Cardiovascular Biomarkers: The Omega-3 Index

Optimal Takeaways

The Omega-3 Index (O3I) reflects the amount of omega-3 EPA and DHA in red blood cell membranes. It is considered an indicator of tissue levels in the body, including cardiac and gastrointestinal tissue. 

An O3I below 8% is associated with an increased risk of cardiovascular disease, sudden death, inflammation, cognitive dysfunction, and depression. A high O3I may reflect excess omega-3 intake.

Standard Range: 2.5 – 16%

The ODX Range: 8 – 16%

Low Omega-3 Index is associated with myocardial infarction, sudden cardiac death, cardiovascular disease, cognitive impairment, major depression, premature birth (Von Schacky 2019), acute coronary syndrome, dementia, non-alcoholic fatty liver disease, eye disease, inflammation, brain dysfunction, all-cause mortality (Davinelli 2020), psychosis (Alqarni 2020), worsening asthma control (Stoodley 2019), compromised red blood cell integrity, increased red cell distribution width (McBurney 2022), type 2 diabetes (Ma 2021), and increased inflammation in conditions such as rheumatoid arthritis, inflammatory bowel disease, psoriasis (Simopoulos 2002).

High Omega-3 Index may be reflective of excess omega-3 intake.

Overview      

The Omega-3 index (O3I) reflects the amount of long-chain omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) in red blood cell membranes or the phospholipid portion of plasma. The index reflects EPA and DHA in tissues as well, including cardiac and gastrointestinal tissues. It is considered a valid biomarker for assessing cardiovascular risk, especially sudden cardiac death (Von Schacky 2019, Harris 2008, Gurzell 2014). The index also reflects omega-3 intake and compliance with intake recommendations (Harris 2013).

Omega-3 fatty acids support the integrity and function of red blood cells as well. A low O3I is associated with compromised cell membrane fluidity and flexibility and an elevated red cell distribution width (RDW). Elevated RDW is a potential marker of inflammation and increased risk of death from cardiovascular disease, lung disease, COVID-19, sepsis, and cancer. In one cross-sectional analysis of 25,485 adults, O3I was significantly inversely associated with RDW. A low O3I and an elevated RDW increase the risk of red blood cell dysfunction and cardiovascular disease. Researchers recommend an O3I above 5.6% to help maintain a healthy RDW, partly by improving antioxidant stability and red cell fluidity and flexibility (McBurney 2022).

The O3I is also inversely associated with neutrophil-lymphocyte ratio (NLR), a marker of systemic inflammation. A low O3I and elevated NLR are associated with an increased risk of chronic disease, including cardiovascular disease and cancer. An O3I above 6.6% was associated with a desirable NLR in a study of 28,871 healthy individuals (McBurney 2022 NLR).

“A low Omega-3 Index fulfills the current criteria for a novel cardiovascular risk factor.” An O3I above 8% is a reasonable therapeutic target to reduce the risk of cardiovascular and inflammatory disorders. An index of 4-8% may be considered intermediate risk, while below 4% is high risk (Harris 2008). A review of the literature conducted in 2014 found that a mean O3I below 8% correlated with an increased risk of CVD (with an O3I of 7.1%), myocardial infarction (O3I 4.88-6.08%), major depression (O3I 2.9%), severe sleep apnea (O3I 4%), and diabetes with an O3I of 3.47% (Von Schacky 2014).

A 2017 meta-analysis of 10 cohort studies revealed that the risk of fatal coronary heart disease was significantly reduced by 15% for every standard deviation increase in the O3I. Dose-response research suggests that increasing EPA and DHA intake by 1.5 grams daily will increase the index by 4%. Researchers confirm that an index below 4% represents increased cardiovascular risk, while an index above 8% is desirable, with ranges from 8-12% observed in clinical research (Harris 2017). The Physicians’ Health Study revealed an 81% reduced risk of sudden death from cardiac causes when the Omega-3 Index was maintained above 4.98%. The highest risk was associated with an O3I below 3.45% (Superko 2013).

Oily cold-water fish, including salmon, sardines, herring, tuna, and trout, are good sources of EPA and DHA. Plant-based foods, such as flaxseeds, chia seeds, and walnuts, are sources of the precursor alpha-linolenic acid, which must be converted to EPA and DHA (Linus Pauling 2019). The omega-3 content of animal-based foods can be enhanced by providing them with a diet high in omega-3s. Only 20% of the world’s population is thought to meet the minimum intake of 250 mg/day for EPA and DHA. Very low O3I values below 4% are seen in North and South America, Europe, the Middle East, Africa, and Southeast Asia (Stanton 2020).

