Contemporary Reviews in Cardiovascular Medicine

Sinus Node and Atrial Arrhythmias

Roy M. John, MBBS, PhD; Saurabh Kumar, BSc(Med)/MBBS, PhD

AbstractAlthough sinus node dysfunction (SND) and atrial arrhythmias frequently coexist and interact, the putative
mechanism linking the 2 remain unclear. Although SND is accompanied by atrial myocardial structural changes in
the right atrium, atrial fibrillation (AF) is a disease of variable interactions between left atrial triggers and substrate
most commonly of left atrial origin. Significant advances have been made in our understanding of the genetic and
pathophysiologic mechanism underlying the development and progression of SND and AF. Although some patients
manifest SND as a result of electric remodeling induced by periods of AF, others develop progressive atrial structural
remodeling that gives rise to both conditions together. The treatment strategy will thus vary according to the predominant
disease phenotype. Although catheter ablation will benefit patients with predominantly AF and secondary SND, cardiac
pacing may be the mainstay of therapy for patients with predominant fibrotic atrial cardiomyopathy. This contemporary
review summarizes current knowledge on sinus node pathophysiology with the broader goal of yielding insights into
the complex relationship between sinus node disease and atrial arrhythmias. (Circulation. 2016;133:18921900. DOI:
10.1161/CIRCULATIONAHA.116.018011.)
Key Words:ablation, catheter atrial fibrillation atrial standstill pacemaker, artificial sick sinus syndrome
sinoatrial node

S inus node dysfunction (SND) and atrial arrhythmias fre-

quently coexist and interact to initiate and perpetuate each
other. Atrial arrhythmias are present in 40% to 70% of patients
at the time of diagnosis of SND.1,2 However, the complex rela-
tionship between the 2 remains ill defined. The documented
degenerative changes in atrial myocardial structure relating to
SND are primarily right atrial. Yet, the majority of triggers
and substrates for atrial fibrillation (AF) originate from the
left atrium. Although progressive biatrial fibrosis is a feature
in patients with structural heart disease and in senescence,
paroxysmal AF that occurs in patients with no structural heart
disease may have a different pathophysiology. SND associ-
ated with this latter condition is likely to be primarily a result
of electric remodeling and potentially reversible. The time
course of the progression of SND and AF3 and their individual
clinical manifestations also vary depending on the underly-
ing pathology. The purpose of this review is to summarize the
state of our knowledge of sinus node (SN) function in both
health and disease, and to understand the complex relationship
between SN disease and atrial arrhythmias.
Structure and Functional
Components of the Sinus Node
In the adult human heart, the SN is a crescent-shaped struc-
ture 1 to 2 cm long and 0.5 cm wide that lies at the junction
of the superior vena cava with the right atrium and lies along
the sulcus terminalis. The node itself is composed of clusters
of pacemaker myocytes arranged in parallel rows with short
digitations that frequently anastomose with the surrounding
atrial tissue. The specialized pacemaker cells are interspersed
with nerves and capillaries and scaffolded by dense connec-
tive tissue to form the SN pacemaker complex. The caudal
portion fragments to merge with the atrial myocardium. The
lack of a distinct encapsulation and the radiating sinoatrial
connections explains the lack of a single breakthrough of the
sinus impulse. The position of the leading pacemaker site
shifts within the node and varies with sympathetic and vagal
stimulation.3
The SN pacemaker cells are interspersed with intersti-
tial collagen that varies in extent as a function of older age.4
Collagen content increases from 24% in the infant to 70% in
the adult heart.5 The fibrous matrix with surrounding fatty
insulation of the SN together with distinct electrophysiologi-
cal properties (see below) provides insulation and prevents the
depression of pacemaker automaticity from the hyperpolariz-
ing electric load of the surrounding atrial myocardium.6
Multiple currents are involved in the activation of the SN.
The predominant inward current in the center of the node is
ICaL. Action potentials with slow upstrokes initiated in the
center spreads peripherally and into the musculature of the
terminal crest. However, in the periphery of the node, INa is
operative and is necessary for providing sufficient inward
current to depolarize the larger mass of atrial tissue. Delayed
rectifier potassium currents facilitate repolarization with slow
decay of Ikr and Iks. The absence of Iki in the SN allows for
membrane repolarization below the threshold of the hyperpo-
larization-activated cyclic nucleotide-gated (HCN) channels

From Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA.
