9
0
Sinus Node Dysfunction
David G. Benditt, Scott Sakaguchi,
Keith G. Lurie, and Fei Lu
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1925
1925
1928
1928
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 conditions that directly alter sinus node or SA structure, such
as ischemic changes, fibrosis or infiltrative 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 importantly, 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 arrhythmias in others, and both strategies may be required in
many individuals.
• Anticoagulation is critical for treatment of many individuals with SND, particularly those with paroxysmal or
persistent atrial fibrillation.
• 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
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1934
Guidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1937
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1937
tachycardia may occur episodically, resulting in a subset
of SND that is often termed bradycardia-tachycardia syndrome (BTS). In others, SND is manifest primarily as inappropriate 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 considered 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. Subsequently, Lown5 used the term sick sinus syndrome to
describe a chaotic atrial rhythm following cardioversion of
atrial fibrillation, while many others contributed to identifying 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 dysfunction 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 publications 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
19 2 5
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chapter
TABLE 90.1. Causes of sinus node dysfunction
Intrinsic sinus node dysfunction
Idiopathic degenerative disease (probably most common)
May include effects of hypertension
Ischemic
Chronic coronary artery disease occasionally involving sinus
node artery
During acute myocardial infarction (particularly inferior wall,
see “Extrinsic” below)
Infi ltrative disorders: amyloidosis, hemochromatosis, tumors
Inflammatory or postinflammatory: pericarditis, myocarditis
Musculoskeletal disorders: Duchenne’s or myotonic dystrophy,
Friedreich’s ataxia
Collagen-vascular disease: lupus erythematosus, scleroderma
Postoperative: Mustard’s procedure, atrial septal defect repair
Extrinsic sinus node dysfunction
Drug effects (see Table 90.2)
Electrolyte disturbances: particularly hyperkalemia
Endocrine conditions: hypothyroidism, or less commonly
hyperthyroidism
Myocardial infarction, acute inferior wall (neural reflex effects)
Neurally mediated bradycardia-hypotension syndromes
Carotid sinus syndrome
Vasovagal syncope
Postmicturition syncope
Cough, sneeze syncope
Others
Miscellaneous
Intracranial hypertension
Obstructive jaundice
nests that may exhibit somewhat slower intrinsic firing 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, sympathetic 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 Therefore, 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 disturbance can cause intranodal conduction block or, alternatively, 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 influence the site of the principal pacemaker within the node.
CAR090.indd 1926
90
09:02:36
09:02:45
09:02:54
09:03:03
FIGURE 90.1. Rhythm strip from illustrating onset of symptomatic 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.
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, fibrosis or infiltrative diseases (so-called
intrinsic SND), or extrinsic factors such as drugs or autonomic 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 associated with SND, the clinical presentation may vary considerably 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 specific knowledge of the underlying mechanism, these interruptions of the
rhythm are often categorized simply as sinus pauses for purposes 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
II
III
V
V1
II
FIGURE 90.2. (A) Rhythm strip showing sinus pauses in a symptomatic 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.
11/24/2006 1:28:07 PM
sin us node dysf u nct ion
of atrioventricular (AV) conduction (e.g., atrial fibrillation
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 incompetence, 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 (particularly atrial fibrillation), and their attendant potential complications (particularly thromboembolism leading to stroke),
is perhaps the most important cause of morbidity and mortality accompanying SND.4,6,7,19 In many cases, atrial tachyarrhythmias and periods of excessive bradycardia are observed
in the same individual at different times (bradycardiatachycardia syndrome) (Fig. 90.3).
Delayed Resumption of Sinus Rhythm
Failure of appropriate physiologic pacemaker function following an episode of tachycardia (i.e., the spontaneous equivalent 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
25 mm/sec
V
II
Certain pathologic states have been associated with the presence 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 inflammatory
disease. Again, however, the significance of such findings 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 findings 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
Q
FIGURE 90.3. Rhythm strip obtained from an older patient with a
history of both palpitations and syncope. The tracing reveals atrial
flutter with a long pause terminated by a ventricular escape beat.
