Using Anti-Inflammatory Omega-3 Fatty Acids to Prevent Atrial Fibrillation After Open Heart Surgery: A Systematic Review

Abstract

Background. Atrial fibrillation is a common postoperative complication following cardiac surgery due to increased inflammation. Omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to prevent arrhythmias and evoke an anti-inflammatory response. Objective. The primary endpoint of this review was to examine the effects of omega-3 PUFAs on postoperative atrial fibrillation (POAF), and the secondary endpoint was to determine if PUFA supplementation influenced markers of inflammation. Results. Primary outcomes showed mixed results. Whether the intervention was omega-3 PUFA alone, in combination with antioxidants, or administered orally versus intravenously, most results were lacking statistical power and significance. Secondary outcomes did show an association between PUFA administration and decreased inflammatory markers (P<0.0001). Conclusions. Differences in route of administration, dose, and length of treatment make it unclear whether higher doses or longer pre-treatments would decrease postoperative atrial fibrillation. Additionally, higher levels of pro-inflammatory mediators have been associated with the onset of POAF; therefore, incorporation of anti-inflammatory omega-3 PUFAs could decrease the production of arrhythmia-causing pro-inflammatory mediators. Currently, there is inconclusive evidence showing omega-3 PUFAs have a direct effect on postoperative atrial fibrillation; however, indirect anti-inflammatory effects may lead to a better understanding between the two for future implications.

Key words: atrial fibrillation, omega-3, PUFA, heart surgery, inflammation

Introduction

Atrial fibrillation (AF) is a common postoperative complication of cardiac surgery.¹ Atrial fibrillation generally occurs 2-3 days after cardiac surgery due to increases in oxidative stress, lipid peroxidation, and inflammation that remains postoperatively for at least 24 hours.^2,3 The incidence of postoperative atrial fibrillation (POAF) is 20-50%, with that number expected to increase due to societal reasons including lifestyle, physical activity, and diet habits.^4,5 Dietary habits have greatly impacted cardiovascular disease as American diets have shifted to include more omega-6 than omega-3 polyunsaturated fatty acids (PUFAs).⁶ 

In a balanced diet, fatty acids of all kinds are used for many cellular processes. Omega-3 PUFAs are long-chain fatty acids that include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids have been shown to protect the heart, prevent arrhythmias, and evoke an anti-inflammatory response.^6-8 When omega-3 PUFA intake is replaced by excessive amounts of omega-6 PUFA, it negatively alters mitochondrial function by increasing lipid peroxidation, mitochondrial uncoupling, and reactive oxygen species production.^5,9,10 Omega-6 PUFA also provokes a pro-inflammatory response by increasing the production of arachidonic acid (AA) derived eicosanoids, such as interleukins (IL) and other inflammatory cytokines.^11-13

Cardiac surgery induces an inflammatory response within the tissue of the heart.¹³ This inflammatory response is normal; however, if there is an excessive amount of pro-inflammatory omega-6 PUFA present, then more IL-1β and IL-6 are available to negatively affect the heart.^11,14 The quantity of these pro-inflammatory agents can be physiologically down-regulated by omega-3 PUFA produced cytokines, such as IL-1ra and IL-10.¹⁴ At the same time, some current studies have shown that up to 98% of people undergoing open heart surgery do not reach the recommended dietary intakes for EPA and DHA omega-3 PUFA.^15,16 Since omega-3 PUFAs are unable to be synthesized by the human body and must be ingested as part of the diet, decreased intake prior to surgery may put patients at a higher risk for exacerbated postoperative inflammation.^6,15,16 Although AF is a common consequence of inflammation after open heart surgery, it remains one of the most challenging to research and document.¹⁷ 

Background

The chemistry of fatty acid classification is outlined in Table 1. The process by which EPA and DHA work together to protect the heart involves the replacement of AA within the phospholipids of the cardiac membrane.^7,14,18 Generally, AA is the major substrate for eicosanoid synthesis.¹¹ Eicosanoids are involved in the inflammatory response by modulating the intensity and duration of the response. Replacing AA with omega-3 PUFA as an eicosanoid substrate prevents AA metabolism, resulting in less available substrate for eicosanoid synthesis and a decrease in inflammatory cells.^5,11,19,20 

