HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Supplemental Data Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Metcalf, R. G Articles by Cleland, L. G Search for Related Content PubMed PubMed Citation Articles by Metcalf, R. G Articles by Cleland, L. G Agricola Articles by Metcalf, R. G Articles by Cleland, L. G

Effects of fish-oil supplementation on myocardial fatty acids in humans^1,2,3

¹ From the Rheumatology Unit (RGM, MJJ, and LGC), the Cardiothoracic Surgery Unit (JRME, JS, and RS), and the Cardiovascular Research Centre (GDY and KR-T), Royal Adelaide Hospital, Adelaide, Australia; the School of Agriculture Food and Wine (RAG) and the School of Medicine (MJJ, LGC, and GDY), University of Adelaide, Adelaide, Australia; and the Hanson Institute, Adelaide, Australia (MJJ and LGC)

² Supported by grants from the National Heart Foundation of Australia, Cardiovascular Lipids Research Grant (Pfizer Australia to GDY), University of Adelaide, and the Royal Adelaide Hospital Research Committee. The fish oil was kindly supplied by Berg LipidTech (Aalesund, Norway).

³ Reprints not available. Address correspondence to RG Metcalf, Rheumatology Unit, Level 4 Eleanor Harrald Building, Royal Adelaide Hospital, North Tce, Adelaide, SA, 5000, Australia. E-mail: rmetcalf{at}mail.rah.sa.gov.au.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: Increased fish or fish-oil consumption is associated with reduced risk of cardiac mortality, especially sudden death. This benefit putatively arises from the incorporation of the long-chain n–3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into cardiomyocyte phospholipids.

Objective: The study examined the kinetics of incorporation of n–3 fatty acids into human myocardial membrane phospholipids during supplementation with fish oil and -linolenic acid–rich flaxseed oil.

Design: Patients with low self-reported fish intake (<1 fish meal/wk and no oil supplements) accepted for elective cardiac surgery involving cardiopulmonary bypass were randomly allocated to 1 of 6 groups: no supplement; fish oil (6 g EPA+DHA/d) for either 7, 14, or 21 d before surgery; flaxseed oil; or olive oil (both 10 mL/d for 21 d before surgery). Right atrial appendage tissue removed during surgery and blood collected at enrollment and before surgery were analyzed for phospholipid fatty acids.

Results: Surgery rescheduling resulted in a range of treatment times from 7 to 118 d. In the fish-oil-treated subjects, accumulation of EPA and DHA in the right atrium was curvilinear with time and reached a maximum at 30 d of treatment and displaced mainly arachidonic acid. Flaxseed oil supplementation yielded a small increase in atrial EPA but not DHA, whereas olive oil did not significantly change atrial n–3 fatty acids.

Conclusion: The results of the present study show that dietary n–3 fatty acids are rapidly incorporated into human myocardial phospholipids at the expense of arachidonic acid during high-dose fish-oil supplementation.

Key Words: Fish oils • fatty acids • n–3 fatty acids • dietary fats • myocardium • humans

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Several cohort (1-5), dietary intervention (6-8), and case-control (9, 10) studies have shown that fish and n–3 polyunsaturated fatty acids (PUFAs) confer significant cardiovascular benefit. The cohort studies documented a 42–67% lower incidence of cardiac death associated with intake of fish or vegetable n–3 fats, and the intervention studies reported a 32–73% lower risk of cardiac death with or without nonfatal myocardial infarction (1-8). A large intervention study using a fish-oil concentrate reported a 45% reduction in sudden cardiac death with fish oil (8). In addition, case-control studies have found that, compared with the lowest quartile, erythrocyte or whole blood n–3 PUFAs in the highest quartile are associated with a 90% reduction in risk of primary cardiac arrest (10) or sudden cardiac death (9).

