G012 Long-chain acylcarnitines regulate ihERG while medium-chain acylcarnitine do not

Abstract

Free fatty acids are the primary substrate used by the heart to generate cellular ATP. Carnitine, acylcarnitine and carnitine-transferase are essential for normal metabolism of long-chain fatty acids in heart. Some of the arrhythmias observed following an ischaemia are attributed to an accumulation of long-chain acylcarnitine into ad out the cells. It has also been observed that a deficiency in a carnitine transporter, OCTN2, normally found in heart, muscle and kidney, leads to a reduced plasma carnitine and acylcarnitine level. Such pathology was associated with the occurrence of ventricular fibrillation and eventually to sudden death. All these data suggest that acyl-carnitine (Acyl-CARs) can regulate ion channels. We studied the effects of different acyl-CARs at different concentrations on the hERG channel activity (IhERG) which is known to participate to lethal arrhythmias. HEK293 cells stably expressing hERG were studied in patch clamp. Acyl-CAR derivatives from medium – (C8 and C10) and long-chain (C16 and C18:1) fatty acids were applied intra- and extracellularly at different concentrations. C8-CAR and C10-CAR had no effect at 3μm and 30μm whether they are applied intra- or extracellularly. C16-CAR and C18-CAR had no effect on the current when applied intracellularly. Extracellularly, 3μm C16-CAR or C18-CAR induced an increase of the current amplitude associated with different effects on the activation and availability properties. At this concentration, the long-chain acyl-CAR induced also a speeding of deactivation kinetic. Long-chain acyl-CARs, but not medium-chain, regulate extracellularly IhERG. When their level varies during diseases like primary systemic carnitine deficiency or ischaemia, there must be an impact on the action potential which can explain some of the cardiac arrhythmias observed.