Arachidonic acid is not only a precursor for pro-inflammatory eicosanoids, but it can also uncouple gap junctions.⁷ This uncoupling leads to conduction slowing and can modify the activity of sodium, calcium, and potassium channels. In laboratory experiments, DHA and EPA PUFA can inhibit different potassium currents that interact with sodium channels. This inhibition decreases myocyte excitability and cytosolic calcium fluctuations. After major surgery, ischemic or damaged cells are especially vulnerable to these depolarization-triggered arrhythmias.^6,17,21-23 Thus, the type of fatty acids incorporated into cardiac membranes is an important determinant of the heart’s electrophysiological response.⁵ 

Dietary changes require several days to several weeks to reach a consistent content high enough to provoke lipid bilayer changes in cardiac tissue.^5,7,21 Rennison and Van Wagoner reported that a 1-month supplementation of PUFA raised the content of those lipids in the right atrial appendage from 5.3% to 11.5%, and decreased the AA content from 21% to 16%.⁵ Because of this, there were two purposes for this review. One was to investigate if omega-3 PUFA would be able to reduce POAF, and the other was to determine if omega-3 PUFA influenced markers of inflammation.

Methods

A literature search was performed on PubMed in August 2017. Key search terms included “atrial fibrillation” and “omega-3 OR PUFA OR fish oil” and/or “surgery.” Articles that were non-human, reviews, meta-analysis, pilots, had poorly-defined dosage, unclear results, or those that admitted to possible bias were excluded. A total of 14 studies were used for analysis. A flow diagram for the selection process is outlined in Figure 1. 

Study Characteristics

All studies were published between 2012 and 2017. Study size ranged from 23-1516 patients. Eleven studies provided PUFA supplementation as the primary intervention,^13,14,24-32 while three provided PUFA along with additional supplementation of antioxidant vitamins C and E.^33-35 Four studies administered intravenous omega-3 PUFA,^27,29,32,33 while the rest was administered orally.^{13,14,24-26,28,30,31,34,35} The diagnosis criteria of POAF varied among the studies. In the Mozaffarian et al²⁵ and Lomivorotov et al²⁹ studies, POAF was defined as lasting for greater than 30 seconds, while in Vasheghani Farahani et al²⁸ and Joss et al,³⁰ the episodes lasted for at least 5 minutes. Conversely, criteria from other studies went as low as 1 minute^34,35 or were not defined by duration, but per physician and need for pharmacological treatment.^24,32 Secondary outcomes examined PUFA and pro-inflammatory cytokine plasma concentrations.^{13,14,24,26,34-36} 

Results

Primary Outcomes

Three of the examined studies used Omacor^®, a PUFA concentrate supplement, for their treatment group.^24,25,31 Each 1-gram capsule of Omacor^® contained 465 mg EPA and 375 mg DHA (1.24:1 EPA:DHA ratio). Wilbring et al³¹ and Mozaffarian et al²⁵ required 10 grams of the supplement be consumed within five days prior to surgery, while Sandesara et al²⁴ required 6 grams two days before surgery. The results of the Sandesara et al²⁴ and Mozaffarian et al²⁵ studies were unsuccessful in reducing POAF (P=0.67 and P=0.74, respectively). However, the Wilbring et al³¹ study did show a statistically significant difference with POAF occurring in 31.3% of the treatment group and 48% of the controls (P=0.017). It is important to note that this study did not state that it excluded those who were already taking omega-3 supplements, which may have affected outcomes.

In two similar studies by Rodrigo et al,^34,35 a 2-gram PUFA supplement (1:2 ratio of EPA:DHA) seven days before surgery in combination with vitamins C (1 gram/day) and E (400 IU/day) two days before surgery were provided. In both studies, the regimen was continued until hospital discharge. In one study, Rodrigo et al³⁵ found that the treatment did not affect POAF outcomes for those less than 60 years old (n=40); however, it did prove to be statistically significant in those greater than 60 years old (n=35, P=0.0076). One consideration of this study’s results is that the small sample sizes may be a limitation to these results. Another important consideration is that those over 60 years old may be more likely to supplement with fish oil at home, which could have affected results since prior fish oil supplementation was not mentioned in the exclusion criteria. 

