Experimental studies suggest that there are multiple, relevant molecular mechanisms which together contribute to producing the beneficial effects of omega-3 fatty acids in a number of ways. These include effecting membrane structure and associated functions, ion channel properties, genetic regulation, synthesis of pro-inflammatory or pre-thrombotic eicosanoids, and production of inflammation-resolving mediators. All of which in turn may reduce cardiovascular risk factors and hinder the development of diseases (3). In prospective observational studies and randomized clinical trials, benefits of omega-3 fatty acids, like DHA and EPA, seem most consistent for coronary heart disease mortality and sudden cardiac death. Potential effects on cardiovascular risk factors, such as plasma triglycerides, heart rate, blood pressure, vascular function, myocardial filling and efficiency, as well as inflammation, are less-well-established.
The reduction of plasma triglycerides has long been recognized as beneficial for cardiovascular health. Omega-3 fatty acids reduce plasma triglyceride levels, which is at least partly due to reduced hepatic very-low-density lipoprotein production rate (4). Lowering their level in the liver results in a reduction of the conversion of carbohydrates to fats and increased breakdown of fatty acids (beta-oxidation). Although plasma triglycerides decrease linearly and dose-dependent across a wide range of consumption of omega-3 fatty acids, the individual response varies considerably (5). The greatest reductions are seen in individuals who already have high baseline triglyceride levels. At typical dietary omega-3 fatty acid doses, only modest triglyceride-lowering occurs. It is unlikely that this contributes appreciably to the reduced cardiovascular risk seen with fish oil supplements in randomized controlled trials or habitual fish consumption in observational studies.
A review of 16 studies showed that a reduction in blood triglycerides of 15–20% could be achieved in patients with elevated triglyceride levels supplemented with 1–2g algal DHA per day regardless of whether or not they were already on cholesterol-lowering medication (statins) (6). There were increases in both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol. Though in the latter case, the levels were small and a shift of LDL particle size towards large, less atherosclerosis-promoting types was observed. A meta-analysis of 11 studies in healthy individuals using DHA algal oil resulted in very similar findings (7).
There does not appear to be significant differences in triglyceride-lowering benefits between DHA alone and DHA/EPA combinations when dosing is based on DHA (8). A meta-analysis showed that although EPA and DHA both reduce triglycerides (though DHA has the greater effect), they have divergent effects on LDL and HDL (9). DHA raised high-density lipoprotein compared with placebo, whereas EPA did not.
Heart rate and blood pressure
The consumption of omega-3 fatty acids lowers the resting heart rate (HR), which at high frequencies can be a major risk factor for sudden death, and systolic and diastolic blood pressure. A meta-analysis of 30 randomized controlled trials (10) showed that fish oil intake (median EPA+DHA dose: 3.5 g/day) reduced HR (about 1.6–2.5 beats per minute), particularly in those with higher baseline HR (above 69 bpm) or longer treatment duration (longer than 12 weeks). The mechanism is not clear, but it could result from electrophysiological pathways or improved filling of the left ventricle of the heart.
The lowering effect that fish oil exhibits on the blood pressure (BP) was estimated in a meta-analysis of 90 andomized controlled trials (11). The intake of fish oil (average EPA+DHA dose: 3.7 g/day) reduced systolic BP by 2.1 mmHg and diastolic BP by 1.6 mmHg. BP effects tended to be larger in populations that were older (above 45 years) and in hypertensive populations (BP higher 140/90 mmHg). Omega-3 fatty acids may contribute to lowering systemic vascular resistance and blood pressure by improving arterial compliance (elasticity).
It is commonly believed that omega-3 fatty acids have anti-thrombotic effects, but in fact bleeding times only increase when extremely high doses are consumed (e.g., 15 grams of EPA/DHA per day). Human trials to date have failed to show consistent effects of omega-3 fatty acids on platelet or coagulation factors (12,13). Thus, at doses of at least up to four grams per day anti-thrombotic effects are unlikely to be a major pathway for lowering cardiovascular disease risk. No risk of excess bleeding has been seen to date in any randomized clinical trial involving consumption of fish or marine oils, even among patients undergoing surgery or taking aspirin or Warfarin (14).
Several trials with healthy adults (15), diabetics (16), and obese people (17) have shown that omega-3 fatty acid supplementation can support endothelial function, demonstrated by improved flow-mediated arterial dilation. Some trials have also found that omega-3 fatty acid consumption lowers circulating markers of endothelial dysfunction (18). Thus, normalization of endothelial function could partly mediate protective effects of omega-3 fatty acids against cardiovascular diseases.
