J. ELECTROCARDIOLOGY 12 (2), 1979, 211-216

Review

Electrophysiologic Testing for Patients with Sinus Node Dysfunction BY MELVIN M. SCHEINMAN, M.D., F . A . C . C . , HAROLD C. STRAUSS, M.D. AND JOSEPH A. ABBOTT, M.D., F . A . C . C . *

SUMMARY Sinus node dysfunction is characterized by various electrocardiographic abnormalities that may be associated with symptoms. These abnormalities include marked sinus bradycardia, sinus pauses (or arrest), sinoatrial exit block, or inability of the heart to resume sinus r h y t h m after direct current cardioversion in patients with atrial fibrillation. 1 Some patients may present with alternating periods of bradycardia and tachycardia. 2 Transient neurologic symptoms such as syncope or dizziness are related to transient cerebral hypoperfusion owing to either brady- or tachyarrhythmias. In clinical practice, it is often difficult to discern w h e t h e r or not symptoms are, in fact, related to sinus node dysfunction. F o r example, chronic sinus bradycardia may be physiologic in older people a and may be completely unrelated to presenting neurologic symptoms. Although continuous a m b u l a t o r y electrocardiographic monitoring is an invaluable diagnostic tool, the limitations o f 24-hour continuous electrocardiographic recordings in indicating the cause of symptoms in patients with suspected cardiac rhythm disorders is well appreciated. 4 In recent years, efforts have also been directed toward establishing objective measures of sinus node function. These measures include noninvasive studies such as exercise stress testing 5,6 and pharmacologic challenge with atropine or isoproterenoW s or invasive electrophysiologic testing. The purpose of this review is to describe the various electrophysiologic testing procedures and their utility and limitations and to attempt to integrate the results of these studies into the total clinical profile. Atrial Overdrive P a c i n g . A u t o m a t i c cells have the property of spontaneous self-discharge because of slow diastolic depolarization. The s i n u s node is t h e d o m i n a n t c a r d i a c pacemaker because its spontaneous discharge rate is normally more rapid than that of other atrial, junctional, or Purkinje pacemakers. Automatic sinus node cells are suppressed by overdrive atrial pacing. In animal preparations the degree of suppression correlates,

within limits, directly with the paced atrial r a t e 2 These findings raised the expectation t h a t the degree of o v e r d r i v e s u p p r e s s i o n would provide not only a m e a n s of distinguishing normal from abnormal sinus node automaticity b u t also a measure of the extent of disturbance of automaticity in patients with sinus node dysfunction. Mandel et al. l~ and subsequently Narula et al. 11 described use of this technique to test sinus node automaticity in man. A multipolar electrode catheter is introduced via a peripheral vein and positioned at the junction between the superior vena cava and the right atrium. This position places the stimulating catheter in close proximity to the sinus node in an attempt to avoid problems of intra-atrial conduction delay that might result in false lengthening of measurements of t h e sinus node r e c o v e r y t i m e (SNRT) or sinoatrial conduction time (SACT). One electrode pair is used for atrial stimulation while another pair is used for recording the high atrial electrogram. Care should be taken to record a true high atrial electrogram with minimal contamination by ventricular depolarization. The intracardiac electrogram is recorded simultaneously with one or more surface electrocardiographic leads. Because p a t i e n t s w i t h sinus node dysfunction fre-

From the Medical Service, San Francisco General Hospital Medical Center; the Department of Medicine, University of California, San Francisco, California; and the Department of Medicine, Duke University Medical Center, Durham, North Carolina. *Cardiology Unit, Veterans Administration Hospital, 2615 E. Clinton Avenue, Fresno, California 93703. Supported in part by the U.S. Public Health Service Grants HL19216, 15190, 07101, and HL20238; and RR30 from the General Research Center's Program of the Division of Research Sources, National Institutes of Health; and by a Research Career Development Award, 1K04HL-00268 to Dr. Strauss. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked 'r in accordance with 18 U.S.C. w1734 solely to indicate this fact. Reprint requests to: Melvin M. Scheinman, M.D., Bldg. 40, Room 4401, San Francisco General Hospital Medical Center, 1001 Potrero Avenue, San Francisco, California 94110.

