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JACC: CLINICAL ELECTROPHYSIOLOGY
VOL. 1, NO. 4, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2405-500X/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacep.2015.05.009
Incidence, Risk Factors, Prognosis,
and Electrophysiological Mechanisms
of Atrial Arrhythmias After
Lung Transplantation
Kongkiat Chaikriangkrai, MD,* Soma Jyothula, MD,*y Hye Yeon Jhun, MD,* Su Min Chang, MD,z
Edward A. Graviss, PHD,x Mossaab Shuraih, MD,k Tapan G. Rami, MD,z Amish S. Dave, MD, PHD,z
Miguel Valderrábano, MDz
ABSTRACT
OBJECTIVES The purpose of this study was to investigate the incidence and timing, risk factors, prognostic
significance, and electrophysiological mechanisms of atrial arrhythmia (AA) after lung transplantation.
BACKGROUND Although new-onset AA is common after thoracic surgery and is associated with poorer outcomes,
prognostic and mechanistic data are sparse in lung transplant populations.
METHODS A total of 293 consecutive isolated lung transplant recipients without known AA were reviewed retrospectively.
Mean follow-up was 28 17 months. Electrophysiology studies (EPS) were performed in 25 patients with AA.
RESULTS The highest incidence of new-onset AA after lung transplantation occurred within 30 days after transplantation (25% of all patients). In multivariable analysis, post-operative AA was associated with double-lung transplantation
(odds ratio: 2.79; p ¼ 0.005) and lower mean pulmonary artery pressure (odds ratio: 0.95; p ¼ 0.027). Patients with
post-operative AA had longer hospital stays (21 days vs. 12 days; p < 0.001). Post-operative AA was independently
associated with late AA (hazard ratio: 13.52; p < 0.001) but not mortality (hazard ratio: 1.55; p ¼ 0.14). On EPS, there
were 14 patients with atrial flutter alone and 11 with atrial flutter and fibrillation. Among all EPS patients, 20 (80%) had
multiple AA mechanisms, including peritricuspid flutter (48%), perimitral flutter (36%), right atrial incisional re-entry
(24%), focal tachycardia from recipient pulmonary vein (PV) antrum (32%), focal PV fibrillation (24%), and left atrial roof
flutter (20%). Left atrial mechanisms were present in 80% of EPS patients (20 of 25) and originated from the
anastomotic PV antrum.
CONCLUSIONS Post-operative AA was independently associated with longer length of stay and late AA but not mortality. Pleomorphic PV antral arrhythmogenesis from native PV antrum is the main cause of AA after lung transplantation.
(J Am Coll Cardiol EP 2015;1:296–305) © 2015 by the American College of Cardiology Foundation.
F
or the past 2 decades, lung transplantation has
adult solid organ transplantations (2). In addition to
been increasingly performed worldwide (1).
traditional risk factors for mortality, such as recipient
Survival after lung transplantation has been
history of diabetes mellitus or use of intravenous
reported in the U.S. Organ Procurement and Trans-
inotropes (1), the impact of atrial arrhythmia (AA)
plantation Network to be among the lowest of all
after lung transplantation on survival has been
From the *Department of Medicine, Houston Methodist Hospital, Houston, Texas; yMethodist J.C. Walter Jr. Transplant Center;
Houston Methodist Hospital, Houston, Texas; zMethodist DeBakey Heart & Vascular Center, Houston Methodist Hospital,
Houston, Texas; xHouston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas; and the kTexas Heart
Institute/St. Luke’s Episcopal Hospital, Houston, Texas. Dr. Rami has received research support from Biosense Webster.
Dr. Valderrábano has received research support from Biosense Webster, Hansen Medical, and Boston Scientific. All other authors
have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript’s audio summary by JACC: Clinical Electrophysiology Editor-in-Chief Dr. David J. Wilber.
Manuscript received January 21, 2015; revised manuscript received April 21, 2015, accepted May 6, 2015.
Chaikriangkrai et al.
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Atrial Arrhythmia and Lung Transplantation
described recently (3–6); however, data from pub-
diseases (11). Group A comprises obstructive
ABBREVIATIONS
lished literature have been inconsistent regarding an
lung diseases (e.g., emphysema); group B
AND ACRONYMS
association between AA and post–lung transplanta-
comprises pulmonary vascular diseases (e.g.,
tion mortality (3–6).
primary pulmonary hypertension); group C is
AA = atrial arrhythmia
AF = atrial fibrillation
Although AA is common after thoracic surgery, the
cystic fibrosis or other immunodeficiency
literature is sparse concerning AA after lung trans-
disorders; and group D consists of restrictive
plantation, specifically with regard to electrophysio-
lung diseases (e.g., idiopathic pulmonary
ARB = angiotensin II receptor
fibrosis).
blocker
logical data. The currently accepted mechanistic
AFL = atrial flutter
CAD = coronary artery disease
paradigm of spontaneous atrial fibrillation (AF) in
The presence of coronary artery disease
non–post-operative settings is that the pulmonary
(CAD) was determined by coronary angiog-
veins (PVs) play a major role (7), yet there is no spe-
raphy. Pulmonary hypertension was de-
ECG = electrocardiogram
cific evidence demonstrating an association between
fined by mean pulmonary artery pressure
EPS = electrophysiology study
PVs and post-operative AA. However, the occurrence
(mPAP) of more than 3.3 kPa (25 mm Hg)
HR = hazard ratio
of AA after lung transplantation has been reported to
obtained with a standard right-sided heart
IQR = interquartile range
be higher than that of other thoracic surgeries, for
catheterization.
