The omega-3 index was defined as the percentage of EPA
DHA in red cells, as determined with a highly standardized analytical method, currently installed in a few laboratories around the world (Harris and von Schacky, 2004
). While mean levels of the omega-3 index differ from population to population, mean levels had a statistically normal distribution in all populations studied so far (von Schacky, 2011
). Therefore, in any population, some individuals have relatively high, and some have relatively low levels, while most are in between. The omega-3 index reflects tissue levels of EPA
DHA, e.g., of the heart (von Schacky, 2011
). A low omega-3 index is a strong predictor of future adverse cardiovascular events (von Schacky, 2011
Using the omega-3 index to answer the question whether EPA
DHA are anti- or pro-arrhythmic provides a clearer picture than the one provided thus far. In Japan, the mean omega-3 index was found to be 9.58% in unselected persons, and the incidence of SCD in the general population 7.8/100,000 person years, while in Western countries, the mean omega-3 index is frequently among 5%, and the incidence of SCD in the general population is 150/100,000 person years (von Schacky, 2010
). In two case–control studies on SCD in the US, levels of omega-3 fatty acids in red cells or whole blood were inversely related to risk for SCD, and a 10-fold difference in risk was reported (von Schacky, 2010
). Thus, a high omega-3 Index, e.g., 8–11%, is associated with a low-risk for SCD, and risk appears to increase with decreasing values of the omega-3 index.
Experimental evidence indicates that acute increases in EPA
DHA concentrations do not have a further anti-arrhythmic effect in tissues already replete with them (Den Ruijter et al., 2010
). Therefore, it is unlikely that an anti-arrhythmic effect can be demonstrated in persons or populations with a high omega-3 index, like in Japan. In keeping, in a large randomized intervention study in persons at elevated risk for cardiovascular disease in Japan (20% of whom had established cardiovascular disease), 1.8
g EPA/day did not reduce SCD (Yokoyama et al., 2007
). Of note, the incidence of SCD in JELIS was 40/100,000, substantially lower than in the general population in Western countries, as mentioned above (von Schacky, 2010
). However, acute increases in EPA
DHA, e.g., by infusion or after a 6-week dietary intervention reduced inducibility of ventricular tachycardias, but only in subjects with low levels (Schrepf et al., 2004
; Metcalf et al., 2008
; Madsen et al., 2010
). Although the latter studies were small and short, current evidence indicates that acute increases of EPA
DHA levels by infusion or a short-term dietary intervention can reduce the probability of ventricular arrhythmias in those with suboptimal levels, but that high tissue levels, reflected by a high omega-3 index, are protective.
A lower omega-3 index also makes other adverse outcomes more likely than a higher omega-3 index: Among the outcomes are ventricular fibrillation during a myocardial infarction (Aarsetoey et al., 2011
), myocardial infarctions (Block et al., 2008
; Park et al., 2009
), mortality after a myocardial infarction (Pottala et al., 2010
), and many more reviewed elsewhere (von Schacky, 2011
). Supporting evidence is provided by plasma measurements of EPA
DHA (e.g., Mozaffarian et al., 2011a
The omega-3 index has a lower biological variability than plasma or whole blood EPA
DHA (Harris and Thomas, 2010
). The level of the omega-3 index is determined by many factors, among them catabolism of EPA
DHA, age, body mass index, and intake of EPA
DHA (von Schacky, 2011
). Intake, however, explains <16 or 12% of the variability of EPA
DHA in the red cell membrane (Ebbesson et al., 2010
; Sala-Vila et al., 2011
). This may partly explain, why epidemiologic studies focusing on intake of EPA
DHA provided less clear results than epidemiologic studies focusing on the omega-3 index (von Schacky, 2010
). In the future, a more widespread use of the omega-3 index in research projects will provide a clearer picture of associations between EPA
DHA and cardiovascular events. Already now, however, the omega-3 index fulfills important criteria of the US Preventive Services Task Force or the American Heart Association for new biomarkers for cardiovascular risk (Helfand et al., 2009
; Hlatky et al., 2009
- Ease and reliability of measurement. The analytical methodology is standardized in three laboratories around the world, and conforms to the rules of Clinical Chemistry (e.g., plausibility checks, proficiency testing).
- Risk predicted independent of conventional risk factors. This has been demonstrated for an American and a Korean population, and was evidenced by a larger area under the curve in comparison to the Framingham index (Park et al., 2009; Shearer et al., 2009).
- Reclassification of persons at intermediate risk (Shearer et al., 2009).
- Therapeutic consequence. In all populations studied so far, an increase in intake of EPA+DHA increased the mean omega-3 index. In meta-analyses, increased intake of EPA+DHA resulted in decreased occurrence of major cardiovascular events (e.g., León et al., 2008; Mozaffarian and Wu, 2011). Whether an omega-3 index based supplementation with EPA+DHA is superior to the current untargeted use of EPA+DHA remains to be formally demonstrated, however.