Low omega-3 blood levels should be considered as a new cardiovascular risk factor, with the same predictive value as cholesterol, homocysteine, or even c-reactive protein, according to William Harris, PhD, co-director of the lipid and diabetes research center at the Mid-America Heart Institute and Saint Luke’s Hospital, Kansas City.

As with these other risk factors, omega-3 levels are relatively simple to assess, by measuring the omega-3 fatty acid content of red blood cell membranes. Testing for omega-3 levels can help physicians determine which patients will most likely benefit from omega-3 supplementation.

Low omega-3 levels are a robust, independent predictor of increased risk for sudden cardiac death. A number of large studies, including the well-publicized GISSI trial, show clear correlations between low omega-3 intake and cardiovascular events. Increased dietary omega-3 intakes can reduce this risk by nearly 50%. But until recently, no one was able to make the link between reported dietary intake and tissue omega-3 levels. Further, no researchers had proposed that omega-3 levels be viewed as a CHD risk factor, nor had anyone recommended an optimal blood omega-3 level for risk stratification.

Dr. Harris and his colleagues recently founded OmegaMetrix, a testing service that aims to make omega-3 testing more widely available and easier to interpret. The OmegaMetrix “Omega-3 Index (O3I),” provides a direct measurement of the amount of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two key omega-3 fatty acids, as a percentage of total fatty acid content in the red cell membranes.

OmegaMetrix is the latest addition to the growing number of functional testing labs, including Great Smokies Diagnostic Laboratories, MetaMetrix, and Body Bio, that offer red cell membrane omega-3 content assessment, in some cases as part of a comprehensive analysis of cell membrane fatty acids. According to Dr. Harris, what is unique about the O3I is that it attempts to put the measurements in a context that provides clinicians with target levels toward which they can tailor supplement strategies.

Patricia Kane, PhD, a nutritional biochemist who founded Body Bio, explains on her company’s website that analysis of red cell membrane fatty acids provides a valuable window into a patient’s fatty acid metabolism. Plasma fatty acids reflect recent dietary intake, while membrane content reflects longer-term metabolic conversion.

Several studies show that red cell membrane content accurately reflects omega-3 content in other tissues, and that it tracks closely with dietary intake. People with low omega-3 intake generally have low red cell EPA-DHA percentages; those with higher intake show higher red cell levels. Those with low baseline red cell content will show higher levels following routine supplementation.

“The O3I is very responsive to dietary intake. If you increase the intake, the red cell levels incorporate more omega-3s, and the O3I goes up,” Dr. Harris told Holistic Primary Care in an interview.

Aim for 8 Percent

Omega-3 fatty acid levels, indicated by DHA and EPA content in red blood cell membranes, are a robust predictor of cardiovascular risk. Patients with the highest RBC content have the lowest risk, while low RBC omega-3 levels correlate with increased risk of cardiac arrest. Adapted from Siscovick et al. JAMA. 1995; 274: 1363–1367, and reproduced with permission from Dr. William Harris, OmegaMetrix, 1-866-677-4900.

A surrogate marker for cardiovascular disease (CVD) only becomes clinically useful if there are well-defined cut points between healthy and unhealthy levels. While many clinicians would agree that increasing omega-3s is good for the heart, there has been little information on target levels or which patients are in greatest need of increased intake.

Dr. Harris asserts that an RBC membrane EPA-DHA content of 8% is cardioprotective. The lowest levels they’ve measured come in around 2%, and this is typical of at-risk individuals with very low dietary omega-3 intake. The highest levels ever measured are around 15%. This is typical in populations with almost exclusively marine-based diets such as Eskimos. Levels of 4% are about average in an unselected US population.

There are not yet any clinical trials to validate the 8% target. Dr. Harris explained that he and his colleagues arrived at the figure through metanalysis of existing omega-3 clinical trials, including GISSI, and converting reported dietary intake into likely RBC membrane levels. They then looked at reported CVD risk in terms of these estimates. Statistically, those at lowest risk would be expected to have red cell levels of 8% or greater, while those at highest risk would be expected to have red cell levels well below 8%.

They also took into account the current American Heart Association risk recommendation that 0.5–1.0 mg per day of combined EPA and DHA, could significantly reduce coronary risk. Supplementation at this level will typically increase the red cell membrane levels to the neighborhood of 8%.

He acknowledged that the 8% cut point is simply a starting point. “It is a preliminary target that will undoubtedly be refined by further research. He also noted that getting accurate RBC omega-3 levels is technically challenging since there is no single standardized methodology. “As I surveyed the literature, I found 9-fold variation in reported mean levels. That’s huge! Our method was developed for research purposes and is highly standardized and controlled.”

Even if the 8% target proves to be incorrect down the road, the vast majority of at-risk individuals will probably benefit from supplementation aimed at that number. “Nobody is going to be hurt if the 8% turns out to be incorrect. If the optimal level proves to be 6% or 10% based on future studies, a patient with a 2% level will still benefit from getting the index up to 8%. Since there are no known adverse effects from omega-3 fatty acids, it is not likely that anyone will be hurt by getting too much.”

Michael Culp, ND, questions that assumption. “I would agree that low EPA and DHA should be considered an independent risk factor for CVD. But you need to look at it in terms of the relative amount of EPA and DHA both in the dietary intake and in the membranes,” said Dr. Culp, who designed Great Smokies’ Essential and Metabolic Fatty Acids analysis.

He believes one must look at EPA/DHA membrane content in the context of the omega-6 fatty acids (arachidonic, gamma-linolenic, linoleic, docosatetraenoic, and eicosadienoic acids), omega-9 (oleic, gondoic, and nervonic), and saturated fatty acids, which are also components of red cell membranes. As with any risk factor, there is a danger in looking at omega-3s in isolation.

