The AV Node: Normal and Abnormal Physiology Rory

Childers

A

DESCRIPTION of the ultrastructure, histology, and morbid anatomy of the atrioventricular (AV) node offers little to our understanding of its function if not accompanied by electrophysiologic verification of the route and manner by which an impulse is conveyed from the atrium to the His bundle. Transmembrane potentials of the AV node have been extensively studied only in the rabbit heart.‘-’ Recently, such studies have fortified a revised description of AV nodal anatomy in this animal.8-‘0 ANATOMY

The rabbit AV node (Fig. 1) consists of a larger open portion containing transitional cells traversed by many connected tissue septa. These transitional cells connect with bands of ordinary nonspecialized atria1 muscle in three distinct areas: a posterior connection under the coronary sinus to the crista terminalis (previously called the posterior internodal tractI’), a middle, and an anterior connection. The separation of the muscle connections of these three groups of transitional cells is determined not by specialization of the atria1 fibers per se, but by the avoidance of atrial orifices: the coronary sinus, separating the posterior from the middle group, and the fossa ovalis separating the middle from the anterior group of transitional cells. The orientation of the latter, and of the scattered fibrous septa, is towards a “knot” of densely packed nonseptated midnodal cells, which they envelope laterally, superiorly, posteriorly, and anteriorly. This envelopment takes place under a fibrous collar, an extension of the central fibrous body, and forms the smaller cZosed portion of the AV node. The midnodal cells connect inferiorly with a long strand of lower nodal cells which leads directly into the His bundle. It can be seen from Fig. 1 that the low nodal cells are contiguous to the transitional layer, both in front and, for a

From the Department of Medicine, The University of Chicago, Chicago, Ill. Reprint requests should be addressed to Rory Childers, M.D., Professor of Medicine, The University of Chicago, Chicago, Ill. 60637. 0 1977 by Grune & Stratton, Inc. Progress

in ckliovascular

Diseases,

Vol.

XIX,

No. 5 (March/April),

considerable extent, posterior to, the midnoldal knot. There is, however, no evidence that the midnode can be bypassed by electrical transfer from the transitional zone to the lower node: the route of the sinus or retrograde impulse is invariably through the midnodal region. The transitional, midnodal, and low nodal cells correspond, respectively, to the traditionally labeled AN, N, and NH zones.’ The anterior hmb of the transitional zone forms an anteverted lip over the fibrous collar but without any distal “bypass” connection. The lip, together with the most posterior extension of the lower nodal cells, constitute electrical “cul de sacs”: that is to say, although antegrade and retrograde impulsesmay be shown to reach these regions,this achievement is incidental to the passageof the main atrioventricular, or ventriculoatrial, wavefront. During antegrade conduction there is a dual atria1 input to the transitional cell layer: from the crista terminalis (CT) and from the coalescingmi.ddle and anterior groupsof transitional cells. Longitudinal dissociation, when it was demonstrated, wasconfined mainly to the more posterior portion of the transitional cell layer. The greatest intranodal delay was shown in the transitional AN region (which is, of course,the larger tissuemass). The site of block during rapid-stimulation Wenckebath sequenceswasthe midnodal N region. The morphological existence of a partial AV nodal bypass,“-r3 from posterior internodal tract to the lower node, has been challenged.” The subject already forms a considerableliterature becausethe question of true internodal tracts is itself controversial.“4-‘6 The problem cannot be ‘ventilated here. It suffices to say (1) there is abundant evidence for physiologically specialized fibers in the atrium,“rg but that their role in P wave aberration2’ in man is not proven, and (2) there is a group of patients with excessivelyabbreviated AV nodal transit times, in whom the functional anatomy is presently obscure.‘l This revised description of the AV node coincides in many respectswith previous anatomical studiesof rabbit, human, and canine nodal ti.ssues. 22-25Studies which deviate from the above may have regarded only the closed portion asthe true node, and allowed the open portion to be desig1977

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C

x “dead

end cells”

Fig. 1. Anatomy. Shown are the closed and open portions of the rabbit AV node. The transitional AN cells are in three groups, which coalesce to envelope the knot of midnodal N cells under a fibrous collar. The low nodal NH cells are electrically continuous with the N cells above and the His bundle anteriorly. Both the posterior extension of the lower, and the anterior extension of the transitional zones are “dead ends” (cul de sacs). (Reproduced by permission of Lea & Febiger, Inc.lO).

nated as atrial or specialized atria1 fibers.” It is clear, however, that further study on both the rabbit and the human AV node is required. At the time of writing, no clear and obvious ultrastructural correlation can be made with the previous description, despite extensive studies.26327

Embryologic Development The AV node is formed from the apposition of a series of diverse tissue elements:2s (1) a rather

CHILDERS

large primordium (derived from invaginated AV ring tissue) which later condenses to become the closed node, and (2) the gradual establishment of a direct contact with this primordium by contributions from the sinus septum, posterior atria1 wall, and other tissue elements. These form the transitional zone of the node. Essential in the electrical separation of atrium and ventricle is the gradual invasion of the primitive A Vving tissue. The latter is bordered externally by A V sulcus tissue, and internally by endocardial cushion. The insulation of the atria from the ventricles is achieved by the gradual invasion of the ring by the sulcus tissue, to form the annulus fibrosus. At the same time contiguous endocardial cushion elements form the atrioventricular valve leaflets. This conversion of cushion to an electrically inert fibrous structure is the means by which the closed node gains its collar (Fig. 2). The fibers of Mahaim are apparently areas where the node and proximal His bundle are still connected to the interventricular septum by virtue of gaps in the AV sulcus tissue. Although there is little functional evidence in the newborn for an intact parasympathetic nervous system, the innervation of the node with acetylcholinesterasestaining cells appears to be fully developed at a relatively early stage.

7Re Blood Supply of the A V Node The right coronary artery (ramus septi fibrosi) supplies the human AV node in 90% of subjects.29 In the remaining lo%, the blood supply is from the left circumflex artery. Thus AV nodal block in myocardial infarction is most commonly seen with inferior or posterior left ventricular necrosis. In the dog heart the nodal blood supply is from the posterior septal (sometimes shared with the anterior) septal arteries. 3o If , however, atrioventricu-

AV Valve Leaflet

Fig. 2. Embryologic development. The nodal primordium is enclosed SW periorly by endocardial cushion tissue (ECT) and inferiorly by AV sulcus tissues. These elements are destined to become respectively the fibrous roof of the closed node, and the annulus fibrosus (AF). Gaps in AV sulcus tissue form nodo-septal and His-septal connections. The latter may persist as Mahaim tracts. The two illustrations on the right show the fate of the primitive AV ring tissue attaching atrium to ventricle: Fibrosis of sulcus tissue and the ECT produce respectively, the annulus fibrosus (AF) and the atrioventricular valve leaflet. (Reproduced by permission of Lea & Febiger, lnc.28)

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lar block occurs with experimental coronary artery occlusion in the dog heart, the site of conduction failure is almost invariably infranodal.31 The arteries in the rabbit AV node have not been experimentally used; a constant landmark is an atria1 septal twig which runs between the coronary sinus and the ventral fibrous body to the septal leaflet of the tricuspid valve.” Primary Role The AV node must be presumed to have three basic functions. Its critical location makes it the sole egress of the sinus impulse from the atria to the ventricles. Delayed intranodal conduction ensures that atria1 systole contributes to ventricular performance by augmenting stretch at the end of diastole. The node also serves as a filter which prevents an excessive number of atria1 impulses from reaching the ventricle in a given minute. At the same time, it protects the ventricle from premature depolarization during its vulnerable phase. Although these three teleologic roles are operative in the human, dog, and rabbit AV nodes, species variation in other respects, anatomic and physiologic, remain to be finally determined. In reviewing AV nodal physiology, one must display evidence from all three animal sources. In many instances here this display has been made qualitative rather than quantitative when it is clearly not speciesspecific. SLOW

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DEPENDENCE

It has long been known that the electrical properties of the AV and sino-atrial (SA) nodes differ profoundly from those of other cardiactissues.To a greater extent these disparities can now be attributed to the fact that conduction within these

