Journal of Clinical InvestigationVol. 44, No. 6, 1965

Deterninants of the Duration of the Refractory Period ofthe Atrioventricular Nodal System in Man *

JOSEPHW. LINHART, EUGENEBRAUNWALD,tANDJOHN Ross, JR.(From the Cardiology Branch, National Heart Institute, Bethesda, Md.)

One of the fundamental characteristics of ner-vous tissue, skeletal muscle, and myocardium istheir refractoriness for short periods following de-polarization (1). This period, during which apropagated action potential cannot be evoked bya stimulus, has been designated the "effective re-fractory period" (2), and the effective refractoryperiod thus limits the maximal rate at which de-polarizations can occur. When normal atrioven-tricular (AV) conduction takes place, the ventricu-lar contraction rate is limited by the AV nodalsystem, which has been shown in experimentalanimals to have a longer effective refractory pe-riod than atrial or ventricular tissue (3). Inspite of the fundamental importance of the refrac-tory period of the AV nodal conduction system,this interval has heretofore been estimated onlyfrom electrocardiograms obtained from patientswith spontaneous cardiac arrhythmias (4). Thepresence of arrhythmias may be associated withabnormalities of conduction, and the analysis ofsuch electrocardiograms does not allow systematicinvestigation of the factors that influence this pe-riod in normal subjects. In the present investi-gation a practical method for the measurement ofthe effective refractory period of the AV nodalsystem in conscious human subjects is described.With this method normal basal values for thisperiod were established, and the effects of tachy-cardia, exercise, atropine, and of various sympatho-mimetic drugs on its duration are presented.

Methods

A bipolar electrode catheter 1 was passed into the rightatrium and positioned against the mid-portion of thelateral wall of the right atrium. A slight bend was

* Submitted for publication October 13, 1964; acceptedFebruary 4, 1965.

t Address requests for reprints to Dr. Eugene Braun-wald, National Heart Institute, Bethesda, Md. 20014.

1 NBIH catheter, United States Catheter & Instru-ment Corp., Glens Falls, N. Y.

maintained near the tip of the catheter to insure ade-quate contact with the wall. The electrodes were con-nected to a stimulus isolation unit, and the leads con-tained a 10,000 ohm resistor, making small changes in re-sistance at the site of stimulation of no practical signifi-cance and preventing large fluctuations of current. Thestimulus isolation unit prohibited the accidental develop-ment of large electrical potentials between the stimulatingcircuit and the other equipment to which the patient wasattached. The stimulators provided a square wave im-pulse of 6 msec duration, and was adjusted to produce acurrent at the right atrial wall of 2.5 to 4.0 ma. Thevoltage setting of the stimulator ranged between 50 and90 v and was set at approximately twice the thresholdlevel. All measurements were made on lead II of thestandard surface electrocardiogram.

The term "refractory period of the atrioventricularnodal conduction system" (AVRP), as used in this paperis, as discussed below, closely analogous to the effectiverefractory period (2) and refers to the longest time in-terval between two stimuli delivered to the atrium, bothof which evoke propagated atrial depolarizations, butthe second of which fails to result in a propagated ven-tricular depolarization. The technique for measuringAVRP was adapted from that described by Krayer,Mandoki, and Mendez for use in the isolated heart-lungpreparation (5). Unless specifically noted, all of the ob-servations were carried out by the "extra-stimulus"method, which consisted of driving the atrium electricallyat a basic regular rate just greater than the sinus rate,and delivering occasional single extra premature stimuliat specific time intervals following these basic drivingstimuli. The longest time interval between a drivingstimulus and a premature stimulus that did not evoke apropagated ventricular depolarization was taken as theAVRP. The technique is illustrated diagrammatically inFigure 1, lines A and B, where Si to S5 represent thebasic driving stimuli. In line A, the extra stimulus, de-livered between S3 and S4, initiates a P wave that arrivesat the AV nodal conduction system when it is no longerrefractory, and a QRS complex results. The time in-terval between the driving and the premature stimuli wasthen shortened in 10 msec steps until the premature im-pulse failed to evoke a QRS complex. In line B thepremature stimulus is delivered so early that the atrialdepolarization wave arrives at a time when the AV nodalconduction system is still refractory, and no QRS com-

2 American Electronics Laboratories, model 104A, Col-mar, Pa.

883

JOSEPH W. LINHART, EUGENEBRAUNWALD,ANDJOHN ROSS, JR.

