Atrial arrhythmias following lung transplantation: A state of the art review

Abstract

Lung transplantation (LT) is now an accepted therapy for end stage lung disease in appropriate patients. Atrial arrhythmias (AA) can occur after LT. Early AA after LT are most often atrial fibrillation, whereas late arrhythmias which occur many months or years after LT are often atrial tachycardia. The causes of AA are multifactorial. The review begins with a brief history of LT and AA. This review further describes the pathophysiology of the AA. The risk factors, incidence, recipient characteristics including intra-operative factors are elaborated on. Since there are no clear and specific guidelines on the management of atrial arrhythmia following LT, the recommended guidelines on the management of AA in general are often extrapolated and used in the setting of post LT arrhythmia. The strategy of rate control vs rhythm control is discussed. The pros and cons of various drug regimen, need for direct current cardioversion and catheter ablation therapies are considered. Possible methods to prevent or reduce the incidence of AA after LT are considered. The impact of AA on the short-term and long-term outcomes following LT is discussed.

Key Words: Lung transplantation; Atrial arrhythmias; Atrial fibrillation; Atrial flutter; Atrial tachycardia; Rate control drugs; Rhythm control drugs; Catheter ablation; Post operative; Anticoagulation

Core Tip: While atrial arrhythmias (AA) after lung transplantation (LT) continue to be challenging, there has been an increase in our understanding of the mechanisms of these arrhythmias. Early arrhythmias are commonly due to atrial fibrillation and late arrhythmias are often atrial tachycardia. While the main treatment of early perioperative arrhythmia is drug therapy or cardioversion, the late stable arrhythmias can now be successfully treated by catheter ablation. Prophylactic measures to prevent arrhythmia are needed. In the absence of specific guidelines to treat AA after LT, further studies are needed to evaluate methods to prevent or reduce the incidence.

INTRODUCTION

Lung transplantation (LT) is now an accepted therapy for appropriate patients with end stage lung disease (ESLD) providing both symptomatic and survival benefits. While the overall results of LT are improving due to better understanding of the mechanisms of allograft rejection, molecular diagnostics, pathophysiology of primary graft dysfunction and surgical techniques, the survival and outcomes of LT is still not as good as those for other solid organ transplants such as heart, kidney, and liver transplantation. While the 1-year and 5-year survival rates for kidney, liver and heart are 90% and 80%[1], 89% and 76%[2], and 89% and 75%[3] respectively, LT lags a little behind with the 1-year and 5-year survival rates at 85% and 59%[4] respectively.

While there are many reasons specific to LT to explain the above figures, atrial arrhythmias (AA) that occur following LT by its adverse effects on haemodynamics and lung pathophysiology, is an important cause for increased mortality and morbidity after LT often leading to prolonged stay in the intensive care unit or in the hospital.

Post-operative atria arrhythmia (POAA) following LT in the early post-operative period includes most commonly atrial fibrillation (AF), followed by atrial flutter (AFL), atrial tachycardia (AT), and supra ventricular tachycardia (SVT). Late AA following LT are more often AT[5]. AF are more common in the early period comprising as much as 85% to 90% of early POAA[6].

Despite the publication of many case series, case reports and meta-analyses in the current literature regarding AA after LT, there are still no clearcut guidelines for the treatment of AF following LT. There are proponents for both rate control and rhythm control strategy with pros and cons for each strategy.

STRUCTURE OF THIS NARRATIVE REVIEW

In this comprehensive state of the art narrative review, the review structure is explained to aid clarity and allow seamless perusal of this manuscript. A historical perspective, followed by description of our understanding of the current scenario and eventual look at future considerations form the essential design of this review.

This review commences with a brief historical perspective of both LT and AA. AF which has been described centuries ago continues to be a formidable obstacle to this day. Then, the literature on AA in general and in the post-operative scenarios including the various strategies of AA treatments are looked at. The focus is on the various randomised trials of AF and the guidelines published for AA to see if some insights from these could be extrapolated to AA which occur following LT.

The definitions of the types of AF and LT are described; and the incidence, peak occurrence, risk factors, and the impact of AA following LT are reviewed. The mechanisms of AA are discussed. The pathophysiological effects of AA following LT and its adverse impact on the newly grafted lung particularly the effects on gas exchange and haemodynamics are elaborated on. The logical need for conversion to sinus rhythm (SR) in LT is explained.

Subsequently, we turn the attention to the currently available evidence of POAA following LT. The treatment options with outcomes are discussed in detail supported by available evidence. Finally, we conclude by looking at possible areas for further studies and research with a view to reducing or even preventing AA following LT.

LITERATURE SEARCH STRATEGY

The key words “lung transplantation”, “atrial arrhythmias”, “atrial fibrillation”, “atrial tachycardia”, “atrial flutter”, “catheter ablation”, “rate control”, “rhythm control”, “outcomes”, “mortality” were used to search PubMed database. Meta analyses, review articles, case series and reports were identified in English language. These articles were carefully studied and used in the preparation of this manuscript. There are 4 meta-analyses on AA following LT published so far which are listed in Table 1[5,7-9]. The great majority of the relevant literature is in the form of case series which are retrospective in nature. We identified 14 studies on catheter ablation (CA) for AA after LT most of which are single case reports or case series of small number of patients. Being a narrative review, the facts and conclusions from these articles are presented in a structured way along with an in-depth discussion. No statistical analysis was carried out.

Table 1 Meta-analyses of atrial arrhythmias following lung transplantation.

Ref.	Year	No. of studies	Total cases	AA	Conclusions
Saglietto et al[5]	2021	7	2068		This study looked only at late AA. Late atrial fibrillation rare–especially in double lung transplant (incidence rate only 0.9%/year)
Saad et al[7]	2017	12	3203	27%	Early AA increases mortality and hospital stay. Predictors of early AA are elderly age, male sex, smoking, HT, hyperlipidaemia, CAD, increased LA diameter, and restrictive lung disease
Waldron et al[8]	2017	9	2653	29.8%	AA was associated with higher mortality, longer hospital stays, increased need for tracheostomy
Fan et al[9]	2016	11	2094	31%	Risk factors include elderly age, male, prior AA, cystic fibrosis, interstitial lung disease, CAD, HT, hyperlipidaemia, LA size. Increases mortality and hospital stay

AA: atrial arrhythmias; CAD: Coronary artery disease; HT: Hypertension; LA: Left atrium.