211

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SCHEINMAN ET AL

quently show evidence of atrioventricular conduction disturbances, it is also desirable to record the His bundle electrogram from a separate electrode catheter that is positioned across the tricuspid valve. In our laboratories, the right atrium is paced using a rectangular pulse of 1-2 msec at 11/2-21/2 times the atrial diastolic threshold for 60 sec. Pacing is abruptly terminated and the interval from the last paced atrial depolarization to the first spontaneous sinus discharge is recorded. The sinus node depolarization is diagnosed on the basis of the contour of the surface P wave and the relationship between the high and low right atrial septum electrogram as recorded from the His bundle electrogram. Recordings should be obtained at rapid paper speed (100-200 mm/sec) using recorders with an accurate paper drive mechanism. Atrial pacing is commenced at a paced cycle length just below the spontaneous cycle length (SCL); then, pacing runs are carried out at increasingly shorter cycle lengths with 45-60 sec rest intervals between runs. The shortest paced cycle length used in our laboratory is 350 msec (or 170 beats/min). Marked prolongation of the SNRT is characteristic of sinus node dysfunction. In addition to recording the first postpacing cycle (SNRT), one should also measure additional postpacing cycle lengths. Previous studies from our laboratories 12 have showed that patients with sinus node dysfunction may have a normal SNRT but have abnormalities in subsequent postpacing cycles. These abnormalities include postpacing cycles which are prolonged and may be multiples of the SCL. The upper limits of normal for postpacing cycles 1-10 have been published. 12 Abnormalities in postpacing cycles 2-10 are known as secondary pauses. The SNRT must be interpreted in relationship to the SCL, because SNRT will, for example, normally be longer in those with slow heart rates. In some laboratories, the SNRT is corrected for the SCL by subtraction (upper limits of normal SNRT-SCL is 45013 or 52511 msec), whereas in others the SNRT is normalized by dividing SNRT by SCL (upper limits of normal for SNRT/SCL = 1.61-1.83 x SCL). 12 In some subjects sinus node suppression may allow for escape of a junctional pacemaker. In this situation care must be used in differentiating the first sinus discharge from retrograde atrial activation by the junctional pacemaker. Sinus node discharge is inferred from the morphology of the surface P waves as well as the high-to-low relationship between high and low right atrial recordings. A pure high right atrial signal is important because it allows for distinction of atrial from ventricular depolarization.

Fig. i summarizes data from 56 consecutive patients with suspected sinus node dysfunction who underwent overdrive pacing studies. Several important observations can be made from these data. First, less than half showed abnormalities in either the first (SNRT) or subsequent (2-10) postpacing cycles. Second, for those showing abnormal responses, abnormalities in postpacing cycles 1-10 (secondary pauses) were more common t h a n abnormalities in SNRT alone. Third, no specific atrial overdrive rate was particularly prone to elicit abnormal responses. These data emphasize the need for multiple pacing runs scanning a relatively broad spectrum of overdrive rates. Limitations of overdrive pacing in assessing sinus node function. A number of laboratories have reported poor correlation between measurements of SNRT and clinical evidence of the sick sinus syndrome.12,14.15 In use of this test one should be aware of several important limitations. First, in the presence of sinoatrial conduction delay, paced atrial depolarizations may not enter (and therefore not suppress) the sinus node. In rare instances, intravenous administration of atropine may result in paradoxic lengthening of the SNRT, 16 presumably due to facilitation of sinoatrial conduction and enhanced suppression of the sinus node. In addition, the laboratory setting may initiate changes in autonomic tone that may mask (enhanced sympathetic tonus) or enhance (increased vagal tone) evidence of sinus node dysfunction. The use of pharmacologic interventions to block autonomic influences is discussed in a subsequent section. Another limitation in the usage of this test is the lack of u n a n i m i t y among different laboratories for the upper limits of normal for these testing procedures. These differences may in part be related to testing o f subjects with abnormal atrioventricular or intraventricular conduction who are assumed to have normal sinus node function. Such subjects may, in fact, have latent sinus node dysfunction. In addition, normal values for SNRT in subjects with slow heart rates (50-60 beats/ min) is still ill-defined, largely because few have been studied and because it is difficult to be certain whether the bradycardia is a manifestation of sinus node disease. Moreover, as emphasized in the previous section, the testing study must include multiple pacing runs using a wide spectrum of driven atrial rates. For example, of the 27 patients with abnormal postpacing responses (Fig. 1), four showed an abnormal response at only one paced cycle length whereas five showed abnormalities at only two paced rates. Clearly, overdrive pacing using a limited number of J. ELECTROCARDIOLOGY, VOL. 12, NO. 2, 1979

