Physiological effects of n-3 PUFA that might influence the risk of cardiovascular disease (CVD) are depicted in . Randomized trials assessed the efficacy of fish oil supplementation in a population after myocardial infarction (MI) with an ejection fraction of 40%. The GISSI-Prevention (GISSI-P) study randomized 11,324 patients to n-3 PUFA within three months after MI. Results demonstrated relative risk reductions in overall mortality (20%), cardiac mortality (30%), and sudden cardiac death (SCD, 45%) with 1
g/day of highly purified omega-3 acid ethyl esters (Omacor) over a 3.5-year period [2
]. Significant benefits emerged within three to four months especially in those with extensive left ventricular dysfunction. Some studies suggest that n-3 PUFA improves heart rate variability as a marker of autonomic function [16
]. Holter monitor recordings showed an increase in heart rate variability (HRV) in the fish oil group [18
]. Observational studies have linked omega-3 FA with the prevention of sudden cardiac death (SCD). Heart rate variability has been shown to be one of the best predictors of the risk of SCD. The data showed clearly that n-3 fatty acids increase HRV. This supports the hypothesis that an increased intake of n-3 fatty acids may reduce the risk of SCD [19
]. However, in a larger cohort assessed in the Japan EPA lipid intervention study (JELIS) there was lack of an effect of fish oil on the incidence of sudden death and heart rate variability [20
Figure 2 Physiological effects of n-3 PUFA that might influence cardiovascular disease (CVD) risk .
Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with considerable morbidity and mortality [21
]. The role of omega-3 FA and its potential antiarrhythmic effect in the prevention of AF have been postulated. AF is a common complication after coronary artery bypass grafting operation (CABG).A prospective randomized study showed the efficacy of fish oil on AF after CABG. Perioperative intravenous infusion of polyunsaturated fatty acids (PUFA) reduced the incidence of AF after CABG leading to a shorter stay in the intensive care unit (ICU) and in hospital [22
]. However, outcome of clinical research has been contradictory, and a definite role of omega-3 FA in the setting of AF has not been demonstrated [23
]. The results of the OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 FA on top of modern guideline-adjusted therapy after myocardial infarction, showed a low rate of SCD, total mortality, and major adverse cerebrovascular and cardiovascular events within 1 year of followup after guideline- adjusted treatment and secondary prevention of acute myocardial infarction [24
]. The results of this study should be interpreted carefully, because it was substantially underpowered. Alpha omega (study of omega-3 fatty acids and coronary mortality) studied n-3 PUFA supplemented margarine in post-MI patients [25
]. The study outcome was neutral, the study was underpowered as well.
GISSI-heart failure (GISSI-HF) was a large adequately powered trial evaluating n-3 PUFA in heart failure [26
]. Results demonstrated a significant and clinically important reduction of all-cause mortality with 1
g Omacor in a heart failure population. n-3 PUFA supplementation showed an absolute risk reduction of 1.8% in all-cause mortality seen over two years of followup. There was little benefit in atherothrombotic events, such as MI or stroke.
Another effect of n-3 PUFA is lowering of plasma triglycerides [27
]. This effect is caused by several mechanisms like reduced hepatic very low-density lipoprotein synthesis, increased fatty acid beta-oxidation, reduced delivery of nonesterified fatty acids to the liver, reduced hepatic enzyme activity for triglyceride synthesis, and increased hepatic synthesis of phospholipids rather than triglycerides.
n-3 PUFA consumption reduces heart rate and systolic and diastolic blood pressure [28
]. The decrease of heart rate is probably caused by direct effects on electrophysiologic pathways [10
] and by indirect effects like the improving of left ventricular diastolic filling or an augmented vagal tone [16
]. According to some trials the reduction of blood pressure is a consequence of increased nitric oxide production, a mitigated vasoconstrictive response to norepinephrine and angiotensin II, enhanced vasodilatory responses, and improved arterial compliance [30
The suspected antithrombotic effects of n-3 PUFA seen in some studies could not be confirmed in some human trials, where n-3 PUFA had no relevant effect on platelet aggregation and coagulation factors [32
Several trials found an improvement of endothelial function in some studies decreased markers of endothelial dysfunction were measured after n-3 PUFA consumption [34
]. The normalization could partly mediate a protective effect against CVD.
In some studies n-3 PUFA consumption improved cardiac filling and myocardial efficiency measured by a reduced workload-specific oxygen demand [35
]. In two trials n-3 PUFA even improved left ventricular function in patients with heart failure [36
The trial results concerning the influence of n-3 PUFA on insulin resistance and diabetes are still contradictory. While some trials found a modestly higher incidence of type 2 diabetes caused by n-3 PUFA consumption, most of the trials did not see any consistent effects on fasting glucose or hemoglobin A1c in patients with non-insulin-dependent diabetes [38
Because of the above-mentioned suspected anti-inflammatory properties of n-3 PUFA, fish oil is already used as an adjunctive therapy for several inflammatory diseases like rheumatoid arthritis [39
]. Nevertheless, the clinical impact of such anti-inflammatory effects, especially at usual dietary doses, is still unclear and will have to be subject of further studies. Possible effects of n-3 PUFA in the cardiovascular system are listed in .
According to numerous meta-analyses, all these possible benefits of n-3 PUFA seem to lead to a significant reduction of mortality by chronic heart disease (CHD) [40