HISTORICAL ASPECTS

Historical aspects of LT

LT is a complex surgical procedure and is now only just over 60 years old. After decades of experimental work in the animal laboratory, in 1963, James Hardy performed the first successful LT in humans[10]. It was a left single LT (SLT) and the patient survived only 18 days. Following this, there were attempts by surgeons, both in North America and Europe, to perform this operation[11]. There were no long term survivors and the main problem was bronchial dehiscence. Furthermore, immunosuppressive therapy was at its infancy. It was only 20 years later, in 1983, when Joel Copper from Toronto General Hospital, reported on the first successful long term survivor following LT[12] . It was a right SLT and the patient survived for 7 years following his operation. In 1986, the first en bloc double LT (DLT) was done which required cardiopulmonary bypass and tracheal anastomosis. To simply the operation further, DLT was performed as two separate sequential LT with a separate bronchial anastomosis for each lung[12]. Subsequently, this surgical procedure became standardised and was practised by surgeons across the globe.

Historical aspects of AA

The first ever reference to AA was with regards to AF. The historical aspects of AF has been well described by Lip and Beevers[13] in an article published in 1995. They suggest that perhaps the earliest reference to AF was by an eminent Chinese physician Huang TN Ching Su Wen between 1696 and 2598 BC. Harvey W in 1628 described AF in animals. There were other researchers who contributed along the way. Mackenzie J was the first to describe the loss of “a” wave in the pulse trace. The invention of electrocardiograph, in 1900, by Einthoven W was the pivotal point who recorded a tracing of AF. It was, then, Lewis T who first correlated the irregular pulse of AF in an electrocardiogram at the University College Hospital, London[14]. Subsequently, with technological advances and pharmacological progress, our understanding of the arrhythmia gradually improved. Despite the advances in electrophysiology and our improved understanding, there are still areas which need further research for better treatment of this elusive arrhythmia, especially after LT.

DEFINITIONS AND RELEVANT ASPECTS OF SURGICAL ANATOMY

To facilitate understanding of AA in the context of LT, some of the terms are defined and elaborated further.

Types of AA and AF

Based on the timing of occurrence, AA can be classified as early (peri-operative) and late AA. Most peri-operative AA are AF and are transient in nature. AF can be further classified into 4 types[15] as defined below.

Paroxysmal AF: The arrhythmia is episodic, lasting for less than 7 days and reverts to SR either spontaneously or due to intervention.

Persistent AF: The AF lasts for more than 7 days, but less than a year.

Long standing persistent AF: The arrhythmia lasts for more than a year.

Permanent AF: As the name implies, the arrhythmia is permanent not responding to any intervention and rate control strategy is followed in these patients.

Surgical aspects of LT: Emphasis on pulmonary vein and left atrial anastomosis

A brief description of the surgical aspect of SLT and DLT, particularly with reference to pulmonary vein (PV) and left atrial (LA) anastomosis is provided to aid the understanding of mechanisms of AA following LT.

Donor LA cuff (Figure 1A) is carefully fashioned just beyond the orifice of the two PVs (superior and inferior) and prepared to be anastomosed to a similar LA cuff in the recipient as described below.

Figure 1 Surgical steps of pulmonary vein anastomosis during lung transplantation. A: Donor left atrial cuff being fashioned on right side (viewed from the head end); B: Recipient pulmonary vein orifices fashioned as a single left atrial cuff on right side (viewed from the foot end); C: Left atrial cuff (pulmonary vein) of the donor being anastomosed to the recipient left atrial cuff (viewed from the foot end). LA: Left atrium.

SLT vs DLT: In SLT, one disease lung (either right or left) is explanted, and the hilum is dissected in preparation for the implantation of the donor lung. The bronchial stump and pulmonary artery (PA) stumps are fashioned, with a vascular clamp on the proximal part of the PA. The LA is dissected at the confluence of the superior and inferior PV. A vascular clamp is applied proximal to the confluence of the PV and the bridging tissue between the superior and inferior PV is divided (Figure 1B). This results in a single LA cuff which is then anastomosed (Figure 1C) to a similarly prepared donor LA cuff which receives the superior and inferior PV of the donor. This procedure, in effect, produces PV isolation (PVI) on the side of the operation. The contralateral side has the native lung with intact hilar connections with the heart.

In DLT, both the diseased lungs are explanted, and the donor lungs are sequentially implanted one after the other as described above using a LA cuff on both the donor and recipient ends. DLT, thus, results in complete PVI on both sides. Thus, establishment of surgical connection and continuity between donor and recipient PV is similar to various surgical maze procedures on LA described by Cox[16] and Cox et al[17], designed in principle to treat AF surgically.

This surgical aspect (unilateral vs bilateral PVI) explains the difference between SLT and DLT with respect to occurrences of AA following LT. Lee et al[18] report a decreased incidence of AA after LT in DLT patients, because the bilateral PV anastomosis blocks electrical impulses, whereas the incidence is higher in SLT. In contrast, however, a meta-analysis by Waldron et al[8] report a higher incidence after DLT. The authors explain the higher incidence by emphasising the fact that there is one more anastomosis with surgical oedema and inflammation–resulting in higher incidence of AA after LT.

Anatomical considerations of the left atrium: In an excellent article titled “Left atrial anatomy revisited”, Ho et al[19] describe in detail the anatomy of the left atrium which would be of interest and very valuable to arrhythmia surgeons and electrophysiologists. The LA muscular walls have the following regions–superior (roof), posterior, septal(medial), left lateral and anterior wall. The muscular fibres of the LA extend as a “sleeve” onto the external surfaces of the PV as they enter the LA. These muscular sleeves of the LA are associated with impulses originating and initiating AA. The PV orifices inside the lateral wall of the LA have an endocardial ridge separating them. The muscular sleeves of the LA wall encircle the PV. These inter-venous (between orifices of PV) muscular sleeves are closer to the epicardial surface. They crisscross from the anterior surface of the superior PV sleeve to the posterior surface of the inferior PV sleeve and vice versa. The above anatomical facts are of electrophysiological importance to both arrhythmia surgeon and electrophysiologist. The vestibule of the LA is the LA outlet surrounding the mitral annulus and the mitral isthmus is that portion between the inferior PV orifice and the attachment of the valve to the mitral leaflet.

