The world’s most important cardiac scientific societies recommend two marine omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) for cardiovascular prevention, for secondary prevention, for treatment of cardiac arrhythmias, and for treatment of congestive heart failure (Perk et al, 2012; Smith et al, 2011; Zipes et al, 2006; McMurray et al, 2012). Nevertheless, many cardiologists do not recommend EPA plus DHA, because they consider EPA plus DHA ineffective. The opinion of the cardiologists is based on neutral results of large intervention trials with clinical endpoints, and their meta-analyses. However, scientific societies also consider other scientific data, like epidemiology, mechanisms, and results of intervention trials on surrogate (e.g. blood pressure, laboratory values) and intermediate parameters (e.g. changes in blood vessels).

Substantial amounts of data based on the HS-Omega-3 Index have been generated in the last ten years. This allows a clearer view on the field, and also allows to resolve the discrepancies between the results of the large trials with clinical endpoints, and the other results mentioned. This is supported by results of investigations on bioavailability and by results from measurements of levels of EPA plus DHA in other compartments. More detailed information can be found in current review articles (von Schacky, 2014a-d; Superko et al, 2013; Harris et al, 2013). In short: A low HS-Omega-3 Index is a cardiovascular risk factor. It is equivalent and sometimes even superior to conventional risk factors. A HS-Omega-3 Index in the target range of 8 – 11% is associated with lower total mortality, lower cardiovascular mortality, less sudden death, less fatal and non-fatal myocardial infarctions than a HS-Omega-3 Index below the target range.

In a systematic review with meta-analysis of epidemiologic studies, a high intake of EPA plus DHA was associated with a lower rate of coronary events by 13%, than a low intake (RR 0.87, 95% Konfidenzintervall CI 0.78-0.97, Chowdury et al, 2014). Assessing diet is subject to substantial uncertainties (Archer et al, 2013). In the same meta-analysis, higher levels of EPA plus DHA in plasma or adipose tissue were associated with a lower rate of coronary events by 25%, than lower levels (RR 0.75, 95% CI .62-0.89, Chowdury et al, 2014). The biologic variability of omega-3 fatty acids in plasma is substantially larger than their biologic variability in erythrocytes (Harris & Thomas 2010). Moreover, the analytical variability of the HS-Omega-3 Index method is 3.9 rel.%, a very low value (Harris & Thomas 2010). Thus, the HS-Omega-3 Index method is probably the only analytical method for fatty acids conforming Clinical Chemistry. This explains, why epidemiologic studies based on the HS-Omega-3 Index have a higher discriminatory power than studies based on analyses of e.g. plasma or even nutrition (table 1). The data in table one are confirmed and expanded by as yet unpublished data from the LURIC study.

According to US Preventive Service Task Force and American Heart Association, novel biomarkers for cardiovascular risk have to fulfill the following four criteria (Helfand et al, 2009; Hlatky et al, 2009):
1. standardized assessment
2. incremental information to conventional risk factors
3. improved risk classification
4. therapeutic consequence

1) As mentioned, the analytical method of the HS-Omega-3 Index conforms the quality management of Clinical Chemistry (constancy checks, plausibility checks, proficiency tests, asf.) (Harris & Thomas, 2009, von Schacky 2014a-d). This is in contrast to other biomarkers for cardiovascular risk, like measuring intima-media thickness with ultrasound, ankle-brachial index, or lipoprotein (a), all of which lack a standardized assessment. Therefore, use of these parameters should be restricted to investigational purposes (von Schacky 2014a-d).

2) In the US, the predictive value of a HS-Omega-3 Index based fatty acid profile for the acute coronary syndrome was bigger than the Framingham Risk Score (bigger area under the curve in c-statistic; Shearer et al, 2009). Similar data have been generated in other populations (von Schacky, 2014a-d).