The other study by Rodrigo et al differed from the first in that it excluded those taking fish oil supplementation three months before the study, was a much larger study (n=203), and included anyone over the age of 18 years.³⁴ The mean age of those in the placebo group was 58.5 years vs 61 years in the supplement group. The outcome of this study showed a statistically significant difference between the treatment and control groups (P<0.001) in both prevention and risk of developing POAF.³⁴ 

Additional studies used various ratios of EPA:DHA in the intervention groups. A study by Vasheghani Farahani et al²⁸ used a 1.5:1 ratio, while Joss et al³⁰ used a ratio of 2:3. Both studies provided the omega-3 PUFA oral supplement for a minimum of five days prior to surgery and continued the supplement after surgery. Although neither study indicated that omega-3 supplementation reduced the occurrence of POAF, the Vasheghani Farahani et al study did find that the treatment group had a significant decrease in the duration of POAF after the initial incident (P<0.01).²⁸ 

Lastly, three studies used Omegaven^®, an intravenously (IV) infused omega-3 supplement that provides approximately 0.15 g fish oil/kg body weight.^27,29,33 Berger et al²⁷ and Lomivorotov et al²⁹ both used the Omegaven^® infusion, but Lomivorotov et al started 24 hours prior to anesthesia, where Berger et al only provided the infusion the night before and the day of surgery. Additionally, Lomivorotov el al provided a postoperative infusion for seven days, where no postoperative infusion was given in the Berger et al study. Even with these differences, both studies produced infinitesimal results. The Stanger et al³³ study also used Omegaven^®, but combined the omega-3 PUFA treatment with vitamins C and E. Results between the treatment and control groups were not statistically significant (P=0.821).³³ A comparison of the Omacor^® and Omegaven^® studies is provided in Table 2. An additional study by Feguri et al³² that provided an intraoperative omega-3 PUFA infusion (not Omegaven^®) did demonstrate prevention of POAF for the treatment groups (P=0.001). An average of 16.6 subjects were used for each group among these four studies, which may not be large enough to boast statistical power. 

Secondary Outcomes

Plasma concentrations of omega-3 PUFA and their pro-inflammatory counterparts’ effects on POAF were also examined. Multiple studies found the intervention group receiving omega-3 PUFA had an increased plasma concentration of EPA and DHA.^24,26,36 Although other studies did not find an association between PUFA concentrations and POAF occurrence, there was an association between increased PUFA plasma levels and decreased pro-inflammatory cytokines.^13,14,27 Berger et al found that IL-6, IL-8, and IL-10 cytokines were all increased after surgery, but those in the treatment group had significantly decreased IL-6 and IL-8 (P<0.0001).²⁷ 

Postoperative increases in inflammatory cytokines can lead to further cardiac oxidative stress. As shown by the Rodrigo et al studies,^34,35 levels of lipid peroxidation measured by malondialdehyde were significantly higher in those who developed POAF (P<0.01).³⁵ This suggests that although there is conflicting evidence that omega-3 PUFA directly affects POAF outcomes, there may be an indirect link between supplementation and decreasing inflammation/oxidation of the cells, which could result in the decreased occurrence of POAF. 

Discussion

The effect of omega-3 PUFA supplementation on decreasing occurrence of POAF has conflicting results. Ever since the historical article published by Calo et al³⁸ in 2005, much research has gone into investigating the true effects of omega-3 PUFA on POAF. Although Calo et al was the first to demonstrate a significant decrease in POAF in those supplemented with omega-3 PUFA,³⁸ the research was limited by lack of blinding and somewhat small sample size (160 subjects). 

Although studies that followed were blinded, half of them examined here did not have more than 160 subjects.^{14,27,29,32,33,35,36} Those that did have more than 160 subjects had conflicting results, but also varied in omega-3 dosage provided and/or were provided in combination with antioxidants and varied in route of administration.^{24-26,28,30,31,34} Differences in study design, sample sizes, treatment, diagnosis of atrial fibrillation, and exclusion criteria^25,31,32 or those previously taking omega-3 PUFA supplements^30,34 all could have had effects on outcomes.²⁸ 

Those with low sample sizes^{14,27,29,32,33,35,36} may not have had the statistical power to detect a statistically significant effect.²⁸ Consequently, those that did produce statistically significant results^14,32,35 may not have the ability to impact clinical practices. To compare, those with higher sample sizes^{24-26,28,30,31,34} had conflicting outcomes, with only two of those studies showing statistically significant results.^31,34 Regardless of sample size, of the studies that produced significant decreases in POAF,^31,32,34,35 both studies by Rodrigo et al^34,35 and the study by Wilbring et al³¹ administered the treatment via oral route. Conversely, the study by Feguri et al³² used an IV route of administration. In the current literature, differences in the dose, length of treatment, and the route of administration make it unclear whether a higher dose or longer pre-treatments would produce more reductions in POAF.^24,25 Due to vast differences in study designs, conclusions on omega-3 PUFA supplementation for prevention of POAF are currently inconclusive and require further investigation of reproducible study designs. 

