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Welcome to the Omega-3-Forum

Evidence-based medicine applied:
Fish oil (triglycerides) should not be substituted for Omacor (EPA+DHA ethyl esters).
Any brand of ethyl esters should not be substituted for Omacor.

Webcast: Highly purified omega-3 fatty acid ethyl esters: what do the data tell us?
European Society of Cardiology (ESC) Congress; August 30, 2011; Paris
Webcast: What makes highly purified omega-3 fatty acid ethyl esters unique?
European Society of Cardiology (ESC) Congress; August 29, 2010; Stockholm
Webcast: Mechanisms of acion of omega-3 fatty acid ethyl esters in congestive heart failure
European Society of Cardiology (ESC) Congress; September 2, 2008; Munich

Deficiency of EPA and DHA in heart failure - a rational teatment target:
Rupp H, Rupp TP, Alter P, Maisch B.
Can J Physiol Pharmacol. 2012;90:55-73 Open Access
Mechanisms involved in the differential reduction of omega-3 and omega-6 highly unsaturated fatty acids by structural heart disease resulting in "HUFA deficiency".

Identification of risks associated with arrhythmic death remains a great challenge.
Although great progress has been made in the prevention of cardiovascular diseases, the mortality remains high for patients after myocardial infarction or heart failure who often die without previous symptoms. Almost half of all cardiovascular deaths can be attributed to this unexpected and not yet predictable cause. Sudden cardiac death (SCD) as a consequence of coronary heart disease has been rated the most important cause of death in the adult population in industrialized societies.

Mechanisms of action of omega-3 fatty acid ethyl esters in heart dysfunction.
Myocardial infarction and severity of coronary artery disease are associated with a higher risk of SCD. In fact, coronary artery disease is known to be present in about 80% of patients who suffer from SCD, whereby the proportion of deaths that are sudden is higher in mild to moderate heart failure (HF). Like in the MERIT-HF study, the incidence of SCD was 64% in New York Heart Association (NYHA) functional class II, 59% in class III and was reduced to 33% in class IV. Preventing SCD is thus particularly important for patients during early progression of heart failure when their pump function is still associated with good quality of life.

Irrespective of the underlying pathophysiology (ischemic or non-ischemic heart failure), SCD is very often caused by ventricular tachycardia that degenerates to ventricular fibrillation. However, the majority of patients who die suddenly during progression of heart failure cannot be identified by current risk stratification. Since the protective action of implantable cardioverter-defibrillators (ICDs) and highly purified EPA+DHA ethyl esters (Omacor) depends on the risk of SCD in a given patient population, efforts should be made to better understand the pathophysiology of HF. Particularly, mechanisms inferred from depressed pump function often monitored by reduced ejection fraction (EF) remain unresolved. EF is a composite of various physiological factors with major contributions from:

i. Remodeling of the hypertrophied cardiocyte and the extracellular matrix leading to depressed "contractility". While fibrosis has long been alleged as contributing factor to malignant arrhythmias, the dysregulated gene expression of hypertrophied cardiocytes (e.g. lack in upregulation of the sarcoplasmic reticulum Ca2+ pump gene, SERCA2, partially corrected by the FOXIB/PPARalpha etomoxir (1,2)) leading to diastolic Ca2+ overload and electric instability has only recently been explored and is not targeted by current therapy. Thus, SCD not only occurs in patients with systolic heart failure but is also not uncommon in patients with diastolic heart failure. Based on the many defects in cardiocyte gene expression and extracellular matrix remodeling, left ventricular hypertrophy (LVH) emerged as a major risk for SCD. LVH occurs as a result of a hemodynamic overload (e.g. surviving myocardium after MI or hypertension). Thus, the anti-arrhythmogenic intervention with Omacor is expected to have a protective action not only in post-MI but also during progression of HF associated with LVH irrespective of its etiology.

ii. The “compensated” stage of concentric hypertrophy can often not be maintained and enlargement of the LV occurs, i.e. dilatation. A deleterious consequence is the rise in wall stress (according to LaPlace, wall stress is increased by an increase in intraventricular pressure and radius and decreased when wall thickness is increased, i.e. as in LVH). Wall stress reflects the tension a cardiocyte has to develop during systole. Since the LVH response is limited e.g. by coronary blood and energy supply, LV dilatation is often not adequately compensated by LVH and a rise in wall stress ensues. A high wall stress has various adverse effects including an increased opening probability of stretch-activated cation channels which raises the risk of ectopic activity. A reduction of diastolic Ca2+ through partial inhibition of the late and fast Na+ current and the L-type Ca2+ current by EPA+DHA would, therefore, be useful. Wall stress is also the major determinant of oxygen consumption of the heart and, thereby, can aggravate latent ischemia. Myocardial stretch can also trigger afterdepolarisations and extrasystoles. Furthermore, the conduction system is often impaired by mechanical stretch resulting in ventricular dysynchrony (a target for resynchronization therapy). While wall stress has been calculated in the past from echocardiography data, it was only recently shown by Alter et al. that the actual wall stress is underestimated and that only volumetric data derived from cardiac magnetic resonance imaging (MRI) permit accurate wall stress assessment (3). The MRI-based wall stress was correlated with raised serum brain natriuretic peptide (BNP), a marker of cardiocyte stretch (4).  MRI-based wall stress is expected to have a greater specificity compared with BNP which nonetheless has a positive predictive value for SCD. The MRI-based wall stress calculation provides the long-sought tool for monitoring progression of heart failure in terms of LV dilatation and LVH (5). It became also possible to predict the LV afterload reduction required for returning wall stress into the normal range. Using “isostress” curves, the systolic pressure had, however, to be reduced in some patients to a level which is too low for maintaining adequate organ perfusion (3).