Correspondence to Dr. Roy M. John, MBBS, PhD, Arrhythmia Service, Cardiovascular Division, Brigham and Womens Hospital, 75 Francis St, Boston,
MA 02115. E-mail rjohn2@partners.org
(Circulation. 2016;133:1892-1900. DOI: 10.1161/CIRCULATIONAHA.116.018011.)
2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.116.018011

1892
 John and Kumar Sinus Node and Atrial Arrhythmias 1893
that carry the funny (If) current.7 The dominant HCN tran-
script is HCN4 carrying the majority of If current.7 The If
current itself is a mixed sodium and potassium current that
triggers spontaneous and repetitive diastolic depolarization
(membrane clock) to activate ICaL within the SN (calcium
clock).8 Other currents include T-type calcium channel (ICaT,)
and the sodium-calcium exchanger (INaCa). Hence, mutation in
genes coding for any of the INa (SCN5A), calcium, and HCN4
results in SN dysfunction. Most of these genetic mutations are
also associated with AF.
In addition, gap junctions composed of connexins (Cx)
that are critical for myocyte electric coupling are variously dis-
tributed within the SN. In the center of the node, electric cou-
pling is weak because Cx43 and Cx40 are poorly expressed or
absent.9 In the periphery, however, electric coupling has to be
stronger to drive the atrial muscle. The periphery of the rabbit
SN expresses 3 connexins (Cx40, Cx43, and Cx45) in keeping
with this postulate. SN dysfunction has been documented in
Cx40 knockout mice.10
Definitions of Terms
Sinoatrial Disease
The term sick sinus syndrome is applied to a clinical syn-
drome to include chronic SN dysfunction, frequently
depressed escape pacemakers, and atrioventricular nodal
conduction disturbances. The term sinoatrial disease is used
interchangeably with sick sinus syndrome and describes
a series of abnormalities that can result in profound sinus
bradycardia, sinus pauses, sinus arrest, sinoatrial nodal exit
block, and chronotropic incompetence, defined as inappro-
priate responses to physiological demands during exercise or
stress. Chronotropic incompetence is often underrecognized
and an important cause of exercise intolerance and a predic-
tor of adverse cardiovascular events.11 Sick sinus syndrome
may also be accompanied by intra-atrial conduction delay,
atrioventricular nodal conduction disturbances, and paroxys-
mal atrial tachycardia as part of the tachycardia-bradycardia
syndrome.
Tachycardia-Bradycardia Syndrome
The syndrome of alternating bradycardia and tachycardia was
originally described in 4 patients by Short12 in 1954. These
patients had periods of atrial flutter or fibrillation with periods
of sinus pauses at termination of the atrial arrhythmia leading
to syncope. The tachycardia-bradycardia syndrome, although
frequently referring to the combination of atrial tachyarrhyth-
mia alternating with pauses (Figure1), could ostensibly be
applied to any combination of tachycardia with bradycardia.
For example, an underlying sinus bradycardia, which in itself
is asymptomatic, may complicate the management of parox-
ysmal AF with rapid ventricular rates. Similarly, persistent or
long-standing AF with periods of fast and slow heart rates,
falls in a similar category. The clinical implication of the
combination of tachycardia and bradycardia is the limitation
imposed on the use of negative chronotropic agents without
the concomitant use of cardiac pacing. However, the recogni-
tion of the exact mechanism of the tachycardia-bradycardia
syndrome has implications for management (see below).
Epidemiology of Sinus Node Disease and
Relationship to Atrial Arrhythmia
The prevalence of SND is estimated to be 1 per 1000 person-
years in adults >45 years of age.13,14 Its incidence increases
with age, occurring in 1 of every 600 patients >65 years of
age.15 SND accounts for significant healthcare use, includ-
ing the need for hospitalization and pacemaker implantation
(accounting for 50% of implant indications in the United
States).13 The natural history of SND is characterized by
progressive rhythm disturbances and adverse cardiovascular
events. The time course can be lengthy and unpredictable; pro-
gression from bradycardia to sinoatrial block or sinus arrest
can extend over an average of 13 years (range, 729 years).16
A characteristic feature, however, is the development of supra-
ventricular arrhythmias, of which AF is the most common.2,17,18
In large population studies, the estimated hazard ratio for new-
onset AF in patients with SND was 4.2.19 AF may be present
concurrently at the time of initial diagnosis of SND in 40% to
70% of patients.1,2,18 In those without clinical AF at the time of
Figure 1. Ambulatory rhythm monitoring
showing a typical example of tachycardia-
bradycardia syndrome with a 6.0-second
sinus pause at the termination of AF. The
pause is interrupted by junctional escape
beats before the resumption of sinus
rhythm. AF indicates atrial fibrillation.
