Pulmonary vein stenosis complicating radiofrequency catheter ablation for atrial fibrillation: A literature review

Accepted Manuscript Pulmonary vein stenosis complicating radiofrequency catheter ablation for atrial fibrillation: A literature review Hawa Edriss, Tatiana Denega, Victor Test, Kenneth Nugent PII:

S0954-6111(16)30140-8

DOI:

10.1016/j.rmed.2016.06.014

Reference:

YRMED 4949

To appear in:

Respiratory Medicine

Received Date: 26 December 2015 Revised Date:

3 May 2016

Accepted Date: 13 June 2016

Please cite this article as: Edriss H, Denega T, Test V, Nugent K, Pulmonary vein stenosis complicating radiofrequency catheter ablation for atrial fibrillation: A literature review, Respiratory Medicine (2016), doi: 10.1016/j.rmed.2016.06.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Pulmonary vein stenosis complicating radiofrequency catheter ablation for atrial

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fibrillation: a literature review

Hawa Edriss MD, Tatiana Denega MD, Victor Test MD, Kenneth Nugent MD

Abstract

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Radiofrequency catheter ablation has become a widely used intervention in the

treatment of atrial fibrillation. Pulmonary vein stenosis (PVS) is one of the most serious

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complications associated with this procedure; the degree of stenosis ranges from mild (<50%) to complete venous occlusion. The natural history of PVS and the risk of progression of existing PVS are uncertain. Symptomatic and/or severe PVS is a serious medical problem and can be easily misdiagnosed since it is an uncommon and relatively new medical problem, often has low clinical suspicion among clinicians, and has a nonspecific presentation that mimics other more common respiratory or cardiac diseases. The

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estimated incidence varies in literature reports from 0% to 42% of ablation procedures, depending on technical aspects of the procedure and operator skill. Most patients with significant PVS remain asymptomatic or have few symptoms. Symptomatic patients usually present with dyspnea, chest pain, or hemoptysis and are usually treated with

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balloon angioplasty and/or stent placement. Little is known about the long term effect of PV stenosis/occlusion on the pulmonary circulation and the development of pulmonary

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hypertension. Evolving technology may reduce the frequency of this complication, but long term studies are needed to understand the effect of therapeutic atrial injury and adverse outcomes. This review summarizes the current literature and outlines an approach to the evaluation and management of these patients.

Key words: Atrial fibrillation, ablation/ pulmonary veins isolation, pulmonary veins stenosis/occlusion, pulmonary hypertension, respiratory symptoms

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Introduction Radiofrequency catheter ablation (RFCA) to treat atrial fibrillation (AF) was first introduced into clinical medicine in 1987. Initially ablation was performed inside the pulmonary veins (PV), and this caused pulmonary vein stenosis (PVS) in some patients.

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Symptoms of pulmonary venous stenosis and/or occlusion secondary to AF catheter ablation can develop anytime between several weeks to several months after the

procedure.1-4 Post-procedural monitoring of symptoms and a high clinical suspicion are

necessary for diagnosis. Later antral ablation and then circumferential ablation around the

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antrum became the standard approach, and this decreased the frequency of PVS. In

addition, the use of an intra-procedural 3-dimensional mapping system and angiography

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has further reduced the reported incidence of PVS.5-7 The purpose of this review is to summarize the current literature on PVS and to remind clinicians, especially pulmonologists and cardiologists to whom most of these cases are referred, about this complication.

Methods

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This literature review included case reports, brief reviews, retrospective studies, and prospective studies. Search strategies used PubMed, MEDLINE, EMBASE, ClinicalKey, and Google Scholar databases. MeSH database search terms included atrial fibrilation, radiofrequency catheter ablation, cryo-ablation, complications, adverse events,

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pulmonary vein, abnormality, and pulmonary hypertension. Reference lists from selected articles were reviewed carefully to identify additional articles. In addition, authors’ names

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from relevant articles were used in searches to identify any missed articles. This information was summarized into a narrative review.

