9 Sinus Node Dysfunction 0 - Springerextras.springer.com/2007/978-1-84628-715-2/fscommand/PDFs/090.pdf · Sinus node dysfunction may be the result of conditions that ... most classic

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Sinus Node DysfunctionDavid G. Benditt, Scott Sakaguchi,

Keith G. Lurie, and Fei Lu

Key Points

• Sinus node dysfunction (SND) encompasses a broad array of disturbances of sinus node or sinoatrial (SA) function that result in chronic or intermittent periods of slow or fast heart beating.

• Sinus node dysfunction may be the result of condi-tions that directly alter sinus node or SA structure, such as ischemic changes, fi brosis or infi ltrative diseases, or extrinsic factors, such as drugs or autoimmune disturbances.

• In children and young adults, intrinsic SA disease has been most commonly associated with presumed direct sinus node damage due to previous atrial surgery, such as closure of atrial septal defects (ASDs), and most impor-tantly, after atrial switch procedures for transposition of the great arteries. However, SND has been observed in patients with unoperated congenital heart disease and even in apparently normal children and adolescents.

• Thromboembolism is the single most important cause of mortality in SND. Its incidence ranges from 15% to 38%.

• Regarding therapy of SND, pacemaker therapy may be appropriate in some cases, drug suppression of arrhyth-mias in others, and both strategies may be required in many individuals.

• Anticoagulation is critical for treatment of many indi-viduals with SND, particularly those with paroxysmal or persistent atrial fi brillation.

• In general, pacemaker therapy is indicated and has proven to be highly effective in patients with SND when bradyarrhythmia has been demonstrated to account for symptoms.

Background

Sinus node dysfunction (SND) encompasses a broad array of disturbances of sinus node or sinoatrial function that result in chronic or intermittent periods of inappropriate slow or fast heart beating. In many patients, both bradycardia and

tachycardia may occur episodically, resulting in a subset of SND that is often termed bradycardia-tachycardia syn-drome (BTS). In others, SND is manifest primarily as inap-propriate heart rate responses for a given level of exertion; these patients are deemed to be exhibiting chronotropic incompetence.

From an historical perspective the concept of SND as a clinical syndrome dates only from the late 1960s and early 1970s,1–3 even though many of the arrhythmias currently considered part of this syndrome had been recognized much earlier. Short’s4 description of the association between atrial bradycardias and tachycardias may reasonably be consid-ered to have provided the initial impetus for development of sinus node dysfunction as a clinical entity. Ferrer’s1,2 work somewhat later was instrumental in bringing the various atrial arrhythmias together as a recognized syndrome. Sub-sequently, Lown5 used the term sick sinus syndrome to describe a chaotic atrial rhythm following cardioversion of atrial fi brillation, while many others contributed to identify-ing various additional important SND features.6–9 For many years the term sick sinus syndrome was the coin of the realm. However, more recently, alternatives such as sinus node dysfunction, sinoatrial disease, and sinoatrial dysfunc-tion have become more widely accepted in the literature. Sinus node dysfunction (SND) is the preferred term in this chapter.

Pathophysiology

The anatomy, histology, and cellular electrophysiology of the sinus node region have been the source of numerous studies and reports. The reader is referred to a few selected publica-tions for an overview.10–14

Initial activation of each beat in the normal heart arises from spontaneously depolarizing pacemaker cells within a relatively diffuse anatomic region that lies laterally in the epicardial groove of the sulcus terminalis of the right atrium.11 Apart from principal pacemaker cells, the sinus node is composed of a variety of comparable pacemaker cell

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Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1934Guidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1937Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1937

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nests that may exhibit somewhat slower intrinsic fi ring rates and consequently are considered to be backup or subsidiary pacemakers.10,12 These backup pacemaker cells or cell groups may be called on to take over under a variety of physiologic and pathologic conditions (e.g., vagal stimulation, sympa-thetic stimulation, electrolyte disturbances, and atrial arrhythmias). The result is an apparent shift of the principal pacemaker site within the sinus node region. In essence, therefore, the sinus node is a pacemaker complex in which periodic shifts of the principal pacemaker site complicate electrophysiologic assessment of sinus node function and may even result in observable alterations of P-wave morphology.11

Conduction of electrical impulses within the elements of the sinus node is normally very slow (2 to 5 cm/s).12 There-fore, the potential for intranodal conduction failure is quite high, and any additional adverse impact on direct cell-to-cell transmission by disease or autonomic nervous system dis-turbance can cause intranodal conduction block or, alterna-tively, can establish the functional substrate needed for reentry (i.e., sinoatrial reentry tachycardia). Importantly, factors extrinsic to the sinus node itself play an important role not only in modulating normal sinus node function but also as contributors to SND.8,14 Both parasympathetic and sympathetic mediators (e.g., acetylcholine, norepinephrine, and epinephrine) alter spontaneous depolarization rates of sinus node cells and may also infl uence the site of the prin-cipal pacemaker within the node.

FIGURE 90.1. Rhythm strip from illustrating onset of symptom-atic bradycardia detected by an insertable loop recorder (ILR, Reveal Plus®, Medtronic, Minneapolis, MN) obtained in a middle-aged male with recurrent but previously undocumented syncope.

TABLE 90.1. Causes of sinus node dysfunction

Intrinsic sinus node dysfunctionIdiopathic degenerative disease (probably most common) May include effects of hypertensionIschemic Chronic coronary artery disease occasionally involving sinus

node artery During acute myocardial infarction (particularly inferior wall,

see “Extrinsic” below)Infi ltrative disorders: amyloidosis, hemochromatosis, tumorsInfl ammatory or postinfl ammatory: pericarditis, myocarditisMusculoskeletal disorders: Duchenne’s or myotonic dystrophy, Friedreich’s ataxiaCollagen-vascular disease: lupus erythematosus, sclerodermaPostoperative: Mustard’s procedure, atrial septal defect repairExtrinsic sinus node dysfunctionDrug effects (see Table 90.2)Electrolyte disturbances: particularly hyperkalemiaEndocrine conditions: hypothyroidism, or less commonly hyperthyroidismMyocardial infarction, acute inferior wall (neural refl ex effects)Neurally mediated bradycardia-hypotension syndromes Carotid sinus syndrome Vasovagal syncope Postmicturition syncope Cough, sneeze syncope OthersMiscellaneous Intracranial hypertension Obstructive jaundice

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FIGURE 90.2. (A) Rhythm strip showing sinus pauses in a symp-tomatic older woman. The slow cycles (left) are approximately twice the cycle length duration of the shorter cycles (right) suggesting 2 : 1 sinoatrial exit block. (B) Rhythm strip showing a pause during sinus rhythm following apparent progressive shortening of the P-P cycle length. This fi nding is indicative of sinoatrial exit block of the Mobitz type 1 (Wenckebach) type.

Manifestations of Sinus Node Dysfunction

Sinus node dysfunction may be the result of conditions that directly alter sinus node or sinoatrial structure, such as ischemic changes, fi brosis or infi ltrative diseases (so-called intrinsic SND), or extrinsic factors such as drugs or auto-nomic disturbances (so-called extrinsic SND)14 (Table 90.1). The resulting clinical picture may be identical in either case, but making the distinction between intrinsic and extrinsic SND has clinical value with regard to treatment strategy.

Given the wide range of causes and arrhythmias associ-ated with SND, the clinical presentation may vary consider-ably from patient to patient.14 Thus, any one or a combination of the following scenarios may be encountered:

Sinus Pauses or Sinus Arrest

Abnormalities of generation of the sinus node impulse (i.e., sinus bradycardia, sinus arrest) and its subsequent emergence into the atrium (i.e., sinoatrial exit block) are perhaps the most classic manifestations of sinus node dysfunction (Figs. 90.1 and 90.2). Either of these phenomena may result in pathologic pauses in the sinus rhythm. Absent specifi c knowl-edge of the underlying mechanism, these interruptions of the rhythm are often categorized simply as sinus pauses for pur-poses of electrocardiogram (ECG) interpretation.

