Digitalis in the Sick Sinus SyndromeThe Effects of Digitalis on Sinoatrial Automaticity

and Atrioventricular Conduction

By TOBY R. ENGEL, M.D. AND STEPHEN F. SCHAAL, M.D.

SUMMARYThe effect of digitalis in patients with sinoatrial node dysfunction was studied. Atrial pacing

studies were performed while His bundle -electrograms were recorded in fourteen patients withsinus bradyeardia, syncope, or related symptoms. Measurements were repeated after 0.01 mg/kgouabain, followed in some by 1 mg atropine. Ouabain produced a significant shortening of sino-atrial recovery time, but no significant change in heart rate. Atropine normalized sinoatrial re-

covery times in most patients. This study demonstrates that digitalis causes an increase in auto-maticity in the sick sinus syndrome as reflected by a shortened sinoatrial recovery time. Theefficacy of contemplated therapeutic agents in sick sinus syndrome can be evaluated by rapidatrial pacing. When clinically indicated, digitalis may be used for congestive heart failure or

tachyarrhythmias in the sick sinus syndrome in the absence of significant A-V conduction disease.

Additional Indexing Words:Atrial pacing Atropine Br;Overdrive suppression Sinoatrial block

T HE SICK SINUS SYNDROME (SSS)' is aheterogeneous grouping of sinoatrial node

dysfunction including sinus bradyeardia, sinus ar-rest, sinoatrial exit block and the bradyeardia-tachy-cardia syndrome.2' 3 Numerous authors have warnedagainst the use of digitalis in the SSS.4-11 Digitalishas been reported to cause or accentuate bradycar-dia,12, 13 which, in SSS, might increase the tendencyto syncope. However, digitalis plays a potentiallyimportant role in management of the SSS, especial-ly in those patients prone to the bradycardia-tachycardia syndrome. Symptoms may be producedduring a supraventricular tachyarrhythmia or dur-ing an asystolic period upon termination of thetachycardia. Digitalis may be efficacious in themanagement of these tachyarrhythmias. Digitalis is

From the Department of Medicine, Ohio State UniversityCollege of Medicine, Columbus, Ohio.

Supported in part by National Heart and Lung Institutegrants HE-5786, HL-5053, HE-5546, HL-5968 and aProgram Project Award #1 P01 HE-11504, and the CentralOhio Chapter of the American Heart Association.

This investigation was performed while Dr. Engel was aPostdoctoral Trainee for the National Heart and LungInstitute.

Address for reprints: Dr. Stephen F. Schaal, Division ofCardiology, Ohio State University College of Medicine,Columbus, Ohio 43210.

Received May 10, 1973; revision accepted for publicationJuly 19, 1973.

Circulation, Volume XLVIII, December 1973

adyeardia-tachyeardia syndrome OuabainSinoatrial recovery time Sinus bradyeardia

also useful in the management of coexisting heartfailure in SSS.5 14 The purpose of this study wasto assess the effects of digitalis on heart rate (HR),sinoatrial node automaticity, and atrioventricular(A-V) conduction in SSS.

MethodsFourteen patients with sinus bradycardia, syncope or

related symptoms such as episodic lightheadednesswere studied without premedication in the post-absorptive state. They represented patients thought tomanifest SSS unrelated to drug therapy in a series of 66patients evaluated for syncope or related symptoms.Thirty of the 66 patients had a heart rate <60beats/ min. No patient received cardioactive medica-tions during the week prior to study. Informed writtenconsent was obtained from all patients. Only onepatient (#10) had an A-V conduction disturbance atrest-a P-R interval prolongation to 0.22 seconds. Atrialpacing was performed from a catheter advanced via theright basilic vein and positioned at the lateral wall ofthe high right atrium. Rectangular stimuli 2 msec induration at 1Y2 diastolic threshold were delivered from aMedtronics (5837) R-wave coupled pulse generator.Sinoatrial recovery times (SART) were recorded afterabrupt termination of rapid atrial pacing at rates from100-160 beats/min.15 SART was measured from thelast paced P wave to the next spontaneous P wave orjunctional beat. SART corrected for HR (CRT) werecalculated by subtracting the unpaced cycle length.'6His bundle electrograms were recorded in all patientsfrom a catheter inserted percutaneously into the femoralvein and placed across the tricuspid valve.'7 Threestandard leads were simultaneously recorded, along

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ENGEL, SCHAAL

with atrial electrograms in most instances. Cycle lengthand intervals measured from the His bundle electro-gram were averaged over at least six successive beats.