Discussion

The current 2014 American Heart Association/American College of

Cardiology/Heart Rhythm Society Guideline for the Management of Patients With Atrial Fibrillation recommends AF ablation as a first line treatment for patients who have recurrent symptomatic paroxysmal AF (PAF) or persistent symptomatic AF refractory to antiarrhythmic medications. Intracardiac mapping of the trigger points of ectopic beats has

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shown that over 90% of AF cases have triggers in the pulmonary veins (PV).8 The intention of catheter ablation is to create a conduction block with a transmural lesion or scar tissue in the ostia or inflow vestibules of the pulmonary veins, thus preventing errant

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electrical signals from being transmitted to the atria.

Pulmonary vein anatomy

The success of the RFCA procedure is dependent on understanding the anatomy of the PVs and the left atrium, the localization of the origin of ectopic electrical activity, the

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temperature generated by the energy source, the contact force applied to the catheter, and the time the catheter remains in contact with the tissue. In most patients, four pulmonary

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veins drain into the posterior part of the left atrium (Figure 1). On the left, the left superior pulmonary vein typically enters at an angle 30 degrees superior to the horizontal plane and drains the left upper lobe. The left inferior pulmonary vein connects to the atrium 30 degrees inferior to the horizontal plane and drains the left lower lobe. The right superior pulmonary vein is 50 degrees superior and drains the right upper and middle lobe; the right inferior pulmonary vein is 20 degrees inferior to the horizontal plane and drains the right

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lower lobe. There is significantly more anatomic variation in the right-sided pulmonary veins; about one-third of patients who were imaged before AF ablation had a right middle pulmonary vein that provided drainage for the right middle lobe, and about 17% of patients had a common ostia for the left pulmonary veins.9 Ho, et al. noted that myocardial sleeves

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of the superior pulmonary veins are longer than inferior pulmonary veins. They suggested that this anatomic peculiarity might explain the reason why the largest number of ectopic

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beats leading to AF originates in the left and right superior PVs.10 Although pre-RFCA 3dimensional imaging techniques, intraprocedural intracardiac echocardiography, and angiography increase the success of this procedure, RFCA is a challenging procedure with complications, particularly PVS.

Pulmonary vein isolation: techniques, strategies, and advances to reduce pulmonary vein stenosis Pulmonary vein stenosis is defined as ≥ 20% reduction of pre-ablation pulmonary venous diameter.11,12 The incidence rate varies significantly in reports and ranges from 0%

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to 42%.3,5,12,13 However, the actual incidence rate is uncertain, since the lack of symptoms or the presence of nonspecific symptoms often results in the underdiagnosis and misdiagnosis of this complication.1,5,7 Most studies indicate that the development and severeity of symptoms are related to the number of vessels involved and the degree of

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stenosis. In addition, the type of ablation (radiofrequency vs. cryothermal), the energy level used, the operators' skills, and the ablation strategy contribute to the development of complications.5,7,14 The power output from the RF catheter is adjusted to maintain a

temperature of 50° to 70 °C at the electrode-tissue interface, and this creates direct tissue

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injury. Conventional RF point-by-point catheter ablation has a higher risk for the

development of PVS than hot ballon catheter ablation or RF catheter ablation using an 17

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anatomic circumferential approach, which in turn, has a higher risk than cryo-ablation.3,15More recently, a circumferential RF ablation approach has been recommended and

results in fewer complications when compared to a distal pulmonary vein or osteal approach.3,18 Rostamian recently reviewed 41 publications to determine the incidence of PVS and changes in incidence over time.19 Since 2004 the mean incidence of PVS has been 2% and the median incidence has been 3.1% in published studies. These rates are

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lower than the incidence rates reported between 1999 and 2004. Therefore, the development of PVS has decreased with accurate and precise positioning of the catheter during the RF application, frequent checking by fluoroscopy, the use of intracardiac echocardiography, and the use of 3-dimensional mapping systems.3,19 However, stenosis

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can still develop even with current technology, including the use of continuous surveillance with intracardiac echocardiography.20