iii. a reduced endogenous production of long-chain desaturated fatty acids by an altered activity of delta-6 and delta-5 desaturase. By this mechanism, EPA+DHA is expected to be reduced which can be viewed as “lipid remodelling”. Particularly crucial is in this respect marked cardiac dilatation. (Rupp et al. unpublished). Any protective action of Omacor or also ICDs will depend on the impact of these factors, whereby an increased wall stress appears to be the most crucial one. Thus, after myocardial infarction, LV dilatation occurs in about 20-30% of patients which appears not to be adequately compensated by LVH resulting most probably in a markedly raised wall stress and thus high risk of SCD. It would thus also be of great interest to examine whether in HF patients with high wall stress the benefit of ICDs is greater and whether a high wall stress can account for the greater benefit of ICDs in ischemic versus non-ischemic HF. It is thus proposed to assess anti-arrhythmogenic effects of EPA+DHA ethyl esters in patients in terms of MRI-based wall stress and the “EPA+DHA level” (6).

SCD and heart failure (Rupp copyright)

Schematic presentation of pathophysiological events raising the risk of SCD. Various vicious cycles raise the risk of SCD and HF. The risk of SCD can be reduced by prophylactic ICD implantation or by prescription omega-3 fatty acids (based on GISSI-P, Omacor) where a low peroxide and p-anisidine value (marker of adverse oxidation of EPA and DHA) is certified which can be monitored also by SPME-GC/ion trap MS in terms of volatile aldehydes/ketones (pungent “fishy” odour; Rupp, unpublished). The ICD indication is given here for the dilated heart of high wall stress where EF is expected to be <35%. However, SCD risk is also high in patients with EF in between 35% and 50% (mild to moderate heart failure) which is considered an important therapeutic target for Omacor.

EPA+DHA ethyl esters (Omacor) in heart failure
The value of adding 1g/day EPA-DHA ethyl esters (Omacor) to standard therapy for heart failure has been established by the results of the recent GISSI-HF trial (7). This randomized, double-blind, placebo-controlled trial, conducted at 357 cardiology or internal medicine centres in Italy under the direction of the GISSI group recruited 7046 patients with heart failure. Omacor therapy was associated with statistically significant benefits on both the co-primary endpoints: time to death from any cause – the adjusted hazard ratio was 0.91 (95.5% CI 0.833–0.998; P = 0.041). For time to all-cause mortality or admission to hospital for any cardiovascular reason the adjusted hazard ratio was 0.92 (99% CI 0.849–0.999; P = 0.009). The effects were consistent across a wide range of prespecified subgroups, including EF > or <40%, aetiology of heart failure (ischemic vs non-ischemic), baseline NYHA grade, diabetes at baseline or age.

The effects of Omacor on the GISSI-HF primary endpoints can also be expressed as
the number of patients that have to be treated for the time of the follow-up to prevent one endpoint event, i.e. number-needed-to-treat (NNT). For all-cause mortality, NNT for Omacor was 56; for all-cause mortality or hospitalization for a cardiovascular cause, the NNT was 44. Said in other words, when 1000 patients are treated with Omacor for ~4 years, 18 lives were saved and 17 cardiovascular hospitalizations were prevented.

It has been pointed out by  Gregg C. Fonarow
(Ahmanson-UCLA Cardiomyopathy Center, Los Angeles) in the Comment "Statins and n-3 fatty acid supplementation in heart failure" to the GISSI-HF study: "...Whilst questions remain about mechanisms of action, optimum dosing, and formulation, supplementation with n-3 polyunsaturated fatty acids should join the short list of evidence-based life-prolonging therapies for heart failure." (Lancet. Online 2008 Aug 29)

Evidence-based therapies for systolic heart failure (from G C Fonarow, Lancet. Online 2008 Aug 29)
Relative-risk reduction in all-cause mortality
Angiotensin-converting-enzyme inhibitors or angiotensin-receptor antagonists
β blockers
Aldosterone antagonists*
Hydralazine-isosorbide dinitrate*
Implantable cardioverter defibrillator*
Cardiac resynchronisation therapy*
n-3 polyunsaturated fatty acid supplementation
*For patients with specific indications.

The results of GISSI-HF mandate, therefore, in our opinion the use of Omacor 1 g/day in heart failure patients. Heart failure guidelines should be amended to reflect this fact.

It shoud be pointed out that a specific medication was used in the GISSI trials, i.e. Omacor and it is unscientific to infer that regular fish oil capsules could be a substitute. It is also not justified to simplify this medication by referring to it as "
n-3 polyunsaturated fatty acid supplementation". It is hoped that this aspect will be corrected in the guidelines. On the other hand, manufacturers of fish oils are encouraged to initiate trials and to assess efficacy or lack of efficacy of their preparations.