1894CirculationMay 10, 2016
diagnosis, new AF develops in 4% to 22% of patients in fol-
low-up.1,2,18 In long-term follow-up, 68% of patients will have
had AF documented by pacemaker diagnostics.2
SND is associated with increased risk of cardiovascular events
including syncope, overt heart failure, and poorly tolerated atrial
arrhythmias. The annual incidence of thromboembolic events is
1%,20,21 and is related to the coexistence of atrial arrhythmias.
The presence of comorbid cardiovascular conditions rather than
SN disease per se predicates mortality risk. For example, risk of
stroke and death was related to the CHA2DS2-VASc score even
in the absence of AF at baseline.22 The presence of AF, even
when subclinical (detected only by pacemaker diagnostic in the
absence of symptoms) portends increased risk of stroke, death,
and the likelihood of the development of clinical AF.23,24
Evidence for Link Between SND and AF
The central paradigm of the clinical association between
AF and SND is likely a combination of anatomic and elec-
trophysiological remodeling. Remodeling is demonstrable at
a structural, ionic, cellular, and genomic level.25 Both SND
and AF become progressively more prevalent with ageing.
The underlying pathological process may remain clinically
silent in some patients, whereas, in others, it is manifest as
clinical SND or AF. Clinical electrophysiological studies have
shown evidence for age-related conduction slowing, altera-
tion in atrial refractory periods, and reduced SN reserve in an
otherwise healthy population.26 Similarly, even in the absence
of atrial arrhythmias, patients with conditions associated with
atrial remodeling and atrial stretch (eg, congestive heart fail-
ure) exhibit altered SN function.2731
In clinical practice, prolongation of SN recovery time
has been noted after conversion of atrial arrhythmias to
sinus rhythm by electric cardioversion or catheter ablation.32
Furthermore, patients with prolonged postcardioversion sinus
pauses are more likely to experience AF recurrence after cath-
eter ablation.33
Pathophysiology Common to SND and AF
SND can be secondary to reduced impulse generation or attrib-
utable to defective conduction out of the node to the surround-
ing atrial myocardium (sinoatrial block). Although temporary
SND can result from a number of extrinsic factors (Figure2),
permanent dysfunction is more commonly attributable to
intrinsic factors such as progressive fibrosis and ischemia, and
infiltrative and inflammatory processes can also act as trig-
gers and substrates for atrial arrhythmia.25,34 Parasympathetic
stimulation, although more likely to produce SN dysfunction,
can also provoke AF (see below).
Interstitial fibrosis is integral to the human SN.5 Age-
induced increase in SN fibrous content correlates with slower
intrinsic heart rate in mammalian hearts. In human hearts,
age-induced increase of right atrial fibrosis correlated strongly
with slowed intrinsic heart rate and prolonged sinoatrial con-
duction time.35 In addition, an age-related decrease in upstroke
velocity of the action potentials has been demonstrated in the
periphery of the rabbit and cat SN and likely represents an
age-related decrease in density of INa in this region.36 This
decrease could also explain the increased sinoatrial conduc-
tion time and sinoatrial exit block of senescence caused by
source-sink mismatch with the surrounding atrial myocar-
dium. In mice, deficiency of the Nav1.5 upregulates transform-
ing growth factor 1 that stimulates fibrosis.37 Fibroblasts can
physically separate the pacemaker cardiomyocytes, slowing
the sinoatrial rhythm through a reduction in mutual entrain-
ment. Atrial arrhythmias interact with these structural changes
by electric remodeling of the SN.38
The pathophysiology of AF is diverse. The majority of
paroxysmal AF is driven by focal sources most commonly
originating from the pulmonary vein muscular sleeves. The
persistent and long-standing forms of the arrhythmia involve
more complicated substrates. Structural remodeling from
repeated episodes of atrial arrhythmias or prolonged persis-
tence of the arrhythmia commonly involves cardiomyocyte
apoptosis, progressive fibrosis, dilatation, and electric decou-
pling.38,39 Concurrently, electric remodeling results from
altered expression and function of the cardiac ion channels
favoring the development of functional reentry. The most
prominent is downregulation of ICaL, and shortening of action
potential duration attributable to enhancement of the inward
rectifier potassium currents (both Ik1 and constitutive acetyl-
choline-dependent current IKAChC). Shortened refractoriness
stabilizes functional reentrant rotors, increasing AF vulner-
ability and sustainability. In addition, alterations in calcium
handling promote diastolic calcium release from the sarco-
plasmic reticulum and ectopic activity. This series of struc-
tural and electric remodeling is responsible for the common
clinical scenarios of early recurrence after cardioversion, pro-
gressive drug resistance of longer-lasting AF and progression
from paroxysmal to permanent AF.
