Fundamentals of clinical cardiology The sick sinus syndrome William J. Scarpa, M.D. Brooklyn, IV. Y.

The term "sick sinus syndrome" has been used to describe a group of clinical states in which one or more of the following signs appeared: (1) persistent, severe, and unexpected sinus bradycardia; (2) cessation of sinus r h y t h m for short intervals with other rhythms supervening; (3) long periods of sinus arrest without escape r h y t h m ; (4) untreated chronic atrial fibrillation with slow ventricular rate; (5) no sinus rhythm after cardioversion; (6)sino-atrial (SA) exit block. The syndrome has been studied clinically and pathologically and is a well-delineated entity. Disorders of the sino-atrial node resulting in bradycardia and asystole have been reported by many authors. '-7 Most reports emphasized the bradycardic features of sino-atrial dysfunction. In 1954, however, Short s n o t e d an association between bradycardia productive of symptoms and paroxysmal supraventricular arrhythmias. Lown 9 first used the term "sick sinus syndrome" to describe certain arrhythmias following DC cardioversion. He had noted "chaotic atrial activity, changing P-wave contour, bradycardia, interspersed with multiple and recurrent ectopic beats, with runs of atrial and nodal tachycardia." Ferrer 1~ extended the definition to include the following signs: (1) persistent, severe, a n d unexpected sinus bradycardia; (2) cessation of sinus r h y t h m for short intervals (sinus arrest), or for longer periods with replacement of this rhythm with ectopic atrial or junctional rhythm; (3) long periods of sinus arrest, without a new pacemaker arising, resulting in periods of total cardiac arrest; (4) chronic atrial fibrillation often accompanied by a slow ventricular rate, the latter From the Department of Medicine, Division of Cardiology , The Long Island College Hospital, and the Cardiac Catheterization Laboratory, The Long Island College Hospital, Brooklyn, N. Y. Received for publication Aug. 25, 1975. Reprint requests: William J. Scarpa, M.D., Cardiac Catheterization Laboratory, The Long Island College Hospital, 340 Henry St., Brooklyn, N. Y. 11201.

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not produced by drug therapy; (5) failure of the heart to resume sinus rhythm after electroversion for atrial fibrillation; (6) episodes of SA exit block not related to drug therapy. After Ferrer's description, many reports followed and various terms were used to describe these phenomena: "inadequate sinus mechanism, ''~ "sluggish sinus node syndrome, ''12 and "sino-atrial syncope. ''13 When an element of tachycardia was associated with the bradycardic aspects, the condition h a s been called "the syndrome of alternating bradycardia and tachycardia ''s or "The bradycardia-tachycardia syndrome 14 (BTS)." Anatomy The sinus node. The sinus node was first described by Keith and Flack "~ in 1907, and its electrophysiologic property as pacemaker of the heart by Wybouw 1~ and Lewis and associates 17 in 1910. Walmsley ~ proposed that the pacemaker of the heart be referred to as the sinus node, rather than sino-atrial or sino-auricular node. This seems more accurate in view of the fact that this structure is near the junction of both the superior vena cava and the sinus intercavorum with both the atrium and the ventricle. In the embryo, the sinus node and atrioventricular (A-V) node arise similarly. Both structures form at the junction of the right and left superior cardinal veins and the sinus venosus, the sinus node appearing in the vicinity of the former and the A-V, the latter. Ultimately, the sinus venosus forms the medial half of the right atrium and a portion of the interatrial septum. The A-V node, migrating with the sinus venosus, assumes an internal position in the adult heart. The sinus node does not migrate for any appreciable distance and, therefore, retains its primitive position.

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Sick sinus syndrome

In the adult heart, the sinus node is 10 to 20 mm. long. It lies near the junction of the superior vena cava and the right atrium. Shaped like a flattened ellipse, it occupies a position t h a t is less than 1 mm. beneath the epicardial surface. The physiologic implications of this location are obvious, the node being vulnerable to m a n y conditions which affect the epicardial surface, e.g., pericarditis29 Perhaps the most interesting aspect of the anatomy of the sinus node is its blood supply. This has been carefully studied by James. ~~ The primary supply is virtually always a single vessel which arises from the proximal few centimeters of the right coronary artery in about 55 per cent of cases and from the proximal few millimeters of the left circumflex artery in about 45 per cent. In its course, this vessel also serves as the blood supply to a major portion of the atrial myocardium and interatrial septum. In addition to being disproportionately large, this vessel passes directly through the center of the sinus node, giving off small lateral branches within the node. The central relation to the node is so constant that it has been stated by Soderstrom ~ that the node resembles an enormous adventitia of its own artery. James and Nadeau 22 have commented on the possibility t hat there is a physiologic relation between the pulsation of the nodal artery and sinus node function. B ot h the central nodal position of the vessel and its proximal origin from the coronary circulation would tend to support this theory. This location would seem to indicate that changes in central aortic pressure would be transmitted quickly to the nodal artery and thereby to the node itself. Indeed, many observations have shown t h a t drugs and procedures which increase the rate of sinus node discharge may decrease the caliber of the artery whereas those which slow the node may increase the caliber of the artery. 2~' The sinus node is composed of several types of cells. A dense collagen framework which surrounds the central artery is found to contain interlacing bundles of fibers. The latter converge into exiting Purkinje fibers in all directions. At the mid portion of the sinus node, the nodal fibers distribute from stellate cells which have a large round nucleus and are known as P cells. These are thought to be the site of actual pacemaking. Under electron microscopic studies, t hey resemble the "leading cells" which H ar a r y :4 has shown

American Heart Journal

to be the dominant pacemakers in myocardial fiber tissue cultures. Although no ganglia are found in the sinus node, it contains numerous nerve endings. The internodal pathways. It has been shown on electrophysiologic studies t h a t the impulse from the sinus node arrives at the A-V node more rapidly than it would if it traversed ordinary myocardium. 2~ This suggests t h a t internodal pathways exist and, indeed, three such tracts have been described: the anterior, middle, and posterior internodal tracts. Although intra-atrial conduction m~y occur along any one of the three, it is preferentially along the anterior tract in most normal hearts. T he normal or usual course for internodal conduction is, however, not completely known at present.

