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Home , Bundle branches, Bundle of His, Intercalated disc, Mitral valve, Purkinje fibers

SPECIAL REVIEW 6 Journal of Cardiac Electrophysiologist (PartII) Ventricular Anatomyforthe unique chance to study the conduction system of the of system conduction the study to chance unique a be will recipient transplant a on assessment biologic molecular or immuno-histochemical technology. existing of limitations technological inherent also but human of availability limited the to due only not rare, is abnormalities such with hearts of . on in advances based successful are studies treatment electrophysiologic targeted a and rhythm Introduction Tel: Jongro-gu, Seoul110-799,Korea National UniversityCollegeofMedicine andHospital,103Daehangno, Jeong-Wook Seo Correspondence: * KimMYisaseniorstudentfromEwhaWoman’s UniversitySchoolofMedicine. E-mail: The functional assessment of abnormal cardiac abnormal of assessment functional The Key words: continuation ofbundlesseenattheimmediatesubendocardiumleftventricle. tissue. C-kitpositivecellsarescattered,buttheirroleisnotwellunderstood.Purkinjeaperipheral intercalated disc.Afinemeshworkofsynaptophysinpositiveprocessesisnotedparticularlyatthenodal cytoplasmic filaments. Myoglobinisexpressedatthecontractile part,whereasCD56isexpressedatthe recognize them.The cellularcharacters oftheconductionbundles aremodifiedmyocardialcellswithless clearly visibleatthesurface. The rightbundlesarehiddenintheseptalmyocardiumanditisnoteasyto septum, wherethesingletrunkramifies intotheleftandrightbundlebranches. The leftbundlebranches are immuno-histochemical characteristics. The bundleofHisislocatedattheinferiorbordermembranous The conductionfibersandPurkinjenetworkoftheventricularmyocardiumhavetheirpeculiarlocation ABSTRACT 82-2-2072-2550, [email protected] 1 2 Morphological assessment or confirmation or assessment Morphological Classical morphological approaches and approaches morphological Classical Fax: ■ conduction system 82-2-743-5530 , DepartmentofPathology,Seoul ■ Purkinje network ■ anterior superior direction and then ramifies into the into ramifies then and direction superior anterior the to segment traversing short a has bundle The 2). 1, (Figure diameter in cm 0.1 and long cm 0.5~0.7 is His of bundle The node. the around seen are fibers nerve some and tissue Fatty cm. 0.7 approximately is node AV the of axis long The artery. nodal AV the around compactly arranged are cells spindle short of cluster A Koch. of triangle the at location subendocardial conduction system The characteristiclocationoftheventricular demonstrated inthesecondpartofreview. are staining, immuno-histochemical and conventional by stained cells, conduction of characteristics histological the review, brief this In heart. human pathology h aroetiua nd i stae i its in situated is node atrioventricular The ■ arrhythmia 울학 과학병리학교실 의과대학 서울대학교 화자학 의학전문대학원 이화여자대학교 ■ electrophysiology 3 김문영 서정욱 right and left bundles (Figure 2). The left bundle and Histological and immuno-histochemical REVIEW its anterior and posterior fascicles are recognized characteristics of the conduction system histologically at the subendocardium of the left ventricular surface of the ventricular septum. The right Cells of the conduction system are mainly bundle is located between the thick bundles of the myocardial cells. The cytoplasm contains SPECIAL right ventricular myocardium and the true septal and they do not have cytoplasmic processes as seen in myocardium. The histological verification of the right neural cells. The conduction cells have less myofibrils bundle is not easier than the left side. than myocardial cells and intimate contact with nerve Masson trichrome staining is one of the convenient endings are noted. Conduction cells at the microscopic methods to differentiate the conduction tissue from level are spindle cells with smaller cytoplasm. The collagenous stroma and pathologic fibrous changes of immuno-histochemical reaction against myoglobin is the myocardium are demonstrable as well through the positive (Figure 3). The intensity of staining by trichrome staining (Figure 3). It is understood that immuno-histochemistry is often influenced by fixation bundles and fascicles are covered with fibrous sheath and other factors so that visual intensity of staining so that rapid conduction from the myocardium is may not be an indicator of the amount of protein. insured, although electrical conduction between cells Neural cell adhesion molecule (NCAM, CD56) is a needs a special gab junction protein or intercalated member of the immunoglobulin super family, disc as revealed by electron microscopy. Side to side mediating intercellular adhesion in the nervous system contact by a parallel alignment of muscle bundles is and and CD56 was up-regulated at the not conductive. It is therefore important to have an ischemic myocardium in human and animal models.4 axial alignment to propagate contractile stimulation. There was a strong positive reaction for CD56 at the