1. Turcani M, Rupp H. Etomoxir improves left ventricular performance of pressure-overloaded rat heart. Circulation. 1997;96:3681-3686.
2. Rupp H, Rupp TP, Maisch B. Fatty acid oxidation inhibition with PPARalpha activation (FOXIB/PPARalpha) for normalizing gene expression in heart failure? Cardiovasc Res. 2005;66:423-426.
3. Alter P, Rupp H, Rominger MB, Vollrath A, Czerny F, Figiel JH, Adams P, Stoll F, Klose KJ, Maisch B. B-type natriuretic peptide and wall stress in dilated human heart. Mol Cell Biochem. 2008;314:179-191.
4. Alter P, Rupp H, Rominger MB, Vollrath A, Czerny F, Klose KJ, Maisch B. Relation of B-type natriuretic peptide to left ventricular wall stress as assessed by cardiac magnetic resonance imaging in patients with dilated cardiomyopathy. Can J Physiol Pharmacol. 2007;85:790-9.
5. Alter P, Rupp H, Rominger MB, Klose KJ, Maisch B. A new methodological approach to assess cardiac work by pressure-volume and stress-length relations in patients with aortic valve stenosis and dilated cardiomyopathy. Pflugers Arch. 2008;455:627-36.
6. Rupp H, Wagner D, Rupp T, Schulte LM, Maisch B. Risk stratification by the "EPA+DHA level" and the "EPA/AA ratio" focus on anti-inflammatory and antiarrhythmogenic effects of long-chain omega-3 fatty acids. Herz. 2004;29:673-85.

7.GISSI-HF Investigators.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1223-1230.

Webcast: New perspectives for an evidence-based therapy with omega-3 fatty acid ethyl esters
Congress of the European Society of Cardiology, Munich, Germany, 02-Sep-08

McMurray, Prof. J. J. V., University of Glasgow, Glasgow, United Kingdom
Successes and failures in congestive heart failure therapy
Marchioli, Prof. R., Laboratory of Clinical Epidemiology, Santa Maria Imbaro, Italy
The GISSI - Heart failure trial
von Schacky, Prof. C., Universität München, Munich, Germany
The role of omega-3 fatty acid ethyl esters in the cardiologist´s treatment armamentarium

Malignant arrhythmias and sudden cardiac death in myocardial infarction.
The major pathophysiological cause of SCD is seen in the electrical instability of the infarct zone and the non infarcted muscle. Because of the loss of contractile tissue, the surviving hypertrophied myocardium is subjected to various adverse neuroendocrine influences. A consequence is an unfavorable cellular and molecular restructuring of the extracellular matrix and the cardiomyocyte. The fibrosis also worsens coronary blood supply and thus amplifies the risk of reinfarction. In approximately one third of post-MI patients, dilatation of the left ventricle occurs. Since dilated hearts exhibit an increased wall stress favouring also the opening of stretch-activated ion channels (1), the resulting electrical instability contributes to the increased risk of ventricular tachyarrhythmias. All these adverse processes contribute to worsening of pump function which is reflected in a reduced EF which is the most often used predictor of malignant arrhythmias. Conventional therapy is, however, only partially directed against mechanisms which promote electrical instability. The remaining electrical instability after MI can be counteracted by modulating the activity of membrane ion channels through incorporation of long-chain omega-3 fatty acids, particularly DHA, in their microenvironment. The administration of Omacor should, therefore, also be seen in the context of the implantable cardioverter defibrillator (ICD) therapy

                              cardiac death pathophysiology (Rupp

SCD prevention by ICDs and Omacor
ICDs are implanted in patients with EF <35-40, whereby the number of patients needed to treat (NNT) to prevent a sudden death was 11 in MADIT-II and 14 in SCD-HeFT. Only in MADIT-I, the NNT was 4 when EF<35% was combined with the presence of non-sustained ventricular tachycardia. Nonetheless, a substantial proportion of patients will die suddenly despite ICD implantation (2). ICD therapy is associated with a relative risk reduction of SCD of approximately 60%, far less than the greater than 90% efficacy that many expect (2). Reducing the incidence of ICD-unresponsive SCD would substantially improve survival and cost-effectiveness related to ICD therapy. Alternatives for reducing SCD risk are thus required. Pharmacological interventions proved not to be successful. Proarrhythmic and negative inotropic effects of class Ia and Ic antiarrhythmics are more pronounced during progression of heart failure. The class III antiarrhythmic D-sotalol which lacks beta-blocking action even increased mortality in post-MI patients with reduced pump function (3). For amiodarone, no significant mortality reduction was observed in chronic HF or after MI and on prognostic terms represents, therefore, no alternative for an ICD. The need of alternatives for SCD prevention is demonstrated also by the fact that in post-MI patients the risk of SCD is increased already at EF<50%. In the GISSI-Prevenzione study, 86% of patients had EF>40% and only 2.5% EF<30%. In the light of ICD guidelines, one would therefore expect only a very limited effect for interventions targeting SCD. This was, however, not the case as seen in the comparison of trials with ICD therapy (2) and the GISSI-Prevenzione study (4-6) with Omacor administration.