Focus has recently changed in the literature on omega-3 PUFA, examining its indirect effects on prevention of POAF by its anti-inflammatory properties.^{13,14,24,26,27,34-37,39,40} In the Cardiovascular Health Study, biomarker levels of omega-3 PUFA were examined.⁴¹ This community-based longitudinal cohort study found that higher total omega-3 PUFA and DHA plasma phospholipid levels were associated with lower risk of overall atrial fibrillation.⁴¹ Additionally, linear regression models and correlation coefficients have identified a significantly high correlation (P<0.0001) between atrial and plasma omega-3 PUFA levels.⁴² This suggests that plasma phospholipid-derived fatty acids can be used to estimate levels of fatty acids within the heart’s atria. 

The potential role of EPA, DHA, and/or AA phospholipid concentrations in the inflammatory process surrounding open heart surgery is being considered.¹³ Bjorgvinsdottir et al found that alterations of pro-inflammatory mediators, such as TNF-β, IL-1β, and anti-inflammatory mediators, such as IL-10 and TGF-β, are associated with preoperative levels of AA and EPA, as well as with the ratios of EPA:AA, DHA:AA, and EPA+DHA:AA in either plasma, lipid membranes, or both.¹³ The release of these pro-inflammatory mediators has been shown to coincide with peak release of C-reactive protein typically two days postoperatively, with higher levels of C-reactive protein associated with onset of POAF.^39,40,43-45 Therefore, incorporation of anti-inflammatory omega-3 PUFA could decrease the production of pro-inflammatory mediators. 

Incorporation of omega-3 PUFA into plasma and lipid membranes is complex.³⁹ Baseline levels of PUFA and duration of treatments, as well as doses and/or ratio of EPA:DHA may have different effects and could vary between individuals due to factors influenced by age, BMI, diabetes, and background diet.^7,39,46 Metcalf et al found that higher proportions of EPA, DHA, EPA+DHA and total omega-3 PUFA were optimally incorporated into plasma and atrial tissues throughout a 1-week fish oil treatment.⁷ The benefit of DHA and EPA uptake into the cardiomyocyte phospholipids is that it is at the expense of pro-inflammatory omega-6 fatty acids, mainly AA.⁷ This displacement of fatty acids in cardiac phospholipids was shown by Metcalf et al in just 1 week using a 6-gram EPA + DHA/day supplementation, a dose which the authors reported was practically optimum in order to incorporate EPA and DHA into the myocardium; a lower dose would likely not provide the same results.⁷ 

Furthermore, a threshold for the incorporation of omega-3 PUFA into membrane phospholipids has been demonstrated.^18,37,40 It has been both estimated and validated by Harris that a cardioprotective target level for the enrichment of DHA and EPA into membrane phospholipids and myocardium appeared to be around 8%.¹⁸ However, this subject will need continued research as Metcalf et al found a U-shaped relationship between red blood cell (RBC) levels of PUFA.³⁷ When compared to the risk for POAF, the risk was the lowest when RBC EPA+DHA was 9.2-10.5% of total fatty acids, but above this level, the risk of POAF increased significantly (P=0.02).³⁷ 

Conclusion

Lipid composition of the cell can affect numerous metabolic activities within the heart, including those that could cause cardiac arrhythmias.⁶ Because oxidative stress is part of the postoperative process, it is suggested that future research focus on combination therapy (PUFA + antioxidants) along with examination of plasma levels of omega-3 PUFA. More adequately powered clinical trials with similar study designs are needed. Currently, there is inconclusive evidence showing omega-3 PUFAs have a direct effect on POAF; however, indirect anti-inflammatory effects may lead to a better understanding between the two for future implications.

Disclosures: The authors have no conflicts of interest to report regarding the content herein.   

Editor’s Note: This article underwent peer review by one or more members of EP Lab Digest’s editorial board.

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