51P R T S2 S3 S4 S5A

Extra StimulusS S S3 S S5

1AVRPt

S S S 5SC SiS2 ,3 7

tAVRPt

FIG. 1. SCHEMATICILLUSTRATION OF THE METHODEM-

PLOYED FOR MEASURINGTHE REFRACTORYPERIOD OF THE

ATRIOVENTRICULAR NODAL SYSTEM (AVRP). For de-tailed explanation see text.

plex is evoked. Figure 2A shows an electrocardiogramin which the premature stimulus, introduced between S2and S3, initiates a P wave and a QRScomplex (althoughthe latter is delayed, and as a consequence S3 is not con-

ducted to the ventricles). In contrast, in the tracingshown in Figure 2B, the premature stimulus (betweenSs and S4) is delivered 30 msec earlier, the atrial de-polarization wave reaches the AV conduction systemduring the AVRP, the impulse is not transmitted to theventricles, and no QRS complex occurs. Since the in-tervals were shortened by steps of 10 msec, alterationsin the AVRPof less than 10 msec could not be detectedby this technique.

After determination of the AVRPby the extra-stimulusmethod described above, the effects of one or more in-terventions on this measurement were studied. When-ever the effects of more than one intervention were de-termined in the same patient, a control measurement was

repeated between the interventions. The effects of in-duced tachycardia on the AVRPwere determined in ninepatients by first making the measurement at a rate justgreater than the sinus rate, and by repeating it 5 minutesafter the rate had been elevated by the electrical pace-maker. The effects of the following drugs infused in-travenously were studied: isoproterenol, 1.0 to 1.5 Ag per

minute (seven patients); methoxamine, 0.95 to 1.40 mg

per minute (two patients); phenylephrine, 60 to 240 ,.tgper minute (six patients) norepinephrine, 1.6 to 3.2 ,gper minute (three patients); and atropine, 0.5 mg to 1.0mg as a single injection (11 patients). In two patientsthe effects of phenylephrine on AVRPwere studied bothbefore and after atropine. In seven patients the effectson the AVRP of leg exercise, consisting of pedaling a

bicycle ergometer in the supine position at 40 rpm at an

external work load of approximately 500 ft-lbs per min-ute for 5 minutes, were determined.

In 15 patients the AVRP was also measured by a

second technique, termed the "increasing rate" method,described in detail previously (6), and diagrammaticallyillustrated in Figure 1C. The basic rate of stimulationwas gradually increased until an interval between stimuliwas reached which was so short that a stimulus resulted

in atrial depolarization but was not transmitted to theventricles.

A total of 33 patients ranging in age from 11 to 59years were studied in the postabsorptive state, 1 hourafter the administration of 100 mg sodium pentobarbital.None of the patients had atrioventricular or intraventricu-lar conduction abnormalities, the P-R intervals and QRSdurations in each patient being normal in the basal state.No patients had experienced congestive heart failure orhad marked limitation of cardiac reserve at the time ofthe study. None of the patients were receiving digitalis,quinidine, or procaine amide, and the serum electrolyteswere always within normal limits. Eleven of the pa-tients had functional heart murmurs, six had mitralstenosis, five had atrial septal defects, and three had mildaortic stenosis. In one patient each the dignosis wasventricular septal defect, mild aortic regurgitation, idio-pathic hypertrophic subaortic stenosis, right ventricularmyxoma, patent ductus arteriosus, cardiomyopathy, statuspostclosure of a ventricular septal defect, and status post-aortic valve replacement for aortic stenosis. In everyinstance the measurements of AVRP followed the diag-nostic cardiac catheterization.

Results

I. Control values. The control values of theAVRPin 20 patients studied by the extra-stimulusmethod averaged 350 ± 53 msec (SD), a valuewhich was significantly shorter (p < 0.01) thanthat obtained by the increasing rate method in 15patients, which averaged 413 + 52 msec.