                      ICD and Omacor (Rupp copyright)

Anti-arrhythmogenic effects of DHA+EPA ethyl esters
In the studies of the GISSI group, 1g omega-3 fatty acids was administered, whereby the relevance of the particular formulation has been underrated particularly in guidelines

i. Ethyl esters but not triglycerides commonly present in fish oils were used. Ethyl esters result in a retarded and sustained uptake of DHA and EPA. After intestinal absorption, long-chain fatty acids reach the coronaries via the thoracic duct and bypass the liver (contrary to amino acids and sugars). It appears that ethyl esters have the advantage of providing a sustained increase in lymphe DHA and EPA levels (7) which are expected to contribute to the critical rise in DHA and EPA required for the antiarrhythmogenic action.

ii. Omacor used in the GISSI trials contains min 84% of the long-chain omega-3 fatty acids DHA and EPA, whereby the ratio of DHA:EPA was 38:46%. An exchange of DHA for EPA or short-chain fatty acids (alpha-linolenic acid) is expected to reduce the antiarrhythmogenic action. In rats with low dose intake of omega-3 fatty acids, DHA but not EPA inhibited ischemia-induced cardiac arrhythmias (8). In the Japan EPA lipid intervention study (JELIS), hypercholesterolaemic patients were treated with daily 1.8g EPA (9). While a 19% relative reduction in major coronary events occurred, the (low) risk of SCD was not reduced further. One should, therefore, not refer in guidelines to 1g omega-3 fatty acids in general when referring to the GISSI trials but to specify the DHA:EPA ratio and to point out that ethyl esters were used. To demonstrate that Omacor differs markedly from regular fish oil preparations, representative gas chromatograms of the constituent fatty acids are given. The high concentration of EPA and DHA and the virtual absence of saturated and omega-6 fatty acids can be achieved only by transesterification of fish oils with ethanol resulting in ethyl esters with subsequent purification of the respective DHA and EPA ethyl esters.

Omacor versus fishoil: gas chromatogram (Rupp

iii. During preparation of ethyl esters more purification steps are involved than in the extraction of triglycerides present in fish oils which is expected to reduce the contamination particularly with methyl mercury which has been associated with an increased risk of MI (10). Body mercury was correlated with omega-3 fatty acids, indicating that omega-3 fatty acids were derived from fish or fish oils contaminated with mercury. It appears, therefore, mandatory to use in post-MI patients DHA+EPA preparations with a minimum of methyl mercury and other environmental pollutants such as PCBs and dioxins. Work is ongoing to determine such pollutants in various DHA+EPA preparations and to assess whether they influence the incidence of dilative cardiomyopathy.

iv. In post-MI patients on standard care (anti-platelet drug, beta-blocker, ACE-inhibitor, statin) a preparation with 1g DHA+EPA in 1 capsule (Omacor) is required. In a number of non positive, i.e. "neutral" studies on patients with ICD (sometimes mislabeled as “negative studies”), the number of capsules was higher than in the GISSI trials which was associated with poor patient compliance. In the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) by Brouwer et al. (7), ICD patients were enrolled for assessing the effect of 2 g of "purified fish oil" (4 capsules/day) vs. placebo (olive oil) on life-threatening arrhythmias. Judged by capsule count, 76% of patients took more than 80% of the fish oil capsules. The primary endpoint (appropriate ICD intervention for ventricular tachycardia or fibrillation or all-cause death) occurred in 30% of patients taking fish oil vs. 33% patients taking placebo (not significant difference). In the study by Leaf et al. (11), ICD patients were randomized to 2.6g EPA and DHA ethyl ester (daily four 1g capsules) or olive oil as placebo for 12 months. Why in this study capsules with only 65% DHA+EPA instead of 84% as in the case of Omacor and the trials of the GISSI group were used, remains intriguing. Compliance with the double-blind treatment was similar in the two groups; however, the noncompliance rate was high (35% of all enrollees). The primary end point, time to first ICD event for ventricular tachycardia or fibrillation confirmed by stored ECG or death from any cause was borderline significant (risk reduction of 28%; P=0.057). For those who stayed on protocol for at least 11 months, the antiarrhythmic benefit of DHA+EPA ethyl esters was improved for those with confirmed events (risk reduction of 38%; P=0.034). This study also argues against the use of capsules with a lower DHA and EPA content, e.g. the approximately 30% DHA+EPA of regular fish oil. The known low compliance with multiple capsule intake (e.g. 32% permanent noncompliance for beta-blocker use in COMET (12)) was also one of the reasons for the production of ethyl esters using transesterification of fish oil triglycerides resulting in the highly concentrated preparation of Omacor. The critical impact of noncompliance can be derived also from the observation that already 2 days after Omacor intake, the serum DHA+EPA level has reached again baseline (Rupp, unpublished). Thus, DHA+EPA has to be released from membranes during an ischemic event which would obviously be more pronounced in MI than in HF or even an ICD event.

In sum, although great progress has been made in elucidating the antiarrhythmogenic action of DHA+EPA and the trials of the GISSI group have provided clear evidence on the clinical effectiveness in arrhythmic event prevention also when compared with ICD therapy, one should be very careful when referring to the active ingredients of Omacor which are ethyl esters and not triglycerides as in fish oils. It is not justified to extrapolate to omega-3 fatty acids in general implicating the use of short-chain omega-3 fatty acids such as alpha-linolenic acid. Also substitution of EPA for DHA is expected to result in a different therapeutic profile. To avoid further confusion, it is suggested to clearly specify the actual ingredients particularly in guidelines and to adhere to the accepted chemical nomenclature.

