EurJClinInvest_2011

Plasma n-3 and n-6 fatty acids and the incidence ofatrial fibrillation following coronary artery bypassgraft surgeryGudrun V. Skuladottir*,†, Ragnhildur Heidarsdottir*,†, David O. Arnar†,‡, Bjarni Torfason†,§, Vidar Edvardsson†,¶,Gizur Gottskalksson‡, Runolfur Palsson†,** and Olafur S. Indridason**

*Department of Physiology, †Faculty of Medicine, School of Health Sciences, University of Iceland, ‡Division of Cardiology,Department of Medicine, Cardiovascular Research Center, §Department of Cardiothoracic Surgery, ¶Children’s MedicalCenter, **Division of Nephrology, Department of Medicine, Landspitali – The National University Hospital of Iceland,Hringbraut, Reykjavik, Iceland

ABSTRACT

Background The anti-inflammatory or anti-arrhythmic effects of n-3 long-chain polyunsaturated fatty acids(LC-PUFA) may decrease the risk of postoperative atrial fibrillation (POAF), but interventional studies haveyielded conflicting results. We examined the association between n-3 LC-PUFA and n-6 LC-PUFA in plasmaphospholipids (PL) and POAF in patients undergoing coronary artery bypass grafting (CABG).

Methods A total of 125 patients undergoing CABG were enrolled in the study. The levels of fatty acids in PLwere measured preoperatively and on the third postoperative day. The endpoint was defined as POAF lasting‡5 min. The incidence of POAF was compared between quartiles of the level of each fatty acid in plasma PL byunivariate and multivariable analysis.

Results The incidence of POAF was 49Æ6%. By univariate analysis, the incidence of POAF increasedsignificantly with each higher quartile of pre- and postoperative docosahexaenoic acid (DHA) and diminishedsignificantly with each higher quartile of pre- and postoperative arachidonic acid (AA). For postoperative total n-3LC-PUFA, there was a significant U-curve relationship where the second quartile had the lowest incidence ofPOAF or 25Æ8%. In multivariable analysis, this U-curve relationship between n-3 LC-PUFA levels and POAF riskwas not significant, whereas the association between POAF and DHA or AA remained statistically significant.

Conclusions This study suggests that n-3 LC-PUFA supplements might prevent POAF in CABG patients withlow baseline levels of these fatty acids in plasma PL, but may be harmful in those with high levels. AA may playan important role in electrophysiological processes.

Keywords Atrial fibrillation, coronary artery bypass grafting, C-reactive protein, n-3 long-chain polyunsaturatedfatty acids, postoperative, preoperative.

Eur J Clin Invest 2011

Introduction

Atrial fibrillation occurs commonly after open-heart surgery

[1]. While advanced age and the increased complexity of the

surgical procedure are both major risk factors for postoperative

atrial fibrillation (POAF) [2], the pathogenesis of the disorder is

largely unknown. Both neurohumoral activation and a robust

inflammatory response after surgery have been implicated in

the development of this arrhythmia [3–6].

n-3 Long-chain polyunsaturated fatty acids (LC-PUFA) have

been viewed as potential preventive therapeutic options in

POAF, because of their anti-inflammatory and ⁄ or anti-arrhyth-

mic action [7,8]. However, the results of recent interventional

studies investigating the effect of n-3 LC-PUFA supplementa-

tion on the incidence of POAF following open-heart surgery

have yielded conflicting results [9–12]. Neither of the two stud-

ies that showed beneficial effects of n-3 LC-PUFA on POAF fol-

lowing coronary artery bypass graft surgery (CABG) included

analysis of n-3 LC-PUFA levels in blood phospholipids (PL)

[9,10]. These studies were conducted in populations expected

to have low baseline levels of n-3 LC-PUFA in plasma PL and

high levels of n-6 LC-PUFA [13]. In contrast, our previous study

European Journal of Clinical Investigation 1

DOI: 10.1111/j.1365-2362.2011.02497.x

ORIGINAL ARTICLE

[11] and a study by other investigators [12] which were carried

out in populations with relatively high baseline levels of n-3

LC-PUFA in plasma PL showed no effect of n-3 LC-PUFA on

AF incidence following open-heart surgery. Thus, n-3 LC-

PUFA treatment may only be effective in the prevention of

POAF in patients with low baseline levels of these fatty acids in

blood PL.

In this study, we examined the association between levels of

n-3 LC-PUFA and n-6 LC-PUFA in plasma PL and the

incidence of POAF in patients undergoing CABG.