The inter-relationship between SND and AF has been vali-
dated by a number of human studies. Detailed electrophysi-
ological mapping performed in patients with SND showed
that such patients exhibit a diffuse atrial myopathy before the
development of clinical AF. In comparison with a control popu-
lation without SND or clinical AF, patients with SND exhibited
global and regional atrial conduction slowing, widespread areas
of atrial scar, and loss of the normal multicentric pattern of SN
activation with caudal shift of the pacemaker complex, and
abnormal and circuitous atrial conduction around lines of block,
as well (Figure3).27 These observations suggest the underlying
development of silent, yet diffuse atrial remodeling that may be
necessary for clinical SND to be manifest. Furthermore, these
findings are also consistent with the notion that a subjugate pro-
cess would be required to afflict normal function of the otherwise
widely distributed anatomic nature of the healthy SN complex40
and the observation that an extensive region of ablation is usu-
ally required to modify or abolish normal SN function.41
Fibrotic Atrial Cardiomyopathy
Kottkamp recently proposed a primary fibrotic atrial cardio-
myopathy as a distinct entity.42 The condition appears to be
distinct from the aforementioned atrial remodeling. Patients
with fibrotic atrial cardiomyopathy have evidence for exten-
sive and progressive atrial scarring that clearly cannot be
explained by age, underlying heart disease, or a long history
of AF. They develop rapid progression of disease in the form
of conversion of paroxysmal to persistent AF, and exhibit lim-
ited response to catheter ablation of AF.43 Although patients
 John and Kumar Sinus Node and Atrial Arrhythmias 1895

Figure 2. Schematic of sinoatrial anatomy and factors that lead to sinus node dysfunction.25,34 The extent of the rabbit sinus node (SN)
with central region (CN, dark brown) and peripheral region (PN, blue) as determined by computer 3-dimensional reconstruction is shown
in the central figure. CAMKII indicates calcium/calmodulin-dependent protein kinase II; IVC, inferior vena cava; RAA, right atrial append-
age; SERCA, sarcoendoplasmic reticulum calcium transport ATPase; and SVC, superior vena cava.

with fibrotic atrial cardiomyopathy may be classified as lone
AF because of the absence of any traditional risk factors for
AF, the extent of structural remodeling evident on mapping is
consistent with an underlying atrial myopathic process with
global and regional conduction slowing, atrial fibrosis, and
impaired SN function.44 MRI imaging with late gadolinium
enhancement demonstrates extensive biatrial fibrosis,45 and
atrial mechanical function is extensively impaired despite a
low CHA2DS2VASc score, increasing the risk of stroke and
necessitating prophylactic chronic oral anticoagulation.39,42
Extreme forms of this fibrotic process may be the cause of the
rare but well-recognized clinical scenario of atrial standstill, a
condition characterized by mechanical and electric silence of
the atria with nonexcitability. The relationship of this entity of
fibrotic atrial cardiomyopathy to the various genetically medi-
ated diseases of sinoatrial dysfunction is unclear.
Genetic Mutations Common to SND and AF
A number of genetic mutations have been identified in famil-
ial SND that follow a Mendelian pattern of inheritance.46 A

Figure 3. Activation (A) and voltage maps (B) in patients without SND (controls) and with SND. Activation map demonstrates the shift
from multicentric (broad red blush; A, Left) to a unicentric activation pattern (small red blush; A, Right). Voltage map (B) shows a diffuse
atrial myopathy (large amount of red color in the B, Right) in patients with SND in comparison with controls without SND (large amount
of green color; B, Left). CS indicates coronary sinus; IVC, inferior vena cava; SND, sinus node dysfunction; and SVC, superior vena cava.
