2008-08-01
Normal Heart Function
In
order to understand atrial fibrillation, it is first important to
become familiar with the basic anatomy and physiology (or function) of
the heart. To review, the heart has 4 chambers: the top 2 chambers,
called the atria, are relatively small and thin; the bottom 2 chambers, the ventricles,
are larger and thicker. Blood that has drained all of the body’s
tissues (except for the lungs) flows through the veins into the right
atrium. The right atrium then contracts, propelling blood across the tricuspid valve and into the right ventricle. The right ventricle then squeezes that blood across the pulmonary valve, through the pulmonary artery and into the lungs. Once in the lungs, the blood is re-supplied with oxygen and continues on its way via the pulmonary veins into the left atrium. The left atrium then contracts, pushing the blood across the mitral valve and into the left ventricle. Finally, the left ventricle squeezes the blood across the aortic valve, through a large artery called the aorta and on to perfuse the tissues of the body.
The normal electrical conduction system of the heart
The right and the left sides of the heart actually work simultaneously,
so that the atria both contract together, and then the ventricles
contract together. These coordinated pumping actions are orchestrated by
the heart’s electrical conduction system, and the sinus node
can be thought of as the conductor of that orchestra. The sinus node is
the normal or physiologic pacemaker. From this structure, situated in
the upper right atrium, the electrical signal responsible for each heart
beat arises. Normally, in response to signals from the brain or the
adrenal glands, the sinus node will speed up as needed (such as during
exercise, anxiety, or excitement) and slow down when appropriate (such
as during rest or sleep).
How
does that sinus impulse activate the heart? It is important to
understand that the muscle cells of the heart (the same cells
responsible for contracting and relaxing the chambers) can conduct
electricity from one cell to the next. For example, an electrical signal
that starts in one part of the right atria can travel from cell to cell
throughout the right atrium and into the left atrium (the right and
left atrium are immediately connected and share the same septum).
Similarly, an electrical impulse that starts in one ventricle can
propagate from one ventricle to the other. Normally, the atria are
separated from the ventricles by a fibrous structure which houses the
tricuspid and mitral valves, making the 2 atria electrically
disconnected from the 2 ventricles. In fact, in a normal heart, there is
only one way for an electrical signal in the atria to communicate down
to the ventricles, and that is via the AV node. The AV node is
situated in the middle of the heart, receiving electrical connections
from the atria and delivering electrical connections to the ventricles.
When
a heart muscle cell is activated by an electrical signal, it contracts.
In sum, a normal heart beat arises in the sinus node and propagates
across the right atrium and the left atrium via cell to cell electrical
connections, resulting in contraction of both atria nearly at the same
time. When it reaches the lower atrial septum, it then continues to the
AV node. After traveling through the AV node, this electrical signal
continues down a network of specialized conduction tissue that spreads
the impulse in an organized fashion throughout the ventricles, resulting
in an organized contraction of each ventricle nearly simultaneously
(Figure 1).
Figure 1.
The normal conduction system of the heart. Yellow arrows demonstrate an
electrical signal originating in the sinus node and propagating through
both the right and left atria. This signal will reach the AV node and
travel through the ventricular conduction system (shown in gold),
ultimately electrically activating the right and left ventricles. The
left atrial appendage, a potential site of blood clot formation in
atrial fibrillation, is also shown. This figure was obtained with
permission from Mr. David Criley at www.blaufuss.org.
As might be obvious from the name, atrial fibrillation is present when the atria are fibrillating (Figure 2). This means that the atria are conducting electrical signals in a disorganized, erratic, and rapid way. Therefore, as the muscular contraction of the heart follows the electrical activity, the atria are contracting in an equally disorganized way. In fact, different parts of the atria (left and right) are contracting and relaxing in a completely uncoordinated manner. Although the exact electrical phenomenon responsible for this rapid and irregular conduction is not yet completely understood, there are 2 general explanations1: one is that there is a focus somewhere in the atrium that is firing very rapidly. Because the atrial tissue is not all able to conduct at such a rapid rate, the impulses reach different parts of the atrium at different times, resulting in a rapid, but disorganized and irregular beating of the atrium. The second explanation is that multiple partially reentrant, or circularly traveling, “wavelets” of electrical excitability are present, propagating around the atrium in a random fashion. It may be that some patients have more of the rapid focus as a cause and others have more of the multiple wavelets as the cause. It is also likely that many (if not all patients) have both- for example, the rapid focus may trigger the atrium to ultimately form multiple electrical wavelets.
Figure 2.
A heart in atrial fibrillation. The yellow arrows illustrate the
chaotic and rapid nature of atrial activation. The gold circle in the
upper left atrium represents a possible focal source of the arrhythmia
(near the left upper pulmonary vein). Note that activation of the
ventricles continues to occur via the AV node. This figure was obtained
with permission from Mr. David Criley at www.blaufuss.org.
In general, there are 4 direct consequences of atrial fibrillation:
· Loss of the atrial contraction
· A rapid pulse
· An irregular pulse
· A risk for stroke
Loss of the atrial contraction:
Because the atria are no longer electrically activated in an organized
fashion, the atrial contribution to ventricular filling (sometimes
called the atrial kick) is lost. Flow does continues to occur
from the veins into the ventricles (driven primarily by a pressure
difference) and so this condition is by no means immediately life
threatening. However, because the efficiency of ventricular filling is
diminished, a patient with atrial fibrillation may experience fatigue or
shortness of breath. In some conditions where the
ventricles need as much help as they can get with filling (such as when
someone has a ventricle that is stiff due to a previous heart attack or
long-standing high blood pressure), the patient may become very
symptomatic with loss of the atrial kick. At times, this can be severe
enough to result in an increase in pressure in the veins filling the
heart, ultimately leading to fluid build-up in the lungs and other
tissues of the body, resulting in something called congestive heart
failure. Of note, if the ventricles are very compliant (ie, easy to
fill), some patients may not experience any problems due to the loss of
the atrial kick.