SINUS NODE DYSFUNCTION

50

213

[~PPC I []CSRT

,~ 40 TUa i--~O

Fig. 1. [] PPC1. Abnormalities in the first postpacing cycle, as defined by Benditt et al.12: SNRT/ SCL > 1.61 for SCL > 800 msec and 1.83 for SCL < 800 msec. [] Corrected SNRT (CSRT) using the criteria of Narula et al.H: SNRT SCL /> 525 msec. [] 2~ The incidence of both pauses (or abnormalities in postpacing cycles 2-10) and abnormal PPC1.

[]2~

+PPC

I

~ , 30 ,,z,~

z

860 TOTAL

pacing runs will result in an inordinate number of false-negative responses. Finally, rapid atrial pacing m a y produce anginal pains in patients with ischemic heart disease or may result in sustained atrial fibrillation or flutter. Estimation of SACT. Premature Atrial Stimulation. Discharge of the sinus node is not registered in either surface or intracardiac leads; therefore, a p a r t from frank sinoatrial exit block, the usual electrocardiographic techniques are ineffective in evaluating sinoatrial conduction. Strauss et al. ~7 introduced a technique for estimating SACT in man. This technique involves introduction of progressively premature atrial depolarizations (A2) during sinus r h y t h m (A~A~). Late diastolic depolarizations result in return cycles (A2Az) that are inversely related to the test cycle (A~A2) and fall in the portion of atrial diastole known as the zone of nonreset. Atrial premature depolarizations elicited earlier in diastole result in plateau responses that fall in the portion of atrial diastole known as the zone of reset. During the zone of reset, it is assumed t h a t t h a t p r e m a t u r e impulse invades the sinus node and that the node subsequently discharges at a rate identical to the spontaneous sinus rate. If these assumptions are accurate, then the difference between return cycle and the spontaneous sinus cycle should equal the time for entrance of A2 into the sinus node and exit of the next sinus impulse into the atrium. In practice, the entire atrial cycle is s c a n n e d by p r o g r e s s i v e l y p r e m a t u r e impulses, and t h e n o r m a l i z e d r e t u r n cycles (A2A3/A~A1) are plotted against normalized test cycles (A~A2/A~A1). The zone of reset is recognized (from the graph) by clusters of plateau points t h a t clearly deviate from the line of identity. The SACT is calculated from those points that fall in the last third of the zone of reset. Earlier points are unsuitable because these p r e m a t u r e atrial impulses m a y encounter atrial or sinoatrial junction refractoriness. Similarly, even earlier premature J. ELECTROCARDIOLOGY, VOL. 12, NO. 2, 1979

660

540

460

400

350

PACED CYCLE LENGTH Imsec)

depolarizations may result in sinoatrial entrance block, incomplete interpolation, or sinoatrial reentry and are also unsuitable for this m e a s u r e m e n t , is B e c a u s e a n t e r o g r a d e sinoatrial conduction differs from retrograde conduction, only total SACT (anterograde and retrograde conduction) is measured by this technique. Overdrive Method for Calculating SACT. More recently, Narula et al.TM described an alternative method for estimating SACT. In brief, atrial pacing is carried out at a rate slightly above the spontaneous rate. Pacing at this rate is assumed to have negligible effects on sinus node automaticity, and hence after abrupt cessation of pacing, the interval from the last paced atrial depolarization to the next spontaneous sinus discharge represents the SCL plus retrograde conduction into the node (from the stimulated atrial depolarization) and anterograde conduction into the atrium (from the first postpacing sinus depolarization). In practice, five testing procedures are performed at rates approximately 10 beats/ min faster than the SCL, and the SACT is calculated as the average of these five determinations. The overdrive method is simpler to perform, does not require a programmable stimulator, and is less apt to provoke cardiac arrhythmias than the extrastimulus method. Further studies, however, are required comparing each of these proposed methods for calculating SACT with direct measurements of SACT either in in vitro preparations 2~ or during cardiac surgery in humans. 21 Limitations of SACT Measurements. Several i m p o r t a n t limitations in t h e use of these techniques for measuring SACT should be discussed. First, neither technique is reliable for estimating SACT in patients with marked sinus arrhythmia because both techniques assume a relatively stable sinus rate. Similarly, abrupt changes in automaticity or intra-atrial conduction during testing invalidate the results. An additional problem common to both

