasma PL and RBC membrane lipids,
reflect the daily use of cod liver oil and/or nÀ3 LC-PUFA supple-
ments by a large proportion of patients in our study. The one-week
course of nÀ3 LC-PUFA treatment resulted in modest changes in
the levels of plasma PL EPA and DHA and almost no change in the
levels of RBC membrane EPA and DHA compared with the baseline
levels. Thus, short-term supplementation with moderate doses of
Fig. 1. Median plasma concentrations of the inflammatory mediators TNF-β, IL-6, hs-CRP, IL-8, IL-10, IL-18, TNF-α, IL-1β, IL-12, IFN-γ, MIP-1α, and TGF-β preoperatively and on
the third postoperative day in patients undergoing open heart surgery. n
Po0.02 and nn
Po0.001 compared with preoperative concentrations. Wilcoxon signed rank test.
L. Bjorgvinsdottir et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 89 (2013) 189–194192

5. nÀ3 LC-PUFA did not have an effect on the inflammatory response
as measured by the changes in the concentration of inflammatory
mediators on postoperative day 3 in the present study.
A more detailed analysis of fatty acid levels in plasma PL and RBC
membrane lipids suggested a potential role for EPA, DHA and/or AA
in the inflammatory process. We found the alterations in the plasma
concentrations of the pro-inflammatory mediators TNF-β, IL-1β,
IFN-γ, and the anti-inflammatory mediators IL-10 and TGF-β in
response to surgery to be significantly, albeit weakly, associated
with the preoperative levels of AA, EPA, and the ratios of EPA/AA,
DHA/AA and EPA+DHA/AA in either plasma PL and RBC membrane
lipids or both, whereas no such association was found with DHA. It
is known that EPA can compete with AA, as the same enzymes,
cyclooxygenase and lipoxygenase, are involved in the metabolism of
these fatty acids, and that eicosanoids derived from EPA have
weaker inflammatory effects than those derived from AA [9,10].
Existing evidence also suggesting that during an acute inflamma-
tory response, macrophages generate the potent anti-inflammatory
and proresolving lipid mediator lipoxin A4 from AA, which in turn
stimulates the production of the anti-inflammatory mediator IL-10
[25]. Consistent with this notion, we observed that higher AA level
and lower EPA level in plasma PL were associated with a greater
increase in IL-10. In contrast, we did not find a significant associa-
tion between AA or EPA in RBC membrane lipids with the changes
in IL-10, suggesting that the content of these fatty acids in plasma
PL may play a greater role in this process.
However, higher levels of AA and lower ratios of DHA/AA and
EPA+DHA/AA in RBC membrane lipids were associated with a
greater decline in TNF-β concentration, again suggesting a poten-
tial anti-inflammatory effect of AA. While the average concentra-
tions of the other three mediators, IL-1β, IFN-γ and TGF-β, did not
change following surgery, the intra-individual variability in
changes of their concentration associated significantly with pre-
operative fatty acid levels. This association was most consistent for
TGF-β as lower AA levels and higher ratios of DHA/AA and EPA
+DHA/AA in both plasma PL and RBC membrane lipids as well as a
higher EPA level in RBC membrane lipids were associated with an
increase in the concentration of this anti-inflammatory cytokine. It
has been demonstrated that TGF-β is produced by numerous cell
types and is one of the most potent chemoattractant for mono-
cytes and other cell types within wounds [26]. TGF-β also down-
regulates the production of pro-inflammatory mediators [5],
inhibits cell proliferation and induces apoptosis [27]. Though these
findings would suggest a possible anti-inflammatory effect of EPA,
the relationship observed between EPA in RBC membrane lipids
and IL-1β implies a pro-inflammatory effect. Taken together, our
findings suggest that the involvement of circulating and mem-
brane EPA and AA in the production of inflammatory mediators
following open heart surgery is greater than that of DHA. More-
over, the role of these fatty acids seems to be complex since EPA
and AA associate with both pro-inflammatory and anti-
inflammatory mediators.
Despite a careful design of the present study, there were several
notable limitations. First, it should be emphasized that the findings
are largely confined to elderly patients undergoing open heart
surgery who have relatively high baseline levels of nÀ3 LC-PUFA
in plasma PL and RBC membrane lipids and may not be representa-
tive for other populations. It should also be noted that we did only
measure the concentrations of inflammatory mediators immedi-
ately prior to surgery and on the third postoperative day. Systemic
inflammatory response following cardiac surgery is complex and
time-dependent, as it involves multiple cell types and a large
network of mediators. Earlier work has demonstrated that cardiac
myocytes are capable of synthesizing inflammatory mediators [1,2],
and that epicardial adipose tissue is a source of several such agents
[4]. Thus, the LC-PUFA EPA, DHA and AA may have local inflamma-
tory effects that are not necessarily reflected by circulating inflam-
matory mediators or the plasma PL or RBC membrane fatty acid
composition although the latter has been shown to correlate well
with the fatty acid composition of atrial myocytes [13]. However, it
might be considered a limitation that we did not measure the fatty
acid levels of cells in pericardial or atrial tissues or in other cell
types, e.g. white blood cells. In addition, it has been well documen-
ted that the inflammatory cascade is initiated immediately after
tissue injury and, therefore, many inflammatory mediators may
peak very early in the postoperative course [6,7,16]. Due to multiple
comparisons our analysis may by chance show a statistically
significant association between the changes in inflammatory med-
iators concentrations and the preoperative levels of the fatty acids in
plasma PL and RBC membrane lipids. We did not adjust for multiple
testing because the design of our study was exploratory in nature
and primarily hypothesis generating. Therefore, additional studies
are needed to examine how EPA, DHA and AA may be associated
with inflammatory mediators in the first hours and 24–48 h
Table 3
Relationship between preoperative levels of fatty acids in plasma phospholipids (PL) or red blood cell (RBC) membrane lipids and the postoperative change in the plasma
concentrations of selected inflammatory mediators, measured immediately before surgery and on the third postoperative day.