(1) Franz MR, Cima R, Wang D, Profitt D, Kurz R. Electrophysiological effects of myocardial stretch and mechanical determinants of stretch-activated arrhythmias. Circulation 1992; 86:968-978.
(2) Anderson KP. Sudden cardiac death unresponsive to implantable defibrillator therapy: an urgent target for clinicians, industry and government. J Interv Card Electrophysiol 2005; 14:71-78.
(3) Doggrell SA, Brown L. D-Sotalol: death by the SWORD or deserving of further consideration for clinical use? Expert Opin Investig Drugs 2000; 9:1625-1634.
(4) GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI- Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999; 354:447-55.
(5) Marchioli R, Avanzini F, Barzi F, Chieffo C, Di Castelnuovo A, Franzosi MG, Geraci E, Maggioni AP, Marfisi RM, Mininni N, Nicolosi GL, Santini M, Schweiger C, Tavazzi L, Tognoni G, Valagussa F. Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations: GISSI- Prevenzione mortality risk chart. Eur Heart J 2001; 22:2085-103.
(6) Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marfisi RM, Mastrogiuseppe G, Mininni N, Nicolosi GL, Santini M, Schweiger C, Tavazzi L, Tognoni G, Tucci C, Valagussa F. 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; 105:1897-1903.
(7) Rupp H, Rupp TP, Wagner D, Alter P, Maisch B. Microdetermination of fatty acids by gas chromatography and cardiovascular risk stratification by the "EPA+DHA level". Herz 2006; 31 (suppl 3):30-49.
(8) McLennan P, Howe P, Abeywardena M, Muggli R, Raederstorff D, Mano M, Rayner T, Head R. The cardiovascular protective role of docosahexaenoic acid. Eur J Pharmacol 1996; 300:83-89.
(9) Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007; 369:1090-1098.
(10) Guallar E, Sanz-Gallardo MI, van't Veer P, Bode P, Aro A, Gomez-Aracena J, Kark JD, Riemersma RA, Martin-Moreno JM, Kok FJ. Mercury, fish oils, and the risk of myocardial infarction. N Engl J Med 2002; 347:1747-1754.
(11) Leaf A, Albert CM, Josephson M, Steinhaus D, Kluger J, Kang JX, Cox B, Zhang H, Schoenfeld D. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation 2005; 112:2762-2768.
(12) Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003; 362:7-13.

How does EPA and DHA work?
Recent emphasis has been placed on malignant arrhythmia risks associated with a low abundance of EPA and DHA in the body. Since free acids of EPA and DHA are required for most of their biological effects including their antiarrhythmogenic action, it appears essential not only to build up stores in the body for their release, but also to provide a sustained uptake of EPA and DHA in the form of ethyl esters
rather than dietary triglycerides which are present in fish or fish oils.

Triacylglycerol from fish Ethyl ester of EPA

The triglyceride on the left contains 2 saturated fatty acids (C16:0, palmitic acid) and a long-chain polyunsaturated omega-3 fatty acid (C20:5, EPA, eicosapentaenoic acid, at the bottom) which have a different chemical structure. On average, triglycerides ("triacylglycerols" in biochemistry textbooks) from fish contain 1 EPA or DHA and 2 other fatty acids. The EPA+DHA concentration of simple extracts of fish, i.e. fish oils, does, therefore, not exceed one third on average. A high concentration can be achieved by breaking up the triglyceride structure via transesterification with ethanol leading to ethyl esters. On a small scale, the transesterification is used for preparing fatty acid methyl esters for gas chromatography
. On the right: the ethyl ester of EPA which is a major (48%) component of Omacor

Ethyl esters provide a retarded and sustained uptake of EPA and DHA in the duodenum
Whether the free EPA and DHA level is raised sufficiently for antiarrhythmic action, depends not only on the fatty acid release from membrane phospholipids involving particularly phospholipase A2 but also on the absorption of orally administered EPA and DHA. In fish, EPA and DHA occur as triglycerides. Regular fish oils contain up to 30% EPA+DHA triglycerides. If a once daily administration of one capsule is required for achieving an intake of 1g EPA+DHA, Omacor has to be used. Triglycerides are transesterified with ethanol resulting in a mixture of saturated and unsaturated ethyl esters. After purification, nearly homogeneous EPA and DHA ethyl esters can be prepared (Omacor / Lovaza). The corresponding ethyl esters should not be referred to as fish oils simply because they contain EPA and DHA.
They are also not 'refined' or 'concentrated' fish oils. It is thus unscientific to refer to the omega-3 preparation used in the trials of the GISSI group as "cheap and simple fish oil". There is also no evidence available that Omacor can be substituted with fish oils. This point should be made clear in guidelines. Fish oil is also not a "generic" of Omacor.

The type of ester bond has important consequences for the absorption kinetics of EPA and DHA. Duodenal uptake rates differ between triglycerides and ethyl esters. Triglycerides are rapidly degraded by pancreatic lipase and, in the case of polyunsaturated fatty acids, by carboxylester hydrolase. Compared with triglycerides, the ethyl esters of EPA and DHA are absorbed more slowly.
This has been shown in rats when EPA and DHA were administered by gavage either as triglycerides or ethyl esters (2). Within 3 h after administration, the recovery in the lymph of the respective fatty acids was greater in the case of triglycerides (2). After 15 h, the recovery from ethyl esters was approximately doubled compared with triglycerides. One of the consequences is that the lymph EPA and DHA level is maintained at a higher level in the second half of a 24-h period which could be of importance, since malignant ventricular arrhythmias are more abundant in the early morning hours (3). Lymph EPA and DHA levels arising from fish consumption during the preceding day would thus be expected to be lower than in the case of an ethyl ester administration. The different absorption kinetics seen in the rat appear to hold also for humans. Thus, the recovery of EPA in the blood was lower within an 8-h period when compared with triglycerides (4), while there was no difference in the long-term incorporation of EPA and DHA involving time periods up to 28 days (5). Although the absorption of ethyl esters is increased by co-ingestion with a high-fat meal, the absorption of EPA ethyl ester was still lower (6).

