This editorial refers to ‘Atrial fibrillation following lung transplantation: double but not single lung transplant is associated with long-term freedom from paroxysmal atrial fibrillation’, by G. Lee et al., on page 2774

Atrial fibrillation (AF) is a complex disease most probably due to multiple aetiopathogenic mechanisms. This arrhythmia usually requires a trigger for initiation and a vulnerable electrophysiological and/or anatomic substrate for maintenance. It is still unclear whether the trigger mechanisms for AF initiation include focal enhanced automaticity, triggered activity, or microre-entry from myocardial tissue inside the pulmonary vein (PV). In spite of an incomplete understanding of the anatomo-functional basis for the initiation and maintenance of AF, various catheter and surgical ablation techniques have been shown to modify the substrate of this arrhythmia, achieving a stable sinus rhythm, free from AF, in a high proportion of cases.

In the past 10 years, catheter ablation techniques in patients with AF have evolved from an initial approach focused on the PVs and their junctions with the left atrium (LA), to a more extensive intervention, mainly, but not exclusively, on the LA myocardium and its neuro-vegetative innervation (Figure 1). It is now recognized that the cornerstone of most catheter and surgical ablation approaches is to isolate the PVs electrically from the LA wall. Despite more or less substantial differences among the various catheter techniques that are currently utilized worldwide, results seem to be uniformly similar, with success rates in the range from 50% to 80% in patients with long-standing, persistent, or paroxysmal AF. Notably, a median of two AF ablation procedures are usually necessary for a successful outcome.1,2

Figure 1

Schematic of the anatomo-functional arrhythmic mechanism and common ablation strategies in paroxysmal and long-standing/persistent AF. (A) Active triggers arising from the atrial myocardium within the PVs and other thoracic veins (CS, vein/ligament of Marshall, and the SVC) are shown in green. Autonomic ganglia and nerves are shown in yellow. Abrupt changes of fibre orientation along the PV antrum and posterior LA wall favouring anatomic re-entry or high frequency rotors are also shown. (B) The two most common approaches for paroxysmal AF: segmental PV isolation for electric disconnection of triggers within the veins; and circumferential ostial PV isolation (one-by-one linear ablation of the PVs). (C) Simultaneous isolation of the ipsilateral PVs, encircling the antrum and additional linear lesions between the superior and inferior PVs. (D) Combinations of more than two techniques are usually necessary for a successful outcome in long-standing or persistent AF. These approaches include (i) PV isolation; (ii) isolation of the thoracic veins and non-PV triggers; (iii) additional linear lesions such as the ‘mitral isthmus’ line connecting the mitral valve and the lesion encircling the LIPV, a ‘roof’ line connecting the lesions encircling the left and right PVs, a ‘right atrial isthmus’ line, and an ‘anterior’ line connecting the roof line to the mitral annulus anteriorly; (iv) ablation of complex fractionated activity; and (v) ablation of autonomic plexuses. CS, coronary sinus; LAA, left atrial appendage; LIPV, left inferior PV; LSPV, left superior PV; RIPV, right inferior PV; RSPV, right superior PV; SVC, superior vena cava.

Figure 1

Schematic of the anatomo-functional arrhythmic mechanism and common ablation strategies in paroxysmal and long-standing/persistent AF. (A) Active triggers arising from the atrial myocardium within the PVs and other thoracic veins (CS, vein/ligament of Marshall, and the SVC) are shown in green. Autonomic ganglia and nerves are shown in yellow. Abrupt changes of fibre orientation along the PV antrum and posterior LA wall favouring anatomic re-entry or high frequency rotors are also shown. (B) The two most common approaches for paroxysmal AF: segmental PV isolation for electric disconnection of triggers within the veins; and circumferential ostial PV isolation (one-by-one linear ablation of the PVs). (C) Simultaneous isolation of the ipsilateral PVs, encircling the antrum and additional linear lesions between the superior and inferior PVs. (D) Combinations of more than two techniques are usually necessary for a successful outcome in long-standing or persistent AF. These approaches include (i) PV isolation; (ii) isolation of the thoracic veins and non-PV triggers; (iii) additional linear lesions such as the ‘mitral isthmus’ line connecting the mitral valve and the lesion encircling the LIPV, a ‘roof’ line connecting the lesions encircling the left and right PVs, a ‘right atrial isthmus’ line, and an ‘anterior’ line connecting the roof line to the mitral annulus anteriorly; (iv) ablation of complex fractionated activity; and (v) ablation of autonomic plexuses. CS, coronary sinus; LAA, left atrial appendage; LIPV, left inferior PV; LSPV, left superior PV; RIPV, right inferior PV; RSPV, right superior PV; SVC, superior vena cava.