Materials and methods

Subjects and study designThis study was a part of a larger prospective, randomized, dou-

ble-blinded, placebo-controlled clinical trial on the use of n-3

LC-PUFA for a week prior to open-heart surgery to prevent

POAF. Details of the study have been presented previously

[11]. In brief, all patients scheduled for elective or semi-emer-

gent open heart surgery between August 2007 and May 2009

were evaluated for participation, and a total of 170 patients

were enrolled. The treatment group received 2240 mg of n-3

LC-PUFA daily, providing 1240 mg eicosapentaenoic acid

(EPA) and 1000 mg docosahexaenoic acid (DHA) as ethyl

esters. The n-3 LC-PUFA was administered orally in capsules

that are commercially available in Iceland (Omega Forte; Lysi

Inc, Reykjavık, Iceland). The placebo treatment consisted of

2000 mg olive oil daily. Exclusion criteria included age < 40, a

history of supraventricular arrhythmias or the current use of

the anti-arrhythmic medications amiodarone and ⁄ or sotalol. To

eliminate confounding resulting from different complexity of

the surgical procedure, subjects undergoing open-heart proce-

dures other than CABG were excluded from this analysis. The

patients answered a questionnaire on lifestyle issues, including

the frequency of fish consumption but not the type of fish

consumed.

All participants received standard care following the surgical

procedure, and all had continuous electrocardiographic moni-

toring while being hospitalized. The study endpoint, POAF,

was defined as an episode lasting more than 5 min. All patients

gave written informed consent. The study was approved by the

Bioethics Committee of Landspitali – The National University

Hospital of Iceland, and the Icelandic Data Protection Author-

ity. Reporting of the study conforms to the STROBE statement

along with references to STROBE and the broader EQUATOR

guidelines [14].

Measurement of CRP and fatty acids in plasmaphospholipidsVenous blood samples were obtained immediately before sur-

gery (preoperative) and on the third postoperative day. Plasma

was separated from whole blood by immediate centrifugation

at 1000 g for 10 min, and the samples were frozen at )76 �C and

stored until the analysis of the fatty acid levels in PL was

performed.

Serum levels of C-reactive protein (CRP) were measured by

an enzymatic sandwich immunoassay (Vitros 5.1 FS Chemistry

System; Ortho-Clinical Diagnostics, Raritan, NJ, USA) prior to

surgery and daily during the postoperative period until the

levels had peaked.

For the analysis of fatty acids in plasma PL, the total plasma

lipid fraction was first extracted with chloroform : methanol

(2 : 1, v ⁄ v), using the method of Folch et al. [15]. The antioxi-

dant butylated hydroxytoluene (BHT, 5 mg per 100 mL) was

added to the extraction medium. The PL were separated on a

thin-layer chromatography plate (Adsorbosil H, Alltech, Deer-

field, IL, USA) using the solvent system petroleum ether ⁄ dieth-

ylether ⁄ acetic acid (80 : 20 : 1, v ⁄ v ⁄ v). The PL fatty acids were

methylated with 14% boron trifluoride ⁄ methanol (Sigma

Chemical Co., St. Louis, MO, USA) for 45 min at 110 �C. The

fatty acid methyl esters were analysed in a HP Series II 5890 A

Gas Chromatograph (Hewlett Packard Co ⁄ Agilent, Palo Alto,

CA, USA) equipped with a flame ionization detector and a

Chrompack CP-WAX 52CB capillary column (25 m · 0Æ32 mm

i.d. · 0Æ2 lm film thickness). The oven was programmed to pro-

vide an initial temperature of 90 �C for 2 min, then increasing

temperature by 30 �C per min to 165 �C and finally by 3 �C per

min to 225 �C. The carrier gas was hydrogen. The fatty acid

methyl esters were identified and calibrated against commer-

cial standards (Sigma Chemical Co.; Nu-Check-Prep, Elysian,

MN, USA). The software HP 3365 Chemstation, Version AÆ02Æ12

(Agilent, Palo Alto, CA, USA), was used for instrumental con-

trol and data acquisition and processing. The results are

expressed as percentage (%) of total fatty acids in plasma PL.

Statistical analysisAs there was no difference in the incidence of POAF between

the n-3 PUFA and placebo groups [11], the treatment assign-

ment was ignored in this analysis. Differences in baseline and

operative characteristics between the patients with POAF

(POAF group) and those without POAF (non-POAF group)

were compared with Wilcoxon–Mann–Whitney test for contin-

uous variables and the chi squared test or Fisher’s exact test for

dichotomous variables. An independent samples t-test was

used to compare the difference in fatty acid composition of

plasma PL between patients with POAF and those without

POAF and a paired t-test to compare changes within groups.

To examine the association between the levels of individual

fatty acids and POAF, we compared the rate of POAF between

quartiles of the fatty acid levels using chi squared test and the

Somers’d for ordinal variables. To examine independent associ-

ation between the quartiles of fatty acid levels and POAF, a

2 ª 2011 The Authors. European Journal of Clinical Investigation ª 2011 Stichting European Society for Clinical Investigation Journal Foundation

G. V. SKULADOTTIR ET AL. www.ejci-online.com

logistic regression analysis was used with POAF as the depen-

dent variable and the quartiles of each fatty acid as a categorical

variable, adjusting for age, BMI, smoking and peak postopera-

tive CRP. Data are presented as median (range), percentages or

mean ± standard error of mean (SEM), unless otherwise noted.

