Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis: Research Challenges and Opportunities

Discussion:

Workshop members reviewed the present state of knowledge related to n-3 fatty acids and cardiac arrhythmia mechanisms. Dietary sources and quantification of n-3 fatty acids, competition between n-3 and n-6 fatty acids, pathways for production of tissue n-3 and n-6 highly unsaturated fatty acids, and the importance of adequate measurements in clinical trials were reviewed. Evidence was presented that the risk of either cardiac arrest or sudden death is associated with low dietary intake and blood levels of polyunsaturated fatty acids and that a fish diet (the DART study) or dietary supplementation with polyunsaturated fatty acids (the GISSI-Prevenzione study) decrease mortality and/or sudden death following myocardial infarction. Although the NHLBI-supported, randomized, double blind Antiarrhythmic Effects of N-3 Fatty Acids study showed no benefit of dietary n-3 fatty acids, a trend toward increased arrhythmias in patients who had high arrhythmic risk and implantable cardioverter defibrillators (ICDs) was observed. By contrast, the NHLBI-supported Fatty Acid Antiarrhythmic Trial (FAAT) did show a strong trend toward benefit in a similar population. A review of animal models showed fewer ischemia- and reperfusion-induced arrhythmias in rats fed n-3 fatty acids (EPA or DHA), but highlighted the limited scope of the animal models studied to date. The evidence for several different mechanisms by which n-3 fatty acids may alter arrhythmias was discussed in detail, including potential effects on cardiac sodium channels, calcium channels, the sodium-calcium exchanger, lipid rafts, calcium release from the sarcoplasmic reticulum, kinases (including PKA and CaMKII), and myocardial oxygen stress. Potential anti-inflammatory properties of n-3 fatty acids and the relationship of inflammatory changes to both atrial and ventricular arrhythmias were discussed. Current gaps in our knowledge include the absence of proof that n-3 fatty acids decrease arrhythmias in patients at risk for sudden death, uncertainty as to which patients may benefit most from supplementation, limited mechanistic data from animal models, and no definitive understanding as to which basic mechanisms transduce effects on cardiac electrogenesis.

Recommendations:

• Prior and ongoing randomized clinical trials should be reviewed and compared in detail. These should include the GISSI-HF trial; two completed, NHLBI-supported, randomized, blinded, ICD trials (FAAT and the Antiarrhythmic Effects of N-3 Fatty Acids trial); and the recently completed Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA). The availability of stored serum samples from all trials should be ascertained so that serum samples might be used to test for inflammatory biomarkers, for example.
• Since the ischemic post-MI population may obtain the greatest benefit from n-3 fatty acids, a randomized, double blind, clinical trial to directly test the effect of n-3 fatty acids on arrhythmia frequency in this population should be considered. Serum samples for inflammatory biomarkers and DNA for genetic studies should be obtained in all future studies.
• N-3 fatty acids may affect cardiac arrhythmia susceptibility through numerous mechanisms, and these mechanisms should be explored further in animals fed diets containing low, medium, and high amounts of polyunsaturated fatty acids. Examples of productive approaches would include programmed electrical stimulation in vivo, optical mapping of isolated hearts, cellular electrophysiology, and molecular and enzymatic measurements. Tissue levels of highly unsaturated fatty acids should also be determined. Genomic, proteomic, and lipidomic approaches, as well as computer and tissue modeling, would also improve understanding of the potential role and scope of n-3 fatty acids in cardiac electrogenesis.
• Preliminary studies that focus on other fatty acids (e.g., alpha-linolenic and sterodonic acids) should be encouraged. Methods to rapidly and efficiently measure fatty acid composition in blood and tissue samples should be explored/developed.

Publication Plans:

• A summary of the meeting is available in the journal, Circulation: London B, Albert C, Anderson ME, et al. Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office Of Dietary Supplements Omega-3 Fatty Acids and their Role in Cardiac Arrhythmogenesis Workshop. Circulation. 2007 Sep 4;116(10):e320-35. The full article is available online at http://circ.ahajournals.org/cgi/content/full/116/10/e320.

NHLBI Contact:

David A. Lathrop, Ph.D, NHLBI, NIH
lathropd@mail.nih.gov

Isabella Liang, Ph.D. NHLBI, NIH
liangi@mail.nih.gov