Electrophysiology The pacemaker cells in the sinus node have been studied by microelectrode technique. This method has shown that t h e s e and other pacemaker cells possess a unique characteristic, viz., spontaneous diastolic depolarization. This occurs in a cyclical or repetitive fashion/~ When the decreasing transmembrane potential reaches a critical threshold value during phase 4 depolarization, membrane permeability abruptly changes, sodium ions move into the cell, and the cell is depolarized to zero potential in relation to the surrounding extracellular fluid. Pacemaker cells have a slower depolarization and repolarization process than nonpacemaker Purkinje fibers. After repolarization, depolarization again o c c u r s - a f t e r self-excitation. T he ionic changes t h a t are associated with this process are not yet entirely clear, but it would seem t hat decreased outward potasslum permeability and inward leakage of sodium are responsible for the spontaneous automaticity that is seen. The automaticity of the sinus node is responsible for the maintenance of a faster rate of recurring self-excitation than other latent pacemaker sites. Changes in this automaticity are mediated primarily by changes in the rate of phase 4 depolarization. There is a profound influence of the autonomic nervous system on the sinus node rate which varies depending upon the demands of the body. As implied in the foregoing anatomic discussion, the sinus node impulse is a result of the discharge of potentials from m a n y pacemaker cells. The potentials of the cells are

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Scarpa slow-rising, associated with slow conduction, and vulnerable to block. Moreover, conduction within the node itself may be inhibited by the stroma and, in the perinodal tissue, the impulse may also become blocked. The latter may occur despite the presence, in the perinodal tissue, of a cell population th at seems to act as an amplifier for exiting impulses.

Pathology and etiology There have been few pathologic studies in cases of the sick sinus syndrome (SSS). The conduction system was studied by Cohn and Lewis ~'~ in a patient with auricular fibrillation and complete heart block. These authors found t h a t the upper end of the SA node was destroyed, there was fatty infiltration of the SA node, the atria were dilated and focally fibrotic, and the A-V node was normal. Rasmussen = reported a case of SA block in which he found extensive fibrosis of the SA node and SA junction. Kaplan, Langendorf, Lev, and Pick ~described the pathologic findings in two patients of the 10 whom they reported. In one case, the SA nodal artery arose from the right coronary artery, both of which showed no narrowing. On histologic examination, some arterioles in the SA node showed narrowing, acute degeneration, or necrosis. All the approaches to the SA node showed fibrosis and elastosis. In addition, chronic inflammation of the A-V node was found. In their second case, edema and hemorrhage of the elastic and collagen fibers of the SA node were noted. The approaches of the SA node had moderate arteriolosclerosis and focal degeneration of muscle cells. This case was one of amyloid heart disease, and amyloid deposits were found in the left atrium. Careful examination of the conduction system of atrium and ventricle, however, failed to show amyloid infiltration. Allensworth, Rice, and Lowe "~8 reported amyloid deposits in the myocardium in two patients with persistent atrial standstill. Rasmussen felt that diphtheria was the etiologic factor in his case, and the two patients reported by Vouvram, Slama, and Temkine ~ developed the sick sinus syndrome during an attack of diphtheria. Although pathologic studies are meager, m any cases of the SSS would appear to occur in patients with coronary artery disease. Indeed, in the report of Rubenstein, Schulman, Yurchak,

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and DeSanctis 1 this was the most common established etiology, being found in 20 of 56 patients. These authors pointed out, however, t h a t in 25 of their patients no etiology for the syndrome could be found. Coronary artery disease, as an etiologic factor, will be discussed further under pathogenesis. Although cardiomyopathy has occasionally been reported to be a cause in the production of the bradycardic syndrome, 2'-3~ its occurrence in most series has been unusual, if not rare. Moss and David 3~in reporting 74 cases of the bradycardia-tachycardia syndrome, noted t hat 51 per cent had associated coronary artery disease. In their series, "idiopathic" cardiac disease accounted for 34 per cent of their cases. T he remainder included hypertension, rheumatic heart disease, congenital heart disease, and cardiomyopathy. In their series of 21 cases of the SSS, Radford and Julian 34 reported one case of a patient who had had a pericardiectomy for calcific tuberculous pericarditis, and one case of dystrophia myotonia. Wan, Lee and Toh, 3~ in a most interesting report from Singapore, were able to document thyrotoxicosis as a possible etiologic factor in six of 15 patients. It is obvious t hat iatrogenic electrocardiographic (ECG) changes consistent with the SSS are common. Digitalis, quinidine, procaine amide, and propranolol can all produce an ECG and clinical picture of the SSS. In some of these patients determination of etiology may be almost impossible, as these are the drugs used to control many of the presenting arrhythmias of the syndrome. It then becomes problematical whether the drug being used for arrhythmia management is the etiologic factor in the production of the syndrome. It is precisely this puzzling situation that makes therapy of the syndrome very difficult at times. Wan, Lee and T oh :~5 cited a patient of theirs with thioridazine hydrochloride-induced SSS manifested by wandering pacemaker, paroxysmal atrial tachycardia, and sinus arrest. As will be discussed below, such a therapeutic-diagnostic dilemma is often seen in cases of the bradycardia-tachycardia group. Propranolol, for example, in use to control a supraventricular arrhythmia, may also result in sinus bradycardia. In the series of cases reported by Radford a n d Julian 34 three siblings were included. Other

November, 1976, Vol. 92, No. 5

Sick sinus syndrome

~

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......... z

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Fig. 1. ECG of M. C. (case 1).

familial cases have been d o c u m e n t e d 3~-:~ and it is probable t h a t there is a small familial incidence of the syndrome. Gambetta, Weese, Ginsburg, and Shapiro :~ reported a patient with the SSS whose family h a d P R prolongation. It is interesting, however, that, of 22 familial members studied, eight h a d prolonged P R and only one, the propositus, the SSS.

