British Journal, I972, 34, 942-952. The sick sinus syndrome A study of iS cases

Shoung How Wan, Guat Siew Lee, and Charles C. S. Toh From the Department of Medicine, Medical Unit II, General Hospital, Sepoy Lines, Singapore 3

Fifteen patients with features of sick sinus syndrome are reported. Their manifestations varied from severe sinus , , and arrest, to paroxysmal supraventricular tachy- , reflecting the underlying unstable . The rhythm can be bradycardic, tachycardic, or mixed. Thyrotoxicosis tops the list of aetiological factors, others being ischaemic heart disease, drug-induced, subarachnoid haemorrhage, , and . Syncope, usually due to prolonged sinoatrial arrest, was the presentingfeature in half of the cases, and some 70 per cent of patients showed radiological evidence of , though clinical cardiac failure was uncommon. Therapeutic responses to vagolytic and sympathomimetic agents were variable, particularly discouraging in patients with mixed bradycardia and . Cardiac pacing may be life-saving in some cases.

Disorders of the sinoatrial node manifest Clinic for unstable sinoatrial rhythms before themselves in various forms. They range from established atrial among I00 newly , multifocal atrial ectopics, diagnosed thyrotoxic patients. runs of , to prolonged sino- The diagnosis of thyrotoxicosis was based on atrial arrest with total cardiac clinical grounds, protein-bound iodine levels, and temporary radio-iodine uptake studies, while the diagnosis of standstill. The hallmark of their expressions ischaemic heart disease was mainly made on is an unstable sinoatrial node with its caprici- clinical and electrocardiographic assessments. ous rhythms till they reach their established Patients diagnosed as having sick sinus syn- stage when they often lapse into chronic atrial drome were followed up regularly at weekly to fibrillation. Such manifestations of the 'sick monthly intervals, and serial electrocardiograms sinus node', or the 'sick sinus syndrome', as taken as occasions arose. Patients with bradycardic defined by Lown (i967), is characterized by rhythms were assessed for their responses to 'chaotic atrial activity with continual changes exercise, intravenous atropine, sympathomimetic in P wave contour with bradycardia inter- agents, and if necessary cardiac pacing. spersed with and The electrocardiograms were analysed, and multiple recurring ectopic manifestations of sick sinus syndrome were classi- beats with runs of atrial or nodal tachycardia'. fied into the following groups based on Ferrer's We have set out to review our experience of classification. I5 patients who showed clinical and electro- cardiographic features of sick sinus syndrome. Group I: persistent and severe sinus bradycardia. Group II: episodes of isolated sinoatrial block1. Subjects and methods Group III: sinoatrial suppression with (a) escape Over a one-year period, from October I969 to rhythm, as in case of transient sinoatrial arrest; October 1970, all patients seen at the Department (b) replacement rhythm, as occurring with chronic of Medicine of the General Hospital, Singapore, suppression of the sinus node, resulting in replace- particularly those attending the Cardiac Clinic, ment of sinus rhythm with an escape mechanism, were screened, and their electrocardiograms scru- e.g. chronic nodal bradycardia; and (c) rescue tinized for manifestations of sick sinus syndrome. rhythm due to delayed emergence ofthe secondary Patients with acute monit- pacemaker resulting in prolonged sinoatrial arrest - ored in the Coronary Care Unit were excluded, as such 'rescues' often take to short bursts of sick sinus syndrome, when present in this group, paroxysmal tachyarrhythmias. was mostly a transient phenomenon. One of us (L.G.S.) also screened the Endocrine (Thyroid) 1 Note: Electrocardiographically, sinoatrial block is distinguished from sinoatrial arrest in that the latter is Received 28 January 1972. a consecutive series of the former. The sick sinus syndrome 943

