Omega-3 Index for cardiovascular health, inflammation

The omega-3 index, the the sum of red blood cell EPA + DHA as a percent of total fatty acids, is an important biomarker for cardiovascular health and systemic inflammation. A comprehensive review of the evidence has become even more important since some trials with limitations have yielded potentially misleading results. The author of a paper published in the journal Nutrients state:

"Recent large trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the cardiovascular field did not demonstrate a beneficial effect in terms of reductions of clinical endpoints like total mortality, sudden cardiac arrest or other major adverse cardiac events. Pertinent guidelines do not uniformly recommend EPA + DHA for cardiac patients. In contrast, in epidemiological findings, higher blood levels of EPA + DHA were consistently associated with a lower risk for the endpoints mentioned."

Metanalyses and epidemiologic studies differ

Elaborating on this on the contradictory evidence, they note:

"...in epidemiologic studies, where intake of EPA + DHA had been found to correlate generally with an up to 50% lower incidence of adverse cardiac events [18,19], and in even sharper contrast to epidemiologic studies based on levels of EPA + DHA, demonstrating e.g., a 10-fold lower incidence of sudden cardiac death associated with high levels of the fatty acids, as compared to low levels."

As a result of this confusion recommendations for EPA + DHA for primary prevention have been curtailed in the US and Europe. Thus the author poses these pertinent questions:

"Why is it that trial results are at odds with results from epidemiology? What needs to be done to better translate the epidemiologic findings into trial results? The current review will try to shed some light on this issue, with a special consideration of the Omega-3 Index."

Measuring erythrocyte fatty acids and the HS-Omega-3 Index

Much of the conflict between trial and epidemiologic results can be explained by methodology. Some of the trials use nutritional surveys instead of actual measurements of EPA and DHA.

"At least some nutritional surveys do not provide valid data [32]. This may explain, why the relation of EPA + DHA in the diet to clinical events has been found to be looser than the relation of levels of EPA + DHA measured in blood to clinical events."

Erythrocyte (red blood cell) measurements of omega-3 fatty acids are biologically relevant, and when employed for the HS-Omega-3 Index are bolstered by rigorous standards.

"The following points argue for the use of erythrocytes: erythrocyte fatty acid composition has a low biological variability, erythrocyte fat consists almost exclusively of phospholipids, erythrocyte fatty acid composition reflects tissue fatty acid composition, pre-analytical stability, and other points [34,35,36,37,38]. In 2004, EPA + DHA in erythrocyte fatty acids were defined as the Omega-3 Index and suggested as a risk factor for sudden cardiac death [39]."

Laboratory methods, however, make a big difference in the quality of the data:

"In fatty acid analysis, methods have a large impact on results: when one sample was sent to five different laboratories offering determination of an Omega-3 Index, results differed by a factor of 3.5 [34]. While results may be internally valid in one laboratory, a difference by a factor of 3.5 makes it impossible to compare results among laboratories. Therefore, the Omega-3 Index was renamed HS-Omega-3 Index^®. In contrast, the laboratories adhering to the HS-Omega-3 Index methodology perform regular proficiency testing, as mandated in routine Clinical Chemistry labs [34]. So far, the HS-Omega-3 Index is the only analytical procedure used in several laboratories. A standardized analytical procedure is a prerequisite to generate the data base necessary to transport a laboratory parameter from research into clinical routine. Moreover, standardization of the analytical procedure is the first important criterion for establishing a new biomarker for cardiovascular risk set forth by the American Heart Association and the US Preventive Services Task Force."

A valuable risk factor indicator

The omega-3 index (HS- version) has proven itself in a variety of clinical contexts.

"...the HS-Omega-3 Index has been measured in many populations. Of note, a lower HS-Omega-3 Index was always associated with a poorer clinical condition."

As demonstrated above, this applies to neuropsychiatric, renal and other conditions as well as cardiovascular disease.

Unpredictable so must be measured

A specific person's result from consuming omega-3 fatty acids in the diet or by supplementation cannot be determined without measuring.