Fig. 3. Transmembrane potentials from AV node. AN cell action potentials recorded during antegrade (A) and retrograde (6) conduction. The dv/dt (displaced) is recorded below. Note the “foot” and diminished upstroke velocity in (B). (Reproduced by permission of Circulation Research. 5 1)

structures is dependent entirely, or in part, on the calcium-dependent slow channe1.32-42The pharmacologic evidence for this can be summarizled: Nodal cells are resistant to tetrodotoxin (which poisons the sodium entry system) at concentrations sufficient to render atria1and Purkinje fibers inexcitable. By contrast, manganeseand verapa,mil (which dislocate the calcium entry system), suppressor depressactivity of nodal cells,while failing to affect, in somestudies, the activity of atria1 or Purkinje fibers. The electrical characteristics of the node, many of which may now be attributed to the slow component, have been known for years, and are summarized in the following. (1) The refractory period lagsbeyond the recovery of the action potential, that is, excitability is not voltage dependent.‘r3(2) Late diastolic threshold is rate-dependent, rising in its milliamperagevalue with successiveincrements in the frequency with which impulsestraverse the structure.43 (3) The curve relating the duration of the refractory period to heart rate is flatter than those of atrium, ventricle, or the His-Purkinje system.“-46 (4) Conduction is, in part, rate dependent, becoming progressively delayed as the driving cycle length is shortened.47xM(5) When heart rate (atrial drive) is increased,severalbeats(six to eight) are required to allow the new and prolonged AV nodal transit time to become stable. This “sluggishness”is reflected also (following a period of rapid atria1 drive) by the persistanceof A-V nodal delay even after a programmedpause:“fatigue.“43’49.50 IN VITRO

STUDIES

OF THE

AV

NODE

TransmembranePotentials Action potentials of the AV node show (Fig. 3) (in comparisonto the atria1or His tissueson either

-Il A-

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\ side of the structure) a lower membrane potential (50-60 mV), the relative absence of a spike, a lower maximum upstroke velocity (about 5 V/set), and a lower conduction velocity [less than 0.05 m/sec’-3]. The upstroke velocity, of the action potential, lowest in the N region, is not entirely a fixed property of each cell prototype, but is in part dependent on the direction of impulse traversal across the node.51Y52 Thus upstroke velocity in an NH cell is greater during retrograde than antegrade propagation. The opposite is true of the rise time of an AN cell (Fig. 3). This feature is unique to the node(s): In other cardiac tissues (atrium, ventricle, His-Purkinje system) intrinsic action potential characteristics are not altered by changes in wavefront direction, unless conduction is physiologically or pathologically impaired.

Action Potential Duration The moment at which the trailing foot of an AV nodal action potential reattains its final resting membrane potential is less decisive, less angulated than in extranodal action potentials. This conceivably explains the paucity of information concerning the effects of rate on action potential duration in the node: the measurement is difficult. Clearly, in comparison to Purkinje fibers,53 rate changes are modest.

Electra tonic Effects Figure 4 shows the manner in which action potential shape is electrotonically altered when conduction of an atrial premature impulse becomes blocked. It can be noted that failure of conduction

CHILDERS

Fig. 4. Transmembrane potentials from rabbit AV node. Each panel shows: Top: Atrial electrograms of stimulated basic (A, ) and premature (A21 atrial beats; Middle: AN cell; Bottom: NH cell. A-F show expanding Al-A2 intervals. (A) AZ blocked proximally. (6) Block above, but sufficiently contiguous to AN, to show an electrotonic “hump.” (Cl Block is immediately distal to AN. which shows a slow rising electrotonically abbreviated action potential. (D-F) With progressively deeper penetration A2 is finally conducted beyond NH. (Reproduced by permission of Circulation Research. 3)

occurs, not because of encroachment on the previous action potential, but to the right of it, refractoriness lagging beyond the recovery of the action potential. At the site of conduction failure, the immediately proximal action potential is electrotonically abbreviated by the polarizing influence of the distal cell(s).3 Also demonstrated is the block of a premature impulse at successively different sites within the node: the more premature the impulse, the more proximally will it meet its demise. If, however, it succeeds in negotiating the NH region, it is most likely to emerge into the His bundle, a reflection of the fact that within the node itself there is a hierarchy of refractory periods, the longest being that of the N region. N cells also have the lowest maximum upstroke velocity and are the site of block when rapid atria1 drive produces Wenckebach sequences.”

Diastolic Excitability Intracellular stimulation of AN and NH cells is possible; N cells are excessively low in excitability and have not been individually stimulated. The comparative late diastolic thresholds, expressed as multiples of 10e6 amps, are: atrium, 0.30; AN cells, 1.20; NH cells, 0.60; His, 0.18; Purkinje, 0.1; ventricle, 0.3.43 In ordinary atria1 or ventricular muscle fibers the threshold current for cell stimulation remains constant from late diastole right up to the foot of the action potential.’ In Purkinjes4 and specialized atrial fibers from Bachmann’s bundle,” threshold is Zower in early diastole, the hallmark of supernormality. In AV nodal cells the flat limb of the strength-interval curve is

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wanting. In terms of current requirements early diastolic > mid-diastolic > late diastolic, threshold.43 The steep portion of the strength-interval curve falls substantially to the right of the nodal action potential, in contrast to other tissues. Significantly, late diastolic threshold rises in AN and NH cells with increases in atrial driving frequency. By way of contrast, diastolic threshold is independent of rate, in atrial, ventricular, and Purkinje muscle fibers.56 Frequency-dependent changes in excitability are seen with quinidine administration,57 severe hyperkalemia,58 and are probably a physiologic property of the SA node.’ This property provides a possible explanation for AV nodal conduction fatigue.43

stimulated to produce a collision at an impaled N cell (Fig. 5) the action potential of the latter shows not only an improved maximum upstrloke velocity but it “fires” substantially earlier than with stimulation of either side alone. These experi-

Tramnodal Conduction and Wavefront Character Fundamental to our understanding of AV nodal conduction is the extent to which variations in the amplitude, upstroke velocity, and general shape of a given action potential is related to (1) the intrinsic ionic mechanism of its cell, and (2) the characteristics of the confronting wavefront. It has been noted that the upstroke velocities in a given cell may change during respective antegrade and retrograde conduction (Fig. 3). When conduction is impaired, but not blocked, nodal action potentials often show double humps, dimples in their plateaus, or initial slow “feet.” Total amplitude is not necessarily related to upstroke velocity, nor even to success of conduction. Electrotonic interaction, a passive process, can profoundly alter action potential shape when conduction failure occurs (Fig. 4). Such an effect was also demonstrated in an artificially prepared gap of depressed conductivity when the dimensions of the latter were optimally small in terms of the tissue’s length-constant.59 The latter has never been measured in the AV node, in which an adequate voltage-clamp is technically Herculean. Evidence that summation might play an important role in nodal conduction is the successful propagation of atrial premature beats at an A1 -A2 interval considerably less than the coupling interval required for propagation by selective intracellular stimulation within the upper node.43 Bisection of the atria1 input to the transitional cell zone of the node defeats premature AV conduction unless both input elements are stimulated, inducing optimal synchrony of the arriving wavefront.5’ If the atrium and the His bundle are simultaneously

6

Fig. 5. Collision in N region. Each panel shows from above downwards the atrial electrogram, the N call (n), and His bundle (h) action potentials, and the dvldr (displaced) of n. (A) and (6) show antegrade and retrlcgrade traversal of the N cell. (CI shows a collision of the two wavefronts at the N cell, which “fires” sooner, with increased upstroke velocity and amplitude. Horizontal bars: Upper = zero potential; lower = 50 msec: vertical = 50 mV. (Reproduced by permission of Circulation Research. s1 )

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ments have two possible implications: (1) converging wavefronts, either one of which would alone produce a local response distal to the point of conduction failure, can together regeneratively convert this local hump to a propagating action potential, and (2) converging wavefronts can cause a cell to regenerate at a membrane potential more negative than with either front alone. The reduced collision “latency,” shown in Fig. 5, may be an expression of a lower “take off” (that is, of a more negative membrane potential). Similarly, not only is the rise time in the AN cell of Fig. 3 greater during antegrade than retrograde conduction, but the steeper action potential lacks the initial “foot” and thus takes off at a more negative membrane potential. This suggests that contrary to previous beliefs’ nodal action potentials may be voltage dependent. In support of this thesis is the improved upstroke velocity produced by “blanket” hyperpolarization of the N regions2 “Geographical summation,” related to AV nodal anatomy, must be considered in relation to the relative or statistical superiority of conduction in the antegrade mode. Block induced by drive alone is located in the N region. Anatomically, the transitional AN cell wavefront potentially confronts the N cells of the midnodal knot in the manner of a smothering pillow (Fig. 1). The contact area of the N cells with the lower nodal zone is by contrast considerably less.” The differences in contact area are unreal unless one assumes that the AN-N confrontation is entirely synchronous on all sides: the chances of such synchronization are probably inversely proportional to the number of cells involved. Studies on the influence of the site of atrial stimulation on AV nodal conduction have produced inconclusive results.60-62 Coronary sinus pacing facilitates AV nodal conduction in a number of patients.” JQ The validity of this observation is entirely dependent on whether the A deflection of the His bundle electrocardiogram63 truly represents activation at the atrio-nodal interface. If coronary sinus pacing presents an input to the node to which the A deflection is lateral, that is, incidental, the change in intranodal conduction is artefactual.