After basal recordings each patient received ouabain,0.01 mg/kg intravenously (not to exceed 0.7 mg) in acorncentration of 0.25 mg/ml over less than 30 sec.Recordings were repeated every 5 min thereafter for atotal of 30 min. Twelve patients received 1 mg atropineintravenously 40 min after ouabain and recordingswere repeated after 4-5 min. Results were expressed asaverages, -+ the standard error of the mean. The meandifference for paired observations was computed with astandard error of the difference and statistical compar-isons were made with a t-test for paired observations.

ResultsThe clinical and laboratory findings in the 14

patients studied are listed in table 1. Ten patientshad a HR < 60 beats/min at rest. All had a maximalSART > 1250 msecl8 19 while 10 patients had amaximal CRT> 400 msec. In our laboratory themaximal SART in 32 patients without symptoms ofSSS or evidence of conduction disease and on nomedication was 958 ± SD 149 msec. The maximalCRT in these patients was 180 + SD 107 msec.The effects of ouabain and atropine on HR,

SART and CRT are listed in table 2. The resultslisted are the maximal changes which routinelyoccurred 25-30 min post-ouabain. Minimal changeswere noted during the first 10 min after ouabain.Ouabain produced no. significant change in HR (fig.1). The mean change in HR was -1.0 beats/min,P > 0.2. Atropine accelerated the HR above 60beats/min in 7 of 9 patients whose HR followingouabain administration was < 60 beats/min. Themean increase in HR after atropine was +17.7beats/min, P < 0.001, an increase of 32%.

In general, ouabain shortened the SART (mean-426 msec, P <0.005) and the CRT (mean -440msec, P < 0.005). The SART was reduced to 1250msec or less in 4 patients. A further reduction inSART (mean -738 msec, P<0.01) and in CRT(mean -491 msec, P < 0.05) was noted afteratropine. Atropine caused a reduction of the SARTto < 1250 msec in 7 of 12 patients (58%) andreduction of the CRT to < 400 msec in 4 of 8patients (50%) whose CRT following ouabainadministration was > 400 msec. Figures 2 and 3illustrate the changes in SART induced by ouabainand atropine.A shortened SART after ouabain was associated

with recovery from a new focus in two patients.Upon termination of atrial pacing, one patientrecovered with a new atrial focus and one patientintermittently recovered with an atrioventricular

(A-V) junctional focus. A third patient intermit-tently recovered with an A-V junctional focus bothbefore and after ouabain.Minimal changes in A-V conduction were noted

following ouabain administration (fig. 4). Twopatients showed a 20 beat/min reduction and sixpatients a 10 beat/min reduction in the pacing raterequired to produce incomplete A-V block withdropped beats, Type I (Wenckebach phenome-non). In five patients there was no change in theatrial pacing rate requisite to produce the Wencke-bach phenomenon. Ouabain produced no clinicallysignificant unpaced A-V conduction abnormalitiessuch as the Wenckebach phenomenon or 2:1 A-Vconduction. A prolongation of the unpaced A-Hinterval was observed in seven patients (meanchange in A-H interval for all patients was + 16.9msec., P< 0.1).

Intraatrial conduction, as measured by the P-Ainterval, was unchanged after ouabain. The H-Vinterval was not changed. The effects of ouabain onintraatrial and A-V conduction are detailed in table3. No dysrhythmias were produced by this dose ofouabain. One patient developed pacing inducedangina after ouabain administration.

EFFECTS OF OUABAIN AND ATROPINEON HEART RATE

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The mean difference between control heart rates anld thoseobtained following ouabain adminlistration to 14 patients isshown, as wsell as the mean difference between postouabainheart rates angd the heart rates after subsequent administra-tion of atropine to 12 patients. SED = standard error of thedifference.

