Author + information
- Received January 21, 2015
- Revision received April 21, 2015
- Accepted May 6, 2015
- Published online August 1, 2015.
- Kongkiat Chaikriangkrai, MD∗,
- Soma Jyothula, MD∗,†,
- Hye Yeon Jhun, MD∗,
- Su Min Chang, MD‡,
- Edward A. Graviss, PhD§,
- Mossaab Shuraih, MD‖,
- Tapan G. Rami, MD‡,
- Amish S. Dave, MD, PhD‡ and
- Miguel Valderrábano, MD‡∗ ()
- ∗Department of Medicine, Houston Methodist Hospital, Houston, Texas
- †Methodist J.C. Walter Jr. Transplant Center; Houston Methodist Hospital, Houston, Texas
- ‡Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas
- §Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas
- ‖Texas Heart Institute/St. Luke's Episcopal Hospital, Houston, Texas
- ↵∗Reprint requests and correspondence:
Dr. Miguel Valderrábano, Division of Cardiac Electrophysiology, Houston Methodist Hospital, 6560 Fannin Street, Suite 1144, Houston, Texas 77030.
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 = 0.005) and lower mean pulmonary artery pressure (odds ratio: 0.95; p = 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 = 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.
For the past 2 decades, lung transplantation has been increasingly performed worldwide (1). Survival after lung transplantation has been reported in the U.S. Organ Procurement and Transplantation Network to be among the lowest of all adult solid organ transplantations (2). In addition to traditional risk factors for mortality, such as recipient history of diabetes mellitus or use of intravenous inotropes (1), the impact of atrial arrhythmia (AA) after lung transplantation on survival has been described recently (3–6); however, data from published literature have been inconsistent regarding an association between AA and post–lung transplantation mortality (3–6).
Although AA is common after thoracic surgery, the literature is sparse concerning AA after lung transplantation, specifically with regard to electrophysiological data. The currently accepted mechanistic paradigm of spontaneous atrial fibrillation (AF) in non–post-operative settings is that the pulmonary veins (PVs) play a major role (7), yet there is no specific evidence demonstrating an association between PVs and post-operative AA. However, the occurrence of AA after lung transplantation has been reported to be higher than that of other thoracic surgeries, for 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 design and patient selection
A retrospective observational study was conducted on consecutive patients who underwent isolated lung transplantation between June 2007 and February 2013. A total of 324 cases of isolated lung transplantation were identified. Patients with a pre-existing history of AA before transplantation were excluded (n = 31), which yielded a final cohort of 293 cases of isolated lung transplantation without prior history of AA. Institutional Review Board approval was obtained from Houston Methodist Hospital for this study.
Data collection and patient characteristics
Information on patient pre-operative demographics, operative data, post-operative clinical features, and clinical events during the follow-up period was collected through review of medical record and lung transplantation registry databases. We categorized primary lung pathology according to the United Network for Organ Sharing classification of lung diseases (11). Group A comprises obstructive lung diseases (e.g., emphysema); group B comprises pulmonary vascular diseases (e.g., primary pulmonary hypertension); group C is cystic fibrosis or other immunodeficiency disorders; and group D consists of restrictive lung diseases (e.g., idiopathic pulmonary fibrosis).
The presence of coronary artery disease (CAD) was determined by coronary angiography. Pulmonary hypertension was defined by mean pulmonary artery pressure (mPAP) of more than 3.3 kPa (25 mm Hg) obtained with a standard right-sided heart catheterization.
Clinical events were examined through systematic review of the medical record database, lung transplantation 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 were under 24-h ECG monitoring from hospital admission until discharge, and only AA that lasted at least 30 s was included. Late AA was defined as AF or AFL that occurred at any time during the follow-up period (≥30 days) after the index transplantation hospital discharge. This included routine follow-up clinic visits at 1, 3, 6, 9, and 12 months and then annually, emergency department visit records, and hospital admission records. AA rhythm was required to be documented in a 12-lead ECG to meet our criteria for late AA. All-cause mortality included any death after lung transplantation. Time to death was calculated from the date of lung transplantation to the date of death. Post-operative length of stay was calculated from the date of lung transplantation to the date of hospital discharge.