A rapid pulse:
At rest, the sinus node normally generates an electrical signal
approximately 60-100 beats per minute. As the pulse is determined by
ventricular contraction (actually by the left ventricle, which is
pumping blood to the body) and as the sinus impulse is normally
propagated down through the AV node and into the ventricles, the normal
resting pulse is also then approximately 60-100 beats per minute (with
normal heart rates often even slower than this). When a catheter that
can record electrical activity is placed inside an atrium during atrial
fibrillation, it will record irregular electrical activity that can vary
considerably in rate, but is most often faster than 350 signals per
minute. Therefore, in atrial fibrillation, the AV node is being
bombarded with these rapid impulses at rates greater than 350 times a
minute. Part of the normal function of the AV node is to protect the
ventricles from such a fast rate, and it therefore does not let every
one of those rapid electrical signals through. However, it is not always
perfect, and so the majority of the time it allows enough of those
signals through to result in a rapid pulse, often between 100-200 beats
per minute. This rapid pulse is likely responsible for the majority of
symptoms a patient feels when in atrial fibrillation: fatigue, shortness
of breath, and palpitations. In rarer circumstances, chest pain and
feeling faint can be caused by an inappropriately fast heart rate.
An irregular pulse: Although
the AV node does not propagate everyone one of those rapid impulses
arising from the atria during atrial fibrillation, it is still being
activated in an irregularly irregular tempo (as opposed to regularly
irregular, which would at least have some kind of pattern to it). Therefore,
in atrial fibrillation, the activation of the ventricles, and therefore
the pulse, is irregularly irregular in timing. It turns out that this
irregular rhythm itself also adversely affects the efficiency of the
heart.2 Although probably not as important as loss of the
atrial kick and the rapid pulse, the irregular pulse itself may
contribute to a patient’s symptoms. In addition, it is often this
irregularly irregular pulse (either palpated by a physician or heard
when listening to the heart) that signals the possibility of underlying
atrial fibrillation. It is important to note that, although atrial
fibrillation is probably the most common cause of an irregularly
irregular pulse, other heart rhythm problems (some more benign, some
more worrisome) can result in a similar kind of pulse.
A risk for stroke:
In the general sense of the term, a stroke occurs when blood flow is
impeded to a section of the brain for a sufficient amount of time so as
to result in loss of function. For example, if the part of the brain
responsible for moving the left arm loses its blood flow for a certain
amount of time, paralysis in the left arm will result. One of the most
common causes of stroke is thromboembolism: “thrombo” is related
to the word “thrombus,” or blood clot. “Embolism” refers to something in
the blood stream that moves from one area to another. Hence,
thromboembolism occurs when a blood clot moves from one place in the
body to the other via the blood stream.
Whenever
blood ceases to flow, it tends to clot. In the fibrillating atria, when
the normally vigorous atrial contraction is lost, blood is no longer
flowing as it should and instead can become static. Therefore, a blood
clot is more likely to form in the fibrillating atria. If such a blood
clot forms and then dislodges into the circulation, it can reach the
brain and result in a stroke. It is well known that people with atrial
fibrillation are at a significantly higher risk for stroke.3
It is important to understand that the risk of stroke in an atrial
fibrillation patient varies considerably and is predominately determined
by the presence or absence of other stroke risk factors (discussed
below in section VI.2.).
Who gets Atrial Fibrillation?
Atrial fibrillation is the most common abnormal heart rhythm (or arrhythmia), affecting several million Americans.4 While essentially anyone can get atrial fibrillation, there are known established risk factors for the disease. The most important risk factor is simply age: of everyone over age 60 in the United States, approximately 4% have atrial fibrillation; of everyone over age 80, approximately 10% have atrial fibrillation. Other important risk factors include a history of high blood pressure (or hypertension), heart failure (meaning the ventricles, particularly the left ventricle, either does not contract strongly or is too stiff to fill properly), and heart valve diseases. In addition, men are at higher risk than women and whites are probably at higher risk than other races. People with coronary artery disease or a previous history of a heart attack also appear to be at higher risk. Finally, people with lung disease and diabetes can also be at higher risk.
Are there different types of atrial fibrillation?
There
are indeed different types of atrial fibrillation, and the disease can
be categorized based on the behavior of the arrhythmia or based on the
characteristics of the patient.1
Atrial
fibrillation can be paroxysmal (in other words, it comes and goes on
its own), it can be persistent (meaning that a person is in it all the
time and would require some kind of treatment by a physician to get out
of it), and it can be permanent (meaning that, even with available
therapies, the atrial fibrillation will not go away). Paroxysmal atrial
fibrillation can be quite unpredictable and the timing, frequency, and
duration of episodes can vary substantially from person to person: some
may have one episode that lasts 10 minutes once a year, while others may
have multiple episodes a week, lasting for hours at a time. Some people
can identify triggers for the onset of their atrial fibrillation, such
as alcohol, exercise, or sleep- these also can vary substantially from
patient to patient. A paroxysmal atrial fibrillation patient can
sometimes develop persistent atrial fibrillation and, after a persistent
episode is converted to a normal rhythm, paroxysmal episodes may
develop. Those with permanent atrial fibrillation typically have had
persistent atrial fibrillation for a long time as, in general, the
longer a person is in atrial fibrillation, the more difficult it is to
get them out of it.
Based
on characteristics of the person, atrial fibrillation can be “lone,”
meaning that the person has none of the risk factors listed above: in
general, if someone is younger than 65 and has no known heart or lung
disease (including hypertension or diabetes), they have lone atrial fibrillation.
In general, as discussed below, these people are felt to have a much
lower risk for stroke and probably have a generally better prognosis
than those with other established heart or lung risk factors.5
It
is also well known that atrial fibrillation can commonly occur after
surgery, particularly after there has been any kind of surgery on the
heart such as coronary artery bypass surgery or a valve replacement.
This post-operative atrial fibrillation is typically felt to be
self-limiting and may not reflect a long-term risk for the disease. Of
note, those with lone atrial fibrillation or post-operative atrial
fibrillation can have paroxysmal, persistent, and even permanent atrial
fibrillation.
Finally, some individuals are thought to have vagal atrial fibrillation.1 To understand this, first one must be familiar with the autonomic nervous system,
the part of the nervous system that tends to bodily functions that are
not directly under our conscious control, such as our heart rate, blood
pressure, digestion, sweating, etc. The autonomic nervous system is
comprised of and constantly influenced by a balance between the sympathetic and parasympathetic nervous systems.
The sympathetic nervous system involves adrenalin, or the “fight or
flight” responses, such as a faster heart rate, a higher blood pressure,
excitement, and anxiety. The parasympathetic nervous system opposes the
sympathetic and generally is more active in the resting state, lowering
the pulse and blood pressure, facilitating gut motility and digestion.