Group IV: isolated (unaccom- sinoatrial arrest, with occasional nodal escape panied by other arrhythmias) as a manifestation of beats, the heart rate being about 40 a minute. She sick sinus syndrome. developed occasional syncopal spells and became very lethargic; she was pale and her extremities cold from a low output state due to bradycardia. Case reports Intravenous atropine accelerated both the atrial The case summaries serve to illus- following may and nodal beats, but resulted in atrioventricular trate the manifestations of sick sinus protean dissociation (see Fig. iB), and this effect lasted syndrome. only for 20 minutes. Atrial pacing via an Elecath Semifloating Electrode inserted by the bedside Case ii (thyrotoxic with sick under intracardiac electrocardiographic monitor sinus syndrome) (Patient No. 3)1 A 21i-year-old into the right was established at 2 volts at Chinese girl was admitted in March 1969 with 8o a minute, only for 5 minutes, thereafter, it re- symptoms of thyrotoxicosis for 2. years, confirmed sulted in a Wenckebach type of response (Fig. i C), by radio-131I study and a large goitre. Her due to abnormality of conduction in the atrial rate varied between 6o and 120o a minute with a myocardium or the AV node. It was then thought blood pressure of 1i5o/6o mmHg. Her heart was appropriate to float the catheter electrode into the clinically enlarged with a soft systolic murmur right , and ventricular pacing was insti- over the left sternal edge, but there was no evi- tuted at 2 volts at 8o a minute (Fig. iD). During dence of cardiac failure. A chest film taken 24 pacing her colour improved and extremities be- years before was said to be normal. Her electro- came warm, and blood pressure rose from i2o/6o cardiograms in March revealed sinoatrial arrest to 14o/9o mmHg. When she was weaned off the with an unstable atrial pacemaker and paroxysmal pacemaker 48 hours later, she returned to sinus . She was started on carbimazole ther- bradycardia, but with sinus rhythm (Fig. iE). apy in April, and as she became euthyroid, she Forty-eight hours of pacing did not achieve any lapsed into sezvere chronic sinus bradycardia and shrinking in the size of the heart on the chest film 1 Patient numbers are listed in Table i. (Fig. 2).

F IG. i Thyrotoxic cardiomyopathy with sick sinuts syndrome treated by ventricular pacing.

(A) Lazy sinus syndrome

(B) Effect of I/V atropine

C-Mr

(C) Atrial pacing with Wenckebach phenomenon

.. I~~~~~~~~f'-

:.... -.;- -I (D) Ventricular pacinj

_____ ~(El Sinus rhythm after 48 hours of pacinq ______944 Wan, Lee, and Toh

woman had symptoms of thyrotoxicosis (un- treated) for 9 months when she was admitted for syncopal spells from prolonged sinoatrial arrest recurring frequently over one week. In fact, monitoring electrocardiograms revealed cyclical rhythms of the following sequence: paroxysmal atrial tachycardia or fibrillation, terminating abruptly in from prolonged sinoatrial arrest, rescued by bradycardia from a lazy sinus node which slowly warmed up only to be suc- ceeded by atrial fibrillation again (Fig. 4A). Sub- sequently she was given intravenous atropine for sinoatrial arrest, but with no effect. Soon after she developed three episodes of Adams-Stokes attacks from cardiac standstill. It was then realized that cardiac pacing was the only solution therapeutic- ally. Accordingly, an Elecath Unipolar Semi- floating Electrode catheter was inserted via the right basilic and manipulated into the right atrium under intra-atrial electrocardiographic monitoring, and atrial pacing was instituted at 70 beats a minute on fixed pacing (Fig. 4B). With stable atrial pacing for 48 hours, she remained per- fectly well, the catheter was taken out on the third day due to phlebitis, and she remained in stable F I1G. 2 Chest film ofpatient with thyrotoxic sinus rhythm thereafter, while her thyrotoxicosis cardiomyopathy, showing gross cardiomegaly gradually came under control with carbimazole with tip of Elecath semnifloating electrode in therapy. 11 ventricular position for pacing. Case 4 (phenothiazine-induced sick sinus syn- drome) (Patient No. 9) A 4i-year-old man was admitted as a known case of schizophrenia with Case 2 (thyrotoxic periodic paralysis with un- the history of having taken about a hundred tab- stable atrial pacemaker) (Patient No. 4) A 2.6- lets of thioridazine hydrochloride (Melleril) (50 year-old Chinese man was admitted with the mg each tablet) on the day of admission. He was complaints of sudden weakness of the legs, and conscious with a pulse rate Of 78 a minute, regular, .4. was found to suffer from thyrotoxicosis with blood pressure I30/70 mmHg. Heart and lungs periodic paralysis (serum potasSiUM, 2-I mEq/1.). were clear, there was no neurological deficit, but He was put on carbimazole therapy, and two weeks the patient refused to talk. Three and a half hours later he was observed to have an irregular pulse. after admission, he suddenly collapsed. Electro- Electrocardiogram (Fig. 3) revealed evidence of cardiogram then revealed paroxysmal atrial fibril- an 'altemating bradycardia and tachycardia' syn- lation amidst runs of multifocal atrial ectopics, drome (Short, I954), with an unstable atrial pace- and sinoatrial arrest. It showed features of maker wandering into the coronary sinus node. 'chaotic atrial mechanism' (Phillips, Spano, and The runs of inverted P waves showed varying PR Burch, i969) characterized by (i) absence of a intervals. This recurred in episodes lasting from dominant atrial pacemaker; (2) P waves of at minutes to hours for a week, then reverted to sinus least three morphologies in a single lead; and (3) rhythm as the patient became clinically euthyroid. varying PP, PR, and RR intervals (Fig. 5). He was resuscitated but remained in and was Case 3 (thyrotoxicosis and bradycardia-tachy- treated with isoprenaline drip later. He died 12 cardia-asystole syndrome) (Cheng, 1968; Adelman hours after admission. There was no documenta- and Wigle, i969) (Patient No. 6) A 63-year-old tion ofthe cardiac rhythm terminally. At necropsy,