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DIGITALIS IN THE SICK SINUS SYNDROME 1203

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ENGEL, SCHAAL

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EFFECTS OF OUABAIN AND ATROPINEON SART

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Changes are expressed as the mean differences between con-trol SART and those obtained following ouabain administra-tion to 14 patients and those obtained after subsequentadministration of atropine to 12 patients. SART = sino-atrial recovery time; SED = standard error of the difference.

Three patients received digitalis subsequent tostudy without pacemaker or other pharmacologicintervention. Reduction in the resting heart rate wasnot produced by digitalis and dysrhythmias werenot noted on long-term in-hospital monitoring.Patient 2 (table 1) experienced a reduction in thefrequency of dizzy spells. Patient 10 noted amarked reduction in angina and effort dyspneaand freedom from syncope. Patient 5 hadbradyeardia-tachyeardia syndrome and was the onlypatient studied with symptoms related to tachycar-dia; she noted a reduction in the frequency andduration of symptoms when taking digitalis.

DiscussionThe SSS1 is often associated with sinus bradycar-

dia and most prominently manifest by symptoms ofsyncope or related symptoms of cerebral insufficien-cy thought to be secondary to dysrhythmias.20Symptoms may be associated with the followingrhythm disturbances: a) sinus bradyeardia, b) per-iods of asystole secondary to spontaneous sinusarrest or S-A exit block, c) paroxysmal atrialtachyarrhythmias, or d) periods of sinus arrest

EFFECTS OF OUABAINAND ATROPINE ON SART

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subsequent to the termination of atrial tachyar-rhythmias. Congestive heart failure, and coronary,cerebral and renal insufficiency are common in theage group suffering from the SSS5 14 and may beaccentuated by bradycardia, tachyarrhythmias, orasystolic periods. Digitalis would thus appear to bean important therapeutic agent in SSS because of itsusefulness in a) control of the ventricular responsein atrial tachyarrhythmias, b) prophylaxis againstatrial tachyarrhythmias and the subsequent periodsof sinus arrest that may occur with termination ofthe tachycardia, c) therapy of the frequentlyassociated left ventricular dysfunction.The results of this study indicate that ouabain

(0.01 mg/kg) produces an abbreviation of therecovery time after atrial overdrive suppression. Weand others have used the response to overdrivesuppression as a measure of sinoatrial nodeautomaticity.15' 16, 21 The relation of overdrive sup-pression to heart rate as reflections of automaticity

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DIGITALIS IN THE SICK SINUS SYNDROME

Table 2

The Effects of Ouabain and Atropine on Sinoatrial Function

Basal Ouabain AtropinePatient HR SART CRT HR SART CRT IIR SART CRTno. (beats/min) (msec) (msec) (beats/min) (msec) (msec) (beats/min) (msec) (ms>ec)

1 .52 2120 960 55 2200 1109 65 820 - 1032 48 1620 370 44 1470 1053 5)9 2220 1203 54 1600 489 54 1400 2894 77 1300 721 77 1200 4215 70 2250 1393 67 920 24 81 900 1596 84 1310 596 75 1250 450 93 1080 4357 49 1750 525 53 1300 170 63 700 -2.508 60 4200 3200 61 3760 2777 77 1900 11219 52 1420 260 44 1350 -14 75* ;570 -230

10 53 1530 400 53 1550 430 80 830 13311 48 2300 1050 48 2000 750 68 1600 71812 56 5000 3930 57 4000 2940 72 1660 83013 55 2400 1310 56 1l50O 440 52 12.50 10014 44 1300 - 63 48 860 -390 97* 730 110

Mean 57.6 2209 1133 56.6 1783 693SEM 3.1 1293 300 -2.8 -256 263Mean (for those receiving atropine) 55.9 1858 765 73.6 1120 276SEM -2.5 -294 -303 4.1 -126 -123

Abbreviations: HR = heart rate; SART = sinoatrial recovery time; CRT = corrected recovery time (SART minus basic cyclelength); SEM = standard error of the mean.