Au tomaticity Occasionally nodal cells show an initial “phase 4 dip,” briefly recording a maximum diastolic value for membrane potential. This cannot be regarded

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as pacemaker activity since the later baseline is flat. Depolarization has been observed only in the NH region;‘94’5 the entire structure was, at one time, regarded as a major center for subsidiary impulse formation (“nodal rhythm”). The less specific term AV junctional rhythm is now used for His bundle or NH pacemakers, and for centers of automaticity which are (presumably) located in the atria1 approaches to the AV node (formerly “coronary sinus,” “coronary nodal” rhythm, etc.64,65 1.

Vagal Fibers The lower limit of vago-cardiac (as opposed to nonvagal cholinergic) innervation is thought to be the NH region. 66 Vagal stimulation can thus still occasionally effect cardiac slowing when the pacemaker is “junctional.“Vagal stimulation, or acetylcholine, greatly augments the disparity between atrial and nodal refractoriness expanding the latter and shortening the former.’ 946 Evidence that the N cell is a relatively pure slow component prototype is the action of acetylchohne, delivered through micropipettes to each of the nodal zones. Hyperpolarization due to an increase in K conductance, though present in both the AN and upper NH regions was considerably less in magnitude than the increase in negativity of membrane potential observed in atria1 tissues.@ More importantly, the progressive loss of upstroke velocity with increasing acetylcholine effect was confined mainly to the N cells. There were clearly electrotonic deteriorations on either side of the latter (low AN region, high NH region). The N cells gradually develop a double hump, which is less likely to be a resolution of the action potential into slow and fast components,38 than a reflection of fractionated and tortuous conduction. If N cells truly function only through the calcium dependent slow component, their activity will be optimal when K conductance is low, a condition reversed by acetylcholine.67 Moreover, the improvement in N cells of rise time and action potential amplitude during epinephrine administration68 is consonant with the known effects of the catechol on the slow component when the latter is “unmasked” by high K concentrations in other tissues.6g Studies of the node in vitro have been mainly confined to qualitative description of action potential characteristics. Success and failure of conduction has been examined after many interventions,

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but it is mainly in clinical and canine studies that the relevant changes have been numerically expressed, using a fixed protocol for their measuremenL7’ AV

NODAL

CONDUCTION

The P-R Interval The oldest and simplestclinical measurementof AV nodal function is the P-R interval, or more precisely, its component A-H interval, recorded during His bundle electrocardiography.63The latter procedure has revolutionized the clinical appraisal of both AV block and many forms of cardiac arrhythmia. Measurementof the A-H interval, although an appropriate refinement, in no way disqualifies the clinical usefulnessof the P-R interval. The infranodal conduction (H-V) of regular beats”3 is not subject to significant alteration by the autonomic nervous system or other physiologic interventions, nor is it prolonged by digitalis, the commonest pharmacologic cause of intranodal delay. Thus, many casesof observedor developed P-R prolongation can be attributed to AV nodal delay, provided the observer recognizes at all times the clinical possibility of an infranodal cause. The normal P-R interval shows certain characteristic diurnal variations dependent on the “setting” of the autonomic nervous system. It tends to be longer after meals.71Additional factors affecting AV nodal transit time include the circulating level of thyroxine, cortisols, and body temperature (AV nodal conduction is enhanced by thyrotoxicosis, hypercorticism, and many cases of fever). The definitive relationship of heart rate to AV nodal conduction is somewhat complex. It cannot profitably be examined in any of the physiologic circumstances that spontaneousZyaugment heart rate (notably exercise) becausethese also causea reduction in AV nodal transit time, mediated by the autonomic nervous system. Clinical or animal study of AV nodal function is invariably executed during imposedatria1drive7’ (endocardial catheter or epicardialelectrode). It is presumedunder these conditions that autonomic impulse traffic is constant (such may not be the caseif at rapid frequencies, the baroreceptor is stimulated by a fall in blood pressure,or if sinusarrhythmia continues to be marked). The concept of basalconduction in the AV node has been reinforced by two recent studies.72-74It

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is a term that can be applied when the transit time acrossthe node is at an irreducible minimum. Conduction is basal when the AV nodal conduction time: (1) fails to abbreviateafter a long pauseor a diminution in heart rate; (2) fails to abbreviate with atropine; and (3) remains,if the heart is slow, unchanged in the face of a modest increment in atria1pacing frequency. Conduction ceasesto be basal when the AV nodal transit time beginsto expand with increasing rates of atrial drive. The relationship of AV nodal conduction time to imposed heart rate is thus a two-function curve, the first part of which ma:ybe flat and the second part fairly steeply-risir~g,72 each increment in atria1 driving rate prolonging AV nodal conduction. This is the essential difference between the AV node and the adjacent structures: atrium, His-Purkinje system, ventricular muscle.In the caseof the latter, prolonged conduction of stimulated basic beats can only occur when “maximum following frequency” is achieved, and each beat is liter-ally encroaching on the refractory period of its predecessor.Basal conduction is often observed(1) in the Nembutal-anesthetized dog at slow atria1 driving frequencies,attainable only through sinus node crush, (2) in many patients with relatively slow heart rates, and (3) in hearts denervated by cardiac transplantation.73,74 Most clinical subjects do not demonstrate basal AV nodal conduction in the restingstate, and will begin to show prolongation of AV nodal conduction upon atria1 pacing at even a modestreduction in cycle length. Under normal clinical circumstances1 : 1 conduction through the node is maintained up to heart rates of 1.50-160/min. at which time second degree block of Wenckebach type (Mobitz I) beginsto appear.48The preciseclinical frequency of basalconduction is difficult to ascertain. Pacingstudieshave not been addressedto this problem, which would require much smallerinitial incrementsin driving frequency than are customarily employed. When AV nodal conduction is not basal, the transit time may be in part a function of tonic adrenergic and parasympathetic impulse traffic to the sino-atria1 and atrioventricular nodes. There is compelling evidence that the division of this traffic is very precisely balancedin the interestsof autoregulation. Evidence for this can be seenin casesof marked sinusarrhythmia. The incre,asein vagal nerve traffic to the AV node effective during the expiratory phaseof respiration, is so matched

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with sinus deceleration, that AV nodal transit time remains unchanged, the AV node being challenged less frequently. If the atria1 rate is fixed by atria1 pacing, respiration will produce phasic changes in AV conduction, the P-R interval becoming prolonged during expiration. Likewise, in atrial flutter or tachycardia, where the input frequency to the node is fixed, AV block is demonstrable by carotid sinus massage, or the valsalva maneuver; it is seldom so elicited during sinus rhythm. A pathologic variant of this behavior is seen when the sinus node is hyporeactive or apparently denervated with respect to the vagus. 75 In this situation during the respiratory cycle, the sinus remains regular, but AV conduction may show Wenckebach cycles. The latter are abolished by atropine, which, however, fails to accelerate the sinus node. Retrograde A V Nodal Conduction In comparing antegrade with retrograde traversal of the AV node, the majority of clinical and animal studies show a higher margin of safety for the antegrade mode,76-79 a possible consequence of wavefront geometry (vide supra). Second degree nodal block is thus more likely to develop at a slower driving frequency with stimulation of the ventricle or His bundle than with atrial drive. In many dog preparations l/l retrograde conduction is only established after antegrade interference by impulses from the sinus node is excluded by surgically crushing the latter. In clinical subjects antegrade interference may similarly confound retrograde control of the atrium. This does not by itself indicate the presence of complete retrograde block. It does indicate that retrograde conduction is “poorer” than antegrade. In pathologic circumstances, retrograde conduction may be seen in a patient with complete antegrade AV block and an artificial ventricular pacemaker. In almost all instances the site of antegrade, unidirectional block is not in the AV node, but in the His-Purkinje system.” THE

REFRACTORY PERIOD THE AV NODE

OF

MeasurementTechniques In Fig. 6 the refractoriness of the AV node is displayed in the traditional two phases,relative and absolute. Premature impulses(A,), delivered to the node in advance of its refractory period, may show the basic (or basal) conduction time to

Al I

Atrium

His

Bundle

A,-A,

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intervals

----------_---__~ -----~-------~-+A, E-

L--.------+---

______

1

1

1

k---------------------d

HI

H, -H,

intervals

Fig. 6. AV nodal refractoriness. Relationship coupling interval, Al -AZ, and the exiting interval bundle (Hi -Hz) with atrial impulses of varying rity.