The mechanism by which eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) confer cardiovascular protection may involve a replacement of arachidonic acid (AA) in vascular and cardiac membrane phospholipids. AA is a precursor of proinflammatory eicosanoids, whereas EPA and DHA have been shown to be anti-thrombotic and anti-arrhythmic, respectively. It has been proposed that the erythrocyte EPA+DHA content (the omega-3 index) could serve as a risk factor for death from coronary artery disease, with EPA+DHA 8% of total erythrocyte fatty acids being proposed as a target to reduce the risk of death from coronary artery disease (11). However, only one small study looked at the incorporation of dietary n–3 fatty acids into human myocardium, and that study used endocardial biopsy specimens from transplanted hearts (12). No studies have examined nontransplanted hearts; in particular, no data exist on the rate of increase in human myocardial EPA and DHA in response to dietary intervention. This information is important for prospective acute dietary interventions, such as for acute coronary syndrome, and is also pertinent in determining the likely time to benefit in longer-term administration of fish oil. Thus, in the present study we examined the rate of incorporation of dietary n–3 PUFAs into human myocardium during fish-oil treatment compared with the effect of flaxseed oil–derived n–3 fatty acids on human myocardial fatty acids.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
Patients accepted for elective on-pump cardiac surgery (coronary artery bypass graft, valve repair or replacement, or both) were recruited if they had not previously had cardiac surgery, were expected to have at least 21 d waiting time before surgery, and if they reported a low frequency of ingestion of fish (1 fish meal/wk) and no fish oil or other oil supplements. The study design was a random, blinded allocation to parallel treatment groups. Randomization was by sealed envelope. Of 6 treatments groups, 5 received a supplement and the other received no test dietary intervention. The dietary treatments were 10 mL/d of either fish-oil concentrate (Berg Lipidtech AS, Aalesund, Norway) for 7, 14, or 21 d before surgery and flaxseed oil or olive oil for 21 d before surgery. The dietary oils contained a total of 1.86% lemon and lime oil flavoring to improve palatability and blinding. The oil was provided in bottles, and the subjects were instructed to take it in fruit juice as described previously (13). The fish-oil concentrate was selected because it contained approximately equal proportions of EPA and DHA, providing a daily intake of 3 g of each fatty acid. The flaxseed oil comparator provided a similar total amount of n–3 PUFAs, but as -linolenic acid (ALA). The olive oil comparator provided <1% of the n–3 PUFA intake of flaxseed oil, also as ALA. The fatty acid composition of the oils is detailed in Table 1.

Subjects who failed to complete the intervention, or from whom an atrial specimen was not obtained at surgery, were replaced as needed by the next available patient to ensure that a total of 30 atrial specimens were obtained from subjects who completed the fish-oil supplementation and 10 from subjects in each of the other groups. Compliance was assessed by interview and by changes in erythrocyte and plasma fatty acid composition. Informed consent was obtained before participation in the study, which was approved by the Research Ethics Committee of the Royal Adelaide Hospital.

Tissue collection procedures
Nonfasting blood was collected into lithium heparin tubes at enrollment and again at the time of admission to the hospital before surgery. Right atrial appendage tissue that is removed as a standard surgical procedure during cannulation of the heart in preparation for cardiopulmonary bypass was collected and placed immediately into ice-cold saline, transferred to the laboratory, removed from the saline, and stored at –70 °C until analyzed.

Fatty acid extraction and analysis
Erythrocyte and plasma phospholipids were extracted as described (14). Atrial samples were cleaned of adipose tissue and clotted blood. Approximately 0.2 g tissue was homogenized in 2 mL saline before mixing with 3 mL methanol. Chloroform (6 mL) was added, the samples were centrifuged (1560 x g, 10 min, room temperature), and the chloroform phase was transferred to a 20-mL scintillation vial and evaporated to dryness.

Phospholipids were separated by thin-layer chromatography and after methanolysis of the phospholipid fractions. Fatty acid methyl esters were analyzed by gas–liquid chromatography as described (15).

Safety
Postsurgical blood loss from mediastinal chest tube drains was recorded at the time of tube removal.

Statistical analysis
Continuous variables were compared by using analysis of variance with post-testing by Tukey-Kramer multiple comparisons test or Kruskal-Wallis with post-testing by Dunn's test as appropriate. Subjects completing the fish-oil treatment were allocated to tertiles on the basis of duration of fish-oil treatment.