F IG.- 3 Patient with thyrotoxic periodic paralysis and sich sinus syndrome V aVR ....~- &VL aVF ......

tt -cm The sick sinus syndrome 945

his heart did not reveal any macroscopical or microscopical pathology. (A) Bradycordia-Tachycordia-Asystole Syndrome F Case 5 ('cardiomyopathy' with sick sinus syn- drome) (Patient No. I3) A 22-year-old man with complaints of mild exertional dyspnoea was noted ..i ' ! .- since I964 to have pulsus bigeminus with a faint systolic murmur over the left sternal edge without WAg.0* evidence of cardiac failure. Radiologically, the heart was slightly on the large side with unremark- *,ble configuration. Electrocardiogram (Fig. 6) revealed intermittent sinoatrial arrest, with nodal escape rhythm coupled by retrogradely activated sinoatrial beats. This resulted in clinical pulsus E bigeminus. He was thought to have a form of cardiomyopathy of unknown origin. He had re- LI mained in such rhythm since I964. It is interesting to note here that while the sinoatrial node itself ,*has completely lost its own rhythmicity, it is cap- able of being retrogradely activated to initiate normally conducted sinus beats. Physical exercise (B) Atriol pacing at 2 SV at 70:/mmi and intravenous atropine, sustained-released iso- > prenaline (Saventrin), did not accelerate the heart significantly. Atrial pacing with a semifloating ! a I 1¶ electrode failed repeatedly to capture the atrium, using stimuli up to 5 volts. Intra-atrial electro- ,Xardiograms confirmed the previously described electrocardiographic features. Finally, he was put VCXLAL on tablet orciprenaline (Alupent) 20-40 mg 6- hourly and his heart rate was maintained at about * 60-70 a minute, and palpitation became less distressing. (C) Sinus rhythm restored after 72 hours pacing

Results I t I i There were iS patients in this series compris-

A .- ing 6 men and 9 women. The slightly higher U, i'*. 7--.-A.**.-j female ratio is probably due to the higher pro- portion of patients with thyrotoxicosis.

Age distribution The age distribution of FIG. 4 Patient with thyrotoxicosis and the i5 patients is shown in Fig. 7. As expected, bradycardia-tachycardia-asystole syndrome: the peak incidence falls on the 6I-70 years age 72 hours of atrial pacing restored sinus rhythm. ogroup, mainly because of the high incidence of ischaemic heart disease at this age group. Thyrotoxicosis, on the other hand, has two the former was responsible for the sinoatrial peaks of incidence generally, i.e. at the teenage disturbances in view of the fact that such dis- group and about middle age, when they may turbances subsided with antithyroid therapy. be complicated by ischaemic heart disease. Drug-induced sinoatrial rhythm disturb- The other miscellaneous causes of sick sinus ances were noted in two patients. The striking .syndrome affect patients of all ages. features among these are, (a) both cases mani- fested as chaotic atrial mechanism, and (b) Aetiology Table i tabulates the aetiology they carried a high mortality in that both and related clinical features in these I5 cases patients perished. V of sick sinus syndrome. The rest, the miscellaneous group, had From this Table, it can be seen that ischae- aetiologies varying from subarachnoid hae- mic heart disease and thyrotoxicosis form the morrhage to myocarditis and cardiomyopathy, ,underlying causes of the sick sinus syndrome while in 2 patients, the underlying causes were in 50 per cent of cases in this series. This may unidentifiable. have to do with the somewhat selective nature of our collection of cases. In three instances Clinical features It is noteworthy that i, where ischaemic heart disease might have co- while the sick sinus syndrome due to ischae- existed with thyrotoxicosis, it was likely that mic heart disease tended to be bradycardic 946 Wan, Lee, and Toh

