Are n -3 Polyunsaturated Fatty Acids Antiarrhythmic in the Absence of Ischemia?

In this issue of Cardiovascular Drugs and Therapy Nodari et al. [1] add to the growing fund of knowledge on the possible antiarrhythmic effects of n-3 polyunsaturated fatty acids (n-3 PUFA). In this relatively small study the investigators found that, compared to placebo, 6 months of supplementation with n-3 PUFA improved a wide range of markers of the risk of ventricular arrhythmias and sudden death in patients with non-ischemic cardiomyopathy and frequent ventricular ectopy. These observations included improved findings on microvolt T-wave analysis, QRS signal averaging, non sustained arrhythmias on Holter, heart rate variability analysis, catecholamine and cytokine plasma levels, left ventricular function, and exercise capacity. The breadth of these potentially beneficial effects is remarkable. Perhaps more remarkable is that these effects were observed in patients with non-ischemic cardiomyopathy. As I will discuss below, to date the antiarrhythmic effects of n-3 PUFA have been demonstrated primarily in ischemic ventricular fibrillation animal models and in patients with coronary artery disease at risk for acute ischemia. The idea that n-3 PUFA might protect against death from heart disease dates back to the observation of a lower than expected risk of coronary artery disease in Greenland Eskimos who have a diet that is especially high in n-3 PUFA [2]. Subsequent observational studies have shown that a diet high in fish especially cold water fatty fish which are rich in n-3 PUFA is associated with a reduced risk of death from heart disease. The concept that n-3 PUFA may reduce cardiac deaths via antiarrhythmic effects is supported by basic science, animal, and human studies. In vitro studies have shown that acutely superfused n-3 PUFA can interact with sodium [3], potassium [4] and calcium ion channels [5, 6] in the cell membrane. Of these interactions the most important appears to be the ability of n-3 PUFA to inactivate sodium channels in the presence of myocardial ischemia [3]. Rats chronically fed a diet high in n-3 PUFA were significantly less likely to have ventricular fibrillation during acute myocardial ischemia than were animals fed a control diet [7]. Similarly, the acute infusion of n-3 PUFA in a dog model of acute ischemic ventricular fibrillation was associated with a marked reduction in the risk of the arrhythmia [8]. The Physician’s Health study showed a reduction in sudden death with higher fish intake but no reduction in the risk of myocardial infarction [9]. When fatty acids levels were examined in this population there was a strong inverse relationship between n-3 PUFA levels but not other fatty acids and the risk of sudden death [10]. Similarly, a case control study that compared patients who had suffered a cardiac arrest and matched controls found significantly higher fish intake and n-3 PUFA levels in controls [11]. The most convincing evidence of an antiarrhythmic effect of n-3 PUFA comes from the GISSI investigators [12] who entered 11,324 patients with a recent myocardial infarction into a study in which subjects were randomized to 300 mg of vitamin E, 850 mg of n-3 PUFA, both vitamin E and n-3 PUFA, or neither. Patients assigned to n-3 PUFA had a 20% reduction in all cause mortality and a 45% reduction in the risk of sudden death. Vitamin E showed no benefit. This significant reduction in sudden death has been interpreted as a strong indicator that the benefit was Cardiovasc Drugs Ther (2009) 23:1–3 DOI 10.1007/s10557-008-6151-6