Triacylglycerol uptake  

Ethyl esters are taken up more slowly than triglycerides but nonetheless are absorbed within 24-h to the same extent as triglycerides.

Ethyl ester uptake  

The slowed uptake of ethyl esters results in a "dual mechanism of action" of EPA and DHA:

1. Sustained uptake
A sustained uptake of EPA+DHA into blood which is expected to be beneficial in ischemic events before EPA+DHA can be released. This could be crucial, since in the case of severe arrhythmias there is little time left for the release of fatty acids from tissue stores. EPA+DHA should already be in the blood.
In contrast to EPA and DHA ethyl esters,  EPA and DHA triglycerides present in fish are more rapidly absorbed and are expected to provide less protection in the early morning hours when the risk of sudden death is high and the triglycerides were consumed the day before. The slowed recovery of ethyl esters in the lymph has been shown by Ikeda et al. (2)  in rats where fatty acids were either given as triglycerides or ethyl esters.

Rates of
                    fatty acid uptake

These data suggest, therefore, that the "retard" formulation of ethyl esters has the advantage of providing increased non-membrane bound EPA and DHA levels which are expected to contribute to the critical rise in EPA and DHA required for an antiarrhythmogenic action. In the case of EPA and DHA triglycerides, a greater amount had to be released from membranes by ischemic events.

These considerations are based on a once daily administration which is relevant in patients after MI being on standard therapy with beta-blocker, ACE inhibitor, anti-platelet drug and statin or patients with HF on beta-blocker, ACE inhibitor, diuretic and aldosterone antagonist.

2. Increased tissue stores
An increased EPA+DHA intake results in a higher EPA+DHA tissue store for release during ischemic events. The size of the tissue store is measured by the "EPA+DHA level". The released free fatty acids EPA and DHA are incorporated in the microenvironment of ion channels and modulate their activity. This is associated with an increased electrical stability as shown by a greater refractory period or hyperpolarisation in cardiomyocytes (10).

                    and DHA effects on ion channels

For the administration of 1 g/day highly purified EPA+DHA ethyl esters (Omacor / Lovaza) to healthy volunteers, it has been shown that whole blood EPA is increased from 0.6% to 1.4% within 10 days while DHA is increased from 2.9% to 4.3%. After withdrawal, EPA and DHA approach baseline values within 10 days (data from Rupp et al. (1)). A gas chromatographic procedure was established which requires only 10 µl of whole blood for the identification of more than 35 fatty acids. A gas chromatogram of Omacor demonstrating its high purity is given here.

A low “EPA+DHA level” represents a risk for sudden cardiac death

The important study by CM Albert et al (11) showed that low whole blood levels of the long-chain omega-3 fatty acids EPA (C20:5n-3) and DHA (C22:6n-3) but not of the long-chain docosapentaenoic acid (C22:5n-3) and not of the
short-chain alpha-linolenic acid (C18:3n-3) were associated with an increased risk of sudden death:

Fatty acid
EPA (eicosapentaenoic acid), long-chain n-3
DHA (docosahexaenoic acid), long-chain n-3
DPA (docosapentaenoic acid), long-chain n-3
alpha-Linolenic acid, short-chain n-3

Based on this study, we proposed the term “EPA+DHA level” for assessing the risk of sudden death (1).
In healthy volunteers, administration of 840 mg/day of EPA+DHA ethyl esters (Omacor / Lovaza) raised the “EPA+DHA level” in whole blood to approx. 6% (1). In the GISS-P trial, this dose of EPA and DHA ethyl esters was associated with a marked protection from sudden death.

Risk of
                    sudden cardiac death
Interrelationship between the EPA+DHA level and risk of SCD. Data are adapted from the epidemiological studies of (open squares) Albert et al. (11) and (open circles) Siscovick et al. (12). The data of Albert et al. (11) include also docosapentaenoic acid and are, therefore, by estimated 0.98 percentage points higher than in our study where docosapentaenoic acid was not included. As in our study involving 840 mg/d EPA+DHA ethyl ester (Omacor / Lovaza) administration, whole blood was analyzed in the study of Albert et al. (11). Data of Rupp et al. (2003) are from (1).

The predicted reduction in the risk of SCD can account in part for the reduced mortality observed in the GISSI-Prevention Study with 840 mg/day EPA+DHA ethyl esters (7, 8, 9). One has, however, to take into account that the above epidemiological studies cannot identify the mechanisms which result in high EPA+DHA levels in particular patients. In our opinion, certain variations occur in the endogenous EPA+DHA production (altered activities of the corresponding desaturases). It appears less likely that the high EPA+DHA levels observed in the US in a subset of the patients arise from a very high fish intake.

                          Prevention Study  

In the GISSI Prevention (Prevenzione) Study (7, 8, 9), patients who survived a myocardial infarction were treated with 1g/day Omacor / Lovaza. Mortality risk was reduced by 20%, cardiovascular mortality risk by 30% and sudden cardiac death risk by 45%.  Since the risk of re-infarction was not affected by Omacor / Lovaza, it appears that the EPA+DHA ethyl esters had a specific action on mechanisms leading to SCD, i.e. an anti-arrhythmogenic action. The patients received standard care (anti-platelet drug, beta-blocker, ACE-inhibitor and at the end of the study also a statin). Noteworthy is that the patients consumed on average approx. 1 fish meal per week and that Omacor exhibited a protection on top of the dietary fish intake.

