Ephrin-B1 Is a Novel Specific Component of the Lateral Membrane of the Cardiomyocyte and Is Essential for the Stability of Cardiac Tissue Architecture Cohesion

International audienceRATIONALE: Cardiac tissue cohesion relying on highly ordered cardiomyocytes (CM) interactions is critical because most cardiomyopathies are associated with tissue remodeling and architecture alterations. OBJECTIVE: Eph/ephrin system constitutes a ubiquitous system coordinating cellular communications which recently emerged as a major regulator in adult organs. We examined if eph/ephrin could participate in cardiac tissue cyto-organization. METHODS AND RESULTS: We reported the expression of cardiac ephrin-B1 in both endothelial cells and for the first time in CMs where ephrin-B1 localized specifically at the lateral membrane. Ephrin-B1 knock-out (KO) mice progressively developed cardiac tissue disorganization with loss of adult CM rod-shape and sarcomeric and intercalated disk structural disorganization confirmed in CM-specific ephrin-B1 KO mice. CMs lateral membrane exhibited abnormal structure by electron microscopy and notably increased stiffness by atomic force microscopy. In wild-type CMs, ephrin-B1 interacted with claudin-5/ZO-1 complex at the lateral membrane, whereas the complex disappeared in KO/CM-specific ephrin-B1 KO mice. Ephrin-B1 deficiency resulted in decreased mRNA expression of CM basement membrane components and disorganized fibrillar collagen matrix, independently of classical integrin/dystroglycan system. KO/CM-specific ephrin-B1 KO mice exhibited increased left ventricle diameter and delayed atrioventricular conduction. Under pressure overload stress, KO mice were prone to death and exhibited striking tissue disorganization. Finally, failing CMs displayed downregulated ephrin-B1/claudin-5 gene expression linearly related to the ejection fraction. CONCLUSIONS: Ephrin-B1 is necessary for cardiac tissue architecture cohesion by stabilizing the adult CM morphology through regulation of its lateral membrane. Because decreased ephrin-B1 is associated with molecular/functional cardiac defects, it could represent a new actor in the transition toward heart failure

I005 Chemical denervation of sympathetic nervous system induces abnormal myocardial architecture

IntroductionThe role of autonomic nervous system (ANS) on heart function modulation is well-known. By contrast, ANS role on myocardial tissue architecture has scarcely been investigated. The aim of the present work was to investigate changes in heart tissue architecture after chemical sympathetic denervation by 6OH-Dopamine (6OH-DA) in mice.MethodsTwo months old mice (n=18) received 3 injections of 6OHDA (200mg/kg, ip) or saline (n = 6) at 3 days of interval. At 15 and 30 days after first injection, ECG was recorded (PowerLab, DSI) under anaesthesia and heart rate spectral variability (HRV) was performed (FFT) in low frequency (LF: 0.15-1.5Hz) and high frequency (HF: 1.5-5Hz) ranges; LH/HF ratio was also calculated. After sacrifice, blood was withdrawn for plasma catecholamine determination (HPLC). Heart tissue was fixed (formaldehyde 10 %) for histology or frozen for western blot analysis (tyrosine hydroxylase, TH).ResultsWhen compared to controls (1410±145 pg/ml) plasma norepinephrine levels were significantly lower at D15 (766±186 pg/ml) and D30 (675±288 pg/ml) after 6OH-DA without significant change in epinephrine levels. TH expression was absent at D15 and present but significantly lower than in controls at D30. When compared to controls (48.5±6.2 %), LF HRV was significantly reduced at D15 (31.6±5.4 %) but not at D30 (58.2±16.2 %) without any change in HF. LF/HF ratio was lower in 6OH-DA treated mice at D15 (0.49±0.13 vs 1.29±0.17 in controls) but was normal at D30 (1.63±0.31). At D15, hearts from 6-OH-DA treated mice exhibited mild structural abnormalities with wavy cardiomyocyte appearance in septum. At D30, histological abnormalities concerned whole myocardium with myocytes intersecting at various angles with bundles wavy appearance. Variability in cell size with anisocaryosis, attenuated myocytes with perinuclear halo and shaped nuclei were observed. No inflammation, interstitial fibrosis or necrosis were noticed.ConclusionThis study suggests that heart denervation induces myocardial tissue disorganization. Relationship between these pathological changes and sympathetic nerve destruction and/ or catecholamine depletion remains to be elucidated. Apart from physiological significance, these results also bring new structural basis to explain increased risk of cardiac disease during human autonomic failure