“2

of input into His prematu-

the His bundle (H,). In clinical electrocardiography, the P-R interval of a slightly premature atrial ectopic beat may be even shorter than that of the sinus beat, when it originates contiguous to the AV node. Progressively premature penetration of the node, during its relative refractory period, produces incremental delay in conduction to a point where the impulse may arrive at the His bundle (Hz) later than the less premature impulses. The movement of Hz in this sequence is thus from right to left and thence to the right again. The relationship of the input coupling interval (Al-AZ) and the exit interval to the His bundle (HI-H,) is displayed in Fig. 7. Points that lie on the line of identity represent unimpaired conduction to the right of the refractory period. Deviation from the line signifiesAV nodal conduction delay (and P-R prolongation). The curve risesas this delay placesthe arrival of premature impulses in the His bundle to the right of the lesspremature preceding impulse. The minimum HI-H2 interval represents, at a given basic driving frequency (Al-Al) the closest achievable exit interval of a pair of impulses and is called the functional refractory period (FRP) of the AV node. Measured at the level of the His bundle44it is a refinement of the originally describedFRP of the AV system,al which was measuredat ventricular level (minimum V1-V2). The earliest impulse to reach the His bundle (the most leftward point on the curve) de-

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Fig. 7. Human AV nodal ness (see a\so Fig. 6). Definition ous refractory periods in secondary concealment zone established here by the latest

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refractoriof varitext. The (X2) is concealed

AZ.

fines in practice the effective refractory period (ERP) of the AV node. If the latter is exceeded by the FRP of the atrium (minimum AI-AZ) no numerical value can be ascribed to it. Such a situation is common when the basic driving cycle length (A, -Al) is long, that is, at slow heart rates. The ERP of the atrium defines the minimal coupling interval (Sr -S,) in which Sz is capable of producing an atrial depolarization; it is in part dependent on the strength of the stimulating test pulse (its multiple of threshold). The conduction of A2 within the atrium is supernormal over a modestly wide range of couThe velocity of conduction may pling intervals.” be increased by as much as 17%. This phenomenon must be allowed for when an atria1 coupling interval (A,-A,) is related to a His bundle coupling interval (H, -Hz): the atrial coupling interval will be shorter in tissue immediately adjacent to the node, than in high right atrial electrograms close to the site of stimulus delivery.” This difficulty is largely, but possibly not completely, resolved if Ar -A2 is always measured in the His bundle electrocardiogram. Concealment Zones Premature impulses, extinguished within the AV node, have important consequences. Blocked impulses are frequently referred to as concealed. Not only is there no deflection in the electrocardiogram to signify their exit from the AV node, the evidence for their penetration into this structure is hidden, unless it alters the behavior of a subsequent beat. This is the essence of concealed conduction in the ECG,s3 the term used when “an impulse manifests its effect by altering the transmission or timing of subsequent beats without being manifest electricalIy.“84 The effect on the subsequent beat is a function of the refractory

460

460

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Millis@ccnds

h-4

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h-4

wake generated in those AV nodal tissue elemlents which were successfully traversed proximal to the site of impulse failure. This phenomenon is illustrated in Fig. 7. The primary concealment :zone (PCZ) embraces all premature impulses which fail to reach the His bundle.47 The latest conceale’d A, (arrow) generates a refractory wake within the node which prevents the conduction of a subsequent premature beat, A3, placed in the secondary concealment zone (SCZ). The position of the latter varies according to AZ’s location within the primary zone. The inner limit of the SCZ is determined by atria1 refractoriness, the duration. and outer limit of the SCZ by the AZ’s refractory wake. Contraction of Ai -A2 within the PCZ abbreviates the atria1 refractory period of A, and thus moves to the left the inner limit of the SCZ. The duration of the SCZ, however, tends to expand progressively. Figure 8 shows a series of secondary concealment zones generated by altering the position of Aa. The progressive reduction of A., -A2 produces abbreviation both of A2’s atria1 refractory period (defining the innermost limit of the SCZ)

A2 ‘F

-1 D

C

scz

6

A

i

II

PCZ

I

140

I

160

I

220

A,-A,,

I

I

I

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300

340

A, -A,

I/

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met.

Fig. 6. Secondary concealment zones K3CZ) astablished by A3 when A, is placed at points A-E within the primary zone (PCZ). (Reproduced and modified by permission of The American Heart Journal.47)

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and the nodal refractory wake generated by A2 (the outer limit of the SCZ). The former shrinks more dramatically than the latter, a reflection of the relative insensitivity of the AV nodal refractory period to “previous cycle length” when compared with extranodal tissues.44s45 In examining Fig. 8 it should be remembered that the intranodal level at which impulses A and B are blocked is most proximal than that of D and E. The duration of the refractory wake in these two respective zones is intrinsically different, the latter being the longer. Noteworthy also is the slight skew (the SCZ of B) which might lend credence to the concept of distinct zones of obstruction in the node rather than a gradation of same. It should, however, be emphasized that when conduction is maximally impaired within a nonhomogeneous structure, the pathway may be tortuous, and variation in conductive behavior in successive experimental runs (basic beats plus premature stimuli) is not unusual. These measurements also assume the absence of longitudinal dissociation within the AV node in this particular experiment. The inner limit of the PCZ is determined by the question: Do all delivered atrial premature impulses enter the AV node? Complete entrance failure would not only be signified by the absence of a succeeding SCZ, the conduction time of A3 to the His bundle should theoretically be the same as it would be in the absence of A2. Although clinical absence of the secondary concealment zone has been offered as evidence of complete AV nodal entrance block, conduction of A3 in these patient volunteers was nevertheless prolonged.” The use of the terms relative and absolute refractoriness is subject to ambiguity. Strictly speaking, absolute refractoriness implies inexcitability, in this case, of the entire AV nodal structure. Thus, it might be postulated that prolonged conduction and concealment of atrial premature beats are both manifestations of relative refractoriness. If, however, the node is regarded as a conduit and this role is examined in terms of success or failure, it is appropriate to label non-propagated concealed impulses as confrontations with the absolute refractory period, while recognizing that the latter term is applicable only to the longest intranodal period of inexcitability. Repetitive Concealment It can be seen from Fig. 7 that a tertiary concealment zone could clearly be defined if a third

RORY

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/ 200

sbo

4bO

CH I LDERS

500,

“SEC

,

Fig. 9. Schematic representation of repetitive AV nodal concealment. Upper portion: Atrium assumed to be driven at maximum frequency for 1 :I AV transmission. Cycle length (Al-Al) is 263 msec. Differing refractory periods of upper and lower levels of AV node (NA and N6) indicated by shaded areas: RA = 200, R6 ~260 msec. A2 defines the duration of the “concealment zone” represented by the disparity between RA and R6 (50 msecj Lower portion: AlVl represents last driven beat. A2 assumed to be blocked at junction of NA and N6. Propagated response A3V3 results in short preceding cycle in NA, and longer preceding cycle in NE, with a resulting increase in the duration of the concealment zone for A4. (Reproduced by permission of Circulation Research. 86 )

premature impulse, &, failed to conduct in the presence of A3 and Az. This repetitive concealment of impulses is the basis for the protection the AV node offers to the ventricle in atria1 fibrillation, where the node is probably confronted by as many as 400 impulses per minute. Clearly, the longer the duration of any concealment zone, the greater is the opportunity for impulses to be blocked. Figure 9 shows how raising the atria1 input frequency in fact achieves this end. From the hierarchy of different nodal refractory periods, the illustration shows two: the upper being shorter than the lower. In the top panel, this temporal discrepancy produces a concealment zone 50 msec in duration. The interpolation of additional atria1 beats (bottom panel) widens this zone to 139 msec. The general effect of repetitive interpolation and concealment is, within the hierarchy of AV nodal refractory periods, an expansion of the disparity between those just proximal to the site of block (short) and those in the distal elements (low). s6 This dispar’ rt y is also directly related to the atria1 input frequency. A clinical example is the immediate reduction in ventricular rate which occurs when atrial flutter is replaced by atria1 fibrillation.