Intraatrial and Atrioventricular Conduction Disturbances

Abnormal intraatrial conduction (e.g., prolonged and/or complex appearing P wave), and in some cases disturbances


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of atrioventricular (AV) conduction (e.g., atrial fi brillation with a slow ventricular response not attributable to drug therapy) are often considered to be elements of SND.

Chronotropic Incompetence

Inappropriate heart rate response (i.e., chronotropic incom-petence, inappropriate sinus tachycardia) such as might be observed during or after physical exertion, while at rest, or during activities of daily living, has been the most recently recognized component of the many features of sinus node dysfunction.15–18

Atrial Tachyarrhythmias

Increased susceptibility to atrial tachyarrhythmias (particu-larly atrial fi brillation), and their attendant potential com-plications (particularly thromboembolism leading to stroke), is perhaps the most important cause of morbidity and mor-tality accompanying SND.4,6,7,19 In many cases, atrial tachyar-rhythmias and periods of excessive bradycardia are observed in the same individual at different times (bradycardia-tachycardia syndrome) (Fig. 90.3).

Delayed Resumption of Sinus Rhythm

Failure of appropriate physiologic pacemaker function fol-lowing an episode of tachycardia (i.e., the spontaneous equiv-alent of a prolonged sinus node recovery time), or delay or absence of restoration of a stable sinus rhythm following overdrive pacing or cardioversion of atrial tachyarrhythmias, may be the basis for lightheaded spells or syncope.

Intrinsic Sinus Node Dysfunction

Certain pathologic states have been associated with the pres-ence of SND in adults and are presumed to have contributed to its development. Coronary atherosclerosis has been most prominent among these.20 However, a causal relationship remains controversial, since both coronary atherosclerosis and sinoatrial disease tend to occur in older individuals and the correspondence, therefore, may be coincidental. The sinus node artery has also been reported to be subject to embolic events as well as occlusive and infl ammatory disease. Again, however, the signifi cance of such fi ndings in the broad range of SND patients remains uncertain.21–24 For example, Shaw et al.24 used postmortem angiography to investigate sinus node blood supply in 25 patients with sinus node disease and compared these fi ndings to those in 54 individuals who died of heart block but in whom sinoatrial (SA) function was believed to be normal. Despite the frequent presence of extensive coronary artery disease (CAD) in SND

patients, greater than 50% stenosis of the sinus node artery was observed in only seven of 25 cases. On the other hand, SA artery disease was not present in any of the 54 heart block patients. Therefore, in perhaps one third of adults with SND, ischemia due to sinus node artery stenosis may have precipi-tated the electrophysiologic disturbance.

Replacement or displacement of normal SA cells by fi brous tissue, with loss of functional components or altera-tion of regional architecture, has been among the more common observations in pathologic examination of cardiac tissues from patients with SND.7,25 Apart from ischemic heart disease, other potential causes include cardiomyopa-thy, surgical trauma, or infl ammation (e.g., pericardial disease, rheumatic heart disease, viral myocarditis, collagen vascular diseases). In some instances the condition appears to be familial in origin26–30; in most cases the etiology of SND is not evident, and the structural changes in the SA region may not be measurably different from the normal increase in fi brous tissue that accompanies aging.

In children and young adults, intrinsic SA disease has been most commonly associated with presumed direct sinus node damage (e.g., hemorrhage, necrosis, suture injury) due to previous atrial surgery, such as closure of atrial septal defects, and most importantly, after atrial switch procedures (Mustard/Senning operation) for transposition of the great arteries.30–35 However, SND has also been observed in patients with unoperated congenital heart disease (including rela-tively benign conditions such as persistent left superior vena cava, as well as lesions of potential hemodynamic signifi -cance) and even in ostensibly normal children and adoles-cents.34,36 Again, in some of these cases a familial disturbance of SA function may have been the cause, but in most instances the origin is unknown.

Extrinsic Sinus Node Dysfunction

Of the extracardiac factors that have an impact on sinus node function without inducing structural changes, cardioactive drugs and autonomic nervous system infl uences are the most important. Electrolyte (e.g., hyperkalemia) and endocrine (e.g., hyperthyroidism) disturbances may also play a role, but far less commonly.

Drugs most often implicated in extrinsic SND include cardiac glycosides, sympatholytic antihypertensives, β-adrenoceptor blockers, calcium channel blockers, and membrane-active antiarrhythmics. Drugs less commonly reported but also known to affect sinus node function include lithium carbonate, cimetidine, amitriptyline, and phenothiazines.13,14

Disturbances of sinus node autonomic control can be responsible for ECG fi ndings suggestive of sinus node disease.8,14,37–40 Therefore, marked sinus bradycardia, sinus pauses, SA exit block, and slow ventricular responses in atrial fi brillation in some cases may be primarily the result of marked hypervagotonia. Conversely, although not widely recognized as a manifestation of SND, persistent or inap-propriate sinus tachycardia may refl ect unbalanced or exces-sive sympathetic activity.

To recap, SND may result from disease states that directly alter the anatomy and function of the pacemaker complex or from external, often reversible, factors (e.g., drugs).

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FIGURE 90.3. Rhythm strip obtained from an older patient with a history of both palpitations and syncope. The tracing reveals atrial fl utter with a long pause terminated by a ventricular escape beat. The history and ECG fi nding tends to support a diagnosis of brady-cardia-tachycardia syndrome (BTS). Q, ventricular escape beat.


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Distinguishing these two major pathophysiologic groups is usually readily achieved, and has obvious prognostic and therapeutic implications.

Epidemiology

Demographics

The incidence of SND is not well established, but it is evi-dent that its prevalence increases with increasing age. One report provided an estimate of only 5 cases in 3000 based on examination of individuals older than 50 years of age (approximate frequency 0.2%).18 However, in the absence of extensive ambulatory electrocardiographic (AECG) monitor-ing, many patients may have been missed. Further, most epidemiologic studies have not clearly differentiated intrin-sic from extrinsic forms of SND. Most likely, both forms are increasing in frequency as more people are living longer, and greater numbers of individuals are being exposed to drugs known to impair sinus node and atrial function.

Most SND patients are recognized in their sixth and seventh decades, although younger patients may also be affected, particularly those individuals who underwent sur-gical repair or palliation of congenital cardiac anomalies in childhood. Currently, various reports suggest that approxi-mately 6% to 24% of pacemaker follow-up clinic patients have a diagnosis of SND. However, this is probably an under-estimate, and the percentage is likely to increase as physi-cians become more aware of the clinical conditions and the potentially wide range of symptoms incorporated within the term SND. In fact, sinus node disturbances now account for more than 50% of patients undergoing new pacemaker implants in many Western countries.

Natural History

The natural history of SND is characterized by a number of concerns apart from solely the frequency and severity of symptomatic arrhythmias. The most important of these addi-tional issues include concomitant disease of the specialized cardiac conduction system, propensity to new-onset atrial tachyarrhythmias (particularly atrial fi brillation), increased risk of thromboembolic complications especially stroke, and ultimately the potential for increased mortality.4,6–8,14,19

The natural course of SND progression has been the subject of several reports.40–45 Five- to 10-year survival statis-tics appear to be similar in patients with SND and patients with other severe conduction system disease.46,47 Thus, when mortality statistics in the former patients were compared with those in otherwise well age- and sex-matched control subjects, Skagen and Hansen48 concluded that patients with SND exhibit a 4% to 5% excess annual mortality in the fi rst 5 years of follow-up. However, among those SND patients without other coexisting disease at time of initial diagnosis, mortality did not differ signifi cantly from that observed in control subjects. The fi ndings of Shaw et al.42 were similar. On the other hand, among other SND patients with a variety of concomitant illnesses (primarily acute and chronic car-diovascular disease), mortality was markedly higher; the latter group exhibited a 4-year survival of 40% versus 85%

for SND patients without coexisting disease and 91% for control subjects.

Sutton and Kenny45 calculated the following overall sur-vival statistics for SND patients: 1 year, 85% to 92%; 5 years, 62% to 65%; 7 years, 52%. However, certain forms of SND appear to have a worse prognosis than others.19 Sinus brady-cardia is reported to be more benign than sinus pauses/arrest, whereas BTS has the worst outlook. In part, these differences may refl ect the relative risk for thromboembolic complica-tions in each setting.

