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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. JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015 AUGUST 2015:296–305 297 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 Chaikriangkrai et al. JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015 AUGUST 2015:296–305 Atrial Arrhythmia and Lung Transplantation 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- Chaikriangkrai et al. JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015 AUGUST 2015:296–305 299 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 Chaikriangkrai et al. JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015 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 Chaikriangkrai et al. JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015 AUGUST 2015:296–305 301 Atrial Arrhythmia and Lung Transplantation 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 Chaikriangkrai et al. JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015 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. JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 4, 2015 AUGUST 2015:296–305 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. REFERENCES 1. Christie JD, Edwards LB, Aurora P, et al. Registry 9. 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