AV

NODE:

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PHYSIOLOGY

371

LW

RAC

,

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RA I)--!,-+

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Fig. 10. Right atrial electrograms and action potentials (AP) recorded from N and NH cells during atrial fibrillation. (A) Note abbreviated AP in N cell when NH is unresponsive, (B) Repetitive concealment; only the first and last impulses succeed in reaching NH. (Reproduced by permission of Circulation Research.87)

In Fig. lOB, where atrial fibrillation is simulated, 1l/21 atria1 impulses reach the N region of the node, but only 2 reach the NH region (and presumably the ventricle). Repetitive concealment is in evidence with abbreviation of the imminently “failing” action potentials. NH cells distal to the blocked site show electrotonic local response “humps.” More importantly, the refractory period generated by the last impulse to successfully engage the NH region will be expanded by the long previous cycle length within this region. Thus, immediately subsequent impulses (not shown) even if they successfully traversed the N region, would find the NH region unreceptive. This is the explanation for the distribution of ventricular cycle lengths in atria1 fibrillation: long cycles tend to be followed by long cycles, and short cycles by short cycles.86-88 Scrutinizing Fig. 10, it is hard to understand how long cycles are euer followed by short cycles unless longitudinal dissociation is invoked. Ex tracardiac Determinants Refractoriness(Fig. 11)

1 Short

of A V Nodal

In grosscontrast to the His-Purkinje system,the refractoriness of the node is profoundly diminished by exercise, which greatly increasesthe ventricular rate in seemingly “well controlled” atrial fibrillation, to values in excessof the exercised sinusnode. The FRP of the node is likewise shortened by sympathetic stimulation, catecholamines,and atropine.” Refractorinessis expanded by digitalis, beta adrenergic blockade, and vagal

Basic Cycle

Length

Long

Relationship of basic or “previous” cycle Fig. 11. length to refractory period duration in right bundle branch and AV node. The curve of the latter (unlike the former) is subject to gross displacement by physiologic and pharmacologic interventions. (Reproduced and modified by permission of Circulation Research.44)

stimulation.47 Figure 11 showsthe curvesrela.ting the functional refractory period to heart rate: for AV node and bundle branch. The longer value of the latter at slow heart rates (or long previous cycle lengths) is the basisfor the occurrence of functional bundle branch block with atria1 premature beats.44

Short

,

Al-Al

I

I

, Long

cycle length

Fig. 12. Display of AV nodal function. Related here to basic driving frequency are FRP (min HI-HZ), ERF’ (earliest A2 propagated), and antegrade transit time (Al-HI 1 of the AV node. The separation of the AV nodal ERP from the FRP of the atrium (earliest A,) defines the primary concealment zone. At slower frequencies (not shown) Al-H, would be almost flat with basal conduction. As the FRP of the atrium would exceed the ERP of the node, measurement of the latter would be impossible. (Reproduced and modified by permission of The Arnerican Heart Joornal.47)

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One satisfactory method of displaying AV nodal function is shown in Fig. 12. Noteworthy is the fact that only a small portion of the curve representing basal conduction is shown. In the dog heart, the effective refractory period invariably expands and the functional refractory period shrinks, with reduction in basic driving cycle length (A, -Al )‘r7 Human studies show considerably more variation.46’48 In some studies, these changes have been absent or even of opposite polarity at successively different pacing frequencies.46 It is unclear at this time whether these anomalies are related to human AV nodal behavior, or to errors implicit in the atrial pacing method. For example, in marked sinus arrhythmia the delivery of A2 may coincide with the nadir of vagal effect, or with its peak. The number of basic beats (A,) selected in each experimental run is also of vital importance. Rapid pacing often causes a transient increase in potassium output from the coronary sinus.56 Time is required for a stable state to be established; it may amount to more than 1 min.” Retrograde Refractory

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the functional refractory period of the node cannot be determined, but is clearly less than that of the infranodal tissue. “Gaps ” in A V Transmission A r’gap”44y91 in AV conduction is signified by failure of conduction during a critical zone of coupling intervals (Al-AZ) with resumption of conduction at even more premature (and seemingly futile) coupling intervals. The mechanism is elementary. If the effective refractory period of the His-Purkinje system is longer than that of the AV node, atria1 premature beats will fail to conduct beyond the His bundle at a critical Ai -AZ interval. Further reduction of the AI-A2 induces such marked intranodal delay that H2 is moved to the right of its previous position and is thus no longer a challenge to the absolute refractory period of the tissues downstream. Gaps should not

Periods in the AVNode

As already stated, retrograde AV nodal conduction is frequently poorer than antegrade.76-79’60 The converse is occasionally and even dramatically, true.79 Noteworthy is the fact that the integrity or adequacy of retrograde conduction cannot be predicted by antegrade performance. The functional retrograde refractory period of the AV node is the minimum Al -AZ achieved, when following His bundle drive (HI-H,), a His premature beat Hz is delivered. The effective retrograde refractory period is the widest Hr -Hz interval at which retrograde conduction fails. These can be measured in animals: catheter stimulation of the human His bundle is impossible. More usable but less specific is the minimum Ai -AZ achieved by basic and premature ventricular stimulation: an expression of refractoriness in the entire ventriculoatrial system. His bundle electrocardiography in some instances permits the graphic registration of retrograde His potentials when the V-H time is physiologically delayed by prematurity. As Fig. 10 demonstrates, at slow heart rates the bundle branches may have a longer refractory period than the node. If the minimum retrograde Hr -Hz interval achievable by premature ventricular stimulation (the functional refractory period of the Purkinje-His system) is too wide to reveal the minimum achievable A1 -AZ

180 a: a -c/s I-

170

160

L 300 ’

I 800

CYCLE LENGTH

I 300

nlsec

Fig. 13. Cumulative effects of drive on AV nodal (A) and His bundle (5) refractoriness. The dotted lines show the reduction of the FRPs at each of three basic driving cycle lengths: 500,400, and 300 msec. The closed circles, open circles, and trianglas show the FRP obtained when a fixed “previous cycle length” of, respectively, 500, 400, and 300 msec is preceded by the basic atrial driving cycle length shown on the horizontal (see text). (Reproduced by permission of The American Journal of Ph ysiology. 93 1

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be confused with true supernormal which is not seen in the AV node.55 Temporal Determinants Period Duration

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373

conduction,

should be amplified with transmembrane potentials from the AV node. Demonstration of “fatigue” in the AV node can be achieved by a protocol similar to that prleviously mentioned. The AV nodal transit time of a beat terminating a programmed pause is examined when the pause is preceded by a wide variety of basic driving frequencies. When the latter are extremely rapid, transit time will have a substantially higher value than that which would obtain when the preceding driving cycle length equals the pause.43*50 Both fatigue and cumulative effect require a sufficiency of basic pulses to become manifest; any other relationship between these two phenomena is presently unexplored.

of Refractory

In clinical, or intact dog studies, abrupt changes in the duration of a tissue refractory period are matched against the length of the antecedent cycle in the given tissue, that is the interval between the two immediately preceding depolarizations. The actual determinant is the duration of the preceding phase 4, or diastolic period;92 the latter cannot be accurately (or easily) measured from epi/endocardial electrograms or from the body surface electrocardiogram. The error inherent in the scrutiny of previous cycle length becomes evident if one compares the duration of phase 4 between two successfully propagating pulses A2 and AS, with that which obtains, at the same AZ-A3 interval, when AZ is concealed. The AV nodal refractory period of A3 will be longer in the latter instance, because action potential abbreviation of the imminently failing AZ will expand its subsequent phase 4. Previous cycle length, or previous diastolic period, do not totally determine the duration of the nodal refractory period. The cumulative effects of basic drive (Al-A,) will significantly effect the duration of AZ’s nodal refractory period.93 This effect is shown in Figure 13. In Panel A, the dotted line represents the shrinkage, with contracting basic cycle length, of the AV nodal FRP, as measured in the last of 14 basic atria1 driven beats, tested at AI-A1 intervals of 500, 400, and 300 msec. The three roughly parallel curves show the refractory period elicited in the beat following a programmed pause (value on the horizontal) when this pause is respectively preceded by atria1 drive at the aforementioned three frequencies. Thus a fixed “previous cycle” length of 300 msec produces a subsequent refractory period of 199 msec when preceding basic drive is 300 msec, but when preceding drive is 500 msec the subsequent refractory period is 216 msec. This experiment

Fig. 14. Functional of AV nodal reentry

anatomy (see text).

