Archives of Cardiovascular Diseases Supplements (2011) 2, 1-91 33 © Elsevier Masson SAS. All rights reserved. activation and inactivation-versus-voltage relations were not changed by the muta- tion alone or in coexpression with the WT. The time constants of fast recovery from inactivation and of fast and slow deactivation analysed between -120 and +20 mV were not changed. The voltage dependent distribution of the current amplitudes among fast-, slow- and non-deactivating fractions were not altered. We conclude that the apparent decrease in current density may in part explain or may have predisposed to the observed LQTS and likely the associated SIDS and TdP. 0364 Invalidation of TRPM4 channel in mouse induces cardiac hypertrophy, slowed conduction and arrhythmias Marie Demion [Orateur] (1), Jérôme Thireau (1), Cécile Cassan (1), Nicolas Seraｿni (2), Franck Aimond (1), Romain Guinamard (3), Pierre Launay (2), Sylvain Richard (1) (1) U1046, Montpellier, France – (2) U699 INSERM, Néphrologie, Paris, France – (3) EA3212, Caen, France Background: One of the main causes of sudden cardiac death is ventri- cular tachycardia/ventricular ｿbrillation. Several molecular and cellular mecha- nisms involved remain to be resolved, and appropriate therapies are still needed. Interestingly, TRPM4 (Transient Receptor Potential Melastatin 4), a Ca 2+ acti- vated non-selective cation channel is expressed in heart. After activation, this protein can decrease the driving force for Ca 2+ entry by promoting the mem- brane depolarization due to massive Na + entry (Launay et al., 2002). Recently, a gain of function mutation in TRPM4 was indirectly implicated to human cardiac trouble rhythm disease (Kruse et al, 2009; Liu et al, 2010). However, the phy- siological role of TRPM4 in the heart is unclear, in particular in rhythm control. So we designed this study to determine the role of TRPM4 in heart biology. Method and results: We used a mouse model with TRPM4 gene invalida- tion (Trpm4 -/- ). Echocardiographic analysis showed that Trpm4 -/- mice exhibit left ventricle hypertrophy and dilation. Electrophysiologic explorations including telemetry electrocardiogram in vigil mice and intracardiac exploration by cathe- terism in vivo demonstrated that Trpm4 -/- mice have no alteration of heart rate but a lengthened PR and QT intervals and QRS duration associated to sino-atrial node pause, atrio-ventricular blocks, atrial ｿbrillation and ventricular extrasys- toles. Using immunoﾀuorescence on frozen cryostat sections, qPCR and cellular electrophysiology, we determined that hypertrophy and conduction disorders are not a consequence of ｿbrosis, cardiomyocyte size and connexins Cx40, Cx43 and Cx45 expression modiｿcations between Trpm4 +/+ and Trpm4 -/- mice. Conclusion: Taken together, all these data suggest that TRPM4 invalidation is associated with pathophysiological phenotype characterized by hypertrophy, arrhythmias and conduction disorders. 0182 Short QT syndrome and carnitine deｿciency: role of IKR, IKS, IK1 and ICaL Fabio Ferro [Orateur] (1), Aude Ouillè (2), Truong-An Tran (3), Patrick Bois (4), Pierre Fontanaud (2), François Labarthe (3), Dominique Babuty (5), Jean-Yves Le Guennec (2) (1) Dipartimento di Biologia Animale e dell’Uomo, Turin, Italie – (2) INSERM U637 Laboratoire de physiopathologie cardiovasculaire, CHU A. de Villeneuve, Montpellier, France – (3) Inserm U921 Nutrition Croissance Cancer, Tours Cedex 1, France – (4) Istitute de physiologie et biologie cellulaire (IPBC) UMR 6187, Poitiers, France – (5) Hôpital Trousseau, Service de Cardiologie B, Tours, France Every year thousands people are victims of sudden cardiac death, usually fol- lowing ventricular ｿbrillation. In most patients, the cause is an identiｿable arrhyth- mogenic cardiomyopathy, but in 5-10% of cases heart is healthy. Some electrical disorders virtually arrhythmogenic have been identiｿed, like ShortQT recently discovered and classiｿed as rare genetic channelopathy. Among all patients with shortQT, there has been found