Author + information
- Tobias Glück, MD and
- Peter Alter, MD∗ ()
- ↵∗University of Marburg, Internal Medicine, Baldingerstrasse, 35033 Marburg, Germany
We read with great interest the recent report by Nigam et al. (1) about the AFFORD (Multi-Center Study to Evaluate the Effect of n-3 Fatty Acids [Omega-3] on Arrhythmia Recurrence in Atrial Fibrillation) trial. Supplementation of 4 capsules fish oil per day (containing a total of 1,600 mg eicosapentaenoic acid, 20:5n-3, and 800 mg docosahexaenoic acid [DHA], 22:6n-3) was shown not to reduce recurrence of atrial fibrillation. In parallel, markers of inflammation or oxidative stress were not affected. Up to now, numerous studies have provided a large variety of potential effects attributed to highly unsaturated fatty acid (HUFA) treatment ranging from marked prognostic improvements in heart failure and antiarrhythmogenic actions to no incremental effects. Due to the divergent results, the question arises whether mechanisms exist beyond an external HUFA intake.
In heart failure, an inverse shift of serum fatty acids occurs; particularly saturated and monounsaturated fatty acids were increased, whereas poly- and highly unsaturated omega-6 and omega-3 fatty acids were decreased (2,3). We have recently shown that increased ventricular wall stress is associated with reduced DHA levels (unpublished data, P. Alter, January, 2015). Similar, but less pronounced effects were found for eicosapentaenoic acid and arachidonic acid (20:4n-6). Because the liver is the major source of endogenous HUFA, pseudocholinesterase activity, a marker of hepatic metabolizing capacity, was examined and shown to be inversely correlated with increased end-diastolic and end-systolic ventricular wall stress, which emphasizes the hypothesis of a cardio-hepatic syndrome (e.g., influenced by congestion). In addition, local variances of the endogenous HUFA metabolism leading to inhomogeneities of HUFA concentrations and effects should be considered.
It was previously shown that systemic HUFA levels in red blood cells and plasma correlate with right atrial concentrations. Oral HUFA supplementation was incorporated into the atrial myocardium (4). However, little is known about cardiac influences on myocardial HUFA levels (5). We recently found significant differences of DHA concentrations among atrial and ventricular myocardium in experimental animals by using gas chromatography/mass spectrometry (atrium 4.69 ± 1.02% vs. ventricle 8.99 ± 2.05%; p < 0.001) (unpublished, P. Alter, January, 2015). It is suggested that different load conditions, in particular increased wall stress, are involved. Because DHA exhibits antiarrhythmogenic actions, the question arises whether reduced atrial DHA levels account for an increased risk of atrial fibrillation. Of note, intermediate DHA metabolism products, particularly tetracosapentaenoic acid (24:5n-3) and tetracosahexaenoic acid (24:6n-3), were increased in atrial, but not in ventricular myocardium after intrapericardial HUFA administration, which was associated with a higher ventricular potential to finalize DHA synthesis. Tetracosahexaenoic acid requires carnitine octanoyltransferase, a family member of carnitine acetyltransferases, for transportation into the endoplasmic reticulum to undergo final beta-oxidation. It was previously shown that carnitine palmitoyltransferase (1b and 2) is reduced in atrial compared with ventricular myocardium. It is proposed to evaluate beta-oxidation as a novel target for endogenous HUFA concentrations. In accordance with the report by Nigam et al. (1), no changes of HUFA levels were found after a challenge with the proinflammatory peroxisome proliferator-activated receptor-alpha agonist fenofibrate or in a talcum-induced pericarditis model.
Up to now, involvement of cardiac load conditions and the differential endogenous HUFA metabolism were not sufficiently taken into account, which may provide a rationale for divergent findings of HUFA treatment in previous trials.
Please note: In memory of Heinz Rupp. Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Nigam A.,
- Talajic M.,
- Roy D.,
- et al.,
- for the AFFORD Investigators
- Rupp H.,
- Rupp T.P.,
- Alter P.,
- Maisch B.