; vv...... A .i I aVR

p

aVL

6-35 Bp syst IIq A i44~~~AV~4444KIAfd aVF

FIG. 5 Thioridazine-induced chaotic atrial mechanism, with sinoatrial arrests and paroxysmal atrial flutter in between. those with thyrotoxicosis tended to be tachy- Only 7 patients with bradycardic rhythm cardic, whether paroxysmal or sustained. had therapeutic trial to assess various cardiac Some 50 per cent ofpatients presented with accelerating agents. The presence of mixed syncopal spells. Such syncope often stemmed rhythms of bradycardia and tachyarrhythmia from prolonged sinoatrial arrest, or severe frequently made it difficult therapeutically, as nodal bradycardia. Only on one occasion was very often drug treatment of will it ascribed to paroxysmal atrial tachycardia. potentiate the other. It was in the background About 70 per cent of patients (io out of i5) of such therapeutic dilemma that our patient had radiological evidence of cardiomegaly, (Case 3) was put on fixed atrial pacing with usually mild. However, clinical cardiac failure overdriving. was exceptional. The electrocardiographic features of sick Discussion sinus syndrome are analysed and tabulated in Diseases of the sinoatrial node assume a wide Table 2. Though the number of patients in spectrum of arrhythmia and conduction de- each group is small, there are certain charac- fects. The term sick sinus syndrome was teristics in each group which are summarized first coined by Lown (I967) to denote the in the Table as 'group characteristics'. group of unstable and chaotic supraventricu- 14- Mortality Of iS patients, 3 died. Both pa- lar rhythm after cardioversion for chronic tients with sick sinus syndrome from drug atrial fibrillation in patients on , while intoxication perished, while another with sub- Ferrer (I968) has reviewed extensively the arachnoid haemorrhage died more from the pathophysiological mechanisms and clinical I underlying disease rather than sick sinus syn- manifestations of sick sinus syndrome. When drome itself. Of those who survived, the such a syndrome is essentially bradycardic, follow-up period varied between three months it has been referred to as 'lazy sinus rhythm' and six years. (Shaw and Eraut, I970) (see Case i). Persist- ent sinus bradycardia is often the early sign of Response to therapy Table 3 shows the sinoatrial node disease. It may be so severe as varied responses to drug treatments and to require permanent atrial pacing (Clarke, pacing. Evans, and Milstein, I970). Such bradycardia The sick sinus syndrome 947

mrirVr = V -* - = t. VP -.u-v- = ; ,ILL -u

LEAD II ~~~~~~~~ - a -*/.->

FIG. 6 Patient with pulsus bigeminus from essentially a chronic nodal bradycardiac rhythm for six years.

should not be confused with the well-known The autonomic system may play a permis- physiological bradycardia of the athletes. sive if not an essential role in these. Physiologically, the sinoatrial node has the Whenprolonged, sinoatrial node suppression highest rate of impulse formation, which gives rise to sinoatrial arrest, of a few beats makes it the dominant pacemaker in the nor- duration, after which cardiac activity may re- mal healthy heart. However, under certain sume with an escape mechanism which may *circumstances, diseases of the sinoatrial node, be atrial, nodal, or even ventricular. whether organic, as in inflammation or infarc- Occasionally, spontaneous sinoatrial acti- tion, or functional from autonomic imbalance, vity may be continuously or even permanently jnay lead to transient or prolonged failure of suppressed, while cardiac function is sustained the spontaneous rhythmicity. by an ectopic atrial or When transient, sinoatrial node suppression which virtually replaces the sinus rhythm. results in sinoatrial block. The possible Patients I3, I4, and IS with chronic nodal ,%mechanisms of this include. (a) A disturbance bradycardia probably belong to this group of of impulse formation; (b) abnormal conduc- sick sinus syndrome. tion of impulses between the sinus node and Sometimes, sinoatrial arrest may continue the atrial muscle - the so-called 'exit block'; for more than a few beats, due to delayed and (c) atrial unresponsiveness due to sub- emergence of an escape pacemaker which, 'hreshold impulse formation in the sinoatrial having been delayed, makes a dire-dash node (Sherf, I969). 'escape' to the rescue, the so-called 'rescue rhythm'. Such sinoatrial arrests often result in Adams-Stokes attacks and the rescue rhythms often take to bouts of ventricular or FIG. 7 Chart showing age distribution of i5 supraventricular tachyarrhythmias. cases of sick sinus syndrome. Atrial fibrillation could be a manifestation of disorders of the sinoatrial node too. Thus, chronic atrial fibrillation with slow ventricular rate unassociated with drug therapy (e.g. bi- nodal disease) is often the established stage of sick sinus syndrome, while transient or paroxysmal atrial flutter or fibrillation, whe- ther accompanied by other forms of arrhyth- mia, could be the early stage of this syndrome. In fact, it is interesting to note that sick sinus syndrome was first coined for the chaotic supraventricular arrhythmia after cardiover- sion in patients with atrial fibrillation main- Age, group tained on digitalis. Here the sick sinus node 948 Wan, Lee, and Toh

TABLE i Summary of aetiology and clinicalfeatures of i5 cases of sick sinus syndrome

