Cardiac Arrhythmias Adv. Cardiol., vol. 22, pp. 71-79 (Karger, Basel 1978)

The Sick Sinus Syndrome WILLIAM J.MANDEL, JAY L.JORDAN and IWAO YAMAGUCHI Division of Cardiology, Cedars-Sinai Medical Center, and Department of Medicine, UCLA Medical Center, Los Angeles, Calif.

'The sick sinus syndrome' is an eponym coined by FERRER [1] referring to a constellation of signs, symptoms and electrocardiographic criteria defining sinus node dysfunction in a clinical setting. These criteria have been described by many investigators [2-7] and include sinus bradycardia, sinus arrest, sino-atrial block, alternating bradyarrhythmias and tachyarrhythmias and carotid hypersensitivity. Anyone or combination of these features may be seen in the typical sick sinus patient who presents with syncope or other evidence of cerebral dysfunction. Symptoms, nevertheless, are a manifestation of failure of escape pacemaker function and not truly a feature of sinus node malfunction.

The sinus node is a highly organized cluster of specialized cells located in the area of the junction between the superior vena cava and the right atrium. Microscopically, three cell types have been described in the sinus node: (1) P cells, (2) transitional cells and (3) working cells [8]. The P cells, so named because of their pale appearance, resemble primitive myocardial cells and are thought to be responsible for sinus node pacemaker function. Recently, a perinodal zone of unique cell type surrounding the sinus node of the rabbit has been identified [9]. These perinodal fibers have electrophysiologic characteristics distinct from the sinus node and normal atrial tissue and represent a buffer zone through which electrical activity must pass on its way out of or into the sinus node.

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The Sinus Node as the Intrinsic Cardiac Pacemaker: Anatomical and Electrophysiologic Considerations



The vascular supply to the mammalian sinus node region comes from a central artery that does not appear to terminate in the sinus node. In man, the sinus node artery originates from the proximal 2-3 cm of the right coronary artery in 55 % of the cases and from the proximal 1 cm of the left circumflex artery in 45 % [10]. Sinus node artery collapse and distension, moreover, appears to playa role in the nature of sinus node discharge. This appears to be due to phase stretching of the periarterial area. Furthermore, recent data has supported the contention that diminished coronary flow, secondary to atherosclerotic disease proximal to the origin of the sinus node artery may result in sinus node dysfunction. The phenomenon of spontaneous phase 4 depolarization is the electrophysiologic characteristic that distinguishes pacemaker cells from all other cells in the body. The emergence of the sinus node as the dominant cardiac pacemaker arises from the fact the cells of the sinus node have the fastest rate of spontaneous depolarization. The electrogenic mechanisms responsible for sinus node depolarization have not been clarified. Nevertheless, two basic features have been suggested. Depolarization, in general, appears related to a slow or Ca++-dependent current as compared to a fast or Na+-dependent current in Purkinje fiber or ventricular muscle. In addition, the phase 4 depolarization appears most likely to be due to a change in potassium permeability.

Role of the Autonomic Nervous System in Modifying the Electrophysiologic Characteristics of the Sinus Node The characteristics of spontaneous sinus node depolarization can be modified by parasympathetic and sympathetic influences. Vagal stimulation or acetylcholine can reduce automaticity by decreasing the slope of phase 4 depolarization as well as by hyperpolarizing the cells [11-13]. In contrast, sympathetic stimulation or catecholamine infusion increases the spontaneous sinus node discharge rate, primarily as a consequence of an increase in the rate of phase 4 depolarization [11-13].

It can now be appreciated that the potential sites of dysfunction responsible for the electrocardiographic and clinical features seen in the sick sinus

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Pathophysiologic Considerations

The Sick Sinus Syndrome


syndrome are numerous. Disturbances in intrinsic electrophysiologic properties of the sinus node, such as the determinants of the rate of spontaneous depolarization, must be considered. Moreover, disturbances of variables extrinsic to the sinus node must also be considered; these include the autonomic nervous system, coronary blood supply, the endocrine system and the conduction properties of the perinodal buffer zone [9,14]. Finally, the interaction between the electrophysiologic properties of the sinus node and humoral factors may be disturbed despite normal intrinsic sinus node, autonomic nervous system and endocrine system function.

Evaluation of Sinoatrial Node Function

When a patient presents with a clinical history of palpitations, vague neurological complaints of intermittent dizziness and lightheadedness, or alarming symptoms such as syncope and diaphoretic episodes, the physician must consider sinus node dysfunction in his differential diagnosis. Electrocardiographic documentation of sinus bradycardia, sinus arrest, SA block or brady- and tachyarrhythmias should further strengthen his suspicion.

Electrocardiographic Monitoring

Treadmill testing assesses the ability of the sinus node to accelerate in an appropriate fashion to internal physiologic chronotropic stimuli. Established norms for standard stress testing protocols for age and sex are available [15]. However, ambulatory monitoring with a Holter device is possibly a more useful physiologic technique for assessing sinus node function if performed during normal daily activities (fig. 1). It is to be emphasized that numerous Holter recordings may be necessary in some patients because of the intermittencies of EeG abnormalities. Patient E.S.