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Cryoballoon ablation was developed to provide a safer alternative for pulmonary vein isolation. This technique requires positioning the cryoballoon near all four PV ostia. The balloons currently used in this procedure are 23mm and 28 mm; the choice depends on the operators experience, PV diameter, and PV configuration. Intraprocedural angiography and 3-dimensional mapping are used to make this decision, and in general the smaller balloon should be used if the vein is ≤ 20 mm in diameter.21 The cold temperature (-50° to70°C) causes intracellular and extracellular ice crystal formation, which causes withdrawal of intracellular water and eventual cell death. It is associated with minimal endothelial disruption and preserves the myocardial architecture. PVS following cryo-energy ablation

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of PV has not been observed in animal studies,22 but a few cases of PVS associated with cryoballoon ablation have been reported in patients. The success rate of AF treatment with cryothermal application is lower than with RF current, and repeat procedures may be necessary. In addition, cryoablation is associated with other complications, such as phrenic

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nerve palsy, gastroparesis, and atrial-esophageal fistula.23 A second generation balloon released in 2012 was designed to create more uniform cooling across the entire distal

hemisphere of the balloon using eight injection tubes and has a higher efficacy than the

four tube first generation device released in 2010. However, PVS has been reported with

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both generation devices.24,25 In addition, the adverse effects of atrial injury over prolonged periods (years) are not known.

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Kuck and colleagues recently reported a multicenter, randomized trial comparing cryoballoon ablation and radiofrequency ablation in patients with drug refractory paroxysmal atrial fibrillation.26 This study included 762 patients with a mean follow-up of 1.5 years. The primary end point (clinical failure) occurred in 34.6% of the cryoballoon group and 35.9% of the RF ablation group. The safety end points were similar in the two groups, and no patients developed PVS. Therefore, the outcomes with these two methods

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are equivalent when performed by experienced operators. At present, the preferred approach for ablation is RFCA placing point to point lesions in a circumferential location around the antrum of PVs using irrigated catheters which can measure contact force and a three-dimensional mapping system. However, the technology for catheter ablation

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continues to evolve, and follow-up periods are short in many studies.

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Pulmonary vein stenosis histopathology Traditional RFCA and the more recently introduced cryoballoon ablation are

effective interventional tools for the restoration of sinus rhythm.6 In experimental animal studies, energy application results in membrane abnormalities leading to cardiomyocyte death, intimal thickening, organizing thrombus, endovascular contraction of the media, deposition of extracellular matrix, and proliferation of the elastic lamina. The development of PVS depends on the amount of energy applied. These animals developed increased pulmonary vascular resistance and decreased cardiac output. However, no statistically significant increase in PA pressure occurred after RF pulmonary vein ablations.27

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All current techniques for ablation cause low grade myocardial injury with the release of cardiac troponin I and CK-MB; the highest levels occurred in patients treated with cryoballoon ablation.28 Histologic examination of pulmonary veno-occlusive disease in patients following RFCA shows markedly thickened vein walls due cardiomyocyte

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death followed by myofibroblast proliferation resulting in luminal sclerosis of the

postcapillary veins and recurrent alveolar hemorrhage. Not only are the large pulmonary veins obstructed, but the small pulmonary veins within the lung and the intrapulmonary arteries exposed to high pressures in the distal pulmonary bed are narrowed.29 Platelet-

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derived growth factors, vascular endothelial growth factor, fibroblast growth factor, and activated receptor tyrosine kinases are involved in this injury response.30,31 New technology using electroporation has the potential to place ablation lines inside the

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pulmonary veins without the development of stenosis, at least in a porcine model.32

Pulmonary vein stenosis evaluation: diagnosis, progression, complications, and long term follow-up

Pulmonary vein stenosis is classified as mild when luminal narrowing is 20-50%,

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moderate when 50–69%, and severe when more than 70%.7,12,33 The severity of symptoms is associated with the degree of stenosis.5,7 Patients may present with progressive dyspnea, chest pain, cough, or hemoptysis. Some patients remain asymptomatic with single-vessel stenosis, even with a complete occlusion, or with mild-moderate stenosis of more than one

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vessel; this is likely due to the compensatory shifts and changes in the pulmonary circulation.1,7 In these cases, recognition of this complication may be delayed or

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unrecognized.