During embryogenesis, there is enlargement of LA walls and the tissue at the ends of the PV get absorbed into the LA wall. This region becomes the posterior wall of the LA. This composite structure which includes both the LA wall along with the incorporated PV is the PV antrum. It is funnel shaped and includes parts of roof of LA and posterior LA wall between the PV. PV antrum isolation–which includes PVI and ablation of all activity in the posterior wall of LA has a higher procedural success rate with lesser incidence of recurrence[20].

Pathophysiology of AA and its adverse effects: The majority of the early POAA are AF. Hence, the pathophysiology and adverse effects of AF after LT will be considered here.

Background status of pulmonary blood flow in waitlisted patients prior to LT

Patients who undergo LT have ESLD with resultant elevated pulmonary vascular resistance (PVR) due to hypoxia. While awaiting an organ, the blood flow across the pulmonary vascular bed gradually reduces due to the high PVR and the inflow to the LA (preload) is chronically reduced. This often results in a small cavity left ventricle with low compliance and diastolic dysfunction.

Sudden changes in pulmonary blood flow following LT

A luxuriant flow across the newly grafted lungs(with low PVR) results in sudden increase in preload to the “unprepared” left heart resulting in pulmonary congestion and pulmonary oedema.

Other adverse effects on lungs due to AA: The loss of “atrial kick” and fall in cardiac output may cause hypotension, requiring adrenergic drugs which may compound the arrhythmogenic problem. Rapid ventricular rates reduce the ventricular filling times resulting in further pulmonary congestion.

Impact on the bronchial blood supply of the newly grafted lungs

Following LT, the dual supply to the lungs are lost and the bronchial tree–notably the bronchial anastomosis relies for nutrition on retrograde blood flow in the bronchial arteries, which in turn, are fed from the vascular plexus between PA and bronchial artery.

In a best-case scenario (i.e., in a stable LT patient), it is apparent that the donor bronchial ischemia is, at best, hypoxic. This hypoxia worsens in the case of AF which reduces both the oxygen content and pressure of the blood–which can impact long term healing. Furthermore, one may speculate that hypotension and hypoxia may even, possibly, lead to the development of chronic allograft lung dysfunction (CLAD), as has been described in patients with hypoxia due to venous thromboembolism[21].

Mechanisms of atrial arrhythmia: AA occurring early are often AF, while those occurring years after LT are AT.

Early AA-post operative “milieu” conducive to development of early AA

The pathogenesis of AA is often multifactorial. The “early” POAA which occurs in the peri-operative period are due to an “inflammatory milieu” with a background of heightened sympathetic drive. The operative trauma and resultant tissue oedema, pericarditis, electrolyte imbalance, haemodynamic instability requiring inotropes which are often arrhythmogenic result in a “milieu” conducive to the development of AA. The stretching of atrial walls which occur with fluid shifts, operative pain and proarrhythmic drugs may further contribute to the arrhythmia.

The landmark electrophysiological report in 1998 by Haïssaguerre et al[22] has demonstrated the PVs to be common sites for ectopic foci from which AA may commence. However, as demonstrated in the Figure 1, there is a complete transection and suturing of the donor and recipient LA cuff at the confluence of the PV–a surgical PVI, which is the surgical procedure for treatment of AF. Thus the scarring and fibrosis at the anastomotic site would be a barrier to the conduction of electrical impulses passing across it. Hence, logical reasoning suggests that in DLT with bilateral PVI, the incidence of AF should be much lower. However, this is not the case and, therefore, it follows that the fore mentioned “inflammatory, arrhythmogenic postoperative milieu” must play a major role in the pathogenesis of early post-operative AF (POAF).

Late AA following LT

Those AA which occur after 3 months to 12 months post LT are referred to as late AA. These are more often organised AT and not AF. With the passage of time, the early arrhythmogenic milieu settles and, early AF often reverts to SR with treatment. It is interesting to note that subsequent AA are often not AF, due to the “protective effect” of the surgical PVI done during the course of LT. This fact is supported by data from Lee et al[18], who reported only 1 instance of late AF 200 LTs (0.5% ); and See et al[23], who reported no instances of AF following LT after 1 year in 130 patients.

Chaikriangkrai et al[24] reported no difference between SLT and DLT as regards the late occurrence of AA, while Lee et al[18] report a significant reduction of late AA following DLT compared to SLT (0.5% vs 12.6%). It can be logically reasoned that in DLT the ectopic foci on both sides are blocked by bilateral PVI, whereas in SLT, the native lung has intact PV connections with LA, accounting for the increased late occurrence of AA.

PV anastomotic site paradox

The PV anastomotic site is both anti-arrhythmogenic and pro-arrhythmogenic, as discussed below.

During the LT operation, while the site of PV anastomosis, which involves a transmural suturing of the donor and recipient LA cuff (similar to the “cut and sew” Cox-Maze operation), heals and forms an electrical barrier to the conductance of impulses from ectopic sited in the PV and, hence, reduces the incidence of late AF.

Paradoxically, excess scarring in the PV anastomosis could also be foci of macro re-entrant AT[23]. In their electrophysiological study of 25 patients with AA after LT, Chaikriangkrai et al[24] report that the native PV is the main site of origin of AA. They suggest that surgical manipulation at the donor PV antrum incites an inflammatory response, which coupled with stretching of atrial walls, contributes to arrhythmogenicity. Interestingly, they also report a higher incidence of AA after DLT when compared to SLT. Uhm et al[25] describe late AT from PV anastomotic line during ultra-high density three-dimensional mapping and radio frequency (RF) CA which was performed 10 months after LT with no recurrence. Of note, they noticed electrical re-connections across anastomotic line for all 4 PVs.

Donor PV as site of origin for AA after LT

Nazmul et al[26] and Sanam et al[27] report cases where electrophysiological studies have demonstrated the site of origin of AA to be from the donor PV.

Possible role of antifibrotics in reducing scar burden at PV anastomosis site

Hussein et al[28] reported on reduced incidence of AF in patients taking mycophenolate as a part of their immunosuppression and suggest that its anti-fibrotic property might play a role. A randomised controlled trial (RCT)[29] demonstrated prevention of recurrence of AF after ablation with use of short term corticosteroids. Whether such an effect occur in post LT patients will require further studies.

Pulmonary venous conduction recovery across PV anastomosis causing late AF

Despite full thickness surgical scar, recovery of electrical conduction across the scar tissue has been reported–especially in patients with prior history of AF before LT.

