Atrial fibrillation: what is the origin of the atrial ectopic beats that trigger the

arrhythmia and what is their meaning?

Dalmo A. R. Moreira MD, PhD

Head of Electrophysiology and Clinical Arrhythmia Section
Dante Pazzanese Institute of Cardiology, So Paulo, Brazil

Although Natan demonstrated the close anatomical relationship between the

atrial myocardium and the veins in the mid 1960s 1 , it was Nonidez in the
decade of 1930 of the last century that called the attention to something at least
intriguing from the physiological point of view, and that can be the main finding
to understand the origin of atrial fibrillation in some conditions 2 . This author
using optical microscopy showed that in the territory around the pulmonary
veins in the left atrium, interspersed with the intimacy of the vascular middle
layer musculature, there was an extensive network of neuroreceptors (figure 1).
The same was demonstrated in the territory of the superior vena cava, a
distribution similar to those neural structures that trigger action potentials
whenever a venous distension occurs. Interestingly, atrial foci (the equivalent to
those neuroreceptor activity) that trigger atrial fibrillation, are located mainly in
the venous territory and ablation techniques for the treatment of atrial fibrillation
by means of catheters, make fibrotic lesions that are exactly close to those
venous regions. It is important to remind that the veins bring blood to the heart
and this might be the rationale to understand to what is going to be discussed in
the next paragraphs.

If the vena cava or pulmonary ectopic beats are the manifestations of the
activity of those neuroreceptors, what would be the role of these structures in
the eventual onset of atrial fibrillation? Why are they located exactly at the
junction of the veins with the atria? The answer that comes to mind at this time
is: protect the lungs from high blood pressure; protect the brain from increased
venous pressure caused by engorgement of the superior vena cava and its
tributaries. How would such protection take place? Reasoning with the
information of physiology, it can be hypothesized that an increase of the heart
rate, reflexively, would be a natural mechanism of vascular emptying, allowing
to relieve the pressure in the venous territory. After the pressure dropped, the
"reflex" would be stopped. On the other hand, frequent shots of those venous
ectopic beats, would cause the initial electrical remodeling, characterized by the
decrease in the duration of the atrial action potential, adapting the atrium to
rapid elevations of the heart rate, when necessary. Secondly, histological
remodeling would occur, an important condition to allow the atrium to work
under unfavorable conditions. These two modalities of remodeling would be the
substrate for the establishment of the paroxysmal, then persistent and, finally,
permanent form of atrial fibrillation. A quick glance at the sites where the
neuroreceptors are concentrated according to Nonidez shows the extraordinary
similarity in the distribution of the atrial ectopic beats, as documented by
Haissaguerre3 during electrical atrial mapping (figure 1). So it is quite possible
that both authors, who are 68 years apart in both publications, are talking about
the same thing.

Figure 1 - Reproduction of the figure drawn by Nonidez from histological

observation of atrial tissue close to the opening of the superior vena cava and
pulmonary vein in the right and left atria, respectively. It can be seen in A and B
the presence of neuroreceptors in the intimacy of the vascular middle layer
musculature, whose stimulus triggered by vascular distension, favors the vessel
"contraction" to empty its contents in both atria 18. In C, according to Nonidez2
the black dots points to the presence of those neuroreceptors in the posterior
wall of the left atrium close to the pumonary veins. In D, atrial ectopic beats
recorded in the veno-atrial territories, mainly in the superior left pumonary vein,
according Haisaguerre3. Note the similarity in the distribution of these ectopic
"foci" and the neuroreceptors.

What would be the evidence to support this theory? First, this process of ectopic
activity generated by neuroreceptors would be similar to what occurs
physiologically in the Bainbridge reflex. An increase in the venous return to the
right atrium and ventricle and from there to the pulmonary artery triggers a
reflex that is manifested by an increase in heart rate, exactly to relieve the
accumulation of blood in the pulmonary artery. It can therefore be related to
increased vascular pressure, distension of receptors in the artery wall, inhibition
of vagal activity, followed by release of the sinus node which would have
increased firing rate. This would facilitate the emptying of blood from the right
ventricle and pulmonary artery. Second, experimental and clinical evidence that
increased left intraventricular pressure increases the frequency of atrial ectopic