Electrophysiology studies and ablation
Patients with post-operative AA were treated medically with a ventricular rate-control strategy (n = 40) and transient administration of antiarrhythmic medications (n = 33). Those with AA that persisted or occurred beyond 1 month after surgery were considered for invasive electrophysiology studies (EPS) and ablation (n = 25). Briefly, vascular access was obtained through the femoral and jugular veins. Multipolar catheters were positioned in the coronary sinus or tricuspid annulus as needed. Intracardiac echocardiography was used to guide transseptal puncture, and 3-dimensional maps of propagation patterns were constructed with the NavX (St. Jude Medical, St. Paul, Minnesota) or CARTO (Biosense-Webster, Diamond Bar, California) mapping systems. Irrigated ablation catheters (Thermocool, Biosense-Webster) were used for radiofrequency ablation.
Independent Student t test was used to compare normally distributed continuous variables. Wilcoxon-Mann-Whitney U test was used to compare non-normally distributed continuous variables. For comparison between categorical variables, chi-square analysis (and Fisher exact test when necessary) was performed.
To identify possible risk factors for post-operative AA, univariable and multivariable analyses with logistic regression models were performed. All study variables with p values <0.25 in univariable analyses were included in multivariable modeling procedures (12).
The risk for developing late AA, new stroke, and death associated with post-operative AA was examined by Cox regression modeling. The assumption of proportional hazard was met by use of graphical methods. All univariable predictors with p values <0.25 were included in the multivariable Cox regression models. The logistic and Cox proportional regression analysis results are presented as odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI), respectively.
All statistical analyses were performed with IBM SPSS/PASW Statistics 20 (SPSS Inc., Chicago, Illinois). A 2-tailed p value <0.05 was considered statistically significant.
The final cohort comprised 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.
New-onset AA after lung transplantation: incidence and timing
New-onset AA occurred in 31% of patients (90 of 293) after lung transplantation. AA incidence exhibited a bimodal distribution, with the highest incidence in the immediate post-operative period (post-operative AA), which accounted for 81% of all AA (73 of 90 cases). The second, smaller peak in AA incidence occurred 3 to 4 years after transplantation (19%; 17 of 90 patients), as demonstrated in Figure 1. The incidence of post-operative AA peaked on the fifth post-operative day (median of 5 days; IQR: 3 to 9 days) and reached 95% by day 15 post–lung transplantation, as shown in Figure 1. Incidence of AF was higher than AFL in the immediate post-operative period; however, incidence of AFL increased as time passed (Figure 1).
Post-operative AA: risk factors
Associations between patient characteristics and post-operative AA are summarized in Table 1. Compared with patients without post-operative AA, those with post-operative AA had a significantly higher mean age (p = 0.006), a greater number were males (p = 0.001), and they had a higher mean body mass index (p = 0.038) but a lower rate of pulmonary hypertension (p = 0.034). Analysis of pre-operative workups revealed that patients with post-operative AA had a significantly larger left ventricular end-diastolic diameter detected by pre-operative echocardiography (p = 0.01) and lower invasive mPAP (p = 0.040) than those without post-operative AA. Patients with post-operative AA underwent double-lung transplantation at a higher rate (p = 0.043) and required vasopressors more frequently in the post-operative period (p = 0.001) than those without post-operative AA. Other patient characteristics and their ORs were not significantly different between the 2 groups (Table 1).
In multivariable analysis, mPAP (OR: 0.95; 95% CI: 0.91 to 0.99; p = 0.027) and double-lung transplantation (OR: 2.79; 95% CI: 1.36 to 5.75; p = 0.005) were significantly associated with post-operative AA, as shown in Table 1.
Post-operative AA: prognosis
Mean follow-up after lung transplantation was 28 ± 17 months. During the follow-up period, 64 deaths, 42 cases of late AA, and 3 strokes occurred.
Post-operative length of stay
Median post-operative length of stay of all patients was 14 days (IQR: 9 to 26 days). Patients with post-operative AA had a significantly higher post-operative length of stay than patients without post-operative AA (21 days [IQR: 13 to 32 days] vs. 12 days [IQR: 8 to 21 days]; p < 0.001).
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 post-operative 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% CI: 4.07 to 1604.32; p = 0.004), history of CAD (HR: 3.89; 95% CI: 1.03 to 14.68; p = 0.045), and pre-transplantation use of statins (HR: 0.17; 95% CI: 0.05 to 0.65; p = 0.009) were independently associated with late AA, as shown in Table 2. There was no significant association between specific type of post-operative AA (AF vs. AFL) and type of late AA (AF vs. AFL) (p > 0.05). The mortality impact of late AA was analyzed by use of Kaplan-Meier statistics. There was no significant difference in median survival between patients with and without late AA (p = 0.749; log-rank test).