The history and ECG fi nding tends to support a diagnosis of bradycardia-tachycardia syndrome (BTS). Q, ventricular escape beat.
CAR090.indd 1927
19 2 7
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 precipitated the electrophysiologic disturbance.
Replacement or displacement of normal SA cells by
fibrous tissue, with loss of functional components or alteration 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 cardiomyopathy, surgical trauma, or inflammation (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 fibrous 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 relatively benign conditions such as persistent left superior vena
cava, as well as lesions of potential hemodynamic significance) and even in ostensibly normal children and adolescents.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 influences 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, βadrenoceptor 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 findings suggestive of sinus node
disease.8,14,37–40 Therefore, marked sinus bradycardia, sinus
pauses, SA exit block, and slow ventricular responses in
atrial fibrillation in some cases may be primarily the result
of marked hypervagotonia. Conversely, although not widely
recognized as a manifestation of SND, persistent or inappropriate sinus tachycardia may reflect unbalanced or excessive 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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chapter
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 evident 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) monitoring, many patients may have been missed. Further, most
epidemiologic studies have not clearly differentiated intrinsic 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 surgical repair or palliation of congenital cardiac anomalies in
childhood. Currently, various reports suggest that approximately 6% to 24% of pacemaker follow-up clinic patients
have a diagnosis of SND. However, this is probably an underestimate, and the percentage is likely to increase as physicians 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 additional issues include concomitant disease of the specialized
cardiac conduction system, propensity to new-onset atrial
tachyarrhythmias (particularly atrial fibrillation), 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 statistics 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 first
5 years of follow-up. However, among those SND patients
without other coexisting disease at time of initial diagnosis,
mortality did not differ significantly 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 cardiovascular disease), mortality was markedly higher; the
latter group exhibited a 4-year survival of 40% versus 85%
CAR090.indd 1928
90
for SND patients without coexisting disease and 91% for
control subjects.
Sutton and Kenny45 calculated the following overall survival 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 bradycardia is reported to be more benign than sinus pauses/arrest,
whereas BTS has the worst outlook. In part, these differences
may reflect the relative risk for thromboembolic complications 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 finding that may diminish given more widespread use of long-term anticoagulant therapy and greater
attention to use of atrial pacing systems when cardiac pacemakers are indicated. Prospective follow-up studies are
essential to verify this potential benefit.
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., physiologic pacing systems, more recent insights regarding the benefits 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 dysfunction) outcomes were examined in 35 untreated symptomatic 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 cardiovascular events requiring treatment (syncope, eight; congestive heart failure, six; sustained atrial fibrillation, 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 approximately 38 months, the incidence of new-onset atrial fibrillation in patients with SND was about 5.2% per year. In paced
patients, however, the incidence of atrial fibrillation 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 theophylline 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 asymptomatic ECG findings, to a wide range of complaints including the following:
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sin us node dysf u nct ion
19 2 9
09:03:12
09:03:21
09:03:30
09:03:39
FIGURE 90.4. Implantable loop recorders (ILR) rhythm strip depicting termination of a period of sinus bradycardia. The P-waves are of
low amplitude but are clearly evident.
170/min,
“dizzy”
• 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, chronotropic incompetence, or paroxysmal or inappropriate tachycardias. However, substantiating a causal relationship
between symptoms and abnormal ECG findings is often difficult. 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 fibrillation
and BTS). Apart from overt stroke, smaller embolic phenomena may be the cause of progressive mental status deterioration or dysfunction of other organ systems.
