Transcriptional regulation of the postnatal cardiac conduction system heterogeneity.

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information. Integration of single-cell and spatial transcriptomics uncover region-specific markers and zonation patterns of expression. Network inference shows heterogeneous gene regulatory networks across the CCS. Notably, region-specific gene regulation is recapitulated in vitro using neonatal mouse atrial and ventricular myocytes overexpressing CCS-specific transcription factors, Tbx3 and/or Irx3. This finding is supported by ATAC-seq of different CCS regions, Tbx3 ChIP-seq, and Irx motifs. Overall, this study provides comprehensive molecular profiles of the postnatal CCS and elucidates gene regulatory mechanisms contributing to its heterogeneity.

Extraction of lumenless pacing leads from the His bundle and left bundle branch area: outcomes of the high-volume centre.

AIMS: The application of conduction system pacing (CSP) in clinical practice is growing, and the need for lead extraction will also increase. The data on outcomes and safety of CSP lead extraction are limited. The aim of this study was to assess procedural outcomes and safety of CSP lead removal. METHODS AND RESULTS: Forty-seven patients from the EXTRACT Registry with the indication for CSP lead removal were enrolled in the study conducted at the Department of Electrocardiology in Katowice, Poland. Extraction technique, outcomes, safety, and complication were evaluated. Forty-three (91.5%) leads were successfully removed, and 41 (87.2%) were removed with traction only. The dwelling time of 28 extracted leads was longer than 1 year, and the oldest extracted lead was implanted for 89 months. Seven (14.9%) leads were removed from the left bundle branch (LBB) area and 36 from the His bundle (HB). Transient complete atrioventricular block occurred during the procedure in two patients. In 27 out of 31 attempts (87.1%), new CSP leads were implanted: nine (33.3%) HB pacing leads and 18 (66.7%) LBB area pacing leads. CONCLUSION: The CSP lead extraction is safe and feasible with a low complication rate and high rate of CSP lead reimplantation.

Observational study of left bundle branch area pacing: implantation of the solia S lead using the selectra 3D sheath at an inclined angle.

BACKGROUND: Left Bundle Branch Area Pacing (LBBaP) is a cardiac pacing technique designed to mimic the natural conduction system of the heart. Traditional right ventricular apical pacing has been associated with increased risks of heart failure and atrial fibrillation. This study investigates the stability and safety of LBBaP using the Selectra 3D sheath (Biotronik) with an inclined angle for implanting the Solia S lead (Biotronik, SE & Co, KG). METHODS: A single-center retrospective study was conducted on 25 patients who underwent LBBaP implantation using the Selectra 3D sheath at our hospital. The procedure involved inserting the Solia S lead into the interventricular septum at an inclined angle. Surgical and postoperative data were collected, including the success rate, depth and angle of electrode insertion, complications, and follow-up data. RESULTS: The success rate of LBBaP implantation was 92%. The length of electrode insertion into the interventricular septum ranged from 12 to 23.0 mm, with an average of 18.1 ± 3.08 mm. The angle formed between the electrode and the septum ranged from 0° to 57.3°, with an average of 35.14°±14.31°. During the 3-month follow-up period, pacing parameters remained stable, and no complications were reported. CONCLUSIONS: LBBaP implantation using the Selectra 3D sheath with an inclined angle for the Solia S implantation demonstrates stability and safety. The procedure boasts a high success rate and offers an effective option for LBBaP implantation.

Conduction System Pacing: Hope, Challenges, and the Journey Forward.

PURPOSE OF THE REVIEW: Cardiac pacing has evolved in recent years currently culminating in the specific stimulation of the cardiac conduction system (conduction system pacing, CSP). This review aims to provide a comprehensive overview of the available literature on CSP, focusing on a critical classification of studies comparing CSP with standard treatment in the two fields of pacing for bradycardia and cardiac resynchronization therapy in patients with heart failure. The article will also elaborate specific benefits and limitations associated with CSP modalities of His bundle pacing (HBP) and left bundle branch area pacing (LBBAP). RECENT FINDINGS: Based on a growing number of observational studies for different indications of pacing therapy, both CSP modalities investigated are advantageous over standard treatment in terms of narrowing the paced QRS complex and preserving or improving left ventricular systolic function. Less consistent evidence exists with regard to the improvement of heart failure-related rehospitalization rates or mortality, and effect sizes vary between HBP and LBBAP. LBBAP is superior over HBP in terms of lead measurements and procedural duration. With regard to all reported outcomes, evidence from large scale randomized controlled clinical trials (RCT) is still scarce. CSP has the potential to sustainably improve patient care in cardiac pacing therapy if patients are appropriately selected and limitations are considered. With this review, we offer not only a summary of existing data, but also an outlook on probable future developments in the field, as well as a detailed summary of upcoming RCTs that provide insights into how the journey of CSP continues.

