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HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Rationale: 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. (Circ Res. 2012;110:688-700.) Key Words: cardiomyocyte Ⅲ extracellular matrix Ⅲ lateral membrane Ⅲ cardiac tissue Ⅲ architecture Ⅲ heart failure T he heart constitutes a particular compact organ relying on strong tissue architecture cohesion and tight cellular interactions that ensure both mechanical and electrochemical coupling. Thus, most cardiopathies are associated with cardiac tissue remodeling and with alterations in architecture involved in disease progression toward heart failure (HF).Despite considerable advances in the field and development of effective drugs, HF still remains a prevalent condition associated with high morbidity and mortality rates. This could be in part explained by still imperfect knowledge of molecular basis at the origin of HF. In fact, to date, most research has focused on cardiomyocyte (CM) contractile dysfunction Original received December 15, 2011; revision received January 16, 2012; accepted January 25, 2012. In December 2011, the average time from submission to first decision for all original research pape...

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Bortezomib is a proteasome inhibitor commonly indicated for the treatment of multiple myeloma and non Hodgkin lymphoma. Cardiac adverse drug reactions of this drug are not clearly established. We report case where direct involvement of bortezomib in the occurrence of heart failure is strongly suspected and 22 other cases spontaneously reported to the French Pharmacovigilance System. This report should increase cardiologist awareness about the risk of heart failure related to this drug. Moreover, these cases underline the need for a systematic cardiac screening in patients exposed to bortezomib.

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