Cardiovascular Research 64 (2004) 387 – 394
www.elsevier.com/locate/cardiores
Review
Identifying and understanding the role of pulmonary vein activity
in atrial fibrillation
R. Khan*
Received 7 May 2004; received in revised form 28 July 2004; accepted 29 July 2004
Available online 11 September 2004
Time for primary review 22 days
Abstract
The perception of atrial fibrillation development has changed drastically over the last decade. The pulmonary veins have been targeted as
the source of arrhythmogenic activity involved in the initiation of atrial fibrillation. This activity appears to be localized in the myocardial
sleeves of the vessels. Extensive study of cells within this tissue has helped create a new model for atrial fibrillation. This review attempts to
show how the development, architecture and electrophysiologic properties of the pulmonary veins influence the initiation and perpetuation of
atrial fibrillation. It also examines the potential long-term effects of pulmonary vein activity on arrhythmia development.
D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Pulmonary veins; Atrial fibrillation; Atrial remodeling; Atrial fibrosis
1. Introduction
Atrial fibrillation (AF) is the most common sustained
cardiac arrhythmia. The Framingham study showed that it
severely increases the risk of mortality in affected patients,
particularly by causing stroke [1].
AF is thought to be initiated in the myocardial sleeves of
the pulmonary veins (PVs) [2]. Chen et al. [3] identified the
presence of automaticity in cells within the myocardial
tissue of the PVs. Pacemaker activity from these cells is
thought to result in the formation of ectopic beats that
initiate AF.
PVs are also thought to be important in the maintenance
of AF. The chaotic architecture and electrophysiological
properties of these vessels provides an environment where
AF can be perpetuated [4–7].
Finally, AF has been associated with remodeling of the
atria, which, in turn, promotes the development of chronic
AF [8]. The activity of PVs is likely to play a role in the
* Tel.: +1 514 287 7617.
E-mail address: [email protected].
structural and electrophysiological changes seen in batrial
remodeling.Q
This article aims to provide a clearer model for the
location, mechanism and possible consequences of AF
initiated in the PVs.
2. The development of AF
AF is a rhythmic perturbation of the heart that primarily
affects the atria. In this phenomenon, the heart is taken out
of normal sinus rhythm due to the production of electrical
impulses originating from atrial myocytes. With up to 600
pulses being generated every minute, syncytial contraction
of the atria is replaced by irregular atrial twitches. The
result, in turn, is ineffective transport of blood to the
ventricles.
Three mechanisms are commonly associated with AF
development: enhanced automaticity, triggered activity and
re-entry [9]. The first, automaticity, involves the ability of a
cell to spontaneously depolarize. Arrhythmia can arise due
to enhanced automaticity from ectopic sites. Increased
automaticity is generally associated with less negative
0008-6363/$ - see front matter D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2004.07.025
Downloaded from http://cardiovascres.oxfordjournals.org/ at Pennsylvania State University on March 3, 2014
McGill University, Faculty of Medicine, 3550 Jeanne Mance, Apt. 1811E, Montreal, Quebec, Canada H2X 3P7
388
R. Khan / Cardiovascular Research 64 (2004) 387–394
Fig. 1. Early and delayed afterdepolarizations. (A) Delayed afterdepolarizations (DAD) are generated after full repolarization. If DADs reach
threshold, a triggered beat (black arrow, right) can arise. (B) Early
afterdepolarizations (EAD) disrupt phase 3 repolarization of the action
potential cycle, leading to the production of triggered beats (black arrow,
right).
of the electrical impulse in a re-entrant pathway, the less
likely it is to encounter cardiac cells that are still refractory
within the pathway. Therefore, slower conduction also
favours maintenance of re-entry and the development of AF.
Current research suggests that AF is caused by a single
ectopic focus and re-entry pathway [12]. As mentioned,
studies have implicated the myocardial tissue of PVs as a
possible origin for ectopic impulses [2].
3. PV myocardial tissue as a possible source of
arrhythmogenicity
Nathan and Eliakim showed the presence of striated
muscle within the tunica media of PVs [13]. Cheung [14]
demonstrated that action potentials could be produced
within these myocardial sleeves. Haissaguerre et al. [2]
were the first to discover that PVs were a source of ectopic
beats possibly involved in the initiation of AF. In fact, this
landmark study found that 94% of ectopic beat foci in
patients with drug-refractory AF originated in the PV
myocardium. They also found that ablation of the PVs
using radio-frequency energy resulted in the disappearance
of triggering ectopic beats. Localization of arrhythmogenicity to the PVs has subsequently been shown in a number
of studies [15,16].
4. Gross anatomical differences between the PVs of
patients with and without AF
In a post-mortem anatomical study, Hassink et al. [6]
showed that PV myocardial sleeves were found in 100% of
patients with AF, whereas similar muscle tissue was seen in
only 85% of patients without AF. In addition, patients with
AF had significantly longer muscle sleeves present.
Similarly, muscle bundles in the superior veins were
substantially longer than those in the inferior veins. Along
with increased length, Guerra et al. [17] using intravascular
ultrasound, found that patients with AF had considerably
thicker PV myocardial tissue, and that arrhythmogenicity
could only be localized to these areas of thickening. Using
PV angiography, Lin et al. [18] suggested that patients with
paroxysmal AF had superior PVs that were dilated as
compared to those without paroxysmal AF. Dilation was
most prevalent at the ostium of the pulmonary veins.
