Abstract-The cardiac sodium channel Na v 1.5 plays a key role in cardiac excitability and conduction. The purpose of this study was to elucidate the role of the PDZ domain-binding motif formed by the last three residues (Ser-Ile-Val) of the Na v 1.5 C-terminus. Pull-down experiments were performed using Na v 1.5 C-terminus fusion proteins and human or mouse heart protein extracts, combined with mass spectrometry analysis. These experiments revealed that the C-terminus associates with dystrophin, and that this interaction was mediated by alpha-and beta-syntrophin proteins.Truncation of the PDZ domain-binding motif abolished the interaction. We used dystrophin-deficient mdx 5cv mice to study the role of this protein complex in Na v 1.5 function. Western blot experiments revealed a 50% decrease in the Na v 1.5 protein levels in mdx 5cv hearts, whereas Na v 1.5 mRNA levels were unchanged. Patch-clamp experiments showed a 29% decrease of sodium current in isolated mdx 5cv cardiomyocytes. Finally, ECG measurements of the mdx 5cv mice exhibited a 19% reduction in the P wave amplitude, and an 18% increase of the QRS complex duration, compared with controls. These results indicate that the dystrophin protein complex is required for the proper expression and function of Na v 1.5. In the absence of dystrophin, decreased sodium current may explain the alterations in cardiac conduction observed in patients with dystrophinopathies. Key Words: Duchenne dystrophy Ⅲ dystrophin Ⅲ ECG Ⅲ mouse Ⅲ sodium channels Ⅲ syntrophin T he main cardiac voltage-gated sodium channel, Na v 1.5, generates the fast depolarization of the cardiac action potential, and plays a key role in cardiac conduction. Its importance for normal cardiac function has been exemplified by the description of numerous naturally occurring genetic variants of the gene SCN5A, which encodes Na v 1.5, that are linked to various cardiac diseases. 1 Among them, the congenital long QT syndrome type-3 and the Brugada syndrome are caused by gain or loss-of-function of Na v 1.5, respectively. 1 Na v 1.5 is the pore-forming ␣-subunit protein of the cardiac sodium channel. It has a molecular weight of Ϸ220 kDa, and may be associated with at least 4 types of auxiliary small (30 to 35 kDa) ␤-subunits. Recently, several proteins that bind directly to Na v 1.5 have been described. 2 However, in most cases the physiological relevance of these interactions remains poorly understood, mainly because of a lack of appropriate animal models. With the exception of ankyrin-G, 3 all these partner proteins interact with the 243-residues-long intracellular C-terminal domain of the channel which contains several protein-protein interaction motifs. 2 Among them, the last three residues of Na v 1.5 (2014-Ser-Ile-Val-2016) constitute a PDZ domain-binding motif to which syntrophins and dystrophin have been shown to interact directly or indirectly, respectively. 4 -6 However, thus far, the role of these interacting proteins in the heart has never been investigated.In this study, by performing mass spe...

SummaryBackgroundStents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy.MethodsThe International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470.FindingsThe trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4·0%) events of disabling stroke or death in the stenting group compared with 27 (3·2%) events in the endarterectomy group (hazard ratio [HR] 1·28, 95% CI 0·77–2·11). The incidence of stroke, death, or procedural myocardial infarction was 8·5% in the stenting group compared with 5·2% in the endarterectomy group (72 vs 44 events; HR 1·69, 1·16–2·45, p=0·006). Risks of any stroke (65 vs 35 events; HR 1·92, 1·27–2·89) and all-cause death (19 vs seven events; HR 2·76, 1·16–6·56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0·0197).InterpretationCompletion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.FundingMedical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union.

Background and Purpose-Hyperperfusion syndrome (HS) after carotid endarterectomy (CEA) has been related to impaired cerebrovascular autoregulation in a chronically hypoperfused hemisphere. Our aim was to provide new insight into the pathophysiology of the HS using magnetic resonance imaging (MRI) studies with diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). Methods-Five out of 388 consecutive patients presented 2 to 7 days after CEA, partial seizures (nϭ5), focal deficits (nϭ5), and intracerebral hemorrhage (nϭ3). In 4 patients, using sequential examinations, we identified vasogenic or cytotoxic edema by DWI; we assessed relative interhemispheric difference (RID) of cerebral blood flow (CBF) by PWI; and we measured middle cerebral artery mean flow velocities (MCA Vm) by transcranial Doppler (TCD). Results-None of the patients presented pathological DWI hyperintensities, consistent with the absence of acute ischemia or cytotoxic edema. In 2 patients, we found an MRI pattern of reversible vasogenic edema similar to that observed in the posterior leukoencephalopathy syndrome. Middle cerebral artery (MCA) mean flow velocities (Vm) were not abnormally increased at any time. PWI documented a 20% to 44% RID of CBF in favor of the ipsilateral to CEA hemisphere. Conclusions-HS can occur in the presence of moderate relative hyperperfusion of the ipsilateral hemisphere. MCA Vm values may not accurately reflect RID of CBF over the cortical convexity. We suggest that the hemodynamic pathogenetic mechanisms of the HS are more complicated than hitherto believed and that they may be more accurately described by the term "reperfusion syndrome." (Stroke. 2005;36:21-26.)

Our study of 30 selected stroke patients with surgical suture of PFO showed a stroke recurrence rate of 0% and no significant complication. Residual right-to-left shunting may be avoided by double continuous suture of the PFO. In the absence of controlled studies to guide individual therapeutic decisions, our findings show that PFO closure can be done safely and may be considered to avoid recurrence in selected patients with long life expectancy and presumed paradoxic embolism.

Abstract-Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. Surgical/Radiofrequency (RF) ablation is a therapeutic procedure that consists of creating lines of conduction block to interrupt AF. The present study evaluated 13 different ablation patterns by means of a biophysical model of the human atria. In this model, ablation lines were abruptly applied transmurally during simulated sustained AF, and success rate, time to AF termination and average beat-to-beat interval were documented. The gold standard Cox's Maze III procedure was taken as reference. The effectiveness of twelve less invasive patterns was compared to it. In some of these incomplete lines (entailing a gap) were simulated. Finally, the computer simulations were compared to clinical data. The results show that the model reproduces observations made in vivo: (1) the Maze III is the most efficient ablation procedure; (2) less invasive patterns should include lines in both right and left atrium; (3) incomplete ablation lines between the pulmonary veins and the mitral valve annulus lead to uncommon flutter; (4) computer simulations of incomplete lines are consistent with clinical results of non-transumural RF ablation. Biophysical modeling may therefore be considered as a useful tool for understanding the mechanisms underlying AF therapies.