MV MV NC RC

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Figure 1.Left ventricular surface of the ventricular septum. The initial cut was made at the commissure of right and non- coronary cusps (RC, NC) of the . After that, 4 cm long tissue blocks, 2 cm above and below the aortic valve, were designed to make 9 pieces of vertical sections, each with 4 mm thickness (#1-9). Block #9 is toward the anterior wall of the left , while block #4 toward the posterior wall. The rest of the septal surface was sectioned horizontal to make blocks (#10-21). MV; , NC; non-coronary cusp, RC; right coronary cusp

VOL.11 NO.2 7 SPECIAL REVIEW 8 Journal of Cardiac fibers is seen around the individual conduction cells. The cells. conduction individual the around seen is fibers positive synaptophysin of meshwork fine a but cells, myocardial the at negative is cells neural the for marker at longer another Synaptophysin, bundles. left was subendocardial discs intercalated two between length the as represented myocytes of length the that noted also is It reaction. strong such show not did bundles and node atrioventricular The 4). (Figure myocardium ventricular the of disc intercalated AO; ,MV;mitralvalve,RC;rightcoronarycuspofaorticTT;tendonTodaro, TV;septalleafletoftricuspidval layers wheretherightbundleislocated(Masson’strichromestain). septum extendingtotheinfundibulum(INF)ofrightventricle. Shortarrowsindicatetheplanebetweenmyocardial intramyocardial rightbundle(shortarrows).D.Asectionatpiece#7ofFig1showingthepartventricular showing anon-branchingbundle(HB),theanteriorfascicleofleft(longarrows)atsurfaceand the membranousseptum,whereposteriorfascicle(longopenarrows)ramifies.C.Asectionatpiece#1ofFig1 the atrialsurface.B.Asectionatpiece#2ofFig1showingnon-branchingHisbundle(HB)inferiorborder Figure 2. A C Arrhythmia A. histologicalsectionatpiece#3ofFig1showingtheatrioventricularnode(AV)overfibrousannulus TV TV TT AV HB MV atrial arrhythmia. atrial cells stem of markers the of one be to known is C-Kit weakest. the is myocardium ventricular and stained faintly is bundle His node. AV and myocardium atrial the at myocytes (Figure5).Thispatternwasthemostprominent the between network slender a was myocardium atrial the at synaptophysin of pattern staining sltdclsa i ude(iue5.Atrioventricular 5). (Figure bundle His at cells isolated D B TV 5 and interstitial Cajal-like cells related with related cells Cajal-like interstitial and INF 6,7 The C-Kit positive cells were rare were cells positive C-Kit The ve HB AO RC REVIEW A B

cs SPECIAL PF

PF

MC MC LV Septum C D

PF PF

MC MC

Figure 3. A. Histological section at piece #16 of Fig 1 showing a cross section of the distal part of the subendocardial left bundle forming (PF) (arrow) separated from the underlying myocardium (MC). B. A section at piece #16 of Fig 1 showing subendocardial nodules overlying left bundles (open arrow & dot line). C. A section at piece #1 of Fig 1 showing thick and continuous subendocardial smooth muscle fibers (open arrow & dot line) stained violet with Masson trichrome but appear negative for myoglobin as shown in D. (A~C; Masson’s trichrome stain, D; Myoglobin) node has some, but rest of area show few positive junctions predominantly composed of Cx45. The His cells. bundle co-expresses Cx45 with Cx43, while its Previous studies on the conduction system of the downstream branches prominently express Cx40. heart showed subsarcolemmal SR (sarcoplasmic Cx43 becomes abundant in the more distal portions of reticulum), but no T-tubule or corbular SR. Connexin the system, while Cx45 is expressed continuously 45 and neurofilament M (NF-M) were found, but from the AV node to the ends of the Purkinje fibers.9 connexin 43 and atrial natriuretic peptide were lacking.1,8 Purkinje network Myocytes of the sinoatrial and atrioventricular (AV) nodes characteristically have small, dispersed gap The Purkinje fibers are part of the ventricular