"Neither a recent meal, even if rich in EPA + DHA, nor severe cardiac events altered the HS-Omega-3 Index [38,58,59,60,61]. However, while long-term intake of EPA + DHA, e.g., as assessed with food questionnaires, was the main predictor of the HS-Omega-3 Index, long-term intake explained only 12%–25% of its variability [46,62,63]. A hereditary component of 24% exists [64]. A number of other factors correlated positively (+) or negatively (−), like age (+), body mass index (−), socioeconomic status (+), smoking (−), but no other conventional cardiac risk factors [47,64,65,66,67,68,69,70,71]. More factors determining the level of the HS-Omega-3 Index, especially regarding efflux remain to be defined. Therefore, it is impossible to predict the HS-Omega-3 Index in an individual, as it is impossible to predict the increase in the HS-Omega-3 Index in an individual in response to a given dose of EPA + DHA."

An excellent predictor when measured

Measured, however, it becomes an excellent predictor beyond the ordinary risk factors:

"Taken together, the HS-Omega-3 Index predicts risk, appears largely independent of conventional risk factors, and adds to the information obtained by conventional risk scoring, thus fulfilling the second criterion for establishing a new biomarker for cardiovascular risk set forth by the American Heart Association and the US Preventive Services Task Force...Moreover, the HS-Omega-3 Index has made it possible to reclassify individuals from intermediate cardiovascular risk into the respective high risk and low risk strata [74,75], the third criterion for establishing a new biomarker for cardiovascular risk [40,41]."

Benefits of increasing the HS-Omega-3 Index

The benefits of improving the omega-3 index are robust:

"Increasing the HS-Omega-3 Index by increased intake of EPA + DHA in randomized controlled trials improved a number of surrogate parameters for cardiovascular risk: heart rate was reduced, heart rate variability was increased, blood pressure was reduced, platelet reactivity was reduced, triglycerides were reduced, large buoyant low-density lipoprotein (LDL)-particles were increased and small dense LDL-particles were reduced, large buoyant high-density lipoproteins (HDL)2 were increased, very low-density lipoprotein (VLDL1) + 2 was reduced, pro-inflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin-1β, interleukins-6,8,10 and monocyte chemoattractant protein-1) were reduced, anti-inflammatory oxylipins were increased."

Moreover, improvements in blood vessel inflammatory lesions are observed:

"Importantly, in a two-year randomized double-blind angiographic intervention trial, increased erythrocyte EPA + DHA reduced progression and increased regression of coronary lesions, an intermediate parameter [95]. Taken together, increasing the HS-Omega-3 Index improved surrogate and intermediate parameters for cardiovascular events."

Why neutral results in some trials?

It's very interesting and important to discern why some trials of EPA + DHA do not seem to produce this magnitude of benefit. One reason is the form of omega-3 fatty acids that were given:

"Thus, involuntarily, the combination used in many of the large trials—An unemulsified ethyl-ester or triglyceride with a low fat meal—guaranteed a very low bioavailability of EPA + DHA."

Another reason is the defect in trial design that plagues most studies investigating nutraceutical therapies: failure to screen those who are deficient in the agent being studied to furnish a cohort who can actually respond positively to the intervention.

"In all large intervention trials conducted so far, study participants were recruited based on clinical conditions, but irrespective of their baseline omega-3 fatty acid status [1,2,3,4,5,6,7,8,9,10,11,12]. In all populations studied so far, the HS-Omega-3 Index had a statistically normal distribution. Thus, the proportion of the study population with high levels was not prone to the effects of EPA + DHA, if any. In order to recruit a study population, in which an effect of EPA + DHA can be demonstrated, recruiting study participants with a low HS-Omega-3 Index is a logical choice."

Additionally, individuals respond differently to the same dose of EPA + DHA which must be customized in clinical practice. Most trials, however, use a fixed dose.

"In all large intervention trials conducted so far, study participants were exposed to a trial-specific, but fixed dose of EPA + DHA or placebo [1,2,3,4,5,6,7,8,9,10,11,12]. The inter-individual variability in response to a fixed dose of EPA + DHA has been found to be large, i.e., vary up to a factor of 13 [42,61]. This fact alone suggests individualizing the dose given in a trial, in order to reach a predefined target range of the HS-Omega-3 Index, e.g., 8%–11%....With levels of omega-3 fatty acids not differing between intervention and placebo or control groups, a difference in study outcome cannot be expected, even if the condition studied would be susceptible to treatment with EPA + DHA. It is worth noting that when a neutral intervention trial was analyzed in a cross-sectional way, EPA + DHA levels directly related to study outcome and less to treatment allocation [101].