II. Tachycardia (Figure 3A). In nine patientsthe AVRPwas first measured at a rate just abovethe spontaneous sinus rate, which ranged from 68to 102 and averaged 84 per minute; at this ratethe AVRPranged between 250 and 430 and aver-aged 344 msec. The atrial rate was then in-creased to between 109 and 131 (average = 120per minute), and the AVRP rose significantly(p < 0.02) to between 340 and 450 msec (aver-age = 399 msec). Thus, abbreviation of the R-Rinterval by an average of 215 msec (30% of con-trol) was associated with a prolongation of theAVRP by an average of 55 msec (16% ofcontrol).

III. Atropine (Figure 3B). In 11 patients theheart rate before atropine ranged between 68 and92 and averaged 77 per minute, while the AVRPranged between 280 and 430 and averaged 344msec. Atropine resulted in an elevation of heartrate to an average of 103 per minute. In contrastto the finding when heart rate was increased by

884

AV NODALREFRACTORYPERIOD IN MAN

electrical stimulation, ANRPdeclined significantly(p < 0.01), falling to between 160 and 330 msec(average = 246 msec'). Thus, an average fall ofthe R-R interval of 195 msec (25% of control)was associated with a decline of the AVRPaver-ag14-ing 98 msec (29%c of control).

IV. Iso protereniol (Figure 3C). In seven pa-tients the control heart rate averaged 82 per minute

and rose to an average level of 95 per minute dur-ing the isoproterenol infusion. AVRPranged be-tween 300 and 500 and averaged 405 msec duringthe control period, falling in each patient to anaverage value of 300 msec, which wvas significantlylower (p < 0.01) than that noted during the coin-trol period. Thus, an average decrease in theR-R interval of 90 msec (12% of control) xvas

EXTRAR T STIMULUSS.i + + So I S3 S4 S5 S6

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DURING DETERMINATION OF AVRP. S1 to S represent electrical stimuli. In tracing A (top)the extra stimulus, delivered between S2 and S,, was transmitted to the ventricles, but in trac-ing B (bottom) the extra stimulus, delivered between S3 and S4, was not transmitted.

885

JOSEPHW. LINHART, EUGENEBRAUNWALD,ANDJOHN ROSS, JR.

HEART RATE70 80 90 100 110 120 140 HEART RATE

60 70 80 90 100 110 120 140

AVRP(MW.

R-R INTERVAL(mFuc}

R-R INTERVAL (mseclHEART RATE

HEART. RATE

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RELATIONSHIP BETWEENTHE AVRPAND THE R-R INTERVAL.

associated with an abbreviation of the AVRP,which averaged 105 msec (26% of control).

V. Exercise (Figure 3D). In seven patientsthe heart rate at rest ranged between 60 and 95and averaged 72 per minute, while the AVRPranged between 320 and 520, averaging 390 msec.

Muscular exercise raised heart rate to a mean

value of 117 per minute, while AVRP fell sig-nificantly (p < 0.01) to an average value of 280msec. Thus, an average decline of the R-R inter-val of 320 msec (28%o of control) was associatedwith an abbreviation of the AVRP, which averaged110 msec (39%o of control).

VI. Phenylephrine and methoxamine (Figure

AVRPCmsecd

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AV NODALREFRACTORYPERIOD IN MAN

4A). The administration of phenylephrine andmethoxamine, in doses sufficient to elevate thesystolic pressure by an average of 56 mmHg andthe diastolic pressure by 28 mmHg, slowed heartrate, from an average value of 75 per minute dur-ing the control period to one of 56 per minute.This was associated with a significant prolonga-tion of the AVRPfrom an average of 326 to 578msec (p < 0.01). Thus, an average increase ofthe R-R interval of 274 msec (34%o of control)was associated with a lengthening of the AVRP,which averaged 252 msec (77%o of control).