Syncope may be a clinical manifestation of SND due to
the hemodynamic impact of either atrial brady- or tachyarrhythmias (Figs. 90.4 to 90.6). Given the older age of the
SND population, however, the risk of ventricular tachyarrhythmias as a contributing factor must always be considered (Fig. 90.7). Additionally, recent studies have implicated
neural reflex vasodepression (i.e., delayed or inadequate vascular response to an arrhythmic stress) as a potential contributing 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 sufficient systemic hypotension to cause a faint.
FIGURE 90.6. An ILR tracing (slow recording speed) illustrating
onset of an atrial tachycardia leading to “feeling dizzy” in an 88year-old man.
Sinus Arrhythmia, Sinus Tachycardia, and
Inappropriate Sinus Tachycardia
Sinus arrhythmia, a heart rate variation most often associated 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 difficult 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
08/06/03 10:52:20
II
V
V1
FIGURE 90.5. An ECG rhythm strip illustrating a long pause following spontaneous termination of an episode of atrial fibrillation
in a BTS patient with recurrent syncope.
CAR090.indd 1929
II
V5
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 ventricular 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, retrograde concealment permitted unmasking the underlying atrial
flutter 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 inappropriate sinus tachycardia (IST)] is a much more common and
clinically troublesome problem, and is in some patients
intertwined with the postural orthostatic tachycardia syndrome (POTS).52,53 Causative factors such as anemia or hyperthyroidism must first 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 ablation procedure. In such cases, reassurance and beta-blockade
therapy may suffice, but are not often sufficient to provide
complete relief. On occasion, but only in very severely
affected individuals, refractory IST necessitates extreme
measures, including attempted transcatheter ablation/modification 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 identification 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 widespread agreement on the duration necessary to qualify as a
sinus arrest; in a given individual it depends on the magnitude of underlying sinus arrhythmia. From a practical perspective, asymptomatic pauses of ≤3 seconds in duration are
relatively common (reported in approximately 2.4% of
patients) and are apparently without clear-cut adverse prognostic implications. On the other hand, pauses >3 seconds
are believed to be relatively rare during ambulatory monitoring (0.8% of patients) and, although their clinical significance may vary, they warrant careful assessment to detect
symptomatic correlations.54,55
CAR090.indd 1930
90
Sinoatrial exit block is usually classified 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 identified 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 specific 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 phenomenon (see earlier discussion).
The reported incidence of CI is probably unreliable, and
has been variable depending on the population being sampled,
and the definition used. Unfortunately, there are no universally accepted clinically applicable diagnostic criteria for CI.
Initially, the diagnostic criteria consisted of a mean heart
rate below the 95% confidence 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 populations have been reported to exhibit CI. Not infrequently,
drug therapy is an important contributing factor. Manifestations 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 manifestation of SND consisting of the coexistence in the same patient
of periods of bradyarrhythmia interspersed with bouts of
atrial tachyarrhythmias (usually atrial fibrillation, but occasionally, atrial flutter or other paroxysmal atrial tachycardias) 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 tachyarrhythmia termination), or both. Therefore, it remains essential to document the symptom-arrhythmia correlation before
11/24/2006 1:28:08 PM
sin us node dysf u nct ion
initiating treatment. Prognosis in the BTS patient population
is worse than in other manifestations of SND, and is particularly 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. Nonetheless, there remains concern that recurrent episodes of
atrial fibrillation also have an adverse direct effect on the
heart. Research indicates that atrial fibrillation itself has an
undesirable impact on atrial electrophysiology and both
atrial and ventricular function.56–60 In essence, atrial fibrillation of increasing duration appears to predispose to progressive shortening of atrial effective refractory periods. This
is a reversible change, at least in short-term studies, by terminating atrial fibrillation. It is presumed that if permitted
to remain, the shorter refractoriness provides an electrophysiologic milieu that favors sustaining (or maintaining)
atrial fibrillation. Additionally, atrial fibrillation has been
associated with a tendency toward atrial dilatation. Together,
the fibrillation-induced changes in atrial electrophysiology
and structure reasonably lead to the notion that “atrial fibrillation begets atrial fibrillation.” Finally, atrial fibrillation
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 inappropriately 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 fibrillation, 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 presumably present. However, although diffuse conduction system
disease is evident in some patients, the predilection for development of clinically relevant AV block has probably been
overemphasized and, more often than not, SND patients
manifest surprisingly rapid ventricular responses during
atrial tachyarrhythmias.