Magnetic resonance imaging has showed similar patterns
of dilation [19,20].
5. Specialized conduction cells may initiate PV activity:
histologic, embryologic and electrophysiologic evidence
For many years, the existence of pacemaker cells
within PVs was questioned. However, Chen et al. [3]
were the first to discover the presence of spontaneously
Downloaded from http://cardiovascres.oxfordjournals.org/ at Pennsylvania State University on March 3, 2014
diastolic potential (e.g., decreased vagal discharge), steeper
phase 4 slope (e.g. cathecholamine, increased fiber stretch,
hypokalemia) and a more negative threshold for action
potential generation.
Triggered activity is pacemaker activity that arises only
after an initial impulse has been generated within the cell.
Triggered activity manifests as either early or delayed
afterdepolarizations. Early afterdepolarizations (EADs) generally follow prolonged action potentials. Calcium currents
during the plateau phase of action potentials may be
responsible for the generation of EADs [10]. Similarly,
delayed afterdepolarizations (DADs) arise in the presence of
cellular calcium overload. The electrogenic Na+/Ca2+
channel removes calcium, in exchange for three sodium
ions [11]. There is therefore a net movement of positive
charge into the cell, bringing it closer to depolarization.
Thus, anything that causes a greater than expected rise in
intracellular calcium levels during systole will result in the
increased likelihood of DADs after sodium–calcium
exchange. Both types of after depolarizations may potentially reach threshold levels, generate action potentials and
be the source of ectopic beats (Fig. 1).
After depolarization, the sodium channels of cardiocytes
are inactivated. The duration of sodium channel inactivity is
known as the refractory period. During the refractory period,
action potentials cannot be generated within these cells
should an ectopic beat arise nearby. However, if the ectopic
beat is able to propagate electrical impulses via another
pathway, the impulse may return to the initially inactive
cardiocytes. Sodium channels will have now had time to
reactivate, therefore action potential may be generated
within these cells and impulse may be propagated further.
The phenomenon of re-entry arises when two separate
pathways continuously activate one another in this manner.
Longer refractory periods of cardiocytes makes re-entry
more difficult because electrical impulses in a re-entrant
pathway may meet cells that cannot generate action
potentials (i.e. due to the fact that they are still refractory).
Thus, decreased refractory periods will obviously lend
themselves more to electrical impulse propagation and
therefore to AF. Similarly, the slower the conduction velocity
R. Khan / Cardiovascular Research 64 (2004) 387–394
Fig. 2. A comparison between model-generated SA nodal cell action
potentials (A) and suspected pacemaker potentials localized within PV
myocardial tissue (B). Both show spontaneous phase 4 depolarizations and
a decreased phase 0 slope.
PV myocyte membranes have a much lower density of
IK1-channels as compared with typical atrial tissue. Of
significance is the fact that these channels are totally
absent in SA nodal cells. IK1-channels are thought to
contribute to cardiocyte resting potential (~ 85 mV), and
there absence could be a reason for the raised (less
negative) maximum diastolic potential of pacemaker cells
within PV myocytes (~ 70 mV). Therefore, decreased
levels of IK1-channels within PV myocytes may facilitate
pacemaker depolarizations.
SA nodal cells also have a characteristic If-current,
whose presence was recently demonstrated within PV
myocytes [26]. If-current is a mix of Na+- and K+-current
that is activated after cellular repolarization. It is thought to
contribute to and enhance depolarization in myocytes
following repolarization, allowing for increased pacemaker
potential in PV cells.
Chen et al. [27] have discovered the presence of ICa2+ tchannels within PV myocytes. The Ca2+-current from these
channels has been shown to aid in the production of
spontaneous depolarizations by causing the release of Ca2+
from the sarcoplasmic reticulum at low voltages (~ 60mV),
allowing for the generation of pacemaker activity. These
channels may also increase the plateau phase of action
potentials, raising the possibility of EADs. Application of
nickel, a specific inhibitor of ICa2+-t-channels, to PV tissue
drastically reduced both triggered activity and automaticity
in PV myocytes [28].
6. Potential effects of disease on PV activity and the
generation of AF
The electrophysiologic properties of PV cardiomyocytes
may change in the presence of disease. Using a ryanodine
receptor blocker, Honjo et al. [29] demonstrated that
alteration of intracellular calcium dynamics results in rapid
firing of cardiocytes in the PVs. In fact, treatment with
ryanodine caused PV myocytes, undergoing typical atrial
action potentials, to develop pacemaker depolarizations.
This study notes that pathologic conditions, such as heart
failure, similarly change the ability of the cell to handle
calcium and therefore may cause AF by this mechanism.
Chen et al. demonstrated that incubation of thyroid
hormone with PVs led to the production of increased
triggered activity in the myocardial sleeves of these vessels
[30]. The study suggested that thyroid hormone caused an
increase in the transient inward currents (most likely due to
+
increased ICa2
L-current) of PV cardiocytes leading to
production of DADs and EADs. Paroxysmal AF associated
with hyperthyroidism may develop in this manner.