Pathogenesis As it would appear t h a t ischemic h e a r t disease accounts for the m a j o r i t y of patients with the SSS, it deserves special mention. As previously noted, the sinus node is particularly vulnerable to vascular occlusive disease since it receives its entire blood supply from a single artery. It should also be r e m e m b e r e d t h a t the same artery supplies m o s t of the atria. Occlusion of this vessel will affect sino-atrial electrical activity. Indeed, sinus node d y s f u n c t i o n occurs in about 5 per cent of acute m y o c a r d i a l infarctions ~ and the sinus node has been f o u n d f r e q u e n t l y to be infarcted in patients who develop atrial arrhythmias. 4~It can be suspected t h a t occlusions of the right coronary a r t e r y or circumflex b r a n c h of the left coronary a r t e r y will be c o m m o n l y associated with atrial a r r h y t h m i a s . This is, in fact, the case, and atrial infarction is exceedingly rare with isolated occlusion of the left anterior descending coronary artery. Electrophysiology. For the purposes of discussion of electrophysiology, general categories of a r r h y t h m i a s in the SSS are: (1) atrial bradyarrhythmias, (2) atrial t a c h y - a r r h y t h m i a s , and (3) atrial b r a d y - t a c h y - a r r h y t h m i a s . Atrial brady-arrhythmias. A reduction in spontaneou~ activity of the sinus node m a y result in sinus bradycardia. Also, sino-atrial exit block of

American Heart Journal

various degrees m a y be m a n i f e s t e d by sinus bradycardia. Complete loss of sinus node function or complete sino-atrial exit block will result in atrial standstill or arrest. The p h e n o m e n o n of sinus b r a d y c a r d i a , in the well-trained athlete is well known. I n the p a t i e n t with s y m p t o m a t i c sinus bradycardis, however, this a r r h y t h m i a m a y have various physiologic causes. These include diminished slope of phase 4 depolarization, increase in a c t i v a t i o n threshold, increased or a u g m e n t e d acetylcholine c o n c e n t r a tions, reduced catecholamines, drugs (such as propranolol), depressed t h y r o i d function, and hypothermia. Sinus b r a d y c a r d i a is p r o b a b l y the most c o m m o n single E C G m a n i f e s t a t i o n of the SSS, being found in 76 per cent of the reported cases of Radford and Julian 34 a n d 22 of 56 of the patients cited b y Schulman, Rubenstein, Yurchak and DeSanctis, 14 CASE1. M. C., a 72-year-oldhousewife, was admitted to the Long Island College Hospital in July, 1974, because of syncope. She had begun to have angina pectoris about 20 years prior to admission. Nitroglycerin was given to her by her private physician. Four years prior to admission, sudden shortness of breath and severe chest pain necessitated admission to another hospital, where she was told that she had had an acute myocardial infarction. Digitalis and diuretic therapy was started, and she continued the former medication until the present admission. In the 2 years prior to admission, the patient began to have syncopal episodes. These were infrequent at first, but in the 2 months prior to admission, two to three episodes per week occurred. The syncopal attacks were not associated with chest pain or palpitations, and each lasted 1 to 2 minutes. On physical examination, the vital signs were normal except for a pulse of 56 per minute. Examination of the heart revealed a regular rhythm and no murmurs were heard. An atrial gallop ($4) was audible at the cardiac apex. The remainder of the physical examination was within normal limits. An ECG on admission showed sinus bradycardia and evidence of old anteroseptal myocardial infarction. Digitalis blood levels were 0.2 ng. per milliliter. Sinus bradycardia persisted, and the

651

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Fig. 2. ECG of M. C. (case 1). patient complained of ligbtheadedness. No syncopal episodes were observed. Three days after admission, premature ventricular contractions were noted to be associated with the sinus bradycardia {Fig. 1). A trial of propantheline failed to result in an increase in the heart rate. On the thirteenth hospital day a permanent transvenous pacemaker was inserted. The patient has remained free of cardiac symptoms in the 18 months following pacemaker insertion. I f impulses from the sinus node are blocked a t its electrophysiologic j u n c t i o n with the a t r i u m , sino-atrial exit block is said to exist. T h i s is manifested by a b r a d y c a r d i a whose i n t e r v a l is a m a t h e m a t i c a l multiple of faster sinus intervals. Simply stated, an expected sinus P wave is n o t present, and the v e n t r i c u l a r response is n o t provoked (unless an escape b e a t occurs) (Fig. 2). Electrophysiologically, this is t h o u g h t to result from a slowing of the exiting c o n d u c t i o n velocity due to refractoriness of the perinodal tissues. In the case of atrial arrest or asystole, a v a r i e t y of electrophysiologic a b n o r m a l i t i e s m a y be responsible. A failure of g e n e r a t o r f u n c t i o n of t h e sinus node, a b n o r m a l i t i e s of perinodal conduction, or atrial inexcitability m a y cause atrial asystole. Its E C G m a n i f e s t a t i o n is the sudden cessation of P waves, with succeeding b e a t s n o t being m a t h e m a t i c a l multiples of faster sinus rates. Atrial b r a d y c a r d i a s are quite often not isolated a r r h y t h m i a s . T h e y m a y indicate diffuse disease and are at times associated with blocks in t h e lower conduction system. Narula, ~ in a s t u d y of atrial bradycardia, f o u n d t h a t over 60 per cent of 75 patients with atrial b r a d y c a r d i a has o t h e r conduction disturbances. T h e s e included abnormalities in the atria, j u n c t i o n a l tissues, a n d HisPurkinje system. T h i s would seem to indicate