The lack of a specific presentation or unique characteristics of PVS makes it very

difficult to diagnose.1,7,11,34,35 Not only is the clinical picture challenging, but the plain chest x-ray, computed tomography (CT) of the chest, and ventilation-perfusion (V/Q) scans can be misleading and suggest other diagnoses, such as pneumonia, pulmonary embolism, tuberculosis, and lung cancer. Plain chest and CT radiography show mainly consolidations and/or pleural effusions.1,7 Ventilation-perfusion scans may reveal mismatched defects.1,14 Previous reports have indicated that many of these patients have been mismanaged and exposed to additional risks, including months to years of treatment

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with antibiotics or anticoagulation and/or surgical intervensions, such as biopsies and even lobectomies.1,7,36,37 Pulmonary vein stenosis can be accurately diagnosed with multislice spiral chest CT angiography (MCTA), magnetic resonanace perfusion imaging, transesophageal echocardiography, and catheter venography.38,39 Post-procedure MCTA or

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magnetic resonance imaging three to four months after PV ablation can help to identify PVS in early stages.

Saad, et al. reported outcomes in 608 patients undergoing RFCA for AF.7 These

patients had spiral CT angiography before and at 3, 6, and 12 months after the procedure.

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Ninety-five patients (15.6%) had PV stenosis post RFCA; 21 had severe stenosis, 27 had moderate stenosis, and 47 had mild stenosis. Patients with severe stenosis had cough (8),

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dyspnea (11), chest pain (6), hemoptysis (5), and no symptoms (8). All patients with severe stenosis had V/Q mismatch on V/Q scans. Patients with symptoms had more than one vein involved. Balloon angioplasty was done in 17 of the 21 patients with severe stenosis, including 10 with stent placement. One patient had pulmonary hypertension which resolved. Symptom improvement occurred in 10 patients. However, eight developed restenosis, and four required a second intervention. Progression of stenosis occurred in 22

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patients (8.8%) of 249 with serial scans; regression occurred in 26 patients (10.4%). Lu, et al. retrospectively evaluated five patients with PVS following RFCA.1 Evaluation included clinical and radiographic imaging between 2012 and 2014. Three patients had chest pain, three had shortness of breath, and two had hemoptysis. Two patients developed

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hypoxemia. All patients in this report were misdiagnosed by pulmonologists. The chest images showed consolidation and pleural effusions. Veins in the left lungs were involved

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in four patients; inferior veins were involved in three patients. Echocardiograms showed pulmonary hypertension in two patients; one of these patients developed progressive dyspnea. Patients with hemoptysis were treated with bronchial artery embolization. During the follow-up studies PV diameter did not change.1 In 2004, Burgstahler and his colleagues studied the utility and diagnostic accuracy

of MCTA in the detection of PVS and compared it to conventional angiography.40 Thirtythree patients were retrospectively evaluated with MCTA scans within 1 day to 380 days after RFCA. These studies were compared to conventional angiography which was performed routinely before and after the RF ablation. Pulmonary vein stenosis was

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detected by conventional angiography in 26 of 73 targeted pulmonary veins (36%); two had severe obstruction (>50%), 14 had intermediate obstruction (20-50%), and 10 had mild obstruction (<20%). Using MCTA, PVS was found in 13 of 73 (17%; one severe, six intermediate, and six mild). The authors concluded that MCTA can identify PVS in some

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patients. However, the severity of stenosis seems to be underestimated, and not all lesions could be accurately detected. 40 Highly accurate results and reproducibility of contrast-

enhanced 3- dimensional magnetic resonance angiography in the detection of PVS after RF catheter ablation has been reported in the literature, but this technology remains expensive

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and unavailable in many health care facilities when compared to CTA.41,42

Yamaguchi and his co-workers recently conducted a prospective observational study with 238 patients who had PAF undergoing radiofrequency hot balloon catheter

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ablation between 2006 and 2009 to evaluate the effectiveness and safety of this procedure.3 Follow-up continued for 75 months (2009-2014). Enhanced 3-dimensional CT was used to evaluate the targeted PV diameter before and at 3, 6, and 12 months following the procedure in all patients. Four patients (1.7%) developed asymptomatic significant PV stenosis (>70% reduction in PV diameter). These four patients were monitored for five

and moderate PVS cases.