example, coronary artery bypass graft surgery (8),
lung resection (9), or heart transplantation (10). During the lung transplantation surgical procedure, some
or all of the recipient’s PVs are surgically modified to
create an anastomosis with the donor’s PVs. Various
portions of the donor’s atrial tissue remnants may be
connected to various portions of the recipient’s PVs
and atrial tissue. Fibrosis at the surgical anastomosis
between heterologous tissues theoretically should act
as a barrier for the propagation of electrical impulses.
The surgical instrumentation at or around the PVs,
where AF commonly originates, suggests a particular
susceptibility of lung transplant recipients to AA.
In this study, we sought to investigate unclear aspects of AA after lung transplantation, including: 1)
its incidence and timing; 2) risk factors; 3) prognostic
significance; and 4) electrophysiological mechanisms.
STUDY
mPAP = mean pulmonary
OUTCOMES. Clinical
artery pressure
events
were
examined through systematic review of the
medical
record
CI = confidence interval
database,
lung
trans-
PAP = pulmonary artery
pressure
PV = pulmonary vein
plantation registry records, and Social Security Death Index searches. The outcomes evaluated in
this study were post-operative AA, late AA, all-cause
mortality, new stroke, and post-operative length
of stay.
Post-operative AA was defined as post-operative
AF or atrial flutter (AFL) within 30 days of the index
hospitalization for lung transplantation. Diagnosis of
post-operative AA in our study required documentation of AA in a 12-lead electrocardiogram (ECG). The
decision to acquire a 12-lead ECG was made by the
patient’s medical team on the basis of suspicion of
cardiac arrhythmia on continuous telemetric ECG
monitoring or other clinical indications. All patients
METHODS
were under 24-h ECG monitoring from hospital
STUDY DESIGN AND PATIENT SELECTION. A retro-
least 30 s was included. Late AA was defined as AF or
admission until discharge, and only AA that lasted at
spective observational study was conducted on
AFL that occurred at any time during the follow-up
consecutive patients who underwent isolated lung
period ($30 days) after the index transplantation
transplantation between June 2007 and February 2013.
hospital discharge. This included routine follow-up
A total of 324 cases of isolated lung transplantation
clinic visits at 1, 3, 6, 9, and 12 months and then
were identified. Patients with a pre-existing history of
annually, emergency department visit records, and
AA before transplantation were excluded (n ¼ 31),
hospital admission records. AA rhythm was required
which yielded a final cohort of 293 cases of isolated
to be documented in a 12-lead ECG to meet our
lung transplantation without prior history of AA.
criteria for late AA. All-cause mortality included any
Institutional Review Board approval was obtained
death after lung transplantation. Time to death was
from Houston Methodist Hospital for this study.
calculated from the date of lung transplantation to
DATA COLLECTION AND PATIENT CHARACTERISTICS.
Information on patient pre-operative demographics,
operative data, post-operative clinical features, and
the date of death. Post-operative length of stay was
calculated from the date of lung transplantation to
the date of hospital discharge.
clinical events during the follow-up period was
ELECTROPHYSIOLOGY STUDIES AND ABLATION. Patients
collected through review of medical record and lung
with post-operative AA were treated medically with
transplantation registry databases. We categorized
a ventricular rate-control strategy (n ¼ 40) and tran-
primary lung pathology according to the United
sient administration of antiarrhythmic medications
Network for Organ Sharing classification of lung
(n ¼ 33). Those with AA that persisted or occurred
298
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beyond 1 month after surgery were considered for
NEW-ONSET AA AFTER LUNG TRANSPLANTATION:
invasive electrophysiology studies (EPS) and ablation
INCIDENCE AND TIMING. New-onset AA occurred in
(n ¼ 25). Briefly, vascular access was obtained through
31% of patients (90 of 293) after lung transplantation.
the femoral and jugular veins. Multipolar catheters
AA incidence exhibited a bimodal distribution, with
were positioned in the coronary sinus or tricuspid
the
annulus as needed. Intracardiac echocardiography
operative period (post-operative AA), which accoun-
was used to guide transseptal puncture, and 3-
ted for 81% of all AA (73 of 90 cases). The second,
dimensional maps of propagation patterns were con-
smaller peak in AA incidence occurred 3 to 4 years
structed with the NavX (St. Jude Medical, St. Paul,
after transplantation (19%; 17 of 90 patients), as
Minnesota) or CARTO (Biosense-Webster, Diamond
demonstrated in Figure 1. The incidence of post-
highest
incidence
in
the
immediate
post-
Bar, California) mapping systems. Irrigated ablation
operative AA peaked on the fifth post-operative day
catheters (Thermocool, Biosense-Webster) were used
(median of 5 days; IQR: 3 to 9 days) and reached 95%
for radiofrequency ablation.