Early Experience of Left Bundle Branch Pacing with Lumenless Lead in a Single Center: A Case Series.

Left bundle branch pacing (LBBP) has been subject to increasing interest over the last few years due to its capacity for physiological conduction and its advantages compared to His bundle pacing. His bundle pacing has certain limitations, such as a small pacing area for the His bundle, a high threshold that leads to battery depletion, a low R-wave amplitude that may result in atrial or His oversensing, and ventricular signal undersensing. In this case series, four patients (two female and two male) aged 62.2 ± 8.4 years old with symptomatic sick sinus disease and no scar tissue in the interventricular septum underwent LBBP. All LBBPs were done with standard LBBP using a lumenless SelectSecure 3830 lead (Medtronic®, Minneapolis, USA) with a fixed helix. The lead parameters showed a good R-wave amplitudes (13 ± 7.4 mV) and a low threshold  (0.77 ± 0.17 V @ 0.4 ms). All patients were discharged on the next day. During follow-up period of 13.3 ± 12.9 months, all patients were well and no complications were noted. In conclusion, LBBP may be as an alternative of novel conduction pacing techniques and can be done relatively easy and safe, even with limited experience center.

Impact of Pulsed Electric Field Ablation on His Bundle Conduction: A Preclinical Canine Study.

BACKGROUND Pulsed field ablation (PFA), as a non-thermal ablation modality, has received increasing attention. The aim of this study was to evaluate the effect of PFA upon His bundle via its implementation with different voltages on the maximum His bundle potential in canines, providing scientific basis for clinical application. MATERIAL AND METHODS Pulsed electrical field energy was delivered from a ablation catheter to the maximum His potential of 7 dogs, followed by a series of electrogram and histology assessments. RESULTS The baseline AH and HV intervals were 55.3±3.7 ms (range, 53.0-59.0 ms), and 34.9±1.3 ms (range, 34.0-36.0 ms), respectively, which were elevated to 65.0±5.4 ms (range, 59.0-70.0 ms) and 35.7±2.7 ms (range, 34.0-37.0 ms) after PFA. Before ablation and immediately after the recovery of third-degree AVB, the AH interval was prolonged (P<0.05) while the HV interval remained unchanged (P>0.05). After ablation, all 7 canines experienced transient third-degree AVB, with a voltage-dependent duration. Masson staining results revealed no apparent damage in His bundle cells. CONCLUSIONS Within a certain voltage range of pulse electric field, ablation of the maximum His potential in canines can result in transient third-degree AVB, providing a new route for guiding safe ablation of para-Hisian arrhythmia.

Retrograde Conduction in Left Bundle Branch Block: Insights From Left Bundle Branch Pacing.