LONGITUDINAL

DISSOCIATION AV NODE

IN THE

The physiology of reentrant excitation hasbeen studied more elaborately and successfullyin the rabbit, canine, and human AV nodes than in any other cardiac structure.g4-106~70 There are two major reasonswhy reentry occurs so commonly in the AV node: (1) The optimal condition for reentrant excitation is nonhomogeneouslyimpaired conduction. The margin of safety for propagation is lowest in the AV node, even at best. Additionally, it is the commonest seat of conduction disturbancesin the heart, pharmacologic,pathologic, or autonomic. (2) Physiologic impairment of conduction occurs with premature ectopic impulses. All of the latter (atrial, junctional, and ventricular) commonly reach the node, where they can induce reentry. Longitudinal dissociationprobably occursin the AN region,” where impaired conduction may be resolved into two functional pathways, grossly at variance in their capacity to propagatethe impulse. In Fig. 14A the antegradeimpulse finds the beta pathway inexcitable but proceedsdown a1ph.a.At the point where these used and unusedtissu#e elements converge into a final common pathway (FCP”), the impulse finds beta is now excitable.

374

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Fig. 15. Dual AV nodal pathways. The P-R interval shows two distinct values. Top and bottom strips: 0.48 sec. Middle strip: 0.21 sec. The change from one pathway to another is twice induced by the interpolation of a ventricular premature impulse WPI). Top strip: the VPI must collide with the sinus impulse in the slow pathway preempting its usual concealed retrograde passage in the fast pathway, the shorter refractory period of which is displaced to the left (“peeled back”: see text): this allows subseauent use of fast pathway. Middle strip: the VPI penetrates the recovered fast pathway rendering it refractory to the imminently following sinus beat.

The circuit is completed with the retrograde arrival of the beta impulse at the atrium, producing an at&Z echo. Atria1 reexcitation will not take place if (1) the impulse dies within beta: that is, if the block in beta is bidirectional rather than unidirectional, and (2) the impulse in beta finds the atrium still refractory, either because retrograde conduction is insufficiently delayed, or because atria1 refractoriness is excessively prolonged. Both (1) and (2) can be achieved by pharmacologic agents, the therapeutic goal in question being the suppression of repetitive loop tachycardia through the atrial-alpha-beta atria1 circuit (reciprocating AV nodal tachycardias: Fig. 14C). Ventricular echoes are produced when retrograde junctional (His) or ventricular impulses enter the same system from below and encounter unidirectional block in one of the pathways. In this instance the FCP must be fully recovered to permit the reentering impulse to reach the ventricle (Fig. 14B). In the antegrade mode (Fig. 14A), AV nodal reentry (single or sustained) is commonly seen, or induced by pacing, in the following clinical circumstances:io7 (1) With second degree block of Wenckebach type, where an atria1 echo occurs at the longest P-R interval, preempting the sinus beat which would otherwise be nonconducted. (2) With atria1 premature beats occurring in the presence of already impaired AV nodal conduction (clinical P-R prolongation). During retrograde conduction (Fig. 14B), AV nodal reentry is seen in (3) junctional (His), subjunctional, or idioventricular rhythm, with retrograde nodal block of Wenckebath type: a ventricular echo follows the beat with the longest R-P interval; (4) When premature beats, originating in the His bundleies or ventricle are conducted back through the node with sub-

stantial delay. Longitudinal dissociation of the AV node is clinically manifest in the absence of echoes by (5) two grossly different P-R intervals in sinus beats, the change from one to the other being sudden (Fig. 15); (6) alternation of the P-R interva1;ro7 (7) atria1 pacing: two grossly different AV conduction times, manifested at different times at the same basic cycle length; a discontinuous curve relating the minimum Hi-Ha to AI-AZ, i.e., two functional refractory periods for the nodes1@“lo6 (Fig. 16). Echoes can be induced in the rabbit and dog heart when AV nodal conduction is impaired, i.e., in situations identical to those previously mentioned. Atrial echoes are easier to evoke in the rabbit ,95 and ventricular echoes are easier to pro-

.

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.

.

.

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. . 1 300

1 350

1 400 A, - At

I 450 (msecj

I 500

I 550

I 600

Fig. 16. Demonstration of dual AV nodal pathways. In many instances (not here) the slow pathway (lefthand curve) is only seen to be used at Al-A2 intervals to the left of the minimum HI-HZ of the fast pathway (righthand curve). The respective functional refractory periods of the two pathways shown here are 510 and 570 msec. (Reproducad by permission of The American Journal of Cardiology. 103 1

AV

NODE:

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Fig. 17. Characteristics heart (see text). (Reproduced tion Research.94)

AND

of

ABNORMAL

PHYSIOLOGY

ventricular echoes by permission of

in dog Circula-

duce in the dog.94 Figure 17 shows the characteristics of ventricular echoes (E-I’) induced in the dog when basic His bundle stimulation (HI-H,) is followed by premature beats (H,) of increasing prematurity, Hr -HZ. The echoes were examined in terms of their arrival time at His bundle rather than the ventricle. The zone during which echoes from the atrium (A,) returned to the His bundle (H’) is signified by a block horizontal bar. The retrograde conduction time H2 -AZ increased progressively with reduction in Hr -Hz. The curve of the atria1 coupling interval AI-A2 defined, with its minimum value, the functional retrograde refractory period of the AV node. The inner limit of the echo zone was the earliest Hz to reach the atrium AZ (the effective retrograde refractory period of the AV node). The two alpha and beta “limbs” of the echo, the retrograde Hz-A2 and antegrade AZ-H’ (crudely corresponding in the ECG to the R-P and P-R intervals, P being retrograde) undergo a complex change. The longer the HZ-AZ, the shorter the AZ-H’. The total echo circuit time HZ-H’ achieved a minimum value with shortening of the Hr -HZ interval and then expanded again. This experiment also showed (not in Fig. 17) that the high value for total circuit time at the outer limit

375

of the echo zone reflected relative refractoriness in the final common pathway (FCP). As retrograde conduction HZ-A2 became more prolonged, the FCP had greater time to recover and was traversed more rapidly (shorter AZ-H’ values). The FCP was found to be in the AV node, not the His bundley4 Clinical case reports and studies using His bundle electrocardiography show certain differences compared with such dog experiments. (1) For obvious reasons, the kind of exacting profile obtained in Fig. 14 has not been, as yet, obtained. (2) Even though two separate P-R intervals are lacking in clinical tracings, longitudinal dissociation may be revealed by a discontinuity in the curve relating HI-H2 to AI-A, intervals. The former “jump” to a considerably higher value as the premature beat starts to use the sfow pathway, that is, at the moment the ERP of the fast p;athway is definedlo (Fig. 16). (3) Of particular note is the variation in the shape of the Hr -Ha curve of the slow pathway; it may show, as expected, progressively longer val.ues, as Al-A2 is reduced; in other cases, the slope is reversed or flat.“’ Echoes are elicited not at all, by some, or by every one of the slow pathway penetrations. In many of these patients, a sudden switch occurred during pacing from fast to slow pathways. In those patients where echoes could not be elicited it is presumed that concealed rctrograde conduction of the unused pathway (the abortive echo) is maintained on a 1 : 1 basis. Discontinuous curves of this kind were first noted in the dog heart. 94 In one study, the data suggested three dissociated pathways.“’ (4) Echoes are frequently concealed or aborted preemptively during ventricular pacing of both the human and the dog heart, when retrograde conduction to the atrium is of Wenckebach type. The cessation of ventricular pacing during maximum retrograde impairment allows the echo to be revealed.“* (5) There is now considerable evidence that the atrium is not always a necessary link in the human echo circuit, in gross contrast to the dog (Fig. 14D). Ventricular echoes can be seen in atrial fibrillation”’ or in the absence of retrograde P waves. The spectrum thus extends from subjects in whom longitudinal dissociation is clinically and experimentally absent, those in whom it is demonstrable, but without echoes, those who show single echoes, and those in whom virtually every echo re-

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sults in sustained loop tachycardia. When the latter is induced, it is probable that it can be documented as a spontaneous event also. In the great majority of patients who are subject to reciprocating AV nodal tachycardia, some impairment of AV nodal conduction is visible during sinus rhythm.“’ Reciprocating AV nodal tachycardia can in many instances be arrested with a single stimulus.” If the refractory period of the atrium is sufficiently brief, it may be preexcited in advance of the imminently arriving retrograde beta impulse with one of the following potential results: (1) The tachycardia is arrested within beta by collision of the atrial and retrograde impulses; alpha, still refractory, is not entered. (2) Same as (I), only the atrial impulse penetrates alpha as far as the FCP. The latter and the inferior entrance to beta are still refractory. (3) Same as (2), but the atria1 impulse successfully reaches the His bundle (and ventricle). (4) Same as (3) but the atrial impulse is able to follow slowly on the heels of the beta impulse, “resetting” or “restarting” the tachycardia. (5) The atrium is preexcited, but not before the emergence of the beta impulse: the resulting atria1 fusion beat fails to arrest the tachycardia. (6) Preexcitation fails to arrest the tachycardia, because the atrium in this particular subject has only an incidental, rather than essential, involvement in the echo pathwayl’e (Fig. 14D). The anatomy of AV nodal reentry can determine experimental rhythmic sequences which appear heretical in terms of the physiology of the undissociated AV node. One celebrated “heresy” is the I, 2, 3, 4 phenomenon in which A4 conducts in the presence, but not in the absence, of A3 .lrr CLINICAL NODAL