Temperature appears to also play an important role in the
arrhythmogenicity of PVs. Chen et al. [31] found that
afterpotentials in cardiomyocytes of PVs could only be
generated at higher temperatures (N38 8C). In the study,
cardiocytes incubated in the highest temperatures (40–41
Downloaded from http://cardiovascres.oxfordjournals.org/ at Pennsylvania State University on March 3, 2014
depolarizing cells in the PVs of dogs. Recently, P cells,
normally found in the AV and SA node, have been
localized to the PVs [21]. These were found in markedly
greater numbers near the ostium of the vessels. The same
study also identified purkinje and transitional cells in PVs.
These cells are commonly found in the Bundle of His and
AV node. The current belief is that spontaneous depolarization in P cells may lead to the production of electrical
impulses that are propagated to the left atrium through
purkinje cells [22].
Embryological evidence supports the idea of specialized conduction cells within the PV myocardium. Using
human embryos, Joengbloed et al. [23] demonstrated that
cells of the developing cardiac conduction system could
be found in PVs prior to birth. The study observed the
addition of CCS-lacZ expressing cardiomyocytes to
developing PVs. CCS-lacZ gene expression is known to
occur only in cells that are part of the developing cardiac
conduction system [24]. Presence of CCS-lacZ expression
was also noted in other tissue involved in arrhythmia,
including Bachmann’s Bundle. Developing PV myocytes
that express CCS-lacZ could be precursors to the
specialized conduction cells found in mature PVs by
Perez-Lugones et al. [21] and they may therefore be a
source of arrhythmogenicity.
Histological and embryological findings correlate with
electrophysiological evidence. Recent studies have found
PV myocytes with spontaneous phase 4 depolarizations,
along with slowed phase 0 rates, both characteristic features
of pacemaker cells in the SA node (Fig. 2) [3]. In addition,
other studies have recorded PV cells with prolonged plateau
phases that show triggered activity [25].
The unique distribution of ion channels in the PV
myocyte membrane may explain its distinctive electrophysiological properties. Chen et al. [26] discovered that
389
390
R. Khan / Cardiovascular Research 64 (2004) 387–394
Both sympathetic and vagal stimulation cause reductions in
ERP [37]. Acetycholine activates IKACH-channels via Gprotein second messengers, resulting again in decreased
ERP and APD [38]. It is postulated that norepinephrine
lowers ERP by activating IP3 and DAG leading to an initial
infux of Ca2+. The presence of the two second messengers
along with Ca2+enhance protein kinase C function, which,
in turn, reduces ICa2+-channel activity. In addition, IKH, an
inward K+-conductance current, has also shown to be
increased under both sympathetic and parasympathetic
stimulation [39]. As mentioned, there is quite an extensive
degree of innervation to the PVs [33]. Therefore, increased
autonomic tone localized in the PVs may be involved in the
development of PAF.
7. Electrophysiological properties of PVs increase the
likelihood of re-entry associated with AF
Myocardial architecture plays an integral role in determining conduction velocity. The principles of anisotropic
conduction emphasize that electrical impulses are propagated more quickly over longitudinal rather than transverse
paths. This is primarily due to the fact that more cell
boundaries per unit distance are encountered within the
latter pathway [40]. A greater number of boundaries imply
increased resistivity and slower impulse conduction. In
addition, longitudinal paths offer maximal intracellular
electrical conduction, rather than conduction through gap
junctions, which again provide greater resistivity. Hamabe et
al. [41] observed that conduction delays occurred in the left
superior PV where myoctye direction changed rapidly (Fig.
3). Hocini et al. [7] also found that sudden changes in PV
myocyte fiber direction correlated with conduction delays.
Additionally, de Bakker et al. [42] noted that a sharp change
in the orientation of a myocyte may cause the disorganized
propagation of an impulse to neighbouring tissue, resulting
in chaotic rather than focal, linear conduction.
Hassink et al. [6] demonstrated patients with AF have
greater amounts of hypertrophy and fibrosis in the myocardial tissue of PVs compared with those without AF (Fig.
4). Fibrotic tissue offers greater resistance to traveling
electrical impulses, slowing down conduction velocity
within cardiac tissue. In addition, fibrous septae are thought
to impair side-to-side electrical conduction in myocytes.
This so-called bcellular uncouplingQ was first documented
by Spach and Dolber who observed decreased transverse
conduction velocities in isolated cardiac tissue associated
with fibrotic septae [43]. Accordingly, quantitative mapping
analysis of the left atrial-PV ostium junction indicated
impulse conduction block or delay at sites noted for the
presence of connective tissue barriers [41]. The fact that
connective tissue septae separating myocyte tissue islands
are much more common in the PVs as compared with the
atria may be why the PVs are the predominant source of AF
development.
AF is characterized by the presence of re-entry pathways. Shorter refractory periods facilitate the maintenance
of AF by increasing the prospect for re-entry. Tada et al.
[4] first noted that the cardiocytes of PVs had varying
refractory periods that lent themselves well to the development of AF. Jais et al. [5] found similar patterns,
identifying reduced refractory periods within the PVs of
patients with AF. In fact, the refractory periods in the
aforementioned study were the shortest to have ever been
documented within the heart.
The effective refractory period (ERP) of a cell is
determined by the flow of ion currents across its membrane.