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years and did not require interventions.3 This report did not include the number of the mild

PVS is a well recognized complication of radiofrequency energy application, but it remains a rare complication after cryo-ablation.14,17,24 Feld, et al. studied cryo-ablation in

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dogs to determine the frequency of PVS with this technology.22 In this study cryothermal energy was applied inside the canine PVs rather than at the ostia. Pulmonary veins were

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assessed by angiography during a follow-up periods of 2 to 7 months, and none of the animals developed PVS. Thomas and his colleagues reported a 45-year-old man who underwent a cryo-ablation for PAF. At a three month follow-up the patient was found to have asymptomatic left superior PVS, approximately 70% by pulmonary venography done as a pre-procedure evaluation prior to the next cryo-ablation for recurrent PAF.24 These authors suggested that mechanical pressure applied by the balloon catheter could contribute to myocardial injury. A prospective observational study with 24 patients with PAF following a cryothermal ablation of 46 pulmonary veins to evaluate for PVS with CTA showed no change of PV diameter of any veins at three months follow-up.43

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In summary, this diagnosis can be difficult and requires careful evaluation with MCTA, magnetic resonance imaging, transesophageal echocardiography, or venography. Risk factors for the development of PVS include large pulmonary vein ostia, the left inferior pulmonary vein location, and possibly increased age.44 However, it is not clear if

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routine serial imaging and early intervention in asymptomatic and/or mildly symptomatic patients have any significant implications for disease progression or development of

secondary complications, such as pulmonary hypertension (PH) and recurrent pneumonia,

since previous reports suggest that progression to symptomatic disease is unlikely in these

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cases.18

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Pulmonary blood flow and hemodynamics in pulmonary vein stenosis

The physiology and hemodynamics of PVS and secondary pulmonary hypertension are poorly understood. Pulmonary vein and/or arterial flow and patterns caused by PVS and the long-term effects of untreated PVS on pulmonary hemodynamics in symptomatic or mildly symptomatic patients have been reported in a only a few studies.Transesophageal echocardiography (TEE) can be used to assess blood flow characteristics in the PVs and

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can diagnose PVS based on dynamic changes of PV blood flow.14,39,45,46 Schneider, et al. retrospectively evaluated the reliability of TEE in assessing PVS in 91 patients after RF ablation.39 Sixteen (17%) developed PVS (13 mild, 3 moderate). In moderate PVS (5070% stenosis) significant increases of blood flow parameters, reductions of vessel

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diameters, turbulence of blood flow, and aliasing were demonstrated by TEE. These investigators concluded that TEE could identify moderate stenosis with a sensitivity of

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84% and specificity of 98%. Mild PVS (30-50% stenosis) detection was more difficult, and TEE had a sensitivity of 48% and specificity of 75% in these cases. Pulmonary vein angiograms were used as a standard for assessment of PVS in this study.39 All patients with PVS in this study were asymptomatic, and echocardiographic signs of pulmonary hypertension were not seen in any patients with PVS.39 Roman, et al. evaluated flow changes in pulmonary arteries due to PVS and correlated it to the degree of stenosis.47 The severity of vein stenosis was estimated by measurement of PV diameter via contrast-enhanced magnetic resonance angiography; hemodynamic measurements were made by phase contrast magnetic resonance imaging.