Two-sided P value < 0Æ05 was considered statistically signifi-

cant. All statistical analyses were carried out using SPSS

software (version 11Æ0, IBM Corporation, Somers, NY, USA).

Results

A total of 125 patients underwent CABG, of whom 62 patients

(49Æ6%) developed POAF. Six patients with missing data on

fatty acid levels, four preoperatively and two postoperatively,

were not included in the respective analyses. The baseline and

operative characteristics of the POAF group compared with the

non-POAF group are shown in Table 1. The POAF group was

older (P = 0Æ003) and their body mass index (BMI) was lower

(P = 0Æ026) compared with the non-POAF group. The plasma

CRP levels peaked on the third postoperative day (median,

range, day 1–10). The median peak CRP level was higher in the

POAF group compared with the non-POAF group, 218Æ0(66Æ0–492Æ0) mg L)1 vs. 201Æ0 (34Æ0–370Æ0) mg L)1, respectively

(P < 0Æ05).

The preoperative plasma PL levels of fatty acids in the two

groups are shown in Fig. 1. The POAF group had lower levels

of arachidonic acid (AA) (P < 0Æ05) and higher levels of DHA

Table 1 Baseline and operative characteristics of patients who did (POAF group) or did not (non-POAF group) developpostoperative atrial fibrillation (POAF)

Non-POAF group (n = 63) POAF group (n = 62) P value

Age (years) 66 (45–79) 69 (45–82)* 0Æ003

BMI (kg m)2) 28Æ4 (20Æ9–41Æ3) 27Æ0 (19Æ1–35Æ0)* 0Æ026

Gender (% men) 84Æ1 79Æ0 0Æ462

Smoking (%) 27Æ0 14Æ5 0Æ086

Fish intake (%, >once a week) 62Æ3 82Æ3* 0Æ013

Cod liver oil intake (%) 54Æ0 56Æ5 0Æ367

n-3 LC-PUFA intake (%) 25Æ4 27Æ4 0Æ364

Use of b blockers (%) 84Æ1 77Æ4 0Æ341

Use of statins (%) 90Æ5 83Æ9 0Æ27

Hypertension (%) 65Æ1 64Æ5 0Æ947

Diabetes (%) 19Æ0 12Æ9 0Æ349

Estimated operative blood loss (mL) 900 (0–2860) 800 (0–6200) 0Æ799

Blood volume in drains (mL) 700 (110–3070) 775 (96–4980) 0Æ664

Peak postoperative CRP level (mg L)1) 197Æ0 (34Æ0–370Æ0) 216Æ5 (36Æ0–416Æ0)* 0Æ042

ECC time (min) 84Æ5 (0–180) 80 (0–183) 0Æ696

Off pump surgery (%) 19Æ0 12Æ9 0Æ349

Aortic cross-clamp time (min) 45 (0–87) 42 (0–120) 0Æ765

Time in intensive care unit (hours) 21Æ5 (4–209Æ5) 22 (14Æ5–213) 0Æ33

Need for inotropic support (n)

None or minor 52 48 0Æ64

Short term 9 10

Long term 2 4

Data are expressed as median (range), percentage or number of subjects. BMI, body mass index; CRP, C-reactive protein; LC-PUFA, long-chain polyunsaturated

fatty acids; ECC, extracorporeal circulation.

*P < 0Æ05, compared with the non-POAF group, Wilcoxon–Mann–Whitney or chi-squared tests.


PLASMA N-3 AND N-6 FATTY ACIDS AND POSTOPERATIVE ATRIAL FIBRILLATION

(P < 0Æ05) compared with the non-POAF group. On the third

postoperative day, the plasma PL levels of AA, EPA and total

n-3 LC-PUFA were lower than preoperative levels (P < 0Æ05),

while those of DHA remained unchanged in both the non-

POAF (Fig. 2a) and POAF groups (Fig. 2b). However, the level

of AA was still significantly lower and the levels of EPA and

DHA were higher in the POAF group compared with the non-

POAF group (7Æ94 ± 0Æ24% vs. 8Æ99 ± 0Æ28%, 2Æ77 ± 0Æ17% vs.

2Æ33 ± 0Æ14%, and 6Æ93 ± 0Æ15% vs. 6Æ40 ± 0Æ14%, respectively,

P < 0Æ05).