The primary nerve involved in the parasympathetic nervous system is the vagus nerve;
therefore, parasympathetic activity is also often referred to as
”vagal.” While some individuals appear to have their atrial fibrillation
triggered by exercise or sympathetic nervous system activity, it seems
that even more patients reliably have a vagal trigger for their atrial
fibrillation. These are the people that experience atrial fibrillation
while asleep, while relaxed, or often after exercise. In some, atrial
fibrillation can actually be terminated with exercise. Often, these
atrial fibrillation patients are very fit and otherwise quite healthy.
It may be that an exaggeration of vagal tone (known to occur at
rest in healthy individuals and otherwise felt to be a very healthy
condition) makes individuals more prone to atrial fibrillation.
How is the diagnosis of atrial fibrillation made?
The majority of the time, the diagnosis is made by an electrocardiogram
(ECG). The electrocardiogram involves having several electrodes placed
on the body. It is painless and typically takes less than 5 minutes.
With this test, the electrical activity of the heart can be seen: a
small wave, called the P wave, corresponds to electrical activation of the atrium during normal sinus rhythm (Figure 3). In a normal rhythm, the larger QRS complex,
representing electrical activation of the ventricles, follows shortly
after the P wave is inscribed. In atrial fibrillation, because there is
no organized atria activity (as described in sections I and II above),
there are no P waves. In fact, the fibrillatory action of the atria are
instead seen as a constantly undulating line, with no regular pattern
(Figure 3). The timing of the QRS complexes are irregularly
irregular, corresponding to the timing of ventricular activation (and
therefore the pulse) described above.
Figure 3. The top recording demonstrates normal sinus rhythm, with deflections called P waves (denoted by asterisks) that represent normally conducting atria. Each P wave is followed by a QRS complex, representing ventricular depolarization (solid arrows). Each QRS complex is followed by a T wave, representing repolarization of the ventricles (dashed arrows). The bottom recording is from the same patient while in atrial fibrillation. Note the absence of P waves and a subtle irregular undulation of the baseline representing atrial fibrillation. The QRS complexes (ventricular activation) occur more rapidly and in an irregularly irregular pattern.
What are the consequences of atrial fibrillation?
There are generally 3 consequences of atrial fibrillation that available therapies address: symptoms, a prolonged rapid rate, and a risk for stroke.
As
described above (Section II), a combination of loss of the atrial kick,
an irregular rate, and an inappropriately rapid pulse can all
contribute to symptoms. Symptoms can vary from patient to patient, but
typically include fatigue, decreased exercise tolerance, palpitations,
and/ or shortness of breath. Not all patients are symptomatic, and some
are clearly much more symptomatic than others. Apart from preventing
long-term damage to the heart or the body, just the subjective
improvement or elimination of symptoms is an important goal in the
treatment of atrial fibrillation (as below).
In
addition to contributing to a patient’s symptoms, a prolonged rapid
ventricular rate can itself damage the heart. If a patient’s heart rate
(meaning the pulse or ventricular rate) is persistently great than
110-120 beats per minute over months on end, a tachycardia induced cardiomyopathy
can develop. This means that the ventricles can actually become dilated
and weak, leading to congestive heart failure (where fluid fills up in
the lungs and the tissues of the body) and an increased risk for other
potentially life threatening arrhythmias in the ventricles. Therefore,
independent of symptoms, it is important to maintain rate control of the ventricles, preventing long-term elevation of ventricular rates.
Finally, as described in Section II, status of blood flow through the
fibrillating atria can lead to the formation of a blood clot which, if
dislodged, can travel and block a blood vessel supplying the brain,
leading to a stroke (Figure 4). Independent of treating symptoms and
achieving rate control, prevention of stroke is always an important
consideration in the treatment of atrial fibrillation.
Figure 4.
This represents a computed tomographic scan (CT scan) of a patient with
atrial fibrillation and a stroke due to embolization of a clot from the
left atrium. Panel A shows the
3-dimensional reconstruction. Importantly, the primary vessels supplying
the right side of the brain appear normal (white asterisk). Panel B
is a cross section of the brain (as if looking straight up at a
horizontally cut “slice”), with contrast dye injected to light up the
blood vessels supplying the brain in white. Note the major blood vessel
on the right (the patient’s left) as denoted by the red arrow. As with
the other blood vessels seen, a symmetric counterpart to this vessel
should normally be observed on the other side. However, as denoted by
the large white arrow, no such artery is seen, demonstrating that this
vessel (the right middle cerebral artery) has been occluded, resulting
in loss of blood flow to the part of the brain that vessel supplies. Panel C
is a cross section of the heart (again, as if looking straight up at a
horizontally cut slice) at the level denoted by the dotted line in panel
A. Because of the contrast dye that has been injected, the inside of
the heart and blood vessels should appear grey or white. Note the black
area denoted by the white arrow- this is in the middle of a part of the
left atrium called the left atrial appendage and represents a blood clot. This image is provided courtesy of Dr. Max Wintermark, Neuroradiology Section, University of California, San Francisco.
Treatment of Atrial Fibrillation
1. Rate versus rhythm control
One way to think about the treatment of atrial fibrillation is to split it into 2 general treatment strategies: rate control,
where one allows the patient to remain in atrial fibrillation, but
concentrates on making sure the rate is well controlled, versus rhythm control, where the strategy is aimed at achieving and maintaining normal sinus rhythm.
Given
everything written above, it would seem intuitive that a rhythm control
strategy would make the most sense. However, large randomized studies
where patients assigned to rate control were compared with those
assigned to rhythm control, failed to demonstrate any benefit of one
strategy versus the other.6, 7 How can this be, given all of
the adverse effects of atrial fibrillation that are so well known? There
are several explanations: first, perhaps most importantly, the means we
have to achieve and maintain sinus rhythm are suboptimal. Both poor
effectiveness and toxicities limit the use of many of the available
therapies (see below, Section VI.b.i.-iii.). In fact, one analysis
suggested that, if normal sinus rhythm was actually achieved, outcomes
were in fact improved.8 The point is that there is a big
difference between undertaking a strategy of trying to achieve and
maintain sinus rhythm and actually being able to do it. Of note, none of
these large studies assessed ablation therapy (discussed below,
Section, VI.b.iii.) as a means of maintaining normal sinus rhythm, and
such studies are currently ongoing.
Second,
patients with significant symptoms were generally not enrolled in the
studies. Therefore, although not clearly proven in large trials,
clinical wisdom and experience dictate that severe symptoms of atrial
fibrillation (that is, symptoms that persist despite adequate rate
control) warrant a rhythm control strategy.