19 31
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 substantiate the diagnosis, and focus therapy. Invasive electrophysiologic 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 symptomarrhythmia 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 longstanding, 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 specific diagnostic observations. If symptomarrhythmia correlation is obtained during a recording, the
Pauses Following Cardioversion
Prolonged asystolic pauses or sustained periods of junctional
or idioventricular escape rhythms following cardioversion
of atrial fibrillation is typically considered a manifestation
of SND. These patients may be at particularly high risk of
adverse effects (particularly proarrhythmia) of antiarrhythmic 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 fibrillation. Current clinical
criteria for making the diagnosis of SRT require that the
CAR090.indd 1931
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.
11/24/2006 1:28:08 PM
19 3 2
chapter
At home
Education
and hook up
90
Away from
home
Algorithm or symptomatic
event detection and
transmission
24/7/365
monitoring
center
Daily,
urgent,
summary
reports
Real-time
analysis
Internet,
phone, fax
Response
reporting
FIGURE 90.9. Images depicting operation of a mobile cardiac outpatient telemetry (MCOT) system.
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 transient. As a result, “event” recorders, MCOT systems, and ILRs
may be more helpful than conventional 24- or 48-hour Holtertype recordings. However, given the older age of the SND
population on average, many patients are simply incapable of
reacting sufficiently 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, specific 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
FIGURE 90.10. Image illustrating the diagnostic screen recording of a prolonged symptomatic bradycardia event detected by an ILR.
Cardiac pacing was indicated and the patient
has been symptom-free since then.
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sin us node dysf u nct ion
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 reflexes, 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 pharmacologic 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 indicated in suspected SND. Currently, the principal indication
for invasive electrophysiologic testing is to confirm a clinical
suspicion when ECG studies are nondiagnostic or impractical. The sensitivity (abnormality on testing versus “true”
abnormality) and specificity (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 characteristic of native pacemakers, namely “overdrive suppression.”58,63–65 Specifically 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, sinoatrial 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 commonly, this correction is obtained by subtracting the baseline 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 assessment of sinus node function. It can be determined by both
indirect and direct techniques. The most popular indirect
method uses timed premature atrial extrastimuli (A 2) introduced at a high lateral right atrial pacing site during sinus
rhythm (A1-A1). With insertion of A 2, the sequence of sinoatrial activation is reversed for one cycle. Assuming that
intrinsic sinus node automaticity is unperturbed by A 2, the
return cycle (A 2-A3) should be equal to A1-A1 plus an interval
equal to both the time required for A 2 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 definition) 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 electrograms 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
CAR090.indd 1933
19 3 3
upper limit of normal for direct SACT. Values are shorter in
children (15 to 91 ms). However, these direct recordings are
difficult 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
confirm the presence of SND in patients in whom the diagnosis is already established, has yielded variable results.
Pooling findings from various studies suggest that the sensitivity (test positives/true positives) and specificity (test negatives/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 commonly used electrophysiologic tests of sinus node function
lack sensitivity but are relatively specific.
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 impressive. An additional desirable attribute of sinus node function
studies would be the capacity to predict whether cardiac
pacing would be beneficial 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 symptoms were suppressed in 12 of 16), and spontaneous resolution of symptoms occurred in 17 patients; five patients
remained undiagnosed. Therefore, although an abnormal
CSRTmax in symptomatic patients tended to suggest that
cardiac pacing would be beneficial, a normal CSRTmax did not
exclude this possibility.