by day 15 post–lung transplantation, as shown in
STATISTICAL ANALYSIS. Independent Student t test
Figure 1. Incidence of AF was higher than AFL in the
was used to compare normally distributed continuous
immediate post-operative period; however, incidence
variables. Wilcoxon-Mann-Whitney U test was used
of AFL increased as time passed (Figure 1).
to compare non-normally distributed continuous
POST-OPERATIVE AA: RISK FACTORS. Associations
variables. For comparison between categorical vari-
between patient characteristics and post-operative
ables, chi-square analysis (and Fisher exact test when
AA are summarized in Table 1. Compared with pa-
necessary) was performed.
tients without post-operative AA, those with post-
To identify possible risk factors for post-operative
operative AA had a significantly higher mean age
AA, univariable and multivariable analyses with lo-
(p ¼ 0.006), a greater number were males (p ¼ 0.001),
gistic regression models were performed. All study
and they had a higher mean body mass index
variables with p values <0.25 in univariable analyses
(p ¼ 0.038) but a lower rate of pulmonary hyperten-
were included in multivariable modeling procedures
sion (p ¼ 0.034). Analysis of pre-operative workups
(12).
revealed that patients with post-operative AA had a
The risk for developing late AA, new stroke, and
significantly
larger
left
ventricular
end-diastolic
death associated with post-operative AA was exam-
diameter detected by pre-operative echocardiogra-
ined by Cox regression modeling. The assumption of
phy (p ¼ 0.01) and lower invasive mPAP (p ¼ 0.040)
proportional hazard was met by use of graphical
than those without post-operative AA. Patients with
methods. All univariable predictors with p values
post-operative AA underwent double-lung trans-
<0.25 were included in the multivariable Cox
plantation at a higher rate (p ¼ 0.043) and required
regression models. The logistic and Cox proportional
vasopressors more frequently in the post-operative
regression analysis results are presented as odds ratio
period
(OR) and hazard ratio (HR) with 95% confidence in-
operative AA. Other patient characteristics and their
terval (CI), respectively.
ORs were not significantly different between the
All statistical analyses were performed with IBM
(p
¼
0.001)
than
those
without
2 groups (Table 1).
SPSS/PASW Statistics 20 (SPSS Inc., Chicago, Illinois).
A 2-tailed p value <0.05 was considered statistically
significant.
F I G U R E 1 Incidence of Post-Operative Atrial Arrhythmia
and Time to Onset After Isolated Lung Transplantation in
RESULTS
PATIENT CHARACTERISTICS. The final cohort com-
prised 293 patients with a mean age of 57 13 years.
Fifty-eight percent of patients were male. Primary lung
pathologies were obstructive lung diseases (group A,
26%), pulmonary vascular diseases (group B, 2%),
cystic fibrosis or immunodeficiency disorders (group C,
7%), and restrictive lung diseases (group D, 65%). The
median lung allocation score before lung transplantation was 38 (interquartile range [IQR]: 34 to 44).
Double-lung transplantation was performed in 63%
of the patients. Mean ischemic time was 205 66 min.
Patients Without Known History of Atrial Arrhythmia
post-
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Atrial Arrhythmia and Lung Transplantation
T A B L E 1 Post-Operative AA
No Post-Operative AA
(n ¼ 220)
With Post-Operative AA
(n ¼ 73)
Univariable
OR (95% CI)
p Value
Multivariable
OR (95% CI)
56 14
60 10
1.03 (1.01–1.06)
0.007
1.03 (1.00–1.07)
0.061
Male
114 (51.8)
54 (74.0)
2.64 (1.47–4.75)
0.001
1.97 (0.95–4.09)
0.069
BMI, kg/m2
25.1 5.6
26.7 5.2
1.05 (1.00–1.10)
0.040
1.05 (0.98–1.13)
0.174
60 (27.3)
17 (23.3)
1.00 (Reference)
–
–
–
5 (2.3)
1 (1.4)
0.71 (0.08–6.46)
0.758
–
–
Characteristics
Age, yrs
p Value
Pulmonary pathology
Group A, obstructive
Group B, vascular
17 (7.7)
4 (5.5)
0.83 (0.25–2.80)
0.764
–
–
138 (62.7)
51 (69.9)