214

S C H E I N M A N ET A L

TABLE I Summary of follow-up (23 months) data from electrophysiologic testing of 69 patients with clinical evidence of sinus node dysfunction. Group I (n =19)

Group II (n =29)

Group III (n =21)

Spontaneous sinus pauses (>2 sec)

9/19 (47%)

1/29 (3%)

4/21 (19%)

Abnormal SNRT*

8/19 (42%)

9/29 (31%)

7/21 (33%)

Abnormal SACT**

6/15 (40%)

7/17 (41%)

4/9 (44%)

Secondary pauses

12/19 (63%)

7/23 (30%)

15/21 (71%)

2/5 (40%)

3/6 (50%)

3/6 (50%)

Study Parameters

Incidence of sudden death * SNRT = sinus node recovery time. ** SACT = sinoatrial conduction time.

methods is possible marked shortening of the estimated SACT 22 resulting from a shift of the p a c e m a k e r from the center of the node to more peripheral sites during pacing. Furthermore, in vitro studies have demonstrated c h a n g e s in a u t o m a t i c i t y a f t e r p r e m a t u r e a t r i a l s t i m u l a t i o n . 2~ Moreover, t h e u p p e r limits of the normal range for SACT vary .considerably among different laboratories, ranging from 198 to 304 msec. 14'24-26These differences are probably due to the inclusion of subjects w i t h coronary a r t e r y o b s t r u c t i o n p r o x i m a l to t h e origin of t h e s i n u s node artery 26 and/or patients with intraventricular conduction delay and possible latent sinus node dysfunction. 24 Studies of subjects without coronary disease (confirmed by coronary angiography) or other known conduction abnormalities or of normal children have shown that the upper limits of SACT are in the 198205 msec range. 14,26-29 It should be emphasized that these techniques allow for the estimation of SACT in humans, b u t these measurements must be considered estimates at best and, because of the limitations alluded to, do not really provide quantitative measurements of SACT. Finally, in vitro studies have clearly shown that sinus pauses m a y be related to intranodal conduction delay or to subthreshold oscillations within sinoatrial nodal cells.3~ Present techniques are clearly limited in discerning these pathophysiologic mechanisms. Clinical correlations. Recent studies have emphasized the frequently poor correlation between abnormalities detected during electrophysiologic testing and clinical manifestations of the sick sinus syndrome. This m a y be related to deficiencies of the testing procedures, variations in severity of the sinus node dysfunction, and changes in autonomic tone d u r i n g t h e t e s t procedure. P a t i e n t s w i t h

sinoatrial node dysfunction and prolonged spontaneous sinus pauses have a statistically significant higher incidence of abnormalities on testing than those with sinus bradycardia alone.31 One explanation for this observation is that patients with prolonged pauses have a more severe form of sinus node dysfunction that is more readily provoked by testing. In addition, Jordan et al.TM recently described the result of electrophysiologic testing before and after combined autonomic blockade (by use of intravenous atropine and propranolol) in patients with sinus node disease. Those patients with an abnormal intrinsic heart rate had a significantly higher incidence of abnormal SNRT than those with a normal intrinsic heart rate. In recent studies from our laboratories, 32 we corroborated these findings and found three subgroups of patients with clinically manifest sinus node dysfunction: one group had an abnormal intrinsic heart rate (and p r e s u m a b l y abnormal intrinsic sinus node function); one had dependence on intact sympathetic tone; and the third had vagal overactivity. The therapeutic implications of these findings are still uncertain. Use of electrophysiologic testing to evaluate drug safety: Recently there has been a great deal of i n t e r e s t in t h e effects of v a r i o u s cardio active drugs on sinus node function. Antiarrhythmic agents 7,33 and digitalis 34 (on rare occasions) m a y result in pronounced deterioration in sinus node function in patients with the sick sinus syndrome. We studied symptomatic b r a d y a r r h y t h m i a s in patients with presumed sinus node disease who were t r e a t e d with the u s u a l doses of commonly used antihypertensive drugs (alpha methyldopa, propranolol, clonidine, a n d guanethidine) 35 In four subjects electrophysiologic testing revealed abnormal control sinus node function and further deterioration of sinus J. ELECTROCARDIOLOGY, VOL. 12, NO. 2, 1979

