How then are omega-3 PUFAs thought to influence CVD progression and reduce mortality? Several pathways have been investigated.

Hypolipidemic. It is well established that omega-3s reduce lipid levels, and this is the basis for the approved indication for use of Lovaza in hypertriglyceridemia. It is generally acknowledged that doses >3-4 g/day are required. The mechanism of omega-3’s triglyceride reduction relates to its favorable effects on reducing hepatic production and secretion of very-low-density lipoprotein (VLDL) and VLDL apo B particles, its favorable effects on plasma lipolytic activity through lipoprotein lipase-mediated clearance, and its ability to stimulate beta-oxidation of other fatty acids in the liver.14

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Generally, omega-3s produce no significant improvements in LDL, except in patients with elevated triglycerides, in whom modest improvements in LDL and HDL are sometimes seen. Even when absolute LDL levels are not significantly impacted by fish-oil supplementation (or even when they increase, as has occasionally been reported), there is evidence that omega-3s may shift particle size to a more benign, “fluffier” LDL, thus favorably impacting the atherogenic profile.

Antithrombotic. Fish oils produce platelet inhibition and reduce fibrinogen. Although some experts contend that higher doses (>3-4 g/day) are required, others argue for a lower threshold. Epidemiologic evidence of fish oil’s anti-clotting effects comes from several studies that link higher intake of fish oil to a reduction in ischemic strokes with coincident increased risk of hemorrhagic strokes. This leads to a net gain in protection, since ischemic strokes outnumber hemorrhagic strokes by 85% to 15%.

Antihypertensive. Fish oil is thought to exert an antihypertensive effect in several ways. It supports flow-mediated vasodilation, enhances vascular reactivity, and may balance autonomic tone by reducing adrenergic drive.

An analysis of randomized trials revealed that consumption of approximately 4.0 g/day of omega-3 fatty acid was associated with a significant 1.7- and 1.5-mm Hg reduction in systolic and diastolic BP, respectively; these reductions were more pronounced in older patients and in individuals with higher BP. Evidence suggests that lowering systolic BP by as little as 2 mm Hg can yield reductions of 4% in CAD mortality.15

Adiponectin. A hormone produced by fat cells, adiponectin plays a role in regulating lipids and glucose. Low levels of this hormone are associated with obesity, and higher levels have been shown to confer protection against heart disease. When administered to obese individuals, 1.8 g/day of EPA increased the level of adiponectin.16

Insulin regulator. To date, research in the area of insulin regulation has been inconclusive. While numerous studies support a role for EPA/DHA in attenuating insulin resistance, and omega-3 deficiency has been associated with the metabolic syndrome, the Agency for Healthcare Research and Quality reports, “Among 18 studies of type 2 diabetes or the metabolic syndrome, omega-3 fatty acids . . . had no effect on fasting blood sugar, or glycosylated hemoglobin, by meta-analysis. Omega-3 fatty acids had no effect on plasma insulin or insulin resistance in type 2 diabetics or patients with the metabolic syndrome, by qualitative analysis of four studies.”17

Antiarrhythmic. The principle cause of sudden cardiac death (SCD) is sustained ventricular arrhythmia. Considerable evidence supports an antiarrhythmic role for omega 3s, probably via autonomic pathways. Studies show that EPA/DHA enhances sympatho-vagal tone, leading to slower heart rates and fewer arrhythmias, and in some studies, reduced incidence of SCD. Omega 3s have also been shown to favorably impact heart rate variability, a marker of autonomic adaptability.

Knowledge of fish oil’s beneficial effects on arrhythmias recently prompted a trial of omega-3 supplementation in patients with implantable cardioverter defibrillators (ICDs). The results—which showed a higher incidence of ICD discharges in consumers of fish-oil supplements—and the consequent negative publicity have dampened enthusiasm over fish oil for this indication.

Some studies have shown impressive results for fish oil in prophylaxis of atrial fibrillation, particularly in patients at risk after coronary artery bypass grafting.18

Anti-inflammatory. Omega-3 fatty acids act as eicosanoid precursors to reduce inflammation. This may impact cardiovascular risk in several ways.

First, chronic inflammation is thought to play a critical role in endothelial damage that leads to compromised vascular reactivity and atherosclerotic changes. Additionally, inflammation promotes unstable plaque, a harbinger of thrombotic events.