Analyses were conducted by using INSTAT version 3.06 (Graphpad Software, San Diego, CA). Regression analysis was used to explore relations between duration of intervention and fatty acid content of atrium and erythrocytes (PRISM version 4.1; Graphpad Software). Best-fit curves were obtained by using the linear and nonlinear regression analytic features of PRISM. For each data set, linear regression, sigmoidal dose-response (variable slope), and second-order polynomial curves were calculated, with the best-fit curve selected by comparison of the r² values.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
To achieve our group size objectives, we enrolled a total of 84 subjects to yield 10 atrial samples in each treatment group as detailed in Figure 1. The required total of 60 subjects was enrolled initially, 24 of whom withdrew for the reasons shown and were replaced.

View larger version (32K): [in this window] [in a new window]   FIGURE 1.. Details of enrollments, specimens obtained, duration of treatment (range), and dropouts for each treatment group. 1Range of actual duration of oil treatment as the result of rescheduling of surgery.

Table 2

Effects of fish-oil consumption on rate of change in tissue fatty acids
The range of days of fish-oil consumption allowed nonlinear regression analysis of EPA, DHA, and EPA+DHA within atrial and erythrocyte phospholipids relative to duration of fish-oil treatment. These relations appeared to be curvilinear and are shown in Figure 2.

View larger version (20K): [in this window] [in a new window]   FIGURE 2.. Increases in eicosapentaenoic acid (EPA; triangles), docosahexaenoic acid (DHA; circles), and EPA+DHA (diamonds) in atrial (closed symbols and solid line) and erythrocyte (open symbols and dashed line) phospholipids in untreated (time = 0 d) and fish-oil-supplemented subjects plotted against duration of fish-oil treatment.

Table 3

Figure 3

View larger version (19K): [in this window] [in a new window]   FIGURE 3.. Exchange of atrial phospholipid eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA; • and solid line) with arachidonic acid (AA; and dashed line) for the untreated (time = 0 d) and fish-oil-supplemented subjects as a function of duration of treatment.

Effect of fish-oil supplementation on atrial and erythrocyte EPA and DHA during the first 10 d of supplementation
During the first 10 d of fish-oil treatment, there was a similarity in absolute differences in erythrocyte and atrial phospholipid EPA+DHA content (mean differences of 2.5% and 2.9% of total fatty acids, respectively) compared with that in the control group (Table 3). In erythrocytes, absolute differences in EPA and DHA during the initial period of treatment were almost identical (1.3% and 1.2%, respectively). However, in atrium, the increment in DHA was more than twice that for EPA (2.0% and 0.9%, respectively), which indicated that during the initial stages of supplementation, DHA accumulated in atrial phospholipids significantly more rapidly than did EPA (P < 0.001).

Effects of flaxseed oil treatment on atrial fatty acids
The flaxseed oil treatment yielded a significantly higher proportion of ALA in atrium relative to a modest untreated comparator level (0.13%; Table 3), and although EPA was 50% higher in the flaxseed oil group, the difference was not significant. Over the ranges of treatment times observed, regression analysis failed to show an effect of duration of flaxseed oil treatment on any of the phospholipid fatty acids examined (data not shown).

Effects of olive oil treatment on atrial fatty acids
No significant differences were found between the olive oil and the control groups for any fatty acid examined (Table 3).

Safety
No significant differences were found in total postsurgical blood loss between any of the groups (Figure 4). Two subjects were returned to surgery to control postoperative bleeding, 1 of whom completed the olive oil arm and 1 allocated to flaxseed oil, but who was subsequently withdrawn because an atrial specimen was not obtained. There were 2 deaths in the immediate postoperative period, 1 in the olive oil group on postoperative day 3 of cardiac and respiratory arrest, and 1 in the control group on postoperative day 20 of respiratory failure.