SINUS NODE DYSFUNCTION

node function after challenge with intravenous propranolol; secondary p a u s e s (abnormalities in postpacing cycles 2-10) were present in all four patients. These observations suggest that electrophysiologic testing plus specific drug challenge m a y be helpful in detecting those patients with sinus node disease at risk of developing adverse drug effects. Electrophysiologic testing and Natural History. Our laboratories are involved in a continuing prospective follow-up study of patients with clinical evidence of sinus node dysfunction who have undergone electrophysiologic testing. The data are summarized in Table 1. To date, 69 patients have been followed for a p p r o x i m a t e l y 23 m o n t h s ( r a n g e 6 - 5 3 months); 23 patients underwent pacemaker insertion (two patients refused) and 46 remain unpaced. Associated cardiac diseases included coronary artery disease (40%), hypertension (17%), valvular heart disease (9%), and cardiomyopathy (9%). Forty percent had p r e d o m i n a n t sinus b r a d y c a r d i a , 27% had s i n u s p a u s e s , a n d 33% had b r a d y c a r d i a tachycardia syndrome. The group as a whole was divided into three subgroups based on relief of symptoms during follow-up evaluation. Group I consisted of 19 patients who underw e n t p a c e m a k e r i n s e r t i o n and responded w i t h s y m p t o m a t i c i m p r o v e m e n t . Group II c o n s i s t e d o f 29 p a t i e n t s in w h o m no pacemaker was inserted but whose symptoms resolved. Group III consisted of 17 unpaced and 4 paced p a t i e n t s who failed to show s y m p t o m a t i c r e s p o n s e , in t h a t t r a n s i e n t neurologic symptoms persisted or recurred; two group II patients refused pacemaker insertion. The incidence of prolonged spontaneous sinus p a u s e s ( > 2 sec) was g r e a t e r in Groups I and III than in Group II. There was no significant difference between groups in the incidence of abnormal corrected SNRT, abnormalities in SACT, or presence of secondary pauses. The incidence of death or sudden death was clearly related to severity of underlying heart disease rather than to any specific testing abnormality or pacemaker intervention. Our preliminary information suggests that patients with prolonged (/> 2.0 sec) spontaneous pauses are more apt to respond to p a c e m a k e r intervention. The type of electrophysiologic test abnormality failed to predict outcome (in terms of death, sudden death, or symptom relief). It should be noted, however, that most patients with marked prolongation of SNRT (1>2.0 sec) underwent p a c e m a k e r i n s e r t i o n and all b u t one responded to this intervention. Finally, survival appears to be more strongly related to the presence of cardiac failure r a t h e r t h a n to p a c e m a k e r i n s e r t i o n or s p e c i f i c t e s t abnormality. J. ELECTROCARDIOLOGY, VOL. 12, NO. 2, 1979