Reproduced from Sanders et al27 with permission of the publisher. Copyright 2004, the American Heart Association.
1896CirculationMay 10, 2016
number of these genetic mutations result in phenotypes that
manifest both SND and AF. The most common of these is
mutations in the SCN5A gene and the HCN gene. SND may
also follow a polygenic pattern of inheritance; genomewide
association studies have also identified polymorphisms at 21
loci, including HCN4 and Nkx-2.5, that determine the heart
rate in healthy individuals.
SCN5A gene mutations result in highly variable clini-
cal presentations with SND as part of, but not unique to, the
phenotype. Examples include Brugada syndrome, congenital
long-QT syndrome type 3, familial atrioventricular block, and
familial dilated cardiomyopathy.47,48 Familial HCN4 muta-
tions affect different areas of the HCN4 protein including
the intracellular C-terminal and the ion pore region, leading
to familial SSS.49 The clinical presentation can vary between
asymptomatic sinus bradycardia and a more clinically impor-
tant phenotype of symptomatic SND and AF.5052
Mutations in calcium channels and calcium-handling
proteins lead to SND but generally result in a more severe
global cardiac phenotype because of the ubiquitous nature
of calcium-handling proteins. Mutations of ryanodine or
calsequestrin 2 result in sinus bradycardia and AF associated
with catecholaminergic polymorphic ventricular tachycar-
dia.5356 Ankyrin-B mutation can cause severe SND by virtue
of abnormalities of ion channel trafficking resulting in the
disruption of the cell membrane and calcium clocks, lead-
ing to an autosomal dominant inherited form of sick sinus
syndrome associated with sudden death and occasionally QT
prolongation.5759 A loss-of-function mutation of ANK2 is
associated with early onset of AF.60 Missense mutations in
the MYH6 gene, encoding the heavy chain subunit of car-
diac myosin is associated with heightened susceptibility to
sick sinus syndrome.61
Figure 4. Rhythm strip showing the effect of adenosine on the sinus node and atrium. Intravenous adenosine terminates an AV node
dependent SVT. After termination, a sinus beat is followed by a burst of atrial fibrillation and prolonged sinus pause. See text for details.
AV indicates atrioventricular; SVT, supraventricular tachycardia; and TACHY, tachycardia.
Genomewide association studies have identified a risk
locus for AF62 on chromosome 4q25. In close proximity is the
PITX2 gene that plays a role in asymmetrical development of
the heart and the gut, and in embryonic rotation.62 PITX2 plays
a critical role in the suppression of formation of the SN in the
left atrium and in the development of the pulmonary myocar-
dium. Heterogeneous PITX2 knockout mice have increased
susceptibility to AF during programmed stimulation. PITX2
is downregulated in human atrial tissue from patients with
AF.63 In the postnatal atria, PTX2 also plays important role
in the integrity of the intercalated discs, and knockout mice
demonstrate evidence for SND.64 Thus PTX2 has generated
considerable interest as having a role in AF and possibly SND
although evidence regarding the expression of PTX2 and its
target genes in AF is still missing.