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Significant hemodynamic changes were observed and included diastolic reversal in the ipsilateral pulmonary artery branch and continuous diastolic forward flow in the contralateral pulmonary artery. Although there was no clear association between the severity of stenosis degree and the amount of flow reversal, severe unilateral PVS leads to

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reduction of arterial pulmonary flow to the same lung.41 Symptoms related to PVS

typically occur with a reduction in lung perfusion by 20-25%.19 Kluge also reported that

PVS causes decreased perfusion identified by magnetic resonance perfusion imaging and that this perfusion improved after venoplasty.48 Changes in the pulmonary blood

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distribution based on the presence of abnormal V/Q scans were reported by Saad, et al.7 Backflow resistance due to pulmonary veins obstruction results in increased

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pulmonary capillary pressure, which could lead to pulmonary hypertension. It is unclear as to why PH develops only in some patients with PVS. Witt, et al, noted that that left ventricular dysfunction may be one mechanism that results in an increase of right ventricular systolic pressures after ablation procedures, especially in those who have underlying cardiac disease, such as valvular and coronary artery disease.49 Another important contributing conditions are the number of stenosed PVs (more than one), and the

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number of previous ablation procedures (Table 1 with data). Right heart catheterization and transesophageal echocardiogram are essential for the diagnosis of PH. In 2005, Arentz and his colleagues prospectively monitored 117 patients after RFCA for 24 months. Eleven patients developed significant PVS (single vessel stenosis in 9 patients, two vessels

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stenosis in 2 patients).18 Right heart catheterization was performed and demonstrated that none of these patients had PH at rest but that 7 patients developed PH during exercise. Di Biase reported that patients with 3 or more stenotic pulmonary veins developed PH at

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rest.34 In most patients the degree of stenosis usually improves or stabilizes, but in a small percentage of patients the stenosis progressed. New pulmonary vein thrombosis and infarction have been reported as a

complication of PVS after AF catheter ablation. 50 A 44-year-old patient developed hemoptysis and pleuritic chest pain six weeks after a successful AF; a CT scan of the chest showed thrombosis of the lingular vein branch, infarction of the lingula, and 50% stenosis of the left superior pulmonary vein. There were no filling defects in the pulmonary arteries.50 In addition, recurrent and drug resistant pneumonias are potential complications

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of PVS due to congestion upstream from the obstruction, and that sometimes requires intervention such as bronchosocpy.14,18,51 Pulmonary vein stenosis treatment The long term progression and management of PVS is still unclear and very

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challenging.30 Yang, et al. and Di Biase, et al. suggest that early intervention in severely

symptomatic PVS improves clinical symptoms and the long-term outcomes.34,46 The main

treatment modality for PVS usually involves balloon angioplasty and/or stent implantation (Figure).5,34,45 Holmes, et al. prefer balloon dilation as a primary intervention and stent

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placement in cases of restenosis.5 However, high rates of restenosis have been observed after both procedures and range from 47% to 72%.2,7,14,45 The restenosis rate after PVS

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stenting seems to be lower.45,52 Major adverse events with angioplasty and stenting include pulmonary hemorrhage, PV tears requiring immediate surgery, and cerebral embolic events.2 The recent use of drug-eluting stents, such as paclitaxel-eluting stents, has reduced the restenosis rate significantly.53,54

Packer and his coworkers reported 23 patients with severe stenosis in 34 pulmonary veins who underwent either dilation followed by stenting or stenting as the initial

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intervention.14 Significant PVS with or without symptoms was treated to prevent development of pulmonary hypertension, progression to total occlusion, and recurrent pneumonia. Fourteen (60%) had restenosis and required repeat stentings (total of 2-4 repeated stentings). Despite restenosis in some pulmonary veins all patients remained

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asymptomatic during follow-up at 7 ± 2 months after intervention.14 Prieto, et al. reported that stent angioplasty was associated with a lower rate of restenosis (33% of stented veins vs.72% balloon dilated veins) and that restenosis was less

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frequent with larger stents (>10mm).45 After the procedure, anticoagulation therapy is required to prevent pulmonary arterial thrombosis. Post-interventional spiral CT studies are essential in identifying reccurrence of PV restenosis.5,7 De Potter reported the use of drug eluting stents in five patients with PVS post ablation.13 The initial experience suggested an excellent patency rate (only one patient required restenting). The efficacy and safety of imatinib (tyrosine kinases inhibitor) and bevacizumab (an antibody against vascular endothelial growth factor) on multivessel congenital PVS are being studied in a prospective open-label FDA-approved study (www.clinicaltrials.gov-NCT00891527).

