Genesis of Cardiac Arrhythmias€¦ · Genesis of Cardiac Arrhythmias ByPAULF.CRANEFIELD, M.D.,...

Genesis of Cardiac ArrhythmiasBy PAUL F. CRANEFIELD, M.D., PH.D., ANDREW L. WIT, PH.D., AND BRIAN F. HOFFMAN, M.D.

A N ARRHYTHMIA is caused by an abnormalityin the rate, regularity, or site of origin of the

cardiac impulse or by certain disturbances in theconduction of the impulse such that the normalsequence of activation of the atria and ventricles isdisturbed. Arrhythmias thus may be said to resultfrom abnormalities of impulse initiation, impulseconduction, or both.

Activity of Automatic CellsThe normal rhythm of the mammalian heart

results from spontaneous excitation of cells in thesinoatrial node. These cells possess the property ofautomaticity.' The transmembrane potential ofworking muscle fibers in the atria or ventriclesdemonstrates a rapid depolarization on excitation(phase 0), a period of variable duration duringwhich the cell repolarizes (phases 1, 2, and 3), andthen a stable resting potential (phase 4), whichpersists until the next propagated impulse arrivesand causes excitation. In contrast, in cells of thesinoatrial node, repolarization is not followed by aperiod during which the transmembrane potential isstable. Instead, immediately after the end ofrepolarization the membrane potential begins todecrease slowly. This slow depolarization duringphase 4 lowers the transmembrane potential towardthe threshold potential, the value of transmembranepotential at which excitation occurs. If the slowdepolarization attains the threshold potential, exci-tation occurs and the cell develops an actionpotential which then propagates to excite adjacentcells and, normally, the rest of the heart.2 All cellswhich demonstrate this slow diastolic depolariza-tion are said to be automatic. This mechanism forspontaneous firing has been called the normalautomatic mechanism to differentiate it from other

From the Rockefeller University, New York, New York,and the Department of Pharmacology, College of Physiciansand Surgeons, Columbia University, New York, NewYork.

Supported in part by Grants HL-11994, HL-14899, andHL-08508 from the National Institutes of Health and bygrants-in-aid from the New York Heart Association and theAmerican Heart Association.

Dr. Wit is a Senior Investigator of the New York HeartAssociation.

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changes in the transmembrane potential which can,under abnormal conditions, initiate automatic fir-ing.3' 4Also, there are other causes for slowdepolarization during phase 4 which are notnecessarily associated with automaticity.5

In addition to the cells of the sinoatrial node anumber of other groups of specialized cardiac cellsalso possess automaticity and can serve as auto-matic pacemakers. These include: cells in thespecialized atrial fiber tracts6 which connect thesinoatrial and atrioventricular nodes and lead fromthe sinoatrial node to the left atrium, cells in andaround the coronary sinus ostium, cells in the moredistal parts of the atrioventricular node (NHregion), and cells in the His-Purkinje system.2 Mostevidence indicates that cells in the more proximalparts of the atrioventricular node (AN and Nregions) do not show automatic firing exceptperhaps under extreme experimental conditions.2The rate at which normally automatic cells fire is

controlled primarily by the activity of the autonom-ic nervous system and secondarily by other changesin the local environment of the cells. Important inrelation to the latter consideration is the extracellu-lar K+ concentration, pH, P02, and the extracellu-lar concentration of Ca+ +. In addition to the localchemical environment of the cells, another signifi-cant regulator of the rate at which an automatic cellwould fire is the frequency at which it has beenstimulated. If an electronic pacemaker or an ectopicfocus gains control of the atrial rhythm and causesactivation at a rate significantly higher than theintrinsic sinus rate, and if these impulses succeed indepolarizing the sinoatrial node, the automaticity ofthe node will be depressed. As a consequence, if theectopic pacemaker stops abruptly, the initialautomatic firing rate of the sinoatrial node will below and automaticity will slowly increase to itsnormal value. This phenomenon, called overdrivesuppression, is common to all normal automaticcells. In this manner the normal sinus pacemaker,by overdriving all subsidiary pacemakers, depressestheir automaticity so that there is less likelihoodthat any one of them will escape and cause anectopic impulse. Disease and the action of manydrugs can abolish overdrive suppression. In fact, theaction of catecholamines and digitalis may reverse

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GENESIS OF ARRHYTHMIAS

the response of an automatic cell to overdrive so

that, instead of depression, overdrive actuallyenhances automaticity and increases the likelihoodof escape rhythms.

Since there are many groups of automatic cells inthe heart, any factor which decreases the intrinsicrate of the normal sinoatrial nodal pacemaker or

which increases the automaticity of other special-ized latent pacemakers can result in an arrhythmia.This may appear as a single ectopic impulse, a

group of ectopic impulses, or a sustained rhythmoriginating at an abnormal site. If an increase invagal activity depresses the automaticity of thesinoatrial node the site of origin of the impulse mayshift to other automatic cells proximal to theatrioventricular node (low atrial rhythm) or to cellsin the His-Purkinje system which are not stronglyinfluenced by vagal activity. Similarly, there may bean increase in automaticity at an ectopic site due toa local increase in sympathetic efferent activity or tosome local change in the condition of the cells suchas those caused by ischemia or stretch.2 If cells atthe ectopic site attain threshold before they are

excited by propagation of an impulse arising in thesinoatrial node, they will serve as pacemaker forone or a series of impulses which may beresponsible for activation of all or parts of theheart.

Ectopic automatic rhythms also may result fromabnormalities in the propagation of an impulsearising in the sinoatrial node. Sinoatrial block may

permit the escape of either subsidiary atrialpacemakers or pacemakers in the lower atrioven-tricular node and His-Purkinje system. Block ofimpulse transmission from the atria to the ventri-cles, either in the atrioventricular node, common

bundle, or bundle branches, ordinarily will result inthe initiation of an ectopic automatic rhythm distalto the site of block. Finally, when two sites ofautomaticity, one proximal to and one distal to theatrioventricular node, are firing at almost the same

rate, there may be a rhythm commonly designatedas isorhythmic dissociation.7 In this case many ofthe normal and ectopic impulses are blocked in theatrioventricular node. The atria and ventricles willbe excited almost simultaneously and at almost thesame rate for considerable periods of time. This isusually interrupted periodically by intervals duringwhich the atrial or ventricular pacemaker assumes

the role of the primary pacemaker. It is quite likelythat a similar relationship may exist between an

ectopic focus and the sinoatrial node but with blockoccurring at the junction between the node and


atrium and also between the normal cardiacpacemaker and any parasystolic automatic focus(see below under parasystole).

Effects of Depressed Excitability

We now consider arrhythmias and abnormalitiesof activation of the heart that result from depressedexcitability and abnormal conduction. The discus-sion is written in terms of the ventricle and of the"<normally" depressed A-V node but the basicprinciples apply to atrial fibers as well.