Using single (SLT) and double lung transplantation (DLT) surgery, the study of Lee et al.3 constitutes a model for unilateral and bilateral isolation of the pulmonary venous antral region. With a remarkable number of patients and 5.4 ± 2.9 years of follow-up, the study provides evidence to support the importance of a complete and ‘durable’ electrical isolation of all the PVs in order to achieve long-term freedom from AF.

Early and late post-procedural AF

Acute AF is a common complication following thoracic surgery in the early post-operative stage. In the study by Lee et al.,3 early AF was more frequent in patients after SLT (28%) and DLT (29%) compared with a control group of patients undergoing non-transplant thoracic surgery (14%). Mechanisms underlying post-operative AF may include changes of atrial electrophysiological properties induced by surgical manipulation, pericardial inflammation, oedema, and/or neurohormonal imbalance.4,5 It is interesting to note that the episodes of early post-operative AF did not predict the subsequent development of ‘late AF’ in the DLT group as no DLT patient developed recurrent AF during long-term follow-up, compared with 33% in the SLT group and 53% in the non-transplant group.

Acute return of PV conduction is also common after successful catheter-based PV isolation. The delayed effect of radiofrequency ablation lesions and transient inflammatory or autonomic disturbances have been suggested as possible causes. Drawing an analogy with catheter ablation techniques, a 3 month ‘blanking period’ is recommended, and recurrences of AF or atrial flutter are not considered as failures of the procedure.6 Therefore, both scenarios (early post-surgical appearance of AF and acute post-ablation AF recurrences) appear to be less dependent on triggers originating from the PVs than AF occurring in other contexts. Still, the topic of early recurrences of AF after catheter ablation is far from being settled.

As previously reported, late recurrences after AF ablation may be due to a variety of factors including late recovery of conduction of previously electrically isolated PVs and, in some cases, emergence of non-PV triggers or foci not properly identified at the initial ablation session.1,2 The time between PV reconnection and AF recurrences is unknown. Progression of atrial fibrosis or clinical factors such as hypertension may also contribute to the development of electrophysiological abnormalities promoting recurrences of AF. In the study by Lee et al., the incidence of late AF following DLT was significantly lower (0.5%) compared with SLT (12.6%) and non-transplant thoracic surgery (11.4%). Surprisingly, although it is known that patients receiving DLT are more prone to other atrial arrhythmias such as atrial flutter and atrial tachycardia,4,5 a low incidence of these incisional arrhythmias was found in this study.

As stated by the authors, an important point in the interpretation of their results is the baseline differences in age, LA dimensions, and the underlying diagnosis among the three groups. Recurrence of PV conduction after catheter ablation is also more likely to occur in older patients with non-paroxysmal AF, hypertension, and a large LA. The major limitation of the present study is how AF was detected during follow-up. In this observational and retrospective study the predominant assessment of AF following hospital discharge was determined by symptoms, or if the arrhythmia was suspected based on routine clinical evaluation. It is well known how a substantial proportion of AF episodes may be asymptomatic and therefore the true incidence of AF can be underestimated. As outlined in the Heart Rhythm Society consensus document on AF ablation,6 ‘success’ should be defined as freedom from symptomatic or ‘asymptomatic’ AF, atrial tachycardia, or atrial flutter lasting 30 s or longer 12 months following AF ablation. The true incidence of AF recurrences remains a limitation for many clinical studies conducted over long follow-up periods.