VOL.11 NO.2 9 SPECIAL REVIEW 10 Journal of Cardiac B. AlessintensepositivereactionforCD56atbundlebranches(doubleheadarrow)andlongintervalintercalateddiscs. Figure 4. B. Thestainingpattern ofC-KitpositivecellsatHis bundle.(x400)(A;Synaptophysin, B;C-kit) Figure 5. A A Arrhythmia A. AnintensepositivereactionforCD56atintercalateddiscs(arrows)ofventricularseptalmyocardialcells. A. Thestainingpatternofsynaptophysin atatrialmyocardiumwasaslendernetworkbetweenthe myocytes. B B conduction system and were originally discovered by distribution of the conduction branches and the rapid REVIEW Tawara.10,11 These fibers conduct excitation (electrical velocity of the conduction system.16 activation) rapidly from the to the Rapid ventricular in post-myocardial ventricular myocardial tissue. The Purkinje fibers are infarction in the canine heart arise from ectopic foci myocardial cells with vacuolated cytoplasm located in (triggered) within the Purkinje fiber network located SPECIAL the ventricular walls of the heart, just beneath the in the subendocardium of the infarct zone in the left .12 Purkinje fibers, being modified ventricle. These spontaneously occurring arrhythmias myocardial cells, contain some contractile protein, but predictably occur between 24 to 48 hours after the amount is small and glycogen and other organelles occlusion. In Purkinje cells dispersed from the occupy the cytoplasm. It has been argued that subendocardium of the infarct zone (Purkinje cells vacuolated Purkinje cells are only seen in the ungulate from a 48-hour infarcted heart), the density and heart, but the vacuolated character is noted in human function of several sarcolemmal ion channels are heart too. There are, however, muscular cells, smooth altered compared to normal Purkinje cells. Little work muscle cells, other than Purkinje fibers found in the has been done on remodeled Purkinje cells, subendocardium (Figure 3C), particularly in hearts particularly Purkinje cells involved in the initiation with failure. and perpetuation of cardiac arrhythmias in diseased From the point of view of ultrastructural composition, hearts.17 the cells of different parts of the cardiac conduction The Purkinje fibers are distinguished from heart system are partly similar. In contrast to the heart muscle cells by a distinct pattern of gene expression. contractile cardiomyocytes, the cells of the cardiac They up-regulate Cx42, a conduction cell-specific conduction system including Purkinje fibers have a gap-junction protein, unique ion channels, and genes small amount of myofibrils, small mitochondria, typically expressed in neuronal cells. In addition, lighter cytoplasm and higher glycogen content, but no conduction cells induce a unique set of myofibrillar T-tubular system. protein genes, such as slow-twitch skeletal muscle The electrophysiologic demonstration of the heavy chain (sMyHC), atrial myosin heavy Purkinje network showed a propagation of excitation chain (aMyHC), and skeletal muscle-type myosin starting from the apex, continuing rapidly towards the binding protein-H (MyBP-H). Purkinje fibers also base of the ventricle resulting in a contractile motion down-regulate heart muscle-specific myofibrillar from the apex to the base.12 Another study using proteins, such as and myosin binding protein- electromechanical wave imaging visually confirmed C (cMyBP-C), which are essential for normal heart that artificially created sinus rhythm and right-atrial muscle contractility.14 Studies on experimental pacing, consisted of a contraction wave that started at animals with ischemic heart disease demonstrate the apex right at the beginning of the QRS complex, alteration in the distribution of propagated along the septum and then the left- immunolabel to the sides of the myocyte, called ventricular posterior wall and finally to the base.13 ‘lateralization’. Gap junction mediated passage of Ventricular pacing, on the other hand, revealed a ionic/molecular signals appears responsible for the disharmonized contraction of the ventricle, confirming spread of the ischaemia-reperfusion injury from that Purkinje fibers have a crucial role in the synchronization myocyte to myocyte that leads to rigour contracture of ventricular contractions.13 A richly trabeculated and cell death. endocardium, in which the endocardial invaginations Gap junction channels are almost absent in the sinus carry the Purkinje tissue partway into the left node, there are few of them in the AV node, but there ventricular endocardium, further increases the speed are a lot of them in fast conducting muscle cells such and area of early ventricular activation. This is a factor as His and Purkinje fibers. This gives rise to the in ventricular synchronous activation together with the anisotropic propagation of depolarization along the