Third,
subjects in the rhythm control arm were often taken off warfarin, the
best drug for stroke prevention, when it appeared that they were indeed
maintaining a normal rhythm during follow-up. However, the stroke rate
was the same in the rhythm and rate control groups.7 This
finding has been attributed to the now well documented fact that
patients can have asymptomatic episodes of atrial fibrillation. In fact,
even in those who are clearly symptomatic during some episodes, a
wearable event monitor (essentially, a portable electrocardiogram)
demonstrates episodes of atrial fibrillation without the patient being
aware.9 Therefore, it is thought that many of these patients
who failed to demonstrate evidence of atrial fibrillation either by
their own report of symptoms or during their doctor visits likely had
asymptomatic episodes that were not documented. Given this data, a
rhythm control strategy is likely not sufficient to negate the need for
warfarin (or anti-stroke) therapy. However, if one performs rigorous
monitoring (such as with a wearable or even an implantable event monitor
that captures every heart beat over a month or longer), some believe
withholding warfarin in those with no evidence of atrial fibrillation
might be safe. For now, this is a decision to be made based on clinical
judgment, and future studies may help guide us in determining if such
monitoring can indeed identify those at a sufficiently low risk for
stroke.
a. Rate Control
While
it is useful to divide general treatment strategies into rhythm control
versus rate control, in reality the great majority of atrial
fibrillation patients undergo some form of rate control. In some cases,
the decision is made that a rhythm control strategy is either unsafe or
so unlikely to work that a rate control strategy alone makes the most
sense. In others who are undergoing rhythm control, intermittent
episodes of atrial fibrillation may yet still occur, and it is important
to have the ventricular rate adequately controlled during those
episodes. Finally, in the majority of patients with atrial fibrillation
presenting to the emergency department or admitted to the hospital, the
first line of therapy is typically rate control. In fact, many of these
patients will spontaneously revert to sinus rhythm within the first 24
hours of their presentation and it is primarily a matter of reducing
their ventricular rate until that happens.
To
review some of the discussion above (Section V.), we control the rate
primarily for 2 reasons: to control or eliminate symptoms (of
palpitations, fatigue, or shortness of breath) and to prevent damage to
the heart (prolonged elevated rates can result in a weakening of the
heart). In patients with underlying heart disease, rate control can be
crucial. For example, in a patient with blocked coronary arteries (or coronary artery disease),
an inappropriately increased ventricular rate will increase oxygen
demand while potentially decreasing supply (at faster rates, the
coronary arteries have less time to fill per heart beat); in a person
who just barley receives enough blood supply (and the oxygen the blood
carries) at a normal heart rate, atrial fibrillation with a fast
ventricular rate can result in an oxygen demand that exceeds oxygen
supply, resulting in the death of heart cells, also called a myocardial infarction
or heart attack. Similarly, in a person with heart failure, either
because the ventricles are weakened in their pumping ability or too
stiff to fill adequately, a fast ventricular rate during atrial
fibrillation can exacerbate the situation, leading to an acute episode
of congestive heart failure, with lungs and body tissue filling with
fluid.
Rarely,
a person may not require rate control. Most commonly, this is seen in
elderly people who have some degree of natural slowing in their heart’s
conduction system due to fibrosis (essentially a build up of scar
tissue). In fact, this scarring of the conduction system that occurs
with age is typically unrelated to other heart disease and is the most
common indication for a pacemaker. Therefore, if the AV node and
conduction fibers traveling from the atria to the ventricles (described
above, Section I.) are unable to conduct an impulse faster than 70 times
a minute for example, atrial fibrillation can never result in a fast
ventricular rate. The other circumstance is even more rare: some
individuals that experience vagal atrial fibrillation
(described in Section III) are under a strong influence of the
anti-adrenalin autonomic nervous system during their episodes, an
influence that can slow AV nodal conduction sufficiently so as to
prevent a fast ventricular response.
i. Medicines for rate control
Rate
control is aimed primarily at slowing the conduction of the AV node.
Therefore, while the atria remain fibrillating at the same rate,
medicines that slow conduction through the AV node can effectively
prevent a fast ventricular rate. Because they only slow conduction, they
do nothing to regularize the rhythm, and the ventricular response
remains irregularly irregular. The agents that are most effective are beta-blockers and calcium channel blockers.
Both of these agents lower blood pressure and in fact are used in many
patients solely for that purpose. Examples of beta-blockers (generic
names) include atenolol, metoprolol, and carvedilol. Different
beta-blockers vary in the exact receptors blocked, absorption in
different tissues, and metabolism. They slow both the SA node and AV
node primarily by blocking sympathetic nervous system influences. They
have proven to be very safe and, in fact, save lives by preventing
recurrent heart attacks and sudden death in patients who have had a
previous heart attack. In addition, they have also been found to prevent
death and help the heart to heal in certain patients with heart
failure. Beta-blockers are generally well tolerated, but have been
reported to cause fatigue, erectile dysfunction, and depression.
Only certain calcium channel blockers, namely non-dihydropyridine calcium channel blockers,
are effective in slowing the AV node and therefore the ventricular rate
during atrial fibrillation. Verapamil and diltiazem are 2 examples,
both slowing AV nodal conduction via a direct effect on calcium
channels. By blocking calcium channels in the heart itself, both can
also potentially worsen the pumping function of a ventricle that is
weakened at baseline. By blocking calcium channels in the gut, both
agents can exacerbate constipation.
In
general, these agents are both quite effective and tend to be tolerated
without any difficulty. Because both lower the blood pressure,
hypotension (a blood pressure that is inappropriately low) can sometimes
limit the dose that can be given. In some rare patients with very low
blood pressure at baseline, the safe use of these agents may be
precluded.
An additional agent that can be used for AV nodal blockade is digoxin. This
medicine is not recommended as a first line agent because it tends to
be less effective than either beta-blockers or calcium channel blockers.1
However, as it does not lower blood pressure or exacerbate poor pump
function of the ventricles, it may be considered as first line in some
patients. However, toxicity due to overdose, kidney failure, or
interactions with other drugs can result in potentially lethal abnormal
heart rhythms.
Some
other agents that are typically used to prevent atrial fibrillation and
maintain sinus rhythm (discussed in more detail below, this Section
VI.1.b.ii.) also slow AV nodal conduction. One of these is sotalol,
which has beta blocking activity. The other is amiodarone, a very
complex and potent antiarrhythmic agent. Amiodarone is somewhat unique
in that, like digoxin, it can block the AV node without significant
effects on lowering blood pressure.