*Junctional rhythm.

is unclear. However, overdrive suppression proba-bly helps to define a critical feature of SSS; i.e., theinability of sinus pacemakers to depolarize aftersuppression by spontaneous tachyarrhythmias. Thesignificant abbreviation of SART and CRT suggests

that digitalis will not accentuate the likelihood ofposttachyeardia asystole in SSS. Digitalis does notcause a significant diminution of heart rate in SSSand therefore symptoms related to bradycardia per

se will not be accentuated.

Table 3

The Effects of Ouabain on A-V Conduction

Basal OuabainPatient P-A A-H H-V P-A A-H H-Vno. (msec) (msec) (msec) Wenckebach* (msec) (msec) (msec) Wenckebach*

1 95 40 140 1302 70 60 140 70 60 1203 110 30 > 160 120 30 1604 80 50 > 160 70 50 > 1605 140 100 40 1606 40 1315 45 160 40 140 45 angina7 30 130 50 110 30 240 50 1008 40 125 4.5 120 45 150 45 1109 40 70 50 >160 50 70 50 16010 30 l5O 40 80 30 150 40 8011 25 140 40 110 20 170 40 9012 40 70 45 >160 40 70 45 >16013 40 100 50 160 45 110 45 16014 40 90 45 >160 40 125 45 160

Meant 36.1 105.0 45.4 37.7 121.9 45.0SEM =2.0 =7.9 =2.0 =3.1 13.8 2.0

Abbreviations: SEM = standard error of the mean.*Lowest rate of atrial pacing at which intermittent A-V block with dropped hearts, Type I (Wenckebach

phenomenon) was observed.tMean and SEM for patients in whom both basal and ouiabain measurements available.

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EFFECTS OF OUABAIN ON A -H CONDUCTION

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The effects of ouabain on A-V conduction as measured bythe change in A-H interval and the change in the atrialpacing rate required to produce incomplete A-V block withdropped beats, Type I (Wenckebach phenomenon). SED =standard error of the difference.

Although digitalis has a negative chronotropiceffect,22 this effect can be eliminated by combinedvagal and sympathetic blockade.23 It might beexpected that the vagomimetic action and thereduction of sympathetic accelerator influences bydigitalis would accentuate the bradycardia andprolonged SART of SSS. However, autonomicdysfunction may be an important determinant ofthe prolonged recovery time, bradyeardia, andperhaps symptoms of SSS.24 Most patients with SSSmay have a high degree of vagal influence and/ordiminished sympathetic tone. The response of theHR and SART to atropine in this group of patients,in a large series of patients studied at our

institution25 and in other reports'5' 16, 18 suggeststhat most patients with SSS have a marked response

to vagolytic agents. The lack of vagomimetic andsympatholytic effect of digitalis in SSS may reflect a

preexistent state of abnormal autonomic tone. Thisis in direct contradistinction to the effects ofdigitalis generally seen in congestive heart failure,in which most patients have decreased parasympa-

thetic and increased sympathetic tone.26Recent observations of hypertension induced by

ouabain27 suggest that sympathetic influences mightbe important in the shortening of SART after

ouabain. This would seem unlikely because thehypertension has been shown to be due to a directsmooth muscle effect producing systemic arteriolarconstriction, and shortening of SART occurredmaximally at the 25-30 minute interval afterouabain.An alternate explanation for abbreviation of

SARTs after ouabain is prolongation of conductionof the pacing stimulus into the sinus node; i.e.,block at the sinoatrial junction. Atrial pacing in thepresence of a ouabain induced prolongation ofsinoatrial conduction might lead to sinoatrial nodeentrance block and a less frequent discharge of thesinus node.28 This might result in less overdrivesuppression and shorter SARTs after ouabain.Preliminary data from our laboratory using theatrial extra stimulus method during spontaneousrhythm suggests that SSS patients with normal A-Vnode conduction do not have abnormalities ofsinoatrial conduction. However, even if prolongedatrial to sinus conduction were the explanation forshortening of SARTs after ouabain, this does notdeter from the usefulness of the SART as a reflec-tion of the response to spontaneous tachyarrhyth-mias in SSS.An altered hemodynamic response to rapid atrial

