NHLBI Workshop
Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis:
Research Challenges and Opportunities
Executive Summary
The National Heart, Lung, and Blood Institute convened a Workshop on
August 29-30, 2005, in Washington, District of Columbia to: (1) review
the epidemiological evidence and data from NHLBI-supported randomized
trials on the role of omega-3 (n-3) fatty acids in susceptibility to cardiac
arrhythmias and sudden cardiac death; (2) explore the basic mechanisms
by which n-3 fatty acids affect cardiac excitability at the cellular and
organ level; (3) identify gaps and barriers in basic understanding of
the effects of n-3 fatty acids on cardiac electrical activity at the cellular,
tissue, and whole body levels; and (4) provide prioritized recommendations
to the NHLBI for additional research studies of the role of n-3 fatty
acids in cardiac arrhythmogenesis.
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
Last updated: November 28, 2007
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