1.30 (0.70–2.44)
0.406
–
–
Pre-operative O2 support, lpm
4 (3–6)
4 (3–6)
0.98 (0.93–1.04)
0.507
–
–
Ventilator/ECMO
6 (2.7)
1 (1.4)
0.50 (0.06–4.18)
0.519
–
–
Group C, immunologic
Group D, restrictive
History of CAD
88 (40.0)
33 (45.2)
1.20 (0.68–2.11)
0.534
–
–
History of hypertension
116 (52.7)
42 (57.9)
1.22 (0.71–2.07)
0.476
–
–
History of diabetes mellitus
69 (31.4)
17 (23.3)
0.66 (0.36–1.23)
0.191
0.48 (0.22–1.07)
0.074
History of dyslipidemia
86 (39.1)
37 (50.7)
1.60 (0.94–2.73)
0.083
1.58 (0.43–5.79)
0.491
History of smoking
88 (40.0)
33 (45.2)
1.24 (0.73–2.11)
0.434
–
–
4 (1.8)
1 (1.4)
0.75 (0.08–6.82)
0.798
–
–
1 (0–1)
1 (0–1)
0.80 (0.47–1.38)
0.429
–
–
0.8 0.3
0.8 0.3
1.20 (0.43–3.35)
0.726
–
–
History of stroke
CHADS2 score
Serum creatinine, mg/dl
Cardiovascular medications
Statins
76 (34.5)
31 (42.5)
1.40 (0.81–2.40)
0.224
0.83 (0.24–3.31)
0.866
Aspirin
50 (22.7)
20 (27.4)
1.28 (0.70–2.35)
0.418
–
–
Beta-blockers
40 (18.2)
13 (17.8)
0.98 (0.49–1.95)
0.943
–
–
ACEI
28 (12.7)
11 (15.1)
1.22 (0.57–2.59)
0.610
–
–
ARB
21 (9.5)
7 (9.6)
1.01 (0.41–2.47)
0.991
–
–
Calcium-channel blockers
36 (16.4)
13 (17.8)
1.11 (0.55–2.23)
0.774
–
–
Diuretic agents
68 (30.9)
18 (24.7)
0.73 (0.40–1.34)
0.311
–
–
0.873
Echocardiographic data
60 6
60 5
1.00 (0.96–1.05)
4.1 0.6
4.4 0.5
1.91 (1.16–3.15)
0.011
1.37 (0.75–2.50)
0.307
IVSD, cm
1.00 0.89
0.92 0.36
0.83 (0.50–1.39)
0.479
–
–
LAV, cm3
40 19
43 21
1.01 (0.99–1.03)
0.315
–
–
LAA, cm2
16 10
16 5
1.00 (0.97–1.04)
0.929
–
–
3.47 1.33
(26 10 mm Hg)
3.20 1.07
(24 8 mm Hg)
0.97 (0.93–1.00)
0.042
0.95 (0.91–0.99)
0.027
0.52 (0.28–0.96)
0.036
–
–
1.00 (0.94–1.06)
0.900
–
–
1.81 (1.02–3.24)
0.044
2.79 (1.36–5.75)
0.005
1.00 (0.99–1.02)
0.765
0.732
LVEF, %
LVEDD, cm
Right-sided heart catheterization data
mPAP, kPa
Pulmonary hypertension
PCWP, kPa
Double-lung transplantation
Lung allocation score
Ischemic time, min
Peak troponin, mg/dl
Vasopressor use
88 (43.6)
1.33 0.67
(10 5 mm Hg)
130 (59.4)
38.2 (33.6–45.0)
18 (28.6)
1.33 0.67
(10 5 mm Hg)
53 (72.6)
37.5 (34.5–43.8)
202 68
217 61
1.00 (1.00–1.01)
0.096
1.00 (0.99–1.01)
6.2 (3.5–12.5)
8.6 (3.6–15.1)
1.00 (1.00–1.01)
0.509
–
–
68 (93.2)
3.12 (1.18–8.21)
0.022
1.81 (0.55–5.98)
0.329
179 (81.4)
Values are mean SD, n (%), or median (range), unless otherwise noted.
AA ¼ atrial arrhythmia; ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin II receptor blocker; BMI ¼ body mass index; CAD ¼ coronary artery disease; CHADS2 ¼ stroke risk score based on
congestive heart failure history, hypertension history, age $75 years, diabetes mellitus history, and previous stroke or transient ischemic attack symptoms; CI ¼ confidence interval; ECMO ¼ extracorporeal
membrane oxygenation; IVSD ¼ interventricular septal diameter; LAA ¼ left atrial area; LAV ¼ left atrial volume; lpm ¼ liters per minute; LVEDD ¼ left ventricular end-diastolic diameter; LVEF ¼ left
ventricular ejection fraction; mPAP ¼ mean pulmonary artery pressure; OR ¼ odds ratio; PCWP ¼ pulmonary capillary wedge pressure.
In multivariable analysis, mPAP (OR: 0.95; 95% CI:
During the follow-up period, 64 deaths, 42 cases of
0.91 to 0.99; p ¼ 0.027) and double-lung trans-
late AA, and 3 strokes occurred.
plantation (OR: 2.79; 95% CI: 1.36 to 5.75; p ¼ 0.005)
POST-OPERATIVE LENGTH OF STAY. Median post-
were significantly associated with post-operative AA,
operative length of stay of all patients was 14 days
as shown in Table 1.
(IQR: 9 to 26 days). Patients with post-operative AA
POST-OPERATIVE AA: PROGNOSIS. Mean follow-up
had a significantly higher post-operative length of
after lung transplantation was 28 17 months.
stay than patients without post-operative AA (21 days
300
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AUGUST 2015:296–305
Atrial Arrhythmia and Lung Transplantation
[IQR: 13 to 32 days] vs. 12 days [IQR: 8 to 21 days];
median survival was 49 months. Significant uni-
p < 0.001).