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These medications might reduce PVS post ablation even if only used for a short period, but this would require a large controlled trial to establish efficacy. DeSimone studied the direct application of paclitaxel/everolimus using a drug-coated balloon in a dog model.55 Drug treated veins did not develop stenosis after ablation, whereas non-treated veins all

as their on controls through the random selection of treated veins.

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developed severe stenosis. This approach needs study in patients who could actually serve

We offer recommendations for post ablation follow-up and management of PVS (Tables 2 and 3).56,57

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Conclusions

Symptoms in patients with PVS secondary to AF ablation develop during variable

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periods following the procedure. The condition is likely underdiagnosed due to lack of specific presentation with inconsistent follow up. Previous reports and available experience suggest that the occurrence and severity of symptoms are related both to the degree of luminal narrowing and to the number of pulmonary veins affected. Post-procedural observation and monitoring of the symptoms and diagnostic imaging modalities, including spiral CT scans or MRI and MRA, should detect this complication. Detecting PVS acutely

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with selective angiogram is relatively simple. However, identification of slowly progressing PVS in follow-up visits is challenging. Transesophageal echocardiography provides reliable, cost-effective, non-invasive follow-up in cases of moderate-severe PVS. Establishing accurate diagnosis of PVS is very difficult. Therefore, a careful review of the

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medical history and follow-up is needed in all the patients who have RFCA to recognize PVS in the early stage. Another important consideration during evaluation for PVS by

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MRA is to include pulmonary arterial system assessment to determine the functional effect of the stenotic vein on the pulmonary flow and hemodynamics. Larger studies to assess the diagnostic accuracy and clinical reliability of non-invasive methods, such as MCTA and phase-contrast MRI, to determine the incidence of PV stenosis following RFA, especially during long-term follow-up, and to demonstrate the effectiveness and safety of drugeluting stents in PVS are needed.Finally, the long term outcomes and complications in these patients who have atrial remodeling and controlled injury of the atrial myocardium are uncertain.

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Figure legends Figure 1shows the posterior surface of the left atrium and the entry of four pulmonary veins based on cardiac CT angiography (a). The arrow indicates a compound right inferior pulmonary vein. Figure 1b shows the endoluminal surface of the left atrium. The arrow

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demonstrates that multiple small branches of the right inferior pulmonary artery enter the

left atrium. The * is over the orifice to the atrial appendage. This image was obtained from the Texas Tech University Health Sciences Center library multimedia collection OPENi

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(beta) on April 10, 2016.

Figure 2A demonstrates an area of stenosis in the right superior pulmonary vein. Figure 2B

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shows this area after balloon angioplasty. Figures were provided by Anurag Singh MD, Department of Internal Medicine, Texas Tech University Health Sciences Center,

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Lubbock, TX.

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Table Patients with pulmonary hypertension after ablation procedure

Patient #2: Two ablations, Symptoms developed months after the procedure

1 patient Arentz 2005 [18]

11/ 117 patients had PVS

Repeat PA 62 mm Hg LA pressure 3 mm Hg CI 1.9 L · min−1 · m−2

Preprocedure: PA systolic pressure 28 mm Hg and a mildly dilated right ventricle

N/A

Postprocedure: PA systolic pressure 85 mm Hg with a dilated right ventricle.