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t h a t atrial b r a d y c a r d i a s are usually not electrical dysfunctions, which occur i n d e p e n d e n t l y of o t h e r arrhythmias. A t r i a l tachy-arrhythmias. I n c l u d e d u n d e r this heading are: sinus t a c h y c a r d i a , p a r o x y s m a l junctional and atrial t a c h y c a r d i a , atrial flutter, and atrial fibrillation. A l t h o u g h these r h y t h m s are not p a r t of the SSS when t h e y exist alone, t h e y form p a r t of the s y n d r o m e w h e n t h e y r e p r e s e n t the escape m e c h a n i s m for the b r a d y c a r d i c atrial rhythms, In addition, chronic atrial fibrillation m a y be considered p a r t of t h e SSS w h e n it is due to p e r m a n e n t electrical silence of the sino-atrial node. Similarly, episodes of t r a n s i e n t atrial fibrillation m a y occur in response to t o t a l cessation of sino-atrial r h y t h m . In m o s t instances, sinus t a c h y c a r d i a results from increased slope of p h a s e 4 depolarization. A variety of chemical and m e c h a n i c a l factors, including catecholamines a n d atrial stretch, are involved. S u p r a v e n t r i c u l a r t a c h y c a r d i a s h a v e been intensively investigated a n d their m e c h a n i s m s elucidated. 4~-44I t has been r e p e a t e d l y s h o w n t h a t paroxysmal supraventricular tachycardia may result f r o m sustained A-V nodal r e - e n t r a n c e . T h a t is, a circulating wave f r o n t of d e p o l a r i z a t i o n occupies a circuit within the atria involving the A-V node in a retrograde fashion, t h e r e b y exciting the atria. Subsequent r e - e n t r y of the A-V node reexcites the ventricles, and so on. R e c e n t l y , it has been shown t h a t r e - e n t r a n c e m a y occur in the sino-atrial node and thus be a source of s u p r a v e n tricular t a c h y c a r d i a 2 5 T h e m e c h a n i s m s of atrial flutter a n d fibrillation r e m a i n in dispute. F o u r theories h a v e h a d

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Sick sinus syndrome

Fig. 3. ECG of C. P. (case 2).

Fig. 4. ECG of C. P. (case 2).

adherents. The circus movement theory, now largely discredited, postulated that a circulating ring of excitation traversed the atria. The unifocal theory postulates that the impulses of flutter and fibrillation all originate in a single ectopic center. The multiple foci and fractionate contraction theories postulate the simultaneous presence of several active pacemaking centers in the atria. Evidence for the last three theorie3 has been cited but no firm conclusion has yet been reached regarding the actual arrhythmogenic mechanism.

About 3 weeks prior to admission, she began to complain of chest pain. This was precordial in location, oppressive, radiated to the left shoulder and arm, but not associated with effort. She denied diaphoresis or dyspnea during the episodes of pain. There was no history of diabetes, rheumatic h e a r t disease, orthopnea, or ankle swelling. On admission, the pertinent physical findings included a blood pressure of 160/90 mm. Hg, The heart r h y t h m was irregularly irregular, but there were no murmurs, gallops, or rubs. The lungs were clear. The remainder of the physical examination was unremarkable. The following laboratory data were normal: CBC. urinalysis. FBS. BUN, PBI, serum cholesterol, uric acid. SGOT, CPK. and LDH. An ECG taken after admission showed atrial fibrillation with a ventricular response of about 130 to 140 per minute (Fig. 3). but was otherwise unremarkable. This arrhythmia continued to occur sporadically during the 7 days after admission. On several occasions the heart r h y t h m reverted spontaneously to sinus bradycardia at a rate of 40 to 50 {Fig. 4). After attempts to control the episodes of atrial fibrillation with antia~Thythmic drugs were unsuccessful, a permanent pervenous pacemaker was inserted. The rate was adjusted to 90 per minute. In the year following insertion, the patient has remained free of palpitations, lightheadedness, or chest pain. Further episodes of atria] fibrillation have not been observed. CASE 3. R. C.. an 81-year-old housewife, was admitted to the Long Island College Hospital in April, 1971. because of weakness. She had a history of diabetes mellitus for 12 years. and was taking phenformin with good control. She denied a past history of chest pain, dyspnea, or ankle edema, but had been taking digoxin (0.25 mg. once a day) for as long as she could remember for "heart trouble." In addition, quinidine sulfate (0.2 Gm. every 4 hours) had been administered for about 4 years. On previous admissions, which had been for cataract surgery and complaints of palpitations, a variety of cardiac rhythms were noted. These included sinus bradycardia, atrial fibrillation with rapid ventricular response, and paroxysmal atrial tachycardia (Fig. 5). In the year prior to the present admission she had felt well, however, and had not been readmitted. For 1 month prior to admission, palpitations recurred and became more severe. These were associated with severe weakness and near-syncope on several occasions. The symptoms lasted from several minutes to several hours. There was never any associated chest pain or dyspnea. On admission, the patient was noted to be in no distress.

As previously noted, these arrhythmias are not sole evidence of the SSS. They are often associated with the brady-arrhythmias, however, and are thus included. Initiation of a supraventricular tachycardia, for example, requires an ectopic atrial beat or its equivalent. This may occur from spontaneous pacemaker activity in the specialized conduction tissue of the atrium, or may result from intra-atrial re-entry in association with asynchrony of repolarization among different myocardial fibers. In either case, the likelih o o d o f o c c u r r e n c e is i n c r e a s e d a t s l o w e r h e a r t r a t e s . 4~ When the brady- and tachy-arrhythmias are associated, the brady-tachy syndrome, a subdivis i o n o f t h e S S S , is s a i d t o e x i s t . T w o c a s e r e p o r t s of this interesting syndrome follow. CASE 2. C. P., a 62-year-old woman, was admitted to the Long Island College Hospital in February, 1974, because of chest pain, Palpitations, and lightheadedness. About 14 years prior to admission, she was told of the presence of systemic hypertension. This had been untreated. For about 7 years, she had had intermittent palpitations, but had never been observed during such an episode. She had no associated dyspnea or chest pain, but had had numerous episodes of lightheadness for about the same length of time. The patient was unable to associate the two symptoms of palpitation and lightheadedness.

