Marine Omega-3 (N-3) Fatty Acids
for Cardiovascular Health:
An Update for 2020

 

 

The omega-3 (n-3) fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in seafood (especially fatty fish), supplements and concentrated pharmaceutical preparations.

 

Long-term prospective cohort studies consistently demonstrate an association between higher intakes of fish, fatty fish and marine n-3 fatty acids (EPA + DHA) or higher levels of EPA and DHA in the body and lower risk of developing cardiovascular disease, especially coronary heart disease and myocardial infarction, and cardiovascular mortality in the general population.

 

This cardioprotective effect of EPA and DHA is most likely due to the beneficial modulation of a number of known risk factors for cardiovascular disease, such as blood lipids, blood pressure, heart rate and heart rate variability, platelet aggregation, endothelial function, and inflammation.

 

Evidence for primary prevention of cardiovascular disease through randomised controlled trials is relatively weak.

 

In high-risk patients, especially in the secondary prevention setting, a few large RCTs support the use of EPA + DHA as confirmed through a recent meta-analysis.

 

This review presents some of the key studies that have investigated EPA and DHA in the primary and secondary prevention of cardiovascular disease, describes potential mechanisms for their cardioprotective effect, and evaluates the more recently published RCTs in the context of existing scientific literature.

 

 

Omega-3 fatty acids are a family of polyunsaturated fatty acids. They are recognizeded by, and named according to, the presence of the closest double bond to the methyl end of the hydrocarbon (acyl) chain being on carbon number three, if the methyl carbon is counted as number one.

 

The most functionally important n-3 fatty acids appear to be eicosapentaenoic acid and docosahexaenoic acid; however, roles for docosapentaenoic acid have also emerged now.

 

EPA and DHA are often referred to as marine n-3 fatty acids because of their association with seafood.

 

The potential for EPA and DHA to have a role in reducing the risk of cardiovascular disease was first identified by studies in the Greenland Inuit, where the low rate of mortality from myocardial infarction and ischaemic heart disease was linked to the very high dietary intake of EPA and DHA.

 

The intake of EPA and DHA is highly correlated
with their concentrations in blood lipids and red blood cells.

 

A number of studies have associated the concentrations of EPA + DHA in blood plasma or serum, plasma lipid fractions, whole blood, red blood cells and adipose tissue with lower cardiovascular morbidity and mortality.

 

More recently, the largest prospective cohort study conducted to date included ~420,000 participants from the National Institutes of Health AARP Diet and Health Study with a 16-year follow-up and reported a significant inverse association between fish and EPA + DHA intake and various mortality outcomes.

 

Cohort studies associating the intake of fish or marine n-3 fatty acids
with cardiovascular or coronary outcomes
have been subject to a number of meta-analyses.

 

The association between EPA or DHA concentration in a body compartment, such as plasma, serum, red blood cells or adipose tissue, and risk of future CHD in adults who were healthy at study entry was investigated by pooling data from 19 studies involving over 45,000 individuals.

 

EPA and DHA were each independently associated with a lower risk of fatal CHD, with a 10% lower risk for each one standard deviation increase in content.

 

The omega-3 index is the red blood cell content of EPA+DHA expressed as a proportion of total fatty acids. Omega-3 index is a marker of both long-term dietary intake of these fatty acids and their tissue levels and is suggested to be a marker of CHD risk. Harris et al. used data from 10 cohort studies and identified a 15% reduction in risk of fatal CHD for each one standard deviation increase in omega-3 index.

 

Mechanisms by which EPA and DHA Reduce the Risk of Cardiovascular Disease

 

 

These risk factors of Cardiovascular Disease include high blood pressure, high serum triglycerides, low high-density lipoprotein (HDL)-cholesterol, elevated post-prandial lipaemia, endothelial dysfunction, cardiac arrhythmia, heart rate and heart rate variability and a tendency towards thrombosis and inflammation.

 

Large numbers of studies, including many RCTs, in humans have investigated the effect of the combination of EPA and DHA on these risk factors and many of these studies have been included in a number of meta-analyses performed in recent years.