Aetiology Patient Sex, Pulse Syncope (cause) Cardio- Principal rhythm Sick sinus Survival -14 No. age rate megaly syndrome to date (Case No.) (yr) group Ischaemic heart disease I M/6I 30-60 0 + Sinus bradycardia + SA II Alive block (8 mth) 2 Ff70 40 0 + Sinus bradycardia I Alive (I2 mth) Thyrotoxicosis 3 (Case i) Ff2i 30-50 + (SA arrest) +++ Nodal bradycardia + SA IIIb Alive arrest (8 mth) v 4 (Case 2) M/2o IIO-150 0 - Wandering pacemaker IIIa Alive (3 mth) 5 F/64 90-200 0 - Paroxysmal atrial fibrilla- IV Alive tion (7 mth) Thyrotoxicosis + mild 6 (Case 3) F/63 Unstable + (SA arrest) + Mixed bradycardia + IIIc Alive VI ischaemic heart disease tachycardia (ii mth) 7 F/66 Unstable o - Paroxysmal atrial fibrilla- IV Alive tion (I2 mth) 8 F/66 Unstable o + Wandering pacemaker + IIIb Alive t, paroxysmal atrial fibrilla- (4mth) tion Drugs: thioridazine 9 (Case 4) M/4I Unstable + (SA arrest) - Wandering pacemaker + IIIb Dead hydrochloride paroxysmal atrial tachy- cardia + SA arrest i Drugs: digoxin Io M/83 Unstable o + Wandering pacemaker + IIIb Dead paroxysmal atrial fibrilla- tion + paroxysmal atrial tachycardia t, Cerebral vascular II M/85 100 - + Wandering pacemaker IIIb Dead accidents Viral 12 F/64 80 + ( ? paroxysmal + Paroxysmal atrial fibrilla- IV Alive atrial tachy- tion (6 mth) cardia) ? Myocarditis cardio- I3 (Case5) M/22 40-50 + (SA arrest) + Nodal bradycardia IIIb Alive myopathy (6 yr) Unknown 14 F/52 30-40 + (bradycardia) - Nodal bradycardia + IIIb Alive wandering pacemaker (22 mth) ,. I5 F/41 30 0 + Nodal bradycardia + SA IIIb Alive arrest (5 mth) SA, sinoatrial.

TABLE 2 Electrocardiographic group characteristics of sick sinus syndrome Group Patient No. SA SA arrest Escape mechanisms Atrial Atrial Group characteristics (Case No.) block fibrill. tachy- Atrial Nodal Ven- cardia tricular

I 2 ------Essentially bradycardic, with or without II I + ------SA block; paroxysmal supraventricular4- tachyarrhythmia conspicuously absent IlIa 4 (Case 2) - + + + - - Rhythm can be bradycardic or tachy- IlIb 3 (Case I) + + + + + - - cardic or mixed; SA arrest or chronic 8 + SA Suppression - + + - suppression, a common feature, with 9 (Case 4) + + + + + + or without SA block; escape mechanisms IO + SA Suppression - + + - may be atrial, nodal, or ventricular; II + SA Suppression - + + - + supraventricular tachycardia often I3 (Case 5) + + - + + - - present: this can (a) recur; (b) lead to 14 + SA Suppression - + - - SA arrest from post-drive suppression-' I5 - SA Suppression - + - - (c) follow SA arrest as a rescue rhythm IIlc 6 (Case 3) + + + + + + IV 5 - - - - - + - Essentially atrial fibrillation, chronic 7 - - + + + + - paroxysmal, and unaccompanied by I2 - + - other arrhythmias The sick sinus syndrome 949

TABLE 3 Response of bradycardic rhythm to therapy Sick sinus Patient Aetiology of sick sinus syndrome Atropine Iso- Orci- Cardiac pacing Post-pacing syndrome No. I. V. prenaline prenaline group I 2 Ischaemic heart disease + o o o II I Ischaemic heart disease + o o o III 3 Thyrotoxic cardiomyopathy AV dissociation + Ventricular Sinus bradycardia III I3 ? Cardiomyopathy + + + Unsuccessful III 14 Unknown - - + o MIII I5 Unknown - o o o III 6 Thyrotoxicosis + mild ischaemic - 0 0 Atrial Sinus rhythm heart disease

A o =Therapeutic agent not tried; - =therapeutic agent tried but no response; ±=therapeutic agent yielded doubtful or marginal response; + =therapeutic agent yielded good response.