American Heart Journal

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Scarpa

;Lii~.i,:

Fig. 5. ECG of R. C. (case 3).

Fi0. 6. ECG of R. C. (case 3).

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Fig. 7. ECG of R. C. (case 3). Vital signs were normal except for an irregular, rapid pulse. Pertinent physical findings were limited to the heart, where atrial fibrillation was present with a ventricular response of 110 ~o 115. A short, midsystolic Grade 2/6 systolic murmur was heard at the lower left sternal border. The remainder of the physical examination was unremarkable. Despite digoxin and quinidine therapy in the aforenoted dosages, her cardiac rhythm varied from sinus bradycardia (Fig. 6) to atrial fibrillation with a ventricular response in excess of 100. Propranolol (80 mg. daily) failed to control the heart rhythm, and several attempts at adjustment of digoxin and quinidine therapy failed to alter the paroxysmal atrial fibrillation or sinus bradycardia. During the tachycardic episodes, the

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patient complained of extreme weakness. On one occasion, a run of ventricular tachycardia was noted. This terminated in a supraventricular rhythm, sinus arrest, and sinus bradycardia with wandering pacemaker (Fig. 7). About 1 month after admission, a temporary pervenous pacemaker was inserted and ventricular pacing initiated at a rate of 85. No further episodes of brady- or tachycardia occurred over the next week. Digoxin was continued, but quinidine was discontinued. Inderal was again given in a dose of 80 mg. daily. About 5 weeks after admission, a permanent pervenous demand pacemaker was inserted. The patient has subsequently remained well and, when readmitted for pacemaker battery replacement 2 years later, had no cardiac

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Sick sinus syndrome

complaints. Heart rhythm was mainly pacemaker-inducedat a rate of 80. Clinical picture Age and sex. T h e r e does .not seem t o be a sexual preponderance of the SSS. In the 31 cases of M a n d e i , Hayakawa, Allen, Danzig, and Kermaier, 47 there were 15 women and 16 men; Radford and Julian 34 reported 11 men and 10 women; in the series of Rubenstein and associates, 1 there were 25 men and 31 women; Moss and Davis '33 review of 74 patients with the bradytachy syndrome included 32 men and 42 women. In most series, the peak incidence of the SSS occurs in the seventh decade. It is worth remembering, however, t ha t the syndrome does occur in childrenY ~ Ferrer ~ has suggested t ha t the SSS may explain some instances of sudden death in young athletes. One of the patients of Wan, Lee, and To h 3~was 21 years old. Ikeme, D'Arbela, and Somers 5~ reported a remarkable series of eight Africans with SSS. All of their patients were age 32 or less, and one was age 10. T h e y did not offer any explanation for this preponderance of youthful patients. Signs and symptoms. T he clinical manifestations of the SSS may be quite difficult to recognize as they may be intermittent, protracted, and multifaceted. Physiologically, most signs and symptoms result from hypoperfusion of vital organs. The brain, h e a r t , and kidneys are most prominently affected. Moss and Davis 33 reported that 48 per cent of their patients with the bradytachy syndrome had cerebral manifestations, viz., syncope or near-syncope and dizziness. Their review of the pertinent literature, however, revealed that 75 per cent of the reported cases had these symptoms. F o r t y of 56 patients reported by Rubenstein and associates 1 had cerebral symptoms; indeed, they noted 10 cerebrovascular accidents in their group. An interesting association in this regard was mentioned in the B r i t i s h M e d i c a l J o u r n a P 1 where it was observed t hat patients with the brady-tachy syndrome are greatly at risk from systemic embolism, presumably because of the changing atrial rhythms. Rubenstein and associates 1reported t h a t eight of their 33 patients with the brady-tachy syndrome had systemic embolization. Cerebral manifestations of the SSS may include such nondescript symptoms as fatigue,

American Heart J o u r n a l

irritability, and forgetfulness. It is impossible to estimate how often an elderly patient with signs and symptoms of "senility" may, in fact, have cerebral manifestations of brady- or tachycardic r h y t h m disturbances. It is incumbent on the clinician to bear in mind this possibility when investigating any patient with cerebral symptoms of obscure origin. Of the cerebral manifestations, the one with most potential hazard is syncope. These cases are not included in the classical Morgagni-Stokes-Adams syndrome, of course, unless the bradycardic r h y t h m is complete heart block. The original report of sinus bradycardia and syncope was made by Laslett ~2in 1909. In the series of Moss and Davis, :~3 25 of 74 patients had syncope. Of these, 65 per cent had a syncopal episode as a result of asystole following tachycardia, 26 per cent due to bradycardia alone, and 9 per cent due to tachycardia alone. Ikeme, D'Arbela, and Somers ~~ stressed the bizarre clinical presentation of some of their patients: two were thought to have psychiatric disorders and two had epileptiform fits. As would be expected, the second most prominent organ producing symptoms in the SSS is the heart itself. Palpitations, angina, and manifestations of congestive heart failure are seen as the initial symptoms in many patients. In others, a sudden or gradual unexplained worsening of these signs and symptoms may occur. Once again, a high index of suspicion is required to make a diagnosis in these cases. These manifestations may result, not only from tachycardia, but from the failure of the heart to become tachycardic under an appropriate stimulus. In certain cases, episodic and sudden unexplained episodes of pulmonary edema m ay be a result of the arrhythmias of the SSS. Similarly, mild ventricular failure can occur from persistent or episodic sinus bradycardia. Angina can, obviously, be caused by the same mechanisms. It cannot be emphasized too strongly that the arrhythmia producing these clinical signs may not be present when the patient comes under professional observation. When, to this problem, is added the fact that other signs of heart disease may be absent in the early stages of sinus node disease, diagnosis becomes particularly difficult. Once again, however, careful and intensive investigation can result in a proper conclusion (see below}. {An intriguing historical speculation in this regard was offered by Livesley, ~:~who attributed the cerebral symptoms and angina