IK1-, IKs- and IKr-channels are all involved in myocyte
repolarization and therefore increased activity of these
channels results in decreased ERP and action potential
duration (APD). Contrastingly, ICa2+-channel activity
increases ERP and APD length. Ehrlich et al. [34] reported
the increased density of IKs- and IKr-channels on PV cell
membranes, as well as reduced ICa2+-current, as compared
to neighbouring left atrial myocytes. In addition, Melnyk et
al. [35] found that HERG protein (associated with IKrchannel) and KvLQT1 protein (pore-forming component for
IKs-channel) were in greater concentrations within PV
myocytes. This distribution of ion channels on PV cellular
membranes obviously helps to allow for the maintenance of
AF. In addition, it also indicates that individuals with
inheritable defects in PV myocyte channel protein expression and function may be predisposed to AF. In fact, Chen et
al. [36] have already shown, via linkage analysis, that
mutation of KvLQT1 in a Chinese family caused a
significant increase in the function of the IKs-channel,
resulting in familial AF.
Autonomic neural regulation appears to significantly
influence the maintenance of cardiac arrhythmias, as well.
8. Distinctive structural organization of myocardial
tissue in pvs facilitates af maintenance
Downloaded from http://cardiovascres.oxfordjournals.org/ at Pennsylvania State University on March 3, 2014
8C) demonstrated the greatest arrhythmogenic activity.
Again, it was suggested that this may be due to the
association of increased transient current with higher
temperatures. Hyperthermia is seen in a variety of conditions such as infection and malignancy, and associations
of these diseases to AF may be through the effects of
increased temperature on PV cells.
Finally, Chen et al. [3] documented increased activity in
PVs after infusion of the vessels with isoproterenol, a betaadrenergic agonist. They noted the increased production of
EADs from cardiomyocytes. In contrast, infusion of phenylephrine, known to cause reflex vagal activation, reduced
focal activity in the PVs [32]. Therefore, autonomic tone
may play a role in the generation of ectopic PV activity. The
extensive innervation of PVs by sympathetic and parasympathetic nerves makes this theory increasingly plausible
[33].
R. Khan / Cardiovascular Research 64 (2004) 387–394
Mechanisms by which fibrosis develops within the PVs
are not as yet known. However, in the atria, angiotensin II
has been known to cause significant fibrosis. Recent studies
indicate that the PV endothelial cells contain angiotensin II
receptors [44]. Binding of this hormone to its receptors
initiates a calcium-dependent second messenger cycle that
results in the production of extracellular kinases (Erks),
which in turn cause the proliferation of fibroblasts and
extracellular matrix. This results in significant fibrosis.
Angiotensin-converting enzyme (ACE) and Erk levels have
been found to be significantly raised in patients with PAF
and CAF [45]. Also, studies have already indicated that
RAS gene polymorphism is correlated to non-familial AF
[46]. Inherent excess production of angiotensin II may
therefore predispose patients to AF because of its effects on
PV architecture.
In all likelihood, angiotensin II does not act alone in
developing PV fibrosis. Recently, Veurheule et al. [47]
found that transgenic mice with increased levels of TGFB1 had increased fibrosis within their atria and were
consequently predisposed to AF development. TGF-B1
plays a major role in mesenchymal cell differentiation
during angiogenesis of the pulmonary vasculature.
Although no direct mechanism of action has been
proposed for the actions of TGF-B1 on the heart, this
compound has been shown to stimulate the release of
collagen and fibronectin from atrial fibroblasts. In
addition, Chen et al. [48] have shown that TGF-B1 is
one of the most potent stimulators of connective tissue
growth factor (CTGF) expression in cardiac myocytes and
fibroblasts. Increases in CTGF levels correlated with
greater levels of cellular fibronectin and collagen I and
III mRNA levels, which again implied greater fibrosis in
cardiac tissue.
Fig. 4. Longitudinal cross-section of a PV at the level of the ostium demonstrating the histologic appearance of a myocardial sleeve within the vessel. Note the
fibrous tissue clearly interdispersed throughout the myocardial sleeve. Increased expression of a variety of genes (such as ccn2) may promote fibrous tissue
production in this area.
Downloaded from http://cardiovascres.oxfordjournals.org/ at Pennsylvania State University on March 3, 2014
Fig. 3. (A) Schematic Reconstruction of a PV. The ostium has a chaotic
structural arrangement, with fibers traveling in different directions. At the
distal end, fibers are less prevalent and run in parallel along the long axis of
the vein. (B) Longitudinal cross-section of a PV at the level of the ostium
showing the non-axial course of muscle fibers within the myocardial sleeve
of the vessel.
391
392
R. Khan / Cardiovascular Research 64 (2004) 387–394
9. If bAF begets AF,Q then does bPV-induced paroxysmal
AF beget PV-induced chronic AFQ?
