Abstract-Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1Ϯ0.

Treatment with USCDT using a shorter delivery duration and lower-dose tPA was associated with improved right ventricular function and reduced clot burden compared with baseline. The major bleeding rate was low, but 1 intracranial hemorrhage event due to tPA delivered by USCDT did occur.

Abstract-Connexin40 (Cx40) is a major gap junction protein that is expressed in the His-Purkinje system and thought to be a critical determinant of cell-to-cell communication and conduction of electrical impulses. Video maps of the ventricular epicardium and the proximal segment of the right bundle branch (RBB) were obtained using a high-speed CCD camera while simultaneously recording volume-conducted ECGs. In Cx40 -/-mice, the PR interval was prolonged (47.4Ϯ1.4 in wild-type [WT] [nϭ6] and 57.5Ϯ2.8 in Cx40-/-[nϭ6]; PϽ0.01). WT ventricular epicardial activation was characterized by focused breakthroughs that originated first on the right ventricle (RV) and then the left ventricle (LV). In Cx40 -/-hearts, the RV breakthrough occurred after the LV breakthrough. Additionally, Cx40 -/-mice showed RV breakthrough times that were significantly delayed with respect to QRS complex onset (3.7Ϯ0.7 ms in WT [nϭ6] Key Words: optical mapping Ⅲ specialized conduction system Ⅲ knockout mice Ⅲ connexin40 I ntercellular coupling via gap junction channels is an important determinant of impulse propagation in the heart. 1 These channels provide a low resistance pathway that is essential for the coordinated spread of electrical activation, which subsequently triggers the contraction of the heart. Recent studies have indicated that alterations in the expression pattern of cardiac connexin proteins may lead to abnormal electrical coupling and arrhythmias. [2][3][4][5][6] Therefore, understanding the role of intercellular communication in impulse propagation is essential.Three connexins, Cx40, Cx43, and Cx45, are thought to be involved in impulse propagation in the myocardium. Detailed immunolocalization studies have shown that each of these proteins has a unique pattern of expression in the adult heart; 6-8 however, the functional role of connexin proteins in impulse propagation remains poorly understood. The presence and expression levels of these connexins vary considerably in cardiac tissues with different conduction properties. 6,8,9 Cx45 is expressed in the atrioventricular node and proximal portion of the ventricular conduction system. 7 Cx43 is expressed in both the atrial and ventricular myocardium. 7,10,11 Immunohistochemistry studies in the mouse heart have indicated that Cx40 is expressed mainly in the atrial myocardium and His-Purkinje system. 7,12,13 Previous studies have shown that deletion of Cx40 did not affect the expression of the other cardiac connexins or the gross structure of the heart. 4,5 On the basis of these studies, it is expected that the targeted deletion of Cx40 will result in conduction deficits in both the atria and specialized conduction system.The gross structure of the adult mouse specialized conduction system has not been studied in any great detail. 14,15 Some histological studies have demonstrated broad similarities between the structure of the specialized conduction system of the mouse and that of larger mammals. 14,16 In the mouse, the atrioventricular (AV) bundle has been shown to give rise...