variable predictors for death were history of smoking
OCCURRENCE OF LATE AA. After discharge from
index hospitalization for lung transplantation, late
AA occurred in 14% of the cohort (42 of 293
patients). The median interval from lung transplantation to late AA was 13.9 months (IQR: 2.4 to
30.8 months). Development of late AA was significantly higher in lung transplant recipients who had
post-operative AA than in recipients without postoperative AA (34% vs. 8%; p < 0.001). Differences
in characteristics of patients with and without late
AA and their associations with late AA are shown in
Table 2. In the multivariable model, post-operative
AA (HR: 13.52; 95% CI: 3.90 to 46.93; p < 0.001),
group B primary lung pathology (HR: 80.83; 95%
(HR: 1.71; 95% CI: 1.05 to 2.79; p ¼ 0.032), postoperative AA (HR: 1.71; 95% CI: 1.02 to 2.86;
p ¼ 0.043), and peak troponin post-operatively (HR:
1.01; 95% CI: 1.00 to 1.01; p ¼ 0.036). In multivariable
analysis, post-operative AA did not have a statistically significant association with death (HR: 1.55; 95%
CI: 0.87 to 2.77; p ¼ 0.139). Only history of smoking
(HR: 2.02; 95% CI: 1.17 to 3.49; p ¼ 0.012) and group D
primary lung pathology (HR: 2.50; 95% CI: 1.17 to 5.33;
p ¼ 0.018 compared with group A pathology) were
independently associated with death. There was no
significant association between mortality and early
AF, early AFL, late AA, late AF, or late AFL (p > 0.05
compared with no AA).
CI: 4.07 to 1604.32; p ¼ 0.004), history of CAD
AA MANAGEMENT AND EPS. A total of 25 patients
(HR: 3.89; 95% CI: 1.03 to 14.68; p ¼ 0.045), and pre-
underwent invasive EPS because of symptomatic AFL
transplantation use of statins (HR: 0.17; 95% CI: 0.05
(56%; 14 of 25 patients) or coexisting AFL and AF
to 0.65; p ¼ 0.009) were independently associated
(44%; 11 of 25 patients). Table 3 shows a summary of
with late AA, as shown in Table 2. There was no
the AA mechanisms. All PV antral arrhythmias could
significant association between specific type of post-
be linked to the native recipient PV antrum on the
operative AA (AF vs. AFL) and type of late AA (AF vs.
anastomotic side. Complex, multicomponent frac-
AFL) (p > 0.05). The mortality impact of late AA was
tionated local electrograms were recorded from the
analyzed by use of Kaplan-Meier statistics. There
PV antrum during PV antral focal tachycardias
was no significant difference in median survival
(Figures 2A and 2B) or PV antral re-entry (Figure 2E).
between
Electrical activity from the donor’s PV antrum was
patients
with
and
without
late
AA
(p ¼ 0.749; log-rank test).
NEW STROKE. New ischemic stroke occurred in 3
cases during the follow-up period. Two cases were in
the post-operative AA group (1.4 years and 3 years
post-transplantation, respectively), and another case
was in the no–post-operative AA group (2 years posttransplantation). All of these patients had no documentation of late AA, and their CHADS2 (congestive
heart failure history, hypertension history, age $75
years, diabetes mellitus history, and previous stroke
or transient ischemic attack symptoms) scores were 1;
therefore, they were not receiving anticoagulation
therapy. The CHADS2 score was not statistically
different between patients in the post-operative AA
group and those in the group without post-operative
AA (1 IQR 0 to 1 for both, p ¼ 0.574). The presence
of a post-operative AA was not associated with new
stroke after lung transplantation during follow-up
(univariable HR: 6.17; p ¼ 0.140).
either absent or dissociated from the atrial activations
(Figure 2C). In 3 patients, 2:1 activation patterns were
demonstrable from the PV antrum to the rest of the
left atrium, but activations were all within the recipient’s native tissue (Figure 2D). We did not find
evidence of electrical connections between the donor
and recipient tissue through the surgical anastomosis. Even after ablation of focal PV tachycardia, reentrant left atrial rhythms were commonly inducible
(Figure 2F). Multiple mechanisms were inducible in
most patients (80%), including multiple mechanisms
of anastomotic PV antral arrhythmia (Figure 3).
Overall, arrhythmias arising from the left atrium only
were present in 80% of the patients, and arrhythmias
arising exclusively from the right atrium were present
in 20%.