Wijffels et al. [8] introduced the concept of batrial
remodelingQ caused by the presence of arrhythmias. Subsequent studies identified slowing of impulse conduction
and reduced ERP in atrial cells after AF [56,57]. Atrial
tachycardia has been shown to reduce ERP primarily
through a decrease in the ICaL-current of myocytes. In
addition, sustained fibrillation has also been associated with
structural changes such as myocyte hypertrophy, myocyte
death and atrial stretch [58,59], which act to reduce
conduction velocity. Both electrophysiological and structural changes of the atria are thought to be involved in the
development of chronic AF, and so the theory that bAF
begets AFQ has been introduced. If this concept is dissected
further, then one notes that PVs are the primary source for
ectopic foci during AF. Therefore, it is likely that the
arrhythmogenic activity of PVs may be an important cause
of batrial remodelingQ. Thomas et al. showed that the bStarQ
model for radio-frequency ablation, where PVs are electri-
cally isolated, resulted in breverse atrial remodelingQ in
patients with AF [60]. The study found that atrial size and
function was restored after surgery. In addition, structural
changes in the atria after remodeling, such as stretch, may
also result in increased PV activity. Kalifa et al. showed that
atrial stretch led to increased intra-atrial pressure causing a
rise in the rate and spatio-temporal organization of electrical
waves originating in the PVs [61]. Rapid atrial pacing
(RAP) has also been shown to reduce ERP and APD within
PV myocytes. Chen et al. showed that RAP reduces the
density of ICa2+-L-and ITo-channels, both involved in the
plateau phase of action potentials [26]. The same study
found that PV myocytes had increased If-currents after RAP.
These changes imply that electrical and structural remodeling increase the likelihood of ectopic PV automaticity and
AF maintenance.
Therefore, rather than bAF begets AF,Q we can have a
variation on that theme where bPV-induced paroxysmal AF
begets PV-induced chronic AF.Q
10. Conclusion
Despite extensive study into the involvement of PV
electrical activity in AF, many questions remain unanswered.
For example, it is as yet unknown why AF, likely generated
by focal activity in the PVs, causes changes in the structural
and electrophysiological properties of atrial tissue, which
further increase the likelihood of chronic AF development.
In addition, thus far, a variety of different types of ionic
currents have been shown to be involved in the generation
of pacemaker potential within PV myocytes. Determining
which of these is the predominant cause of arrhythmogenicity will help in improving our current model for PVinitiated AF. Such knowledge may also lead to further
development of pharmacological interventions for AF. Chen
et al. [3] have already documented that beta-adrenergic
blockers, ACh, calcium-channel blockers and adenosine
reduce spontaneous activity in PVs.
Along with understanding the development of pacemaker
potentials, it is extremely important to fully elucidate the
biological pathway by which fibrotic tissue is deposited in
the PVs. Recent evidence has shown that the effects of
angiotensin II in the heart are partially mediated through
myocyte production of CTGF [62]. In addition, there is also
evidence that angiotensin II increases the production of
TGF-B1 within cardiac tissue. As TGF-B1 is the most
potent stimulator of CTGF, it may be that all three of these
molecules increase the amount of fibrous tissue within the
heart via a common sequential pathway (angiotensin
IIYTGF-B1YCTGF). However, to determine the exact
contributions of CTGF and TGF-B1 to AF, their individual
effects on PV myocardial tissue must be examined. Knowledge of these specific effects is imperative as correlations
between AF and CTGF and TGF-B1, both known to be
involved in a variety of fibrotic disorders (pancreatitis,
Downloaded from http://cardiovascres.oxfordjournals.org/ at Pennsylvania State University on March 3, 2014
Correlations between TGF-B1 and CTGF within the heart
introduce another possible genetic component to AF, as well
as to other fibrotic cardiac diseases. The ccn2 (CTGF) gene
is known to be overexpressed in a number of fibrotic diseases
[49]. Blom et al. [50] have found that polymorphisms in the
promoter regions of the ccn2 gene led to increased transcription of the gene and higher levels of myocyte CTGF in
patients with ischemic heart disease. Thus, inherent overexpression of CTGF during PV angiogenesis (prior to birth)
may cause the development of fibrous patches that separate
myocyte networks within the PVs. Immunostaining has
identified the presence of CTGF in the lung, heart and
vasculature of mouse embryos [51]. Myocardial tissue in the
PVs may be greatly affected because of its proximity to
angiogenic sources in these areas.
Along with fibrosis, the reduced synthesis of gap
junction proteins, connexins, has been suggested to contribute to arrhythmia development. Most experimental work
has focused on the correlation between changes in the
cellular level of connexin-43 (Cx-43) and ventricular
dysrhythmia. Differences in Cx-43 expression levels
between PV myocytes and other cardiac cells have not
been significant. However, recently, Verheule et al. [52]
reported that the PVs had a reduced density of connexin-40
(Cx-40) within their myocardial sleeves as compared with
adjoining left atrial tissue. The implied decreased electrical
coupling of cardiocytes would result in lowered conduction
velocity, promoting AF maintenance. Evidence of this came
from the study by Dupont et al. [53], where they found that
patients who develop AF after surgery had reduced levels of
Cx-40. In addition, mice lacking Cx-40 have been shown to
have both conduction block and increased AF development
[54,55].
R. Khan / Cardiovascular Research 64 (2004) 387–394
Acknowledgements
Special thanks to Sapna Rawal for her invaluable help.
References
[1] Benjamin EJ, Wolf PA, DTAgostino RB, Silbershatz H, Kannel WB,
Levy D. Impact of AF on the risk of death: the Framingham heart
study. Circulation 1998;98:946 – 52.