Although concomitant cardiac and renal disease affects mortality in SND patients, systemic embolism is perhaps the most common and potentially preventable cause of death. Embolic events (primarily cerebrovascular embolism) are reported to account for 30% to 50% of deaths in these patients,19,49–51 a fi nding that may diminish given more wide-spread use of long-term anticoagulant therapy and greater attention to use of atrial pacing systems when cardiac pace-makers are indicated. Prospective follow-up studies are essential to verify this potential benefi t.

For the most part, studies of SND natural history are somewhat dated and their current utility is impaired by both the subsequent evolution of treatment options (e.g., physio-logic pacing systems, more recent insights regarding the ben-efi ts of minimizing ventricular pacing, and aggressive anticoagulation), and the current trend to classify a broader array of individuals within the SND “net” (e.g., individuals with chronotropic incompetence).

In the Theopace study,44 (a randomized study comparing theophylline treatment to cardiac pacing in sinus node dys-function) outcomes were examined in 35 untreated symp-tomatic patients (>45 years) with sinus bradycardia (<50 bpm) or sinoatrial block. Patients were followed for an average of 17 ± 15 months. During this period, 20 of 35 patients had cardio-vascular events requiring treatment (syncope, eight; conges-tive heart failure, six; sustained atrial fi brillation, four; and poorly tolerated atrial tachycardias, two). In the 1986 Sutton and Kenny45 review of multiple studies encompassing more than 1.1 million patients with a mean follow-up of approxi-mately 38 months, the incidence of new-onset atrial fi brilla-tion in patients with SND was about 5.2% per year. In paced patients, however, the incidence of atrial fi brillation was only one fi fth as great if atrial pacing was used compared with patients having single-chamber ventricular pacemakers. Thus, cardiovascular complications are common in untreated SND patients, suggesting that an aggressive treatment stance (encompassing pacing and pharmacotherapy) may well be warranted, but would best be undertaken in the setting of a follow-up registry. In the Theopace study,44 therapy with the-ophylline or dual-chamber pacing was associated with a lower incidence of heart failure, while pacemaker therapy was also associated with a lower frequency of syncope.

Clinical Recognition

Clinical and Electrocardiogram Features

Clinical manifestations of SND vary from seemingly asymp-tomatic ECG fi ndings, to a wide range of complaints includ-ing the following:


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• Syncope• Dizziness• Shortness of breath• Palpitations• Fatigue and lethargy• Stroke• Premature mental incapacity

Arrhythmic symptoms in SND patients may be the result of intermittent or persistent excessive bradycardia, chrono-tropic incompetence, or paroxysmal or inappropriate tachy-cardias. However, substantiating a causal relationship between symptoms and abnormal ECG fi ndings is often dif-fi cult. Additionally, many disturbances such as personality changes, memory loss, diminished exertional tolerance, and gastrointestinal disturbances are very subtle in older patients. Finally, systemic embolism is a well-known complication of certain types of SND (especially persistent atrial fi brillation and BTS). Apart from overt stroke, smaller embolic phenom-ena may be the cause of progressive mental status deteriora-tion or dysfunction of other organ systems.

Syncope may be a clinical manifestation of SND due to the hemodynamic impact of either atrial brady- or tachyar-rhythmias (Figs. 90.4 to 90.6). Given the older age of the SND population, however, the risk of ventricular tachyar-rhythmias as a contributing factor must always be consid-ered (Fig. 90.7). Additionally, recent studies have implicated neural refl ex vasodepression (i.e., delayed or inadequate vas-cular response to an arrhythmic stress) as a potential con-tributing cause of symptoms. Failure to vasoconstrict promptly in the face of a bradycardic or tachycardic crisis may be due to aging or drugs or both, and increases the odds that an arrhythmia results in suffi cient systemic hypoten-sion to cause a faint.

Sinus Arrhythmia, Sinus Tachycardia, and Inappropriate Sinus Tachycardia

Sinus arrhythmia, a heart rate variation most often associ-ated with respiratory cycles (rate increases with inspiration and decreases with expiration), is commonly present in healthy individuals, and is not of concern. Extreme degrees of sinus arrhythmia, however, must be differentiated from pathologic sinus pauses (a task usually made relatively easy by the cyclical nature of sinus arrhythmia).

Normal sinus tachycardia (NST) is usually a physiologic phenomenon indicating an appropriate response to demands arising from exercise, fever, anemia, etc. As a rule, NST rarely results in heart rates greater than 180 beats/min in the adult under appropriate physiologic circumstance (the approximate upper limit for sinus rate can be calculated as 220-age in years). Characteristically, sinus tachycardia in response to an appropriate stimulus exhibits a relatively rapid (but not usually abrupt) onset and a gradual slowing after removal of the provoking event. Occasionally, it may be diffi cult to differentiate sinus tachycardia from pathologic rhythm disturbances.52 In this regard, sinus node reentry tachycardia (albeit rarely a sustained arrhythmia) has all the ECG features of NST. However, vagomimetic maneuvers or administration of adenosine usually promptly terminates

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FIGURE 90.4. Implantable loop recorders (ILR) rhythm strip depict-ing termination of a period of sinus bradycardia. The P-waves are of low amplitude but are clearly evident.

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FIGURE 90.5. An ECG rhythm strip illustrating a long pause fol-lowing spontaneous termination of an episode of atrial fi brillation in a BTS patient with recurrent syncope.

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FIGURE 90.6. An ILR tracing (slow recording speed) illustrating onset of an atrial tachycardia leading to “feeling dizzy” in an 88-year-old man.

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FIGURE 90.7. An ECG recording from a 60-year-old woman with “lightheaded spells.” Patient had underlying left bundle branch block (LBBB) (see left). An episode of probable nonsustained ven-tricular tachycardia (VT) was recorded during a relatively minor symptomatic episode; VT was the cause of the patient’s spontaneous symptoms. Note that at the termination of the VT episode, retro-grade concealment permitted unmasking the underlying atrial fl utter in this patient.


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sinus node reentry tachycardia (SRT) while having only a transient slowing effect on NST. The syndrome of intractable nonphysiologic sinus tachycardia [often termed inappropri-ate sinus tachycardia (IST)] is a much more common and clinically troublesome problem, and is in some patients intertwined with the postural orthostatic tachycardia syn-drome (POTS).52,53 Causative factors such as anemia or hyper-thyroidism must fi rst be excluded before making a diagnosis of IST.

The basis for IST is not certain, and in fact the syndrome is most likely multifactorial. Currently it is believed that there may be abnormal enhanced automaticity within the sinus node or nearby atrial regions, possibly contributed to by diminished parasympathetic control. Fortunately, the problem is often short-lived (although usually many months in duration) when it occurs as a consequence of a recent infectious illness, or as a consequence of a surgical or abla-tion procedure. In such cases, reassurance and beta-blockade therapy may suffi ce, but are not often suffi cient to provide complete relief. On occasion, but only in very severely affected individuals, refractory IST necessitates extreme measures, including attempted transcatheter ablation/modi-fi cation of the sinoatrial region. Long-term results of these interventions have been less than satisfactory to date. When apparent IST is associated with POTS,53 attention should be focused on the autonomic issues, as attempts to suppress the heart rate alone are not generally very effective.

Sinus Bradyarrhythmias

Sinus bradycardia, usually defi ned as a persistent sinus rate <50 beats/min during waking hours, is the most common bradyarrhythmia associated with SND (Figs. 90.1 and 90.4). However, in some individuals, heart rates as low as 35 to 40 beats/min may be perfectly normal. Such rates are often present in young athletes at rest and in many adults during sleep. As a rule, these latter individuals are without any symptoms attributable to inappropriately slow heart rates, and they also exhibit normal heart rate responses during physical exertion (i.e., normal chronotropic competence). On the other hand, the presence of symptoms, or the identifi ca-tion of coexisting chronotropic incompetence implies that the sinus bradycardia may be an indicator of SND.

