Letter by Pignier and Le Grand Regarding Article “Acute Administration of Fish Oil Inhibits Triggered Activity in Isolated Myocytes From Rabbits and Patients With Heart Failure”
To the Editor:
We read with a great interest the article by den Ruijter et al,1 which showed that acute application of ω3-polyunsaturated fatty acids (DHA and EPA) reduced action potential duration and decreased diastolic and systolic intracellular calcium in myocytes from pathological hearts explanted from rabbits and humans. Consequently, ω3-polyunsaturated fatty acids abolished triggered activity and reduced the number of delayed afterdepolarizations and calcium levels after transients.
The purpose of our letter is to point out that a major mechanism is missing from those proposed by the authors: inhibition by ω3-polyunsaturated fatty acids of the persistent sodium current. In contrast to the well-known rapid sodium channels that activate and inactivate very quickly, a different mode of gating has been reported. Channels that fail to inactivate completely produce a late or persistent sodium current that is responsible for a long-lasting influx of Na+, which is converted in Ca2+ overload through the activation of the reverse mode of the Na+–Ca2+ exchanger. Persistent sodium current (INa) amplitude is increased in patients with an history of cardiac ischemia2 and in some patients with mutations in the SCN5A gene. Therefore, enhancement of persistent INa is observed and is associated with cellular damages and left ventricular dysfunction in a variety of pathological states, including heart failure.3,4 It has now become apparent that persistent INa plays an important role in the genesis of ischemia-induced ventricular damages and also in arrhythmias observed in failing hearts and that persistent INa represents an attractive target to focus on to provide protection from Na+-induced Ca2+ overload. We previously reported5 that DHA and EPA, in a same range of concentration used in the study by den Ruijter et al,1 concentration-dependently reduced the persistent INa artificially induced with veratridine, as well as the one involved in LQT3 syndrome.
We do not claim that inhibition of persistent INa by ω3-polyunsaturated fatty acids is the unique mechanism to prevent triggered activity in myocytes, but we strongly believe that this effect constitutes a key mechanism for the reduction of the abnormalities of calcium homeostasis in failing heart.
den Ruijter HM, Berecki G, Verkerk AO, Bakker D, Baartscheer A, Schumacher CA, Belterman CNW, de Jonge N, Fiolet JWT, Brower IA, Coronel R. Acute administration of fish oil inhibits triggered activity in isolated myocytes from rabbits and patients with heart failure. Circulation. 2008; 117: 536–544.
Pignier C, Revenaz C, Rauly-Lestienne I, Cussac D, Delhon A, Gardette J, Le Grand B. Direct protective effects of poly-unsaturated fatty acids, DHA and EPA, against activation of cardiac late sodium current: a mechanism for ischemia selectivity. Basic Res Cardiol. 2007; 102: 553–564.