[2] Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G,
et al. Spontaneous initiation of AF by ectopic beats originating in the
pulmonary veins. N Engl J Med 1998;339:659 – 66.
[3] Chen YJ, Chen SA, Chang MS, Lin CI. Arrhythmogenic activity of
cardiac muscle in pulmonary veins of the dog: implication for the
genesis of AF. Cardiovasc Res 2000;48:265 – 73.
[4] Tada H, Oral H, Ozaydin M, Greenstein R, Pelosi Jr F, Knight BP, et al.
Response of pulmonary vein potentials to premature stimulation. J
Cardiovasc Electrophysiol 2002;13:33 – 7.
[5] Jais P, Hocini M, Macle L, Choi KJ, Deisenhofer I, Weerasooriya R,
et al. Distinctive electrophysiological properties of pulmonary veins
in patients with AF. Circulation 2002;106:2479 – 85.
[6] Hassink RJ, Aretz HT, Ruskin J, Keane D. Morphology of atrial
myocardium in human pulmonary veins: a postmortem analysis in
patients with and without AF. J Am Coll Cardiol 2003;42:1108 – 14.
[7] Hocini M, Ho SY, Kawara T, Linnenbank AC, Potse M, Shah D, et al.
Electrical conduction in canine pulmonary veins: electrophysiological
and anatomic correlation. Circulation 2002;105:2442 – 8.
[8] Wijffels MC, Kirchhof HJ, Dorland R, Allessie MA. AF begets AF. A
study in awake chronically instrumented goats. Circulation 1995;92:
1954 – 68.
[9] Fuster V, Alexander R, OTRourke R, Roberts R, Spencer K, Wellens
H. Hurst’s the Heart. 10th ed. Toronto7 McGraw-Hill; 2001.
[10] Zipes DP. Mechanisms of clinical arrhythmias. Pace 2003;26:
1778 – 92.
[11] Nattel S. New ideas about AF 50 years on. Nature 2002;415:
219 – 26.
[12] Mansour M, Mandapati R, Berenfeld O, Chen J, Samie FH, Jalife J.
Left-to-right gradient of atrial frequencies during acute AF in the
isolated sheep heart. Circulation 2001;103:2631 – 6.
[13] Nathan H, Eliakim M. The junction between the left atrium and the
pulmonary veins An anatomic study of human hearts. Circulation
1966;34:412 – 22.
[14] Cheung DW. Electrical activity of the pulmonary vein and its
interaction with the right atrium in the guinea-pig. J Physiol 1981;
314:445 – 56.
[15] Hwang C, Karagueuzian HS, Chen PS. Idiopathic paroxysmal AF
induced by a focal discharge mechanism in the left superior pulmonary
vein: possible roles of the ligament of Marshall. J Cardiovasc
Electrophysiol 1999;10:636 – 48.
[16] Chen SA, Hsieh MH, Tai CT, Tsai CF, Prakash VS, Yu WC, et al.
Initiation of AF by ectopic beats originating from the pulmonary
veins: electrophysiological characteristics, pharmacological responses,
and effects of radiofrequency ablation. Circulation 1999;100:
1879 – 86.
[17] Guerra PG, Thibault B, Dubuc M, Talajic M, Roy D, Crepeau J, et al.
Identification of atrial tissue in pulmonary veins using intravascular
ultrasound. J Am Soc Echocardiogr 2003;16:982 – 7.
[18] Lin WS, Prakash VS, Tai CT, Hsieh MH, Tsai CF, Yu WC, et al.
Pulmonary vein morphology in patients with paroxysmal AF initiated
by ectopic beats originating from the pulmonary veins: implications
for catheter ablation. Circulation 2000;101:1274 – 81.
[19] Yamane T, Shah DC, Jais P, Hocini M, Peng JT, Deisenhofer I, et al.
Dilatation as a marker of pulmonary veins initiating AF. J Interv Card
Electrophysiol 2002;6:245 – 9.
[20] Takase B, Nagata M, Matsui T, Kihara T, Kameyama A, Hamabe A,
et al. Pulmonary vein dimensions and variation of branching pattern
in patients with paroxysmal AF using magnetic resonance angiography. Jpn Heart J 2004;45:81 – 92.
[21] Perez-Lugones A, McMahon JT, Ratliff NB, Saliba WI, Schweikert
RA, Marrouche NF, et al. Evidence of specialized conduction cells in
human pulmonary veins of patients with AF. J Cardiovasc Electrophysiol 2003;14:803 – 9.
[22] Chen SA, Yeh HI. Specialized conduction cells in human pulmonary
veins: fact and controversy. J Cardiovasc Electrophysiol 2003;14:
810 – 1.
[23] Jongbloed MR, Schalij MJ, Poelmann RE, Blom NA, Fekkes ML,
Wang Z, et al. Embryonic conduction tissue: a spatial correlation with
adult arrhythmogenic areas. J Cardiovasc Electrophysiol 2004;15:
349 – 55.
[24] Rentschler S, Vaidya DM, Tamaddon H, Degenhardt K, Sassoon D,
Morley GE, et al. Visualization and functional characterization of the
developing murine cardiac conduction system. Development 2001;
128:1785 – 92.