ASPECTS OF AV PERFORMANCE

If the QRS is normal, a P-R interval of greater than 0.2 set is often regarded (with statistical justification) as evidence of abnormal AV nodal delay (first degree AV nodal block), Although clinicians tend to regard second degreeAV nodal block of Wenckebach type (Mobitz type I) as a more seriousimpairment, it is extremely common for the two gradesto appear in the samerhythm strip, especially when there are minor changesin atria1 rate. The major causesof clinical AV nodal block include active rheumatic fever; digitalis (where effect and toxicity are crudely but work-

CHILDERS

ably assigned,respectively, to first and second degree AV block), myocardial infarction (block lasting only hours or days in the majority of patients), and a host of other drugs and diseases in which block is temporary or permanent. The poorer prognosisof infranodal block is due to the fact that it is lessfrequently a temporary condition. A common etiologically inexplicable finding in senior citizens is a grossly prolonged P-R interval (0.3-0.5 set) in an ECG otherwise normal. These patients may have no other signsor symptoms of heart disease.Although the AV conduction disturbance is entirely reversible with atropine, suggestingexcessive“vagotonia,” many such patients are subject to syncope, the slightest increment in vagal tone producing symptomatic ventricular asystole. Wenckebach,in his classicdescription of second degree AV nodal block,rl* analyzed the distal cycles (R-R intervals) and noted that the pattern consisted of progressiveshortening followed by a pause. The first cycle following the pause was longer than that which preceded it (the major increment in AV nodal conduction occurring with the second beat), and this cycle was invariably longer than that which preceded the pause (the last beat having the smallestincrement in conduction time). These criteria are often absent in Wenckebach sequenceswhen (1) the AV ratio showshigh numbers (18 : 17, 11 : 10, etc.); (2) the AV ratio is constantly changing(2/l and 312 commonly alternate); (3) the proximal cycle, sinusP waves, show variation in rate (as with sinus arrhythmia, or SA nodal Wenckebach, a common companion); (4) when a large increment in AV nodal transit time precedesthe dropped beat with widening of the final cycle prior to the pause(concealed reentry may be causal”’ ; (5) when the sequence is interrupted by atria1 echoesor other abnormal beats. Mobitz type II block, signified by sudden conduction failure without antecedent changein AV conduction, is most characteristically seen when the site of obstruction is in the His-Purkinje system. Seldoman expressionof AV nodal block, it is simulated by Wenckebach sequenceswith highnumber AV ratios and is seen with suddenvagal volleys (carotid massage)and other rapidly changing states. In 2 : 1 AV nodal block, the P-R interval of the electrocardiogram is heavily dependent on the

AV

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depth of intranodal concealment by the previo’cls nonconducted sinus impulse (P wave). When 2 : 1 block is about to become 3 : 2 (a “better” ratio), conduction may seem to deteriorate because the P-R of the conducted beat becomes prolonged.s3 The change signifies relatively imminent success in the propagation of the nonconducted beat, which by penetrating more deeply within the node, is presenting a refractory wake long enough to delay the conduction of the subsequent beat. The AV nodal conduction of atria1 flutter impulses (ca 300/min) is almost invariably 2/l. The site of block is probably very high in the AN zone. At 150/min, the node is transmitting at a rate approximating the maximum l/l ratio obtained by atria1 pacing. Digitalization generally introduces a second lower zone of block through which the alternate impulses conduct in Wenckebach sequences. Three-to-one block is uncommon in flutter; higher ratios tend to be unstable. One-to-one conduction of flutter (rates 270-300/min) is seen when, without digitalis, the atria1 rate is reduced by quinidine, the atropine-like effect of which shortens refractoriness and transit time in the AV node. It is also seen when, without digitalis, a highly adrenergic/vagolytic situation is present (shock, etc.) The digitalis dose required to control the ventricular rate in atria1 flutter is almost always greater than that required for atrial fibrillation. This reflects the greater AV nodal concealment opportunities offered by the higher atria1 frequency of the latter. “Peeling Back” the Nodal Refractory

377

PHYSIOLOGY

Barrier

Electrocardiographically, in situations where AV nodal conduction is impaired, the introduction of premature beats (atria1 or ventricular) can dramatically change the subsequent rhythmic sequence. 6s9113 Intranodal invasion by the ectopic impulse will displace the refractory period to the left. Ventricular premature beats can by this means shorten the subsequent P-R interval. Placed appropriately, they may also, by retrograde concealment, prolong or block the AV conduction of the next sinus beat’14-l16 (see also Fig. 15). In Fig. 18A the basic rhythm is 2: 1 AV nodal block. Alternate P waves encounter and are blocked by a prolonged refractory period. In (B) a subsidiary pacemaker in the bundle of His has developed a rate slightly faster than half the sinus rate. The fundamental AV conduction ratio is thus obscured by interference. The His pacemaker re.

Fig. 18. Interference of His and presence of basic 2: 1 AV nodal block

sinus pacemakelrs (see text).

in

currently displaces the refractory period of the node to the left by retrograde penetration. In some instances, there is a collision of impulses. This “peeling back” of nodal refractoriness occasionally permits antegrade conduction to take place. In (B) only the last sinus beat conducts to the ventricle, an event which would occur infrequentIy. in such a tracing, “supernormal” AV nodal conduction might be falsely envoked. True supernormality does not exist in the AV node..55 The Autonomic Nervous System and the A VNode Stimulation of the sympathetic nervous system enhances nodal conduction and shortens refractoriness. The opposite effect is achieved by vagal stimulation.47 For this reason, this structure is like its sister sinus node, influenced by the baroreceptor and by those metabolic and pharmacologic states which “prime,” or render less effective, the achievemerrts of a given volley of adrenergic or cholinergic impulse traffic. Disorders of acid-base metabolism profoundly affect the achievements of autonomic nerve stimulation, but in opposite ways. Acidemia or local tissue acidosis reducles th.e activity of acetylcholinesterase and thus potentiates the vagal effect. ‘17 By contrast, acidemia reduces the effectiveness of adrenergic nerve impu1ses.l” In a given vagal volley, the time taken to achieve a measured effect in the AV node is 200 msec, the peak activity being observed at 350400 msec. 11g,120If the reflex arc of the baroreceptor is included in this measurement, the time from QRS to overt effect on the AV node is about 500-600 msec. r*r This time measurement is important in 2/ 1 AV nodal block with ventriculophasic arrhythmia.‘22~‘23 In this condition there is systolic hypertension. The arterial pulse wave causes the carotid baroreceptor to initiate a short vagal volle:y. The latter produces alternation in the sinus cycle lengths: the P-P interval sandwiching a QRS is shorter than that which does not; every conducting P wave has been transiently delayed in its appear-

378

ante by the antecedent vagal effect on the SA node. A 2: 1 AV block may be fortified, or even sustained in some instances if the effect of the vagal volley reaches the AV node simultaneously with, or in advance of the confronting “nonconducted” sinus impulse. In sick cardiac patients, evidence for baroreceptor autoregulation of AV nodal conduction is occasionally seen. Cyclic variation in heart rate, P-R interval and blood pressure occur: the latter reaches a peak when the P-R is short and the heart rate maximal. Thereafter the rate SIOWS, the P-R expands, and the blood pressure begins to fall (presumably the result of sympathetic withdrawal). With maximal P-R intervals (sometimes with P inside the Q-T interval, and thus no longer providing an atrial “kick”), the blood pressure and heart rate reach their minimum and the sympathetic system is again reflexly stimulated. Digitalis and A V Nodal Conduction ’ 24 Simple prolongation of the P-R interval by cardiac glycosides is atropine-reversible. In therapeutic doses the agent cannot prolong AV conduction in the denervated transplanted heart.74 In toxic doses, a direct effect may produce complete heart block,125 frequently accompanied by junctional acceleration. The possible means by which digitalis potentiates vagal tone include an increase in the excitability of the vagus nerve and an increase in the sensitivity of SA and AV nodal cells to acetylcholine. Thus, vagal intervention by carotid sinus massage will produce a greater measurable result after priming with digitalis, but this effect will be reduced in early untreated heart failure, in which vagal tone is generally reduced. Digitalis will fail to slow the ventricular rate of atria1 fibrillation when its expanding effect on AV nodal transit time and refractoriness is opposed or overcome by “adrenergic/vagolytic states,” such as exercise, fever, pulmonary embolism, hypoxia, shock, or thyrotoxicosis. Other Drugs and Electrolyte Disorders In the intact dog, the precise effect of hyperkalemia on AV nodal conduction is made difficult by its attendant effects on the adjacent atrium and His bundle. The latter tissues, together with ventricular myocardium, show a biphasic change in conduction which is at first enhanced, and later markedly delayed. 126 Thus, the early enhancement of AV conduction may in part be extranodal. In