Table 2 shows the incidence of POAF according to quar-

tiles of pre- and postoperative AA, EPA, DHA and total n-3

LC-PUFA levels in plasma PL. There was a significant differ-

ence in POAF incidence between quartiles of both pre- and

postoperative AA levels (P = 0Æ05 and P = 0Æ006, respec-

tively), with a significant trend for a decreasing incidence of

POAF with higher quartiles (P = 0Æ008 and P = 0Æ003, respec-

tively). The incidence of POAF was also significantly differ-

ent between quartiles of preoperative DHA levels (P = 0Æ023),

but in the case of postoperative DHA levels, the difference

did not quite reach statistical significance (P = 0Æ068). There

was, however, a significant trend for an increasing incidence

of POAF with higher quartiles of both pre- and postoperative

DHA levels (P = 0Æ003 and P = 0Æ008, respectively). No signif-

icant difference in POAF incidence was observed between

the quartiles of preoperative total n-3 LC-PUFA levels

(P = 0Æ41), nor was there a significant trend for an increase in

incidence (P = 0Æ13). Postoperatively, a nonsignificant trend

toward an increase in the POAF incidence between the

quartiles of total n-3 LC-PUFA levels was observed

(P = 0Æ055). However, the association between the total n-3

LC-PUFA levels and the POAF incidence was significant

(P = 0Æ014), with the second quartile of total n-3 LC-PUFA

levels having the lowest POAF rate (25Æ8%), significantly

lower than the first (P = 0Æ05), third (P = 0Æ02) and fourth

(P = 0Æ002) quartiles (Fig. 3). The trend was similar for EPA

albeit nonsignificant.

There was a significant direct association between age and

the levels of total n-3 LC-PUFA and an inverse association with

the levels of AA. Moreover, those who reported use of cod liver

oil supplementation and more frequent fish consumption more

than once per week were significantly older than those who did

not. In the subsequent logistic regression analysis, adjustments

were therefore made for age, as well as BMI, smoking and max-

imal peak postoperative CRP. Figure 4 shows the adjusted odds

ratio of POAF for each quartile of the fatty acids where the

Figure 1 Preoperative plasma phospholipid levels (% of totalfatty acids) of arachidonic acid (AA, 20:4n-6), eicosapentaenoicacid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), andtotal n-3 long-chain polyunsaturated fatty acids (LC-PUFA) inthe nonpostoperative atrial fibrillation (non-POAF) group andPOAF group. Values are mean ± SEM. *P < 0Æ05, comparedwith the non-POAF group, independent samples t-test.

Figure 2 Plasma phospholipid levels (% of total fatty acids) ofarachidonic acid (AA, 20:4n-6), eicosapentaenoic acid (EPA,20:5n-3), docosahexaenoic acid (DHA, 22:6n-3) and total n-3long-chain polyunsaturated fatty acids (LC-PUFA) in the non-postoperative atrial fibrillation (non-POAF) group (a) and POAFgroup (b), immediately before surgery (preoperative) and onthe third postoperative day. Values are mean ± SEM. *P < 0Æ05,compared with the preoperative values, paired samples t-test.



lowest quartile is the reference. The patients with preoperative

AA levels in the third quartile had significantly lower odds

ratio of POAF (OR 0Æ246, 95% CI 0Æ071–0Æ845) (Fig. 4a), and

postoperatively, the patients in the second (OR 0Æ260, 95% CI

0Æ076–0Æ886) and fourth quartiles (OR 0Æ145, 95% CI 0Æ040–0Æ531)

had significantly lower odds ratio of POAF (Fig. 4b) than

patients who had levels in the reference quartiles. Those in the

highest quartile of both pre- and postoperative DHA levels had

a significantly higher odds ratio of POAF than the lowest one,

with OR of 3Æ358 (95% CI 1Æ026–10Æ995) (Fig. 4e) and 4Æ902 (95%

CI 1Æ395–17Æ222) (Fig. 4f), respectively. For the postoperative

total n-3 LC-PUFA level, there was a nonsignificant U-curve

association with POAF with patients in the second quartile hav-

ing a lower odds ratio of POAF (OR 0Æ452, 95% CI 0Æ132–1Æ550)

than those in the first, third and fourth quartiles, but this

difference was not significant (Fig. 4h).

Discussion

In this prospective cohort study of patients undergoing CABG

surgery, we found that lower levels of DHA and higher levels

of AA in plasma PL were associated with decreased risk of

POAF. For total n-3 LC-PUFA levels, there was a trend toward

a U-curve relationship, suggesting that these fatty acids may be

of benefit in populations with low intake of n-3 LC-PUFA.

Our findings are somewhat surprising and contradict the

widely held belief that the anti-inflammatory and proposed

anti-arrhythmic effects of n-3 LC-PUFA may be of value in

preventing POAF and other arrhythmias [16,17]. Indeed, two

recent open label studies demonstrated that short-term EPA

and DHA administration might be promising as a therapy for

prevention of AF following CABG surgery [9,10]. One of these

studies performed by Calo and coworkers in Italy [9] showed

Table 2 Incidence of postoperative atrial fibrillation (POAF) according to quartiles of arachidonic acid and n-3 LC-PUFA levels inplasma phospholipids*

Quartiles P value

1 2 3 4 v2† Somers’d‡

Preoperative (n = 30) (n = 30) (n = 31) (n = 30)