BACKGROUND: Biventricular pacing is a well-established therapy for patients with heart failure (HF), left bundle branch block (LBBB) and left ventricular (LV) dysfunction. Left bundle branch pacing (LBBP) has emerged as an alternative to biventricular pacing. OBJECTIVES: The aim of this study was to assess the retrograde conduction properties of the left bundle branch in patients with nonischemic cardiomyopathy and LBBB during LBBP and its clinical implications. METHODS: Patients undergoing successful LBBP for nonischemic cardiomyopathy with LV ejection fraction (LVEF) ≤35% and LBBB were included. Continuous recording of His potential was performed using a quadripolar catheter. Unidirectional block was defined as retrograde His bundle activation during LBBP with stimulus to His potential (SH) duration less than or equal to antegrade HV interval and bidirectional block as VH dissociation or SH duration greater than HV interval. HF hospitalization, ventricular arrhythmias, and mortality were documented. RESULTS: A total of 165 patients were included. The mean follow-up duration was 21.8 ± 13.1 months. Bidirectional block (group I) was observed in 82% (n = 136), and these patients were noted to have advanced HF stage and prolonged baseline QRS duration. Unidirectional block (group II) with intact retrograde conduction was observed in 18% (n = 29) and was associated with narrow paced QRS duration and higher LVEF during follow-up. Super-response (LVEF ≥50%) was observed in 54.4% (n = 74) in group I compared with 73.3% (n = 22) in group II (P = 0.03). The OR for LVEF normalization was 4.1 (95% CI: 1.26-13.97; P = 0.02), with unidirectional block compared with bidirectional block in patients with LBBB and LV dysfunction. Adverse clinical outcomes as measured by a composite of HF hospitalization, ventricular arrhythmias, and mortality were significantly higher in group I compared with group II (12.5% vs 0%; P = 0.04). CONCLUSIONS: Bidirectional block in LBBB was characterized by advanced HF symptoms, while unidirectional block was associated with better clinical outcomes after cardiac resynchronization therapy by LBBP.

A His bundle pacing protocol for suppressing ventricular arrhythmia maintenance and improving defibrillation efficacy.

BACKGROUND: The excitable gap (EG), defined as the excitable tissue between two subsequent wavefronts of depolarization, is critical for maintaining reentry that underlies deadly ventricular arrhythmias. EG in the His-Purkinje Network (HPN) plays an important role in the maintenance of electrical wave reentry that underlies these arrhythmias. OBJECTIVE: To determine if rapid His bundle pacing (HBP) during reentry reduces the amount of EG in the HPN and ventricular myocardium to suppress reentry maintenance and/or improve defibrillation efficacy. METHODS: In a virtual human biventricular model, reentry was initiated with rapid line pacing followed by HBP delivered for 3, 6, or 9 s at pacing cycle lengths (PCLs) ranging from 10 to 300 ms (n=30). EG was calculated independently for the HPN and myocardium over each PCL. Defibrillation efficacy was assessed for each PCL by stimulating myocardial surface EG with delays ranging from 0.25 to 9 s (increments of 0.25 s, n=36) after the start of HBP. Defibrillation was successful if reentry terminated within 1 s after EG stimulation. This defibrillation protocol was repeated without HBP. To test the approach under different pathological conditions, all protocols were repeated in the model with right (RBBB) or left (LBBB) bundle branch block. RESULTS: Compared to without pacing, HBP for >3 seconds reduced average EG in the HPN and myocardium across a broad range of PCLs for the default, RBBB, and LBBB models. HBP >6 seconds terminated reentrant arrhythmia by converting HPN activation to a sinus rhythm behavior in the default (6/30 PCLs) and RBBB (7/30 PCLs) models. Myocardial EG stimulation during HBP increased the number of successful defibrillation attempts by 3%-19% for 30/30 PCLs in the default model, 3%-6% for 14/30 PCLs in the RBBB model, and 3%-11% for 27/30 PCLs in the LBBB model. CONCLUSION: HBP can reduce the amount of excitable gap and suppress reentry maintenance in the HPN and myocardium. HBP can also improve the efficacy of low-energy defibrillation approaches targeting excitable myocardium. HBP during reentrant arrhythmias is a promising anti-arrhythmic and defibrillation strategy.

Mid-term performance of His bundle pacing and usefulness of backup leads.

Ventricular backup leads may be considered in selected patients with His bundle pacing (HBP), but it remains unknown to what extent this is useful. A total of 184 HBP patients were studied. At last follow-up, 147 (79.9%) patients retained His bundle capture at programmed output. His bundle pacing lead revision was performed in 5/36 (13.9%) patients without a backup lead and in 3/148 (2.0%) patients with a backup lead (P = 0.008). One patient without a backup lead had syncope due to atrial oversensing. Thus, implantation of ventricular backup leads may avoid lead revision and adverse events in selected HBP patients.

Left bundle branch area pacing in heart failure: A systematic review and meta-analysis with meta-regression.