an associated genetic mutation in only few. Hence the cause of shortQT syndrome can also be one or more unknown muta- tions or secondary of other pathologies. We have identiｿed a family with Short QT syndrome related to systemic carnitine deｿciency caused by membrane car- nitine transporter mutation. We studied the effect of carnitine and its derivatives TOPIC 07-1 – Arrythmia, repolarisation, conduction disturbances May 12 th , Thursday 2011 0476 Mutations in TRPM4 cause autosomal dominant isolated cardiac con- duction disease H Lui [Orateur] (1,2), L El Zein (1,2), R Guinamard (3), A. Bozio (4), A. Mégarbané (5), G. Blaysat (6), E. Vilain (7), Patrice Bouvagnet (1,2,4) (1) EA 4171 Université de Lyon, Lyon, France – (2) Laboratoire Cardiogénétique, Hôpitaux de Lyon, Lyon, France – (3) EA 3212 Université de Caen, Caen, France – (4) Service Cardiologie Pédiatrique, Hôpitaux de Lyon, Lyon, Lyon, France – (5) Unité de Génétique Médicale, Université Saint Joseph, Beyrout, Liban – (6) Service de Cardiologie Pédiatrique, CHU Grenoble, Grenoble, France – (7) Service de Cardiologie, Hôpital Necker-Enfants Malades, Paris, France Introduction: Isolated cardiac conduction block is a relatively common condition in the young and the elderly populations. Genetic predisposing factors have long been suspected because of numerous familial case reports. Deciphering genetic predisposing factors of conduction blocks may give a hint at stratifying conduction block carriers in a more efｿcient way. Methods and Results: One Lebanese family (L1) and 2 French fami- lies (F1 and F2) with autosomal dominant isolated cardiac conduction blocks were used for linkage analysis. In these 3 families, affected individuals had right bundle branch block, left anterior or posterior hemiblock, AV block either alone or in combination but no left bundle branch blocks. A maximum combined multipoint lod score of 10.5 was obtained on a genomic interval including more than 300 genes. After screening 12 genes of this interval for mutation, we found a heterozygous missense mutation of the TRPM4 gene in each family: p.Arg164Trp (F1), p.Ala432Thr (L1) and p.Gly844Asp (F2). These missense mutations change a conserved residue and were not observed in more than 300 chromosomal controls. This gene encodes the TRPM4 channel, a calcium-activated non-selective cation (CAN) channel of the tran- sient receptor potential melastatin (TRPM) ion channel family. Furthermore, we showed by immunohistochemistry that wild-type TRPM4 channel signal level is higher in bovine atrial cardiomyocytes than in common ventricular cells but is highest in Purkinje ｿbers. Small bundles of highly TRPM4 positive cells were found in the subendocardium and in rare intramural bundles. Conclusion: The TRPM4 gene is a causative gene in isolated cardiac conduc- tion disease and TRPM4 channel is highly expressed in cardiac Purkinje ｿbers. 0303 HERG point mutation R148W lowers current density by 29% in co- expression with the WT but does not change kinetic properties of the channel Asma Mechakra [Orateur] (1), Yohann Vincent (1), Mohamed Chahine (2), Philippe Chevalier (1), Gilles Millat (1), Georges Christé (1) (1) Université Lyon 1 – Hospices Civils de Lyon, ERM Neurocardiologie, 2e étage, escalier D, Lyon Cedex 08, France – (2) Centre de recherche Université Laval Robert-Giffard, Québec, Canada A mutation of hERG (R148W) at heterozygous state was discovered in two newborns who died from SIDS, one with prolonged QTc and Torsade de Pointes (TdP); and in an adult man with QTc>500 ms, atrio-ventricular block and TdP. The electrophysiological properties of this N-terminal hERG mutant were explored in Xenopus oocytes injected with either 54 ng of WT/hERG RNA or 54 ng of R148W/hERG or a mixture of half of each. R148W alone produced a current similar to the WT (369±76 nA (mean±sem), n=13 versus 342±55 nA in WT, n=13), while the coexpression of 1/2 WT + 1/2 R148W lowered the current by 29% versus WT (243±35 nA, n=13, p<0.05). Parameters of the steady-state ▼ ▼