may take time to 'warm up' before assuming to sinoatrial arrest. The duration of such over- dominance after cardioversion. drive suppression of the sinoatrial node has The rhythm in sick sinus syndrome may be been found to be directly proportional, within classified as follows. (i) Bradycardic, as in limits, to the rate and period of the over- Groups I and II; (ii) tachycardic, as in Group driving tachycardia. Our patient (Case 3) with ,JV mostly; and (iii) mixed rhythms, mainly in untreated thyrotoxicosis is an example of this Group III. fascinating arrhythmia. Reviewing the published work one finds In I957, Dewhurst described 'malignant that long before the sick sinus syndrome was auricular arrhythmias' in 4 patients with t coined, various forms of allied disorders of paroxysms of separate kinds of atrial arrhyth- similar nature were described. Thus, Short mias following one another closely. They (I954) first described the syndrome of alter- were noted for their unstable rhythms, ob- nating bradycardia and tachycardia where stinacy to conventional therapeutic agents sinus bradycardia was complicated by (e.g. digitalis, quinidine, etc.), progressive paroxysmal tachyarrhythmia. Of 4 patients he cardiac failure, and grim prognosis. described, 3 suffered from aortic or mitral Not only are the rhythms of sick sinus syn- s valvular diseases. One such syndrome was drome unstable but they may be chaotic. In seen in our series in a patient with thyrotoxi- fact, 'chaotic atrial mechanisms' (Phillips et cosis with periodic paralysis (Case 2). In this al., I969) have been described in patients with connexion, it is interesting that while all (a) absence of dominant pacemaker, (b) P Short's patients failed to respond to routine waves of at least three morphologies in a single therapy with digitalis, procainamide, and lead, and (c) varying PP, PR, and RR inter- intravenous atropine, one of them was ren- vals. Chaotic atrial mechanisms may be inter- dered free from the arrhythmia for I8 months mittent or sustained, and are often associated after total thyroidectomy. This syndrome with atrial fibrillation. In Burch's series, 3 per s described by Short later comes to bear the cent of patients with chaotic atrial mechan- name ofbrady-tachycardia syndrome in recent isms were thyrotoxic and 58 per cent of pa- reports. tients were receiving digitalis; it carried a Allied to the above-mentioned syndrome is poor prognosis with a hospital mortality of 52 -the bradycardia-tachycardia-asystole syn- per cent. For comparison, it is noteworthy drome first described by Adelman and Wigle that 2 out of 3 such patients in our series were (I969) in which the cardiac rhythm occurs in - . cyclical sequence as given in the order of the associated with drug toxicity thioridazine syndrome. It is believed (Zipes and Wallace, hydrochloride and digitalis, while the third I969) that in this syndrome, bradycardia due was found in a thyrotoxic patient (Patient to the depressed sinus node predisposes to No. 8). Both the former died while the latter 4the emergence of ectopic tachyarrhythmia, survived. which in turn, through the mechanism of Similar to chaotic atrial mechanisms is ' post-drive suppression' from membrane 'multifocal atrial tachycardia' described by hyperdepolarization (Lange, I965), further Shine, Kastor, and Yurchak (I968). In view suppresses, in its wake, the already depressed of the characteristic resemblances to 'chaotic intrinsic rhythmicity ofthe sinus node, leading atrial mechanisms', it has been recently 950 Wan, Lee, and Toh labelled as chaotic atrial tachycardia (Lipson tem. In our series, the patient with subarach- and Naimi, I970). noid haemorrhage (Patient No. ii) developed an unstable sinoatrial rhythm with runs of Aetiology of sick sinus syndrome There wandering pacemakers. is a host of aetiological factors in the causation of the sick sinus syndrome. Drugs It is well established that digitalis The to the sinoatrial node, like any could induce a host of cardiac arrhythmias, other artery in the coronary system, can be and the depressant effect on the sinoatrial involved by arteriosclerosis. Circulatory in- node (and other pacemakers) could well be re- sufficiency and injury to the sinoatrial node sponsible for various manifestations of sick can result in transient manifestations of sick sinus syndrome. In fact, sick sinus syndrome sinus syndrome, including sinoatrial block and was first described in digitalized patients sub- arrest (Rossi, I969), and damage to the sino- jected to cardioversion for chronic atrial atrial node in acute myocardial infarction is fibrillation. not an uncommon cause of transient atrial As for thioridazine hydrochloride, it has fibrillation and other atrial arrhythmias. been well documented that many psychiatric The significant incidence of atrial arrhyth- drugs, particularly members of the pheno- mias in thyrotoxicosis and the frequency with thiazine group, in susceptible individuals, which they disappear when thyroid hyper- could induce wide ranges of atrial or ventricu- function is controlled suggest that thyroxine lar arrhythmias (Burda, I968; Kelly, Fay, and influences atrial automaticity and excitability, Laverty, I963). either directly or indirectly. When thyroid hor- moneisadministered to embryonic heart before nerve elements appear, it causes an accelerated Myocarditis and cardiomyopathy In these rate and sometimes an irregular heart (Marko- broad categories of heart disease, whether the witz and Yater, I932). When given to dogs pathological process is inflammatory, infiltra- with denervated , it causes tachycardia tive, or degenerative, the sinoatrial node may (Martius and Hess, I95I). This indicates that be involved, and in the earlier stages, as in an thyroid hormone has a chronotropic effect irritative phenomenon, paroxysmal and tran- directly on myocardium. It is also believed sient episodes of arrhythmias could result. that thyroid hormone accelerates the heart and Sometimes, neurovegetative changes in the potentiates emergence of the ectopic pace- ganglionic plexus supplying the sinoatrial maker by sensitizing beta-receptors of the node (Rossi, I969) associated with the diseases heart to circulating catecholamines (Brewster may play a role in the genesis of sick sinus et al., I956). Norepinephrine most closely syndrome as well. Thus both chagasic cardio- simulates the physiological effects of hyper- myopathy (Brasil, I9s5) and diphtheritic myo- thyroidism. It is on this basis that beta- have been found to show sinoatrial blockers have been advocated for the sympto- node ganglionic plexus degeneration - causing matic treatment ofpatients with thyrotoxicosis the so-called 'automatic sinoatrial block'. (Howit and Rolands, I966; McLean, I967). Whatever the underlying diseases, it may However, it may be difficult to account for the be said that sick sinus syndrome results either existence of severe bradycardiac rhythms from direct structural damage to the sinoatrial (such as lazy sinus rhythm) in the thyrotoxic node whether ischaemic in origin or other- patient. None the less, whatever the unstable wise; or from sympathetic-parasympathetic supraventricular rhythm, these patients tend imbalance as a result of (i) disturbances from ultimately to end up in established atrial circulating hormones or drug agents, or (ii) fibrillation. neurovegetative derangement of the gangli- Apart from abnormalities in ST and T onic fibres to the sinoatrial node by the disease waves to simulate patterns of myocardial in- process. farction (Byer, Ashman, and Toth, I947; Cropp and Manning, I960), subarachnoid Management The management of patients haemorrhage may also induce arrhythmias, with sick sinus syndrome has been a challeng- particularly of the supraventricular variety. ing and difficult problem. Treatment with Thus, Hunt, McRae, and Zapf (I969) re- vagolytic drugs for the bradycardic rhythm ported 6 cases of sinus bradycardia and 2 in- whether sinus bradycardia, nodal rhythm, or stances of wandering pacemakers in 20 pa- sinoatrial block or arrest, stems from the tients with primary subarachnoid haemor- belief that these may be due to vagotonic rhage. The possible mechanisms producing effect. Generally, responses to atropine, sick sinus syndrome in subarachnoid hae- sympathomimetic agents such as isoprenaline morrhage probably involve the autonomic sys- (including sustained-release isoprenaline) The sick sinus syndrome 951