Tachy-brady syndrome
Not surprisingly, a side effect of all these medicines is that the
pulse can become too slow. This is of particular significance when a
person has intermittent (or paroxysmal) atrial fibrillation; in that circumstance, they
may go very fast during atrial fibrillation, requiring high doses of AV
nodal blockers (such as calcium channel blockers or beta-blockers) to
prevent the pulse from going to fast, but, when in sinus rhythm, those
same agents (which also slow conduction of the sinus node) can result in
too slow of a heart rate. In fact, in many patients, the same scarring
of the conduction system that occurs with age may affect the atria and
make the same person more prone to atrial fibrillation. Therefore, it is
not uncommon to see a person with very slow heart rates during sinus
rhythm (typically attributed to age-related scarring in or around the
sinus node) with intermittent atrial fibrillation (perhaps due to
scarring of the atrium). Often in these people, termed as having sick sinus syndrome,
the AV node is healthy, resulting in a rapid ventricular response
during atrial fibrillation. Such patients are also often deemed as
having tachy-brady syndrome:
“tachycardia” means a fast heart rate and “bradycardia” means a slow
heart rate, and these patients exhibit both. Treatment can often be
quite challenging in this circumstance as the medicines necessary to
prevent fast heart rates during atrial fibrillation can exacerbate the
bradycardia that occurs with sinus rhythm. When this is an issue, the
treatment is to place a permanent pacemaker, which prevents the heart
from going to slow.10 Then, medicines can be given to prevent the heart from going to fast, and the patient remains protected against bradycardia.
ii. AV nodal Ablation
Sometimes,
a patient either cannot tolerate AV nodal blocking medicines or such
medicines are ineffective at preventing fast heart rates during atrial
fibrillation. Reasons for not tolerating AV nodal blockers are mentioned
above: briefly, this would be due to too low of a blood pressure on the
medicines or too slow of a heart rate during episodes of sinus rhythm.
When either AV nodal blockers are not tolerated or are ineffective,
there is a straightforward and very effective procedure that can be
performed: AV nodal ablation. Because this results in permanent heart
block (ie, no electrical connection between the atria and the
ventricles), a pacemaker must always be placed. This procedure is
performed under moderate sedation, meaning that an intravenous line (an
IV) is placed and medicines to make a person comfortable and usually a
bit sleepy (but not unconscious) are given. Some numbing medicine (such
as lidocaine or xylocaine) is introduced into the skin in the groin
(typically the right groin) overlying a major vein that runs from the
leg into one of the big veins
that empties into the heart. Using landmarks of the external body, the
operating physician then introduces a needle into that leg vein (called
the femoral vein). Leaving the needle there, a floppy wire is
then threaded through the needle and into the vein. The needle is taken
out, leaving the wire in place, and a long plastic tube, termed a sheath,
is place over the wire. The wire is then removed, leaving the sheath in
the vein. The sheath has a one-way valve in it, such that blood can not
flow from the vein outside, but other long plastic catheters can
be introduced into it from outside. After all of the air has been
removed from the sheath by drawing back blood, removing any air, and
flushing with fluid, an ablation catheter is introduced through
the sheath, up the vein, and into the heart under visualization by an
X-ray camera. This ablation catheter has 3 capabilities: 1) It can
record electrical activity, 2) It can pace the heart, and 3) It can
deliver radiofrequency energy, which can burn and kill heart tissue.
Under X-ray guidance and by interpreting the electrical signals recorded
by the catheter, the area of the AV node can be identified. Once there,
radiofrequency energy is delivered until the AV node can no longer
conduct electrical signals from the atria to the ventricles (Figure 5).
This procedure is highly effective and will prevent atrial fibrillation
from ever resulting in a rapid ventricular response or a rapid pulse.
Studies have shown that this procedure can result in an improvement in
quality of life and exercise tolerance for some patients with atrial
fibrillation.11 After this procedure, medicines are no longer needed to slow the heart rate.
Figure 5.
This is a radiograph (or X-ray image) taken during an AV node ablation
procedure. The wire arising from above (dashed arrow) is a previously
placed pacemaker lead that enters from a vein in the arm, continues down
the large vein that enters the top of the right atrium (the superior vena cava),
continues through the right atrium and then is screwed into the high
interventricular septum in the right ventricle. The electrode catheter
entering from below (solid arrow) arises from a vein in the leg, through
the major vein that empties into the bottom right atrium (the inferior vena cava),
and continues to be placed over the area of the AV node. The exact
location of the AV node is found by analyzing signals recorded from the
tip of this catheter. The tip of this catheter is also capable of
delivering radiofrequency energy, thereby burning/ablating the AV node
and ceasing any electrical conduction through it. (This image is
provided courtesy of Dr. Nitish Badhwar, Cardiac Electrophysiology
Section, University of California, San Francisco.)
It
is important to understand 2 things regarding this procedure: Once
done, the patient is absolutely dependent on the pacemaker. Typically,
the procedure is done with the goal of leaving the patient with an
“escape” rhythm, or an automatic focus that will generate a ventricular
beat should the pacemaker fail, but this can not be guaranteed. Second,
this procedure does nothing to eliminate the atrial fibrillation itself
and so the patient’s atria continue to fibrillate as they would have
prior to the procedure. Of note, because the patient is dependent on the
pacemaker and because all electrical communication is interrupted
between the atria and the ventricles, the ventricular rhythm (and
therefore the pulse) is actually regular. As noted above (Section II.),
some of the adverse effects of atrial fibrillation are felt to be due to
the irregularly irregular rhythm, and this regularized rhythm may in
part contribute to the beneficial effects of this procedure.
b. Rhythm Control
As discussed above, the primary reason to choose a rhythm control
strategy is for symptom control. There are several options to help an
atrial fibrillation patient both achieve and maintain normal sinus
rhythm (ie, rhythm control).
i. Cardioversion
Cardioversion simply
refers to the process of converting from an abnormal rhythm to a normal
rhythm. For atrial fibrillation, this can be achieved in 3 ways: 1) It
can be spontaneous (as in the case of individuals with paroxysmal atrial
fibrillation), 2) It can be done electrically, and 3) It can be done
with a medicine.
Electrical cardioversion is extremely effective in the short term and can restore sinus rhythm in the majority of patients.1
The problem is that atrial fibrillation often recurs and so maintaining
sinus rhythm becomes an issue in and of itself. Electrical
cardioversion is performed under deep sedation, with the patient made
sleepy enough via medicines administered via an IV line so as not to
feel the electric shock that is administered. Although the shock can be
delivered using hand-held paddles, more commonly it is now done with 2
adhesive pads (typically one on the chest and one on the back). A shock
of DC energy, typically somewhere between 100 and 360 joules is
delivered. The procedure is generally very safe and well tolerated.