Sinus pauses (i.e., an abrupt prolongation of the atrial cycle length) may be due to sinus “arrest” or sinoatrial exit block (Fig. 90.2). The term sinus pauses implies failure of an expected atrial activation of sinus node origin, and may be due to either failure of the sinus node to depolarize (sinus arrest) or failure of the impulse to exit the sinus node into the atrium (sinus exit block). Currently, there is no wide-spread agreement on the duration necessary to qualify as a sinus arrest; in a given individual it depends on the magni-tude of underlying sinus arrhythmia. From a practical per-spective, asymptomatic pauses of ≤3 seconds in duration are relatively common (reported in approximately 2.4% of patients) and are apparently without clear-cut adverse prog-nostic implications. On the other hand, pauses >3 seconds are believed to be relatively rare during ambulatory monitor-ing (0.8% of patients) and, although their clinical signifi -cance may vary, they warrant careful assessment to detect symptomatic correlations.54,55

Sinoatrial exit block is usually classifi ed in a manner analogous to the AV blocks, and occurs when there is either delay or failure of a sinus impulse to exit the nodal region. First-degree sinus node exit block (i.e., slowed conduction out of the node) cannot be readily identifi ed by ECG inspection alone. In second-degree sinoatrial exit block, there is periodic failure of a sinus impulse to exit the node and generate a P wave. This may occur in a form analogous to type I AV block, in which case Wenckebach periodicity may be suspected by recognition of progressive P-P interval shortening preceding a pause in the atrial rhythm (a “dropped” P wave). In more severe grades of second-degree sinoatrial exit block, several sinus impulses may fail to exit the node. Within limits imposed by underlying periodic irregularity of sinus impulse generation (i.e., sinus arrhythmia), the distinctive ECG feature of this pause is that its duration is a whole number multiple (or approximately so) of the immediately preceding P-P interval. Overall, there is relatively little clinical utility to determining the specifi c nature of the type of exit block. The need for treatment is based almost exclusively on the clinical implications associated with the resultant pause in the cardiac rhythm, and in the absence of an apparent adverse drug effect, a cardiac pacemaker is required.

Chronotropic Incompetence

The term chronotropic incompetence (CI) implies inability of the heart to adjust its rate appropriately in response to metabolic demand.18 Technically, both inadequate heart rate responses as well as IST could be incorporated within CI. Currently, however, IST is usually considered a separate phe-nomenon (see earlier discussion).

The reported incidence of CI is probably unreliable, and has been variable depending on the population being sampled, and the defi nition used. Unfortunately, there are no univer-sally accepted clinically applicable diagnostic criteria for CI. Initially, the diagnostic criteria consisted of a mean heart rate below the 95% confi dence limit for age and sex, or failure to achieve 90% of age/sex predicted maximum heart rate.

As many as 60% of pacemaker-treated and elderly popula-tions have been reported to exhibit CI. Not infrequently, drug therapy is an important contributing factor. Manifesta-tions of CI may include either failure to achieve, or delay in achieving, maximal heart rate during exertion, inadequate submaximal heart rate during activities of daily living, rate instability during sustained exercise, or abrupt heart rate slowing after exercise is completed.

Bradycardia-Tachycardia Syndrome and Persistent/Permanent Atrial Fibrillation

Bradycardia-tachycardia syndrome is a common manifesta-tion of SND consisting of the coexistence in the same patient of periods of bradyarrhythmia interspersed with bouts of atrial tachyarrhythmias (usually atrial fi brillation, but occa-sionally, atrial fl utter or other paroxysmal atrial tachycar-dias)4,6,714,19 (Fig. 90.3). Symptoms may result from either the rapid heartbeat or the bradycardic component (which is often at its most severe immediately after spontaneous tachyar-rhythmia termination), or both. Therefore, it remains essen-tial to document the symptom-arrhythmia correlation before



initiating treatment. Prognosis in the BTS patient population is worse than in other manifestations of SND, and is particu-larly more severe than the prognosis observed in patients who manifest sinus bradycardia alone. Systemic embolism is a particular concern in BTS patients, requiring initiation of anticoagulation, especially in the older (>65 years of age) individual.

Success has been achieved in providing anticoagulation treatment strategies for reducing risk of embolism in SND patients with intermittent atrial tachyarrhythmias. None-theless, there remains concern that recurrent episodes of atrial fi brillation also have an adverse direct effect on the heart. Research indicates that atrial fi brillation itself has an undesirable impact on atrial electrophysiology and both atrial and ventricular function.56–60 In essence, atrial fi bril-lation of increasing duration appears to predispose to pro-gressive shortening of atrial effective refractory periods. This is a reversible change, at least in short-term studies, by ter-minating atrial fi brillation. It is presumed that if permitted to remain, the shorter refractoriness provides an electro-physiologic milieu that favors sustaining (or maintaining) atrial fi brillation. Additionally, atrial fi brillation has been associated with a tendency toward atrial dilatation. Together, the fi brillation-induced changes in atrial electrophysiology and structure reasonably lead to the notion that “atrial fi bril-lation begets atrial fi brillation.” Finally, atrial fi brillation appears to have a long-term adverse impact on ventricular function itself. Of the several factors that contribute to this effect, the most important are the impact of sustained inap-propriately high heart rates on the ventricle (the concept of so-called tachycardia-mediated cardiomyopathy),61,62 and the potential for repetitive coronary artery embolism.

Persistent or permanent atrial fi brillation, particularly in association with a slow ventricular response (unrelated to drugs), is considered to be part of the spectrum of sick sinus syndrome. In the case of individuals with slow ventricular rates, concomitant AV conduction system disease is presum-ably present. However, although diffuse conduction system disease is evident in some patients, the predilection for devel-opment of clinically relevant AV block has probably been overemphasized and, more often than not, SND patients manifest surprisingly rapid ventricular responses during atrial tachyarrhythmias.

Pauses Following Cardioversion

Prolonged asystolic pauses or sustained periods of junctional or idioventricular escape rhythms following cardioversion of atrial fi brillation is typically considered a manifestation of SND. These patients may be at particularly high risk of adverse effects (particularly proarrhythmia) of antiarrhyth-mic drugs.

Sinus Node Reentrant Tachycardia

The inherently slow conduction properties of the sinus node region provide a substrate for reentrant rhythms [so-called sinus node reentry tachycardia (SRT)]. The frequency with which clinical SRT is responsible for symptoms in SND patients is uncertain, but it is very low compared to other tachyarrhythmias such as atrial fi brillation. Current clinical criteria for making the diagnosis of SRT require that the

arrhythmia have a P-wave morphology (and preferably an intraatrial activation sequence) nearly identical to that observed during sinus rhythm in that patient and that it can be both initiated and terminated by atrial extrastimuli. Vagal maneuvers, verapamil, or adenosine will usually suddenly terminate SRT.

Diagnostic Techniques

A careful medical history, in conjunction with application of experienced clinical suspicion, provides the best tool for identifying SND patients. Thereafter, careful use of selected noninvasive diagnostic tools is usually adequate to substan-tiate the diagnosis, and focus therapy. Invasive electrophysi-ologic tests are only rarely indicated, and have largely been disappointing in terms of clinical utility. The optimum outcome of the diagnostic evaluation is to obtain a symptom-arrhythmia correlation; however, this is often not achieved.

Noninvasive Diagnostic Testing

Ambulatory ECG (AECG) recordings, exercise testing, and, to a much lesser extent, pharmacologic assessment of sinus node autonomic control are techniques of relatively long-standing, and remain the principal noninvasive techniques used in the diagnosis of suspected SND.

Ambulatory ECG monitoring comprises a range of technologies including conventional Holter recorders (now predominantly solid-state devices rather than magnetic tape recorders), wearable “event” monitor systems, mobile cardiac outpatient telemetry (MCOT), and implantable loop recorders (ILRs) (Figs. 90.8 and 90.9). These instruments provide the most specifi c diagnostic observations. If symptom-arrhythmia correlation is obtained during a recording, the

FIGURE 90.8. Image of an insertable loop recorder (Reveal®, Medtronic, Minneapolis, MN). The small size can be appreciated by comparison with the fi nger holding the device.