Further support for antiarrhythmogenic effects of omega-3 fatty acids was provided in the study of Calo et al. (14). Two 1 g capsules of EPA and DHA ethyl esters were administered during hospitalization in patients undergoing coronary artery bypass graft surgery (CABG). Postoperative atrial fibrillation developed in 27 patients of the control group (33.3%) and in 12 patients of the EPA and DHA ethyl ester group (15.2%) (P = 0.013). There was no significant difference in the incidence of nonfatal postoperative complications, and postoperative mortality was similar in the EPA and DHA ethyl ester treated patients (1.3%) versus controls (2.5%). After CABG, the EPA and DHA ethyl ester treated patients were hospitalized for significantly fewer days than controls (7.3 ± 2.1 days vs. 8.2 ± 2.6 days, P = 0.017).

In view of the present evidence, it is suggested to include the determination of fatty acid profile in the list of investigated parameters in patients with cardiovascular disease, particularly in patients after MI. This would strengthen the rationale of therapeutic regimens with EPA and DHA ethyl esters, as specified in current guidelines (15,16). Since only 10 µl of whole blood are required, it does rarely require additional blood sampling. By monitoring the EPA+DHA level, patients could be identified who are at an increased risk of SCD irrespective of their underlying disease. Furthermore, longitudinal changes in the EPA+DHA incorporation can be monitored and it can thus be assessed whether a required EPA+DHA level has been reached.

For reducing pro-inflammatory eicosanoids and cytokines, a higher “EPA+DHA level” is required which can be achieved with an intake of 2 - 4 g/day of 84% EPA+DHA ethyl esters. For assessing influences from pro-inflammatory eicosanoids and cytokines, the EPA/arachidonic acid ratio (“EPA/AA ratio”) appears as a useful diagnostic parameter and deserves further investigation 

Avoid misconceptions:

EPA+DHA level and Omega-3 level are not the same

If we want to specify the percentage of the long-chain omega-3 fatty acids EPA and DHA, then we use the term EPA+DHA level. Why do we not use the term "Omega-3 level"? There is a simple answer: omega-3 includes also other omega-3 fatty acids. There are conditions where the Omega-3 level changes not, however, the EPA+DHA level. In one of our experiments, rats were fed linseed oil which is rich in the omega-3 alpha-linolenic acid. The Omega-3 level markedly increased, but not the EPA+DHA level. Why should we say, the omega-3 level did not increase because we (contrary to textbook knowledge) defined omega-3 level as sum of only EPA+DHA?

Linseed oil feeding and change in fatty

Fish meals are not a substitute for Omacor

To assess the role of dietary EPA+DHA intake, fatty acids were determined in fish dishes of the cafeteria of the Philipps University Marburg. The EPA+DHA content of the popular Alaska Pollock was 125±70 mg/100 g

EPA + DHA in fish

A once daily fish dish can thus not provide the 840 mg/day EPA+DHA administered in the GISSI trials in the form of ethyl ester which markedly reduced the risk of SCD in post-MI patients. Nonetheless, at least two preferably oily fish meals per week should be consumed as preventive measure by persons without coronary artery disease. With documented coronary heart disease, it was advised to consume approximately 1 g/day of EPA+DHA (16).

Fish oils must not be substituted for Omacor
Great progress has been made in prevention of cardiovascular diseases. A major contribution came from randomized double blind clinical trials. Therapy is based on the outcome of these trials and we are privileged to live in the age of evidence-based medicine. Why do we mention this in the context of omega-3 fatty acids? In contrast to the nomenclature of pharmaceuticals, the term "omega-3 fatty acids" is often used in an unscientific manner. While in the trials of the GISSI group Omacor was administered, the impression is often generated that "omega-3 fatty acids or "omega-3 PUFAs" were administered. It is implicated that it does not matter whether Omacor or other preparations of "omega-3 fatty acids" are used. Incidentally, the other preparations are cheaper (less costly to prepare because of less stringent regulations in case of OTC nutrition supplements). So this misconception is readily accepted. But do these other "omega-3" preparations work? The answer is: we don't know, there is no evidence available at all. So in this respect we turn away from evidence-based medicine. A patient who survived an MI should be treated based on the outcome of the trials of the GISSI group and not on the basis of assumptions. Obviously, manufacturers of fish oil capsules are invited to do clinical trials and to prove the efficacy of their products. In view of the huge sales of fish oils, it should not be a financial burden for the companies to support these trials.
If physicians prescribe Omacor and pharmacists recommend substitution with fish oils, they are - in our opinion - in breach of their own ethical guidelines. Pharmacists must be aware of the differences and cannot mislead patients. Pharmacists have to give customers proper information. The ethical code states that pharmacists "must assist patients in making informed decisions" by providing them with "necessary and relevant information" (see also the recent discussion on homeopathic remedies. Put in simple terms: fish oils are not "generics" of Omacor. It has been argued that the level of EPA+DHA is some type of surrogate endpoint and as long as a specified (high) level is reached, it does not matter how it is reached. What is the evidence for this? There is no evidence!

