The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.
Keywords: atrial fibrillation; docosahexaenoic acid; eicosapentaenoic acid; fatty acids, omega-3.