INTRODUCTION: Left bundle branch area pacing is an alternative to biventricular pacing. In this study, we aim to summarize the available evidence on the feasibility, efficacy, and safety of left bundle branch block area pacing (LBBAP). OBJECTIVES: The study summarizes the available evidence on the feasibility, efficacy, and safety of left bundle branch block area pacing (LBBAP). BACKGROUND: Cardiac resynchronization therapy (CRT) reduced mortality and hospitalizations in heart failure (HF) patients with a left ventricular ejection fraction (LVEF) ≤ 35% and concomitant LBBB. Recently LBBAP has been studied as a more physiological alternative to achieve CRT. METHOD: A search of PubMed, EMBASE, and Cochrane databases were performed to identify studies examining the role of LBBAP for CRT in heart failure. Comprehensive meta-analysis version 4 was used for meta-regression to examine variables that contribute to data heterogeneity. RESULT: Eighteen studies, 17 observational and one randomized controlled trial (RCT) were examined. A total of 3906 HF patients who underwent CRT (2036 LBBAP vs. 1870 biventricular pacing [BVP]) were included. LBBAP was performed successfully in 90.4% of patients. Compared to baseline, LBBAP was associated with a reduction in QRS duration (MD: -47.23 ms 95% confidence interval [CI]: -53.45, -41.01), an increase in LVEF (MD: 15.22%, 95% CI: 13.5, 16.94), and a reduction in NYHA class (MD: -1.23, 95% CI: -1.41, -1.05). Compared to BVP, LBBAP was associated with a significant reduction in QRS duration (MD: -20.69 ms, 95% CI: -25.49, -15.88) and improvement in LVEF (MD: 4.78%, 95% CI: 3.30, 6.10). Furthermore, LBBAP was associated with a significant reduction in HF hospitalization (odds ratio [OR]: 0.44, 95% CI: 0.34, 0.56) and all-cause mortality (OR: 0.67, 95% CI: 0.52, 0.86) compared to BVP. CONCLUSION: LBBAP was associated with improved ventricular electrical synchrony compared to BVP, as well as better echocardiographic and clinical outcomes.

Conduction latency in left bundle branch pacing in heart failure patient.

Since the introduction of left bundle branch pacing (LBBP), a search for precise parameters confirming successful capture of conduction system was conducted. Most of the proposed electrocardiographic criteria refer to patients with narrow QRS complexes. We present a patient with heart failure in whom cardiac resynchronization was achieved using conduction system pacing. While measuring left ventricular activation time, an isoelectric interval of 74 ms between stimulus and R-wave appeared resulting in prolongation of V6 RWPT to 124 ms. Considering the immediate narrowing of QRS complexes following LBBP, the observed latency most probably reflects prolonged conduction time through the His-Purkinje system.

Result of the left bundle branch area pacing data collection registry, an international multicenter study of conduction system pacing with a Tendril STS 2088 stylet-driven lead.

INTRODUCTION: Left bundle branch area (LBBA) pacing (LBBAP) has been proposed as an alternative therapy option in patients indicated for cardiac pacing to treat bradycardia or heart failure. The aim of the study was to evaluate the safety and effectiveness of LBBAP in patients implanted with a Tendril 2088 stylet-driven lead. METHODS: The international retrospective data collection registry included 11 sites from 5 countries globally. Patients with attempted implants of the Tendril lead in the LBBA were followed for at least 6 months post the implant attempt. The primary safety and efficacy endpoints were freedom from LBBAP lead-related serious adverse events and the composite of LBBA capture threshold of ≤2.0 V and R-wave amplitudes ≥5 mV (or ≥value at implant), respectively. RESULTS: Of 221 patients with attempted implants of the Tendril 2088 lead in the LBBA, 91.4% (202/221) had successful implants for LBBAP. Regardless of the LBBAP implant success, all patients were followed for at least 6 months (8.7 ± 7.3 months). Baseline characteristics: 44% female, 84% ≥65 years old, 34% coronary artery disease, and 86% of primary indications for pacemaker implant. Both primary safety and effectiveness endpoints were met (freedom from LBBAP lead-related serious adverse device effects of 99.5% and electrical performance composite success rate of 93%). The capture thresholds in LBBAP at implant and 6 months were 0.8 ± 0.3 V@0.4 ± 0.1 ms and 0.8 ± 0.3 V@0.4 ± 0.1 ms. The rate of patients with capture threshold rise ≥1 V was 1.5% through 6 months. The R-wave amplitudes in LBBAP at implant and 6 months were 9.3 ± 3.2 mV and 10.6 ± 3.0 mV. CONCLUSIONS: This large multicenter study demonstrates that the stylet-driven Tendril™ STS 2088 lead is safe and effective for LBBAP with high success and low complication rates.