"Any" brand of ethyl ester must not be substituted for Omacor
Fish oils are different from Omacor, so clearly they cannot be substituted for Omacor. But what about "omega-3 ethyl esters" in general? Again the same situation: in the GISSI trials, Omacor was used but not "any" brand of ethyl esters. There are indeed major differences in the preparations. This is exemplified by the comparison of two ethyl ester preparations, referred to as preparation A and preparation B. Although preparation A and preparation B contain 90% omega-3 fatty acids, preparation B contains only 20% DHA and 60% EPA while preparation A contains 38% DHA and 46% EPA. Furthermore, by including various minor omega-3 fatty acids, the total omega-3 fatty acid content is raised in preparation B to 90%, although the biological role of these minor (including also short-chain) omega-3 fatty acids remains unresolved. Therefore, preparation B is clearly not a substitute for preparation A. Since no clinical trials have been done with preparation B, we consider it unethical to come up with a substitution simply because preparation B is cheaper than preparation A (Omacor). Again the argument comes up that the EPA+DHA level might be a good enough surrogate endpoint or predictor of sudden death. Too often we have learned that predictions for cardiovascular endpoints turned out to be wrong. A very recent example is the lack of efficacy of a statin in heart failure despite its pleiotropic actions.

                      2006 Microdetermination of fatty acids

(1) Rupp H, Wagner D, Rupp T, Schulte L, Maisch B. Risk stratification by the "EPA+DHA Level" and the "EPA/AA Ratio". Focus on anti-inflammatory and antiarrythmogenic effects of long-chain omega-3 fatty acids. Herz 2004; 29:673-685.    Also available as PDF
(2) Ikeda I, Imasato Y, Nagao H, et al. Lymphatic transport of eicosapentaenoic and docosahexaenoic acids as triglyceride, ethyl ester and free acid, and their effect on cholesterol transport in rats. Life Sci 1993;52:1371–9.
(3) Kozak M, Krivan L, Semrad B. Circadian variations in the occurrence of ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2003;26:731–5.
(4) Lawson LD, Hughes BG. Human absorption of fish oil fatty acids as triacylglycerols, free acids, or ethyl esters. Biochem Biophys Res Commun 1988;152:328–35.
(5) Luley C, Wieland H, Grünwald J. Bioavailability of omega-3 fatty acids: ethylester preparations are as suitable as triglyceride preparations. Akt Ernährungsmed 1990;15:123–5.
(6) Lawson LD, Hughes BG. Absorption of eicosapentaenoic acid and docosahexaenoic acid from fish oil triacylglycerols or fish oil ethyl esters co-ingested with a high-fat meal. Biochem Biophys Res Commun 1988;156:960–3.
(7) GISSI-Prevenzione Investigators. Dietary supplementation with ω-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione Trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447–55.
(8) Marchioli R, Avanzini F, Barzi F, et al. Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations: GISSI-Prevenzione mortality risk chart. Eur Heart J 2001;22:2085–103.
(9). Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by ω-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.
(10) Leaf A, Xiao YF, Kang JX, et al. Prevention of sudden cardiac death by ω-3 polyunsaturated fatty acids. Pharmacol Ther 2003;98:355–77.
(11)  Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002; 346:1113-1118.
(12) Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG, Albright J, Bovbjerg V, Arbogast P, Smith H, Kushi LH. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995; 274:1363-1367.

(13) Leaf A, Albert CM, Josephson M, Steinhaus D, Kluger J, Kang JX, Cox B, Zhang H, Schoenfeld D. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation 2005;112:2762-2768
(14) Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E, Meo A, Pandozi C, Stai-bano M, Santini M. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery by-pass surgery: a randomized, controlled trial. J Am Coll Cardiol 2005;45:1723-1728.
(15) Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-57.
(16)  Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR, Vahanian A, Verheugt W, Wijns W. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003;24:28-66.
"Make everything as simple as possible, but not simpler."

Be more precise:
the "EPA+DHA level"
Not all omega-3 fatty acids are the same (see textbooks of biochemistry) and their protective effects depend on the chain length and number of double bonds. Only long-chain omega-3 fatty acids (EPA+DHA) but not the short-chain omega-3 alpha-linolenic acid have been shown to reduce risk of sudden death (Albert CM et al.).

If e.g. the "omega-3 level" is calculated, obviously also the omega-3 alpha-linolenic acid has to be included (or you redefine what you mean with omega-3 and simply ignore textbook knowledge). Thus, terms like "omega-3 level" are too broad and not appropriate when referring to benefits observed in the GISSI-Prevention and GISSI-HF trials.

There is also a discrepancy between the design of well-controlled trials and the inprecise specification of the medication used. To our knowledge, the ratio of DHA:EPA in the GISSI trials was 1: 1.2 and not the reverse. This ratio is found in Omacor, i.e. 38% DHA and 46% EPA. These  prescription omega-3 fatty acid ethyl esters must not be referred to as "cheap and simple fish oil" and also not as "highly purified fish oil". Fish oil contains triglycerides whereas Omacor contains ethyl esters. Triglycerides but not ethyl esters are split by pancreatic lipase and thus rapidly absorbed. Ethyl esters result in a retarded sustained EPA and DHA absorption. It should not be tolerated that the public is misled in this respect.

Recent questions:
Monitoring beyond omega-3 fatty acids?

The arachidonic acid:EPA ratio needs to be re-evaluated.

Gas chromatography
How to work safely with hydrogen: use a hydrogen generator.

Sample preparation and standardization
Use alkaline conditions in the transesterification with methanol. The typical BF3/method results in a loss of EPA and DHA. Details are given in Rupp et al.

Alternative tests
Are the "fast" GC methods an alternative?

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  November 12, 2013