Fig. 1. A Holter monitor strip from a patient with symptomatic bradycardiatachycardia syndrome. Note that the supraventricular tachycardia at a rate of 140/min terminates with a prolonged period of sinus arrest. This asystolic period ends with a sinus beat and then, subsequently, marked sinus bradycardia.

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Testing the Interaction between the Sinus Node and the Autonomic System

The signs, symptoms and electrocardiographic features of the sick sinus syndrome may be secondary to sinus node unresponsiveness to appropriate autonomic activity. To test this possibility, pharmacologic methods for increasing the sinus node rate may be employed. Step-wise intravenous infusion of a ,B-stimulating agent such as isoproterenol should cause a prompt sinus rate acceleration of equal to or greater than 25 % above control in normal subjects. In contrast, hypersensitivity to parasympathetic tone can be tested by the intravenous administration of Tensilon. A hypersensitive response to parasympathomimetic drugs would be reflected by a profound slowing of the sinus rate.

Testing the Integrity of the Autonomic Nervous System

A characteristic clinical presentation of the sick sinus syndrome may result from primary dysfunction of the autonomic nervous system. To test this possibility, provocation of autonomic activity should be attempted by mechanical or pharmacologic means. Carotid massage, the performance of the Valsalva maneuver or neosynephrine-induced hypertension should normally produce slowing of the heart rate by reflex responses of the autonomic nervous system. In contrast, lowering the blood pressure by titrated nitroprusside infusion should normally result in a reflex increase in heart rate. Finally a comment should be made about the determination of the 'intrinsic heart rate'. This technique, developed by Jose, utilizes a concentrated intravenous dose of propranolol and atropine which will effectively produce 'total' autonomic block. The resultant sinus drainage rate will allow for a determination of intrinsic sinus function unrelated to the effects of autonomic tone. Therefore, sinus node dysfunction may be related to an intrinsic (sinus node itself) or extrinsic (autonomic) defect.

The technique of atrial overdrive pacing leads to suppression of the sinus node in normals and in patients with the sick sinus syndrome [16]. The maximum sinus pause in normals, when corrected for the basic sinus rate [corrected sinus node recovery time (SANRTc) = observed SANRT - basic

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Pacing Studies

The Sick Sinus Syndrome



1 sec





Fig. 2. The effect of atrial overdrive pacing on sinus node function. The left femoral artery pressure (LFA) and a lead 2 electrocardiographic lead are shown. The first four complexes are paced at a rate of 130/min. Following termination of pacing, a period of sinus arrest of more than 5 sec ends with a sinus beat. The arterial pressure calibration is shown to the right of the figure.

sinus cycle length], is 450 msec. In some patients with the sick sinus syndrome, specifically those patients with intrinsic sinus node dysfunction, the SANRTc is consistently prolonged beyond the normal duration [17] (fig. 2). Recent evidence suggests that patients in whom pathological disturbances exist predominantly in the autonomic nervous system, demonstrate normal SANRTc. A comment should be made concerning the findings of secondary pauses. The pauses seen following the first sinus beat after anodime are possibly related to entrance or exit block.

The phenomenon of SA block probably occurs in the perinodal buffer zone and can present as an apparent slowing of the rate of discharge of the sinus node [18]. The technique of induced, progressively premature, atrial depolarizations has been used to test sinus node and perinodal function [9]. If the test cycle length (AIA2 intervals) is plotted against the return cycle length (A2A3 intervals), four types of responses have been identified: (I) compensatory pause, resulting from a late diastolic extrastimulus that fails to depolarize the sinus node because of collision with the normal sinus depolarization; (2) sinus node reset, produced by premature depolarization of the sinus node by the extrastimulus resulting in an A2Aa interval of shorter duration than a compensatory pause; (3) interpolation, produced by failure of the extrastimulus to enter the sinus node but not causing a barrier to the conduction to the atrium of the next impulse, and (4) sinus node re-entry

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Testing the Conduction Properties of the Perinodal Buffer Zone



which results from reflection of the extrastimulus producing an early 'sinus' depolarization (fig. 3). STRAUSS et al. [9] have determined that, with this method, one can evaluate not only sinus node function, but also estimate sinus-to-atrial conduction time. Assuming that the period of time elapsed from onset of the atrial extrastimulus to the time it resets sinus node is equal to the time that reset depolarization of the sinus reaches the atrium, the sinus-to-atrial conduction time can be calculated by taking one-half of the mean duration from A2 to As. Values greater than 120 msec are abnormal.


