High-Resolution Optical Mapping of the Right Bundle Branch in Connexin40 Knockout Mice Reveals Slow Conduction in the Specialized Conduction System

Abstract

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...

Relative Contributions of Connexins 40 and 43 to Atrial Impulse Propagation in Synthetic Strands of Neonatal and Fetal Murine Cardiomyocytes

“…Whereas studies in anesthetized mice have revealed a marked prolongation in the duration of the P wave, 27,36,40,41 prolongation of the P wave has been reported to be minor or absent in conscious animals. 42,43 Direct measurements with optical mapping revealed a highly abnormal pattern of electrical excitation and propagation in the right atria of adult Cx40 Ϫ/Ϫ mice, 43 attributable to circumscribed intraatrial conduction slowing in …”

Ion Channel Subunit Expression Changes in Cardiac Purkinje Fibers

“…35 Thus, functional effects of changed Cx expression may be difficult to predict directly, particularly when alterations in multiple isoforms are observed. On the other hand, Cx40 knockout clearly slows His-Purkinje system conduction in the mouse, 36 and decreases in Cx43 expression slow ventricular conduction. 37 There is evidence that colocalization of Cx40 and Cx43 in PFs may be functionally important.…”

From Mouse to Whale

“…[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] The collected data fall into 4 different categories based on the mode in which they were reported in the literature for each of the 3 parameters (ie, PR, HR, and BM): (1) measurements from single animals, (2) multiple animal measurements reported as mean values without SD, (3) multiple animal measurements reported as means with SDs, and (4) values reported as ranges without means or SDs. For convenience, the allometric equation YϭY 0 · BM b can be transformed into a logarithmic form, lnYϭlnY 0 ϩb · lnBM, which describes a straight line of the form yϭinterceptϩbx.…”