Abnormalities in ConductionThe presence of localized depression of excitabil-

ity can explain a variety of electrocardiographicphenomena.5' 8 Depression of a bundle of Purkinjefibers can reduce conduction velocity from thenormal value of 2-3 m/sec to 0.05-0.1 m/sec (fig. 1).Such depression in a segment of the bundle of Hiswould result in first-degree heart block. First-degreeheart block caused in part by slowed conduction inthe ventricular conducting system has been docu-mented by His bundle recording.9 Similar delay in abundle branch could give rise to ventricularaberration or bundle-branch block, even in responseto a nonpremature impulse, whereas aberrancycaused by premature activation or high rateprobably results from conduction infringing on therelative refractory period (before completerepolarization of the previous impulse). Similarslowing of conduction of nonpremature impulseshas been shown in fibers depressed by phase 4depolarization.10Conduction through depressed fibers also shows

increased sensitivity to changes in rate which mayresult in variable degrees of delay and block (fig.2). Conduction block may occur without a notice-able increment in conduction delay (second-degreetype II block) (fig. 2B) or transmission of theimpulse through the depressed cardiac fibers mayshow the Wenckebach phenomenon (second-de-gree type I block) (fig. 3). In the normalventricular conducting system such increases in ratedo not cause conduction delay or block unlessexcitation occurs before completion of repolariza-tion of the previous impulse.

These findings provide an explanation of manyelectrocardiographic observations. An increase inheart rate can result in a transition from normalintraventricular conduction to bundle-branch blockand even to complete heart block." Records of theactivity of the His bundle in the human heart haveshown that many disturbances of atrioventricular

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A

B

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Figure 1

Effects of localized depression on conduction in a bundle ofPurkinje fibers. (A) Diagram of the preparation with loca-tion of stimulating electrodes S, and S2, and recording elec-trodes 1, 2, and 3. The crosshatched area where recordingelectrode 2 is located has been depressed by local elevationof KO+ to 15 mM. (B) Tracing shows that conduction beforedepression is rapid; when the bundle is stimulated at S, theimpulse conducted from one end of the bundle to the otherin less than 5 msec. In C, after depression of the centersegment (note the depressed action potential in trace 2)conduction between electrodes 1 and 3 required 150 msec.

Conduction velocity fell in the depressed part of thebundle to about 0.07 m/sec from a normal value of about3 m/sec. Calibrations: vertical, 100 mv; horizontal, 500 msec.

conduction occur in the bundle of His or the bundlebranches rather than in the A-V node. In Mobitztype II A-V block, conduction block apparentlyoccurs in the ventricular conducting system.'2' 1.3 Aprogressive increase in the degree of block has beendemonstrated with increasing atrial rate13 (see fig.2). The Wenckebach phenomenon in the ventricu-lar conducting system may appear as incompletebundle-branch block progressing in severity tocomplete bundle-branch block, complete blockcorresponding to the dropped beat of the Wencke-bach period.'3-' If Wenckebach periodicity occurs

in the common bundle, above its bifurcation, only a

progressive prolongation of the P-R interval culmi-nating in A-V block is observed on the electrocar-diogram without aberrant activation of the ventri-cles.13

A

2

B

C

Er

Figure 2

The effects of increasing rate on conduction through a de-pressed segment in an unbranched bundle of canine Purkinjefibers similar to that shown in figure 1A. Recording electrode2 was located in the depressed center segment, while elec-trodes 1 and 3 were at either normal end. (A) At a driverate of 50/min every impulse is conducted with delay. (B)At 60/min 4:3 conduction block appears (second-degreetype II block). (C, D, and E) At rates of 75, 100, and140/min there is a progressive increase in the degree ofconduction block. Calibrations: vertical, 100 mv; horizontal,350 msec.

Depression of excitability may also cause unidi-rectional block (fig. 4). One-way block located in aperipheral twig of the Purkinje fiber network mightproduce no obvious changes in the electrocardio-gram but obvious changes would occur if one-way

2

Figure 3

Wenckebach cycles in a bundle of canine Purkinje fibers.Recording electrode 2 was located in the depressed centersegment, while electrodes 1 and 3 were at either normal end.Note the lengthening of the action potential in trace 2after the dropped beat of the Wenckebach cycle. As a result,the next impulse reaches the depressed segment during itsrefractory period and is blocked, resulting in a 2:1 cycle aftereach Wenckebach cycle. Calibrations: vertical, 100 mv; hori-zontal, 100 msec.


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Figure 4

Unidirectional conduction block in the segment of a bundleof canine Purkinje fibers depressed with high K+ (middletrace). (A) Stimulation at one end of the bundle results inconduction. The recording sites shown in the lower, middle,and top traces were activated in that order. (B) Stimulationat the other end of the bundle results in activation of record-ing site in top trace (nearest stimulating electrode) but con-

duction block in the depressed area (middle trace). Calibra-tions: vertical, 100 mv; horizontal, 500 msec.

block of normal forward conduction were present inthe common bundle or in both of the bundlebranches. Studies in man have shown that many

cases of complete heart block are caused byconduction block in the common bundle or itsbranches.16 One-way block at those sites couldprevent conduction from the atrium to the ventriclewhile allowing conduction from the ventricle to theatrium. 17

Concealed ConductionA premature impulse of atrial origin that fails to

evoke a ventricular contraction may affect propaga-tion of the next atrial impulse, for example byprolonging the P-R interval. Such effects show thatapparently nonconducted impulses may conductpart way through the A-V node or even part way

into the ventricular conducting system, leavingchanges of excitability in their wake. Such impulsesare said to have undergone "concealed conduc-tion";'18 19 what is actually "concealed" is, of course,

the exact site at which block occurred. Block of a

premature impulse in the A-V nodal area isprobably rather common20 and is detected by thefact that the next atrial impulse is either blocked or

reaches the ventricle with delay. If a prematureimpulse of atrial origin is conducted through theA-V node and blocked in the ventricular conductingsystem, the next impulse may be conductednormally in the ventricular conducting systembecause it must undergo normal A-V nodal delaybefore reaching the point where the previous im-

pulse died out. That delay allows time for re-

covery of the area where the premature impulsewas blocked. In addition, the time needed forrecovery is reduced because a premature action


potential in the ventricular conducting system isshorter than a normal action potential.2 The factthat such impulses can propagate into the ventricu-lar conducting system before blocking thus remains"concealed" even from ordinary electrocardiograph-ic technics and can be shown only by direct recordsof the activity of the bundle of His or the bundlebranches.The effect of a blocked impulse on the following

impulse depends on the site of block, on the timeneeded for the following impulse to reach the siteof block, and on how long it takes the area in whichblock occurred to recover its excitability. We havefound that in depressed Purkinje fibers the timerequired for complete recovery of excitabilityfar exceeds that needed for complete repolariza-tion,21 which greatly prolongs the period duringwhich conduction of a subsequent beat may beimpaired. In figure 5A, a premature impulseoriginating in normal tissue blocks within thedepressed area and creates refractoriness thatblocks the next driven impulse, even though thatimpulse arose long after complete repolarization inthe normal area. In figure 5B, the impulse followingthe blocked impulse is conducted but with anincreased delay of 50 msec. Block of this type indepressed ventricular conducting fibers and itseffect on a subsequently conducted atrial impulsewithin the ventricular conducting system wouldappear electrocardiographically as A-V block of apremature atrial impulse followed either by blockof the next impulse or by aberrant conduction ofthe next impulse. This effect can be seen even at anormal or low heart rate and has been reported inthe human heart.18

A

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B

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Figure 5

Concealed conduction in a depressed segment of a bundleof canine Purkinje fibers. Recording electrode 1 wvas lo-cated in the depressed area and electrode 2 in a normalarea. The premature impulse arising in the normal area isindicated by an arrow. (See text for discutssion.) Calibrations:vertical, 100 mv; horizontal, 500 msec.