View larger version (11K): [in this window] [in a new window]   FIGURE 4.. Total postsurgical blood loss recorded from mediastinal chest tube drains at the time of tube removal. Dots represent individual subjects; lines represent median values. One subject in the olive oil group was returned to surgery to control postoperative bleeding. No significant differences were found between the 3 fish-oil tertiles (P = 0.83, ANOVA), so these were combined. No significant differences in blood loss were found between any of the treatment groups (P = 0.77, Kruskal-Wallis test).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study describes, for the first time, a time course of the incorporation of long-chain n–3 PUFAs from dietary fish-oil treatment into human myocardial membranes. Even though the American Heart Association recommends a daily intake of 1 g EPA+DHA for persons with diagnosed heart disease, little information is available on the effects of dietary n–3 PUFA supplementation on myocardial fatty acid amounts in humans. At the dose of fish oil used in the present study, EPA and DHA accumulated rapidly within atrial phospholipids, and this was at the expense of long-chain n–6 fatty acids, mainly AA. Also, DHA accumulated in atrial phospholipids more rapidly than did EPA early during treatment with fish oil, even though DHA and EPA were present in equal proportions.

Information regarding the complete fatty acid profile of human myocardium is scarce. Early studies on human myocardium focused only on fatty acids that constituted the major proportions (saturates, oleic acid, LA and AA, and DHA) (16-18). Subsequent studies, which provide more comprehensive details of the long-chain PUFA content of human myocardium, used papillary muscle harvested during mitral valve replacement (19, 20), unspecified myocardial material obtained at autopsy (21), and endocardial biopsy samples from the interventricular septum obtained from heart transplantation recipients (12). Although no published data are available on comparisons of the fatty acid profile between the ventricle and atrial appendage, the fatty acid profile in atrial myocardium of the subjects in our untreated group was similar to that found in papillary muscle (19) and autopsy material (21). The fatty acid profile obtained from heart transplant patients (12) differs from these reports and from the results presented herein in that mean EPA and DHA amounts were substantially lower. These discrepancies may be in part explained by the effects of cardiac transplantation or the use of immunosuppressive agents. For example, in animal studies, cardiac denervation redirects cardiac energy metabolism from oxidation of glucose to oxidation of fatty acids (22), andcyclosporine reduces intestinal fat absorption (23). These effects could conspire to perturb proportions of myocardial fatty acids after cardiac transplantation, with depletion of long-chain n–3 PUFAs being compensated for by higher amounts of saturated and monounsaturated fatty acids (19, 21), which can be synthesized endogenously. A further possibility to consider is the mode and location of the biopsy, ie, percutaneous instrumental endocardial biopsy of interventricular septum compared with open excision of myocardium from other sites. Storage conditions could also contribute to differences.

The beneficial effects of dietary n–3 fatty acids are thought to accrue from their incorporation into cardiomyocyte phospholipids with consequent effects on myocardial membrane function and release as free fatty acids by the action of phospholipase A₂ (24). In the time course analysis of the GISSI-P study, the survival curves for total mortality, coronary artery disease mortality, cardiovascular disease mortality, and sudden death began to diverge after 60 d from the start of treatment (25), and did not become significantly different until 90 d for total mortality, 120 d for sudden death, and 240 d for coronary artery disease and cardiovascular disease mortality. Gradual accretion of n–3 fatty acids into membrane phospholipids (26) may result in a delay in protection afforded by eating fish or taking a fish-oil supplement until an effective level is reached. Incorporation of n–3 PUFAs into red blood cells is known to vary between individuals and to be potentially influenced by several factors, including age, body mass index, presence of diabetes (27), and background diet, especially n–6 PUFA intake (28). Individual differences may also occur in the incorporation of EPA and DHA into myocardium. The present study provides insight into the likely extent of this variability.

Survivors of myocardial infarction are at greatest risk of sudden death in the first month after the myocardial infarction with an event rate about 3-fold higher than that for the period from 1 to 6 mo after myocardial infarction (29). If the cardioprotective effects of fish oil arise from EPA or DHA within cardiac phospholipids, it follows that initial, high-dose fish-oil supplementation, which rapidly elevates cardiac levels of EPA and DHA, could be helpful during this period of vulnerability to life-threatening ventricular arrhythmias.