DISCUSSION
The primary results in our study were the bimodal
ALL-CAUSE MORTALITY. Overall, death occurred in
distribution of time to occurrence of new-onset AA
22% of the cohort (64 of 293 patients; median time to
after lung transplantation, analysis of risk factors for
death ¼ 3.1 months; IQR: 0.9 to 13.3 months), 30% in
new-onset AA, and analysis of its prognostic impli-
the post-operative AA group (22 of 73 patients) versus
cations. In addition, our study included the largest
19% in the group without post-operative AA (42 of
series
220 patients). Kaplan-Meier statistics showed overall
findings in lung transplant recipients who developed
in
the
literature
of
electrophysiological
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T A B L E 2 Late AA
No Late AA
(n ¼ 251)
With Late AA
(n ¼ 42)
56 14
61 11
1.04 (1.01–1.07)
0.015
1.03 (0.97–1.09)
0.364
Male
140 (55.8)
28 (66.7)
1.59 (0.83–3.02)
0.159
0.89 (0.27–2.93)
0.852
BMI, kg/m2
25.3 5.6
26.7 5.2
1.05 (0.99–1.11)
0.103
1.00 (0.90–1.10)
0.955
66 (26.3)
11 (26.2)
1.00 (Reference)
3 (1.2)
3 (7.1)
4.21 (1.16–15.26)
Characteristics
Age, yrs
Univariable
HR (95% CI)
p Value
Multivariable
HR (95% CI)
p Value
Pulmonary pathology
Group A, obstructive
Group B, vascular
–
0.028
1.00 (Reference)
80.83 (4.07–1604.32)
–
0.004
20 (8.0)
1 (2.4)
0.33 (0.04–2.57)
0.291
–
–
162 (64.5)
27 (64.3)
1.32 (0.65–2.67)
0.438
–
–
Pre-operative O2 support, lpm
4 (3–6)
2 (2–5)
0.97 (0.90–1.04)
0.369
–
–
Ventilator/ECMO
7 (2.8)
0 (0)
0.05 (0.01–>100)
0.586
–
–
Group C, immunologic
Group D, restrictive
History of CAD
99 (46.5)
22 (57.9)
1.54 (0.81–2.95)
0.188
3.89 (1.03–14.68)
0.045
History of hypertension
131 (52.2)
27 (64.3)
1.63 (0.87–3.06)
0.131
1.40 (0.42–4.65)
0.586
2.41 (0.73–7.96)
0.149
71 (28.3)
15 (35.7)
1.57 (0.83–2.95)
0.165
History of dyslipidemia
History of diabetes mellitus
104 (41.4)
19 (45.2)
1.30 (0.71–2.39)
0.404
–
–
History of smoking
103 (41.0)
18 (42.9)
1.04 (0.57–1.93)
0.891
–
–
History of stroke
5 (2.0)
0 (0)
0.05 (0.01–>100)
0.543
–
–
CHADS2 score
1 (0–1)
1 (1–2)
1.08 (0.59–1.99)
0.808
–
0.8 0.2
0.8 0.3
2.11 (0.67–6.70)
0.204
0.78 (0.12–5.10)
0.799
0.009
Serum creatinine, mg/dl
–
Cardiovascular medications
Statins
96 (38.2)
11 (26.2)
0.65 (0.32–1.28)
0.212
0.17 (0.05–0.65)
Aspirin
61 (24.3)
9 (21.4)
0.86 (0.41–1.81)
0.699
–
Beta-blockers
41 (16.3)
12 (28.6)
2.04 (1.04–3.99)
0.037
1.06 (0.28–4.01)
–
0.933
ACEI
33 (13.1)
6 (14.3)
1.26 (0.53–2.98)
0.606
–
–
ARB
25 (10.0)
3 (7.1)
0.62 (0.19–2.00)
0.423
–
–
Calcium-channel blockers
40 (15.9)
9 (21.4)
1.50 (0.72–3.14)
0.280
–
–
Diuretic agents
72 (28.7)
14 (33.3)
1.44 (0.75–2.73)
0.271
–
–
–
Echocardiographic data
60 6
60 4
1.01 (0.95–1.06)
0.851
–
4.2 0.6
4.3 0.6
1.25 (0.71–2.21)
0.447
–
–
IVSD, cm
1.00 0.83
0.89 0.41
0.73 (0.33–1.62)
0.443
–
–
LAV, cm3
40 19
44 18
1.01 (0.99–1.04)
0.176
LAA, cm2
16 9
17 8
1.01 (0.98–1.05)
0.360
–
–
3.47 1.20
(26 9 mm Hg)
3.60 1.60
(27 12 mm Hg)
1.01 (0.98–1.04)
0.508
–
–
LVEF, %
LVEDD, cm
0.99 (0.96–1.02)
0.543
Right-sided heart catheterization data
mPAP, kPa
Pulmonary hypertension
PCWP, kPa
Double-lung transplantation
Lung allocation score
Ischemic time, min
Peak troponin, mg/dl
89 (39.2)
17 (44.7)
1.18 (0.62–2.23)
0.620
–
–
1.33 0.53
(10 4 mm Hg)
1.33 0.80
(10 6 mm Hg)
1.01 (0.94–1.08)
0.874
–
–
157 (62.8)
26 (61.9)
0.98 (0.53–1.84)
0.959
–
–
37.8 (33.8–45.0)
38.2 (33.9–43.6)
1.00 (0.98–1.02)
0.795
–
–
204 67
213 63
1.00 (1.00–1.01)
0.361
–
–
7.0 (3.7–12.5)
8.0 (4.1–17.8)
1.00 (0.99–1.01)
0.728
–
–
Vasopressor use
212 (84.5)
35 (83.3)
1.26 (0.56–2.87)
0.575
–
–
Post-operative AA
48 (19.1)
25 (59.5)
6.08 (3.25–11.38)
<0.001
13.52 (3.90–46.93)
<0.001
Values are mean SD, n (%), or median (range), unless otherwise noted.