Transmurality as the key for success

In our opinion, the most important question that arises from this study is whether transmural or complete lesions of all right and left PVs are important or necessary for achieving stable long-term sinus rhythm. Some investigators have suggested that complete electrical isolation of the PVs may not be crucial for a successful outcome.1 As Lee et al. describe in their article, the surgical technique used in the DLT patients leads to antral isolation of the PVs, analogous to catheter-based PV isolation. Recovery of PV conduction and atrial tachyarrhythmias is a dominant finding after continuous circular lesion around the ipsilateral PVs in patients with AF.7 With the use of a pure anatomical approach, it is possible to prevent AF in a significant proportion of patients undergoing catheter ablation. The ability to create a full-thickness lesion that completely disconnects PV varies depending on the catheter technique or energy used. Different contributing architectural factors for catheter-based treatment of AF can determine the success of the procedure. These factors may include (i) the complex LA endocardial structure; (ii) a non-uniform myocardial thickness; (iii) a flow-mediated cooling effect by the intramyocardial atrial arteries; and (iv) the epicardially located inter-PV muscular connections.8–10 The need for transmural lesions to achieve complete disconnection of individual PVs is unclear. Residual myocardial continuity leads to conduction gaps, possibly causing the failure of the procedure. Although it can be debated, the study of Lee et al. provides the first clinical validation that complete and transmural isolation of all the PVs may be necessary to increase long-term success rates.

Transmural PV isolation is a shared consequence of DLT and cardiac transplantation operations.5 However, cardiac transplantation also involves posterior LA isolation and a more complete cardiac denervation, providing added benefit in preventing AF. Despite recent studies showing no clear benefit,11 additional linear lesions targeting the posterior LA wall have been demonstrated to increase the success rate of catheter ablation in persistent and long-standing AF.12 Different atrial regions contribute to the fibrillatory process and to the maintenance of AF, emphasizing the role of structural discontinuities and heterogeneous fibre orientation favouring anatomic re-entry or anchoring rotors.13 Abrupt changes in muscular thickness and fibre orientation transmurally along the myocardial bundles of the posterior atrial wall are a substrate for slowing conduction and seem to play an important role in maintaining AF.14

Experimental studies have shown that initiation and maintenance of AF can be favoured by both parasympathetic and sympathetic stimulation. A non-uniform regional distribution of the cardiac nerves and differential patterns of innervation have been observed in human hearts.15 Complete vein denervation seems to be an additional predictor of long-term benefit after circumferential PV ablation of AF.16 As can be seen in Figure 2, during lung transplantation surgical anastamoses 2–3 cm proximal to the PV orifice involve nerves and ganglions of the autonomic nervous system present at the veno-atrial junction and thus have the potential to improve outcome.

Figure 2

(A) Dissection showing the subepicardial myocardial fibres viewed from the superior–posterior aspect. The myocardial tissue encircles the veno-atrial junction. (B) Cross-section in a specimen of a 65-year-old subject stained with the van Gieson technique to show the myoarchitecture along the entire thickness of the PVs and LA walls. The LA musculature lies external to the venous wall between the adventitia and the venous media in a fine matrix composed of collagen, elastic fibres, and blood vessels. Note the abrupt changes in muscular thickness and fibre orientation transmurally along the PV antrum and posterior atrial wall. Surgical antral isolation of the PVs may partially involve the autonomic ganglia and nerves (dotted line). (C) Cross-section along the left superior PV to show the mixed arrangement of myocardial fibres making up the wall of the LA and the vein. Note the presence of collagenous septa between the myocardial fibres and the autonomic nervous system elements mainly located in the fat pads on the epicardium. Epi and Endo mark the orientation for epicardial and endocardial surfaces, respectively. LAA, LA appendage; SVC, superior vena cava.