pacing or a change in the temporal relationshipbetween atrial and ventricular contraction afterouabain administration might relate to the abbre-viation of SART seen. The role of possible hemody-namic alterations will require further investigation.Many patients with SSS also demonstrate defec-

tive A-V conduction.21 24,29 Patients with incom-plete A-V block with dropped beats noted onresting electrocardiograms were not included in thisstudy. However, slight abnormalities of A-V con-duction could be elicited by atrial pacing in one-third of the patients studied. Digitalis would appearto be contraindicated in SSS in the presence of sig-nificant A-V conduction disease as manifested byP-R interval prolongation or dropped beats on aresting electrocardiogram. However, although oua-bain depressed A-V conduction in all but one of ourpatients, none developed Wenckebach phenomenonduring spontaneous rhythm. This finding is not un-expected if one postulates both increased parasym-pathetic and decreased sympathetic influence inSSS. The effect of digitalis on A-V conduction isabolished by chronic total cardiac denervation.30Thus the preexistent state of autonomic tone couldonce again explain the blunted vagomimetic andsympatholytic response of A-V conduction to digi-talis in these patients.

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DIGITALIS IN THE SICK SINUS SYNDROME

The clinical observations by Rubinstein et al.5 inthe bradyeardia-tachyeardia syndrome are consis-tent with the present findings. Digitalis was givento 17 patients with bradyeardia-tachyeardia syn-drome and was of benefit to ten by decreasing thefrequency of tachyarrhythmias or control of theventricular response. In an effort to abolish thebradyeardia, digitalis was withdrawn from 14patients with SSS, without effect. These observa-tions are consistent with our findings that digitaliscauses an abbreviation of SART and CRT in SSSwithout a significant slowing of HR. In mostinstances a need for permanent transvenous pace-maker therapy will not be eliminated by digitalistherapy. However, digitalis may be used with safetyin the SSS or the bradycardia-tachycardia syndromein the absence of clinically significant A-V conduc-tion disease.

AcknowledgmentThe authors wish to thank Mrs. Marlene Griffen and Miss

Margaret Ladd Douglas for their invaluable technicalassistance and Mrs. Margaret Chambers for her aid inpreparation of the manuscript.

References1. FERRER MI: The sick sinus syndrome in atrial disease.

JAMA 206: 645, 19682. SHORT DS: The syndrome of alternating bradyeardia

and tachycardia. Br Heart J 16: 208, 19543. SCHULMAN CL, RUBENSTEIN JJ, YURCHAK PM,

DESANCTIS RW: The "Sick Sinus" Syndrome:Clinical spectrum. (abstr) Circulation 42 (suppl III):III-42, 1970

4. KAPLAN BM, LANGENDORF R, LEv M, PICK A: The"Sick Sinus Syndrome": Mechanisms, pathology andtreatment. (abstr) Am J Cardiol 26: 641, 1970

5. RUBENSTEIN JJ, SCHULMAN CL, YURCHAK PM,DESANCTrIs RW: Clinical spectrum of the Sick SinusSyndrome. Circulation 46: 5, 1972

6. EASLEY RM JR, GOLDSTEIN S: Sino-atrial syncope. AmJ Med 50: 166, 1971

7. TABATZNIK B, MOWER MM, SAMSON EB, PREMPREE A:Syncope in the "Sluggish Sinus Node Syndrome."(abstr) Circulation 40 (suppl III): III-200, 1969

8. MCNALLY EM, BENCHIMOL A: Medical and physiolog-ic considerations in the use of artificial cardiacpacing. Am Heart J 75: 380, 1968

9. RASMUSSEN K: Chronic sinoatrial heart block. AmHeart J 81: 38, 1971

10. FRUEHAN CT, OBEID AI, SMULYAN H, EIcH RH: SickSinus Syndrome: One year's experience. (abstr)Circulation 42: (suppl III): III-154, 1970