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Reentrant Excitation

Reentry of excitation in the ventricle requires thatthe impulse that excites the ventricle somehow findsa separate pathway in which it can travel and fromwhich it can emerge at the end of the refractoryperiod to reenter the ventricle and elicit a secondactivation. The impulse destined to reenter theventricle must survive for some 300 msec if it is tooutlast the ventricular refractory period.22 If theimpulse is conducted in a short pathway functional-ly isolated from the heart, conduction velocity inthat pathway must be very slow. Since very slowconduction has long been assumed to be present inthe atrioventricular (A-V) node, a particular formof arrhythmia, the nodal return systole or echo beat,has long been regarded as reentrant.17' 23 In nodalreturn extrasystoles an impulse that arises in theatrium or ventricle and is conducted into the A-Vnode also "returns" from the node to the chamber inwhich it originated. Such return extrasystoles are

explained by assuming circus movement of excita-tion in or near the A-V node.23Most models offered to explain such circus move-

ment are essentially identical with those first pro-

posed by Schmitt and Erlanger24 and shown in figure6. The upper diagram in figure 6 shows a strand ofthe ventricular conducting system (D) bifurcatinginto two branches (B and C), both of which joinventricular muscle. The arrow at D indicates an

impulse that travels with normal velocity via C andthe ventricular muscle to reach B but does nottravel from A to B because of one-way block in thatbranch (stippled area). Activity can, however, enterthe depressed area via its far end at B. Ifconduction from B to A is very slow, the impulsemay not reach A until the fibers at A and D haverecovered their excitability. If that occurs, theimpulse will continue past A and into D to reexcitethe entire heart and give rise to a reentrantextrasystole. Reentry via conduction around such a

circuit can occur only if the depressed area is thesite of one-way block and if conduction through it isvery slow. In the lower diagram in figure 6 the path-ways are not discrete separate branches; they couldbe different fibers or bundles of any type. The lowerdiagram of figure 6 thus contains the elementsnecessary for reentry within a syncytial structure,i.e., reentry dependent on longitudinal dissociationof function.We find that reentry in response to a premature

or a nonpremature impulse readily occurs in thepresence of slow conduction and unidirectional

D

A~~~~~~I

Figure 6

Models for reentry proposed by Schmitt and Erlanger.2h~(See text for description.) The upper figure is based onfigure 6 of Schmitt and Erlanger and consists of a Purkinjefiber bundle (D) which divides into two branches (B and C).These two branches are connected distally by ventricularmuscle. The stippled segment (A-B) is an area of unidirec-tional conduction block. The lower figure is based on figure5 of the same work. A and B indicate two parallel musclefibers with lateral connections. (Reproduced from Amer JPhysiol,24 by permission.)

block in unbranched bundles or in networks of theventricular conducting systeM.25' 26 That circusmovement in a loop of depressed ventricularconducting fibers can cause premature beatS26 iSdemonstrated in figure 7. An impulse travelingdown the bundle to the loop can enter the loop inonly one direction (branch a) because of unidirec-tional block in branch c (lower branch) (fig. 7C).Figure 7A and C shows that if the impulse isblocked in both limbs of the loop there is no reentryinto the main bundle. If the impulse that enters theupper part of the loop (branch a) is delayed butnot blocked at the depressed area, it travels aroundthe loop, reenters the main bundle, and gives rise toan extrasystole or premature beat (fig. 7B and D).A sinus impulse could therefore enter a bundleleading to such a depressed loop; the impulsereentering the bundle from the loop would travel


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Ca 2c~~~~2~~~~~~~~~bD c 3

< ~~~~~~~~b

Figure 7

Single circus movement in a loop of canine Purkinje fibersdepressed by high K+. (A) Action potentials recorded duringconduction block in the loop, and (B) single circus move-

ment. (C and D) Diagrams of the praparation and locationof the stimulating electrode (S1) and the recording electrodes(1, 2, 3). The branches of the loop are indicated by a, b,and c. The pathway of propagation shown by arrows in Ccorresponds to the action potentials shown in A. Note onlysingle depolarizations at sites 1 and 2 and the absence ofdepolarization at site 3 indicating block. The pathway ofpropagation in D corresponds to the records shown in B.In B the first depolarization at site 1 and the depolarizationat 2 are followed by delayed activation at 3 (a site of uni-directional block). This is followed by the reentrant impulseat 1 (second depolarization). Calibrations: vertical, 100 mv;horizontal, 500 msec.

back into the rest of the ventricular conductingsystem and ventricle as an extrasystole. If thisoccurred after every sinus impulse a bigeminalrhythm would occur.

In figure 7, the impulse, once past recording site2, is not subject to further delay and travels aroundthe loop fairly rapidly. It may therefore enter theupper branch again and reach site 2 while it is stillrefractory. A repetitive circling of excitation aroundthe loop is thus not possible. If there are two sites ofdelay or slow conduction around the entire loop an

impulse might travel around the loop repeatedly,sending impulses out any branch that it passed on


its trip around the loop.26 Such continuous circusmovement could result in a tachycardia. Not alltachyeardias result from reentry but many may,particularly in patients in whom coupled prematureventricular systoles appear and show the same QRSconfiguration as the systoles of the tachycardia. Inthose instances the first beat of the paroxysm oftachycardia often appears with fixed coupling to theQRS of the last normal beat.27 Paroxysmal ventricu-lar tachycardia can often be precipitated by anapplied ventricular premature stimulus and termi-nated by an appropriately timed ventricular stimu-lus.28' 29 Similar findings have been reported forsupraventricular tachycardias resulting from con-tinuous reentry within the A-V node.30 Theseobservations can readily be explained in terms ofthe mechanisms described above; premature stimu-lation may result in the slow conduction needed forreentry and a single applied stimulus during thetachycardia would cause another impulse to enterthe loop, making it refractory to the circulatingimpulse.We have also found that depression of a short

segment of an unbranched bundle of Purkinje fiberscan lead to reentrant excitation of a kind analogousto an A-V nodal return extrasystole.25 The impulseentering the depressed area in the bundle is slowedand, after considerable delay, continues in theforward direction while a reentrant impulse isreflected backward in the direction from which theinitiating impulse arrived (fig. 8). In this sort ofreentry by "reflection" the impulse need notcontinue in the forward direction; block in theforward direction combined with reentry in theretrograde direction has been observed.25 A possiblemechanism for reflection is shown schematically infigure 8C, in which the model shown in figure 6 ismodified by enlarging the area of depression. Theconditions shown in this diagram presumably couldarise in depressed fibers located anywhere in theheart.A depressed 8-10-mm segment of unbranched