Cardiomyopathy linked to lamin A/C mutations is fre-
quently associated with conduction abnormality and atrial
arrhythmias. Selective apoptosis has been documented in
the conduction system of mice models with lamin A/C muta-
tions.65 In a genetic atrial cardiomyopathy attributable to
Natriuretic Peptide Precursor A gene mutation, progressive
fibrosis leading to atrial standstill occurred in affected family
members over several years of follow-up and may represent
an extreme form of fibrotic atrial cardiomyopathy.66
Cholinergic Effects on SN and Atrial Arrhythmias
Vagal stimulation provoking marked sinus bradycardia and AF
is well recognized in clinical practice (Figure4). Adenosine
shortens the atrial refractory period via its effects on the
IkAch,Ado channels. The effect is not uniform and leads to marked
dispersion of refractoriness within the atrium, creating the
substrate for functional reentry and fibrillation. In pacing-
induced canine models of heart failure, marked upregulation
 John and Kumar Sinus Node and Atrial Arrhythmias 1897
of adenosine A1 receptors occurs with increased sensitivity to
adenosine induced SN dysfunction and AF.67
Bradycardia Predisposes to AF
Whereas SND and diffuse atrial myopathy demonstrably
coexist, providing a working substrate for AF, bradycardia,
in itself, may also facilitate the development of AF through
the increased likelihood of atrial ectopy and greater disper-
sion of refractoriness.68 In the cardiovascular health study, low
heart rates were associated with an increased risk for AF in
the elderly.69 An intriguing experimental study using isolated
rabbit atrial sections that incorporated the SN and pulmonary
veins suggested an interaction between SN tissue, atrial myo-
cardium, and pulmonary vein tissue.70 When the connection
between SN and the pulmonary vein were interrupted in this
preparation, pulmonary venous musculature demonstrated
more burst firing and early after-depolarizations in response
to provocative agents in comparison with control rabbits with
intact connections. Thus, the loss of SN overdrive modula-
tion on subsidiary pace-making cells likely facilitates the gen-
eration of ectopic arrhythmias. Increased spontaneous activity
attributable to the If current has been demonstrated in canine
pulmonary vein sleeves after rapid atrial pacing.71
Effect of Atrial Arrhythmias on SN Function
Rapid atrial pacing or atrial arrhythmia is well documented to
result in SND. In canine models, persistent rapid atrial pac-
ing for >2 weeks and pacing-induced AF resulted in SND evi-
denced by prolonged SN recovery time and slower intrinsic
hearts; these changes are gradually reversed after termination
of AF.72 Yeh et al73 reported downregulation of the HCN chan-
nels and reduced If current in atrial arrhythmias. In experiments
of isolated right atrial tissue of dogs with pacing-induced AF,
the superior part of the SN showed reduced responsiveness
to caffeine stimulation and was unable to serve as the lead-
ing pacemaker site. This area of the node had reduced RyR2
expression in keeping with a defective calcium clock being
responsible, in part, for the SND in this pacing-induced model
of AF.74 In human studies, even short duration of pacing or
paroxysmal episodes of AF is associated with SN remodeling
and reduced SN reserve or dysfunction.75,76 Following ablation
of atrial flutter, corrected SN recovery time decreased by 35%
3 weeks after ablation, suggesting that the atrial arrhythmia
has a reversible effect on SN function.32
Time Course of Recovery of SN Function After
Termination of AF
Although reversal of atrial remodeling has been demon-
strated in numerous animal and human studies,77 reversal
of SN remodeling has not been specifically addressed. In
canine studies, atrial pacing for up to 8 weeks induces atrial
remodeling and SND, which partially reversed after 1 week
of resumption of sinus rhythm.72 Cardioversion of persistent
AF in humans resulted in reversal of SN function by 1 week
in 1 study that occurred earlier than reversal in AF-induced
changes in atrial refractoriness.78 In patients with paroxysmal
AF and prolonged sinus pauses, a gradual improvement in SN
function was noted after catheter ablation of AF.76 Patients
exhibited an increase in the mean heart rate, maximal heart
rate, heart rate range, and corrected SN recovery times in com-
parison immediately postablation with reevaluation at 2 years
postablation.76 In some patients, however, reversal of atrial
remodeling may not occur and may in fact progress despite
successful elimination of AF with catheter ablation.43 This
suggests that some patients may have an underlying indepen-
dent myopathic process that progresses inexorably indepen-
dent of efforts directed at reversal of the remodeling-inducing
stimuli.45,79
Management of Atrial Arrhythmias and SND
Drug Therapy for Atrial Arrhythmias in the
Presence of SND
In the presence of significant bradycardia, the use of antiar-
rhythmic drugs is often restricted by the risk of further wors-
ening bradycardia. In otherwise healthy athletic patients with
paroxysmal AF, a baseline resting sinus bradycardia is often
attributable to a high vagal tone. Adequate chronotropic
response can often be demonstrated during exercise testing,
unlike in the elderly patients with true SND where chronotropic
incompetence is usually the rule. In the absence of significant