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Fig. 8. ECG of M. P. (case 4).

suffered by the famous English physician and anatomist, John Hunter, to persistent and inappropriate sinus bradycardia.) ECG manifestations. The most frequent single arrhythmia in the SSS is sinus bradycardia, being reported in 76 per cent of the patients of Radford and Julian24 The series of Moss and Davis 33 had exactly the same incidence of sinus bradycardia. As noted under electrophysiology, a variety of other supraventricular arrhythmias occur. These have included sinus arrest, junctional bradycardia, wandering atrial pacemaker, supraventricular ectopic beats, intermittent sinus arrest, and sinus node exit block. As previously mentioned, an inadequate sinus rate following DC cardioversion may be a sign, often the initial one, of SSS. In like manner, the use of a cardioactive drug to treat a supraventricular arrhythmia may result in the appearance of another arrhythmia as the initial one in the diagnosis of SSS. The occurrence of ventricular arrhythmias in the SSS is unusual. Only 10 per cent of the patients of Moss and Davis 33 had ventricular tachycardia Or fibrillation. Rubenstein and associates 1 did not report any patients with ventricular tachycardia o r fibrillation in their 56 patients, and Radford and Julian 34 gave an incidence of 8 per cent. In the 10 cases of Kaplan and associates, 2 there were no ventricular arrhythmias. When such arrhythmias occur, they would seem to be an escape mechanism in response to one of the atrial bradycardic arrhythmias. The tachycardic arrhythmias of the bradytachy syndrome are mainly supraventricular, and include supraventricular tachycardia and paroxysmal atrial tachycardia as the most frequent. In decreasing incidence, atrial flutter and fibrillation and multiple supraventricular tachy-arrhythmias may be encountered. 656

It would be expected that associated ECG abnormalities, in addition to arrhythmias, might be present, and this is, indeed, the case. A norm al ECG does not, of course, exclude the SSS. Myocardial infarction is frequently encountered, as are bundle branch block and ventricular hypertrophy.

Diagnosis History. As in all clinical medicine, the history remains the cornerstone of diagnosis of the SSS. Palpitations. angina, and symptoms of congestive heart failure may be an integral part of the history. Sudden onset of these symptoms, or the aggravation of a previously stable clinical condition. may point to the proper diagnosis. When syncope is the presenting symptom, a broader diagnostic investigation is indicated, including metabolic and neurologic disorders. When these are excluded, however, a search for the SSS may be indicated, particularly in the presence of cardiac symptoms. It should be mentioned t h a t the patient with syncope of cardiac origin usually has episodes that are sudden, brief, and leave few, if any, sequelae. Associated cerebrovascular disease may, of course, alter the presentation. The clinician should carefully question the patient with syncope regarding any cardiac symptoms. On occasion a history of palpitation will be elicited, and. may be noted by the patient to immediately precede the syncopal episode. The fact that cardioactive drugs such as quinidine and procaine amide may expose a previously unsuspected sick sinus cannot be too strongly emphasized. In a not unusual sequence, a patient is given one of these drugs to control a tachycardic rhythm, and responds with an episode of prolonged sinus arrest or asystole. Physical examination. Aside from a resting heart rate that may be below 60. or the detection November, 1976, Vol. 92, No. 5

Sick sinus syndrome

of an a r r h y t h m i a , physical findings are u s u a l l y of little help in establishing the diagnosis of the SSS. ECG. This, of course, is the final p a r a m e t e r of diagnostic investigation. In detection of t h e SSS, several m e t h o d s h a v e been e m p l o y e d . A m b u l a t o r y (Holter) E C G t a p e m o n i t o r i n g h a s greatly advanced the diagnosis of cardiac a r r h y t h m i a s . T h e episodic b r a d y - or t a c h y c a r d i a s of the SSS m a y be d o c u m e n t e d b y this m e t h o d , and it is p a r t i c u l a r l y v a l u a b l e in the case where routine electrocardiography is n o t f o r t u i t o u s l y p e r f o r m e d during an a r r h y t h m i a . Occasionally, a r r h y t h m i a s are recorded even in t h e absence of s y m p t o m s b u t are, of course, diagnostic w h e n s y m p t o m s and a r r h y t h m i a concur. A l t h o u g h m a n y a r r h y t h m i a s will be d o c u m e n t e d in a 12 hour recording, the m o r e recent a v a i l a b i l i t y of totally portable 24 h o u r m o n i t o r i n g s y s t e m s m a k e s prolonged surveillance easier. C o n s e q u e n t ly, the longer period of recording is indicated in a l m o s t all cases. I t is w o r t h e m p h a s i z i n g t h a t the bradycardic aspects of t h e s y n d r o m e m a y be detectable only during sleep. T h i s m a k e s a 24 h o u r recording a l m o s t m a n d a t o r y . Ferrer 49 m e n tioned a p a t i e n t with a sleeping r a t e of 28 b e a t s per m i n u t e whereas the r a t e during t h e d a y was 60. P r o v o c a t i v e tests.