dTNF-β (pg/mL) dIL-1β (pg/mL) dIL-10 (pg/mL) dIFN-γ (pg/mL) dTGF-β (pg/mL)
Betaa
P R2
Beta P R2
Beta P R2
Beta P R2
Beta P R2
Plasma PL
AA À0.013 0.868 0.029 À0.101 0.214 0.031 0.163 0.044 0.047 0.000 0.997 0.022 À0.217 0.007 0.065
EPA À0.016 0.847 0.029 0.058 0.478 0.025 À0.191 0.018 0.057 0.127 0.116 0.037 À0.013 0.873 0.021
DHA 0.130 0.118 0.044 0.159 0.055 0.045 À0.034 0.683 0.023 0.158 0.057 0.044 0.101 0.226 0.030
EPA/AA ratio À0.359 0.991 0.029 0.129 0.117 0.037 À0.195 0.017 0.057 0.116 0.158 0.034 0.072 0.384 0.025
DHA/AAratio 0.096 0.255 0.037 0.221 0.008 0.065 À0.132 0.117 0.037 0.107 0.204 0.032 0.234 0.005 0.069
EPA+DHA/AA ratio 0.052 0.532 0.031 0.191 0.022 0.054 À0.177 0.034 0.050 0.122 0.147 0.035 0.167 0.046 0.045
RBClipids
AA À0.240 0.003 0.091 À0.154 0.061 0.042 0.072 0.383 0.026 À0.110 0.181 0.030 À0.264 0.001 0.080
EPA 0.072 0.385 0.042 0.221 0.008 0.063 À0.064 0.447 0.025 0.182 0.030 0.049 0.198 0.018 0.050
DHA 0.144 0.102 0.054 0.121 0.176 0.031 À0.035 0.693 0.022 0.011 0.907 0.019 0.165 0.064 0.037
EPA/AA ratio 0.107 0.198 0.048 0.227 0.006 0.066 À0.062 0.457 0.025 0.168 0.044 0.045 0.219 0.009 0.058
DHA/AA ratio 0.196 0.021 0.070 0.175 0.041 0.046 À0.064 0.459 0.000 0.077 0.368 0.024 0.237 0.005 0.063
EPA+DHA/AA ratio 0.170 0.044 0.062 0.203 0.017 0.055 À0.063 0.463 0.025 0.144 0.180 0.030 0.239 0.005 0.065
a
Standardized beta coefficient (β) for the fatty acid from each regression model. The analysis of the relationship between arachidonic acid (AA), eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) and selected inflammatory mediators is adjusted for age, body mass index (BMI) and smoking. Bold P values indicate significant
relationship by multivariable linear regression analysis. R2
represents the proportion of the variability in the change in an inflammatory mediator which is explained by
the model.
L. Bjorgvinsdottir et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 89 (2013) 189–194 193

6. following open heart surgery in both young and elderly patients.
Finally, we only examined a limited number of inflammatory
mediators so that additional studies will be required to explore
the role of other mediators of inflammation.
In conclusion, our findings support the notion that the levels of
EPA and AA in plasma PL and/or cell membrane lipids may affect
the inflammatory response following open heart surgery. How-
ever, both these fatty acids associate with pro-inflammatory and
anti-inflammatory mediators, suggesting a complex role in the
inflammatory process that occurs during the postoperative period.
Additional studies are needed to better characterize the influence
of nÀ3 LC-PUFA on the postoperative inflammatory response,
which may be better elucidated by measuring the concentrations
of inflammatory mediators earlier following surgery and at multi-
ple time points.
Acknowledgements
The contribution to this work by the patients, the staff at
Landspitali—The National University Hospital of Iceland, and Lilja
G. Steinsdottir, Laboratory Assistant at the University of Iceland, is
greatly appreciated.
Sources of support: Supported by grants from the Icelandic
Research Fund (RANNIS, Grant No. 080411021), the University of
Iceland Research Fund, and the Landspitali—The National Univer-
sity Hospital of Iceland Research Fund.
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