and orciprenaline, are discouraging. Only group. The mortality of the syndrome is de- 3 out of our 7 patients with bradycardic pendent on both the predominant arrhythmic rhythm had a favourable response to any one pattern and the underlying condition. The of these drugs. Digitalization for supraven- high mortality in the drug-induced group is tricular tachyarrhythmia in sick sinus syn- probably due as much to brain damage and drome does not seem practical in patients with metabolic disturbance as to the arrhythmia mixed bradycardia and tachycardia as ob- itself. served by Short (I954). The main difficulties involved in therapy of We wish to thank Professor 0. T. Khoo and mem- t sick sinus syndrome stem from a number of bers of the staff of the department for referring factors. patients with unstable sinoatrial rhythm to us for investigation and treatment. i) The rhythm is often unpredictable, coming on in paroxysms. 2) The rhythms are often mixed, with brady- cardia intermingled with tachycardia. References A The underlying aetiology in some cases is Adelman, A. G., and Wigle, E. D. (I969). The brady- 3) cardia, tachycardia, asystole syndrome. Canadian not identifiable or not remediable, e.g. arterio- Medical Association Journal, 100, 75. sclerotic ischaemic heart disease; or even if Brasil, A. (1955). Autonomical sino-atrial block; a new remediable, as in thyrotoxicosis, it may take disturbance of the heart mechanism. Arquivos time, so that arrhythmia will have to be dealt Brasileiros de Cardiologia, 8, I59. Brewster, W. R., Isaacs, J. P., Osgood, P. F., and King, with in the mean time. T. L. (1956). The haemodynamic and metabolic 4) The management of intermittent but pro- interrelationships in the activity of epinephrine, > longed sinoatrial arrest is even more difficult. nor-epinephrine and the thyroid hormones. Circu- Apart from attempting to treat the underlying lation, 13, I. Burda, C. D. (I968). Electrocardiographic abnormali- cause, atrial pacing may help. In cases with ties induced by thioridazine (Mellaril). American alternating bradycardia and tachycardia, or Heart Journal, 76, 153. bradycardia-tachycardia-asystole syndrome, Byer, E., Ashman, R., and Toth, L. A. (I947). Electro- atrial pacing at a high rate may be the answer cardiograms with large upright T waves and long QT intervals. American Heart_Journal, 33, 796. (Rokseth, Gedde-Dahl, and Foss, 1970); it Cheng, T. 0. (I968). Transvenous ventricular pacing takes care of the severe bradycardia and tem- in the treatment of paroxysmal atrial tachyarrhyth- porary asystole, while it suppresses the tachy- mias alternating with sinus bradycardia and stand- cardia by overdriving with fixed rate pacing, still. American Journal of Cardiology, 22, 874. Clarke, M., Evans, D. W., and Milstein, B. B. (I970). or, failing that, it still allows for the safe ad- Sinus bradycardia treated by long term atrial pac- ministration of antiarrhythmic agents without ing. British Heart Journal, 32, 458. having to worry about aggravating the brady- Cropp, G. J., and Manning, G. W. (I960). Electro- cardic rhythm. This was life-saving in Patient cardiographic changes simulating myocardial and infarction associated with spontaneous No. 3 (Case i). However, the high frequency intracranial haemorrhage. Circulation, 22, 25. of atrial and atrioventricular disturbances in Dewhurst, W. (1957). Malignant auricular arrhythmia. these patients often compels one to resort to British HeartJournal, 19, 387. fixed or demand pacing from the right ven- Ferrer, M. I. (I968). The sick sinus syndrome in atrial disease. J7ournal of the American Medical Associa- tricle. tion, 206, 645. Howit, G., and Rowlands, D. J. (I966). Beta-sympa- thetic blockade in hyperthyroidism. Lancet, I, 628. Conclusions Hunt, D., McRae, C., and Zapf, P. (I969). Electro- cardiographic and serum enzyme changes in sub- It appears from this series that the sick sinus arachnoid haemorrhage. American Heart Journal, syndrome may be caused by varied aetio- 77, 479- logical factors, with thyrotoxicosis heading the Kelly, H. G., Fay, J. E., and Laverty, S. G. (I963). list. Untreated, the toxic state hastens the pro- Thioridazine hydrochloride (Mellaril): its effects on the electrocardiogram and a report of two fatali- gression of this arrhythmia to atrial fibrilla- ties with electrocardiographic abnormalities. Cana- tion. Control of toxicity generally cures the dian Medical Association Journal, 89, 546. syndrome though not invariably so (Case i). Lange, G. (I965). Action of driving stimuli from in- Therapy is difficult in view of the diverse trinsic and extrinsic sources on in situ cardiac pace- maker tissues. Circulation Research, 17, 449. manifestations within the same patient from Lipson, M. J., and Naimi, S. (1970). Multifocal atrial x-sinoatrial arrest and bradycardia arrhythmia tachycardia (chaotic atrial tachycardia). Circulation, to atrial tachycardia and chaotic atrial rhythm. 42, 397. In view of the unpredictability of response to Lown, B. (I967). Electrical reversion of cardiac the sympathomimetic and vagolytic drugs, arrhythmias. British Heart Journal, 29, 469. McLean, A. G. (I967). Adrenergic beta-blockade in cardiac pacing is more reliable in both the thyrotoxic crisis. Medical Journal of Australia, 2, bradycardiac and paroxysmal tachycardiac 229. 952 Wan, Lee, and Toh