VII. Phenylephrine and atropine (Figure 4B).In two patients the effects of phenylephrine werefirst studied, as described above, and after a sec-ond control measurement atropine was adminis-tered. After redetermination of the AVRPphenylephrine was reinfused to produce an iden-tical elevation of arterial pressure. In these twopatients the individual effects of phenylephrine andatropine on both the AVRPand the R-R intervalwere similar to those already described (Figure4A and Figure 3B). However, when phenyl-ephrine was reinfused after atropine, neither theAVRPnor the R-R interval was altered.

VIII. Norepinephrine (Figure 4C). The ad-ministration of norepinephrine to three patientsslowed heart rate from an average of 78 per minuteto 70 per minute while AVRP increased from anaverage value of 330 to 410 msec.

Discussion

Previous studies on the refractory period of theAV nodal conduction system have been carriedout in a variety of experimental animal prepara-tions. Krayer and collaborators showed that epi-nephrine shortens the functional refractory periodof the AV nodal system in the isolated canineheart-lung preparation (5). Subsequently Men-dez, Aceves, and Mendez found that pentobarbitaland cardiac glycosides prolong this period andthat at certain dose levels this action of the glyco-sides could be reduced by prior sympathetic de-nervation (7, 8).

Rosenblueth, Mendez, and their respective col-laborators indicate that the functional refractoryperiod of excitable tissue is the shortest attainableinterval between two induced responses when thesecond stimulus is delivered at 2 or more times the

threshold intensity (1, 3, 9). They emphasized,however, that this value is attended by an errorequal to any difference that might occur in thepropagation time from the point of stimulationto the point of recording between the first and sec-ond responses. In the present investigation onman it was observed that this error was incon-stant and frequently quite large. For example, inthe tracing reproduced in Figure 2A, the ven-tricular depolarization resulting from the inter-posed stimulus was delayed by 120 msec. Thispotential error results primarily from variationsin the conduction velocity in the AV conductionsystem, which can be altered by influences that alsomodify the duration of the AVRP. Accordingly,rather than determining the shortest period be-tween two induced responses, we measured thelongest interval between two stimuli that could beachieved when the second stimulus failed to evokea propagated ventricular depolarization. Thismeasurement conforms closely- to the "effectiverefractory period" defined by Hoffman andCranefield (2), although the strength of the in-terposed stimulus in our study was not maximalbut only twice the diastolic threshold level. Sincethe stimulus was applied to the atrium, ratherthan directly to the AV node, alterations of con-duction velocity within the atrium would modifythe duration of the AVRP. However, in thepresent investigation no detectable alterations inatrial conduction, as determined from the durationof the atrial depolarization wave, occurred.

In the interpretation of changes in the AVRPobserved in the present investigation the complexi-ties of AV conduction, which have recently beenreviewed (10, 11), must be considered. Thus,many findings are consistent with the hypothesisthat decremental conduction occurs in the AVconduction system (10), and recordings of trans-membrane action potentials have shown that con-duction is slowest across a narrow zone at theatrial margin of the AV node (12). In the iso-lated rabbit heart, Cranefield, Hoffman, and Paesde Carvalho have shown that the failure of AVtransmission caused by acetylcholine takes placein fibers at the atrial margin of the node (13),whereas lower portions of the node appear to beinvolved in the failure of transmission caused bytachycardia (10).

Thus, although determination of the AVRP

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does not simply provide a measurement of theperiod during which the AV node is totally inex-citable or unresponsive, the measurement doesprovide an assessment of the time interval follow-ing a stimulus during which the AV nodal con-duction system is incapable of transmitting an im-pulse that can initiate a propagated ventriculardepolarization. From the present investigation inman it is apparent that this period is not a staticone, but that many common interventions can pro-foundly modify its duration. Tachycardia, pro-duced by electrical stimulation of the atrium,tended to lengthen the AVRP slightly, a findingthat correlates with the longer duration of theAVRPwhen it is measured by the increasing ratethan when it is determined by the extra-stimulusmethod. It has previously been observed in nor-mal human subjects that when the rate of stimula-tion of the right atrium is increased the intervalbetween the stimulus and the QRSincreases (14).Although the results of the present study are op-posite to those described by Mendez, Gruhzit, andMoe in the anesthetized, open-chest, acutely dener-vated dog heart (3), they are consistent with theobservation of a reduced amplitude and rate ofrise of the transmembrane potential in the atrialpart of the AV node during rapid electrical stimu-lation of the atrium (10). Therefore the shorten-ing of the AVRPthat occurred when tachycardiawas induced by the administration of atropine andisoproterenol or by muscular exercise is even morestriking when it is considered that tachycardia perse tends to lengthen this interval.

