Kwak, Brenda R.

Mach, François

Shah, Dipen C.

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Cardiovascular Research 55 (2002) 703–705www.elsevier.com/ locate /cardioresEditorialA starting point for structure function relationships in the caninepulmonary veins*Brenda R. Kwak , Dipen C. Shah, Franc¸ois MachFoundation for Medical Research, Division of Cardiology, University Hospital, 64 Avenue de la Roseraie, 1211 Geneva 4, SwitzerlandReceived 27 June 2002; accepted 27 June 2002See article by Verheule et al. [6] (pages 727 –738) in compatible with a physically small circus movementthis issue. reentry circuit (based on nonuniform anisotropy) wasThe recent demonstration of the effectiveness of catheter found to be confined to the myocardial sleeve of theablation of the pulmonary veins as a curative treatment for superior vena cava with intermittent conduction to the rightparoxysmal atrial fibrillation (AF) has prompted efforts to atrium. During both tachycardia as well as programmedexamine in detail the sleeves of atrial myocardium encas- stimulation in sinus rhythm, evidence of marked slowing their left atrial ends [1]. Multi-electrode catheter conduction was found; notably, conduction was faster inmapping of spontaneous episodes of AF in patients show the long axis of the vein as compared to perpendicularly.that the majority (.90%) of paroxysms begin with earliest In contrast to such abnormal impulse conduction, the firstactivation at the ostium or within the pulmonary veins [2]. beat(s) of the initiation of a paroxysm of AF displaysConsistent initiation of paroxysms of AF from tissue in characteristics compatible with triggered activity thoughthis region reinforces the probability of distinctive structur- abnormal automaticity cannot be ruled out. These abnor-al or functional characteristics being responsible for such mal impulses likely trigger a reentrant arrhythmia, thatanatomical localization. spreads to involve the atria. Thus, a combination ofActivation mapping within the confines of the pulmon- arrhythmia mechanisms is very likely responsible for AF.ary veins is limited by their diameter (about 15–17 mm), The myocardial fiber arrangement, their coupling by meanscomplex branching structure as well as the limitations of of gap junctions and the intervening fibrous tissue certainlyaccess through a transseptal puncture. A preformed loop affect the milieu for reentry by affecting the wavelength ofshaped multi-electrode catheter positioned orthogonal to the tissue. Whether they similarly affect or promotethe venous long axis, at the relevant ostium or within the abnormal impulse generation is not clear though somevein, provides a slice of circumferential activation [3], degree of protection or isolation from normal currents ofwhile the integration of an additional longitudinal mapping surrounding cells is felt to be necessary for abnormalability e.g. with a basket catheter provides the maximal automaticity.currently and clinically possible mapping coverage of the In this context we can view the results of Verheule et al.vein. Nevertheless, this leaves unmapped territory in the [6] as a starting point for understanding the role of thefirst order branches. Though decremental conduction, pulmonary veins in initiating and maintaining atrial fibril-spontaneous activity as well as exit block have been lation. At both light and electron microscopic levels, theydocumented within the veins or at their junction with the did not find any significant differences in myocyte mor-left atrium using the above catheters [2,4], there is limited phology between pulmonary vein and atrial myocardium.detail about the electrophysiology of this region. A recent Significantly, the authors found no structural evidence ofreport described basket catheter mapping of a tachycardia abnormal nodal like ‘pale cells’ which have been proposedoriginating in the superior vena cava—a thoracic vein with as the origin of abnormal impulse generation [7]. Thea structure similar to the pulmonary veins [5]. Activation authors believe that based on the results of connexinimmunolabelling, the venous myocardium is tightly cou-pled to atrial myocardium and remark only upon the spiral*Corresponding author. Tel.: 141-22-382-7238; fax: 141-22-382-arrangement of myofibers as well as the lesser degree of7245.staining for one type of gap junction protein (see below).E-mail address: brenda.kwakchanson@medecine.unige.ch (B.R.Kwak). Their histological findings are essentially in tune with what0008-6363/02/$ – see front matter  2002 Elsevier Science B.V. All rights reserved.PI I : S0008-6363( 02 )00532-1704 B.R. Kwak et al. / Cardiovascular Research 55 (2002) 703 –705others have found: the thickness of the myocardial sleeve junction abnormalities may lead to the slow conductiondecreased towards the pulmonary end with bundles of and/or heterogeneous wavefront propagation characteristicmyocardial fibers being separated by fibrous tissue only at for micro-reentrant electrical circuits underlying most ofthis level. They also found sharp transitions in fiber these cardiac arrhythmias remains, however, a matter ofarrangements which have in fact been found to correlate debate [26]. In their study of the myocardial sleeve,with zones of activation delay and even conduction block Verheule et al. [6] described large gap junctions at[8]. Closer to the left atrial end, Verheule et al. describe intercalated disks, abundant expression of Cx43 and re-more longitudinally oriented fibers on the epicardial side duced Cx40 expression compared to the left atrium. Thewhereas a circumferential pattern was observed close to authors therefore conclude that conduction in pulmonarythe endocardium essentially throughout the length of the veins is maintained by abundant Cx43, and that it is likelymyocardial sleeve. Anisotropic conduction delays favour- tissue geometry, i.e. the circumferential orientation of theing reentry may therefore be prominent at the overlap myocytes in the myocardial sleeves, rather than gapregion of these two fiber orientations. junctional communication that may provide a substrate forGap junctions are clusters of transmembrane channels reentry. Although this conclusion seems justified on thethat connect the cytoplasmic compartments of neighboring basis of their data, a recent study by Dupont et al. [27]cells, thus enabling the direct exchange of ions and small describing that patients prone to develop AF after surgerymolecules. Molecular cloning studies have demonstrated appear to have higher levels of Cx40 in the atrial myocar-that gap junction channels are formed by members of a dium than those who do not, should be kept in mind.family of related proteins called connexins (Cx) in verte- The current study of Verheule et al. [6] describes abrates. There are about 20 different connexin types in the homogeneous expression of low levels of Cx40 and highhuman and mouse genome [9,10]. The commonly used levels of Cx43 in the pulmonary vein sleeves. This is innomenclature distinguishes Cx by their molecular mass surprising contrast to an earlier report of Yeh and col-deduced from their respective sequences. The 43-kDa leagues [28] who have studied for the same reason theprotein Cx43 is the most abundant in the heart and has myocardial sleeve in the canine superior vena cava. Inbeen found in almost all parts of the organ, with the addition to differences in assembly of cardiomyocytes andexception of the sinoatrial and atrioventricular nodes. The their spatial orientation, they observed areas of atypicalsecond important cardiac connexin, Cx40, is specifically connexin expression featuring a center rich in Cx43present in the atria and in the ventricular conduction labeling surrounded by a periphery of scattered tiny Cx40system (for reviews, see Refs. [11,12]). Other cardiac labels. Consequently, these authors suggest that tissueconnexins display a restricted expression pattern. Thus, geometry and variation in connexin distribution couldCx45 expression has been reported in nodal tissues and the potentially combine to create a substrate for heterogeneityconduction system [13], Cx46 in the sinoatrial node [14], of electrical coupling. Increase in heterogeneity of gapCx50 in atrioventricular valves [15], and finally Cx37 in junction distribution has also been observed in a well-the endocardial endothelium [10]. It is well known that defined animal model of sustained AF, as originallyeach type of gap junctional channel has unique inherent described by Wijffels et al. (AF begets AF [29]). In thisgating properties, permeabilities to various molecules and study, the development of heterogeneity of Cx40 dis-ions as well as regulation by second messengers [16–19]. tribution displayed a strong correlation with the timeIn addition, Cx are dynamic proteins with half-lives