In their elegant study, Hussein et al[28] report on the occurrence of recovery of electrical conduction across PV anastomosis following LT. Out of 755 LT patients, 51 patients had prior AF compared to 704 patients without prior AF. The incidence of late AF was 21% (11 out of 51) in patients with prior AF. In those without prior AF, the incidence of late AF was very low 2.8% (21 out of 704 patients). Recovery of electrical conduction was confirmed in patients who underwent CA. Despite ablation, AF recurred in these patients requiring further ablation.

Difference in the incidence between AA following heart transplantation and DLT

Heart transplantation (HT), during recipient cardiectomy, involves excision of the superior vena cava, ganglionic plexus around the heart and PV. In LT, the posterior LA wall and junction of PV are left in situ[30]. This explains the lower incidence of AA following HT of 10% to 20%, when compared to LT which has an incidence of 16% to 45%, as discussed in the following section.

Recent studies on POAF: POAF has been studied extensively in surgical patients including those undergoing general surgery, cardiac surgery, and thoracic surgery. However, LT patients form a small subset and in comparison, literature of POAF in the setting of LT is limited.

A meta-analysis[31] of POAF after non cardiac surgery included 28 studies enrolling 2612816 patients. Among patients with POAF, there was an increased risk of myocardial infarction, 30-day mortality and stroke in non-cardiac surgical patients. The risk of stroke was higher in nonthoracic surgical patients.

In a recent 2023 scientific statement, Chyou et al[32] define triggers and substrates for the development of AA in acute hospital setting.

Clinical aspects of AA following LT

Incidence of AA following LT: While AA is reported to affect 1.5% to 2% of the general population[33], the incidence of AA following LT is higher than the incidence of AA following HT and non-transplant surgery.

The incidence of AA following LT in various case series ranges from 16%[34] to 45%[35] among adult patients and the incidence among paediatric patients ranges from 11% to 15%[36,37]. The incidence of AA following LT in the 3 meta-analyses[7-9] ranges from 27% to 31%. These incidences are higher than the incidences of AA following HT[38,39] or other non-transplant thoracic surgery.

The incidence of POAF after non transplant surgery[40] is reported as follows: (1) Overall after cardiac surgery-30%; (2) Non-cardiac thoracic surgery[41]; and (3) Non-cardiothoracic general surgery-0.39%[42].

Table 2 lists the incidences of POAF following various types of surgeries. It can be seen in the table that the highest incidence of POAF occurs in those undergoing LT, which suggests that mechanisms which maybe unique to LT may play a role[32,33,36-38,40].

Table 2 Incidence of post operative atrial fibrillation after different categories of surgery.

Description	Incidence (%)
Transplant surgery
Lung transplantation[32,33]	17 to 46
Heart transplantation[36,37]	10 to 20
Thoracic surgery[38]
Overall cardiac surgery	Approximately 30
Coronary artery bypass surgery	Approximately 10 to 20
Thoracic (non-cardiac) surgery[38]
Overall	Approximately 15
Pneumonectomy	Approximately 30
General (non-cardiothoracic) surgery[40]	0.39

The peak incidence of early AA after LT is within 5 days of the operation[24].

Risk factors for the development of AA

Older age: This risk factor is perhaps the most identified factor across many studies[43-46] and one meta-analysis[9].

Male sex: It has been identified as risk factor for AA post LT by several studies[24,34,43,47,48].

High body mass index: A few studies[24,43,44,47] identified high body mass index as a risk factor. Of note, Mason et al[49] described extremes of weight as a risk factor for AF after LT.

Recipient lung disease: Several studies have identified ILD as a risk factor. However, Barnes et al[45] reported COPD to be a risk factor for AA. In contrast, a review by Roukoz et al[6] and a meta-analysis by Fan et al[9] report low incidence of POAF in patients with cystic fibrosis. Idiopathic PA hypertension has been reported as a risk factor for AA after LT[49]. Kim et al[44] report elevated right atrial (RA) pressure and prolonged ventilation (which causes high RA pressure)to be a risk factor.

Pre transplant PA pressure: The evidence is conflicting as regards the risk of POAF in the setting of high PA pressure (PAP). Chaikriangkrai et al[24] report an inverse relationship between PAP and AF after LT, resulting in higher incidence of POAA in patients with low PAP. Mason et al[49] found no effect of PAP on the occurrence of AA after LT. In contrast to the above finding, Jesel et al[50] reported pre-transplant elevated systolic PAP as a predictor for development of late AA following LT.

Type of operation-SLT vs DLT: Some authors[24,49,51] report higher incidence of AF in patients who underwent DLT. In contrast, Lee et al[18] report low incidence of late AA after DLT.

LA enlargement: increases risk of AA after LT[48,52]. LA enlargement and higher filling pressure leads to chronic stretching of the atrial musculature leading to fibrosis and electrical remodelling; thus resulting in a higher incidence of AA.

History of prior AF: It is a risk factor[6,48] for AA after LT. Xia et al[47] compared the incidence of POAF in patients with and without Maze procedure (which was performed during LT in patients with prior AF). The incidence of POAF was still higher in the Maze group and the authors therefore recommend ligation of LA appendage in this subgroup to prevent stroke.

EFFECT OF AA ON MORTALITY AFTER LT

Table 3[6-9,35,44,48,51,53-55] and Table 4[24,45,46,49,50,56] list the various studies reporting on the effect of AA on mortality after LT. The occurrence of AA after LT has been associated with increase in mortality. Three out of the 4 meta-analyses[7-9] report an increase in mortality due to AF after LT. Furthermore, there are several studies[51,53-55] which report an adverse effect of AA on the survival following LT. Of note, there are also a few studies[24,45,46,50,56] which did not find any effect of AA after LT on mortality.

Table 3 Studies demonstrating increased mortality due to atrial arrhythmias after lung transplantation.

Ref.	Year	Study type	Effect on mortality
Magnusson et al[53]	2022	Case series	Increase
Kim et al[44]	2020	Case series	Increase
Roukoz et al[6]	2018	Review	May be increased
Waldron et al[8]	2017	Meta-analysis	Increase
Saad et al[7]	2017	Meta-analysis	Increase
D'Angelo et al[54]	2016	Case series	Increase
Fan et al[9]	2016	Meta-analysis	Increase
Orrego et al[48]	2014	Case series	Increase
Henri et al[51]	2012	Case series	Increase
Isiadinso et al[35]	2011	Case series	Increase
Garcia et al[55]	2011	Case series	Increase

Table 4 Studies demonstrating no effect on mortality due to atrial arrhythmias after lung transplantation.