AA level (%)§ 5Æ63–7Æ54 7Æ57–8Æ70 8Æ75–10Æ73 10Æ87–15Æ42

Incidence (%) 70Æ0 46Æ7 41Æ9 36Æ7 0Æ050 0Æ008

EPA level (%) 0Æ91–2Æ13 2Æ18–3Æ15 3Æ20–4Æ58 4Æ64–9Æ03


DHA level (%) 3Æ96–5Æ76 5Æ78–6Æ54 6Æ60–7Æ53 7Æ55–9Æ85


n-3 LC-PUFA level (%) 5Æ60–8Æ90 8Æ94–10Æ91 10Æ94–13Æ22 13Æ27–18Æ74


Postoperative (n = 30) (n = 31) (n = 31) (n = 31)

AA level (%) 4Æ97–6Æ92 6Æ96–8Æ17 8Æ18–9Æ53 9Æ57–16Æ57


EPA level (%) 0Æ89–1Æ61 1Æ66–2Æ17 2Æ24–3Æ36 3Æ39–6Æ12


DHA level (%) 4Æ24–5Æ81 5Æ87–6Æ54 6Æ61–7Æ54 7Æ58–9Æ48


n-3 LC-PUFA level (%) 6Æ00–8Æ61 8Æ68–9Æ87 9Æ94–11Æ56 11Æ66–16Æ62


*The n-6 Long-chain polyunsaturated fatty acid (LC-PUFA) arachidonic acid (AA); n-3 LC-PUFA include eicosapentaenoic acid (EPA), docosapentaenoic acid

(22:5n-3) and docosahexaenoic acid (DHA).†Pearson’s chi squared statistics.‡Somers’d statistics for trend in association between ordinal variables.§Levels are expressed as a percentage of total fatty acids.



that the incidence of POAF in patients supplemented with

capsules containing EPA and DHA as ethyl esters for at least

5 days before surgery was 15% compared with 33% in the con-

trol group. In the other study, which was carried out by Heidt

and coworkers in Germany [10], a lower incidence of POAF

was observed in patients who received an intravenous infusion

of EPA and DHA as emulsion of highly refined fish oil, at least

12 h preoperatively and immediately following surgery com-

pared with the control group (17Æ3% vs. 30Æ6%, respectively).

The blood levels of the EPA and DHA were not assessed in

either of these studies. Both studies were conducted in popula-

tions reported to have low baseline levels of n-3 LC-PUFA in

plasma PL [13,18]. However, it is likely that the short-term

treatment with EPA and DHA resulted in increased levels of

these fatty acids in plasma PL. This suggestion is supported by

a study that showed an increase in the levels of EPA and DHA

in plasma PL within 8 h postprandially, when healthy volun-

teers received fish oil supplements [19]. The favourable effect of

n-3 LC-PUFA on POAF was recently contradicted by two dou-

ble-blind placebo-controlled studies, including our own study,

which found no benefit of short-term fish oil supplementation

on the risk of AF after CABG surgery [11,12]. Cod liver oil,

which is a rich source of EPA and DHA, is a commonly used

dietary supplement in Iceland, particularly among the elderly.

The cod liver oil consumption is reflected in relatively high

baseline plasma levels of these n-3 LC-PUFA in the Icelandic

population [20], including the patients in our study. The levels

of the n-3 LC-PUFA in serum PL were also relatively high at

entry in patients participating in the study carried out in the

United Kingdom [12]. Furthermore, n-3 LC-PUFA supplemen-

tation resulted in significantly higher levels of EPA and DHA

in PL in both serum [11,12] and right atrial tissue [12] compared

with the control group. These findings and our present observa-

tion of a U-curve relationship between the levels of total n-3

LC-PUFA in plasma PL and POAF suggest that n-3 LC-PUFA

administration may be beneficial for prevention of POAF in

patients with very low baseline levels of total n-3 LC-PUFA in

plasma PL. Moreover, our findings indicate that relatively high

levels of n-3 LC-PUFA in plasma PL, in particular DHA, appear

to have no protective effect and may even increase the risk of

POAF. The variable type of fish oil products used, the route

and ⁄ or the treatment period of administration might explain

the difference in the results of the aforementioned studies. Calo

and coworkers [9] administered fish oil through a nasogastric

tube in the immediate postoperative period, whereas Heidt and

coworkers [10] administered the oil intravenously. Improved

delivery of n-3 LC-PUFA during a critical part of the postopera-

tive period may be important for successful prevention of

POAF. In addition, different preparations may confer differen-

tial anti-arrhythmic effects or be incorporated into PL and cell

membranes in a variable fashion [21].