Abbreviations as in Table 1.
post-operative AA, giving important insight into
followed by a second, lower peak at 3 to 4 years post-
electrophysiological mechanisms.
transplantation. In contrast to post-operative AA,
AA INCIDENCE, RISK FACTORS, AND PROGNOSTIC
which was composed mainly of AF, late AA comprised
SIGNIFICANCE. We showed that the incidence of
AF and AFL equally. This distribution is consistent
new-onset AA after lung transplantation displayed a
with a previous study that revealed the second rise in
bimodal distribution, with the highest incidence
occurrence of AA was attributable to AFL rather than
in the early post-operative period, within 30 days,
AF (13). Our cumulative incidence of post-operative
302
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AUGUST 2015:296–305
Atrial Arrhythmia and Lung Transplantation
T A B L E 3 Mechanisms of Post-Operative Atrial Arrhythmia by
Electrophysiology Studies
Atrial fibrillation
Cavotricuspid isthmus–dependent atrial flutter
post-operative AA after lung transplantation is still
inconsistent (3–6). Differences in patient demo-
11 (44)
Atrioventricular node re-entrant tachycardia
evidence showing the risk of death associated with
graphics and management might have contributed to
3 (12)
this inconsistency.
12 (48)
Incisional right atrial flutter
6 (24)
We also showed that post-operative AA predicted
PV focal atrial tachycardia (juxta-anastomotic)
8 (32)
occurrence of AA after the index hospital discharge
PV antral re-entry (juxta-anastomotic)
5 (20)
(late AA), as reported previously (14). This finding
PV antral fibrillation (juxta-anastomotic)
6 (24)
Roof-dependent atrial flutter
may have important clinical implications, because
5 (20)
Perimitral atrial flutter
9 (36)
anticoagulation therapy in those with high risk for
stroke (e.g., CHADS2 score $2) and continuous
Mechanism categories
Single mechanism
ambulatory ECG monitoring could be considered in
5 (20)
Multiple mechanisms
patients
20 (80)
Exclusively right atrial mechanisms
Left atrial mechanisms
with
post-operative
AA
on
hospital
5 (20)
discharge. History of CAD and statin therapy have
20 (80)
also been identified as independent predictors for
late AA. These results were consistent with previous
Values are n (%).
literature, which demonstrated an association be-
PV ¼ pulmonary vein.
tween AF and CAD (19,20); however, the impact of
pre-operative statin use on new-onset AF after
AA was also similar to other previous studies that
reported a cumulative incidence of post-operative AA
at 19% to 28% before hospital discharge (4,13–16), 39%
within 14 days (3), and 34% by 4 weeks (5,16). In our
noncardiac surgery remains unsettled (21). In terms of
prognosis related to late AA, we did not detect a difference in survival between those with and without
late AA.
study, the peak incidence of post-operative AA was at
AA
5 days post-transplantation, which was consistent
ARRHYTHMOGENESIS. Our study provides a notable
MECHANISMS:
IATROGENIC
PV
ANTRAL
with the previous studies that reported the peak in-
mechanistic understanding of post-operative AA.
cidences of combined AA between 2 and 5 days after
Multiple mechanisms of AA were present, often in the
transplantation (3,4,15) but earlier than the peak
same patient. Typical peritricuspid AFL was the most
incidence of pure AFL, which was between 10 and 12
common arrhythmia, but usually it was present in
days (17).
combination with other mechanisms or was induced
In this study, we found invasive mPAP to be
during EPS. Electrophysiological mechanisms of AA
inversely associated with post-operative AA. Previous
can be roughly divided into right atrial mechanisms
literature reporting a relationship between pulmonary
(peritricuspid or right atrial incisional re-entry) and
artery pressure (PAP) and post–lung-transplantation
left atrial mechanisms (anastomotic PV antral, roof, or
AA is inconsistent and includes positive (5), no
perimitral re-entry). See et al. (13) determined that
significant (4), or even negative (18) relationships
anastomotic regions are common sites of focal activa-
between
tion; however, some AAs have also been reported to
invasive
PAP
and
post-operative
AA.
The explanation of this finding discrepancy are un-
originate from the donor’s side, with conduction
clear. Several theories for the inverse relationship
across the anastomosis, as previously suggested in
between PAP and post-operative AA have been pro-
both lung (13) and heart (22,23) transplantation. In our
posed, which include the protective effect of higher
study, we could not demonstrate such connectivity
right-sided heart pressures for development of
between heterologous tissues over the surgical anas-
post-operative AA secondary to dilation of the left
tomosis. In our series, the origin of focal PV antral
atrium (18).
arrhythmogenesis was consistently the native PV
With regard to prognosis, our study detected an
antrum, an otherwise well-documented origin of atrial
impact of post-operative AA on mortality, post-
arrhythmias (7). We propose that the surgical anasto-
operative length of stay, and occurrence of late AA
mosis creates an inflammatory process and atrial
after being discharged from the lung transplantation
stretching in the native PV antrum that leads to its
hospital stay; however, the association of post-
arrhythmogenesis. This is further supported by
operative AA and higher mortality became insignifi-
our observation that double-lung transplantation,
cant after adjustment in the multivariable analysis.
compared with single-lung transplantation, was asso-
These findings suggested that post-operative AA
ciated with an increased risk of post-operative AA.