Septal venous channel perforation during left bundle branch area pacing: a prospective study.

AIMS: To characterize the diagnosis, frequency, and procedural implications of septal venous channel perforation during left bundle branch area pacing (LBBAP). METHODS AND RESULTS: All consecutive patients undergoing LBBAP over an 8-month period were prospectively studied. During lead placement, obligatory septal contrast injection was performed twice, at initiation (implant entry zone) and at completion (fixation zone). An intuitive fluoroscopic schema using orthogonal views (left anterior oblique/right anterior oblique) and familiar landmarks is described. Using this, we resolved zonal distribution (I-VI) of lead position on the ventricular septum and its angulation (post-fixation angle θ). Subjects with and without septal venous channel perforation were compared. Sixty-one patients {male 57.3%, median age [interquartile range (IQR)] 69.5 [62.5-74.5] years} were enrolled. Septal venous channel perforation was observed in eight (13.1%) patients [male 28.5%, median age (IQR) 64 (50-75) years]. They had higher frequency of (i) right-sided implant (25% vs. 1.9%, P = 0.04), (ii) fixation in zone III at the mid-superior septum (75% vs. 28.3%, P = 0.04), (iii) steeper angle of fixation-median θ (IQR) [19 (10-30)° vs. 5 (4-19)°, P = 0.01], and (iv) longer median penetrated-lead length (IQR) [13 (10-14.8) vs. 10 (8.5-12.5) mm, P = 0.03]. Coronary sinus drainage of contrast was noted in five (62.5%) patients. Abnormal impedance drops during implantation (12.5% vs. 5.7%, P = NS) were not significantly different. CONCLUSION: When evaluated systematically, septal venous channel perforation may be encountered commonly after LBBAP. The fiducial reference framework described using fluoroscopic imaging identified salient associated findings. This may be addressed with lead repositioning to a more inferior location and is not associated with adverse consequence acutely or in early follow-up.

Current of injury amplitude during left bundle branch area pacing implantation: impact of filter settings, ventricular pacing, and lead type.

AIMS: Monitoring current of injury (COI) during left bundle branch area pacing (LBBAP) implantation is useful to evaluate lead depth. Technical aspects for recording COI amplitude have not been well studied. Our aims were to evaluate the impact of high-pass filter settings on electrogram recordings during LBBAP implantation. METHODS AND RESULTS: Consecutive patients with successful LBBAP implantation had unipolar recordings of COI at final lead position at different high-pass filter settings (0.01-1 Hz) from the tip electrode during sensing and pacing, and from the ring electrode during sensing. Duration of saturation-induced signal loss was also measured at each filter setting. COI amplitudes were compared between lumenless and stylet-driven leads. A total of 156 patients (96 males, aged 81.4 ± 9.6 years) were included. Higher filter settings led to significantly lower COI amplitudes. In 50 patients with COI amplitude < 10 mV, the magnitude of the drop was on average 1-1.5 mV (and up to 4 mV) between 0.05 and 0.5 Hz, meaning that cut-offs may not be used interchangeably. Saturation-induced signal loss was on average 10 s at 0.05 Hz and only 2 s with 0.5 Hz. When pacing was interrupted, the sensed COI amplitude varied (either higher or lower) by up to 4 mV, implying that it is advisable to periodically interrupt pacing to evaluate the sensed COI when reaching levels of ∼10 mV. Lead type did not impact COI amplitude. CONCLUSION: High-pass filters have a significant impact on electrogram characteristics at LBBAP implantation, with the 0.5 Hz settings having the most favourable profile.

His potential injury as the end point of screwing by a continuous recording technique in His bundle pacing: A case report.