course of stabilization of AF in the instrumented goats,ranging from 1 to 5 hours, indicating that gap junction suggesting the involvement of gap junction remodeling inchannels are fully exchanged several times per day [20,21]. the pathogenesis of sustained AF [30]. Interestingly,This provides another mechanism to regulate direct cyto- radiofrequency cathether ablation has been shown toplasmic cross-talk between cells under normal or eliminate pacing-induced sustained AF in combinationpathological conditions. with a reduction in Cx43 in dogs atria [31]. Thus, asIn their search for a substrate for focal activity leading already suggested by Spach and Starmer in 1995, therapeu-to AF, Verheule et al. [6] investigated gap junctions around tical strategies aimed at altering the topology of gapthe veno-atrial transition using immunostainings for Cx43 junctions may produce better results than conventionaland Cx40. In the past decade, numerous publications have pharmacological anti-arrhythmic therapy [32]. In thisreported changes in ventricular gap junction expression respect it is worth mentioning the recent development oflevels and patterns that may predispose to the common and synthetic peptides acting on gap junctional coupling (suchoften fatal arrhythmias observed with acute ischemia, as AAP10 [33,34]) that appear to be effective in reducingchronic myocardial infarction, hypertrophy and heart fail- dispersion of action potential duration in the ischemicure [22–25]. Indeed, two main forms of gap junction isolated rabbit heart.abnormality are frequent in various human heart diseases: Since no animal model of spontaneously initiating AFa redistribution of Cx43 from end-to-end-located interca- exists, it is less likely that one would find significantlated disks to the lateral cell borders and a global reduction abnormality in normal canine pulmonary veins. However,of Cx43 throughout the myocardium. Whether these gap the role of thoracic veins in artificially induced butB.R. Kwak et al. / Cardiovascular Research 55 (2002) 703 –705 705[15] Gourdie RG, Green CR, Severs NJ. Immunolabelling patterns of gapspontaneously maintained AF is important given that therejunction connexins in the developing and mature rat heart. Anatis experimental data showing that surgical isolation of theEmbryol 1992;185:363–378.pulmonary veins (and atrial appendages) rendered AF [16] Bruzzone R, White TW, Paul DL. Connections with connexins theinduction impossible in a sheep theophylline infusion molecular basis of direct intercellular signaling. Eur J Biochemmodel [35]. Heart failure models producing structural 1996;238:1–27.[17] Elfgang C, Eckert R, Lichtenberg-Frate H. Specific permeability andremodeling may be more relevant clinically and moreselective formation of gap junction channels in connexin-transfectedlikely to show evidence of pathological changes. Al-HeLa cells. J Cell Biol 1995;129:805–817.together, this study of canine pulmonary veins provides a [18] Kwak BR, Hermans MM, De Jonge HR. Differential regulation ofuseful starting reference point of normalcy and will distinct types of gap junction channels by similar phosphorylatingwithout doubt serve as a detailed basis for future studies conditions. Mol Biol Cell 1995;6:1707–1719.[19] Cao F, Eckert R, Elfgang C. A quantitative analysis of connexin-towards the mechanisms for focal AF in various types ofspecific permeability differences of gap junctions expressed in HeLapathological models.transfectants and Xenopus oocytes. J Cell Sci 1998;111:31–43.[20] Laird DW, Puranam KL, Revel JP. Turnover and phosphorylationdynamics of connexin43 gap junction protein in cultured cardiacA cknowledgements myocytes. Biochem J 1991;273:67–72.[21] Beardslee MA, Laing JG, Beyer EC. Rapid turnover of connexin43in the adult rat heart. Circ Res 1998;83:629–635.This work was supported by grants from the Swiss [22] Smith JH, Green CR, Peters NS. Altered patterns of gap junctionNational Science Foundation (MHV [3234-066311.01 to distribution in ischemic heart disease. An immunohistochemicalBK and [3200-065121.01 to FM). study of human myocardium using laser scanning confocal micro-scopy. Am J Pathol 1991;139:801–821.[23] Peters NS, Green CR, Poole-Wilson PA. 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A starting point for structure function relationships in the canine pulmonary veins

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