Ref.	Year	Study type	Effect on mortality
Barnes et al[45]	2020	Case control study	No effect
Campos Silva et al[46]	2018	Case series	No effect
Jesel et al[50]	2017	Case series	No effect
Raghavan et al[56]	2015	Case series	No effect
Chaikriangkrai et al[24]	2015	Case series	No effect
Mason et al[49]	2007	Case series	No effect

Conditions which confer protection against AA after LT

Elevated systolic PAP have been found to be protective against the development of AA after LT[34]. While the authors acknowledge that the precise reason for this observation remains unknown, they propose that the higher pressures in the PA leads to a smaller LA size, volume with resultant decrease in the LA stretching and thus reduce incidence of AA post LT.

Goals of treatment of AA

The main goals of treatment include: (1) Relief of symptoms; (2) Prevention of thromboembolism and stroke; and (3) Prevention of tachycardia induced cardiomyopathy.

After optimising general measures, these goals can be achieved by specific measures using either or both rate control and rhythm control strategy. However, achieving SR is more physiological with re-attainment of “atrial kick” and more importantly, preventing negative structural and electrical remodelling of the atria.

General measures, especially in early post-operative period, consist of addressing various factors which increase the likelihood of AA post-operatively. These measures include correction of electrolyte abnormalities–especially potassium (to maintain levels around 4.5 mEq/L) and magnesium; minimising the use of adrenergic drugs and weaning as early as possible, minimising sudden large fluid shifts, providing adequate pain relief[51], and maintaining adequate oxygenation with reassurance to allay anxiety.

Rate control methods[57] use drugs which block conduction across atrio ventricular node and include beta blockers (BB), calcium channel blockers (CCB) and digoxin. Rate control was the preferred strategy in the early 2000s with numerous trials demonstrating non-inferiority to rhythm control[58]. Some of these landmark trials include the AFFIRM trial[59], the STAF study[60], the PIAF trial[61] and RACE study[62]. These trials demonstrated only non-inferiority of rate control methods to rhythm control methods.

Rhythm control methods include anti-arrhythmic drugs (AAD), electrical cardioversion and CA. With improvements and advancements, rhythm control strategies started gaining popularity, with clinicians re-visiting rhythm control methods.

Guidelines for treatment of AF detailing the various options in different clinical scenarios have been provided by the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS), European Society of Cardiology and Canadian Cardiovascular Society (CCS). In an excellent review article, Cheung et al[63] has published in 2021 an updated comparison of the guidelines for the management of AF by AHA[64], CCS[65] and ESC[66]. Although there are similar recommendations by all three societies, the authors point out many differences between the guidelines and highlight the existing uncertainty in the management of AF.

More recently, the 2023 guidelines for the management of AF by ACC, AHA and HRS was published in 2024[67]. These guidelines updated the earlier 2019 and 2016 AHA guidelines for management of AF. These guidelines provide a class IIa recommendation for the use of BB and posterior pericardiotomy to prevent POAF.

RATE CONROL VS RHYTHM CONTROL STRATEGY

While rate control strategy has been shown to be non-inferior to rhythm control strategy, with no difference in outcomes in the general population, there is a trend towards rhythm control of AA recently. A recent article, in 2024, debates rate control strategy vs rhythm control strategy in the management of AF[68]. The authors conclude that rate control strategy would be appropriate in elderly patients, dilated LA, with multiple comorbidities and long-standing persistent AF. On the other hand, the authors recommend rhythm control strategy in young symptomatic patients with heart failure and in patients who are intolerant of rate control medications.

Han et al[69], in a recent meta-analysis and systematic review analysing early rhythm control vs rate control, conclude that adopting early rhythm control is associated with lower risk of heart failure, stroke, and mortality.

Table 5 lists the studies detailing the different treatment strategies for AA after LT[8,23,46,48,49,51,54,56]. A meta-analysis by Waldron et al[8], out of 791 patients with AF, 62% were treated with rate control drugs, while rhythm control drugs were used only in 47%. Several studies[23,48,49,54,56] use rate control strategy as first line for AA following LT. A study by Silva et al[46] used rhythm control as the first line, while Henri et al[51] used both strategies equally.

Table 5 Treatment strategy in various studies of atrial arrhythmias after lung transplantation, n (%).

Ref.	Year	Study type	Lung transplantation patients	Atrial fibrillation patients	Rate control	Rhythm control	Direct current cardioversion
Campos Silva et al[46]	2018	Case series	74	32 (43)	6	72	25
Waldron et al[8]	2017	Meta-analysis	2653	791 (30)	62	47	37
D'Angelo et al[54]	2016	Case series	652	198 (30)	42	6	33
Raghavan et al[56]	2015	Case series	131	46 (35)	87	53	35
Orrego et al[48]	2014	Case series	366	93 (25)	40	28	13
Henri et al[51]	2012	Case series	224	65 (29)	40	46	28
See et al[23]	2009	Case series	127	40 (32)	56	15	15
Mason et al[49]	2007	Case series	333	68 (20)	27	8	36

Rate control strategy

In the early 2000s, rate control therapy for AA was preferentially pursued.

The main drugs used for controlling ventricular rate includes: (1) BB; (2) Non dihydropyridine CCB (ND-CCB); and (3) Digoxin.

While digoxin is often used as a reserve, the targets of rate control differ between the guidelines. The American guidelines[64] recommend a target HR < 80/mt while the European[66] and Canadian[70] guidelines recommend HR around 110/mt.

Rate control is recommended in asymptomatic patients, elderly patients, those with markedly enlarged LA, long standing AF, those in HF (especially CCB).

BB: These agents work as both rate and rhythm control agents. The 2023 AHA guidelines provide a class IIa recommendation for use of short term beta blocker to prevent AF after cardiac surgery[67]. They also showed promise as an effective prophylactic agent against AF after LT in a study analysing 831 patients out of which 413 (47%) developed AF. It is noteworthy that prophylactic beta blocker therapy was associated with 93% reduction in the incidence of AF[71].

ND-CCB: Drugs such as Veerapamil and CCB achieve rate control by their effects on blocking conduction across the atrioventricular node. They are best avoided in patients with heart failure. These drugs may increase the serum levels of tacrolimus, a potent anti-rejection drug belonging to the calcineurin inhibitor class, and therefore need to be used with caution in LT patients. Frequent monitoring of tacrolimus levels may be required, if these drugs have to be used.