[25] Spector P, Po S, Scherlag B. Electrophysiology of canine pulmonary
veins. Pacing Clin Electrophysiol 2003;26:995 [Abstract].
[26] Chen YJ, Chen SA, Chen YC, Yeh HI, Chan P, Chang MS, et al.
Effects of rapid atrial pacing on the arrhythmogenic activity of single
cardiomyocytes from pulmonary veins: implication in initiation of AF.
Circulation 2001;104:2849 – 54.
[27] Chen YC, Chen SA, Chen YJ, Tai CT, Chan P, Lin CI. T-type calcium
current in electrical activity of cardiomyocytes isolated from rabbit
pulmonary vein. J Cardiovasc Electrophysiol 2004;15:567 – 71.
[28] Huser J, Blatter LA, Lipsius SL. Intracellular Ca2+ release contributes
to automaticity in cat atrial pacemaker cells. J Physiol 2000;524:
415 – 22.
[29] Honjo H, Boyett MR, Niwa R, Inada S, Yamamoto M, Mitsui K, et al.
Pacing-induced spontaneous activity in myocardial sleeves of
pulmonary veins after treatment with ryanodine. Circulation
2003;107:1937 – 43.
[30] Chen YC, Chen SA, Chen YJ, Chang MS, Chan P, Lin CI. Effects of
thyroid hormone on the arrhythmogenic activity of pulmonary vein
cardiomyocytes. J Am Coll Cardiol 2002;39:366 – 72.
[31] Chen YJ, Chen YC, Chan P, Lin CI, Chen SA. Temperature regulates
the arrhythmogenic activity of pulmonary vein cardiomyocytes.
J Biomed Sci 2003;10:535 – 43.
Downloaded from http://cardiovascres.oxfordjournals.org/ at Pennsylvania State University on March 3, 2014
glomerulosclerosis, etc.), may allow for the implication of
AF as one component of a larger systemic disease(s). If a
common link between these disorders can be elucidated,
treatment methods for PV-derived AF may have significant
impact on the therapy of systemic conditions.
In regards to current therapy, AF has been noted even
after successful electrical isolation of PVs [63]. This may be
due to the presence of arrhythmogenic tissue in other areas
of the heart. Myocardial sleeves, similar to those found in
PVs, have been identified in the walls of the coronary sinus.
The anatomy of this vessel should be further examined in
the hope of definitively identifying pacemaker potential
cells as a source of ectopic electrical firing. Electrophysiologic studies have recently shown the importance of the
coronary sinus in the perpetuation of AF [64].
More generally, clarifying the role of the PVs in AF may
allow for more specific, less invasive treatment and may
make prevention increasingly viable.
393
394
R. Khan / Cardiovascular Research 64 (2004) 387–394
[48] Chen MM, Lam A, Abraham JA, Schreiner GF, Joly AH. CTGF
expression is induced by TGF-beta in cardiac fibroblasts and cardiac
myocytes: a potential role in heart fibrosis. J Mol Cell Cardiol
2000;32:1805 – 19.
[49] Leask A, Holmes A, Abraham DJ. Connective tissue growth factor: a
new and important player in the pathogenesis of fibrosis. Curr
Rheumatol Rep 2002;4:136 – 42.
[50] Blom IE, van Dijk AJ, de Weger RA, Tilanus MG, Goldschmeding R.
Identification of human ccn2 (connective tissue growth factor)
promoter polymorphisms. Mol Pathol 2001;54:192 – 6.
[51] Surveyor GA, Brigstock DR. Immunohistochemical localization of
connective tissue growth factor (CTGF) in the mouse embryo between
days 7.5 and 14.5 of gestation. Growth Factors 1999;17:115 – 24.
[52] Verheule S, Wilson EE, Arora R, Engle SK, Scott LR, Olgin JE.
Tissue structure and connexin expression of canine pulmonary veins.
Cardiovasc Res 2002;55:727 – 38.
[53] Dupont E, Ko Y, Rothery S, Coppen SR, Baghai M, Haw M, et al. The
gap-junctional protein connexin40 is elevated in patients susceptible
to postoperative AF. Circulation 2001;103:842 – 9.
[54] van Rijen HV, van Veen TA, van Kempen MJ, Wilms-Schopman FJ,
Potse M, Krueger O, et al. Impaired conduction in the bundle branches
of mouse hearts lacking the gap junction protein connexin40.
Circulation 2001;103:1591 – 8.
[55] Verheule S, van Batenburg CA, Coenjaerts FE, Kirchhoff S, Willecke
K, Jongsma HJ, et al. Cardiac conduction abnormalities in mice
lacking the gap junction protein connexin40. J Cardiovasc Electrophysiol 1999;10:1380 – 9.
[56] Gaspo R, Bosch RF, Bou-Abboud E, Nattel S. Tachycardia-induced
changes in Na+ current in a chronic dog model of AF. Circ Res
1997;811:1045 – 52.
[57] Fareh S, Villemaire C, Nattel S. Importance of refractoriness
heterogeneity in the enhanced vulnerability to atrial fibrillation
induction caused by tachycardia-induced atrial electrical remodeling.
Circulation 1998;98:2202 – 9.
[58] Ausma J, Thone F, Wouters L, Allessie M, Borgers M. Structural
changes of atrial myocardium due to sustained atrial fibrillation in the
goat. Circulation 1997;96:3157 – 63.