Purkinje fibers capable of giving rise to reentry byreflection could be located anywhere in theconducting system from the His bundle to a distalperipheral twig. The electrocardiographic manifes-tations of such reentry would vary depending onthe location of the depressed area. In the commonbundle it could result in various degrees of A-Vblock associated with return extrasystoles (fig. 9).Were the depressed segment in a peripheral twig

of the conducting system, the electrocardiographicmanifestations of the events depicted in figure 9

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AA B

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Figure 8

Reentry (reflection) in a linear bundle of canine Purkinjefibers. (A) Diagram of preparation showing location of stim-ulating electrodes (S1 and S2) and recording electrodes (a,b, c). The center segment, depressed by high K+, is indi-cated by crosshatched area. The bundle is being stimulatedat Si only. (B) In the first group of action potentials I

shows conduction of impulse originating at Si without re-

entry; conduction from a to c, through the depressed area,

required 100 msec. In the second group of action potentialsI shows conduction of another impulse from Si with a

marked increase in the conduction delay between recordingsites b and c to 250 msec. A reentrant impulse II returningin the opposite direction is shown at recording sites b and a.

(C) Diagrammatic representation of a possible pathway ofimpulse propagation during reentry in two parallel fibers.Severely depressed area indicated by crosshatches, moder-ately depressed area by stipples. Impulse I is completelyblocked in upper fiber at area of unidirectional block buttraverses the moderately depressed area in lower fiber, thenreenters upper fiber to travel in the reverse direction as

impulse II. Calibrations: vertical, 100 mv for traces a and c

and 50 mv for trace b; horizontal, 250 msec.

would be completely different. Nothing might beseen on the electrocardiogram apart from occasion-al extrasystoles since the focal ventricular delay,concealed retrograde conduction in the small twig,and focal ventricular block might well not bedetected.

Fixed and Variable CouplingDuring the time between the appearance of

the QRS complex evoked by the sinus impulse andthe appearance of the reentrant extrasystole theimpulse is traveling through the pathway that leadsto reentry. This event is not seen on theelectrocardiogram because the amount of tissue that

I1 1 31 1 1 4i 51

cb

1 23 4 2 ~~~34 5 6Figure 9

Patterns of reentry arising at a depressed segment in a bun-dle of canine Purkinje fibers similar to that shown in figure8A. The position of the recording electrodes a, b, and c arethe same as in figure 8. Driving stimuli are indicated byshort vertical lines and by numbers on trace a in each record.Propagation is from a to b to c, conduction between b and coccurring with variable delay. When propagation is suffi-ciently delayed between b and c, a reentrant impulse is seen(e.g. impulses A-3', B-5') to reenter from c to b to a. Werethis depressed segment in the common bundle the stimulusartifact would represent arrival of atrial excitation at theatrial margin of the A-V node, trace a would represent theresponse of the common bundle just beyond the node, traceb the response of the depressed region of the common bun-dle, and trace c the response of the common bundle justbeyond the depressed segment. In A at a regular atrial rate,the first sinus impulse, 1, would evoke normal ventricularactivation with a slightly prolonged P-R interval on theelectrocardiogram. The second impulse, 2, would activatethe ventricles after even greater prolongation of the P-Rinterval since conduction from b to c is slower; a reflectedreentrant impulse which appears in trace b is blocked withinthe depressed segment before conducting back to site a(concealed reentry) so that no reentrant premature systolewould appear on the electrocardiogram. The third sinus im-pulse, 3, would be followed by venticular activation after amarkedly prolonged P-R interval caused by conduction delayin the His bundle (since conduction between b and c hasnow markedly increased) and would be followed by anatrial return beat originating in the depressed region (re-entrant impulse from b to a). The fourth sinus beat wouldbe blocked in the A-V junction, still refractory from thereentrant impulse; the fourth stimulus does not elicit anaction potential since it occurs during repolarization of thereentrant impulse. (B) A different combination of theseevents is shown. Calibrations: vertical, 100 mv for tracesa and c and 50 mv for b; horizontal, 500 msec. Based onfigure 4 of our earlier article.25 (Reproduced from Circ Res,by permission.)

comprises this pathway is small and becauseconduction through it is slow.7 If the pathway thatleads to reentry in a loop of Purkinje fiber bundlesis always the same and if the impulse always travelsthrough it at the same speed, the interval betweenthe QRS complex of the dominant rhythm and theextrasystole will be fixed and the result will be abigeminal rhythm with fixed coupling. If theconduction time through the pathway leading toreentry varies, the coupling interval will vary (fig.10).Variable or progressive conduction delay in a

depressed segment can also result in variableCirculation, Volume XLVII, January 1973

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Figure 10

Variable coupling intervals of reentrant impulses due to in-

creasing conduction time in a reentrant pathway. The mech-anism of reentry and location of recording sites 1, 2, and 3in the reentrant pathway are shown in figure 7B and D.The first depolarization in trace 1 of each panel is the stim-ulated action potential which propagates to site 2 givingrise to the action potential in trace 2 and then to site 3(action potential in trace 3), finally reemerging to reexcite atsite 1; the second depolarization in 1 is the reentrant im-pulse. Conduction delay between sites 2 and 3 is variable;in A when conduction between these recording sites was

215 msec the coupling interval between the stimulated beatand the reentrant impulse at recording site 1 was 330 msec.

As conduction time between sites 2 and 3 increased to 285msec (B) to 345 msec (C) to 360 msec (D), the couplinginterval at site 1 increased to 400 msec (B) to 450 msec (C)to 490 msec (D). Calibrations: vertical, 100 mv; horizontal,500 msec.

coupling intervals in reentry resulting from reflec-tion, as in figure 9 in which Wenckebach periodsappeared at a constant drive rate. When conduc-tions through the depressed segment required 320msec, as in impulse A-3, the coupling interval of thereentrant impulse to the previous impulse was 425msec. Impulse B-5 was delayed only 200 msec inthe depressed segment and the coupling interval ofthe reentrant impulse was decreased to 285 msec.

Wenckebach periods may also occur in thereentrant pathway either in a loop of Purkinje fiberbundles or in the depressed segment of an

unbranched bundle of Purkinje fibers. A progressiveincrease in conduction delay in the reentrantpathway would result in progressive lengthening ofthe coupling intervals of the extrasystoles. Duringthe blocked beat of the Wenckebach cycle therewould be no reentrant extrasystole.Mack and Langendorf31 and Langendorf and


Pick32 have reported intermittent ventricular bi-geminy in which progressive lengthening of thecoupling intervals was followed by dropping out ofthe ectopic impulse causing intermittence of thebigeminy and which therefore may be due to such aWenckebach cycle in the reentrant pathway.