Figure 2

(A) Dissection showing the subepicardial myocardial fibres viewed from the superior–posterior aspect. The myocardial tissue encircles the veno-atrial junction. (B) Cross-section in a specimen of a 65-year-old subject stained with the van Gieson technique to show the myoarchitecture along the entire thickness of the PVs and LA walls. The LA musculature lies external to the venous wall between the adventitia and the venous media in a fine matrix composed of collagen, elastic fibres, and blood vessels. Note the abrupt changes in muscular thickness and fibre orientation transmurally along the PV antrum and posterior atrial wall. Surgical antral isolation of the PVs may partially involve the autonomic ganglia and nerves (dotted line). (C) Cross-section along the left superior PV to show the mixed arrangement of myocardial fibres making up the wall of the LA and the vein. Note the presence of collagenous septa between the myocardial fibres and the autonomic nervous system elements mainly located in the fat pads on the epicardium. Epi and Endo mark the orientation for epicardial and endocardial surfaces, respectively. LAA, LA appendage; SVC, superior vena cava.

The presence of atrial innervation within the myocardium of the LA suggests that non-transmural lesions could have a clinical impact during catheter ablation. However, the autonomic nervous system elements are mainly present in the fat pads on the epicardial surface of the left atrial wall and therefore transmural lesions are needed to denervate the atria. The contribution of the neural inputs to the ablation areas points to a complex interplay of anatomical and electrophysiological substrates for the genesis and recurrence of AF.

The study of Lee et al.3 demonstrates the importance of ‘durable’ electrical isolation of all right and left PVs as the cornerstone in catheter and surgical strategies for the long-term prevention of AF. Their findings represent an additional piece of the complex and still unassembled puzzle that is the pathophysiology of AF recurrences after catheter ablation, and reinforce the need of a better understanding of the anatomo-functional substrate of the arrhythmia.

Conflict of interest: none declared.