Alterations in the activity of both the sympa-thetic and parasympathetic nervous systems affectboth the AV conduction system and the sinoatrialnode. However, the relationship between the R-Rinterval and the duration of the AVRPwas not alinear one, and indeed, the relative changes in theduration of the AVRP induced by atropine, iso-proterenol, phenylephrine, methoxamine, and nor-epinephrine were often greater than the simultane-ous changes that occurred in the duration of theR-R interval. The abbreviation of the AVRPassociated with the administration of atropine andof isoproterenol is interpreted, respectively, as theeffect of the withdrawal of parasympathetic influ-ences from, and of the activation of adrenergic re-ceptors in, the AV conduction system. Muscularexercise shortened the AVRPin a manner similar

to atropine or isoproterenol, and it is likely thatboth stimulation of sympathetic receptors and re-duction of parasympathetic inhibition were in-volved in the response. On the other hand, phenyl-ephrine and methoxamine, two sympathomimeticpressor drugs that have no direct cardiac effects(15), simultaneously prolonged this period andslowed the sinus rate.

The finding in two patients that phenylephrinedid not alter the AVRP after atropine supportsthe view that phenylephrine has no direct effect onthe AVconduction system, although since only twopatients were studied these results cannot be con-sidered conclusive. It is well known that theslowing of heart rate produced by these drugs isreflexly mediated, and it has been shown, bothin the dog and in man, that the efferent limb of thereflex to the sinoatrial node that is stimulated byelevating arterial pressure, is mediated only bythe parasympathetic system ( 16). The finding thatatropine completely prevented the prolongation ofthe AVRPinduced by phenylephrine (Figure 4B)indicates that as a consequence of baroreceptorstimulation, the AV conduction system, like thesinoatrial node, is inhibited only by parasympa-thetic stimulation, withdrawal of tonic sympa-thetic activity playing no detectable role. Norepi-nephrine, like isoproterenol, stimulates adrenergicreceptors in the heart, and it might therefore beexpected to abbreviate the AVRP. However, theprolongation of the AVRPthat occurred with nor-epinephrine was probably reflex in nature, conse-quent to its pressor action, and this effect prob-ably masked any direct action of the catechola-mine. Since only three patients received norepi-nephrine, however, these results must be consid-ered to be tentative.

The chief finding that emerges from this studyis that the AV conduction system in conscious hu-man subjects is affected by many influences, bothdirect and reflex. In general, the effects of anygiven stimulus on the rhythmicity of the sinoatrialnode (as reflected in the R-R interval) are di-rectionally similar to those on the AV system (asreflected in the AVRP), although in many in-stances the relative effect on the latter is greaterthan on the former. Under most clinical cir-cumstances, effects on the sinoatrial node, sincethey alter ventricular rate, are more obvious thaneffects on the AV system. Nevertheless, the

889

JOSEPH W. LINHART, EUGENEBRAUNWALD,ANDJOHN ROSS, JR.

AVRP is of considerable clinical importance,since it limits the ventricular rate in patients witha variety of supraventricular tachycardias, includ-ing atrial fibrillation. Furthermore, the delay inconduction imposed by the AV system regulatesthe time interval between the contractions of theatria and ventricles and thereby plays a funda-mental role in regulating the atrial contributionto ventricular filling (17).