Cardiac filling and myocardial efficiency
There is growing evidence in human studies with healthy adults as well as patients with chronic heart failure that suggests omega-3 fatty acid consumption improves both early (energy-dependent) and late (compliance-dependent) left ventricular diastolic filling (19). Such effects could partly relate to long-term improvements in ventricular compliance, due to reduced systemic vascular resistance. In at least one randomized controlled trial, fish oil consumption also improved myocardial efficiency, reducing workload-specific myocardial oxygen demand without reducing peak performance (20). In some clinical trials, omega-3 fatty acid consumption also improved left ventricular ejection fraction in patients with established heart failure (21).
Insulin resistance and diabetes
At present, it is unclear whether omega-3 fatty acids have clinical effect on diabetes in humans. In a meta-analysis of 26 randomized controlled trials, fish oil supplementation (2 to 22 g/day) slightly raised fasting glucose in patients with type 2 diabetes and lowered fasting glucose in patients with type 1 diabetes (22). Two additional meta-analyses of 18 and 23 clinical trails found no overall effects of fish oil (0.9 to 18 g/day) in patients with type 2 diabetes (23,24).
Omega-3 fatty acids are precursors of anti-inflammatory mediators, such as resolvins and protectins and thus have anti-inflammatory properties, which assist in the resolution of inflammation. However, it remains unclear whether such effects are clinically meaningful, especially at doses typical of dietary intake. In several trials, omega-3 fatty acid supplementation reduced blood levels of certain inflammatory biomarkers (25) while the findings for other markers were mixed (26). Fish oil is a proposed adjunctive therapy for inflammatory diseases such as rheumatoid arthritis (27), and meta-analyses of randomized controlled trials found that high-dose omega-3 fatty acid supplementation (1.7 to 9.6 g/day) reduced morning stiffness and joint pain in patients with rheumatoid arthritis (28).
Although results from in-vitro studies and animal experiments as well as at least some human studies remain compelling (29–31), confirmation of clinically relevant anti-arrhythmic effects of omega-3 fatty acids has remained elusive. Due to the absence of suitable biomarkers, quantification is difficult. It is not clear if potential benefits are due to direct effects on myocyte electrophysiology or more indirect influences such as improve-ments in myocardial efficiency, autonomic tone, local inflammatory responses, and the like.
Numerous meta-analyses of large randomized controlled trails indicate that consumption of fish or omega-3 fatty acids significantly reduces mortality due to coronary heart disease (CHD), including fatal myocardial infarction and sudden cardiac death, in populations with and without established cardiovascular disease (CVD) (32,33). Not all clinical trials have demonstrated reductions in CHD mortality (e.g., the Alpha-Omega, Omega, JELIS, DART 2 and SU.FOL.OM3 trials). Among these, only the DART 2 trial (34), conducted on men with stable angina, was adequately designed to detect such effects. However, the limitations of DART 2 make it difficult to interpret this trial’s findings showing no effect (3). The final common pathway for most cardiac deaths is arrhythmia, in which omega-3 fatty acids have been shown to be potentially beneficial. Clinical effects on nonfatal coronary events cannot yet be considered established.
Meta-analyses of observational studies suggest that fish consumption reduces risk of ischemic stroke (35), but stroke incidence has not been significantly affected in fish oil trials (36). Reasons for these differing findings remain unclear, with possibilities including inadequate statistical power in the trials (which were not designed to evaluate stroke as an endpoint) or insufficient length of treatment periods during the trials (3).
In vitro and animal experiments suggest that omega-3 fatty acids could reduce onset of atrial fibrillation (AF) by direct anti-arrhythmic effects. A number of human studies have further evaluated potential effects. Adequate fish or dietary omega-3 fatty acid consumption was associated with lower AF incidence in some (37) but not other (38) large observational cohorts.
Fish or dietary omega-3 fatty acid consumption has been associated with lower incidence of heart failure in some prospective observational studies (39, 40). An investigation found this relationship to be strongest for eicosapen-taenoic acid. It showed a 50% reduction of incidence of congestive heart failure (CHF) among participants with the highest intakes compared to those with the lowest intakes (41). In a randomized controlled trail among nearly 7,000 patients with established heart failure, omega-3 fatty acid supplementation (1 g/day) reduced total mortality by 8% (42). Potential effects of omega-3 fatty acids on preventing heart failure incidence require further study.