[59] Aime-Sempe C, Folliguet T, Rucker-Martin C, Krajewska M,
Krajewska S, Heimburger M, et al. Myocardial cell death in
fibrillating and dilated human right atria. J Am Coll Cardiol
1999;34:1577 – 86.
[60] Thomas L, Boyd A, Thomas SP, Schiller NB, Ross DL. Atrial
structural remodelling and restoration of atrial contraction after linear
ablation for AF. Eur Heart J 2003;24:1942 – 51.
[61] Kalifa J, Jalife J, Zaitsev AV, Bagwe S, Warren M, Moreno J, et al.
Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during AF. Circulation
2003;108:668 – 71.
[62] Ahmed MS, Oie E, Vinge LE, Yndestad A, Oystein Andersen G,
Andersson Y, et al. Connective tissue growth factor—a novel
mediator of angiotensin II-stimulated cardiac fibroblast activation in
heart failure in rats. J Mol Cell Cardiol 2004;36:393 – 404.
[63] Shah D, Haissaguerre M, Jais P, Hocini M. Nonpulmonary vein foci:
do they exist? Pacing Clin Electrophysiol 2003;26:1631 – 5.
[64] Oral H, Ozaydin M, Chugh A, Scharf C, Tada H, Hall B, et al. Role of
the coronary sinus in maintenance of AF. J Cardiovasc Electrophysiol
2003;14:1329 – 36.
Downloaded from http://cardiovascres.oxfordjournals.org/ at Pennsylvania State University on March 3, 2014
[32] Tai CT, Chiou CW, Wen ZC, Hsieh MH, Tsai CF, Lin WS, et al. Effect
of phenylephrine on focal AF originating in the pulmonary veins and
superior vena cava. J Am Coll Cardiol 2000;36:788 – 93.
[33] Gardner E, OTRahilly R. The nerve supply and conducting system of
the human heart at the end of the embryonic period proper. J Anat
1976;121:571 – 87.
[34] Ehrlich JR, Cha TJ, Zhang L, Chartier D, Melnyk P, Hohnloser SH,
et al. Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties. J Physiol
2003;551:801 – 13.
[35] Melnyk P, Ehrlich J, Villeneuve L, Nattel S. Immunohistochemical
comparison of ion channel distribution in cardiomyocytes of
pulmonary veins versus left atrium. Circulation 2002;106:II – 90
[Abstract].
[36] Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, et al.
KCNQ1 gain-of-function mutation in familial AF. Science
2003;299:251 – 4.
[37] Takei M, Furukawa Y, Narita M, Ren LM, Karasawa Y, Murakami
M, et al. Synergistic nonuniform shortening of atrial refractory
period induced by autonomic stimulation. Am J Physiol 1991;261:
H1988 – 93.
[38] Ohmoto-Sekine Y, Uemura H, Tamagawa M, Nakaya H. Inhibitory
effects of aprindine on the delayed rectifier K+ current and the
muscarinic acetylcholine receptor-operated K+ current in guinea-pig
atrial cells. Br J Pharmacol 1999;126:751 – 61.
[39] Ehrlich JR, Cha TJ, Zhang L, Chartier D, Villeneuve L, Hebert TE,
et al. Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein
myocardial sleeves and left atrium. J Physiol 2004;557:583 – 97.
[40] Sano T, Takayama N, Shimamoto T. Directional difference of
conduction velocity in cardiac ventricular syncytium studied by
microelectrodes. Circ Res 1959;7:262 – 7.
[41] Hamabe A, Okuyama Y, Miyauchi Y, Zhou S, Pak HN, Karagueuzian
HS, et al. Correlation between anatomy and electrical activation in
canine pulmonary veins. Circulation 2003;107:1550 – 5.
[42] de Bakker JM, Ho SY, Hocini M. Basic and clinical electrophysiology
of pulmonary vein ectopy. Cardiovasc Res 2002;54:287 – 94.
[43] Spach MS, Dolber PC. Relating extracellular potentials and their
derivatives to anisotropic propagation at a microscopic level in
human cardiac muscle. Evidence for electrical uncoupling of sideto-side fiber connections with increasing age. Circ Res 1986;58:
356 – 571.
[44] Satoh K, Ichihara K, Landon EJ, Inagami T, Tang H. 3-Hydroxy-3methylglutaryl-CoA reductase inhibitors block calcium-dependent
tyrosine kinase Pyk2 activation by angiotensin II in vascular
endothelial cells. Involvement of geranylgeranylation of small G
protein Rap1. J Biol Chem 2001;276:15761 – 7.
[45] Goette A, Staack T, Rocken C, Arndt M, Geller JC, Huth C, et al.
Increased expression of extracellular signal-regulated kinase and
angiotensin-converting enzyme in human atria during AF. J Am Coll
Cardiol 2000;35:1669 – 77.
[46] Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, et al.
Renin-angiotensin system gene polymorphisms and AF. Circulation
2004;109:1640 – 6.
[47] Verheule S, Sato T, Everett T, et al. Increased vulnerability to AF in
transgenic mice with selective atrial fibrosis caused by overexpression
of TGF-beta1. Circ Res 2004;94:1458 – 65.