The displacement of myocardial AA by EPA and DHA may provide additional benefits to those provided by the n–3 fatty acids alone. In isolated neonatal rat cardiomyocytes, addition of AA in the free fatty acid form can be both pro- and anti-arrhythmic. The pro-arrhythmic effect is attributable to oxygenated metabolites of AA, because the addition of cyclooxygenase and lipoxygenase inhibitors ablates this effect, while leaving the anti-arrhythmic effect of free AA intact (30). In an early study reporting the fatty acid profiles of human myocardium obtained from autopsy, it was observed that the AA-to-DHA ratio in cases of sudden cardiac death was substantially higher than in cases of accidental death who had no evidence of coronary artery disease (31).

Dietary flaxseed oil supplementation resulted in atrial EPA being 50% higher than in controls, although this was a nonsignificant difference, whereas there was no effect on atrial DHA. This failure of dietary ALA to influence plasma and tissue DHA, while increasing tissue ALA and EPA, has been shown previously (32, 33). It was suggested that the specificity of these effects may be explained through competitive inhibition by ALA of ⁶ desaturase metabolism of 24:5n–3 to 24:6n–3, which is putatively involved in the multistep conversion of EPA to DHA (34, 35). Although the daily intake of EPA+DHA with fish oil (6.3 g) was quantitatively similar to that of ALA with flaxseed oil (5.8 g), flaxseed oil was 10% as effective as fish oil in elevating atrial EPA and atrial EPA+DHA. The mean increments in atrial EPA and EPA+DHA with flaxseed oil treatment were 0.26% and 0.6%, respectively, of total atrial phospholipid fatty acids, whereas these values were 2.5% and 6.2%, respectively, with fish oil.

The olive oil–supplemented group was included to determine the suitability of use of olive oil as a placebo oil in future studies into the anti-arrhythmic effects of n–3 fatty acids. It was previously reported that oleic acid has no anti-arrhythmic properties (36, 37), and the results of the present study show that olive oil treatment in a dose of 10 mL/d does not affect n–3 fatty acids in atrial tissue. By comparison, healthy volunteers given 7 g corn oil/d (which delivers 3.5 g LA/d) for 20 wk reduced mean erythrocyte content of EPA+DHA from 5.5% to 4.5% of total phospholipid fatty acids (11). Thus, olive oil appears to be a more suitable comparator oil for studies into the effects of dietary n–3 PUFAs on tissue long-chain n–3 PUFAs.

In conclusion, we showed that EPA and DHA in cardiac phospholipids can be increased substantially within 1 wk through daily consumption of fish oil providing 6 g EPA+DHA/d. The kinetics of incorporation of EPA and DHA into human myocardium observed in this study provides an indication of practically achievable, optimal rates of EPA and DHA incorporation that are not likely to be matched by lower doses of fish oil. Our findings provide a foundation for further studies into the optimal use of fish oil as a preventive against life-threatening arrhythmias that are most prone to occur early after myocardial infarction.

	ACKNOWLEDGMENTS

 
We thank all of the administrative, theater, and ward staff of the Cardiothoracic Surgical Unit of the Royal Adelaide Hospital for their invaluable assistance in conducting this trial and the staff of the Child Nutrition Research Unit, Flinders Medical Centre, Adelaide, for fatty acid analyses.