215

Clinical usage of electrophysiologic testing. We believe that electrophysiologic testing is of value in symptomatic patients who show some evidence of possible sinus node dysfunction (i.e., chronic sinus bradycardia) but in whom prolonged Holter recordings and complete medical and neurologic evaluation fail to reveal the cause of the symptoms. If during pacing studies prolonged pauses are induced that provoke symptoms identical to those produced naturally, then we think that this is an e x c e l l e n t i n d i c a t i o n for p e r m a n e n t pacem a k e r insertion. Similarly, patients with the bradycardia-tachycardia syndrome m a y experience symptoms only on transition from tachycardia to bradycardia, and therefore efforts to simulate tachycardia by atrial overdrive pacing m a y again allow for provocation of symptoms as well as prolonged pauses. In addition, electrophysiologic testing is indicated for those patients with sinus node dysfunction who are being considered for permanent atrial pacemaker insertion. It is well known that patients with sinus node disease m a y h a v e c o n c o m i t a n t a b n o r m a l i t i e s in atrioventricular conduction. Therefore, His bundle electrograms should be obtained bef o r e i n s e r t i o n of a t r i a l p a c e m a k e r s to evaluate atrioventricular conduction in these patients. Finally, it is appreciated that electrophysiologic testing is in its infancy and that the full evaluation of these testing procedures is still incomplete. REFERENCES 1. FERRER,M I: The sick sinus syndrome in atrial disease. JAMA 206:645, 1968 2. SHORT, D S: The syndrome of alternating bradycardia and tachycardia. Br Heart J 16:208, 1954 3. AGRUS, N S, ROSIN, E Y, ADOLPH, R J AND FOWLER, N O: Significance of chronic sinus bradycardia in elderly people. Circulation 46:924, 1972 4. VAN DURME,J P: Tachyarrhythmias and transient cerebral ischemic attacks. Am Heart J 89:538, 1975 5. ABBOTT, J A, HIRSCHFELD,D, KUNKEL,F W ANDSCHEINMAN,M M: Graded exercise testing in patients with sinus node dysfunction. Am J Med 62:330, 1977 6. MANDEL, W J, HAYAKAWA,H, ALLEN, H N, DANZIG, R AND KERMAIER,A I: Assessment of sinus node function in patients with the sick sinus syndrome. Circulation 46:761, 1972 7. STRAUSS,H C, SCHEINMAN,M M, LABARRE,A, BROWNING,D J, WENGER,T L AND WALLACE, A G: Review of the significance of drugs in the sick sinus node syndrome. In The Sinus Node. Structure, Function and Clinical Relevance, F I M BONKE, ed. Martinus Nijhoff, The Hague, 1978, pp 103-111 8. GEORGE, C F, CONNOLLY,M E, FENYVESI, T, BRIANT, R AND DOLLERY,C T: Intravenously administered isoproterenol sulfate dose-

216

9. 10.

11. 12.

13.

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15.

16.

17.

18. 19.

20.

21.

22.

SCHEINMAN ET AL

response curves in man. Arch Intern Med 130:361, 1972 LANGE, G: Actions of driving stimuli from intrinsic and extrinsic sources on in situ cardiac pacemaker tissues. Circ Res 17:449, 1965 MANDEL, W, HAYAKAWA,H, DANZIG, R AND MARCUS, H S: Evaluation of sino-atrial node function in man by overdrive suppression. Circulation 44:59, 1971 NARULA,O S, SAMET, P AND JAVIER, R P: Significance of sinus-node recovery time. Circulation 45:140, 1972 BENDITT,D G, STRAUSS,H C, SCHEINMAN,M M, BEHAR, V S AND WALLACE,A G: Analysis of secondary pauses following termination of rapid atrial pacing in man. Circulation 54:436, 1976 JORDAN,J L, YAMAGUCHI,I AND MANDEL,W J: Studies on the mechanism of sinus node dysfunction in the sick sinus syndrome. Circulation 57:217, 1978 SCHEINMAN,M M, KUNKEL, F W, PETERS, R W, HIRSCHFELD, D S, SCHOENFELD, P L, ABBOTT, J A AND MODIN, G A: Atrial pacing in patients with sinus node dysfunction. Am J Med 61:641, 1976 GUPTA,P K, LICHTSTEIN,E, CHADDA,K D AND BADUI, E: Appraisal of sinus nodal recovery time in patients with sick sinus syndrome. Am J Cardiol 34:265, 1974 REIFFEL, J A, BIGGER, J T AND GIARDINA, E-G V: '~Paradoxical" prolongation of sinus nodal recovery time after atropine in the sick sinus syndrome. Am J Cardiol 36:98, 1975 STRAUSS, H C, SAROFF, A L, BIGGER, J T, J r AND GIARDINA,E-G V: Premature atrial stimulation as a key to the understanding of sinoatrial conduction in man. Presentation of data and critical review of the literature. Circulation 47:86, 1973 GOLDREYER, B N AND DAMATO, A N: Sinoatrial-node entrance block. Circulation 44:789, 1971 NARULA, O S, SHANTHA, N, VASQUEZ, M, TOWNE, W D AND LINHART,J W: A new method for m e a s u r e m e n t of sinoatrial conduction time. Circulation, 58:706 1978 MILLER,H C AND STRAUSS,H C: Measurement of sinoatrial conduction time by premature atrial stimulation in the rabbit. Circ Res 35:935, 1974 HARIMAN, R J, KRONGRAD, E, BOXER, R A, CRAMER, M, BOWMAN,F O, JR, MALM,J R AND HOFFMAN, B F: A method for recording of extracellular sinoatrial electrograms during cardiac surgery in man. Am J Cardiol 41:375, 1978 (abstract) BONKE, F I M, BOUMAN, L N AND VAN RIJN, H E: Change of cardiac rhythm in the rabbit