Since the time required for an impulse to conductthrough a depressed segment tends to increase withincreasing rate, or decreased preceding cyclelength, one would expect the coupling interval ofreentrant beats to vary also with the heart rate orchanges in preceding cycle length. If the dominantrhythm is irregular, as the ventricular rate may beduring atrial fibrillation or during sinus arrhythmia,the coupling interval of reentrant beats may varywith the length of the preceding cycle. If the lengthof the preceding cycle is short, block may occur inthe pathway leading to reentry just as it does athigh regular rates. Langendorf et al. postulated thiseffect to explain intermittent ventricular bigeminyin which ventricular premature beats with fixedcoupling occur only after long preceding cycles.33

Effect of Rate on the Frequency of ReentryAn increase in rate of the dominant rhythm may

reduce the frequency with which reentrant extrasys-toles appear. This is readily understood in terms ofthe effects of increasing rate on conduction in adepressed segment; 1:1 conduction with delay in adepressed segment at slow rates changes toprogressively higher degrees of block as the rateincreases (fig. 2). If 2:1 block appears in thepathway that leads to reentry, a bigeminal rhythmwould be converted to a rhythm in which everyother activation of the ventricle is followed by anextrasystole.

If the dominant rate is high enough to producetotal block in the pathway that leads to reentry noreentrant extrasystoles will be seen. Impulsesnevertheless may regularly enter the pathway thatleads to reentry, their block within that pathwaybeing an example of concealed conduction. Con-cealed conduction in the pathway that leads toreentry obviously can affect the next impulse thatenters that pathway. In a heart in which eachimpulse of a regular sinus rhythm evokes abigeminal response of the ventricle due toreentry, a premature sinus impulse might beblocked in the pathway that leads to reentry. Thepremature sinus impulse would thus evoke a singleQRS complex rather than a bigeminal response, andthe depression caused by block of the prematureimpulse in the pathway that leads to reentry might

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block the next potentially reentrant impulse andthis in turn might block the next. A singlepremature activation of the ventricle might thuscause the disappearance of one or many extrasysto-les that would have appeared had the rhythmremained regular.

If an impulse blocks early in its passage throughthe pathway that leads to reentry the rest of thatpathway is spared an excitation. The result may bemore complete recovery in the pathway leading toreentry so that the next impulse entering it isconducted rapidly enough to reach the ventricleduring the refractory period, i.e., reentry isconverted to concealed reentry. In figure 9 con-cealed reentry of impulse B-2' blocks forwardconduction of impulse B-3; as a result impulse B-4 isconducted more rapidly than would be expectedfrom its position in the Wenckebach cycle and doesnot give rise to reentry. On the other hand, block ofan impulse in the pathway that leads to reentry maydelay the conduction of the next impulse throughthat pathway, slowing it enough to allow it toreenter the ventricle. An example of conversion ofconcealed reentry to frank reentry by this mecha-nism is shown in figure 9 in which concealedreentry of impulse A-2' delays conduction ofimpulse A-3 enough so that impulse A-3' becomesfully reentrant.The special case in which the impulse is blocked

just before it reaches and reenters the ventricle (fig.11) has been called concealed reentry31' 33 but theterm seems an appropriate one to describe anyinstance of block within the pathway that leads toreentry. We have seen block just prior to reentryboth during reentry caused by circus movement andduring reentry caused by reflection.25 26 Thephenomenon was postulated by Damato in aningenious explanation of Wenckebach periods inthe A-V node.34

Reentry may occur frequently at a slow heartrate, disappear at a moderate rate, become morefrequent at a higher rate, and become less frequentat a still higher rate (see fig. 6 in our earlierarticle25). Such behavior is understandable in termsof the mechanisms described above. At a low heartrate conduction through the pathway that leads toreentry may be slow enough to permit reentry; theincrease in conduction velocity often seen when rateis increased may cause the impulse to conductso rapidly through the pathway that leads to reentrythat it reaches the ventricle while it is refractory,so that no reentry occurs. Such improved conduc-tion may result from postexcitatory hyperpolariza-

A

2

3

B 9

c 3

Figure 11

Concealed reentry in a depressed loop of canine Purkinjefiber bundles. (A) Recordings of action potentials from sites1, 2, and 3 in the reentrant pathway, shown diagrammaticallyin B. The branches of the loop are indicated by a, b, and c.An impulse initiated near recording site 1 may propagatedown the main bundle near site 2 and block before travelingaround the loop. This occurs for the left group of actionpotentials in A. The impulse may also enter the loop inbranch a (but not branch c due to unidirectional block) andtravel around the loop to reexcite site 2, but block beforereturning to site 1. This is indicated by the right group ofimpulses in A and constitutes reentry which may be con-cealed on the electrocardiogram since it would not reexcitethe ventricles. Calibrations: vertical, 50 mv; horizontal, 500msec.

tion of depressed fibers secondary to the morefrequent activation. Reentry reappears at higherrates because of the appearance of rate-dependentdelay in the pathway that leads to reentry; and afurther fall in the frequency of reentry results asstill higher rates lead to complete block in thepathway leading to reentry. The disappearance ofreentrant extrasystoles may thus result from eitherof two quite different mechanisms. In one, reentryvanishes because of improvement in conductionthrough the pathway leading to reentry; in theother, reentry vanishes because of impairment ofconduction in the pathway leading to reentry.The dependence of the frequency of extrasystoles

on rate is of particular significance in myocardialinfarction with sinus bradycardia or in advanceddegrees of atrioventricular block in which theoccurrence of frequent extrasystoles has often beendescribed.35 Such ventricular arrhythmias havesuccessfully been prevented by increasing theventricular rate either by catecholamines or by


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electrical pacemakers. Either of the two mecha-nisms described above may operate in the disap-pearance of the extrasystoles.

Summation, Inhibition, and ParasystoleOur recent studies have revealed two important

electrophysiologic properties of depressed Purkinjefibers, namely summation and inhibition.8'22 If asegment of a bundle of Purkinje fibers is sodepressed that bidirectional conduction block oc-curs, excitation of either normal end of the bundlewill give rise to an action potential which willpropagate to the depressed area and die out in thatregion (fig. 12). However, excitation of both endsof the bundle will result in summation of thesubthreshold responses in the depressed centersegment, giving rise to an action potential in that

SIA

region. If a branch arises in the center of thedepressed segment, activity evoked by summationcan travel out the branch (fig. 12). This phenome-non of summation in depressed regions of theventricular conducting system can result in reen-trant extrasystoles as previously discussed.8

Interaction between impulses traveling toward ajunction of depresse,d fibers can also result ininhibition.8 In this situation the action potentialfrom one end of the Purkinje bundle is able toexcite the depressed region while the actionpotential from the other end is not. However, animpulse traveling down the ineffective end of thebundle may die out in the depressed area, alteringits excitability and thereby preventing or inhibitingthe excitation that would otherwise occur when theeffective end of the bundle is excited (fig. 13).The term parasystole is usually used to describe

the occurrence of premature beats which occur atvarying coupling intervals after a preceding beat.Such premature systoles may occur early in thebasic cycle but they often appear late enough tocause fuision beats. In addition, the intervalsbetween successive parasystolic impulses are either

2 _

1 3 3 1 3

i;2. 2 ---

Figure 12

Summation in a depressed segment resulting in propagationof activity out a branch arising in that segment. (A) Thelocation of the depressed area (shaded), the branch from thedepressed area, the stimulating electrodes (S1 and S2), andthe recording electrodes (1, 2, and 3). (B) The left-handpanel shows that excitation of the right end of the bundle(S2) evokes an action potential at site 3 which dies out inthe depressed area; no response is seen at site 2 in thebranch or at recording site 1. The middle panel shows thatexcitation of the left end of the bundle (S,) evokes an actionpotential at site 1 but no activity at sites 2 and 3. In theright panel, when both ends of the bundle are excitedsimultaneously (sites 1 and 3) summation occurs in thedepressed segment and the surmmated action potentialtravels out the branch as indicated by the action potentialat site 2. (C) Diagrammatic representation of these events.Calibrations: vertical, 100 mv; horizontal, 1 sec. (B repro-duced from Circ Res,8 by permission.)