11. WAN SH, LEE GS, TOH CCS: The Sick Sinus Syndrome.Br Heart J 34: 942, 1972

12. DUBNOW MH, BURCHELL HB: A comparison of digitalisintoxication in two separate periods. Ann Intern Med62: 956, 1965

13. MARRIoTT HJL, MYERBURG RJ: Recognition and treat-ment of cardiac arrhythmias and conduction distur-

Circulation, Volume XLVlII, December 1973

bances. Sinus bradyeardia. In The Heart, editedby HURST JW, LOGUE RB. New York, McGraw-Hill,1966, p 494

14. ERAUT D, SHAW DB: Sinus bradyeardia. Br Heart J33: 742, 1971

15. MANDEL W, HAYAKAWA H, DANZIG R, MARCUS HS:Evaluation of sinoatrial node function in man byoverdrive suppression. Circulation 44: 59, 1971

16. NARULA OS, SAMET P, JAVIER RP: Significance of thesinus-node recovery time. Circulation 45: 140,1972

17. SCHERLAG BJ, LAU SH, HELFANT RH, BERKOWITZ WD,STEIN E, DAMATO AN: Catheter technique forrecording His bundle activity in man. Circulation39: 13, 1969

18. MANDEL WJ, HAYAKAWA H, ALLEN HN, DANZIG R,KERMAIER AI: Assessment of sinus node function inpatients with the sick sinus syndrome. Circulation46: 761, 1972

19. RIos JC, BASHOUR T, CHENG TO, MOTOMIYA T: Atrialpacing in sick sinus node syndrome. (abstr)Circulation 46 (suppl II): II-211, 1972

20. WALTER PF, REm SD JR, WENGER NK: Transientcerebral ischemia due to arrhythmia. Ann Intern Med72: 471, 1970

21. ROSEN KM, LoEB HS, SINNO MZ, RAHIMTOOLA SH,GUNNAR RM: Cardiac conduction in patients withsymptomatic sinus node disease. Circulation 43: 836,1971

22. SHERLAG BJ ABELLEIRA JL, NARULA OS, SAMET P:The differential effects of ouabain on sinus, A-Vnodal, His bundle and idioventricular rhythms. AmHeart J 81: 227, 1971

23. TEN EIcK RE, HOFFMAN BF: Chronotropic effect ofcardiac glycosides in cats, dogs, and rabbits. Circ Res25: 365, 1969

24. ENGEL TR, BOUDOULAs H, SCHAAL SF: The relationshipof sinoatrial dysfunction to atrioventricular conduc-tion. (abstr) Clin Res 21: 417, 1973

25. BouDouLAs H, ENGEL TR, SCHAAL SF: The effect ofpharmacologic agents and atrial pacing (AP) onsinoatrial (SA) function and atrioventricular (AV)conduction. (abstr) Circulation 46 (suppl II): II-39,1972

26. ECKBERG DL, DRABINSKY M, BRAUNWALD E: Defectivecardiac parasympathetic control in patients with heartdisease. N Engl J Med 285: 877, 1971

27. KUMAR R, YANKOPOULOS N, ABELMANN W: Ouabaininduced hypertension in a patient with decompensa-ted hypertensive heart disease. Dis Chest 63: 105,1973

28. STRAUSS HC, SAROFF AL, BIGGER JT JR, GIARDINAEGV: Premature atrial stimuation as a key to theunderstanding of sinoatrial conduction in man.Circulation 47: 86, 1973

29. NARULA OS: Atrioventricular conduction defects inpatients with sinus bradyeardia. Circulation 44:1096, 1971

30. SCHALL SF, SUGIMOTO T, WALLACE AG, SEALY WC:Effects of digitalis on the functional refractory periodof the AV node: Studies in awake dogs with andwithout cardiac denervation. Cardiovasc Res 4: 356,1968

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TOBY R. ENGEL and STEPHEN F. SCHAALAtrioventricular Conduction

Digitalis in the Sick Sinus Syndrome: The Effects of Digitalis on Sinoatrial Automaticity and

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

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