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advanced clinical hyperkalemia the P waves are absent. The QRS is widened but the rhythm is presumed in many instances to be sinoventricular.rg There is a twofold basis for this assumption: specialized atrial fibers are highly resistant in vitro to hyperkalemia, retaining their action potentials long after ordinary atria1 muscle has become inexcitable;” the rationale for sinoventricular conduction is the presence of internodal tracts of such specialized fibers.” Clinical support for this thesis is the fact that when P waves are rapidly restored by dialytic reduction of K their reappearance does not herald any dramatic change in cardiac rate. In vitro studies show that in most instances a high potassium concentration was without appreciable effect on AV nodal transmission.‘27 When the latter was prolonged, the delay was largely attributable to atria1 and His membrane depolarization. In many cases AV nodal action potentials increased in amplitude with hyperkalemia. Low potassium concentrations on the other hand selectively depressed conduction through the N region of the node, with decrease in action potential amplitude. When digitalis produces advanced AV nodal block, it is not worsened by hyperkalemia unless the latter prolongs conduction in supra and infranodal tissues.127 In another study, quinidine, which clinically enhances AV nodal conduction by virtue of its atropine-like effect, was only found to prolong AV conduction by virtue of its highdosage effect on the adjacent extranodal tissues.‘** Both reserpine and propranolol prolong AV nodal conduction and expand the FRP of the node almost entirely by antiadrenergic means.rz9 In the case of the latter, this effect is reversed by glucagon. Verapamil, by its presumed depression of the slow-component, selectively depresses AV nodal conduction and abolishes AV nodal reentry.‘30,‘31 Acute Myocardial Infarction AV nodal block is preeminently seen in posterior or inferior infarction. Latent conduction defects may thereafter be revealed by atria1 pacing.‘32 Block is most often temporary and is absent at discharge in the majority of patients.‘33 The nature of the atropine-reversibility’34 of block induced by AV nodal ischemia is controversial. It has been assumed13’ without convincing evidence that infarction on the posterior-inferior surface of the heart initiates a generalized vagal reflex. A more tenable explanation is that AV nodal ischemia, an acidic tissue state, reduces sympathetic effective-

AV NODE:

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nessin the AV node, and, by partial inactivation of acetylcholinesterase’17’118enhances vagal effect with resultant block. A V Conduction in the Neonate Rapid AV conduction and sinus tachycardra in the newborn may be attributed to both diminished vagal tone and relative supersensitivity to sympathetic impulse traffic. 136The abbreviation of AV nodal refractoriness in premature or newborn mammals allows excessively premature atria1 impulsesto invade even the vulnerable period of the ventricle.137-‘39 The question of whether these findings can be extrapolated to the human newborn, or provide an explanation for some “crib deaths,” is unanswered at this time.140-*42The lack of protection afforded by the AV node at this ageis fortunately mirrored by the clinical rarity of atria1 fibrillation, although atria1 tachycardia may produce ventricular ratesof 280/min with progressiveheart failure.143 PATIENTS

WITH

HABITUALLY

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SHORT

p-R 1NTERVA~S21,62,79,131,144-146 Certain patients with true sinus rhythm (as opposed to that of a peri-AV nodal pacemaker)habitually showacceleratedAV nodal conduction, invoking the possibility of an AV nodal bypasstract. i2,i6 This group, in whom there may be a predisposition to atria1 tachyarrhythmia (the LownGanong-Levine syndrome147) have none of the stigmata of the Wolff-Parkinson-White syndrome other than a short P-R interval (0.11 set). Nor are they patients with basal AV conduction, because atrial pacing either fails to produce any increment in AV nodal transit time or alternatively, demonstrates it only at excessively high driving frequencies.” The measurablevaluesfor AV nodal refractoriness are likewise abbreviated.‘@’ A second group of patients fail to show expansionof the AV nodal transit time only in the retrograde mode during ventricular pacing.79”31 There is no evidence that these patients are liable, or more liable, to a loop tachycardia, the particular physiology of which would be native to a posterior internodal tract-low node-high node-atrium pathway of reentry. In the absenceof a morphological confirmation of the bypasstract, the functional anatomy in these clinical subjectsremainsspeculative,and can be resolvedinto the following possibilities:(1) The shortened AV nodal conduction times are a function of an infant AV node retained into adult life,

that is, remainingexcessivelysmallor maintaining, for whatever reason, the accelerated conduction that characterizes the neonatal electrocardiogram (vide supra). (2) A true AV nodal bypass tract. (3) A unidirectional Kent bundle in the AV junction capable of conducting the impulse directly from high ventricular septalmuscleto atrium. The latter would, of course,provide an explanation for those patients who only show accelerated re,trograde conduction. Antegrade use of a septal Kent bundle would give rise to a delta wave aswell asa short P-R interval. Unidirectional antegradeblock has been confirmed in Kent bundlesand is a cause of paroxysmal supraventricular tachycardia.14’ (4) Some of thesecasesmay have dual AV nodal pathways with clinical expressiononly of the faster of the two.‘45 THE AV NODE PARKINSON-WHITE

IN THE WOLFFSYNDROME149

When there is a functioning accessorypathway acrossthe AV groove, the QRS is a fusion beat. The latter is formed by the coalescenceof an initial Kent bundle wavefront in the ventricle (delta wave) and the orthograde wavefront normally produced when the sinusimpulse invades ventricular muscle.The conduction velocity of the Kent bundle, though extremely rapid, is not subject to the samemarked variability as the autonomicahy innervated AV node. The relative contribution of these two wavefronts, and the degreeof resultant QRS aberration, are almost exclusively a function of the AV nodal transit time. When the latter is excessively short, almost no delta wave will be seen: the ventricular massof tissueectopically depolarized by the Kent bundle impulse will be small. As AV nodal conduction becomes prolonged, the anomalouswavefront becomesresponsible for a greater portion of the QRS, which becomesincreasingly widened and aberrant in :shape becauseof asynchrony. Where there is critical delay or block in the AV node, “total” Kent bundle activation ensues:the QRS resemblesa ventricular ectopic impulse. The simplest expression of the physiology describedabove is the grossQRS aberration produced when an atria1premature impulse, excessively delayed in the node, allows the Kent bundle to enjoy exclusively; the activation of the ventricle. Other lessimportant (or rare) factors affecting QRS morphology in this syndrome are the Kent transit time and the location of the Kent bundle. The influence of the latter is complex. The

380

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Kent bundle may feed a portion of myocardium that would normally be depolarized late in the QRS. Aberration could be potentially enhancedby the late coalescenceof wavefronts. If, at the same AV nodal transit time, the myocardium servedby Kent “belongs” early in the normal sequenceof ventricular activation, aberration will be less.Potentially cancelling this disparity is the fact that the “late” ventricular locations may also be late in terms of the activation sequence of the atrium. The node is traditionally entered in the middle of the sinus P wave; a left atria1 Kent bundle would be entered after this event. A Kent bundle location late in the normal sequenceof ventricular activation is, however, important in clinical studies,

where atria1 pacing may be performed at a site contiguous to the Kent bundle and remote from the approachesto the AV node. The AV node is important to the pharmacologic treatment of the typical circus tachycardia of the Wolff-Parkinson-White syndrome, in which impulsesuse the normal antegraderoute, but reenter the atrium through the Kent bundle. The total circuit time, that is, the ventricular rate, can be greatly depressedby agents which delay conduction in the AV node (digitalis, verapamil, betaadrenergic blockade). These agentsare commonly used in both the arrest and prevention of loop tachycardias.

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CHILDERS

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