Markowitz, C., and Yater, W. M. (I932). Response of Sherf, D. (I969). Editorial. The mechanism of sino- explanted to thyroxin. American atrial block. American J'ournal of Cardiology, 23, Journal of Physiology, 100, I62. 769. Martius, C., and Hess, B. (I95I). The mode of action Shine, K. I., Kastor, J. A., and Yurchak, P. M. (I968). of thyroxin. Archives of Biochemistry and Bio- Multifocal atrial tachycardia; clinical and electro- physics, 33, 486. cardiographic features in 32 patients. New England Phillips, J., Spano, J., and Burch, G. (I969). Chaotic Journal of Medicine, 279, 344. atrial mechanism (C.A.M.). American Heart Jour- Short, D. S. (1954). The syndrome of alternating nal, 78, 171. bradycardia and tachycardia. British Heart Journal, Rokseth, R., Gedde-Dahl, D., and Foss, P. 0. (1970). I6, 208. Pacemaker therapy in sino-atrial block complicated Zipes, D. P., and Wallace, A. G. (I969). Artificial atrial by . British Heart Journal, and ventricular pacing in the treatment of arrhyth- 32, 93. mias. Annals of Internal Medicine, 70, 885. Rossi, L. (I969). Disturbances in impulse conduction - sino-atrial arrest, sino-atrial block and atrial stand- still. In Histopathologic Features ofCardiac Arrhyth- mias. Casa Editrice Ambrosiana, Milan. Shaw D. B., and Eraut, D. C. (I970). Sinus brady- cardia, sino-atrial block and lazy sinus syndrome. Requests for reprints to Dr. C. C. S. Toh, De- In Proceedings of the British Cardiac Society. partment of Medicine, Medical Unit II, General British Heart Journal, 32, 557. Hospital, Sepoy Lines, Singapore 3.