B c

2 1~ -

3

3

1-1 -2

2r r2

Figure 13

Inhibition in a depressed segment. The records were ob-tained from a preparation resembling that shown in figure12A; the arrangement of stimrulating and recording elec-trodes was also similar to that shown in figure 12A. (A)Excitation of the left end of the bundle results in excitationat site 1 and propagation into the depressed segment andout the branch (site 2); conduction to the other end of themain bundle does not occur as indicated by the absence ofactivity at 3; this is shown diagrammatically below A. (B)An impulse arising at the right-hand end of the bundle re-sults in an action potential at site 3 but travels neitherthrough the bundle nor out the branch and does not excitesites 1 and 2. This is shown in the diagram below B. (C)When the right end of the bundle (site 3) is excited beforethe left end (site 1) the impulse that arises in the right endand dies out in the depressed segment blocks propagationfrom the left end of the bundle into the branch. There isno depolarization at site 2. This is showni in the diagranmbelow C. Calibrations: vertical, 100 my; horizontal, 500msec.

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equal or are multiples of a common denominator.7Premature systoles with fixed coupling may alsoresult from parasystole.6 7

Parasystole is assumed to result from an auto-matic focus (parasystolic focus) within the atriumor ventricle that is protected from the basic rhythmof the heart by entrance block that prevents thesinus impulse from entering the parasystolic focusand depolarizing its fibers. Exit block supposedlyconfines parasystolic impulses to the parasystolicfocus. The existence of a focus guarded by bothentrance and exit block can become known only ifintermittent relief of exit block allows the focus toexcite either the atrium or the ventricle. Parasystoleis frequently encountered in chronically diseasedhearts or in association with myocardial infarction.38The focus itself, or the necessary conditions of en-trance and exit block may therefore be inferred toresult from severe depression of cardiac tissue. Theappearance of slow conduction, unidirectional block,summation, and inhibition in depressed Purkinjefibers suggests possible mechanisms for the occur-rence of certain types of parasystole, including thosewith fixed coupling.

In the depressed ventricular conducting system,the degree of depression may vary markedlybetween regions separated by only a few millime-ters. A small area may show a resting potential of-70 to -80 mv and display spontaneous activity,while an adjacent area, only slightly more depolar-ized, may be inexcitable and cause both entranceand exit block between the spontaneously activefocus and the rest of the heart. Conduction from theparasystolic focus to the rest of the heart is blockedin the inexcitable region (exit block); conduction ofthe sinus impulse into the area of the parasystolicfocus is also blocked in this region (entranceblock). If a sinus impulse penetrated into thisdepressed area of block at a time when it couldsummate with the impulse arising from theparasystolic focus, the impulse arising by summa-tion might propagate out a branch and excite theheart (fig. 14; compare with fig. 12). For this tohappen, the action potentials of the dominant sinusbeat and the parasystolic focus would both have toinvade the depressed area during the interval inwhich summation could occur. If that interval werevery short, the summated impulse would arise at atime quite closely determined by the time of thedominant impulse, and the extrasystoles that arosewould show fixed coupling to the dominant beat. Ifthe interval in which summation occurs were fairlylong, then impulses could arise by summation near

A t

23B

23D

23

C

3

3i K

2 l'4

Figure 14

Relief of exit block of a parasystolic focus by sumnmtion.The location of the recording sites 1, 2, and 3 are shown inthe diagram of the Purkinje fiber bundle at the lower right.The lightly stippled area in which site 1 is located is thesite of spontaneous activity resulting from phase 4 depolar-ization. This is surrounded by a more severely depressedregion indicated by the darkly shaded area where recordingsites 2 and 3 are located. (A) The top trace (1) shows thespontaneously firing Purkinje fiber; the middle trace (2)shows the adjacent area of depression failing to be excitedby this automatic activity (exit block); and the bottom trace(3) shows that electricaUy stimulated action potentials at S2are unable to penetrate through the depressed area to excitethe automatic focus (entrance block), or to propagate outthe branch where site 2 is located. The bottom trace couldrepresent depolarizations from the spread of impulses fromthe sinus node into the area of depressed fibers. (B, C, andD) When the spontaneous action potentials in trace 1 andthe driven action potentials in trace 3 occur within a par-ticular interval, summation occurs to give rise to an actionpotential (trace 2) which can propagate out the branch andexcite the heart. Calibrations: vertical, 100 mv; horizontal,500 msec.

the beginning or the end of that interval and theirdelay with respect to the time of the dominantimpulse would be variable so that fixed couplingwould not be observed.

Inhibition might also influence the occurrence ofpremature impulses caused by a parasystolicmechanism. Impulses originating in the sinus nodecould inhibit conduction from the automaticparasystolic focus by the mechanism shown infigure 13, and thereby prevent_ emergence of theparasystolic impulse into the ventricles. Inhibitionof this type would only occur if both the sinus nodeand parasystolic focus fired within a certaininterval. If the parasystolic focus fired at a timewhen neither refractoriness of the ventricle nor exitblock caused by inhibition were present, then animpulse could emerge from the parasystolic focusand excite the ventricle.


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Finally, foci of spontaneous activity that areunable to excite the ventricle because of exit blockmay be able to do so if the exit block is relieved forreasons that have nothing to do with the previousimpulse. Fluctuations of excitability at the site ofexit block may, for example, occur in parallel withfluctuations in the level of sympathetic activity.

Cause of One-Way BlockOne-way block is fairly readily induced in the

heart.24 Conduction in one direction through awholly normal bundle of cardiac fibers often takesslightly longer than conduction in the otherdirection. In bundles of cardiac fibers the branchingand interconnection and the frequency of appear-ance of tight junctions are not uniform along thelength of the fiber; that alone could explain someasymmetry of conduction. Any such preexistingasymmetry might well be greatly exaggerated bydepression. More importantly, an asymmetry ofdepression can create an asymmetry of excitability.If one end of a bundle is less well perfused, forexample, conduction velocity will depend on thedirection of conduction. If a point where two fibersof a bundle join is severely depressed, conduction ineach of the fibers toward the point of junction mayresult in transmission of the impulse by summationat the point of junction. During conduction in theother direction, the point of convergence becomes apoint where one fiber divides into two fibers and atthat point block will occur. Asymmetries ofconduction up to and including one-way conductionmay thus result either from asymmetries ofdepression of excitability or from asymmetries of ananatomic kind and usually result from both beingpresent.

