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

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

I031 Aorta dilatation and arterial remodelling in patients with fabry disease under enzyme replacement therapy

PurposeFabry disease is a deficiency of lysosomal enzyme α-galactosidase A leading to accumulation of glycosphyngolipids in cardiac and vascular tissues. Although enzyme replacement therapy decreases glycosphingolipids storage in tissues, we have described a continuous vascular hypertrophy whereas the aortic stiffness was paradoxically decreasing under long-term enzyme therapy. Preliminary results reported that Fabry's aorta diameters under treatment were more dilated in comparison to control group. The objective of this study is to determined parallelism between presumed aorta dilatation, aortic stiffness and arterial remodeling in treated Fabry patients.Methods41 treated patients were enrolled (38±12 yrs) with arterial measurements of a) radial and carotid intima-media thickness, diameter, local pulse pressure and distensibility obtained with echotracking device; b) aortic stiffness obtained through carotid to femoral pulse wave velocity with tonometry and c) aorta diameters (sinus, ascending and descending tubule, arch aortic) assessed by magnetic resonance imaging examinations.ResultsPulse wave velocity was positively correlated with ascending and descending aorta tubules diameters in univariate analysis (respectively R2=0.13, P< 0.05; R2=0.11, P<0.05) and after adjustment on body surface area, pulse pressures ratio and hypertension (respectively P<0.05 and P=0.01). Aorta diameters (ascending, descending tubule and arch aortic) were positively correlated with carotid diameter (respectively R2=0.44, P<0.0001, R2=0.32, P=0.0001 and R2=0.34, P=0.0001) and after adjustment as previously (respectively P=0.0001, P<0.05 and P<0.001). No correlations were found among all aorta diameters and radial diameter and between aorta sinus and carotid and radial artery properties. Carotid stiffness was positively correlated with ascending, descending tubules and arch aortic diameters (respectively R2=0.38, P<0.0001; R2=0.29, P<0.0005 and R2=0.23 P<0.005) and after adjustments as previously adding pulse wave velocity (P<0.0001, P<0.0005 and P<0.01).ConclusionThis study underlies interrelation between aortic diameters, aortic stiffness, elastic and muscular arteries geometry and carotid stiffness in patients with Fabry disease under enzyme therapy

J006 Beta-adrenergic stimulation activates protein kinase C-epsilon through Epac in cardiomyocytes

Protein kinase C (PKC) activation is classically considered as independent of the β-adrenergic pathway. However, the cAMP-activated exchange factor Epac was recently shown to activate phospholipase C. β-A stimulation is thus likely to stimulate PKC. We evaluated in cardiomyocytes whether βA stimulation could activate PKCɛ. Rat neonatal cardiomyocytes were subjected to isoproterenol stimulation (ISO). Inositol trisphosphate production was increased by 50 % by 1μm ISO (p<0.05) and PKCɛ was translocated to particulate fractions (western blot) in the perinuclear area (confocal microscopy) in a PKA-independent manner since it was not inhibited by an infection with an adenovirus encoding a protein kinase A (PKA) inhibitor. Instead, PKCɛ activation was Epac dependent since 8-CPT, an Epac activator, induced the same PKCɛ translocation as ISO and siRNAs of Epac completetly inhibited PKCɛ activation. The same translocation of PKCɛ in PF induced by βA stimulation was found in adult isolated rat hearts perfused by ISO with a sarcolemmmal membrane localization. This was associated with a phosphorylation of connexin-43 on ser368 that was blocked by the PKC inhibitor BIM. In conclusion, these data demonstrate a new interconnection between β-adrenergic and PKC pathways via Epac in cardiac cells with a potential role in cell-to-cell communications

K011 Effet d’un gain de fonction du récepteur AT1a sur la régulation cardiovasculaire des souris mutées