BACKGROUND: His bundle pacing (HBP) engaged electrical activation of both ventricles by stimulating the His-Purkinje network, which could avoid marked ventricles dyssynchrony. The lead was given three to five clockwise rotations at the site with the His potential to anchor the interventricular septum. In 2018, the Multicenter His Bundle Pacing Collaborative Working Group recommended that the His bundle capture threshold should be lower than 2.5 V/1 ms in non-pacing-dependent patients, and pacing-dependent patients should have a lower adjacent ventricular capture threshold as self-backup. Therefore, to avoid safety issues such as loss of capture caused by increased threshold, we believe that more stringent criteria should be adopted in patients with atrioventricular block (AVB). In previous studies, the connection cable needed to be disconnected during the screwing. When the procedure was finished, the performer found that the patients with His bundle injury could obtain a lower threshold than those without His bundle injury. Although no studies of new bundle branch block (BBB) or AVB by the acute His bundle injury was reported. However, It is worrying that the damage of His bundle seems random during the procedure. How to balance avoiding severe injury with a lower capture threshold? At present, we report a case of light His injury and lower His capture threshold under continuous intracardiac electrocardiogram monitoring.

Left bundle branch area versus conventional pacing after transcatheter valve implant for aortic stenosis: the LATVIA study.

BACKGROUND: Atrioventricular block (AVB) is a frequent complication in patients undergoing transcatheter aortic valve implantation (TAVI). Right apex ventricular pacing (RVP) represents the standard treatment but may induce cardiomyopathy over the long term. Left bundle branch area pacing (LBBAP) is a promising alternative, minimizing the risk of desynchrony. However, available evidence with LBBAP after TAVI is still low. OBJECTIVE: To assess the feasibility and safety of LBBAP for AVB post-TAVI compared with RVP. METHODS: Consecutive patients developing AVB early after TAVI were enrolled between 1 January 2022 and 31 December 2022 at three high-volume hospitals and received LBBAP or RVP. Data on procedure and at short-term follow-up (at least 3 months) were collected. RESULTS: A total of 38 patients (61% men, mean age 83 ±â€Š6 years) were included; 20 patients (53%) received LBBAP. Procedural success was obtained in all patients according to chosen pacing strategy. Electrical pacing performance at implant and after a mean follow-up of 4.2 ±â€Š2.8 months was clinically equivalent for both pacing modalities. In the LBBAP group, procedural time was longer (70 ±â€Š17 versus 58 ±â€Š15 min in the RVP group, P  = 0.02) and paced QRS was shorter (120 ±â€Š19 versus 155 ±â€Š12 ms at implant, P  < 0.001; 119 ±â€Š18 versus 157 ±â€Š9 ms at follow-up, P  < 0.001). Complication rates did not differ between the two groups. CONCLUSION: In patients with AVB after TAVI, LBBAP is feasible and safe, resulting in a narrow QRS duration, either acutely and during the follow-up, compared with RVP. Further studies are needed to evaluate if LBBAP reduces pacing-induced cardiomyopathy in this clinical setting.

Outcomes of combined left bundle branch area pacing with atrioventricular nodal ablation in patients with atrial fibrillation and pulmonary disease.

INTRODUCTION: Concomitant left bundle branch area pacing (LBBAP) with atrioventricular (AV) nodal ablation is emerging as a viable management option in atrial fibrillation refractory to medical management. Its viability in patients with pulmonary disease and atrial fibrillation is unknown. METHODS AND RESULTS: This is a retrospective, observational cohort study in consecutive patients who underwent concomitant LBBAP with AV nodal ablation with advanced pulmonary disease at the Cleveland Clinic Fairview Hospital between January 2019 and January 2023. Patient characteristics, comorbidities, and medication use were extracted via chart review. Rates of hospitalizations, medication use, and structural disease seen on echocardiography were compared before and after the procedure. There were 27 patients with group 3 pulmonary hypertension who underwent the procedure. In the 24 months preprocedure, there were 114 admissions for heart failure or atrial fibrillation compared to 9 admissions postprocedure (p < .001). Mean follow up was 17.3 ± 12.1 months. There were no significant complications or lead dislodgements. Echocardiographic characteristics were similar prior to and after pacemaker implantation. Use of medications for rate and rhythm control was common preprocedure, and was reduced dramatically postprocedure. CONCLUSION: This small, retrospective cohort study suggests concomitant LBBAP with AV nodal ablation may be safe and efficacious for management of atrial fibrillation in patients with advanced pulmonary disease.