“In some individuals, marked increases in omega-3s will reduce antibody production, in effect creating an immunodeficient state,” he told Holistic Primary Care. While not likely to be a major clinical problem for most patients, it could be for someone who is already struggling with immunodeficiency disorders.

Likewise, someone with low levels of arachidonic acid relative to omega-3s is more prone to schizotypal symptoms. Essential fatty acids need to be viewed in relation to one another, and also in light of the individual’s current health profile and past medical history. “Is 8% (omega-3) truly better than 2%? It really depends on the patient. Health is never one-sided and never dependent on a single variable. You have to think about relative amounts, not absolute amounts,” said Dr. Culp. He also cautioned against taking a simplistic “more is always better” attitude toward omega-3s or any other nutrient.

Dr. Harris agrees, in principle. While cardiovascular risk seems to show a clear inverse correlation with the O3I, he does not expect one would obtain much added benefit from pushing the O3I beyond 10%.

Supplementation Usually Necessary

While patients at-risk for CVD should be encouraged to eat cold-water oily fish (if they like it), this is not adequate to bring someone with a very low O3I up to the 8% range. The desired effect almost always requires supplementation, typically at a dose of 1 gram per day of a 500 to 1,000 mg combined DHA-EPA mixture, ideally in a 50:50 ratio.

According to Dr. Culp, the fastest way to increase red cell membrane omega-3 content is to get the patient on a fat-restricted diet while they supplement with omega-3s. This drives up the proportion of omega-3s in the bloodstream relative to other fatty acids. “Putting a gram of omega-3s on top of a steady diet of McDonald’s really isn’t going to do much. But putting omega-3s on top of something like the Ornish diet certainly will.”

120 Days Will Do It

Dr. Harris has found that daily supplementation with 1 gram DHA-EPA can raise the O3I from 2%–4% to 8% or better within 3–4 months. “A red cell’s life is approximately 120 days, so you have to wait the full 4 months for complete turnover before you reach a new steady state. However, you do begin to see changes in membrane fatty acid composition within a few weeks. The O3I is like a hemoglobin A1c for omega-3 fatty acids. It reflects chronic EPA and DHA intake, not day to day fluctuations.”

While flax seed is considered by many as a good source of omega-3 fatty acids, Dr. Harris said that it will not have as much impact on red cell membranes as fish oil. “Flax will raise the EPA level slightly, but adds nothing to the DHA component, and you really need both.”

Omega-3 supplementation could be particularly beneficial for certain subgroups of patients, including those with pre-existing CHD (bearing in mind that high doses of omega-3s could enhance the effect of warfarin), those with clear elevated risk for CHD, anyone with multiple CHD risk factors, with a family history of sudden cardiac death, and diabetes or the nephrotic syndrome.

An Independent Risk Factor

Tissue omega-3 levels are a completely independent cardiac risk factor, said Dr. Harris. While increasing omega-3 will help reduce risk of coronary events, bear in mind that it will not, in and of itself, have direct effects on cholesterol, triglycerides, or blood pressure. Many at-risk patients will still likely need prescription medications, dietary changes, and other interventions to attenuate other risk factors.

The good news is that omega-3 supplements can be safely taken with most drugs used to treat CVD. As a stand-alone preventive measure or an adjunct to drug therapy, omega-3’s are quite a bargain. Even the most expensive brands are obtainable for well under a dollar per day.

The role of omega-3 testing in both clinical practice and future CVD research remains to be determined. Dr. Harris and his team at St. Luke’s Hospital will continue their work to better define the appropriate cut points. He believes the test could have applications well beyond cardiovascular disease.

“There is some evidence that people at risk for Alzheimer’s disease have low omega-3 levels, so supplementation could potentially benefit this population as well.” There is also evidence that omega-3’s can ameliorate depression, bipolar disorder, schizophrenia, post-partum depression and ADHD. Red cell membrane analysis could become a valuable method of risk evaluation and treatment monitoring in these conditions.

Omega-3 Testing Strategies

OmegaMetrix plans to make their Omega-3 Index test available to the medical community within the next few months.The test will cost $80, with a 10-day turnaround from date of sample receipt. Physicians wanting more information should contact Dr. Harris via email at: wharris@saint-lukes.org or by calling toll-free, 866-677-4900.

Great Smokies Diagnostic Lab offers a comprehensive Essential and Metabolic Fatty Acids profile based on gas chromatography and mass spectroscopy analysis of red cell fatty acid content. In addition to omega-3s, the test panel provides measures of omega-6, omega-9, trans, and saturated fat levels, and provides information on membrane fluidity, inflammatory eicosanoid precursors, and other clinically significant facets of fatty acid metabolism. Turnaround time is one week, at a cost of approximately $200. For more information, visit: www.gsdl.com or call 800-522-4762

MetaMetrix Clinical Laboratory offers a comprehensive fatty acid profile based on red cell membrane content that includes omega-3s, omega-6s, omega-9s, saturated fats, trans fats, as well as principal indicators of essential fatty acid deficiencies. The lab also offers a Cardiovascular Health Profile that measures total cholesterol, LDL, HDL, TGL, lipoprotein (a), coenzyme Q10, vitamin E, lipid peroxidase, homocysteine, c-reactive protein and other clinically relevant risk indicators. Turnaround time is 10 days. Visit: www.metametrix.com or call 800-221-4640.

Body Bio: Founded by Patricia Kane, PhD, one of the pioneers in cell membrane lipid analysis, Body Bio offers complete red cell membrane essential fatty acid analysis, as well as comprehensive plasma nutrient profiles. Visit: www.bodybio.com, or call 888-320-8338.