Cette étude est réalisée chez des souris knock-in qui expriment un gain de fonction du récepteur AT1A de l’angiotensine II (AngII). Des résultats préliminaires ont montré que ces animaux mutants (AT1AMUT) avaient une élévation modéré et permanente de la pression artérielle (PA) (+ 20mmHg) associée à une prolongation des effets presseurs de l’AngII (Billet et al. J Clin Invest 2007, 117 : 1914-1925).L’objectif de ce travail est de caractériser au plan fonctionnel cardio-vasculaire les souris mutées.La PA est mesurée en continu par télémétrie durant 48 heures chez 5 mâles sauvages (AT1AWT) et 5 mâles mutés. L’intervalle entre deux battements cardiaques (intervalle pulsé, IP) est converti en fréquence cardiaque (FC). Les variabilités de la PA systolique (PAS) et de l’IP sont étudiées par l’analyse spectrale. La sensibilité du baroréflexe spontané est exprimée par le gain de la fonction de transfert entre la PAS et l’IP.La double mutation induit le jour comme la nuit une augmentation de la PAS et une augmentation de la FC (PAS jour : AT1AMUT 127.9±5.9, AT1AWT 104.9±5.4mmHg ; PAS nuit AT1AMUT 141.4±6.1, AT1AWT 115.2±6.6 mmHg ; FC jour : AT1AMUT 481.3±18.4, AT1AWT 409.7±6.0 bat/min ; FC nuit AT1AMUT 551.1±14.9, AT1AWT 467.6±5.9 bat/min). L’activité motrice des souris n’est pas modifiée par la mutation. L’AT1AMUT présente une augmentation significative de la variabilité de PAS la nuit qui n’est pas observée chez l’AT1AWT. La variabilité de IP est significativement réduite par la mutation le jour. Le Gain des zones LF et de HF est significativement réduit chez AT1AMUT, le jour et la nuit.Cette double mutation, associée à un gain de fonction du récepteur AT1A, induit ainsi une élévation de la PA accompagnée d’une diminution de la sensibilité du baroréflexe spontané. L’élévation tensionnelle pourrait résulter d’un mécanisme périphérique, avec une vasoconstriction liée à l’activation du récepteur AT1A, ou d’un mécanisme central : inhibition du baroréflexe par une activation des récepteurs AT1A cérébraux. L’AngII est en effet connue pour inhiber le baroréflexe, ce qui pourrait induire une activation sympathique élevant la PA.* Projet soutenu par l’attribution d’une Allocation Doctorale Région Ile-de-France

Reversal of the lift force on an oblate bubble in a weakly viscous linear shear flow

We compute the flow about an oblate spheroidal bubble of prescribed shape set fixed in a viscous linear shear flow in the range of moderate to high Reynolds numbers. In contrast to predictions based on inviscid theory, the numerical results reveal that for weak enough shear rates, the lift force and torque change sign in an intermediate range of Reynolds numbers when the bubble oblateness exceeds a critical value that depends on the relative shear rate. This effect is found to be due to the vorticity generated at the bubble surface which, combined with the velocity gradient associated with the upstream shear, results in a system of two counter-rotating streamwise vortices whose sign is opposite to that induced by the classical inviscid tilting of the upstream vorticity around the bubble. We show that this lift reversal mechanism is closely related to the wake instability mechanism experienced by a spheroidal bubble rising in a stagnant liquid

Influence of slip on the dynamics of two-dimensional wakes

We study numerically the two-dimensional flow past a circular cylinder as aprototypical transitional flow, and investigate the influence of a generic slipboundary condition on the wake dynamics. We show that slip significantly delaysthe onset of recirculation and shedding in the wake behind the cylinder. Asexpected, the drag on the cylinder decreases with slip, with an increased dragsensitivity for large Reynolds numbers. We also show that past the criticalshedding Reynolds number, slip decreases the vorticity intensity in the wake,as well as the lift forces on the cylinder, but increases the sheddingfrequency. We further provide evidence that the shedding transition can beinterpreted as a critical accumulation of surface vorticity, similarly torelated studies on wake instability of axisymmetric bodies. Finally, we proposethat our results could be used as a passive method to infer the effectivefriction properties of slipping surfaces.

Modelling complex pathways between late-life depression and disability: evidence for mediating and moderating factors

Previous research has consistently shown an association between depression and disability in the elderly but little is known about the mechanisms linking the two. Recent longitudinal population studies have shown considerable inconsistency in the criteria used to establish causality and terms such as mediation and effect modification have been frequently applied incorrectly in terms of the inferences drawn. We underline the necessity to adopt more stringent theoretical criteria for the establishment of intermediary effects in the relationship between depression and disability to better identify cross-validated potential intervention points for reducing the risk of disablement and depression.

NLR volume 56 issue 1 Cover and Back matter

ICE volume 30 issue 11 Cover and Front matter

ICE volume 30 issue 5 Front matter