The authors’ responsibilities were as follows—RGM, MJJ, LGC, and GDY: designed the study and obtained funding; RGM and KR-T: conducted the study; RAG: responsible for the analyses of fatty acids; RGM: analyzed the data and wrote the first draft of the manuscript; JRME, JS, and RS: provided significant advice and consultation. All authors contributed to the final draft of the manuscript. None of the authors had any conflicts of interest.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312:1205–9.[Abstract]
2. Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med 1997;336:1046–53.[Abstract/Free Full Text]
3. Albert CM, Hennekens CH, O'Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA 1998;279:23–8.[Abstract/Free Full Text]
4. Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287:1815–21.[Abstract/Free Full Text]
5. Dolecek TA, Grandits G. Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial (MRFIT). World Rev Nutr Diet 1991;66:205–16.[Medline]
6. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 1989;334:757–61.
7. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343:1454–9.[Medline]
8. GISSI Investigators. Dietary supplementation with n–3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447–55.[Medline]
9. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n–3 fatty acids and the risk of sudden death. N Engl J Med 2002;346:1113–8.[Abstract/Free Full Text]
10. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n–3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995;274:1363–7.[Abstract/Free Full Text]
11. Harris WS, von Schacky C. The omega-3 index: a new risk factor for death from coronary heart disease? Prev Med 2004;39:212–20.[Medline]
12. Harris WS, Sands SA, Windsor SL, et al. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation 2004;110:1645–9.[Abstract/Free Full Text]
13. Cleland LG, Proudman SM, Hall C, et al. A biomarker of n–3 compliance in patients taking fish oil for rheumatoid arthritis. Lipids 2003;38:419–24.[Medline]
14. James MJ, Ursin VM, Cleland LG. Metabolism of stearidonic acid in human subjects: comparison with the metabolism of other n–3 fatty acids. Am J Clin Nutr 2003;77:1140–5.[Abstract/Free Full Text]
15. Metcalf RG, Mantzioris E, Cleland LG, James MJ. A practical approach to increasing intake of n–3 fats: use of novel foods enriched with n–3 fats. Eur J Clin Nutr 2003;57:1605–12.[Medline]
16. Fletcher RF. Lipids of human myocardium. Lipids 1972;7:728–32.[Medline]
17. Gudbjarnason S, Oskarsdottir G, Doell B, Hallgrimsson J. Myocardial membrane lipids in relation to cardiovascular disease. Adv Cardiol 1978;25:130–44.[Medline]
18. Shenolikar I. Fatty acid profile of myocardial lipid in populations consuming different dietary fats. Lipids 1980;15:980–2.
19. Rocquelin G, Guenot L, Justrabo E, Grynberg A, David M. Fatty acid composition of human heart phospholipids: data from 53 biopsy specimens. J Mol Cell Cardiol 1985;17:769–73.[Medline]
20. Rocquelin G, Guenot L, Astorg PO, David M. Phospholipid content and fatty acid composition of human heart. Lipids 1989;24:775–80.[Medline]
21. Sexton PT, Sinclair AJ, O'Dea K, Sanigorski AJ, Walsh J. The relationship between linoleic acid level in serum, adipose tissue and myocardium in humans. Asia Pac J Clin Nutr 1995;4:314–8.
22. Drake-Holland AJ, Van der Vusse GJ, Roemen TH, et al. Chronic catecholamine depletion switches myocardium from carbohydrate to lipid utilisation. Cardiovasc Drugs Ther 2001;15:111–7.[Medline]
23. Sigalet DL, Kneteman NM, Thomson AB. Reduction of nutrient absorption in normal rats by cyclosporine. Transplantation 1992;53:1103–7.[Medline]
24. Leaf A, Kang JX, Xiao Y-F, Billman GE. Clinical prevention of sudden cardiac death by n–3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n–3 fish oils. Circulation 2003;107:2646–52.[Free Full Text]
25. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n–3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105:1897–903.[Abstract/Free Full Text]
26. Marangoni F, Angeli MT, Colli S, et al. Changes of n–3 and n–6 fatty acids in plasma and circulating cells of normal subjects, after prolonged administration of 20:5 (EPA) and 22:6 (DHA) ethyl esters and prolonged washout. Biochim Biophys Acta 1993;1210:55–62.[Medline]
27. Sands SA, Reid KJ, Windsor SL, Harris WS. The impact of age, body mass index, and fish intake on the EPA and DHA content of human erythrocytes. Lipids 2005;40:343–7.[Medline]
28. Cleland LG, James MJ, Neumann MA, D'Angelo M, Gibson RA. Linoleate inhibits EPA incorporation from dietary fish-oil supplements in human subjects. Am J Clin Nutr 1992;55:395–9.[Abstract/Free Full Text]
29. Solomon SD, Zelenkofske S, McMurray JJ, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med 2005;352:2581–8.[Abstract/Free Full Text]
30. Kang JX, Leaf A. Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A 1994;91:9886–90.[Abstract/Free Full Text]
31. Gudbjarnason S, Hallgrimsson J. Prostaglandins and polyunsaturated fatty acids in heart muscle. Acta Biol Med Germ 1976;35:1069–80.[Medline]
32. Mantzioris E, James MJ, Gibson RA, Cleland LG. Dietary substitution with an alpha-linolenic acid-rich vegetable oil increases eicosapentaenoic acid concentrations in tissues. Am J Clin Nutr 1994;59:1304–9.[Abstract/Free Full Text]
33. Mantzioris E, James MJ, Gibson RA, Cleland LG. Differences exist in the relationships between dietary linoleic and alpha-linolenic acids and their respective long-chain metabolites. Am J Clin Nutr 1995;61:320–4.[Abstract/Free Full Text]
34. Blank C, Neumann MA, Makrides M, Gibson RA. Optimizing DHA levels in piglets by lowering the linoleic acid to -linolenic acid ratio. J Lipid Res 2002;43:1537–43.[Abstract/Free Full Text]
35. Cleland LG, Gibson RA, Pedler J, James MJ. Paradoxical effect of n–3–containing vegetable oils on long-chain n–3 fatty acids in rat heart. Lipids 2005;40:995–8.[Medline]
36. Kang JX, Leaf A. Protective effects of free polyunsaturated fatty acids on arrhythmias induced by lysophosphatidylcholine or palmitoylcarnitine in neonatal rat cardiac myocytes. Eur J Pharmacol 1996;297:97–106.[Medline]
37. Kang JX, Xiao YF, Leaf A. Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A 1995;92:3997–4001.[Abstract/Free Full Text]