In the current study, we observed a novel inverse associa-

tion between AA levels in plasma PL and POAF. Earlier

studies have shown that the prostaglandin series derived

from AA have arrhythmic effects, which may be opposed by

free AA and EPA, indicating a distinction in the effect of the

fatty acids themselves and their metabolic products on car-

diac arrhythmia [17]. The human body contains excess of AA

as it is the most abundant dietary n-6 PUFA in the Western

diet along with its precursor linoleic acid [22]. In contrast, the

synthesis of EPA and DHA is limited in humans and, there-

fore, these fatty acids must come from the diet in order to

meet physiological needs [23]. It has been shown that dietary

n-3 LC-PUFA are incorporated into plasma PL, red blood

cells and myocardial tissue within 1 week of their ingestion,

causing a reduction in the AA levels in PL within a period of

1 month [24]. Thus, the balance between n-6 and n-3 LC-

PUFA in the diet determines their ratio in cell membranes

[25]. Our study showed the postoperative plasma PL levels of

AA and EPA, the source of n-6 and n-3-eicosanoids, to be

decreased compared to the preoperative levels, both in

patients who developed POAF and those who did not. This

finding may be explained by the increase in heparin-

enhanced plasma phospholipase A2 activity in patients

undergoing cardiac surgery [26]. In contrast, no change was

observed in the relatively high preoperative levels of DHA in

plasma PL in either group. A differential release of LC-PUFA

1

Quartiles of n-3 LC-PUFA

Freq

uenc

y of

PO

AF

(%)

100

80

60

40

20

2 3 4

Figure 3 Frequency of postoperative atrial fibrillation (POAF)based on quartiles of n-3 long-chain polyunsaturated fattyacids (LC-PUFA) measured on the third postoperative day. SeeTable 2 for the range of n-3 LC-PUFA levels (% of total fattyacids) in each quartile.



from PL may be important for their biological role in inflam-

matory and electrophysiologic processes.

It has been proposed that the inflammatory response may be

a contributing factor in the development of POAF [3–6]. It has

therefore been speculated that short-term n-3 LC-PUFA treat-

ment may be effective in the prevention of POAF by shifting

the AA-derived eicosanoid pathway to the less-inflammatory

EPA-derived pathway [27]. Several studies have shown EPA-

and DHA-rich diets to be associated with low levels of pro-

inflammatory and high levels of anti-inflammatory markers

[28–30], while the lack of effect of dietary n-3 LC-PUFA on

inflammatory markers has also been reported [31]. The associa-

tion of POAF with the peak postoperative CRP concentration in

our study suggests that inflammation may have a role in the

(a)

(c) (d)

(f)

(g) (h)

(b)

(e)

Figure 4 Adjusted odds ratios and 95% confidence intervals of POAF for quartiles of preoperative and postoperative levels of fattyacids in plasma phospholipids in patients undergoing coronary artery bypass graft surgery. (a) Preoperative and (b) postoperativearachidonic acid (AA) levels; (c) preoperative and (d) postoperative eicosapentaenoic acid (EPA) levels; (e) preoperative and (f) post-operative docosahexaenoic acid (DHA) levels; (g) preoperative and (h) postoperative n-3 long-chain polyunsaturated fatty acids(LC-PUFA) levels. The models were adjusted for age, body mass index, smoking and maximal peak postoperative C-reactiveprotein. See Table 2 for the range of fatty acid levels (% of total fatty acids) in each quartile.



pathogenesis of this disorder [4,5,32]. However, no decrease in

the incidence of POAF in the patients undergoing CABG was

observed, despite relatively high n-3 LC-PUFA levels in their

plasma PL.

The relative balance between pro- and anti-inflammatory

factors may to some extent depend on baseline levels of AA and

EPA, nonesterified (free) in the circulation, or esterified in

plasma PL and in cell membrane PL, yielding a complex interac-

tion of these substances [25]. In addition, it has been suggested

that the ratio between the nonesterified AA and EPA in the cir-

culation and in cells could be more important than the AA and

EPA content or ratio in plasma PL and cell membranes for the

anti- and pro-inflammatory state in humans [8], as AA is metab-

olized to both pro- and anti-inflammatory eicosanoids [33].

The rate of POAF was relatively high in our study. This may,

at least in part, be related to our strict diagnostic criteria of only

a 5-min episode to define POAF as well as the use of continuous

electrocardiographic monitoring throughout their hospital stay

in all patients. However, other studies have also reported

similar rates of POAF [12].

Although the present study is prospective and well designed,

it is somewhat limited by the relatively small sample size. In a

larger sample, the association between plasma levels of n-3 LC-

PUFA and the risk of POAF could have been investigated more

thoroughly by comparing quintiles or deciles of n-3 LC-PUFA

levels. In particular, a larger study would be required to exam-

ine more closely the U-curve relationship between total n-3 LC-

PUFA in plasma PL and POAF suggested by our investigation.

Conclusions

The results of our study show that relatively high baseline or

postoperative levels of total n-3 LC-PUFA in plasma PL do not

prevent POAF following CABG surgery. A U-curve relation-

ship between total n-3 LC-PUFA in plasma PL and risk of

POAF may exist in the postoperative state and explain why

studies in populations with low baseline n-3 LC-PUFA levels

have demonstrated a beneficial effect. The inverse association

between AA levels and POAF is also of great interest. Whether

such an effect is mediated through anti-arrhythmic or anti-

inflammatory mechanisms remains unclear, although our study

supports a role for inflammation in the pathogenesis of POAF.