3) Risk classification by the Framingham Risk Score was improved: Individuals, who were considered to have intermediary risk could be reclassified to high or low risk in a more precise manner (Shearer et al, 2009). In Korea, the Framingham Risk Score predicts poorly, and more pronounced data were generated there (Park et al, 2009). Current investigations in collaboration with Framingham, LURIC and others will add precision to this area.

4) Increasing the HS-Omega-3 Index decreased heart rate, increased heart rate variability, lowered blood pressure and platelet aggregability, lowered triglycerides and various pro-inflammatory cytokines, lowered atherogenic small dense LDL, and increased anti-atherogenic large buoyant LDL(Harris et al Am J Cardiol 2006; 98:1393-5, Carney et al Psychosom Med 2010;72:748; Dewell et al J Nutr Res 2011;141:2166; Skulas-Ray et al Ann Behav Med 2012;44:301. Larson et al, Thromb Haemost 2008;100: 634, Harris et al, Lipids 2008;43:805, Duda et al Cardiovasc Res 2009;81:319,Dewell et al J Nutrition 2011;141:2166, Blocket al World J Cardiovasc Dis2012;2:14, Skulas-Ray Am J Clin Nutr 2011;93:243, Schuchardt et al PLEFA 2011;85:381, Shearer et al J Lipid Res. 2012;53:2429, Maki et al J Clin Lipidol 2011;5:483). Taken together, a large number of surrogate parameters for cardiovascular disease were improved by an increase of the HS-Omega-3 Index.

In our own randomized controlled intervention trial with EPA and DHA, progression of coronary lesions was reduced, and regression increased by an increase of erythrocyte EPA plus DHA from <4% to >8%. The fatty acid analytical method was different at the time, and therefore cannot be directly compared to data generated with the HS-Omega-3 Index method. However, clearly the “natural” course of coronary atherosclerosis was mitigated by increasing erythrocyte EPA plus DHA (von Schacky et al, 1999). This mid-sized intervention trial demonstrated a positive effect on an intermediary parameter of coronary artery disease.

As mentioned, large intervention trials did not demonstrate a reduction in clinical events by increased ingestion of EPA plus DHA (discussed in more detail in von Schacky, 2014). Two issues in the design of these studies are likely to be responsible for these neutral results:
– bioavailability: without an accompanying high-fat meal, bioavailability of EPA in capsules is minimal (Schuchart & Hahn, 2013). In almost all large intervention trials, participants were advised to take the study capsules with breakfast, a low-fat meal in most countries (von Schacky, 2014).
– Trial design: For all large intervention trials, participants were recruited irrespective of baseline levels of EPA plus DHA (von Schacky, 2014). In every population studied so far, the HS-Omega-3 Index had a statistically normal distribution (von Schacky, 2014). The response of the HS-Omega-3 Index to increased intake of EPA plus DHA varies from Person to Person by a factor of up to 13 (Köhler et al, 2011). In combination, both facts lead to overlapping levels of EPA plus DHA during the trial – as already demonstrated in a large intervention trial (Muhlhausler et al, 2014). A trial, where Verum and Placebo or control group are no different in terms of the intervention will not demonstrate a difference in outcome.
A new generation of trials, recruiting participants with a low baseline HS-Omega-3 Index, and using variable doses of EPA plus DHA to reach a predefined treatment goal (e.g. a HS-Omega-3 Index of 8 – 11%) is likely to have clearer results.

The HS-Omega-3 Index needs to be compared to other novel biomarkers for cardiovascular risk. In the European guidelines for cardiovascular prevention, imaging procedures like coronary calcium scoring, assessment of carotid intima-media thickness or the ankle brachial index are suggested as a means for further risk stratification, while laboratory parameters like hs-CRP, Fibrinogen or homocysteine are seen more critically (Perk et al, Eur Heart J 2012;33:1635;). Rarely is coronary calcium measured in a standardized way in clinical routine, rather in studies, and pertinent intervention trials have not yet been performed. Similar things can be said about assessing intima-media thickness, or the ankle-brachial index. The standardized analytical procedure and the existing intervention trial rather support hs-CRP. However, practical problems hamper its use in clinical routine. If the authors of the guidelines would apply the criteria of the American Heart Association and/or of the US Preventive Service Task Force anwenden (Helfand et al, 2009, Hlatky et al, 2009), use of the HS-Omega-3 Index would have to be recommend, because it fulfills almost all those criteria completely.