To recap, a variety of invasive electrophysiologic techniques 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 ventricular pacemakers. The risk appears to be greater among
individuals presenting with atrial tachyarrhythmias compared to those who primarily manifest sinus bradycardia.
Further, thromboembolic events are less frequent in atrially
paced (i.e., atrial pacemakers and perhaps dual-chamber pacemakers) patients (1.6%) compared to those who receive only
single-chamber ventricular-based pacing systems.67 Overt
thromboembolic events (most notably, stroke) are substantially reduced by anticoagulant therapy, especially in patients
with recurring or permanent atrial fibrillation, and especially
in women.67–69 The increasingly aggressive use of anticoagulation in these patients, by medical practitioners of a wide
range of specialties, offers the potential of having an important beneficial impact on stroke rates in this population.
11/24/2006 1:28:09 PM
25 mm/sec
V
II
19 3 4
chapter
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 significant infranodal
conduction system disease.
The presence of concomitant specialized cardiac conduction 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., approximately 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 influences
may be important with regard to the occurrence and worsening 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 conduction 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 consideration 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 arrhythmias, as well as the disease setting. Thus, in many cases of
idiopathic SND, treatment focuses on avoidance of drugs
CAR090.indd 1934
90
that may aggravate the problem, and on prevention of arrhythmia-related complications (notably anticoagulation for prevention 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 processes 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 interest is retained. On the other hand, elimination of certain
drugs may be instrumental for preventing arrhythmic symptoms in SND.
Sinus node dysfunction patients are often exposed to a
wide range of drugs that may exacerbate or unmask underlying susceptibility to bradycardia (Table 90.2). For example,
cardiac glycosides, β-adrenergic blockers, calcium channel
blockers, and membrane-active antiarrhythmic agents (especially 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 materials, lithium carbonate, cimetidine, and adenosine have been
associated with depression of sinus node function.
Anticoagulation is critical for treatment of many individuals with SND, particularly those with paroxysmal or
TABLE 90.2. Some of the more commonly used drugs affecting
sinus node function
Antiarrhythmic drugs
Amiodarone: may be associated with de novo evidence of sinus
node dysfunction
Flecainide, propafenone, sotalol: may exacerbate sinus node
dysfunction
Quinidine, disopyramide, procainamide: less often worsens sinus
node function, possibly due to vagolytic properties
Antihypertensives (sympatholytic)
α-methyldopa, reserpine, clonidine
β-adrenergic blocking drugs
Without intrinsic sympathomimetic action (ISA): propranolol,
nadolol, etc.
With ISA, less severe effects: pindolol, acebutolol, etc.
Ophthalmic drops: Timoptic
Calcium channel blockers
Verapamil and diltiazem more prominently than nifedipine
Cardiac glycosides (rarely a clinical problem)
Miscellaneous
Cimetidine
Lithium
Phenytoin
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sin us node dysf u nct ion
persistent atrial fibrillation. The anticoagulation guidelines
have been widely reported and the reader is referred elsewhere for additional information.35
19 3 5
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.
Pacemaker Therapy
Guidelines for implantation of cardiac pacemakers are periodically 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 encompassing those “clinical manifestations that are directly
attributable to the slow heart rate: transient dizziness, lightheadedness, near syncope or frank syncope as manifestations
of transient cerebral ischemia, and more generalized symptoms 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 physiologic heart rate response in many SND paced patients. Consequently, 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 physiologic benefit at higher paced rates. Therefore, for individuals
in whom AV conduction is suspect, a dual-chamber rate-adaptive 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 benefit of
reducing atrial fibrillation risk, and thereby diminishing the
risk of thromboembolism.73–78 Further, the beneficial 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 findings suggest that optimum
benefit 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 ventricular 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-
CAR090.indd 1935
Clinical Trials in Cardiac Pacing for Sinus
Node Dysfunction
The Theopace study44 provided the first randomized controlled trial of pacing versus medical therapy in SND. Patients
were randomized to no therapy, theophylline, or dual chamber 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 theophylline-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 benefits of atrial-based pacing [i.e., singlechamber atrial (AAI), or AV paced] over single-chamber ventricular pacing (VVI). In the initial report, 225 SND patients
were randomized to AAI or VVI pacing. At 3.3 years followup the atrial fibrillation and stroke incidence did not differ
substantially in the two groups, but the combined finding 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 fibrillation,
thromboembolism, heart failure, and stroke. Further, allcause 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 significantly 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 measures. The authors reported no significant difference in
various outcome measures between groups, although findings were more supportive of dual-chamber pacing in SND.