Note the therapeutic target range for the Omega-3 Index of 8%-10%. Positive results are typically forthcoming when the study cohort is deficient:

"Conversely, if a trial reports a positive result, it is likely to have been conducted in a study population with low baseline levels of EPA and DHA, like congestive heart failure: a positive result of a large trial was reported [6], and we found a low mean HS-Omega-3 Index in patients with congestive heart failure (unpublished data, Table 1). A similar case can be made for major depression (Table 1, references [44,50,51,84])."

The author concludes:

"In an inconsistent manner, EPA and DHA are either recommended or not included in guidelines of cardiac scientific societies. The use of EPA and DHA is not supported by results of recent intervention trials or their meta-analyses. However, epidemiologic data based on assessments of diet and, even more so, data based on levels of EPA + DHA measured in humans, clearly demonstrate that EPA + DHA are associated with a low risk for total mortality, sudden cardiac arrest, and fatal and non-fatal myocardial infarctions. For a number of reasons, like a standardized analytical procedure and a large data base, levels of EPA + DHA are best assessed with the HS-Omega-3 Index."

Readers may also be interested in Omega-3 fatty acids and depression in adolescents.

Update on fatty acids and aging

A study just published in BMJ (The British Medical Journal) on omega-3 fatty acid and healthy aging offers further evidence for the benefits of higher levels. This study is distinctive as the first to ever report on omega-3 biomarkers and aging. The authors determined to...

"...determine the longitudinal association between serial biomarker measures of circulating omega 3 polyunsaturated fatty acid (n3-PUFA) levels and healthy ageing."

They examined data from 2622 adults for cumulative levels of  fatty acids, including α-linolenic acid from plants and eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid from seafoood. When correlated with survival without chronic diseases (ie, cardiovascular disease, cancer, lung disease, and severe chronic kidney disease), the absence of cognitive and physical dysfunction, or death from other causes they found that EPA and DPA stood out for their benefits.

"Higher levels of long chain n3-PUFAs were associated with an 18% lower risk (95% confidence interval 7% to 28%) of unhealthy ageing per interquintile range after multivariable adjustments with time-varying exposure and covariates. Individually, higher eicosapentaenoic acid and docosapentaenoic acid (but not docosahexaenoic acid) levels were associated with a lower risk: 15% (6% to 23%) and 16% (6% to 25%), respectively. α-linolenic acid from plants was not noticeably associated with unhealthy ageing (hazard ratio 0.92, 95% confidence interval 0.83 to 1.02)."

These results stand to reason:

"Long chain n3-PUFAs show several physiological effects that support the biologic plausibility of our results.751Human trials show favorable effects on blood pressure, endothelial function, plasma triglycerides, heart rate, and potentially inflammation.7 Experimental and animal studies suggest potential benefits for arrhythmias,751carcinogenesis,8 bone mass,52 and neurogenesis.53 Evidence for other effects, such as those on cognitive function and mental health, is mixed.545556 Mechanistically, long chain n3-PUFA alter fluidity of cellular membranes and responses of transmembrane protein receptors, influence gene expression by binding to fatty acid specific receptors, and serve as precursors to bioactive eicosanoids and specialized resolvers of inflammation.78953"

They conclude:

"Among older adults, a higher cumulative level of the circulating long chain n3-PUFAs eicosapentaenoic acid, docosahexaenoic acid, and eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid combined were associated with a lower likelihood of unhealthy ageing. Docosahexaenoic acid from seafood and α-linolenic acid from plants were not associated with a lower likelihood of unhealthy ageing. These findings encourage the need for further investigations into plausible biological mechanisms and interventions related to n3-PUFAs for the maintenance of healthy ageing, and to support guidelines for increased dietary consumption of fish in older adults."

Update: 25% relative risk reduction in MACE

And Medscape reports on the results of the REDUCE-IT trial, demonstrating that 4 grams per day of pure EPA reduced major cardiovascular events by 25%. This is particularly important because earlier studies on the cardiovascular effects of EPA have been under-dosed.

"The 25% relative risk reduction in major cardiovascular events seen with Vascepa [brand of EPA] is comparable to that seen with atorvastatin, one of the most successful drugs of all time," he said, "and the benefit of Vascepa was seen on top of statin therapy therefore is addressing an unmet medical need.""Clearly, lowering low-density lipoprotein cholesterol (LDL-C) alone is not enough," he said. "That can give a relative risk reduction of 25% to 35%, but this leaves a residual risk of 65% to 75%. The additional 25% relative risk reduction seen in this study is the single most impressive advance for preventative cardiovascular drug therapy since the advent of the statins."