beats. Some authors have demonstrated that in the heart failure experimental
model in dogs there was a significant increase in the frequency of atrial ectopic
beats4. In a clinical counterpart observation, a very interesting study has
recently shown that patients with a pacemaker who detect pulmonary resistance
due to an increased amount of fluid (caused by clinical decompensation)
present a significant simultaneous increase in the frequency of atrial ectopic
beats5. This is a clear demonstration of the relationship between vascular
pressure and ectopy frequency. Both in the experimental model and in the
clinical study, the increase in heart rate was present. Why ? Conceptually, to
relieve lung pressure.
Another aspect that should be discussed based on the above considerations is
what the entity "atrial fibrillation" means. Leaving aside the indisputable
complications associated with it, such as heart failure and systemic
thromboembolism, what is the significance of the onset of atrial fibrillation in
some situations? It is noteworthy that this arrhythmia complicates the evolution
of many heart diseases like dilated or hyperthrophic cardiomyopathies. These
are conditions that trigger intense compensation mechanisms to maintain
cardiac output under adequate conditions. And why would atrial fibrillation arise
under these conditions? It would be an exaggerated mechanism of electrical
response to chronically maintained stress situations. In an initial phase, there
would be the appearance of atrial ectopic beats, with their persistence they
would be followed by tachycardias ending in atrial remodeling, followed by atrial
fibrillation properly. This would be the pathophysiological sequence.
Clinical experience confirms that patients who arrive at the emergency room
with decompensated heart failure and atrial fibrillation, diuretics followed by

intense diuresis are enough to restore sinus rhythm without the use of
antiarrhythmic drugs. This is a demonstration that the diuretic improves the
responsiveness of the heart because it would decrease its overload (decrease
in atrial pressure, atrial and vascular distension, and also may decrease the
frequency of atrial ectopic beats that maintain atrial fibrillation). An interesting
publication has shown that the dispersion of P waves and even their increased
duration, marks of an electrical disturbance caused by atrial distension,
decrease after the elimination of liquids through intense diuresis 6. The acute
modification of the P wave in this condition is a very strong evidence of the
reduction of the repercussion of the atrial overload on its electrical activity, and
may also indicate that the latter may be a transient adaptation caused by the
first. Based on this reasoning sequence, it could be inferred that atrial fibrillation
should be the manifestation of a heart that is being extremely demanded by the
"physiological" mechanisms of compensation.
To support this latter statement, it is sufficient to review the studies related to
atrial fibrillation that arises in the postoperative period of cardiac surgery 7. This
is a real situation of acute stress to which the heart is subjected. Such studies
clearly demonstrate that patients who evolve in the immediate postoperative
period with atrial fibrillation, have a higher mortality rate than those under the
same conditions but without atrial fibrillation. It is also emphasized that the
clinical evolution is less favorable even if the arrhythmia is reversed 8. This
indicates that it is not the rhythm disturbance itself that is the key factor that
determines long-term evolution. This arrhythmia would be an indication of an
already diseased heart, incapable to respond in a physiological way to the
compensation mechanisms that arise in the postoperative period. Likewise,

other conditions of great cardiac stress have the same clinical picture. Patients
who develop atrial fibrillation in the acute phase of myocardial infarction have a
greater impairment of ventricular function and, therefore, a lower survival rate 9.
Patients who underwent coronary stent implantation and who develop atrial
fibrillation have a more reserved prognosis than those under the same
conditions but do not develop this arrhythmia 10. The main problem is not atrial
fibrillation itself but the heart, instead.
What are the implications of all this theory that is presented here in relation to
atrial fibrillation? First, it would be to try to understand the real meaning of this
arrhythmia in clinical practice. Secondly, when it does arise, make efforts not
only for its treatment but try to understand the causative mechanism and
remove it to improve the heart's response conditions. Thirdly, knowing that
potent risk factors may facilitate the onset of arrhythmia, treat them early; here
would come the concept of primary prevention of atrial fibrillation. Fourthly, for
its treatment, do not use only antiarrhythmic drugs because atrial fibrillation is
not just a rhythm disturbance but the manifestation of a heart that is being
demanded and is not being eventually able to respond to that demand in an
appropriate way. This set of implications forms the condition in which the
understanding of the pathophysiology of arrhythmia helps the way it is treated.
Obviously all this thinking does not apply to patients in whom atrial fibrillation is
the primary cardiac rhythm disorder, a condition in which the arrhythmia must
arise for a reason intrinsically related to some change in the electrical activity of
the atrial myocyte when, undoubtedly, the attempts to treat should be pursued
by non-pharmacological techniques.

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