19 32 c h a p t e r 9 0

basis for symptoms is then clear, and for the most part, the treatment direction is immediately established (Fig. 90.10).

In most SND patients, symptoms are infrequent and tran-sient. As a result, “event” recorders, MCOT systems, and ILRs may be more helpful than conventional 24- or 48-hour Holter-type recordings. However, given the older age of the SND population on average, many patients are simply incapable of reacting suffi ciently rapidly to employ conventional event recorders effectively. Mobile cardiac outpatient telemetry offers continuous wireless telemetry (Cardionet®, San Diego, CA) and permits recognition of events by a central monitoring

station even if the patient is unable to respond. Such patients may also be well served by ILRs (Figs. 90.9 and 90.10).

As a rule, exercise testing is not useful for identifying most forms of SND. Maximum and minimum heart rates recorded during formal exercise testing often do not differ substantially between control subjects and SND patients.16,17 On the other hand, as discussed earlier, specifi c forms of exercise testing may be helpful in identifying CI. Further, several observations during such testing may be pertinent in management of individual patients. For example, exercise testing may permit differentiating those patients with

Educationand hook up

At home 24/7/365monitoring

center

Daily,urgent,

summaryreports

Away fromhome

Algorithm or symptomaticevent detection and

transmission

Real-timeanalysis

Internet,phone, fax

Responsereporting

FIGURE 90.9. Images depicting operation of a mobile cardiac outpatient telemetry (MCOT) system.

FIGURE 90.10. Image illustrating the diag-nostic screen recording of a prolonged symp-tomatic bradycardia event detected by an ILR. Cardiac pacing was indicated and the patient has been symptom-free since then.



resting sinus bradycardia but essentially normal exercise heart rate responses (e.g., physically trained individuals) from patients with CI.

Assessment of sinus node responses to pharmacologic interventions, and to a lesser extent neural refl exes, may be of value in understanding the basis for SND, but is not often needed in clinical practice. Overall, the most popular of these tests is the assessment of intrinsic heart rate (IHR; sinus node rate when neural control is essentially eliminated) by phar-macologic autonomic blockade (usually propranolol 0.2 mg/kg IV, followed by atropine 0.04 mg/kg IV).8,14 Normal values for IHR can be approximately predicted (IHRp) from the linear regression: IHRp = 118.1 − (0.57 × age).8

Invasive Testing

As noted above, invasive diagnostic testing is rarely indi-cated in suspected SND. Currently, the principal indication for invasive electrophysiologic testing is to confi rm a clinical suspicion when ECG studies are nondiagnostic or impracti-cal. The sensitivity (abnormality on testing versus “true” abnormality) and specifi city (normality on testing versus “true” normality) of using both sinus node recovery time (SNRT) after rapid atrial pacing and sinoatrial conduction time (SACT) to detect SND are in the range of 70% and 90%, respectively.

The most widely used invasive electrophysiologic test of sinus node function takes advantage of a physiologic charac-teristic of native pacemakers, namely “overdrive suppres-sion.”58,63–65 Specifi cally in this case, the time taken for sinus node activity to return following termination of a period of rapid atrial stimulation (i.e., the SNRT) is used to identify underlying SND.13,53 However, the SNRT measurement is dependent on multiple factors such as autonomic tone, sino-atrial conduction properties, the patient’s sinus cycle length at time of study, and the magnitude of sinus arrhythmia present. The SNRT is usually corrected for baseline sinus cycle length [i.e., corrected SNRT (CSNRT)]. Most com-monly, this correction is obtained by subtracting the base-line sinus cycle length from the SNRT: CSNRT = SNRT − sinus cycle length. The usual normal value is <525 ms.

The measurement of SACT, although less widely used than SNRT, remains a second basic tool for invasive assess-ment of sinus node function. It can be determined by both indirect and direct techniques. The most popular indirect method uses timed premature atrial extrastimuli (A2) intro-duced at a high lateral right atrial pacing site during sinus rhythm (A1-A1). With insertion of A2, the sequence of sino-atrial activation is reversed for one cycle. Assuming that intrinsic sinus node automaticity is unperturbed by A2, the return cycle (A2-A3) should be equal to A1-A1 plus an interval equal to both the time required for A2 to enter the node and the time taken for the next sinus impulse to exit the node. Thus, the total conduction time into and out of the node (SACT by defi nition) may be estimated. Although the reported upper limit of normal SACT value varies somewhat in the literature, 205 ms is commonly used.

Techniques for direct recording of sinus node electro-grams and thereby obtaining direct estimate of SACT are feasible in the clinical electrophysiology laboratory.54,55 A value of 112 ms (one direction) appears to be a reasonable

upper limit of normal for direct SACT. Values are shorter in children (15 to 91 ms). However, these direct recordings are diffi cult to obtain, and of limited clinical utility. As a result, this method is not widely used in current clinical practice.

In terms of summarizing clinical utility, the ability of the various available electrophysiologic testing maneuvers to confi rm the presence of SND in patients in whom the diag-nosis is already established, has yielded variable results. Pooling fi ndings from various studies suggest that the sensi-tivity (test positives/true positives) and specifi city (test nega-tives/true negatives) of a combined testing procedure (i.e., incorporating both corrected SNRTmax [CSRTmax] and SACT) to be 70% and 90%, respectively. Therefore, the most com-monly used electrophysiologic tests of sinus node function lack sensitivity but are relatively specifi c.

Equal in importance to detecting sinus node disease during electrophysiologic testing is determining whether it is the cause of the patient’s symptoms. Unfortunately, the predictive capability of such testing has not been very impres-sive. An additional desirable attribute of sinus node function studies would be the capacity to predict whether cardiac pacing would be benefi cial among symptomatic patients (i.e., dizziness, syncope). In a report by Gann et al.,66 30 of 68 symptomatic patients had prolonged maximal values of CSRT (CSRTmax), and 25 of the 26 of these patients who agreed to pacemaker implantation obtained symptomatic relief. Of the 38 symptomatic patients with normal CSRTmax, pacemakers were eventually placed in 16 (in whom symp-toms were suppressed in 12 of 16), and spontaneous resolu-tion of symptoms occurred in 17 patients; fi ve patients remained undiagnosed. Therefore, although an abnormal CSRTmax in symptomatic patients tended to suggest that cardiac pacing would be benefi cial, a normal CSRTmax did not exclude this possibility.

To recap, a variety of invasive electrophysiologic tech-niques have been developed over the years in an effort to distinguish normal from abnormal sinus node function. Unfortunately, although each has contributed to better understanding of sinus node physiology, none has proved very effective in the clinical setting.

Complications

Thromboembolism is the most important cause of morbidity in SND.14,19,42–45 The incidence is approximately 15% at 38 months among patients with SND without pacemakers, and is essentially the same in patients with single-chamber ven-tricular pacemakers. The risk appears to be greater among individuals presenting with atrial tachyarrhythmias com-pared to those who primarily manifest sinus bradycardia. Further, thromboembolic events are less frequent in atrially paced (i.e., atrial pacemakers and perhaps dual-chamber pace-makers) patients (1.6%) compared to those who receive only single-chamber ventricular-based pacing systems.67 Overt thromboembolic events (most notably, stroke) are substan-tially reduced by anticoagulant therapy, especially in patients with recurring or permanent atrial fi brillation, and especially in women.67–69 The increasingly aggressive use of anticoagu-lation in these patients, by medical practitioners of a wide range of specialties, offers the potential of having an impor-tant benefi cial impact on stroke rates in this population.