VOL.11 NO.2 11 SPECIAL REVIEW 12 Journal of Cardiac magnitude to increase susceptibility to arrhythmia. to susceptibility increase to magnitude sufficient of practice, in is, ventricle human failing the in reduction Cx43 the of extent and nature the that view the to support considerable lend models mouse in findings The models. theoretical in predicted than reduction junction gap overall of levels severe less at substrate arrhythmogenic an create to operatively co- act to appears levels Cx43 reduced with combined cardiac musclefiberorientation. .BoyettMR,DobrzynskiH.The sinoatrialnodeisstillsettingthe 1. References infarcts andhypertrophiccardiomyopathy. myocardial failure, heart in arrhythmias in involved factors important the of one is 43 connexin of activity the of characterization Molecular glycogen. of amount large a and elements contractile of numbers small of manifestation a is which cytoplasm, vacuolated is hearts ungulate in fibers Purkinje of feature morphological key The network. Purkinje the of activation the after apex the from begin to contraction myocardial allow will This network. Purkinje the named system, conduction ventricular the of part distal the with continuum a form branches bundle Conclusion wave-front collisionsintheventricularmyocardium. and patterns activation abnormal creating thereby dormant, remain normally that junctions myocyte ventricular working Purkinje/ numerous across impulse the of propagation to leads Cx43 ventricular declining from resulting coupling of reduction survival, term longer for selected mice knockout Cx43 cardiac-restricted In adults. young in arrhythmia to due death cardiac sudden of cause common most the , hypertrophic in disordered particularly is arrangement junction gap Cx43 The eeoeet o gp ucin distribution junction gap of Heterogeneity It is important that the His bundle and the left the and bundle His the that important is It Arrhythmia 15 9 17. 11. James TN.Thedevelopmentofideasconcerningtheconduction 10. Silverman ME,Hollman A.DiscoveryofthesinusnodebyKeith 12.Ijiri T,AshiharaYamaguchiTakayamaK,Igarashi .KostinS,PopescuLM.Adistincttypeofcellinmyocardium: 7. 13.Konofagou EE,LuoJ,SalujaD,CervantesDO,Coromilas 2. Anderson RH,YanniJ,BoyettMR,ChandlerNJ,DobrzynskiH. 14. 4. Gattenlohner S,WallerC,ErtlG,BultmannBD,Muller-Hermelink 3. Seo J-W.VentricularAnatomyfortheElectrophysiologist(PartI). 8. Baruscotti M,RobinsonRB.Electrophysiologyandpacemaker 6. Morel E,MeyronetD,Thivolet-BejuyF,ChevalierP.Identification 16. Boineau JP.Leftventricularmuscleband(VMB):thoughtsonits KanjM,SalibaW.Basicarrhythmiaphysiologymechanisms.In: 15. 9. Severs NJ,BruceAF,DupontE,RotheryS.Remodellingofgap 5. Stamm C,LieboldA,SteinhoffG,StrunkD.Stemcelltherapyfor pace 100yearsafteritsdiscovery. Cardiovasc Res Cardiovasc interstitial Cajal-likecells(ICLCs). The anatomyofthecardiacconductionsystem. cardiac ischemia. in humanischemiccardiomyopathyandaratmodelofchronic areup-regulated HK, MarxA.NCAM(CD56)andRUNX1(AML1) 2010. 2009;22:99-113. function ofthedevelopingsinoatrialnode. veins. and distributionofinterstitialCajalcellsinhumanpulmonary junctions andconnexinexpressionindiseasedmyocardium. ischemic heartdisease:beginningorendoftheroad? method formodelingthepurkinjefibersofheart. Shimada T,NambaHaraguchiR,NakazawaK.Aprocedural conduction-relevant velocityestimationinvivo. Fujikura K.Noninvasiveelectromechanicalwaveimagingand 2010;50:208-215. London: Informa;2007. Natale A,WazniO,eds.Handbookofcardiacelectrophysiology. Circ Physiol Circ Transplant Boyden PA,HiroseM,DunW.Cardiac Purkinjecells. 2006;29(suppl 1):S56-S60. system oftheheart. 2007;93:1184-1187. and Flack:onthecentennialoftheir1907publication. muscle. transcription factorprogramdistinctfromcardiacandskeletal Purkinje fibersoftheavianheartexpressamyogenic Takebayashi-Suzuki K,PauliksLB,EltsefonY,MikawaT. physiologic andclinicalimplications. Sci Rhythm . 2008;58:481-486. Heart Rhythm Heart . 2010;7:127-135. Dev Biol Dev . 2006;15(suppl1):S47-S56. . 2007;293:H2613-2623. . 2008;80:9-19. . 2001;234:390-401. Am J Pathol J Am . 2008;5:1063-1067. Ulster Med J Med Ulster . 2003;163:1081-1090. J Cell Mol Med Mol Cell J Circ Res Circ . 1982;51:81-97. Eur J Cardiothorac Surg Cardiothorac J Eur . 2007;100:1543-1545. Am J Physiol Heart Physiol J Am . 2009;13:295-308. Ultrasonics Clin Anat Clin J Physiol J Heart Heart Cell . . . .