This article has been cited by other articles:

				F. Gao, D. Kiesewetter, L. Chang, K. Ma, S. I. Rapoport, and M. Igarashi Whole-body synthesis secretion of docosahexaenoic acid from circulating eicosapentaenoic acid in unanesthetized rats J. Lipid Res., December 1, 2009; 50(12): 2463 - 2470. [Abstract] [Full Text] [PDF]

				K. B. Shah, M. K. Duda, K. M. O'Shea, G. C. Sparagna, D. J. Chess, R. J. Khairallah, I. Robillard-Frayne, W. Xu, R. C. Murphy, C. Des Rosiers, et al. The Cardioprotective Effects of Fish Oil During Pressure Overload Are Blocked by High Fat Intake: Role Of Cardiac Phospholipid Remodeling Hypertension, September 1, 2009; 54(3): 605 - 611. [Abstract] [Full Text] [PDF]

				J. H. Rennison and D. R. Van Wagoner Impact of Dietary Fatty Acids on Cardiac Arrhythmogenesis Circ Arrhythm Electrophysiol, August 1, 2009; 2(4): 460 - 469. [Full Text] [PDF]

				J. W. Fetterman Jr. and M. M. Zdanowicz Therapeutic potential of n-3 polyunsaturated fatty acids in disease Am. J. Health Syst. Pharm., July 1, 2009; 66(13): 1169 - 1179. [Abstract] [Full Text] [PDF]

				H. Aarsetoey, V. Ponitz, H. Grundt, H. Staines, W. S. Harris, and D. W. T. Nilsen (n-3) Fatty Acid Content of Red Blood Cells Does Not Predict Risk of Future Cardiovascular Events following an Acute Coronary Syndrome J. Nutr., March 1, 2009; 139(3): 507 - 513. [Abstract] [Full Text] [PDF]

				M. K. Duda, K. M. O'Shea, A. Tintinu, W. Xu, R. J. Khairallah, B. R. Barrows, D. J. Chess, A. M. Azimzadeh, W. S. Harris, V. G. Sharov, et al. Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction Cardiovasc Res, February 1, 2009; 81(2): 319 - 327. [Abstract] [Full Text] [PDF]

				J. H. Lee, J. H. O'Keefe, C. J. Lavie, R. Marchioli, and W. S. Harris Omega-3 Fatty Acids for Cardioprotection Mayo Clin. Proc., March 1, 2008; 83(3): 324 - 332. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Supplemental Data Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Metcalf, R. G Articles by Cleland, L. G Search for Related Content PubMed PubMed Citation Articles by Metcalf, R. G Articles by Cleland, L. G Agricola Articles by Metcalf, R. G Articles by Cleland, L. G