In addition, the crossover from VVIR to DDDR was substantial, amounting to approximately 50% of SND patients randomized 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 significant improvement
in quality-of-life indices as measured by the Short Form (SF36) 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
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chapter
90
point (all-cause mortality or stroke) did not differ in the two
groups. However, there was a significant reduction in atrial
fibrillation 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 justifiably 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
first 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 significant), but cardiovascular death did not differ in the two
groups. On the other hand, the annual rate of atrial fibrillation was significantly less in the physiologic pacing group
(5.3% vs. 6.6%, annual relative risk reduction, 18%, p = .05).
The atrial fibrillation benefit became increasingly apparent
with longer follow-up (>2 years). Patients with structurally
normal hearts and no prior atrial fibrillation history appeared
to show greatest benefit.76,77
In terms of the specific context of assessing cardiac
pacing in SND, the CTOPP trial data are difficult 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 difficult to evaluate the impact of the pacing intervention. In
this regard, a substudy analysis of CTOPP results was undertaken, looking at findings 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 benefited by
selection of physiologic pacing systems. The benefit in terms
of atrial fibrillation suppression is probably of greatest practical importance. Further, the apparent benefit 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 function patients require pacing for bradyarrhythmias or atrial
fibrillation suppression. In the setting of normal AV conduction, 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 probably prudent to favor a dual-chamber AV pacing system.
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 ventricular atrial arrhythmia susceptibility.
Among the specialized pacing techniques that seemed
to be of greatest intuitive potential benefit 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 susceptibility to intraatrial reentry (particularly of the form that
results in episodes of atrial fibrillation). The most thoroughly
studied of these methods is so-called dual-site atrial pacing.86
Single-site Bachmann’s bundle pacing has also been advocated.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 coronary 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 duration. However, to date the results have been disappointing.
In the Dual-site Atrial Pacing in Paroxysmal Atrial Fibrillation (DAPPAF) trial,84,86 findings tended to show a trend
toward benefit only in patients in whom atrial fibrillation
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 Overdrive (DAO), St. Jude Medical, St. Paul, MN].88,89 In regard to
DAO, findings in the Atrial Dynamic Overdrive Pacing Trial
(ADOPT) studies (St. Jude Medical) revealed a significant
reduction of atrial fibrillation 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 defibrillators have
been made available that have the capability for automatically 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, implantable atrial defibrillators (which of necessity must also offer
ventricular fibrillation shock capacity for safety purposes)
have had only very limited clinical acceptance. Nevertheless, such devices may have a niche role to play in some very
symptomatic individuals.
Specialized Pacing Techniques
Pacemaker Recalls and Medical Advisories
Specialized pacing techniques or algorithms within the pacemakers programmable feature set may further help to prevent
atrial fibrillation episodes, or at least reduce the overall
burden of arrhythmia (i.e., the time duration the patient is
in atrial fibrillation per month or year) for SND patients. In
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
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sin us node dysf u nct ion
increasingly difficult position. They must be continuously
vigilant for new problems, and provide their patients with
appropriate management advice. The balance between advising continued monitoring versus recommending premature
device explantation with its attendant additional medical
risks (e.g., infection, bleeding) is often a difficult and precarious one. Fortunately, while SND patients often benefit from
pacing therapy, they are only infrequently pacemaker dependent. Consequently, the need for urgent device replacement
is uncommon in this clinical setting.