Rarely, skin burns at the site of the adhesive pads or paddles can
occur. Even more rarely, dangerous rhythms resulting from the electric
shock can occur, but fortunately a second administration of electricity
and/or medicines through the IV line are typically sufficient to take
care of such an event. The procedure is generally done on an outpatient
basis and the patient is usually sent home a few hours after arrival.
Cardioversion
with medicines is generally not as successful as using DC energy.
However, the advantage is that the process is painless and therefore
does not require any sedation. One advantageous application is called
the “pill in the pocket” approach. In certain patients with very
symptomatic and infrequent episodes of paroxysmal atrial fibrillation,
an antiarrhythmic medicine that has the capability to pharmacologically
cardiovert can be taken at home on an as needed basis. Although these
agents are not 100% effective, those proportion of events that can be
averted can often prevent emergency room visits and potentially,
admissions to the hospital.12
Stroke prevention during and after cardioversion
One
very important aspect of cardioversion is stroke prevention. Available
evidence suggests that the time before and after a cardioversion is
performed (regardless of the mode, whether spontaneous, electric, or
pharmacologic) is a particularly high risk period for stroke.1 Strokes in atrial fibrillation are thought to occur due to the formation of a thrombus (or
blood clot as above in Sections II and V) primarily in a part of the
left atrium called the left atrial appendage. One concern is that, with
the transition from atrial fibrillation to normal sinus rhythm, a
preexisting clot can become dislodged. Just as important is the concern
that a thrombus might form shortly after the cardioversion. Normally,
the left atrial appendage contracts with great vigor, keeping blood
moving and preventing blood from clotting inside of itself. With atrial
fibrillation, the contracting function of the left atrial appendage can
decrease. Of particular interest to anyone undergoing cardioversion, the
left atrial appendage function can actually decrease further upon the
transition from atrial fibrillation to normal sinus rhythm. The primary
determinant of the severity and duration of what is called left atrial
appendage “stunning” appears to rely on the duration of atrial
fibrillation prior to the cardioversion. In fact, the generally accepted
time frame after which this is felt to become a real concern is 48
hours; although there is no rigorous evidence to support this,
cardioversion within 48 hours of the onset of atrial fibrillation is not
generally thought to be associated with a substantial reduction in left
atrial appendage function (and therefore not thought to be associated
with a substantial risk for stroke).
However,
many scheduled cardioversions occur well after 48 hours of atrial
fibrillation, and therefore 1 of 2 strategies can be employed to reduce
the risk for stroke. First, the patient with atrial fibrillation can be
treated with warfarin for 3 weeks prior to the cardioversion.1
Importantly, simply taking warfarin for this amount of time is
insufficient. The warfarin must be maintained at a consistently
therapeutic level, as determined by the international normalized ratio (INR) blood test during that period of time. Alternatively, a special ultrasound of the heart or echocardiogram can
be performed to visualize the left atrial appendage in order to confirm
the absence of a thrombus. The majority of echocardiograms are
performed by placing an ultrasound transducer on the chest wall (called a
transthoracic echocardiogram). However, the left atrial
appendage is in the back of the heart, far away from the chest wall. It
just so happens that the tube we use to swallow (the esophagus),
connecting our mouth to our stomach, runs directly behind the left
atrial appendage. Therefore, in order to visualize the left atrial
appendage well, a transesophageal echocardiogram is performed,
during which the patient is sedated and an ultrasound probe is advanced
into the esophagus. If no left atrial appendage thrombus is observed,
the cardioversion can be performed shortly, or immediately thereafter .1, 13
Regardless of whether 3 weeks of therapeutic warfarin or a
transesophageal echodcardiogram is employed prior the procedure, all of
these patients require at least 4 weeks of therapeutic anticoagulation
to prevent stroke due to left atrial appendage stunning. Although
warfarin is the ideal agent for this purpose, it often takes several
days to reach a therapeutic level and therefore other agents (such as
intravenous unfractionated heparin or subcutaneous low molecular weight heparin) are sometimes used to “bridge” the warfarin therapy.
ii. Antiarrhythmic medicines for the maintenance of normal sinus rhythm
Several antiarrhythmic agents can be used to help a person maintain sinus rhythm.1
Typically, these will be used in patients with paroxysmal atrial
fibrillation or after cardioversion in patients with persistent atrial
fibrillation. As noted above (Section VI.1.), the primary reason to use
these agents are to treat symptoms only as there is no data to support
their use for any long term benefit. These agents have traditionally
been medicines that block certain ion channels responsible for different
aspects of the heart’s normal conduction. Many are not well tolerated
and only those mentioned in current guidelines will be briefly touched
on here.1 In large part, by blocking certain ion channels, these antiarrhythmic drugs can also be proarrhythmic (in
other words, they can actually increase the propensity to certain
arrhythmias). As currently available agents are not specific to atrial
tissue, the primary concern in using many of these agents involves the
potential for dangerous (and even life threatening) proarrhythmia in the
ventricles. Therefore, the choice of antiarrhythmic agents relies
largely on the risk of proarrhythmia of the individual being treated,
which itself depends on the presence and/ or nature of any underlying
heart disease.
In those with no underlying heart disease (as above, Section III., so-called lone atrial fibrillation patients),
the risk of proarrhythmia is felt to be very low. First line agents for
this group would include flecainide, propafenone, and sotalol. Although
these agents are not the most potent, they can be very effective for
many patients and are generally well tolerated. If these agents fail (or
have adverse effects), either dofetilide or amiodarone can be
considered. Dofetilide tends to be quite effective and is generally well
tolerated; however, it can induce a dangerous ventricular rhythm called
torsades de pointes, and patients (even those with no underlying
heart disease) need to be rigorously monitored in the hospital for at
least 3 days before it can be safely prescribed. Amiodarone is probably
the most effective agent available for the maintenance of normal sinus
rhythm, but it has multiple potential toxicities, including adverse
effects involving the thyroid, lung, liver, skin, eyes, and nervous
system, that classically occur when the medicine is used over a long
period of time. Therefore, in general, the use of amiodarone should be
avoided in young, otherwise healthy people unless absolutely needed.