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 post-transplantation). 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 = 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 = 0.140).
Overall, death occurred in 22% of the cohort (64 of 293 patients; median time to death = 3.1 months; IQR: 0.9 to 13.3 months), 30% in the post-operative AA group (22 of 73 patients) versus 19% in the group without post-operative AA (42 of 220 patients). Kaplan-Meier statistics showed overall median survival was 49 months. Significant univariable predictors for death were history of smoking (HR: 1.71; 95% CI: 1.05 to 2.79; p = 0.032), post-operative AA (HR: 1.71; 95% CI: 1.02 to 2.86; p = 0.043), and peak troponin post-operatively (HR: 1.01; 95% CI: 1.00 to 1.01; p = 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 = 0.139). Only history of smoking (HR: 2.02; 95% CI: 1.17 to 3.49; p = 0.012) and group D primary lung pathology (HR: 2.50; 95% CI: 1.17 to 5.33; p = 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).
AA management and EPS
A total of 25 patients underwent invasive EPS because of symptomatic AFL (56%; 14 of 25 patients) or coexisting AFL and AF (44%; 11 of 25 patients). Table 3 shows a summary of the AA mechanisms. All PV antral arrhythmias could be linked to the native recipient PV antrum on the anastomotic side. Complex, multicomponent fractionated local electrograms were recorded from the PV antrum during PV antral focal tachycardias (Figures 2A and 2B) or PV antral re-entry (Figure 2E). Electrical activity from the donor’s PV antrum was 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, re-entrant 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%.
The primary results in our study were the bimodal distribution of time to occurrence of new-onset AA after lung transplantation, analysis of risk factors for new-onset AA, and analysis of its prognostic implications. In addition, our study included the largest series in the literature of electrophysiological findings in lung transplant recipients who developed post-operative AA, giving important insight into electrophysiological mechanisms.
AA incidence, risk factors, and prognostic significance
We showed that the incidence of new-onset AA after lung transplantation displayed a bimodal distribution, with the highest incidence in the early post-operative period, within 30 days, followed by a second, lower peak at 3 to 4 years post-transplantation. In contrast to post-operative AA, which was composed mainly of AF, late AA comprised AF and AFL equally. This distribution is consistent with a previous study that revealed the second rise in occurrence of AA was attributable to AFL rather than AF (13). Our cumulative incidence of post-operative 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 study, the peak incidence of post-operative AA was at 5 days post-transplantation, which was consistent with the previous studies that reported the peak incidences of combined AA between 2 and 5 days after transplantation (3,4,15) but earlier than the peak incidence of pure AFL, which was between 10 and 12 days (17).
In this study, we found invasive mPAP to be inversely associated with post-operative AA. Previous literature reporting a relationship between pulmonary artery pressure (PAP) and post–lung-transplantation AA is inconsistent and includes positive (5), no significant (4), or even negative (18) relationships between invasive PAP and post-operative AA. The explanation of this finding discrepancy are unclear. Several theories for the inverse relationship between PAP and post-operative AA have been proposed, which include the protective effect of higher right-sided heart pressures for development of post-operative AA secondary to dilation of the left atrium (18).
With regard to prognosis, our study detected an impact of post-operative AA on mortality, post-operative length of stay, and occurrence of late AA after being discharged from the lung transplantation hospital stay; however, the association of post-operative AA and higher mortality became insignificant after adjustment in the multivariable analysis. These findings suggested that post-operative AA was a marker of a higher-risk patient. The current evidence showing the risk of death associated with post-operative AA after lung transplantation is still inconsistent (3–6). Differences in patient demographics and management might have contributed to this inconsistency.
We also showed that post-operative AA predicted occurrence of AA after the index hospital discharge (late AA), as reported previously (14). This finding may have important clinical implications, because anticoagulation therapy in those with high risk for stroke (e.g., CHADS2 score ≥2) and continuous ambulatory ECG monitoring could be considered in patients with post-operative AA on hospital discharge. History of CAD and statin therapy have also been identified as independent predictors for late AA. These results were consistent with previous literature, which demonstrated an association between AF and CAD (19,20); however, the impact of pre-operative statin use on new-onset AF after 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.