Indications for Pacing in Sinus
Node Dysfunction71
CLASS I
1. SND with documented symptomatic bradycardia due
to intrinsic SA disease or to extrinsic factors that may not
be readily reversible or substituted for (autonomic disturbances, essential drug therapy)
2. Symptomatic chronotropic incompetence
CLASS II
1. 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 possible 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 III
1. 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 tachyarrhythmia control currently have limited application in SND.
Several types of ablation, however, may prove helpful in
specific circumstances:
• Transcatheter radiofrequency ablation of the His bundle
with placement of a cardiac pacemaker remains useful
in many patients with refractory primary atrial tachyarrhythmias, 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 addition, 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 achieving better heart rate control and by reducing hospitalization 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 flutter. Success rates in the
mid- to high 90% range are expected. However, while
this procedure prevents recurrent flutter, the effectiveness of the underlying sinus node is uncertain. A permanent pacemaker may yet be needed.
CAR090.indd 1937
19 37
• Attempts to ablate foci of atrial arrhythmogenesis,
particularly pulmonary vein and other venous sources
of paroxysmal atrial fibrillation 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 fibrillation ablation is
changing as experience grows. Constant monitoring of
the recent literature is essential.
Surgical “maze” operations can be effective in selected
atrial fibrillation 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 permanent cardiac pacemaker will usually be warranted.
Guidelines
The principal guideline statements (and some useful commentaries) pertinent to SND patients are as follows:
• The 2002 revision of the American College of Cardiology/
American Heart Association (ACC/AHA/NASPE) guideline 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
fibrillation106
• The ESC guidelines on management (diagnosis and treatment) of syncope, updated 2004107
• American Heart Association Council on Clinical Cardiology and Heart Rhythm Society science advisory statement on the role of permanent pacing to prevent atrial
fibrillation108
• Drugs for cardiac arrhythmias: a treatment guideline
from the Medical Letter109
• A commentary on translation of clinical trials into clinical 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
identified in individual patients. It is as a result of its electrocardiographic 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 dysfunction patients is largely dictated by symptoms and electrocardiographic findings (Fig. 90.12). Whereas arrhythmia
suppression is often an important goal, it is equally important to reduce both susceptibility to syncope and falls,
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19 3 8
chapter
90
SND: Diagnostic and treatment strategy
Key symptoms / Presentation
Syncope/near-syncope, palpitations, exertional intolerance, stroke, fatigue
Most important diagnostic step
• Symptom-arrhythmia correlation: AECG (“Event” recorder, MCOT, ILR)
• Exercise evaluation for chronotropic incompetence
Key symptomatic diagnostic findings
• Symptomatic sinus bradycardia
• Sinus pauses, arrest, exit block
• Chronotropic incompetence
• Bradycardia-tachycardia syndrome
Chronotropic incompetence
• Eliminate reversible causes
(drugs, hypothyroidism, etc.)
• Anticoagulation for Afib/Flutt
• Evaluate exercise needs
• Eliminate reversible causes
• Ablation/antiarrhythmia
[ADL assessment, formal
(drugs, hypothyroidism, etc.)
drugs*
exercise test (CAEP, MPREP
• Depends on arrhythmia and • Rate-adaptive cardiac pacing
protocols)]
(atrial-based dual-chamber
ptn-specific issues
preferred if not permanent AF) • Atrial-based rate adaptive
• Atrial-based rate-adaptive
• Minimize RV pacing by device pacing minimizing RV
pacing
programming/algorithms
stimulation
Brady-tachy syndrome
Symptomatic
bradyarrhythmias
documented
and risk of thromboembolic complications. In addition,
treatment should focus on diminishing symptoms of exertional intolerance by providing appropriate chronotropic
support, usually by use of physiologic rate-adaptive pacing
systems.
15.
16.
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