Determination of the role of dietary n-3 LC-PUFA in prevention

of POAF and in other arrhythmia management requires further

study. Better understanding of the pathogenesis of POAF is

essential for development of effective therapeutic strategies for

the prevention and treatment of this common disorder.

Acknowledgements

This work was supported by grants from the Icelandic

Centre for Research (RANNIS, Grant No. 080411021), the

University of Iceland Research Fund, and the Landspitali –

The National University Hospital of Iceland Research

Fund. The contribution of the participants, employees at

Landspitali – The National University Hospital of Iceland,

and Lilja G. Steinsdottir, Laboratory Assistant at the

University of Iceland, is gratefully acknowledged.

Contributions

All authors contributed to the design of the study. GVS, RH,

DOA and OSI collected and analysed the data; OSI performed

statistical analysis; GVS and OSI interpreted the data and wrote

the initial draft of the manuscript. All authors contributed to

the final form of the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Address

Department of Physiology (G.V. Skuladottir, R. Heidarsdottir),

Faculty of Medicine, School of Health Sciences, University of

Iceland (G.V. Skuladottir, R. Heidarsdottir, D.O. Arnar, B.

Torfason, V. Edvardsson, R. Palsson); Division of Cardiology,

Department of Medicine, Cardiovascular Research Center

(D.O. Arnar, G. Gottskalksson); Department of Cardiothoracic

Surgery (B. Torfason); Children’s Medical Center

(V. Edvardsson); Division of Nephrology, Department of

Medicine (R. Palsson, O.S. Indridason), Landspitali – The

National University Hospital of Iceland, Hringbraut, Reykjavik,

Iceland.

Correspondence to: Gudrun V. Skuladottir, PhD, 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: [email protected]

Received 21 September 2010; accepted 28 January 2011

References1 Kaireviciute D, Aidietis A, Lip GY. Atrial fibrillation following car-

diac surgery: clinical features and preventative strategies. Eur HeartJ 2009;30:410–25.

2 Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiacsurgery. Ann Intern Med 2001;135:1061–73.

3 Bruins P, te Velthuis H, Yazdanbakhsh AP, Jansen PG, vanHardevelt FW, de Beaumont EM et al. Activation of thecomplement system during and after cardiopulmonary bypasssurgery: postsurgery activation involves C-reactive protein andis associated with postoperative arrhythmia. Circulation1997;96:3542–8.

4 Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, CarnesCA et al. C-reactive protein elevation in patients with atrial arrhyth-mias: inflammatory mechanisms and persistence of atrial fibrilla-tion. Circulation 2001;104:2886–91.



5 Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rau-taharju P, Kronmal RA et al. Inflammation as a risk factor for atrialfibrillation. Circulation 2003;108:3006–10.

6 Lo B, Fijnheer R, Nierich AP, Bruins P, Kalkman CJ. C-reactive pro-tein is a risk indicator for atrial fibrillation after myocardial revascu-larization. Ann Thorac Surg 2005;79:1530–5.

7 Leaf A, Kang JX, Xiao Y-F, Billman GE. Clinical prevention of sud-den cardiac death by n-3 polyunsaturated fatty acids and mecha-nism of prevention of arrhythmias by n-3 fish oils. Circulation2003;107:2646–52.

8 Calder PC. Polyunsaturated fatty acids and inflammatory processes:new twists in an old tale. Biochimie 2009;91:791–5.

9 Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de RuvoE et al. N-3 Fatty acids for the prevention of atrial fibrillation aftercoronary artery bypass surgery: a randomized, controlled trial. J AmColl Cardiol 2005;45:1723–8.

10 Heidt MC, Vician M, Stracke SK, Stadlbauer T, Grebe MT, BoeningA et al. Beneficial effects of intravenously administered N-3 fattyacids for the prevention of atrial fibrillation after coronary arterybypass surgery: a prospective randomized study. Thorac CardiovascSurg 2009;57:276–80.

11 Heidarsdottir R, Arnar DO, Skuladottir GV, Torfason B, EdvardssonV, Gottskalksson G et al. Does treatment with n-3 polyunsaturatedfatty acids prevent atrial fibrillation after open heart surgery?Europace 2010;12:356–63.

12 Saravanan P, Bridgewater B, West AL, O’Neill SC, Calder PC,Davidson NC. Omega-3 fatty acid supplementation does not reducerisk of atrial fibrillation after coronary artery bypass surgery: arandomized, double-blind, placebo-controlled clinical trial. CircArrhythm Electrophysiol 2010;3:46–53.