A ~ 1000


B~ 1000





400 600





Fig. 3. The effect of premature atrial systoles on sinus node function. A Effect of a late diastolic extrasystole is seen. The basic sinus cycle length is 1,000 msec. The premature beat occurs at a coupling interval of 850 msec (85 % of control) and is followed by a sinus beat after a pause of 1,150 msec (115 % of control). The atrial extrasystole did not depolarize the sinus node and the next sinus beat occurred on time. Therefore: 850 + 1,150 = 2,000 msec or 2 times the basic sinus cycle length. B The more frequently observed phenomenon of sinus node reset following atrial premature systoles is demonstrated. Here the atrial extrasystole is initiated at coupling interval of 650 msec (65 % of control). The next sinus beat occurs, as in A, after 1,150 msec (115 % of control). However, the two intervals add up to less than two spontaneous sinus cycles (650 + 1,150 = 1,800 msec). Therefore, the sinus node has been depolarizing by the extrasystole, causing the next spontaneous sinus depolarization to occur earlier. C An even earlier premature depolarization is demonstrated (400 msec; 40 % of control). The next sinus beat occurs very early (600 msec). However, the two intervals (400 + 600 msec) add up to a normal spontaneous sinus cycle, indicating that the extrasystole did not alter the normal sinus discharge rate. Therefore, the extrasystole was interpolated. D Here, the most unusual situation is depicted. A very early atrial extrasystole is initiated (300 msec; 30 % of control) and is followed by an early spontaneous discharge. Note that the sum of two intervals (300 + 400 msec) are less than the spontaneous sinus cycle length. Furthermore, the first beat after the extrasystole has a normal P wave morphology. This phenomenon is considered to represent re-entry of the extrastimulus utilizing the perinodal zone, i. e., a sinus node echo.

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The Sick Sinus Syndrome


His Bundle Recordings

Disturbances of the conduction system in the sick sinus syndrome are often not confined to the region of the sinus node. Frequently abnormal conduction properties and refractory periods are co-existent within the specialized AV conduction tissue. The finding of abnormal electrophysiologic properties within the A V junction supports the diagnosis of the sick sinus syndrome and alerts the physician to the potential for AV block with associated rhythm and hemodynamic disturbances.

Medical management of patients with symptomatic sinus dysfunction is frequently unsuccessful. This failure is related to (1) the lack of responsiveness to pharmacologic agents (atropine-like drugs, isoproterenol), (2) the short half-life of these drugs and (3) intolerable side effects. Therefore, the vast majority of patients are managed by implantation of permanent pacemakers; transvenous ventricular demand units are most frequently employed. However, in some patients adequate cardiac output can only be obtained by atrial or AV sequential pacing. Furthermore, the occurrence of associated tachyarrhythmias may be suppressed by stabilizing the rate but, most often, supplemental antiarrhythmic drugs are needed. In many patients antiarrhythmic drugs can only be given safely following AV sequential or ventricular pacemaker implantation becuase of exaggeration of associated AV conduction disturbances and/or further depression of the abnormal sinus function. Selection of the type of pacemaker for use in the sick sinus patient with the brady-tachy syndrome have their tachyarrhythmia phase eliminated if a stable atrial rate can be achieved. However, if ventricular pacing is utilized, intact V-A conduction is necessary to control the atrial rate. In addition, the atrial contribution to ventricular filling may be essential for adequate hemodynamic performance. Atrial pacing therefore appears to be the most appropriate site for permanent pacing. Nevertheless, many of these patients have AV conduction abnormalities and/or need agents (digitalis, inderal) which depress AV node conduction. Therefore, an A-V sequential mode may be ideal for a singificant number of patients with sinus node dysfunction. In summary, the sick sinus syndrome is the designation of a constellation of clinical signs and symptoms in association with electrocardiography crite-

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Management of the Sick Syndrome



ria for sinus node dysfunction. The underlying mechanisms responsible for the characteristic features of this syndrome are numerous and complex. Furthermore, co-existent disease of more distal portions of the conduction system are common. Continuous Holter monitoring, determination of the sinus node recovery time and the technique of induced atrial premature depolarizations are the most reliable methods for supporting the diagnosis of the sick sinus syndrome. Although a few patients can be managed medically, the majority of patients require permanent pacing. Finally, the tachyarrhythmias associated with this syndrome may not be benefitted by pacing alone and may require the addition of antiarrhythmic drugs.




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The Sick Sinus Syndrome




GOLDBERG, A. N.; MORAN, J. F., and RCSNEKOV, L.: Multistage electrocardiographic exercise tests. Am. J. Cardioi. 26: 84-92 (1970). MANDEL, W. H.; HAYAKAWA, H.; DANZIG, R., and MARCUS, H. S.: Evaluation of sinoatrial node function in man by overdrive suppression. Circulation 44: 59-66 (1971). MANDEL, W. J.; HAYAKAWA, H.; ALLEN, H. N.; DANZIG, R., and KERMAlER, A.I.: Assessment of sinus node function in patients with the sick sinus syndrome. Circulation 46: 761-769 (1972). GOLDREYER, B. N. and DAMATO, A. N.: Sino-atrial node entrance block. Circulation 44: 789-802 (1971).

Dr. W. J. MANDEL, Division of Cardiology, Publication Office, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048 (USA)

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The sick sinus syndrome.

Cardiac Arrhythmias Adv. Cardiol., vol. 22, pp. 71-79 (Karger, Basel 1978) The Sick Sinus Syndrome WILLIAM J.MANDEL, JAY L.JORDAN and IWAO YAMAGUCHI...
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