References

1
Stabile
G
Turco
P
La Rocca
V
Nocerino
P
Stabile
E
De Simone
A
Is pulmonary vein isolation necessary for curing atrial fibrillation?
Circulation
 , 
2003
, vol. 
108
 (pg. 
657
-
660
)
2
Cappato
R
Negroni
S
Pecora
D
Bentivegna
S
Lupo
PP
Carolei
A
Esposito
C
Furlanello
F
De Ambroggi
L
Prospective assessment of late conduction recurrence across radiofrequency lesions producing electrical disconnection at the pulmonary vein ostium in patients with atrial fibrillation
Circulation
 , 
2003
, vol. 
108
 (pg. 
1599
-
1604
)
3
Lee
G
Wu
H
Kalman
JM
Esmore
D
Williams
T
Snell
G
Kistler
PM
Atrial fibrillation following lung transplantation: double but not single lung transplant is associated with long-term freedom from paroxysmal atrial fibrillation
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
2774
-
2782
First published on 11 July 2010. doi:10.1093/eurheartj/ehq224
4
See
VY
Roberts-Thomson
KC
Stevenson
WG
Camp
PC
Koplan
BA
Atrial arrhythmias after lung transplantation: epidemiology, mechanisms at electrophysiology study, and outcomes
Circ Arrhythm Electrophysiol
 , 
2009
, vol. 
2
 (pg. 
504
-
510
)
5
Dizon
JM
Chen
K
Bacchetta
M
Argenziano
M
Mancini
D
Biviano
A
Sonett
J
Garan
H
Comparison of atrial arrhythmias after heart or double-lung transplantation at a single center. Insights into the mechanism of post-operative atrial fibrillation
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
2043
-
2048
)
6
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. European Heart Rhythm Association (EHRA); European Cardiac Arrhythmia Scoiety (ECAS); American College of Cardiology (ACC); American Heart Association (AHA); Society of Thoracic Surgeons (STS), Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, Damiano RJ Jr, Davies DW, Haines DE, Haissaguerre M, Iesaka Y, Jackman W, Jais P, Kottkamp H, Kuck KH, Lindsay BD, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Natale A, Pappone C, Prystowsky E, Raviele A, Ruskin JN, Shemin RJ
Heart Rhythm
 , 
2007
, vol. 
4
 (pg. 
816
-
861
)
7
Ouyang
F
Antz
M
Ernst
S
Hachiya
H
Mavrakis
H
Deger
FT
Schaumann
A
Chun
J
Falk
P
Hennig
D
Liu
X
Bänsch
D
Kuck
KH
Recovered pulmonary vein conduction as a dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: lessons from double Lasso technique
Circulation
 , 
2005
, vol. 
111
 (pg. 
127
-
135
)
8
Cabrera
JA
Ho
SY
Climent
V
Fuertes
B
Murillo
M
Sánchez-Quintana
D
Morphological evidence of muscular connections between contiguous pulmonary venous orifices: relevance of the interpulmonary isthmus for catheter ablation in atrial fibrillation
Heart Rhythm
 , 
2009
, vol. 
6
 (pg. 
1192
-
1198
)
9
Cabrera
JA
Ho
SY
Climent
V
Sánchez-Quintana
D
The architecture of the left lateral atrial wall: a particular anatomic region with implications for ablation of atrial fibrillation
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
356
-
362
)
10
Ho
SY
Cabrera
JA
Tran
VH
Farré
J
Anderson
RH
Sánchez-Quintana
D
Architecture of the pulmonary veins: relevance to radiofrequency ablation
Heart
 , 
2001
, vol. 
86
 (pg. 
265
-
270
)
11
Tamborero
D
Mont
L
Berruezo
A
Matiello
M
Benito
B
Sitges
M
Vidal
B
de Caralt
TM
Perea
RJ
Vatasescu
R
Brugada
Left atrial posterior wall isolation does not improve the outcome of circumferential pulmonary vein ablation for atrial fibrillation: a prospective randomized study
J Circ Arrhythm Electrophysiol
 , 
2009
, vol. 
2
 (pg. 
35
-
40
)
12
Sanders
P
Hocini
M
Jaïs
P
Sacher
F
Hsu
LF
Takahashi
Y
Rotter
M
Rostock
T
Nalliah
CJ
Clémenty
J
Haïssaguerre
M
Complete isolation of the pulmonary veins and posterior left atrium in chronic atrial fibrillation. Long-term clinical outcome
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
1862
-
1871
)
13
Markides
V
Schilling
RJ
Ho
SY
Chow
AW
Davies
DW
Peters
NS
Characterization of left atrial activation in the intact human heart
Circulation
 , 
2003
, vol. 
107
 (pg. 
733
-
739
)
14
Klos
M
Calvo
D
Yamazaki
M
Zlochiver
S
Mironov
S
Cabrera
JA
Sanchez-Quintana
D
Jalife
J
Berenfeld
O
Kalifa
J
Atrial septopulmonary bundle of the posterior left atrium provides a substrate for atrial fibrillation initiation in a model of vagally mediated pulmonary vein tachycardia of the structurally normal heart
Circ Arrhythm Electrophysiol
 , 
2008
, vol. 
1
 (pg. 
175
-
183
)
15
Tan
AY
Li
H
Wachsmann-Hogiu
S
Chen
LS
Chen
PS
Fishbein
MC
Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrial-pulmonary vein junction
J Am Coll Cardiol
 , 
2006
, vol. 
48
 (pg. 
132
-
143
)
16
Pappone
C
Santinelli
V
Manguso
F
Vicedomini
G
Gugliotta
F
Augello
G
Mazzone
P
Tortoriello
V
Landoni
G
Zangrillo
A
Lang
C
Tomita
T
Mesas
C
Mastella
E
Alfieri
O
Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation
Circulation
 , 
2004
, vol. 
109
 (pg. 
327
-
334
)

Author notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehq224

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