Carotid sinus massage. T h i s h a s been advocated as a provocative test for the SSS. T h e response to this m a n e u v e r , which should be done only with E C G monitoring, is difficult to interpret a t times. Ajuiss, Rosin, a n d A d o l p h 54 h a v e reported t h a t significant sinus slowing m a y o c c u r in elderly persons with sinus b r a d y c a r d i a w h o are a s y m p t o m a t i c . In his series of 31 cases of t h e SSS, however, Mande147 r e p o r t e d seven with an a b r u p t sinus arrest lasting longer t h a n 3 seconds. In four, this response was the m a j o r m a n i f e s t a t i o n of sinus node disease. A p a u s e longer t h a n 3 seconds with carotid sinus massage is highly suggestive of i n a p p r o priate sinus node responsiveness a n d sinus node disease. Such a response should, a t least, a l e r t t h e physician and w a r r a n t s f u r t h e r investigation. Besides this response, however, we h a v e n o t e d t h a t an escape r h y t h m m a y s u p e r v e n e w h e n carotid sinus pressure is applied. CASE4. M. P., a 51-year-old white male house painter, was admitted to the Long Island College Hospital in October, 1973, because of syncope. About 4 months before, he had been American Heart Journal

admitted because of transient left hemiplegia and slurring of speech. His symptoms gradually regressed, and an ECG showed inferior wall myocardial ischemia and an old anteroseptal myocardial infarction. He also stated that he had had episodic retrosternal pain with effort or emotion. In the 3 or 4 weeks before admission, he began to have nearsyncopal episodes. These lasted a few minutes, occurred without warning, and were without sequelae. Although he never lost consciousness, the patient described extreme weakness and lightheadedness during these episodes. Carotid sinus pressure in his private physician's office resulted in a similar episode and was associated with a period of asystole lasting about 3 seconds. Physical examination was unremarkable on admission, and an ECG showed sinus rhythm and a probable old anteroseptal myocardial infarction. A rhythm strip during massage of the left carotid sinus showed conversion of a sinus bradycardia to an idioventricular rhythm (Fig. 8). A permanent pervenous pacemaker was subsequently inserted. The patient has remained free of syncopal attacks since.

COMMENT. In retrospect, it would seem t h a t the episode of " c e r e b r o v a s c u l a r insufficiency" on t h e first admission was, in fact, r e l a t e d to an a r r h y t h m i a of the SSS. Valsalva maneuver. T h i s m a y also be employed to d e m o n s t r a t e sinus node dysfunction. Further, it m a y be used to distinguish the SSS from physiologic sinus b r a d y c a r d i a of the elderly. In the latter situation, the increase in h e a r t r a t e during the strain p h a s e (phase II), occurs, as does subsequent slowing of the h e a r t rate, during the blood pressure overshoot (phase IV). In p a t i e n t s with the SSS, the blood pressure responses to Valsalva m a n e u v e r occur, b u t t h e r e is little or no change in pulse rate. Once again, however, this procedure is not diagnostic of sinus node disease, b u t m a y be used as c o n f i r m a t o r y evidence a n d as the stimulus for f u r t h e r investigation, Atropine administration. T h e i n t r a v e n o u s administration of a t r o p i n e m a y exclude the SSS. This drug will reveal the vagal etiology of sinus bradycardia by eliminating it. F e r r e r 49 has s t a t e d t h a t , if i n t r a v e n o u s atropine sulfate (1 to 2 mg.) does not increase sinus b r a d y c a r d i a to a sinus r a t e exceeding 90 per minute, a n d if, a f t e r atropine, sinus node recovery t i m e r e m a i n s prolonged a f t e r overdrive (see below), the diagnosis of a failing SA node is made. Rosen, Loeb, Senno, R a h i m t o o l a , and G u n n a r 5~ r e p o r t e d the response to intravenous atropine of 11 p a t i e n t s w i t h a p p a r e n t sinus node disease. A l t h o u g h eight w e r e considered responsive to the drug, w i t h 25 to 125 per cent increase in h e a r t rate, no p a t i e n t developed a sinus r a t e greater t h a n 90 b e a t s per minute. An interesting associated finding in this series was t h a t all patients receiving a t r o p i n e developed 657

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facilitation of A-V conduction with shortening of PR and P H intervals. Also, in two patients, the sinus node response to atropine was considered "sluggish," in th a t junctional foci accelerated prior to the increase in sinus rate. A t r i a l pacing. This is considered by most authorities to be the most valuable provocative test in the SSS. Atrial pacing in the sick sinus syndrome is generally performed by the placement of a pacing catheter in the right atrium at the right atrial-superior vena caval junction or within the coronary sinus. Reliable pacing is maintained with minimum current, and is begun at 90 beats per minute. The pacing rate is then increased by 10 beat increments to 150 beats per minute. Each pacing period is of 2 minutes' duration. At the end of each period, pacing is abruptly terminated and the interval from the last pacing stimulus to the onset of the next P wave is measured. If atrial asystole occurs, the interval to the junctional escape beat is used. This represents the sinus node recovery time. Narula, Samet, and Javier, ~ however, introduced the concept of the corrected sinus node recovery time (CSRT) as being a more accurate assessment of sinus node function. The CSRT is defined as the difference between the recovery interval following tachypacing and the average resting P-P interval. Although sinus node suppression may be found after atrial pacing of the normal heart, it is related to the resting or control sinus rate, with slower control rates being associated with longer maximum pauses. In the heart with a diseased or malfunctioning sinus node, the C S R T will be prolonged to a greater degree then normal. Ferrer 49 felt t h a t the degree of overdrive suppression is best expressed as a percentage of the control rate. In her view, at a resting rate of 75 to 85 beats per minute, the maximum pause is between 115 and 128 per cent of the control cycle length (or pauses of 800 to 900 msec.). With a control r hyt hm of sinus bradycardia at a rate of 45 to 60, pauses of 1,200 to 1,400 msec. duration represents the critical figure beyond which abnormal suppression is diagnosed. At control rates of 60 beats per minute, a pause of 125 per cent of control {1,250 msec.) is strongly suggestive of SSS. If a sinus bradycardia of 45 beats per minute is the control rhythm, a pause of 1,700 msec. or more is diagnostic even though the percentage increase is 120 per cent. In their study of 46 patients, Mandel, Haya-