AA mechanisms: iatrogenic PV antral arrhythmogenesis
Our study provides a notable mechanistic understanding of post-operative AA. Multiple mechanisms of AA were present, often in the same patient. Typical peritricuspid AFL was the most common arrhythmia, but usually it was present in combination with other mechanisms or was induced during EPS. Electrophysiological mechanisms of AA can be roughly divided into right atrial mechanisms (peritricuspid or right atrial incisional re-entry) and left atrial mechanisms (anastomotic PV antral, roof, or perimitral re-entry). See et al. (13) determined that anastomotic regions are common sites of focal activation; however, some AAs have also been reported to originate from the donor’s side, with conduction across the anastomosis, as previously suggested in both lung (13) and heart (22,23) transplantation. In our study, we could not demonstrate such connectivity between heterologous tissues over the surgical anastomosis. In our series, the origin of focal PV antral arrhythmogenesis was consistently the native PV antrum, an otherwise well-documented origin of atrial arrhythmias (7). We propose that the surgical anastomosis creates an inflammatory process and atrial stretching in the native PV antrum that leads to its arrhythmogenesis. This is further supported by our observation that double-lung transplantation, compared with single-lung transplantation, was associated with an increased risk of post-operative AA. Surgically, double-lung transplantation involves a more extensive area of cut-and-sew than single-lung transplantation, which theoretically would lead to a higher inflammatory response and greater atrial stretching than single-lung transplantation (24). The specific propagation patterns are pleomorphic and range from focal atrial tachycardias (often with 2:1 propagation) to secondary macro–re-entrant patterns in the left atrium (perimitral, peritricuspid) and often coexist in individual patients. These findings may have important clinical implications in consideration of alternative lung transplantation surgical techniques or intraoperative prophylactic interventions for AA; however, further research is needed.
First, our study was a retrospective observational cohort study, and therefore, a causal relationship could not be assumed; there might still be a confounding effect despite our best attempts to adjust for this by statistical means. Second, to satisfy the definition of AA in our study, AF and AFL had to be documented in a 12-lead ECG. We decided on this definition because we observed that numerous artifacts on a telemetric ECG could appear similar to an AA rhythm but were not confirmed on a 12-lead ECG. This could have led to underestimation of AA incidence, especially during the acute post-transplantation period. AA is usually paroxysmal and short-lived in nature; however, whether these short-lived AA occurrences affect outcomes is not clear. To have the most accurate detection of AA, precise, continuous cardiac rhythm monitoring must be used for all study participants, regardless of symptoms or degree of clinical suspicion of AA, which is not practical clinically. Additionally, late AA in our study was mostly symptomatic late AA, because no ambulatory, continuous ECG monitoring was used in our patients. The patients were evaluated with a 12-lead ECG on the basis of clinical suspicion of AA. Third, despite our relatively long-term follow-up, some of the more organized AA can certainly have much more delayed onset, and this may potentially explain the differences in findings between our study and previous literature. Finally, EPS were only performed on a small proportion of selected patients on the basis of their clinical presentations; therefore, the findings may be limited in their generalizability.
New-onset AA is common after adult lung transplantation. Its incidence exhibited a bimodal distribution over time from transplantation, with the highest occurrence during the post-operative period. Development of post-operative AA has prognostic implications for length of stay and occurrence of late AA after hospital discharge but not for survival. From our clinical and electrophysiological findings, we propose that the surgical anastomosis creates an inflammatory process and anatomic distortion in the native PV antrum that leads to its arrhythmogenesis.
COMPETENCY IN MEDICAL KNOWLEDGE: Post-operative atrial arrhythmia is common after lung transplantation. Development of post-operative atrial arrhythmia has prognostic implications for the occurrence of late atrial arrhythmia after hospital discharge but not for survival. The arrhythmogenesis of post-operative atrial arrhythmia is from inflammatory processes at the surgical anastomosis sites and anatomic distortion in the native pulmonary vein antrum.
TRANSLATIONAL OUTLOOK: Although continuous electrocardiogram monitoring was used for all patients during the entire hospitalization, underestimation of the arrhythmia incidence could still have occurred, especially during the acute post-transplantation period, because atrial arrhythmia is usually paroxysmal and short-lived in nature.
The authors appreciate the help of Jennifer P. Connell, PhD, for critical reading and editing of the manuscript.
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.
- Abbreviations and Acronyms
- atrial arrhythmia
- atrial fibrillation
- atrial flutter
- angiotensin II receptor blocker
- coronary artery disease
- confidence interval
- electrophysiology study
- hazard ratio
- interquartile range
- mean pulmonary artery pressure
- pulmonary artery pressure
- pulmonary vein
- Received January 21, 2015.
- Revision received April 21, 2015.
- Accepted May 6, 2015.
- American College of Cardiology Foundation
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