SummaryA technique was devised for measurement of

the refractory period of the atrioventricular con-duction system (AVRP) in man. A bipolar elec-trode catheter was placed against the right atrialwall and stimulated the right atrium at a constantrate just above the sinus rate. Extra impulseswere interposed between the regular stimuli; thetime intervals between these extra impulses andthe preceding stimuli were then shortened pro-gressively. The time interval at which AV con-duction just failed was taken as the AVRP. In20 unanesthetized patients, studied in the basalstate, the AVRPaveraged 350 msec. In nine pa-tients, atrial tachycardia, induced by rapid electri-cal stimulation of the right atrium, prolonged theAVRP. In seven patients muscular exerciseshortened the AVRPby an average of 10 msec.Isoproterenol (seven patients) and atropine (11patients) resulted in reductions of the AVRPsimilar to those observed during exercise. Ele-vations of arterial pressure with methoxamine orphenylephrine in eight patients prolonged AVRPby an average of 252 msec. Since this prolonga-tion could be prevented by atropine, it was con-sidered to result from reflex vagal stimulation.Thus, in any given patient the AVRP is affectedprofoundly by many influences, including sympa-thetic and parasympathetic stimuli.

References1. Rosenblueth, A., J. Alanis, and J. Mandoki. The

functional refractory period of axons. J. cell. comp.Physiol. 1949, 33, 405.

2. Hoffman, B. F., and P. F. Cranefield. Electrophysi-ology of the Heart. New York, McGraw-Hill,1960, p. 253.

3. Mendez, C., C. C. Gruhzit, and G. K. Moe. In-fluence of cycle length upon refractory period of

auricles, ventricles, and A-V node in the dog.Amer. J. Physiol. 1956, 184, 287.

4. Katz, L. N., and A. Pick. Clinical Electrocardiog-raphy. I. The Arrhythmias. Philadelphia, Lea &Febiger, 1956, p. 30.

5. Krayer, O., J. J. Mandoki, and C. Mendez. Studieson veratrum alkaloids XVI. The action of epineph-rine and of veratramine on the functional refrac-tory period of the auriculo-ventricular transmis-sion in the heart-lung preparation of the dog. J.Pharmacol. exp. Ther. 1951, 103, 412.

6. Morrow, D. H., T. E. Gaffney, and E. Braunwald.Studies on digitalis VIII: Effects of autonomicinnervation and of myocardial catecholamine storesupon the cardiac action of ouabain. J. Pharmacol.exp. Ther. 1963, 140, 236.

7. Mendez, R., and C. Mendez. The action of cardiacglycosides on the refractory period of heart tissues.J. Pharmacol. exp. Ther. 1953, 107, 24.

8. Mendez, C., J. Aceves, and R. Mendez. The anti-adrenergic action of digitalis on the refractory pe-riod of the A-V transmission system. J. Pharma-col. exp. Ther. 1961, 131, 199.

9. Rosenblueth, A. Functional refractory period ofcardiac tissues. Amer. J. Physiol. 1958, 194, 171.

10. Hoffman, B. F., and P. F. Cranefield. Electrophysi-ology of the Heart. New York, McGraw-Hill,1960, pp. 132-175.

11. Scher, A. M. Excitation of the heart in Handbookof Physiology, Section 2, Circulation, W. F. Hamil-ton and P. Dow, Eds. Washington, D. C., Ameri-can Physiological Society, 1962, pp. 294-298.

12. Hoffman, B. F., A. Paes de Carvalho, W. C. Mello,and P. F. Cranefield. Electrical activity of singlefibers of the atrioventricular node. Circulat. Res.1959, 7, 11.

13. Cranefield, P. F., B. F. Hoffman, and A. Paes deCarvalho. Effects of acetylcholine on single fibersof the atrioventricular node. Circulat. Res. 1959,7, 19.

14. Warner, H. F., and D. H. Lewis. Effect of increasedpulse rate on circulatory dynamics in normal restingman. Fed. Proc. 1961, 20, 131.

15. Goldberg, L. I., R. D. Bloodwell, E. Braunwald, andA. G. Morrow. The direct effects of norepineph-rine, epinephrine, and methoxamine on myocardialcontractile force in man. Circulation 1960, 22,1125.

16. Glick, G., and E. Braunwald. The relative roles ofthe sympathetic and parasympathetic nervous sys-tems in the reflex control of heart rate. Circulat.Res. 1965, 16, 363.

17. Braunwald, E., and C. J. Frahm. Studies on Star-ling's law of the heart. IV: Observations on thehemodynamic functions of the left atrium in man.Circulation 1961. 24. 633.

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