(}58

kawa, Danzig, and Marcus 57 evaluated SA node function in 46 patients, three of whom had the SSS. They found a CSRT of 1,041 __ 56 msec. in the normal patients and 4,732 + 415 msec. in those with the SSS. In another series of 31 patients with SSS, Mandel and associates 47 found a mean maximum postpacing C S R T of 3,164 _+ 334 msec. in 29. In this series, they considered a normal SCRT to be 1,073 _ 67 msec. Although atrial pacing is frequently used as a diagnostic aid in the SSS, false negatives m a y occur. This may be seen because of SA-node entrance block, as an adequate challenge by SAnode overdrive is based on the assumption t h a t all of the rapid atrial depolarizations enter the SA node. If entrance block exists, the SA node will be challenged by a smaller number of paced beats than the atrial myocardium. In contrast to the aforementioned studies, Gupta, Lichstein, Chadda, and Badin reported sinus node recovery time in 17 patients with the SSS, compared with 15 controls. In the 15 control subjects, the CSRT ranged from 0 to 375 msec. in 17 patients with the SSS, the C S R T was normal in 11 (150 to 350 msec.) and prolonged in only six (480 to 5,690 msec.). They recommend repetition of atrial pacing after the intravenous administration of atropine to elicit an abnormal response in patients with a normal C S R T and the SSS. In their series of seven patients with SSS who underwent repeat atrial pacing after atropine administration, four had no significant change in CSRT, but three had junctional escape r h y t h m following cessation of atrial pacing. A similar effect was noted by Narula, Samet, and Javier ~ in four of 10 patients with SSS studied after atropine. Bashour, Hemb, and Wickramesekaran ~9 noted the same phenomenon. In summary, although atrial tachypacing remains a valuable diagnostic tool in SSS, falsenegative responses occur. T he physician should be alert for these and proceed to other investigative procedures, including atropine administration, where indicated.

Therapy The therapeutic dilemma facing the physician treating the SSS by pharmacologic means has already been alluded to: viz., the agent used to treat one extreme of arrhythmia may precipitate the other extreme. The classical example is the use of atropine or isoproterenol to treat a brady-

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Sick sinus syndrome

cardic r h y t h m with resulting t a c h y c a r d i a . I t is this dilemma t h a t has resulted, since 1966, in the increased use of the p e r m a n e n t artificial pacemaker to t r e a t the SSS. Before t h e r a p y is instituted, however, it m u s t be first decided which p a t i e n t is in need of treatment. In their excellent article on the b r a d y t a c h y syndrome, Moss and Davis :~:~suggested t h a t patients requiring t h e r a p y be divided into those with m a j o r or minor s y m p t o m s . T h e m a j o r category includes cerebral, coronary, or l o w , o u t p u t problems. The minor categories include mild ankle edema, subjective palpitations, a n d an uncomfortable awareness of slow, rapid, or irregular heartbeat. A l t h o u g h the m a j o r s y m p t o m s require t h e r a p y of a more intense n a t u r e , the patient with only m i n o r s y m p t o m s m a y be managed with low-dose diuretics, reassurance, and anxiety-reducing medications. Obviously, a s y m p t o m a t i c a r r h y t h m i a s of lifethreatening potential should be vigorously a n d immediately treated as follows. P a c e m a k e r t h e r a p y remains the f o u n d a t i o n of t r e a t m e n t for the s y m p t o m a t i c patient. D r u g s such as atropine usually are either ineffective or productive of intolerable side effects. B o t h atrial and ventricular pacing have been used and their efficacy repeatedly demonstrated. 33, :~4, ~o In the absence of A-V c o n d u c t i o n disturbances, atrial pacing should be considered because of its advantages of m a i n t e n a n c e of n o r m a l electrophysiologic conduction p a t h w a y s and preservation of atrial t r a n s p o r t function. I t should also be remembered t h a t atrial pacing m a y p r e v e n t the exhibition of atrial t a c h y a r r h y t h m i a s by overdrive. T h e suitability of atrial pacing, however, is dependent upon the n o r m a l c y of A-V conduction, and this can be determined a c c u r a t e l y only with His bundle recording: In institutions which do n o t have the capability of this technique, e v a l u a t i o n of A-V conduction can also be carried o u t by atrial tachypacing. 47. 5~. 57 If the P R interval remains less t h a n 0.22 second during atrial t a c h y pacing at rates of 120 to 140 per minute, p e r m a nent atrial pacing can be safely performed. If, however, A-V block is clinically evident, or is noted with atrial tachypacing, or in the presence of bifascicular c o n d u c t i o n disturbances, ventricular pacing is the t h e r a p y of choice. T h e significant incidence of A-V c o n d u c t i o n disturbances in the SSS m u s t be c o n s t a n t l y recalled in these considerations. Rosen and associates 5~ f o u n d t h a t

American Heart Journal

53 per cent of their patients with SSS had such a disturbance. Thus, in most cases of SSS, p e r m a n e n t ventricular pacing remains the t h e r a p y of choice. This approach is of obvious value in r e d u c t i o n of s y m p t o m s due to bradycardia. T h e a c c o m p a n y ing atrial t a c h y a r r h y t h m i a s , however, are rarely controlled by this m e t h o d alone. S u c h control m a y occur if ventriculoatrial c o n d u c t i o n is present and the atrial depolarization following each paced ventricular beat suppresses ectopic atrial rhythms. In the absence of such a fortuitous set of circumstances, however, o t h e r t h e r a p y to suppress ectopic atrial r h y t h m s m u s t be sought. Pharmacologic t h e r a p y is the usual choice. Ventricular pacing will allow the use of certain drugs, such as propranolol, w i t h o u t concern for the bradycardic effects of such agents. Similarly, quinidine, procaineamide or digitalis can be administered w i t h o u t the d a n g e r of f u r t h e r bradycardia. The author acknowledges the help and encouragement of Dr. John N. Edson in the preparation of this paper. The secretarial assistance of Mrs. Maryann Brown is also gratefully acknowledged. REFERENCES

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