13 Crowe FL, Allen NE, Appleby PN, Overvad K, Aardestrup IV, John-sen NF et al. Fatty acid composition of plasma phospholipids andrisk of prostate cancer in a case-control analysis nested within theEuropean prospective investigation into cancer and nutrition. Am JClin Nutr 2008;88:1353–63.

14 Simera I, Moher D, Hoey J, Schulz KF, Altman DG. A catalogue ofreporting guidelines for health research. Eur J Clin Invest 2010;40:35–53.

15 Folch J, Lees M, Sloane Stanley GH. A simple method for the isola-tion and purification of total lipides from animal tissues. J Biol Chem1957;226:497–509.

16 DeCaterina R, Giannessi D, Mazzone A, Bernini W, Lazzerini G,Maffei S et al. Vascular prostacyclin is increased in patients ingestingw-3 polyunsaturated fatty acids before coronary artery bypass graftsurgery. Circulation 1990;82:428–38.

17 Li Y, Kang JX, Leaf A. Differential effects of various eicosanoids onthe production or prevention of arrhythmias in cultured neonatalrat cardiac myocytes. Prostaglandins 1997;54:511–30.

18 Abbatecola AM, Cherubini A, Guralnik JM, Andres Lacueva C,Ruggiero C, Maggio M et al. Plasma polyunsaturated fatty acids andage-related physical performance decline. Rejuvenation Res2009;12:25–32.

19 Sadou H, Leger CL, Descomps B, Barjon JN, Monnier L, Crastes dePaulet A. Differential incorporation of fish-oil eicosapentaenoate

and docosahexaenoate into lipids of lipoprotein fractions as relatedto their glyceryl esterification: a short-term (postprandial) and long-term study in healthy humans. Am J Clin Nutr 1995;62:1193–200.

20 Skuladottir GV, Gudmundsdottir S, Olafsson GB, Sigurdsson SB,Sigfusson N, Axelsson J. Plasma fatty acids and lipids in twoseparate, but genetically comparable, Icelandic populations. Lipids1995;30:649–55.

21 Dyerberg J, Madsen P, Møller JM, Aardestrup I, Schmidt EB. Bio-availability of marine n-3 fatty acid formulations. ProstaglandinsLeukot Essent Fatty Acids 2010;83:137–41.

22 Simopoulos AP. Evolutionary aspects of diet, the omega-6 ⁄ omega-3ratio and genetic variation: nutritional implications for chronicdiseases. Biomed Pharmacother 2006;60:502–7.

23 Rapoport SI, Rao JS, Igarashi M. Brain metabolism of nutritionallyessential polyunsaturated fatty acids depends on both the diet andthe liver. Prostaglandins Leukot Essent Fatty Acids 2007;77:251–61.

24 Metcalf RG, James MJ, Gibson RA, Edwards JR, Stubberfield J,Stuklis R et al. Effects of fish-oil supplementation on myocardialfatty acids in humans. Am J Clin Nutr 2007;85:1222–8.

25 Simopoulos AP. The importance of the omega-6 ⁄ omega-3 fatty acidratio in cardiovascular disease and other chronic diseases. Exp BiolMed 2008;233:674–88.

26 Nakamura H, Kim DK, Philbin DM, Peterson MB, Debros F, KoskiG et al. Heparin-enhanced plasma phospholipase A2 activity andprostacyclin synthesis in patients undergoing cardiac surgery. J ClinInvest 1995;95:1062–70.

27 Fritsche K. Fatty acids as modulators of the immune response. AnnuRev Nutr 2006;26:45–73.

28 Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, LauretaniF et al. Relationship of plasma polyunsaturated fatty acids tocirculating inflammatory markers. J Clin Endocrinol Metab2006;91:439–46.

29 Micallef MA, Munro IA, Garg ML. An inverse relationship betweenplasma n-3 fatty acids and C-reactive protein in healthy individuals.Eur J Clin Nutr 2009;63:1154–6.

30 Farzaneh-Far R, Harris WS, Garg S, Na B, Whooley MA. Inverseassociation of erythrocyte n-3 fatty acid levels with inflammatorybiomarkers in patients with stable coronary artery disease: TheHeart and Soul Study. Atherosclerosis 2009;205:538–43.

31 Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Willett WC,Rimm EB. Habitual dietary intake of n-3 and n-6 fatty acids inrelation to inflammatory markers among US men and women.Circulation 2003;108:155–60.

32 Tselentakis EV, Woodford E, Chandy J, Gaudette GR, Saltman AE.Inflammation effects on the electrical properties of atrial tissue andinducibility of postoperative atrial fibrillation. J Surg Res2006;135:68–75.

33 Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL,Appel LJ et al. Omega-6 fatty acids and risk for cardiovasculardisease: a science advisory from the American Heart AssociationNutrition Subcommittee of the Council on Nutrition, PhysicalActivity, and Metabolism; Council on Cardiovascular Nursing;and Council on Epidemiology and Prevention. Circulation2009;119:902–7.



EurJClinInvest_2011

Documents

Transcript of EurJClinInvest_2011