was a marker of a higher-risk patient. The current
Surgically, double-lung transplantation involves a
Chaikriangkrai et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015
AUGUST 2015:296–305
Atrial Arrhythmia and Lung Transplantation
F I G U R E 2 PV Antral Arrhythmogenesis
Pulmonary vein (PV) antral tachycardia arose from the inferior aspect of the native and anastomotic left PV antrum (A, B). The site of origin had complex, prolonged
fractionated signals consistent with local conduction slowing, as marked by the red arrow (B). The donor PV was not part of the arrhythmia and had dissociated
signals (C). Focal activations arose from the native, anastomotic right inferior PV antrum with a 2:1 conduction pattern over the neighboring left atrium, as shown by the
red arrow (D). The site of origin was the native PV antrum, as shown by the close proximity of the recording sites, acquired by the circular multipolar catheter in
the same position. Coexisting roof-dependent (E) and perimitral flutter (F) in the same patient was seen, with an area of slow conduction (ablation site indicated by the
red arrow and asterisk in E). Abl ¼ ablation site; CS ¼ coronary sinus; d ¼ distal; HIS ¼ His bundle; IVDS ¼ interventricular septal dimension; p ¼ proximal; RA ¼ right
atrium.
more extensive area of cut-and-sew than single-lung
or intraoperative prophylactic interventions for AA;
transplantation, which theoretically would lead to a
however, further research is needed.
higher inflammatory response and greater atrial
STUDY LIMITATIONS. First, our study was a retro-
stretching than single-lung transplantation (24). The
spective observational cohort study, and therefore, a
specific propagation patterns are pleomorphic and
causal relationship could not be assumed; there
range from focal atrial tachycardias (often with 2:1
might still be a confounding effect despite our best
propagation) to secondary macro–re-entrant patterns
attempts to adjust for this by statistical means. Sec-
in the left atrium (perimitral, peritricuspid) and often
ond, to satisfy the definition of AA in our study, AF
coexist in individual patients. These findings may have
and AFL had to be documented in a 12-lead ECG. We
important clinical implications in consideration of
decided on this definition because we observed that
alternative lung transplantation surgical techniques
numerous artifacts on a telemetric ECG could appear
303
304
Chaikriangkrai et al.
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Atrial Arrhythmia and Lung Transplantation
F I G U R E 3 Multiple Expressions of PV Antral Arrhythmogenesis in 1 Patient
The anastomotic left pulmonary vein (PV) was the origin of focal atrial tachycardia (A), counterclockwise PV re-entry (B), clockwise PV antral re-entry (C), and figure-8
re-entry (D). AB ¼ ablation site; CS ¼ coronary sinus; d ¼ distal; p ¼ proximal; RA ¼ right atrium.
similar to an AA rhythm but were not confirmed on a
CONCLUSIONS
12-lead ECG. This could have led to underestimation
of AA incidence, especially during the acute post-
New-onset AA is common after adult lung trans-
transplantation period. AA is usually paroxysmal
plantation. Its incidence exhibited a bimodal dis-
and short-lived in nature; however, whether these
tribution
short-lived
the highest occurrence during the post-operative
AA
occurrences
affect
outcomes
is
over
time
from
transplantation,
with
not clear. To have the most accurate detection of AA,
period.
precise,
monitoring
prognostic implications for length of stay and oc-
must be used for all study participants, regardless of
currence of late AA after hospital discharge but not
symptoms or degree of clinical suspicion of AA, which
for survival. From our clinical and electrophysio-
is not practical clinically. Additionally, late AA in our
logical findings, we propose that the surgical anas-
study was mostly symptomatic late AA, because no
tomosis
ambulatory, continuous ECG monitoring was used in
anatomic distortion in the native PV antrum that
our patients. The patients were evaluated with a
leads to its arrhythmogenesis.
continuous
cardiac
rhythm
Development
creates
an
of
post-operative
inflammatory
AA
process
has
and
12-lead ECG on the basis of clinical suspicion of AA.
ACKNOWLEDGMENT The
Third, despite our relatively long-term follow-up,
help of Jennifer P. Connell, PH D, for critical reading
some of the more organized AA can certainly have
and editing of the manuscript.
authors
appreciate
the
much more delayed onset, and this may potentially
explain the differences in findings between our study
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
and previous literature. Finally, EPS were only per-
Miguel Valderrábano, Division of Cardiac Electro-
formed on a small proportion of selected patients on
physiology, Houston Methodist Hospital, 6560 Fan-
the basis of their clinical presentations; therefore, the
nin Street, Suite 1144, Houston, Texas 77030. E-mail:
findings may be limited in their generalizability.
[email protected].
Chaikriangkrai et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015
AUGUST 2015:296–305
Atrial Arrhythmia and Lung Transplantation
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: Post-
TRANSLATIONAL OUTLOOK: Although continuous
operative atrial arrhythmia is common after lung trans-
electrocardiogram monitoring was used for all patients
plantation. Development of post-operative atrial
during the entire hospitalization, underestimation of the
arrhythmia has prognostic implications for the occurrence
arrhythmia incidence could still have occurred, especially
of late atrial arrhythmia after hospital discharge but not
during the acute post-transplantation period, because
for survival. The arrhythmogenesis of post-operative
atrial arrhythmia is usually paroxysmal and short-lived in
atrial arrhythmia is from inflammatory processes at the
nature.
surgical anastomosis sites and anatomic distortion in the
native pulmonary vein antrum.
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KEY WORDS atrial arrhythmia, atrial
fibrillation, atrial flutter, lung transplant
305