Digoxin: Digoxin has been used for more than 2 centuries[72] as a cardiac drug. It received approved by Food and Drug Administration for treatment of AF in 1954 and has been used for several decades since then[73]. Two Meta-analyses[74,75] report that use of digoxin in AF is associated with higher mortality. It is, therefore, only recommended as a second line therapy in patients who are intolerant of BB or ND-CCB, although the RATE-AF RCT[76] showed no difference between digoxin and bisoprolol.

Rhythm control strategy

This includes the following: (1) Electrical direct current (DC) cardioversion; (2) AAD; and (3) CA.

Electrical DC cardioversion: DC cardioversion was first reported as a therapy for AF in 1963[77]. It is most helpful in cases of haemodynamic instability in the immediate post-operative setting. Intravenous heparin or low molecular weight heparin is given prior to DC cardioversion. If available, a trans oesophageal echocardiogram to rule out thrombus in LA appendage is recommended. Electrical cardioversion for AF has been discussed elaborately in prior publications[78,79].

AAD: While the list of AAD are extensive, the following discussion will be limited to a few of the commonly used drugs.

Amiodarone: While amiodarone has an excellent rhythm controlling property in restoring and maintaining SR after AF[80] and is commonly used in the general population, its side effects can be significant. Pulmonary toxicity in particular is worrisome[81], especially in patients who have had LT as these lungs are “precious”.

Table 6 lists some of the publications discussing the use of amiodarone in AA following LT[34,35,43-45,53,81]. There are many studies which demonstrate safety of use in LT populations[43] and some authors[45] use amiodarone as the first-line of drug therapy in patients with AA after LT. Some studies do not mention any amiodarone related side effects[34,44], despite 89% (24/27) of patients with AA taking amiodarone[34]. However, there are also studies which caution against the use of amiodarone in patients after LT in view of increased mortality with use of amiodarone for AA after LT. Magnusson et al[53] noted an increase in mortality in patients taking amiodarone for AA after LT, but note that there was no relation of amiodarone intake and development of CLAD. Isiadinso et al[35] reports a high mortality of 64% (24/38 patients) who were treated with amiodarone for AA after LT.

Table 6 Studies describing amiodarone use in atrial arrhythmias following lung transplantation, n (%).

Ref.	Year	Study type	Atrial fibrillation patients	Amiodarone use	Notes
Magnusson et al[53]	2022	Case series	159	63 (40)	Amiodarone increase mortality but not chronic lung allograft dysfunction
Hathaway et al[43]	2021	Case series	102	77 (79)	No difference between amiodarone and others. Safe to use
Kim et al[44]	2020	Case series	46	6 (13)	No mention of any amiodarone related adverse effect
Barnes et al[45]	2020	Case control study	100	48 (alone), 26 (combination)	Recommend amiodarone as the first drug to be used
Malik et al[34]	2013	Case series	27	24 (88.9)	No mention of any amiodarone related adverse effect
Isiadinso et al[35]	2011	Case series	62	38 (65)	24 out of 38 (64%) of patients treated with amiodarone died
Diaz-Guzman et al[81]	2009	Case report	1	1 patient	Amiodarone pulmonary toxicity–resolved with cessation and steroids

Amiodarone pulmonary toxicity: The concerns of pulmonary toxicity[82] is the main issue, in addition to the other side effects of amiodarone such as hepatic, thyroid and ocular side effects. A prospective trial, reported in 1994, which compared amiodarone and verapamil in thoracic surgery patients had to be stopped due to life threatening adult respiratory distress syndrome in the amiodarone arm[83]. In an editorial, Mathru et al[84] discusses the possible mechanisms of amiodarone pulmonary toxicity (APT). In the post-operative lung, physiologic changes in the fluid status such increase pulmonary capillary pressure, alterations in endothelium, and impaired lymphatic flow may increase the likelihood of APT. High oxygen concentrations during lung operations may further accentuate the acute lung injury due to amiodarone. Epithelial–mesenchymal transition (EMT) is an event which leads to pulmonary fibrosis[85]. Weng et al[86] suggest that amiodarone may cause pulmonary fibrosis by the EMT and transforming growth factor β1 which can be increased by amiodarone. Klebsiella pneumoniae has been shown to trigger EMT in airway epithelial cells inducing fibrosis[87]. Thus, one can speculate that a co-existent infection with Klebsiella can, possibly, exacerbate the fibrotic response in the lungs.

The risk factors for developing APT include older age and duration of amiodarone therapy[88]. Daily amiodarone consumption of 400 mg for greater than 2 months or 200 mg for more than 2 years increases the risk of APT[89,90]. The diagnosis of APT is by exclusion. Prompt cessation of the drug is mandatory. Steroids help in resolution and may be needed for months to prevent recurrence.

Moreover, in the transplant population where immunosuppression is mandatory, the use of amiodarone can possibly increase the risk of infection.

Flecainide

In appropriate patients, flecainide is used as a first line drug for SVT/AF in some units. It must not be used in patients without coronary artery or structural heart disease due to increased mortality. Of note, the CAST trial[91] was stopped before completion due to increased mortality in the flecainide arm. Furthermore, it is vital that AV nodal blocker (BB or CCB) is administered concurrently with flecainide to prevent rapid ventricular rate. Echt et al[92] describe the pharmacology, the guidelines for administration and use of flecainide.

Sotalol

Sotalol is used as rhythm control drug. In a meta-analysis by Kerin et al[93], sotalol was found superior to placebo and amiodarone in restoring ad maintaining SR. However, it causes QT prolongation and torsade de pointes as reported in PAFAC trial[94,95]. The QT interval of each patient must be checked prior to administration of this drug.

Ibutilide

Ibutilide is used as a single dose (1 mg) intravenous drug for rapid termination of AF or AFL[96]. A second dose may be repeated if there is no response in 30 minutes. It can be used in patients with structural heart disease, however, it causes QT prolongation and hence avoided in patients with QT interval more than 440 msec.