19 3 4 c h a p t e r 9 0

The presence of concomitant specialized cardiac conduc-tion system disease has long been associated with SND (Fig. 90.11). However, its clinical impact is uncertain and remains a source of debate. In a review of multiple published reports,45 8.4% of patients evolved conduction system disturbances over a mean follow-up time of 34.2 months (i.e., approxi-mately 2.7% per year). For the most part, the conduction disturbances were minor. In one report, only one of 30 SND patients followed over a 5-year period experienced high-grade AV block (i.e., <1% incidence of progression per year), and that patient had marked H-V interval prolongation on entry into the study.31 Finally, it appears that iatrogenic infl uences may be important with regard to the occurrence and worsen-ing of conduction system disease. Antiarrhythmic drugs are the greatest potential contributors to this problem. Thus, careful control of patient exposure to antiarrhythmic drugs and other agents that manifest direct effects on the conduc-tion system (e.g., tricyclic antidepressants) may be important for diminishing risk of AV block.

In terms of mortality, 5- to 10-year survival statistics appear to be similar in both SND patients, and patients with other comparable severe forms of conduction system disease (see Clinical Recognition, above).

Treatment

Treatment of patients with SND must be individualized. Symptoms are often absent and no therapy is needed apart from patient education, avoidance of certain drugs, and perhaps anticoagulation. However, when symptoms do occur, they may be due to either brady- or tachyarrhythmias, or to both. Therefore, pacemaker therapy may be appropriate in some cases, drug/ablation suppression of arrhythmias in others, and both strategies may be required in many individuals.

Treatment of symptomatic SND encompasses consider-ation of the following issues:

1. The underlying electrophysiologic and arrhythmic disturbance

2. The effects of a wide variety of drugs on sinus node function

3. The role of anticoagulation 4. Current indications for and available modes of cardiac

pacing 5. The evolving contribution of transcatheter or surgical

ablation

Decisions regarding treatment strategy must of necessity consider the severity and nature of symptomatic arrhyth-mias, as well as the disease setting. Thus, in many cases of idiopathic SND, treatment focuses on avoidance of drugs

that may aggravate the problem, and on prevention of arrhyth-mia-related complications (notably anticoagulation for pre-vention of embolic events). However, physicians must bear in mind the potential for reducing mechanical stress, and diminishing adverse impact of autonomic tone, by directing treatment toward ameliorating the underlying disease pro-cesses wherever possible. In this regard, recent insights suggest that angiotensin-converting enzyme inhibitors, acting either directly by cellular effects or indirectly by reducing wall stress, may reduce arrhythmia risk in this setting.70

Pharmacologic Treatment

Drugs (excluding anticoagulants for the moment) are rarely used to treat bradycardic manifestations of SND any more. Theophylline is perhaps the only agent for which some inter-est is retained. On the other hand, elimination of certain drugs may be instrumental for preventing arrhythmic symp-toms in SND.

Sinus node dysfunction patients are often exposed to a wide range of drugs that may exacerbate or unmask underly-ing susceptibility to bradycardia (Table 90.2). For example, cardiac glycosides, β-adrenergic blockers, calcium channel blockers, and membrane-active antiarrhythmic agents (espe-cially sotalol and amiodarone) are used to treat coexisting paroxysmal atrial tachyarrhythmias. Some of these drugs, and many other bradycardia-promoting sympatholytic agents, are used to treat hypertension, a common problem in the generally older SND population. In addition, certain less commonly used agents such as radiographic contrast materi-als, lithium carbonate, cimetidine, and adenosine have been associated with depression of sinus node function.

Anticoagulation is critical for treatment of many indi-viduals with SND, particularly those with paroxysmal or

VII

25 m

m/s

ec

AB AB AB AB

FIGURE 90.11. An ECG recording showing both sinus bradycardia and intermittent atrioventricular (AV) block in an elderly patient with both sinus node dysfunction (SND) and signifi cant infranodal conduction system disease.

TABLE 90.2. Some of the more commonly used drugs affecting sinus node function

Antiarrhythmic drugsAmiodarone: may be associated with de novo evidence of sinus node dysfunctionFlecainide, propafenone, sotalol: may exacerbate sinus node dysfunctionQuinidine, disopyramide, procainamide: less often worsens sinus node function, possibly due to vagolytic propertiesAntihypertensives (sympatholytic)α-methyldopa, reserpine, clonidineβ-adrenergic blocking drugsWithout intrinsic sympathomimetic action (ISA): propranolol, nadolol, etc.With ISA, less severe effects: pindolol, acebutolol, etc.Ophthalmic drops: TimopticCalcium channel blockersVerapamil and diltiazem more prominently than nifedipineCardiac glycosides (rarely a clinical problem)MiscellaneousCimetidineLithiumPhenytoin


s i n u s node dy s f u nc t ion 19 3 5

persistent atrial fi brillation. The anticoagulation guidelines have been widely reported and the reader is referred else-where for additional information.35

Pacemaker Therapy

Guidelines for implantation of cardiac pacemakers are peri-odically reviewed and summarized by the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures.71 In terms of SND, symptomatic bradycardia is the principal indication for cardiac pacemaker implantation. The Task Force defi ned symptomatic bradycardia as encom-passing those “clinical manifestations that are directly attributable to the slow heart rate: transient dizziness, light-headedness, near syncope or frank syncope as manifestations of transient cerebral ischemia, and more generalized symp-toms such as marked exercise intolerance or frank congestive heart failure.”

Due to concomitant CI, the tracking of native atrial rates by cardiac pacemakers may not provide an optimal physio-logic heart rate response in many SND paced patients. Conse-quently, physiologic sensors (e.g., piezoelectric accelerometers, respiratory sensors) in most current-generation pacing systems offer a valuable backup system to better support heart rate. Additionally, there has been a growing appreciation of the importance of providing not only pacing systems that ensure an appropriate heart rate response (without excessive periods of ventricular pacing), but also, whenever possible, an atrial pacing component to stabilize atrial rhythm and to maintain and normalize the AV relationship. In this regard, while both of these features can be provided in some patients through the use of single-chamber rate-adaptive atrial pacing (AAIR mode), often a prolonged PR interval diminishes the physio-logic benefi t at higher paced rates. Therefore, for individuals in whom AV conduction is suspect, a dual-chamber rate-adap-tive pacing system with algorithms designed to minimize ventricular pacing have been favored in the United States, although at least one recent study raises doubt as to whether this approach is appropriate.72

In general, cardiac pacemaker therapy is indicated and has proved highly effective in patients with SND when bradyarrhythmia has been demonstrated to account for symptoms.71,73–82 Further, although recent studies have been variously interpreted in the literature, two of the largest studies, Mode Selection in Sinus Node Dysfunction (MOST) and Canadian Trial of Physiologic Pacing (CTOPP), support the view that pacing techniques that endeavor to maintain a normal AV relationship appear to diminish heart failure hospital admission rates, and offer the additional benefi t of reducing atrial fi brillation risk, and thereby diminishing the risk of thromboembolism.73–78 Further, the benefi cial impact appears greatest in those individuals who are likely to pace most often (i.e., those who exhibit low baseline resting heart rates).75,78 Finally, recent fi ndings suggest that optimum benefi t is obtained if atrial pacing is favored and ventricular stimulation is minimized as much as possible.79–81 Reducing ventricular stimulation diminishes adverse effects of ven-tricular pacing on overall cardiac mechanical function, and susceptibility to heart failure. In fact, the evidence with regard to diminishing ventricular pacing has become so con-

vincing that newer generations of implantable pacemakers increasingly incorporate special algorithms designed to reduce the frequency of nonessential ventricular pacing, while still providing backup pacing capability if needed.

Clinical Trials in Cardiac Pacing for Sinus Node Dysfunction

The Theopace study44 provided the fi rst randomized con-trolled trial of pacing versus medical therapy in SND. Patients were randomized to no therapy, theophylline, or dual cham-ber rate-adaptive (DDDR) pacing. Very severe SND patients were excluded (i.e., resting heart rates <30 bpm, sinus pauses >3 seconds). During follow-up (approximately 1.5 years on average), pacing and theophylline patients had less heart failure than did untreated patients, but only pacing proved advantageous with regard to syncope occurrence (paced 6%, theophylline 17%, untreated 23%). Further, pacing was far better tolerated than the other two treatment strategies. Withdrawal due to adverse events or treatment intolerance was a common problem in untreated patients (51%) and the-ophylline-treated patients (42%).