Cause of Very Slow ConductionIt is easier to explain total conduction block than

it is to explain depression of conduction severeenough to reduce conduction velocity to 1% of itsnormal value without producing block. Whencardiac Purkinje fibers are depolarized to amembrane potential of about -50 mv the systemresponsible for the normal rapid upstroke issuppressed, so that the membrane loses its ability todevelop an increase in sodium permeability and anormal rapid depolarization.39 What remains is theability of the membrane to undergo an activedepolarization which conducts very slowly andwhich may depend on Ca + + rather than Na + tocarry membrane current; we have called this theCirculation, Volume XLVII, January 1973

slow response.21 These responses are enhanced bythe addition of catecholamines.40 It is thus possiblethat the reentrant arrhythmias that arise in an areaof depressed excitability do so because such areas ofdepressed excitability respond with an actionpotential that is different in kind from the actionpotential of normal cardiac fibers.The ventricular arrhythmias commonly associated

with coronary artery disease might well result fiompartial depolarization and depression of excitabilityin focal or extensive areas of the ventricularconducting system secondary to hypoxia and poorperfusion. The most dramatic instance of such poorperfusion is that seen in acute myocardial infarc-tion. Ischemia caused by a sudden coronaryocclusion results in the leak of large amounts of K+from the intracellular to the extracellular space41and depolarizes cardiac muscle. Ischemia alsocauses an increased release of catecholamines42which could produce the enhancement of the slowresponse that is seen when catecholamines areadded to depressed Purkinje fibers in vitro.Recent observations offer direct support to a role

for the slow response in chronic arrhythmias and inthe arrhythmias of myocardial infarction. Actionpotentials of Purkinje fibers taken from the hearts ofvery old dogs subject to extrasystoles are normal insome areas and have the characteristics of a slowresponse in other areas (fig. 15 A-C). Similar slowpotentials have been found in areas of myocardialinfarction produced by ligation of the anteriordescending coronary artery in dogs43 44 (fig. 15 D,E).Whether the response of depressed fibers is or is

not fundamentally different from that of normalfibers, there is no doubt that partial depolarizationcan cause slow conduction. The arrhythmias seen indisorders that result in chronic hypoxia of cardiacmuscle, such as valvular insufficiency or cardiacfailure, might result from such depression ofexcitability. Phase 4 depolarization that fails toreach threshold can profoundly depress excitabilityand conduction.'0 It is also known that somepreparations of atrial and ventricular muscleremoved from diseased human hearts and studiedin vitro can show low maximum diastolic potentials,slow depolarization, and a low conductionvelocity.45 Ventricular muscle removed from cats inexperimentally induced right heart failure alsoshows low resting potentials and low rates ofdepolarization.46

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A

B

2-

c1

2---

2 -

Figure 15

Depressed action potentials in pathologic hearts. (A) Lead IIelectrocardiogram from a 15-year-old dog with spontaneousventricular arrhythmias. (B and C) Action potentials re-corded from a bundle of Purkinje fibers removed from theheart of this dog. The lower trace shows normal-appearingaction potentials. Action potentials in the upper trace havecharacteristics of the slow response. Note that an increasein stimulus rate in C results in conduction block in thedepressed region. (D and E) Action potentials recorded fromsubendocardial Purkinje fibers on the anterior papillarymuscle of the canine heart, 24 hours after coronary ligation.Action potential in the upper trace recorded from fiber,surviving the extensive myocardial infarction. Action poten-tial in the lower trace was recorded from the normal marginof the infarcted area. Again, in E, conduction block inthe infarct readily occurs when the rate of stimulation isincreased. (Friedman PL, Wit AL: Unpublished observa-tions.)

Oscillatory DepolarizationsThere is a large body of evidence to show that

the transmembrane potential of cardiac fibers canundergo oscillatory changes.47 48 Such changescentered around the baseline of the maximumdiastolic potential may wax to the point at whichthey can generate a tachycardia; yet they appear todiffer fundamentally from the phase 4 depolariza-tions characteristic of the sinoatrial node. Oscillatorychanges also arise in partially depolarized fibers.Many oscillatory potentials are "afterpotentials,"i.e., they follow or are provoked by a precedingimpulse. Oscillatory afterpotentials may arise eitherduring or after repolarization of the previous action

potential.47 Oscillatory afterpotentials provoked bythe preceding impulse might cause bigeminalarrhythmias.

Concluding Remarks

Depression of a short.segment of cardiac fiberscan produce a bewildering variety of arrhythmias.These arrhythmias depend on the occurrence in thedepressed area of slow conduction, one-way block,summation, and inhibition which in turn maydepend on not yet fully explored properties of theslow response. The sensitivity of many arrhythmiasto changes in heart rate or in prematurity ofexcitation is understandable in terms of thesensitivity to such changes of conduction through adepressed area. The variety of arrhythmias thatarises from focal depression is greatly increased bythe fact that the same sort of behavior in adepressed area will produce quite different arrhyth-mias according to where that depressed area islocated.The fact that reentry can account for so many

properties of premature systoles by no meansproves that all such systoles arise from reentry.Parasystole, phase 4 depolarization, and oscillatorychanges in membrane potential are fully capable ofcausing arrhythmias. Recent studies have, however,provided direct proof for the existence of reentry asa cause for arrhythmias, so that reentry based onslow conduction and one-way conduction may nowbe regarded as an established fact rather than as anattractive hypothesis.

References1. HOFFMAN BiF, CRANEFIELD PF: Physiologic basis of

cardiac arrhythmias. Amer J Med 37: 670, 19642. HOFFMAN BF, CRANEFIELD PF: Electrophysiology of

the Heart. New York, McGraw-Hill, 19603. CHANG JJ, SCHMIDT RF: Prolonged action potentials

and regenerative hyperpolarizing responses in Pur-kinje fibers of mammalian heart. Pfluegers Arch 272:127, 1960

4. MATSUDA K, HOSHI R, KAMEYAMA S: Effects ofaconitine on the cardiac membrane potential of thedog. Jap J Physiol 9: 419, 1959

5. CRANEFIELD PF, KLEIN HO, HOFFMAN BF: Conduc-tion of the cardiac impulse: I. Delay, block and one-way block in depressed Purkinje fibers. Circ Res 28:199, 1971

6. HOGAN PM, DAVIs LD: Evidence for specialized fibersin the canine right atrium. Circ Res 23: 387, 1968

7. KATZ LN, PICK A: Clinical Electrocardiography: I. TheArrhythmias. Philadelphia, Lea & Febiger, 1956

8. CRANEFIELD PF, HOFFMAN BF: Conduction of thecardiac impulse: II. Summation and inhibition. CircRes 28: 220, 1971


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9. ROSEN KM, RAHIMTOOLA SH, CHUQUIMIA R, LOEBHS, GUNNER RM: Electrophysiological significance offirst degree atrioventricular block with intraventricu-lar conduction disturbance. Circulation 43: 491,1971