Anticoagulation strategy during DC cardioversion: Anticoagulation prior to DC cardioversion is needed to reduce the incidence of stroke[97]. In haemodynamically unstable patients due to AF with fast ventricular rate of short duration (less than 48 hours), intravenous heparin or subcutaneous low molecular weight heparin can be used prior to DC cardioversion. In stable patients with AF of longer duration, the recommendation is 3 weeks of oral anticoagulants prior to DC cardioversion. Vitamin K antagonists (VKA) were traditionally used for anticoagulation, however now non-vitamin K antagonist oral anticoagulants (NOAC) are being increasingly used. Use of transesophageal echocardiogram to assess for thrombi in the LA appendage is recommended, whenever possible. However, transesophageal echocardiogram may cause oesophageal perforation and shock after LT[98] and heart LT[99]. Of note, Roukoz et al[6] report their practice now of using cardiac magnetic resonance imaging in preference to transesophageal echocardiogram given the risk of oesophageal perforation. Post DC cardioversion, VKA or NOAC are recommended for at least 4 weeks[100].

CA: Following surgical ablation operations such as maze procedure, first described by Cox in 1987[101], less invasive ablative procedures have developed. One of the pioneers in developing CA is Scheinman and Rutherford[102] who initially used DC for ablation. Subsequently, radiofrequency energy was developed. The history and development of CA has been well chronicled[102-104].

As regards CA for AA following LT, the publications are limited to case series and case reports only. LT offers unique insights to the understanding of mechanisms of AA and the role of CA in their treatment. CA are used when medical therapy fails and are mostly done for late AA, most of which are AT and AFL. An review article on management of AA after lung transplant[105] considers electrophysiological interventions on late AA after LT, in addition to medical management.

Case series on CA for AA after LT: Table 7 lists the case series of patients with AA after LT who were treated by CA[23,24,28,52,106]. There are 5 case series[23,24,28,52,106] published on CA for AA after LT. These case series which were published between 2009 and 2021 include 55 patients. As regards timing of intervention, CA were often done more than 6 months after LT, except 1 patient who had CA as early as 28 days after LT. Most of the AA were AT. Recurrence of AT have been reported[23,28,52], requiring re-ablation. Freedom from recurrence of AA has been reported in 75% of patients in 3 case series[23,28,106].

Table 7 Case series on catheter ablation for atrial arrhythmias following lung transplantation, n (%).

Ref.	Year	LT patients	AA patients, n (% of LT)	CA patients, n (% of AA)	Time to CA	Outcome
Mariani et al[106]	2021			15		75% free from recurrence at median of 19 months (6-86 months)
Hussein et al[28]	2017	755	32 (4.2)	8 (25)	43 months (20-54 months)	At 3 years, 6 (75) stayed in SR. 2 patients had recurrence and 1 had re-do CA
Chaikriangkrai et al[24]	2015	293	Early 48 (16.3), late 42 (14.3)	25 (8.5)		80% of late AA were from left atrium. 20% of late AA were from right atrial
Azadani et al[52]	2011	269	35 (13)	3 (8.6)	Patient (no. 1) = 1 year. Patient (no. 2) = 28 days. Patient (no. 3) = 18 months	Patient (no. 1) = no recurrence at 1 months. Patient (no. 2) = no recurrence at 6 months. Patient (no. 3) = recurrence at 8 months and had second ablation
See et al[23]	2009	127	40 (31.5)	4 (12)		2 patients reverted to SR. 1 patient had 3 prior ablations. All 4 patients remained free of AA, 3 without anti arrhythmic drugs

AA: Atrial arrhythmias; CA: Catheter ablation; LT: Lung transplantation; SR: Sinus rhythm.

Case reports on CA for AA after LT: Table 8 lists the individual case reports where CA was used for AA after LT. There are 9 case reports of CA for AA after LT published till date[25-27,107-111].

Table 8 Case reports on catheter ablation for atrial arrhythmias following lung transplantation.

Ref.	Year	Type of atrial arrhythmias	How long after lung transplantation	Site of foci	Type of catheter ablation	Outcome	Notes
Guan et al[109]	2020	AT	10 years	Left PV-LA anastomosis	Radiofrequency	AT terminated	No recurrence in 3 months
Uhm et al[25]	2018	AT	10 months	PV anastomotic line–left side	RFCA	Reverted	No recurrence in 6 months. Electrical reconnection in all 4 PVs
Baykaner and Cooper[110]	2018	AFL	7 years	Left PV site	RFCA	Reverted
Itoh and Yamada[111]	2017	AFL	14 years	PV-LA right	RFCA	Reverted	Electrical reconnection noted
Sanam et al[27]	2015	AFL	9 years	Donor PV	RFCA	Reverted
Nazmul et al[26]	2011	AT	1 year	Left upper PV	RFCA	Reverted	No recurrence in 4 years
Nguyen and Marcus[107]	2010	AFL	2 months	PV-LA	RFCA	Reverted	No recurrence in 6 months
Sacher et al[108]	2008	AT	10 months	LA	RFCA	Reverted

AFL: Atrial flutter; AT: Atrial tachycardia; LA: Left atrium; PV: Pulmonary vein; RFCA: Radiofrequency catheter ablation.

Timing of CA after LT: Among these 9 case reports, some case reports[25,26,107,108] describe CA done within 18 months of LT (ranging from 2 months to 18 months). There are also case reports[27,109-111] which describe CA done many years (ranging from 7 years to 14 years) after LT. While the all patients reverted to SR, electrical reconnection of PV across suture lines were demonstrated in 2 case reports[25,111].

These studies demonstrate that CA has now evolved to be a safe procedure for those patients who develop late AA not responding to medical therapy.

Methods to prevent AA after LT: General measures such as meticulous attention to electrolyte levels, oxygenation, pain relief, optimal fluid balance and minimal use of adrenergic drugs when needed would prevent precipitation of AA, in the setting of a “pro-arrhythmogenic milieu”.

Specific methods aimed at preventing or even reducing the incidence of AA after LT have not been successful. The incidence continues to remain the same even now. Some centres report that prophylactic use of drugs such as ND-CCB (diltiazem), BB (metoprolol) and digoxin has not been effective in reducing the incidence of AA after LT. Whited et al[112] reported a pilot study where intra-operative application of amiodarone gel was performed on the PV anastomotic suture line. This small study appeared to reduce the incidence of POAA when compared to historical controls. Further data is needed prior to consideration as a prophylactic measure.

In a letter to the editor, Bazaz et al[113] describe an intra-operative technique during PV anastomosis where they used a bipolar radiofrequency clamp to “electrically” isolate the PV anastomotic line. They used this technique in a 65-year-old man who had intra-operative AF, but no AF for until 2 years follow-up after DLT.