SN disease, -blockers, possibly those with intrinsic sympatho-
mimetic activity, are useful to prevent rapid heart rates during
paroxysms of AF. Among the class 1c drugs, both propafe-
none and flecainide have minimal effects on the normal SN but
worsen SN function in the presence of SN disease. Propafenone
has an additional -blocking effect that is more prominent in
slow acetylators and is a less attractive choice. Class III antiar-
rhythmics such as dofetilide have a higher incidence of tors-
ade de pointes in the presence of marked sinus bradycardia. Ikr
blockade can also have direct effect on SN function.80
Pacing for the Treatment of SND
If no reversible cause is evident, cardiac pacing is the only
effective treatment for SND. Early randomized studies dem-
onstrated that rate-responsive AAI or DDD pacing confers a
lower risk of AF, stroke, and pacemaker syndrome than with
VVI pacing.1,21,81 Atrial-based pacing can prevent potential trig-
gers of AF such as bradycardia, ectopic beats, and mechanical
stretch caused by atrioventricular dyssynchrony. The benefit
from AAI-only pacing may be somewhat mitigated in patients
with long PR intervals that may be the result of diastolic mitral
regurgitation.18 However, right ventricular pacing with the
DDD mode is known to worsen heart failure especially with
preexisting left ventricular dysfunction.82 Minimal ventricular-
pacing algorithms can be useful for the prevention of AF.82
In pacing for SN disease, algorithms to suppress AF, such
as continuous atrial overdrive pacing or triggered atrial pac-
ing, alone or in combination, have been evaluated in small
trials with short follow-up periods, but clinically important
effects on AF have not been consistently demonstrated.83
Similarly, alternative sites of pacing such as Bachmann bundle
pacing, biatrial pacing, or dual-site pacing have failed to show
consistent benefit.83
Reverse Remodeling of SN After Ablation for AF
Symptomatic sinus pauses on cessation of an atrial arrhythmia
are conventionally considered an indication for cardiac pacing
1898CirculationMay 10, 2016
followed by antiarrhythmic therapy to control AF. However,
the main drawbacks of this strategy are continued tachycardia
symptoms with poor efficacy of drugs, the long-term mor-
bidity associated with cardiac pacing, and the low likelihood
of influencing outcomes such as stroke. There are emerging
data that successful control of the atrial arrhythmia with abla-
tion can result in resolution of the bradyarrhythmia, avoiding
the need for cardiac pacing.76,84,85 In nonrandomized studies,
a strategy of primary ablation for paroxysmal AF was supe-
rior to pacing and antiarrhythmic drug use.84,86 Moreover, the
majority of patients who underwent AF ablation no longer had
an indication for pacing. However, continued surveillance is
necessary in the postablation phase; early recurrences of atrial
arrhythmias following an ablation may reproduce symptom-
atic sinus pauses. Formal randomized trials of such strategies
will require multicenter efforts because symptomatic sinus
arrest in relation to paroxysmal AF occurs only in 8% to 10%
of patients with atrial arrhythmias.84 Nevertheless, offering
ablation as a first-line treatment an attractive option especially
in younger patients in whom long-term pacing is associated
with morbidity.
Summary and Future Directions
There has been significant progress in our understanding of
the electrophysiological mechanisms and remodeling pro-
cesses that result in the harmful interaction between atrial
arrhythmias and SND. The 2 arrhythmias share several com-
mon etiologies. However, their individual clinical manifesta-
tions are highly variable. It is clear that, in some patients, AF
and SND may result from pure electric remodeling such that
treatment of 1 may provide freedom from the other, at least for
the short term. In others, even in the absence of obvious struc-
tural disease, progressive structural remodeling facilitates the
initiation and propagation of both arrhythmias. Improved rec-
ognition of the underlying pathology is important to enhance
our ability to design better therapeutic strategies. In this
regard, imaging studies that can define the extent of fibrosis
will be critical in better definition of the atrial substrate. The
ability of implantable devices to detect early atrial arrhyth-
mias and to alert us to their presence has already influenced
therapies aimed at preventing cardioembolic strokes. Large-
volume data from these implantable and noninvasive moni-
toring devices will improve our understanding of the natural
history and rate of progression of both arrhythmias. The ever-
expanding information base on the genetic abnormalities that
cause SND and AF promises earlier diagnosis and implemen-
tation of interventions to improve outcomes.
Acknowledgments
We thank Dr William G. Stevenson for constructive criticism on the
manuscript.
Disclosures
Dr John receives consulting fees/honoraria from St. Jude Medical
and Biosense Webster. Dr Kumar is a recipient of the Neil Hamilton
Fairley Overseas Research scholarship cofunded by the National
Health and Medical Research Council and the National Heart
Foundation of Australia; and the Bushell Travelling Fellowship
funded by the Royal Australasian College of Physicians.
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