In essence, the Theopace study supports the seemingly intuitive concept that pacing for bradyarrhythmias in SND is effective and relatively well tolerated. The next question is, Which pacing mode is optimal?

The Danish prospective trial67,83 provides strong evidence favoring the benefi ts of atrial-based pacing [i.e., single-chamber atrial (AAI), or AV paced] over single-chamber ven-tricular pacing (VVI). In the initial report, 225 SND patients were randomized to AAI or VVI pacing. At 3.3 years follow-up the atrial fi brillation and stroke incidence did not differ substantially in the two groups, but the combined fi nding of fewer strokes and thromboembolism favored AAI. In the subsequent report at 5.5 years follow-up, AAI paced patients were clearly showing lower incidence of atrial fi brillation, thromboembolism, heart failure, and stroke. Further, all-cause mortality was less in AAI paced patients, although when various preimplant variables were accounted for, it was cardiovascular death rather than total mortality that was statistically signifi cantly reduced.

In the Pacemaker Selection in the Elderly (PASE) trial,73 175 patients with SND and 201 patients with AV block were randomized to DDDR or single chamber rate-adaptive (VVIR) pacing. This was a single-blind trial in patients aged 65 or older, with the primary end point being quality-of-life mea-sures. The authors reported no signifi cant difference in various outcome measures between groups, although fi nd-ings were more supportive of dual-chamber pacing in SND. In addition, the crossover from VVIR to DDDR was substan-tial, amounting to approximately 50% of SND patients ran-domized to VVIR. This occurrence, largely attributed to symptoms suggestive of pacemaker syndrome, speaks strongly toward dual-chamber pacing offering improved quality of life. In fact, after crossover there was a signifi cant improvement in quality-of-life indices as measured by the Short Form (SF-36) questionnaire. A similar conclusion can be derived from the much larger MOST study.74 In this case, 2010 SND patients were randomized to either ventricular pacing (n = 996) or dual-chamber pacing (n = 1014), and followed for a median of 33 months. Ignoring the crossover issue, the primary end


19 3 6 c h a p t e r 9 0

point (all-cause mortality or stroke) did not differ in the two groups. However, there was a signifi cant reduction in atrial fi brillation risk (hazard ratio, 0.79, p = .008) and improvement in heart failure scores (p < .001). From a practical point of view, however, one cannot ignore crossovers, and PASE and MOST have been justifi ably criticized for this oversight.82,84 In this case, nearly one third of VVIR paced patients were crossed-over due to adverse symptoms.

The CTOPP study randomized patients undergoing fi rst pacemaker implants (for SND or AV conduction system disease) to ventricular-based single chamber devices (n = 1474), or more physiologic AAI or DDD pacing systems (n = 1094).75 Among these individuals, total mortality tended to be lower in physiologic paced patients (not statistically sig-nifi cant), but cardiovascular death did not differ in the two groups. On the other hand, the annual rate of atrial fi brilla-tion was signifi cantly less in the physiologic pacing group (5.3% vs. 6.6%, annual relative risk reduction, 18%, p = .05). The atrial fi brillation benefi t became increasingly apparent with longer follow-up (>2 years). Patients with structurally normal hearts and no prior atrial fi brillation history appeared to show greatest benefi t.76,77

In terms of the specifi c context of assessing cardiac pacing in SND, the CTOPP trial data are diffi cult to assess since only about 40% of patients carried some element of that diagnosis. Further, many of the patients may have required pacing only for brief periods of time, making it dif-fi cult to evaluate the impact of the pacing intervention. In this regard, a substudy analysis of CTOPP results was under-taken, looking at fi ndings in individuals with slower versus faster resting heart rates at entry. The presumption was that patients with lower heart rates would pace more often, and thus more clearly demonstrate differences among pacing modes. In this analysis, Tang’s group76,78 found that slower unpaced heart rates were accompanied by an increasing annual cardiovascular death or stroke rate. Physiologic paced patients did not evidence this increase. Thus, to the extent that unpaced slow heart rates are a marker (albeit not very strong) of SND, these individuals were probably benefi ted by selection of physiologic pacing systems. The benefi t in terms of atrial fi brillation suppression is probably of greatest practi-cal importance. Further, the apparent benefi t was sustained when the data were reexamined several years later.78

To recap, in current practice it remains preferable to employ atrial-based pacing methods when sinus node func-tion patients require pacing for bradyarrhythmias or atrial fi brillation suppression. In the setting of normal AV conduc-tion, the use of atrial-single-chambered pacing (AAI, AAIR) can be readily defended, and is cost-effective.67,82–85 The risk of abrupt-onset heart block in this circumstance is low. On the other hand, where AV conduction is suspect (e.g., fi rst-degree block, Wenckebach phenomenon at heart rates <130 bpm), or a patient is being treated with antiarrhythmic drugs, it is prob-ably prudent to favor a dual-chamber AV pacing system.

Specialized Pacing Techniques

Specialized pacing techniques or algorithms within the pace-makers programmable feature set may further help to prevent atrial fi brillation episodes, or at least reduce the overall burden of arrhythmia (i.e., the time duration the patient is in atrial fi brillation per month or year) for SND patients. In

addition, techniques that favor atrial pacing while decreasing the likelihood of ventricular stimulation are increasingly being made available in recent generation pacemakers. It is anticipated that these most recent additions to pacemaker system capabilities, by diminishing long-term adverse pacing effects on ventricular function, may also reduce both ven-tricular atrial arrhythmia susceptibility.

Among the specialized pacing techniques that seemed to be of greatest intuitive potential benefi t was the use of multisite or selective site atrial pacing. The objective of this technique is to reduce disease-related or aging-related intraatrial conduction delays, and thereby diminish suscep-tibility to intraatrial reentry (particularly of the form that results in episodes of atrial fi brillation). The most thoroughly studied of these methods is so-called dual-site atrial pacing.86 Single-site Bachmann’s bundle pacing has also been advo-cated.87 The dual-site pacing approach employs the use of two atrial pacing leads (although more could be used). The favored pacing sites are the right atrial freewall, and either the coro-nary sinus os or the more distal aspect of the coronary sinus (i.e., the left atrium). The objective of reducing intraatrial delay can be appreciated by observing a reduced P-wave dura-tion. However, to date the results have been disappointing. In the Dual-site Atrial Pacing in Paroxysmal Atrial Fibrilla-tion (DAPPAF) trial,84,86 fi ndings tended to show a trend toward benefi t only in patients in whom atrial fi brillation occurred fewer than one time per week. Further assessment of the technique is nevertheless warranted.

Certain available pacemakers contain programmable techniques designed to better control the atrial rhythm and suppress atrial tachyarrhythmias [e.g., Dynamic Atrial Over-drive (DAO), St. Jude Medical, St. Paul, MN].88,89 In regard to DAO, fi ndings in the Atrial Dynamic Overdrive Pacing Trial (ADOPT) studies (St. Jude Medical) revealed a signifi cant reduction of atrial fi brillation episodes with this algorithm.89 However, only in relatively few cases will an algorithm solve the problem adequately. More often, both pacing and drugs are needed. Finally, implantable atrial defi brillators have been made available that have the capability for automati-cally terminating atrial tachyarrhythmias, most often by relatively low-energy electrical shocks.90,91 A report from the Medtronic Jewel AF trial comprising 144 device implants followed for 12.6 ± 6.2 months, revealed the system to be safe and relatively well tolerated, although pain is a clear-cut limitation to greater acceptance of this strategy. The median duration of successfully treated episodes was approximately 9 minutes. Further, there was no apparent diminution of patient activated shocks over time, suggesting that patients were able to tolerate treatments adequately. To date, implant-able atrial defi brillators (which of necessity must also offer ventricular fi brillation shock capacity for safety purposes) have had only very limited clinical acceptance. Neverthe-less, such devices may have a niche role to play in some very symptomatic individuals.