Universal Interconnection Technology Workshop Proceedings

The Universal Interconnection Technology (UIT) Workshop - sponsored by the U.S. Department of Energy, Distributed Energy and Electric Reliability (DEER) Program, and Distribution and Interconnection R&D - was held July 25-26, 2002, in Chicago, Ill., to: (1) Examine the need for a modular universal interconnection technology; (2) Identify UIT functional and technical requirements; (3) Assess the feasibility of and potential roadblocks to UIT; (4) Create an action plan for UIT development. These proceedings begin with an overview of the workshop. The body of the proceedings provides a series of industry representative-prepared papers on UIT functions and features, present interconnection technology, approaches to modularization and expandability, and technical issues in UIT development as well as detailed summaries of group discussions. Presentations, a list of participants, a copy of the agenda, and contact information are provided in the appendices of this document

H011 Aortic valve remplacement normalizes sympathetic nerve activity in patient with severe aorticv stenosis

IntroductionIn patients with aortic stenosis, reduced cardiac output may increase sympathetic nerve activity. However, the magnitude of the increase in sympathetic activity in such patients and the effect of valve replacement (VR) on this activity are unknown.MethodsIn this preliminary study, we prospectively included 24 patients (mean age=76,0±8,7 years) with severe aortic stenosis (defined for <0,60cm2/m2). Holter-EKG recording (lasting 24hours) allowed heart rate variability analysis (temporal and spectral parameters) and QT dynamicity calculation. The latter was assessed by plotting QT and RR intervals to obtain a liner characterized by its slope linear. 24-h Holter recordings, clinical, biological and morphological data were collected before and after aortic valve eplacement.ResultsValve replacement induced a significant improvement in cardiac output. Holter EKG parameters evaluating the sympathetic nervous system activity showed a decrease of SDNN, VLF and LF. Hence, SDNN/5mn, eflecting sympathetic modulation of heart rate, calculated on 24hours significantly decreased after aortic valve replacement (42,1±25,0 to 27,27±24ms; p<0,05). Significant changes of EKG parameters are summarized in table below (* for p<0.05). None of parameters evaluating QT dynamicity were significantly modified after aortic valve replacement.ConclusionThis study shows for the first time the beneficial effect of aortic valve replacement on the sympathetic nervous tone. We plan to follow up these patients and assess occurrence of cardiovascular complications (i.e. Heart failure, atrial fibrillation). Complimentary results will allow us to identify SNS measurement

Head to head comparison of quantitative flow ratio using 4-French and 6-French catheters versus fractional flow reserve.

To validate QFR using 4-F diagnostic catheters compared to using 6-F guiding catheters, with conventional guidewire-based FFR as the reference standard, using independent core laboratory analysis. Quantitative Flow Ratio (QFR) allows Fractional Flow Reserve (FFR) calculation based on the coronary angiogram, using 5- or 6-French (F) catheters. However, the use of 4-F diagnostic catheters to perform coronary angiography is currently routine in some centers. We included all consecutive patients with stable coronary artery disease and indicated for physiological assessment. QFR was performed using a 4-F diagnostic catheter, then QFR was performed using a 6-F guiding catheter while conventional FFR was measured using a pressure guidewire. Angiograms were sent to two separate core laboratories. One hundred lesions in 67 consecutive patients with QFR performed using 4-F and 6-F catheters, and with conventional FFR, were included. Pearson's correlation coefficient was for QFR 4-F vs. FFR 0.91 [0.87-0.94], for QFR 6-F vs. FFR 0.90 [0.86-0.94], and for QFR 4-F vs. QFR 6-F 0.93 [0.90-0.95]. Receiver-operator characteristic curves (ROC) comparing the ability to predict an FFR value above or below 0.80 with QFR 4-F and 6-F were generated. The area under the ROC curve (AUC) vs. FFR was 0.972 [0.95-0.99] for QFR 4-F and 0.970 [0.94-0.99] for QFR 6-F. Our study demonstrated the feasibility of performing QFR analysis from angiograms obtained by 4-F catheters, and showed a good correlation with QFR performed using 6-F catheters as well as with conventional FFR performed using a pressure guidewire