Western diets tend to be high in omega-6s and low in omega-3s with an unbalanced ratio of up to 20:1. Returning to a pre-industrialized level for omega-6 to omega-3 intake of 4 to 1 or lower can help support omega-3 metabolism and a healthy omega-3 Index (Simopoulos 2002). If preformed EPA and DHA consumption is inadequate, supplementation may be warranted. Daily supplementation with 460-980 mg of EPA and 380-760 mg of DHA for eight weeks increased mean O3I from 4.9% to 8.4% (Fischer 2014).

References  

Alqarni, Ayedh et al. “Comparison of erythrocyte omega-3 index, fatty acids and molecular phospholipid species in people at ultra-high risk of developing psychosis and healthy people.” Schizophrenia research vol. 226 (2020): 44-51. doi:10.1016/j.schres.2019.06.020

Davinelli, Sergio et al. “Metabolic indices of polyunsaturated fatty acids: current evidence, research controversies, and clinical utility.” Critical reviews in food science and nutrition, 1-16. 14 Feb. 2020, doi:10.1080/10408398.2020.1724871

Fischer, Robert et al. “Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway.” Journal of lipid research vol. 55,6 (2014): 1150-64. doi:10.1194/jlr.M047357

Harris, William S. “The omega-3 index as a risk factor for coronary heart disease.” The American journal of clinical nutrition vol. 87,6 (2008): 1997S-2002S. doi:10.1093/ajcn/87.6.1997S

Harris, William S., Clemens von Schacky, and Yongsoon Park. "Standardizing methods for assessing omega-3 fatty acid biostatus." The Omega-3 fatty acid deficiency syndrome: opportunities for disease prevention. Nova Science Publishers, Inc., 2013. 385-398.

Harris, William S et al. “The Omega-3 Index and relative risk for coronary heart disease mortality: Estimation from 10 cohort studies.” Atherosclerosis vol. 262 (2017): 51-54. doi:10.1016/j.atherosclerosis.2017.05.007

Gurzell, Eric A et al. “Is the omega-3 index a valid marker of intestinal membrane phospholipid EPA+DHA content?.” Prostaglandins, leukotrienes, and essential fatty acids vol. 91,3 (2014): 87-96. doi:10.1016/j.plefa.2014.04.001

Ma, Mu-Yuan et al. “Omega-3 index and type 2 diabetes: Systematic review and meta-analysis.” Prostaglandins, leukotrienes, and essential fatty acids vol. 174 (2021): 102361. doi:10.1016/j.plefa.2021.102361McBurney, Michael I et al. “Omega-3 index is directly associated with a healthy red blood cell distribution width.” Prostaglandins, leukotrienes, and essential fatty acids vol. 176 (2022): 102376. doi:10.1016/j.plefa.2021.102376

McBurney, Michael I et al. “The omega-3 index is inversely associated with the neutrophil-lymphocyte ratio in adults'.” Prostaglandins, leukotrienes, and essential fatty acids vol. 177 (2022): 102397. doi:10.1016/j.plefa.2022.102397

Simopoulos, Artemis P. “Omega-3 fatty acids in inflammation and autoimmune diseases.” Journal of the American College of Nutrition vol. 21,6 (2002): 495-505. doi:10.1080/07315724.2002.10719248

Stanton, Alice V et al. “Omega-3 index and blood pressure responses to eating foods naturally enriched with omega-3 polyunsaturated fatty acids: a randomized controlled trial.” Scientific reports vol. 10,1 15444. 22 Sep. 2020, doi:10.1038/s41598-020-71801-5

Stoodley, Isobel et al. “Higher Omega-3 Index Is Associated with Better Asthma Control and Lower Medication Dose: A Cross-Sectional Study.” Nutrients vol. 12,1 74. 27 Dec. 2019, doi:10.3390/nu12010074

Superko, H Robert et al. “Omega-3 fatty acid blood levels: clinical significance and controversy.” Circulation vol. 128,19 (2013): 2154-61. doi:10.1161/CIRCULATIONAHA.113.002731

von Schacky, Clemens. “Omega-3 index and cardiovascular health.” Nutrients vol. 6,2 799-814. 21 Feb. 2014, doi:10.3390/nu6020799

von Schacky, C. “Verwirrung um die Wirkung von Omega-3-Fettsäuren : Betrachtung von Studiendaten unter Berücksichtigung des Omega-3-Index” [Confusion about the effects of omega-3 fatty acids : Contemplation of study data taking the omega-3 index into consideration]. Der Internist vol. 60,12 (2019): 1319-1327. doi:10.1007/s00108-019-00687-x