Pacemaker Recalls and Medical Advisories

Pacemaker systems are not without technical limitations.92,93 Over the years, and particularly relatively recently, the potential for even rare device failures to become public knowledge rapidly through Internet communication has placed physicians and pacemaker follow-up clinics in an



increasingly diffi cult position. They must be continuously vigilant for new problems, and provide their patients with appropriate management advice. The balance between advis-ing continued monitoring versus recommending premature device explantation with its attendant additional medical risks (e.g., infection, bleeding) is often a diffi cult and precari-ous one. Fortunately, while SND patients often benefi t from pacing therapy, they are only infrequently pacemaker depen-dent. Consequently, the need for urgent device replacement is uncommon in this clinical setting.

Indications for Pacing in Sinus Node Dysfunction71

CLASS I1. SND with documented symptomatic bradycardia due

to intrinsic SA disease or to extrinsic factors that may not be readily reversible or substituted for (autonomic distur-bances, essential drug therapy)

2. Symptomatic chronotropic incompetence

CLASS II1. Class IIa: SND occurring spontaneously or as a result

of necessary drug therapy in which heart rates <40 bpm occur in symptomatic patients but in whom it has not been possi-ble to establish a clear-cut correlation between symptom occurrence and bradycardia

2. Class IIb: In minimally symptomatic patients with chronic heart rates ≤30 beats/min while awake

CLASS III1. Sinus node dysfunction in asymptomatic patients,

including individuals with marked sinus bradycardia or sinus pauses, but in whom no symptoms have developed or in whom reversible extrinsic factors such as nonessential drug therapy can be eliminated

Ablation

Percutaneous cardiac ablative techniques for tachyarrhyth-mia control currently have limited application in SND. Several types of ablation, however, may prove helpful in specifi c circumstances:

• Transcatheter radiofrequency ablation of the His bundle with placement of a cardiac pacemaker remains useful in many patients with refractory primary atrial tachyar-rhythmias, including those in whom drug therapy is associated with intolerable side effects. There has been considerable clinical experience gained over the years with the so-called ablate and pace technique.94,95 In addi-tion, it has also been the subject of multicenter clinical trials, with favorable outcomes. In particular, quality of life is clearly improved in most patients both by achiev-ing better heart rate control and by reducing hospitaliza-tion frequency. On the other hand, the patient becomes pacemaker dependent and requires careful monitoring from that perspective.

• Ablation is generally very effective for both typical and many forms of atypical atrial fl utter. Success rates in the mid- to high 90% range are expected. However, while this procedure prevents recurrent fl utter, the effective-ness of the underlying sinus node is uncertain. A perma-nent pacemaker may yet be needed.

• Attempts to ablate foci of atrial arrhythmogenesis, particularly pulmonary vein and other venous sources of paroxysmal atrial fi brillation have been increasingly successful. The technique is most useful in patients without, or at least no more than minimal, structural atrial disease.96–102 Further, while the reported results of focal ablation procedures are increasingly encouraging, complications such as pulmonary venous stenosis with secondary pulmonary hypertension have been reported. Finally, the methodology of atrial fi brillation ablation is changing as experience grows. Constant monitoring of the recent literature is essential.

Surgical “maze” operations can be effective in selected atrial fi brillation patients.103–105 In general, this operation is reserved for those individuals who are undergoing a cardiac operation for other reasons (e.g., valve replacement/repair, coronary artery bypass graft). In these cases, the resulting sinus rhythm can be assumed to be inadequate, and a per-manent cardiac pacemaker will usually be warranted.

Guidelines

The principal guideline statements (and some useful com-mentaries) pertinent to SND patients are as follows:

• The 2002 revision of the American College of Cardiology/American Heart Association (ACC/AHA/NASPE) guide-line update for implantation of cardiac pacemakers and antiarrhythmia devices71

• The ACC/AHA/European Society of Cardiology (ESC) guidelines for the management of patients with atrial fi brillation106

• The ESC guidelines on management (diagnosis and treat-ment) of syncope, updated 2004107

• American Heart Association Council on Clinical Cardi-ology and Heart Rhythm Society science advisory state-ment on the role of permanent pacing to prevent atrial fi brillation108

• Drugs for cardiac arrhythmias: a treatment guideline from the Medical Letter109

• A commentary on translation of clinical trials into clini-cal practice: use of results in formulating guidelines110

• A commentary on pharmacologic and nonpharmacologic options to maintain sinus rhythm: guideline-based and new approaches111

Summary

Sinus node dysfunction (SND) is a multifaceted syndrome. Its origins are multifactorial, and usually are not readily identifi ed in individual patients. It is as a result of its elec-trocardiographic manifestations that the SND diagnosis is established, and the appropriate treatment strategy is based. Electrophysiologic testing (EPS) may assist with making a diagnosis in some cases, but for the most part EPS has limited utility.

The diagnostic and treatment strategy in sinus node dys-function patients is largely dictated by symptoms and elec-trocardiographic fi ndings (Fig. 90.12). Whereas arrhythmia suppression is often an important goal, it is equally impor-tant to reduce both susceptibility to syncope and falls,


19 3 8 c h a p t e r 9 0

and risk of thromboembolic complications. In addition, treatment should focus on diminishing symptoms of exer-tional intolerance by providing appropriate chronotropic support, usually by use of physiologic rate-adaptive pacing systems.

References

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3. Rubenstein JJ, Schulman CL, Yurchak PM, DeSanctis RW. Clinical spectrum of the sick sinus syndrome. Circulation 1972;46:5–13.

4. Short DS. The syndrome of alternating bradycardia and tachy-cardia. Br Heart J 1954;16:208–214.

5. Lown B. Electrical reversion of cardiac arrhythmias. Br Heart J 1967;29:469–489.

6. Easly RM Jr., Goldstein S. Sino-atrial syncope. Am J Med 1971;50:166–177.

7. Kaplan BM, Langendorf R, Lev M, et al. Tachycardia-bradycardia syndrome (so-called sick sinus syndrome): pathology, mecha-nisms and treatment. Am J Cardiol 1973;31:497–508.

8. Jordan JL, Yamaguchi I, Mandel WJ. Studies on the mechanism of sinus node dysfunction in the sick sinus syndrome. Circula-tion 1978;57:217–223.

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SND: Diagnostic and treatment strategyKey symptoms / Presentation

Most important diagnostic step

Key symptomatic diagnostic findings

Brady-tachy syndrome Symptomaticbradyarrhythmias

documented

Chronotropic incompetence

Syncope/near-syncope, palpitations, exertional intolerance, stroke, fatigue

• Symptomatic sinus bradycardia• Sinus pauses, arrest, exit block

• Chronotropic incompetence• Bradycardia-tachycardia syndrome

• Symptom-arrhythmia correlation: AECG (“Event” recorder, MCOT, ILR)• Exercise evaluation for chronotropic incompetence

• Anticoagulation for Afib/Flutt• Ablation/antiarrhythmia drugs*• Depends on arrhythmia and ptn-specific issues• Atrial-based rate-adaptive pacing

• Eliminate reversible causes (drugs, hypothyroidism, etc.)• Rate-adaptive cardiac pacing (atrial-based dual-chamber preferred if not permanent AF)• Minimize RV pacing by device programming/algorithms

• Eliminate reversible causes (drugs, hypothyroidism, etc.)• Evaluate exercise needs [ADL assessment, formal exercise test (CAEP, MPREP protocols)]• Atrial-based rate adaptive pacing minimizing RV stimulation

FIGURE 90.12. Schematic summarizing a diagnostic and treatment approach to the most common manifes-tations of SND. The reader should also review American College of Cardiology/American Heart Association (ACC/AHA) guidelines on antiarrhythmia drug choices for atrial fi brillation/fl utter before initiating arrhyth-mia suppression drugs (*). ADL, activities of daily living; AECG, ambulatory ECG; Afi b, afi brillation; Flutt, fl utter; MCOT, mobile cardiac outpatient teleme-try; RV, right ventricle; ILR, implantable loop recorder.


s i n u s node dy s f u nc t ion 19 3 9

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9 Sinus Node Dysfunction 0 - Springerextras.springer.com/2007/978-1-84628-715-2/fscommand/PDFs/090.pdf · Sinus node dysfunction may be the result of conditions that ... most classic