In those with coronary artery disease (or blocked coronary arteries) or any history of a myocardial infarction (or a heart attack), flecainide and propafenone are felt to be dangerous and should therefore be avoided.14
In those with heart failure due to weakened ventricles, only dofetilide
and amiodarone are felt to be safe options. Finally, in those with very
thick ventricles, amiodarone is the only agent that can be used safely.
iii. Ablation of atrial fibrillation
Recently,
in an attempt to reproduce the great success of catheter ablation for
the treatment of various arrhythmias (such as for AV nodal ablation
described above in Section VI.1.a.ii), an interest in curing atrial
fibrillation by catheter ablation is growing.15
This procedure involves placing multiple electrode catheters in the
heart, and the focus of ablation is typically on the left atrium.
Because the left atrium is not immediately accessible via the veins that
drain into the right atrium, a transseptal approach is required:
approximately 20-30% of all adults will have a small hole in the septum
between the right and left atrium that can be used, and, in the
remainder, a needle is used to puncture the septum (in the area of a
very thin membrane that is the remnant of the hole present during fetal
development). A long sheath is then advanced over the long needle, the
long needle is removed, and the ablation catheter is then maneuvered
into the left atrium. Because the blood in the left atrium is contiguous
with blood flow to the brain and other vital organs, heparin (an
intravenous anticoagulant) is always infused immediately after left
atrial access is obtained in order to avoid any potentially dangerous
blood clot formation on the catheter (which, if dislodged, could result
in a stroke). Although the exact technique by which curative left atrial
ablation is performed varies somewhat from institution to institution,
the general goal is to burn atrial tissue just outside the opening to
the veins that empty blood into the left atrium from the lungs (the pulmonary veins).
The general goal is to electrically isolate these pulmonary veins from
the rest of the left atrium (Figure 6), and the proposed mechanisms
behind the effectiveness of this strategy involve several concepts:
first, there is some evidence that automatic focal electrical
depolarizations arising from the pulmonary veins may be responsible for
initiating atrial fibrillation in some people; by electrically isolating
the veins, these impulses can not be propagated to the atrium and
therefore theoretically not initiate atrial fibrillation. In addition,
some believe that the series of burns delivered sufficiently disrupts
the atrial substrate so as to disallow any of the reentrant wavelets
from forming or sustaining (see Section II.). The vagal input to the
atrium arises from several focal collections of nerves called ganglionic plexi,
which happen to sit very near the openings of the pulmonary veins.
There is some evidence that the effectiveness of the left atrial
ablations depends largely on the ablation of these ganglia (something
that may be accomplished while burning around each of the veins).
Multiple explanations and techniques exist, but the procedure appears to
be effective in approximately 60-80% of cases. Unfortunately, the risks
of the procedure, although low (typically 4% or less), can be severe,
including stroke, perforation of the heart, and very rarely, even death.
Therefore, appropriate patient selection for this procedure is
critical: young, otherwise healthy candidates with paroxysmal atrial
fibrillation will likely benefit the most from this procedure with the
lowest risk. The procedure continues to evolve, with techniques and
equipment under constant development to improve the success and minimize
the risk of the procedure, potentially allowing for the safe
application of the procedure to a much broader patient population. For
now, given that it is an invasive procedure which carries some risk, the
general recommendation is that it be reserved for patients that are
symptomatic despite medical therapy and have failed at least one
antiarrhythmic agent (as described in Section VI.1.b.ii.).1, 15
In some circumstances, if a patient is very motivated to have the
procedure and is felt to be a good candidate by his/her treating
physicians (ie, felt to have a chance of high success and low risk), the
procedure can be considered as first line therapy.
Figure 6.
These panels demonstrate an example of one atrial fibrillation ablation
technique. On the right panel, 2 catheters can be seen arising from a
large vein (the inferior vena cava) below the heart, into and
through the right atrium, across the interatrial septum (see text for
method of crossing the septum) and into the left atrium. Of note, both
catheters were introduced into the body via a vein in the leg. On the
left panel, the ends of the catheters placed just outside the entrance
of the left upper pulmonary vein are illustrated: the heated straight
catheter delivers radiofrequency energy and thereby burns/ ablates
atrial tissue; the circular catheter aids in recording electrical
signals and can be helpful in determining when a structure (such as a
pulmonary vein) has been “electrically isolated.” This figure was
obtained with permission from Mr. David Criley at www.blaufuss.org.
In general, until more data is available, the procedure should not be
considered a substitution for warfarin therapy. As above (Section VI.1),
some believe that with rigorous monitoring of the heart rhythm with
wearable monitors for a month or more at a time, the absence of atrial
fibrillation may provide enough evidence to safely discontinue warfarin
therapy. Importantly, as below, the best candidates for the procedure
(younger patients with lone atrial fibrillation), do not typically
require warfarin therapy anyway.
2. Stroke Prevention
The most effective agent to prevent stroke in atrial fibrillation patients is warfarin.1, 3
This medicine blocks the action of vitamin K, rendering the blood less
prone to clot. Not surprisingly then, the primary adverse effect of
warfarin is bleeding. In fact, dosing of warfarin involves a nearly
constant effort to reach the balance between optimal stroke protection
and minimal bleeding risk. Unfortunately, the potency of warfarin can be
very unpredictable, from person to person and over time in the same
person. Part of this inter-individual variability probably has something
to do with different genes that can determine the way that warfarin is
metabolized. Certainly, the potency of warfarin is determined in large
part by diet: foods such as leafy green vegetables that contain more
vitamin K will inhibit more of warfarin’s actions. Because of its
unpredictable nature, the effect of warfarin must be measured regularly
and the dose adjusted accordingly. A simple and readily available blood
test measures the international normalized ratio (or INR), a
measure of the blood’s clotting ability. A “normal” INR, for instance in
someone not on warfarin, is approximately 1. A variety of large studies
have shown that the optimal effectiveness of warfarin and the minimal
bleeding risk in the setting of atrial fibrillation occur when the INR
is between 2 and 3. Therefore, individuals on warfarin therapy must have
regular blood tests, with a healthcare provider carefully reviewing the
results and adjusting the dose of the medicine. Typically, tests and
adjustments are more frequent during the initiation of therapy, and the
goal is to require only monthly tests if a stable dose (with a stable
INR between 2 and 3) can be achieved. Despite this, it is well
recognized that even some of the most compliant and motivated patients
will sometimes have INRs that are too low or too high. It is also
important for patients on warfarin to avoid foods high in vitamin K and,
perhaps more importantly, to maintain a consistent diet in vitamin K
containing foods. Finally, warfarin patients must also be aware of
interactions with other drugs (which are, unfortunately, quite common). Healthcare
providers that prescribe and adjust warfarin can often be very helpful
in counseling patients regarding these important interactions.