Sudden cardiac death is responsible for some 15% of all deaths (Zipes et al, 2006). Mostly individuals, who consider themselves in good health, die from sudden cardiac death. Risk factors either define a small population, like the MADIT-criteria, the basis for implantation of a cardioverter-defibrillator (Zipes et al, 2006). Results from mechanistic studies indicate that EPA plus DHA inhibit the conversion of ventricular tachycardia (hemodynamically frequently tolerated) to ventricular fibrillation (usually not tolerated) (von Schacky, 2012). In a case-control study, the erythrocyte fatty acid composition of victims of sudden cardiac death was analyzed, and compared to the erythrocyte fatty acid composition of healthy controls (Siscovick et al. 1995). The probability for sudden cardiac death increased with decreasing percentages of EPA plus DHA in erythrocytes, and a 10 fold difference was observed between the highest and the lowest quartile (Siscovick et al, 1995). Similar findings were reported from the Physicians’ Health Study (Albert et al, 2002). Of note, little relation was found between intake of EPA plus DHA and sudden cardiac death (Siscovick et al, 1995). This puts the neutral findings of the only intervention trial aiming at prevention of sudden cardiac death with EPA plus DHA into perspective (Rauch et al, 2010). A low HS-Omega-3 Index was associated with increased risk for ventricular fibrillation during acute ischemia in a myocardial infarction (Aarsetøy et al, 2008), and a low HS-Omega-3 Index was associated with sudden cardiac death (Aarsetøy et al, 2011). Interestingly, an increase of the HS-Omega-3 Index by 1% was associated with a 58% lower risk for ventricular fibrillation during a myocardial infarction ((95% CI: 0.25–0.76%)( Aarsetøy et al, 2011). Current guidelines of the American and European cardiac societies mention EPA plus DHA as a therapeutic possibility in patients with ventricular arrhythmias and coronary artery disease (Level of Evidence B, Grade of recommendation IIb, Zipes et al, 2006). Currently, more data is being generated in collaboration with various registries. Nevertheless, the data so far supports the conclusion that risk for ventricular fibrillation depends on the HS-Omega-3 Index, and that a HS-Omega-3 Index based supplementation with EPA plus DHA is an option for prevention of sudden cardiac death.

Epidemiology, mechanisms of action an some clinical trials support the notion that EPA plus DHA prevent atrial fibrillation (von Schacky, 2012). Low levels of EPA plus DHA in plasma phospholipids are associated with a high likelihood to develop atrial fibrillation, as compared to high levels of EPA plus DHA (Wu et al, 2012). This indicates that a low HS-Omega-3 Index is associated with subsequent development of atrial fibrillation; this is currently investigated.

Low levels of EPA plus DHA in plasma phospholipids are associated with a 50% increased risk for subsequent development of congestive heart failure, as compared to high levels (HR 0.52; 95%CI 0.38 – 0.72]; p for Trend <0.001) (Mozaffarian et al, 2011). Our own unpublished data indicate that patients with congestive heart failure have a low HS-Omega-3 Index (mean < 4%). In a large randomized intervention trial with clinical endpoints in patients with congestive heart failure, EPA plus DHA reduced total mortality and re-hospitalizations (GISSI-HF, 2008). Therefore, EPA and DHA are recommended in the pertinent European guidelines (levels of evidence B, level of recommendation IIb, McMurray et al, 2012). In our opinion, although a pertinent trial has not yet been conducted, EPA plus DHA should be used in congestive heart failure with the aim of a HS-Omega-3 Index of 8 – 11%.

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