 

These meta-analyses demonstrate that EPA and DHA lower triglycerides, lower the blood pressure (both systolic and diastolic), reduce the heart rate and increase heart rate variability and reduce platelet aggregation, whilst appearing to increase both low density lipoprotein (LDL)- and HDL-cholesterol.

 

Regarding vascular endothelial function, EPA and DHA have been demonstrated to improve flow-mediated dilatation and arterial compliance. Furthermore, EPA and DHA have been reported to decrease the plasma or serum concentrations of pro-inflammatory eicosanoids like thromboxane B2 and leukotriene B4.

 

A recent systematic review of the scientific literature concluded that EPA and DHA appear to have differential effects on a number of cardiometabolic outcomes. For example, regarding modulation of blood lipids, whilst both EPA and DHA lowered blood triglycerides, there was evidence for a slightly larger triglyceride-lowering effect for DHA.

 

Whilst neither EPA nor DHA affected total cholesterol concentrations to a significant degree, there was an independent effect on other blood lipid parameters, with EPA lowering the HDL3-cholesterol subfraction and DHA increasing the more cardioprotective HDL2-cholesterol.

 

DHA also increased LDL-cholesterol more than EPA, an effect observed more in men than in women, and increased LDL particle size, an effect which was not observed with EPA.

 

DHA appears to be more effective than EPA at lowering blood pressure and heart rate in normotensive individuals, whilst neither EPA nor DHA had any effect in hypertensive diabetic patients.

 

DHA also appeared to increase vasodilatory effects and reduce constrictor effects in the vasculature. Both EPA and DHA were equally effective at increasing systemic arterial compliance.

 

Furthermore, from the limited comparative studies available, DHA seemed to be more effective than EPA at lowering a wide range of pro-inflammatory biomarkers in subjects with subclinical inflammation. Both EPA and DHA, however, were effective at reducing biomarkers of oxidative stress.

 

Trusted Authority Views on Marine n-3 Fatty Acids and Cardiovascular Disease

 

In 2010, the European Food Safety Authority (EFSA)
concluded that EPA and DHA help to maintain normal cardiac function,
normal blood pressure and normal blood concentrations of triglycerides
in the general population.

The American Heart Association (AHA) also
supports the use of marine n-3 fatty acids.

 

 

Conclusions

 

There is a large body of evidence gathered from long-term prospective cohort studies that consistently demonstrates an association between higher intakes of fish, fatty fish and marine n-3 fatty acids (EPA+DHA) or higher levels of EPA and DHA in the body and lower risk of developing CVD, especially CHD, having an MI and cardiovascular mortality in the general population.

 

This cardioprotective effect of EPA and DHA is plausible considering the robust identification of mechanisms that show that EPA and DHA beneficially modulate a number of known risk factors for CVD, such as blood lipids, blood pressure, heart rate and heart rate variability, platelet aggregation, endothelial function and inflammation. Despite this, evidence for primary prevention of CVD through RCTs is relatively weak.

 

Surveying these trials serves to highlight a number of factors which may have contributed to the positive outcomes reported and why other trials have had less conclusive or even null findings.

 

Such factors include a sufficiently high dose of EPA alone or of a combination of EPA + DHA; sufficient duration of supplementation; supplementation in post-MI patients to begin relatively soon post-MI; and the adequate powering of studies to detect an effect on the primary outcome which may have a low rate of occurrence.

 

Nevertheless, background intakes of EPA and DHA can be highly variable both within and between individuals, with significant changes occurring simply by eating a single meal of fatty fish. Finally, the bioavailability of EPA and DHA can vary:
(a) among individuals due to physiological differences,
(b) according to the intake of meals in relation to supplements and
(c) perhaps according to the time of day, thus influencing how much of these bioactive fatty acids is actually available to exert their effects.

 

Both EPA and DHA beneficially modify a range of risk factors, although DHA may be more effective.

 

 

 

 

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References:

“Marine Omega-3 (N-3) Fatty Acids for Cardiovascular Health:  An Update for 2020”  Int. J. Mol. Sci. 2020, 21(4), 1362;  https://doi.org/10.3390/ijms21041362