The
only other alternative to warfarin that has thus far proven safe and
effective in preventing strokes in the setting of atrial fibrillation is
a daily aspirin. Although bleeding risk with aspirin is in general less
than that of warfarin, bleeding does remain a concern (particularly
gastrointestinal bleeding). It is also clear that aspirin is not as
effective as warfarin in preventing stroke. Determining who should
receive what anti-stroke treatment depends on a physician’s assessment
of the person’s stroke risk.
Because warfarin therapy involves some risk, the appropriate candidates
for warfarin therapy are those in whom the benefit exceeds the risk.
For example, in young lone atrial fibrillation patients (specifically,
those younger than 60 with no heart or lung disease including
hypertension), the risk of stroke is very low- warfarin is actually
contraindicated in these patients because the risk of the therapy
outweighs the very small benefit it might provide. Determining the
additional risk factors for stroke in atrial fibrillation patients is
critical in determining whether or not warfarin therapy is appropriate:
increasing age (≥ 75 years old is a cut-off that has been used),
hypertension (even if effectively treated), weakened ventricles (or
heart failure), diabetes, and a history of stroke or transient ischemic attack (TIA)are
the most important risk factors. According to current guidelines, if a
patient has 2 or more of these risk factors, they should be on warfarin.116
There are other risk factors, including female gender and underlying
coronary artery disease, that may confer some extra risk and may aid in
the decision making. If a person only has one of these risk factors,
either warfarin or aspirin therapy is felt to be acceptable and should
be determined by the physician’s assessment of bleeding and stroke
risks. Of note, a previous history of stroke by itself is felt to be a
particularly important risk factor.
Conclusions
Atrial
fibrillation is an extremely common heart rhythm disorder with multiple
potential adverse consequences. While the diagnosis is straightforward,
the management can be quite complex and requires a comprehensive
evaluation of a particular patient’s risks. Excellent
reference articles include the following: a comprehensive review
contained in the joint American College of Cardiology/ American Heart
Association/ European Society of Cardiology guidelines.1 The full text is available free at: http://circ.ahajournals.org/cgi/content/full/114/7/e257
An outstanding review regarding curative atrial fibrillation ablation is provided by the Heart Rhythm Society.15 The full text can be found on the webpage: http://www.hrsonline.org/Education/AFib360/Guidelines/index.cfm
Finally, a clearly illustrated and animated program on electrocardiograms and supraventricular arrhythmias is available at http://www.blaufuss.org/
(note: the complimentary tutorial can be found at the bottom of this
home page, with animation on normal conduction, atrial fibrillation, and
ablation under “SVT tutorial.”).
To learn more about the treatment of arrhythmias at the University of California, San Francisco (UCSF), please visit www.ucsfhealth.org/arrhythmia
References
1. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC
2006 guidelines for the management of patients with atrial
fibrillation--executive summary: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines
and the European Society of Cardiology Committee for Practice Guidelines
(Writing Committee to Revise the 2001 Guidelines for the Management of
Patients With Atrial Fibrillation). J Am Coll Cardiol
2006;48(4):854-906.
2. Naito
M, David D, Michelson EL, Schaffenburg M, Dreifus LS. The hemodynamic
consequences of cardiac arrhythmias: evaluation of the relative roles of
abnormal atrioventricular sequencing, irregularity of ventricular
rhythm and atrial fibrillation in a canine model. Am Heart J
1983;106(2):284-91.
3. Singer
DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic
therapy in atrial fibrillation: the Seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3
Suppl):429S-456S.
4. Chugh
SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and
natural history of atrial fibrillation: clinical implications. J Am Coll
Cardiol 2001;37(2):371-8.
5. Jahangir
A, Lee V, Friedman PA, Trusty JM, Hodge DO, Kopecky SL, et al.
Long-term progression and outcomes with aging in patients with lone
atrial fibrillation: a 30-year follow-up study. Circulation 2007;115(24):3050-6.
6. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, et al. A
comparison of rate control and rhythm control in patients with
recurrent persistent atrial fibrillation. N Engl J Med
2002;347(23):1834-40.
7. Wyse
DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A
comparison of rate control and rhythm control in patients with atrial
fibrillation. N Engl J Med 2002;347(23):1825-33.
8. Corley
SD, Epstein AE, DiMarco JP, Domanski MJ, Geller N, Greene HL, et al.
Relationships between sinus rhythm, treatment, and survival in the
Atrial Fibrillation Follow-Up Investigation of Rhythm Management
(AFFIRM) Study. Circulation 2004;109(12):1509-13.
9. Page
RL, Wilkinson WE, Clair WK, McCarthy EA, Pritchett EL. Asymptomatic
arrhythmias in patients with symptomatic paroxysmal atrial fibrillation
and paroxysmal supraventricular tachycardia. Circulation
1994;89(1):224-7.
10. Gregoratos
G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, et al.
ACC/AHA/NASPE 2002 guideline update for implantation of cardiac
pacemakers and antiarrhythmia devices: summary article: a report of the
American College of Cardiology/American Heart Association Task Force on
Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998
Pacemaker Guidelines). Circulation 2002;106(16):2145-61.
11. Wood
MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after
ablation and pacing therapy for atrial fibrillation : a meta-analysis.
Circulation 2000;101(10):1138-44.
12. Alboni
P, Botto GL, Baldi N, Luzi M, Russo V, Gianfranchi L, et al. Outpatient
treatment of recent-onset atrial fibrillation with the
"pill-in-the-pocket" approach. N Engl J Med 2004;351(23):2384-91.
13. Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, et al. Use
of transesophageal echocardiography to guide cardioversion in patients
with atrial fibrillation. N Engl J Med 2001;344(19):1411-20.
14. Preliminary
report: effect of encainide and flecainide on mortality in a randomized
trial of arrhythmia suppression after myocardial infarction. The
Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med
1989;321(6):406-12.
15. Calkins
H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, et al.
HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical
ablation of atrial fibrillation: recommendations for personnel, policy,
procedures and follow-up. A report of the Heart Rhythm Society (HRS)
Task Force on catheter and surgical ablation of atrial fibrillation.
Heart Rhythm 2007;4(6):816-61.
16. Gage
BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation
of clinical classification schemes for predicting stroke: results from
the National Registry of Atrial Fibrillation. JAMA 2001;285(22):2864-70.