10. SINGER DH, LAZZARA R, HOFFMAN BF: Interrelationshipbetween automaticity and conduction in Purkinjefibers. Circ Res 21: 537, 1967

11. SHERN MA, RYTAND DA: Intermittent bundle branchblock: Observations with special reference to thecritical heart rate. Arch Intern Med (Chicago) 91:448, 1953

12. DAMATO AN, LAU SH, HFLFANT RH, STEIN E, PATTONRD, SCHERLAG BJ, BERKOWITZ ED: A study of heartblock in man using His bundle recordings. Circula-tion 39: 297, 1969

13. NARULA OS, SAMET P: Wenckebach and Mobitz II A-Vblock within the His bundle and bundle branches.Circulation 41: 947, 1970

14. ROSENBAUM MB, NAU GJ, LEVI RJ, HALPERN S,ELIZARI MV, LAZZARI JO: Wenckebach periods in thebundle branches. Circulation 40: 79, 1969

15. FREIDBERG HD, SCHAMROTH L: The Wenckebachphenomenon in left bundle branch block. Amer JCardiol 24: 591, 1969

16. NARULA OS, SCHERLAG BJ, JAVIER RP, HILDNER FJ,SAMET P: Analyses of the A-V conduction defect incomplete heart block utilizing His bundle electro-grams. Circulation 41: 437, 1970

17. SCHERF D, COHEN J: The Atrioventricular Node andSelected Cardiac Arrhythmias. New York, Grune &Stratton, 1964

18. LANGENDORF R: Concealed A-V conduction: The effectof blocked impulses on formation and conduction ofsubsequent impulses. Amer Heart J 35: 542, 1948

19. LANGENDORF R, PICK A: Concealed conduction:Further evaluation of a fundamental aspect ofpropagation of the cardiac impulse. Circulation 13:381, 1956

20. HOFFMAN BF, MOORE EN, CRANEFIELD PF: Functionalproperties of the atrioventricular conduction system.Circ Res 13: 308, 1963

21. CRANEFIELD PF, WIT AL, HOFFMAN BF: Conduction ofthe cardiac impulse: III. Characteristics of very slowconduction. J Gen Physiol 59: 227, 1972

22. CRANEFIELD PF, HOFFMAN BF: Editorial: Reentry:Slow conduction, summation and inhibition. Circula-tion 44: 309, 1971

23. MENDEZ C, MOE GK: Demonstration of a dual A-Vnodal conduction system in the isolated rabbit heart.Circ Res 19: 378, 1966

24. ScHMirr FO, ERLANGER J: Directional differences in theconduction of the impulse through heart muscle andtheir possible relation to extrasystolic and fibrillarycontractions. Amer J Physiol 87: 326, 1928-1929

25. WIT AL, HOFFMAN BF, CRANEFIELD PF: Slowconduction and reentry in the ventricular conductingsystem: I. Return extrasystole in canine Purkinjefibers. Circ Res 30: 1, 1972

26. WIT AL, CRANEFIELD PF, HOFFMAN BF: Slowconduction and reentry in the ventricular conductingsystem: II. Single and sustained circus movement in


networks of canine and bovine Purkinje fibers. CircRes 30: 11, 1972

27. BELLET S: Clinical Disorders of the Heart Beat. Phila-delphia, Lea & Febiger, 1963

28. ZIPEs DP: The contribution of artificial pacemaking to

understanding the pathogenesis of arrhythmias. AmerJ Cardiol 28: 211, 1971

29. WELLENS HJ, SCHUILENBERG RM, DURRER D: Electricalstimulation of the heart in patients with ventriculartachycardia. Circulation 46: 216, 1972

30. BIGGER JT JR. GOLDREYER BN: The mechanism ofsupraventricular tachycardia. Circulation 42: 673,1970

31. MACK I, LANGENDORF R: Factors influencing the time ofappearance of premature systoles (including a

demonstration of cases with ventricular prematuresystoles due to reentry but exhibiting variable cou-

pling). Circulation 1: 910, 195032. LANGENDORF R, PICK A: Mechanisms of intermittent

ventricular bigeminy: II. Parasystole, and parasystoleor reentry with conduction disturbance. Circulation11: 431, 1955

33. LANGENDORF R, PICK A, WINTERNITZ M: Mechanismsof intermittent ventricular bigeminy: I. Appearanceof ectopic beats dependent upon length of theventricular cycle; the "rule of bigeminy." Circulation11: 422, 1955

34. DAMATO AN, VARG~ESE PJ, LAU SH, GALLAGHER JJ,

BOBB GA: Manifest and concealed reentry: Amechanism of A-V nodal Wenckebach phenomenon.Circ Res 30: 283, 1972

35. GREGORY JJ, GRACE WJ: The management of sinusbradyeardia, nodal rhythm, and heart block for theprevention of cardiac arrest in acute myocardialinfarction. In Acute Myocardial Infarction andCoronary Care Units, edited by Friedberg CK. NewYork, Grune & Stratton, 1961

36. PICK A: Parasystole. Circulation 8: 243, 195337. LANGENDORF R, PICK A: Parasystole with fixed

coupling. Circulation 35: 304, 196738. CHUNG EK: Parasystole. Progr Cardiovasc Dis 11: 64,

196839. WEIDMANN S: The effect of the cardiac membrane

potential on the rapid availability of the sodium-carrying system. J Physiol 127: 213, 1955

40. CARMELIET E, VEREECKE J: Adrenaline and the plateauphase of the cardiac action potential. Pfiueger Arch313: 300, 1969

41. HARRIs AS: Potassium and experimental coronary

occlusion. Amer Heart J 71: 797, 196642. GRIFF1THS J, LEUNG F: The sequential estimation of

plasma catecholamines and whole blood histamine inmyocardial infarction. Amer Heart J 82: 171, 1971

43. LAZZARA R, ABELLEIRA JL: Intracellular recordings frominfarcted canine endocardium. Fed Proc 31: 387,1972

44. FRIEDMAN PL, STEWART J, HOFFMAN BF, WIT AL:Electrophysiological properties of Purkinje fiberssurviving myocardial infarction. (Abstr) Circulation46 (suppl II): II-10, 1972

45. SINGER DH, TEN EICK RE: Aberrancy: Electrophysio-logic aspects. Amer J Cardiol 28: 381 1971

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46. BAssETr AL, GELBAND H, HOFFMAN BF: Alteration inelectrical and mechanical properties of cat ventricularmuscle following partial chronic pulmonary arteryobstruction. (Abstr) Circulation 44 (suppl II): II-99,1971

47. TRAUTWEIN W: Mechanisms of tachyarrhythmias and

extrasystoles. In Cardiac Arrhythmias, edited bySandoe E, Flensted-Jensen E, Olesen KH. Sodertalje,Sweden, Astra, 1970

48. SCHERF D, ScHoTT A: Extrasystoles and AlliedArrhythmias. London, William Heinemann MedicalBooks, 1953


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PAUL F. CRANEFIELD, ANDREW L. WIT and BRIAN F. HOFFMANGenesis of Cardiac Arrhythmias

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1973 American Heart Association, Inc. All rights reserved.

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