Narayan[114] in his critical appraisal of posterior left pericardiotomy for prevention of AF (PALACS) trial[115], concludes by confirming that “it is an important trial in the right direction” towards preventing POAF, by a simple procedure which prevents pericardial collection and POAF. This simple procedure while not reported in LT may be considered to see if the prophylactic effect of this procedure is effective in LT patients as well.

Suggested approach to treatment of AA following LT

Attention to the general measures as described above must prioritise the post-operative management in preventing AA.

In the event of AA, all corrective general measures-including potassium and magnesium level optimisation, fluid balance, oxygenation and pain relief are undertaken.

In case of stable patients, rate control strategy may be undertaken safely along with anticoagulation. BB would be the first line drugs. In case of haemodynamic instability, electrical DC cardioversion may be considered. Intravenous dose of ibutilide may also be considered, provided the QT intervals are not prolonged.

Rhythm control is needed when rate control is ineffective or in the presence of heart failure. Flecainide would be a preferred drug–provided there is no structural heart disease or coronary artery disease and concomitant AV nodal blocking drug must be administered.

Amiodarone, although used as a first line drug in many units, is preferably avoided. It may only be reserved until other options have been considered and exhausted, given its risk profile, including mortality.

Late AA when not responding to AAD or presence of intolerable side effects, may be referred for CA, which has been demonstrated to be effective and safe in experienced units.

Drugs, combinations and their safety profile

After undertaking all the general measures such as electrolyte correction, optimising oxygenation, allaying anxiety, and providing pain relief; attention is then turned to drug therapy. Frequently a combination of drugs may be required in some patients with AF after LT.

Flecainide and BB: Flecainide often requires the use of BB or CCB because of likelihood of tachycardia. Also, structural heart disease must be ruled out, prior to initiating therapy with flecainide. They must be avoided in patients with prolonged QT interval.

Flecainide and CCB: Patients intolerant of BB may be treated with CCB. However, CCB are best avoided in patients with heart failure. Concomitant use of CCB with tacrolimus can increase serum levels of tacrolimus and this drug combination is avoided if possible. In case of necessity to use CCB, serum tacrolimus levels must be monitored. Furthermore, patients with LT have a propensity to develop paralytic ileus postoperatively due to neuropraxia of vagal nerves. Since CCBs like verapamil causes constipation due to smooth muscle relaxation, abdominal distention must be watched out for.

Amiodarone: It is used as drug of first choice for AF after LT in some units[45]. However, it is avoided in many units in view of its pulmonary toxicity. Given that the transplanted lungs are precious, many units avoid amiodarone as a therapy for AF. However, it may have to be used in cases of resistant AF, when a watchful policy has to be adopted.

Digoxin: By virtue of its positive ionotropic effect, it can be used in patients with heart failure.

Special clinical situations

The use of either rate or rhythm control has been discussed so far. This section deals with clinical situations at a high risk of developing AA or those having persistent AF despite treatment.

Patient at high risk of developing AF: It is well known that patients with dilated LA, systemic hypertension and ventricles with reduced compliance are at higher risk of developing POAF. The usage of BB in these patients would prove to be beneficial. In those intolerant of BB CCB may be used, provided there is no heart failure. Such patients must be closely monitored looking at maintenance of correct levels of potassium and magnesium and all other general measures. Ensuring adequate pain relief and avoidance of hypoxia is of paramount importance. Use of statins and vitamin D supplements, by virtue of their anti-inflammatory effect, have been reported to reduce the incidence of POAF[116].

Persistent AF: Some patients do not respond to the usual drugs and rate control has to be achieved because long standing tachycardia, by itself, can depress left ventricular function. In such patients, attempts must be made to identify any correctable cause. Pericardial effusion can be a cause of persistent AA and an echo cardiogram is mandatory to rule out the same. Significant pericardial collections may require drainage percutaneously or surgically. Co-existent sepsis, renal or liver failure have to be treated.

Some patients may need a combination of drugs including BB, flecainide, amiodarone, digoxin, and sotalol. Review of the drug chart daily and looking for the drug interaction and safety profile becomes mandatory. Patients with acute liver failure must not be given amiodarone. Combination of beta blocker, amiodarone or digoxin need constant monitoring of the heart rate and to avoid significant bradycardia. DC cardioversion may be needed after ensuring all general measures have been taken. In stable patients anticoagulation must be given for a few weeks prior to DC cardioversion. Transoesophageal echocardiogram is an alternate approach to rule out LA clot prior to DC cardioversion in patients who can’t wait long.

Future directions

A survey on early AF after LT, reported by Simon et al[117], reported that standardised and protocolised treatment was practised only in 4 of 12 units. Given that the incidence is still common, this study emphasises the need for further research to develop protocols for prevention, early recognition and treatment of this common condition after LT.

During medical management, the rhythm control strategy is more physiological and logically more appealing. Unfortunately, it suffers from significant adverse effects of AAD. Development of newer molecules of AAD without their side effects would be of great benefit to this group of patients and further research involving prospective safety studies is needed.

“Out-of-the-box” lateral thinking in the surgical steps of LT, particularly in relation to PV anastomosis might lead operative steps which can be critical in preventing POAF. RF ablation lesions applied during surgery maybe refined further, without adding to the complexity of the LT procedure.

There are lacunae in our current understanding of AA, particularly in electrophysiology. LT offers an unique opportunity for researchers to study mechanisms of AA and response to ablation. While CA techniques result in conversion to SR occurs, CA techniques suffer from recurrences and need for further intervention and drugs post intervention. Evaluation of possible role of antifibrotics after CA to prevent recurrences and strategies to prevent electrical reconnection which leads to recurrences could be a line of future research.

Understanding electrical reconnection and their timing and anatomical locations can help in further refinement of ablation techniques with better outcomes in the future.

CONCLUSION

AA after LT continues to occur and is an important cause of morbidity and even mortality. With improving outcomes following LT, older and sicker patients with risk factors for POAF are being transplanted more often. The incidence and adverse influence of AA will be considerable. Further research is needed in areas that would minimise the incidence, morbidity and mortality associated with AA after LT. Meticulous attention to detail in ensuring that all general preventive measures have been done is the first step. Tailoring the therapy for each individual patient, based on their characteristics and co-morbidities would ensure that the most appropriate therapy is provided.