23. 24.

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35.

after an atrial p r e m a t u r e beat. Circ Res 24:533, 1969 KLEIN, H O, SINGER, D H AND HOFFMAN, B F: Effects of atrial premature systoles on sinus rhythm in the rabbit. Circ Res 32:480, 1973 DHINGRA,R C, WYNDHAM,C, AMAT-Y-LEON,F, DENES, P, WU, D AND ROSEN, K M: Sinus nodal responses to atrial extrastimuli in patients without apparent sinus node disease. Am J Cardiol 36:445, 1975 ENGEL, T R, BOND, R C AND SCHAAL, S F: First-degree sinoatrial heart block: sinoatrial block in the sick sinus syndrome. Am Heart J 91:303, 1976 BREITHHARDT, G, SEIPEL, L AND LOOGEN, F: Sinus node recovery time and calculated sinoatrial conduction time in normal subjects and patients with sinus node dysfunction. Circulation 56:43, 1977 JORDAN, J, YAMAGUCHI, I AND MANDEL, W J: Characteristics of sinoatrial conduction in patients with coronary artery disease. Circulation 55:569, 1977 MASINI, G, DIANDA, R AND GRAZIINA, A: Analysis of sino-atrial conduction in man using p r e m a t u r e a t r i a l stimulation. Cardiovasc Res 9:498, 1975 KUGLER, J D AND GILLETE, P C: Sinoatrial conduction time in children. Circulation 56 (Suppl III): 95, 1977 (abstract) Lu, H H, LANGE, G AND BROOKS, C M: Factors controlling pacemaker action in cells of the sinoatrial node. Circ Res 17:460, 1965 SCHEINMAN,M M, STRAUSS,H C, ABBOTT,J A, EVANS, G T, PETERS, R W, BENDITT, D G AND WALLACE, A G: Electrophysiologic testing in patients with sinus pauses and/or sinoatrial exit block. Eur J Cardiol 8:51, 1978 MASSIE, B, O'YOUNG, J , SCHEINMAN, M, STRAUSS, H, PETERS, R AND DESAI, J: The significance of autonomic blockade in the evaluation of sinus node dysfunction. Am J Cardiol 41:443, 1978 (abstract) BREITHARDT,G AND SEIPEL, L: The influence of drugs on sinoatrial conduction time in man. In Cardiac Pacing: Diagnostic & Therapeutic Tools, B Lf2DERITZ,ed. Springer, Berlin, 1976, pp 58-72 MARGOLIS,J R, STRAUSS, H C, MILLER, H C, GILBERT, M AND WALLACE,A G: Digitalis and the sick sinus syndrome. Clinical and electrophysiologic documentation of a severe toxic effect on sinus node function. Circulation 52:162, 1975 SCHEINMAN,M M, STRAUSS,H C, EVANS, G T, RYAN, C, MASSIE, B AND WALLACE,A G: Adverse effects of s y m p a t h o l y t i c a g e n t s in patients with hypertension and sinus node dysfunction. Am J Med 64:1013, 1978

J. ELECTROCARDIOLOGY, VOL. 12, NO. 2, 1979