Postprocedure: High-velocity turbulence within the LA at the junction of both superior PVs

Two ablations, Symptoms developed 4-6 weeks after the last ablation

PA 80/40 mmHg PCWP 50s mmHg

Performed (no data available)

Mild aortic, mitral, and tricuspid regurgitation TR velocity 3.6 m/s Doppler evidence of stenosis of all PVs N/A

Time since PV ablation 50±15 months

No PH at rest During exercise, 7/11patients had PH with mean PA from the upper 30s to lower 50s mmHg; 3/7 patients had increase

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Repeat PA 58 mm Hg LA pressure 23 mm Hg CO of 4.78 L/min PVR of 586 dynes·cm2/s PA 54 mm Hg PCWP 16 mm Hg PVR of 512 dynes · cm2/s CI 3.1 L · min−1 · m−2

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PA systolic pressure 65 mm Hg

Transesophageal ECHO PA systolic pressure 88 mm Hg high-velocity turbulence (2.5 m/s) within the LA near the ostia of both superior PVs

N/A

Stenosis and Treatment 4 PVs with stenosis Balloon dilation Successful

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Patient #1: Symptoms developed 2-3 months after the procedure

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Robbins 1998 [49]

Right heart catheterization PA 41 mm Hg PCWP 16 mm Hg CO 7.0 L/min PVR 287 dynes · cm2/s

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3PVs with stenosis Balloon dilation Successful

4PVs with stenosis Stenting Restenosis and balloon dilation; lobectomy

8/11 had 1 PV stenosis 3/11 had 2 PVs stenosis Treatment not reported

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Two ablations

PA 42 mmHg PCWP 22 mmHg with tall V waves left PCWP 34 mmHg with flattening of V waves sPA 60 mm Hg PCWP 34 mm Hg pressure gradient between PVs and LA (PCWP–LAP) 22 mm Hg PA 40 mmHg Right lower PCWP 15 mm Hg

Mild mitral regurgitation without signs of PH (no data)

Mielczarek, 2015 [52]

Several weeks after ablation

1 patient

Nehra 2009 [53] 1 patient Lu 2015 [1] 5 patients with PVS

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1 patient

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3/18 patients had pulmonary hypertension at rest All had 3 or more stenosed veins

RVSP 5560 mm Hg

Patient #1 Chest pain 16 months

NA

Patient # 2 Chest pain 20 months

NA

N/A

4 patients had single vein occlusion, 4 patients had single vein occlusion and other mild (<50%) lesions, 5 patients had 2 totally occluded veins, 5 had a single vein occlusion with other significant vein stenosis (>50%), Cannulation, dilation, and stent placement Outcome not reported 1 PV with severe stenosis Treatment not reported

N/A

2 PVs with stenosis Balloon dilatation and stent placement Successful

EF 62%.

N/A

2PVs with stenosis Pneumonectomy Successful

PA systolic 58 mmHg

NA

1 PVO No treatment Increased dyspnea

PA systolic 55 mmHg

NA

1 PVO No treatment No change in symptoms

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16/ 1780 patients

Diagnosis with CT 4/18 remained asymptomatic

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Di Biase 2006 [30]

in PCWP to 20s to 30 mmHg, possibly due to LV dysfunction; no decrease in PVR

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plus 2 referred cases

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CI-cardiac index, CO-cardiac output, LA- left atrium, LAP- left atrial pressure, LV-left ventricle, m –mean, N/A-not available, PA-pulmonary artery pressure (mean if single value given), PCWP- pulmonary capillary wedge pressure, PV-pulmonary vein, PVO- pulmonary vein occlusion, PVS- pulmonary vein stenosis, RV- right ventricle, RVSP-right ventricular systolic pressure, SPAP-systolic pulmonary artery pressure

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Comprehensive follow-up

Interval history and physical examination, quality of life questionnaire

Possible pulmonary vein stenosis

Interval history and physical examination

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Electrocardiogram, chest x-ray, computed tomography of the chest with contrast Electrocardiogram, chest x-ray, BNP

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Interval history and physical examination

Electrocardiogram, Holter monitor

Electrocardiogram, chest x-ray, 6-minute walk test, BNP

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Electrocardiogram

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Table 2 Possible strategies for post-ablation management Routine follow-up Interval history and physical examination Palpitations, other symptoms Interval history and physical potentially attributable to examination arrhythmias Respiratory symptoms Interval history and physical examination

Chest x-ray, computed tomography with venous angiography, consider echocardiogram with right ventricular systolic pressure measurements

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Table 3 Treatment approaches in patients with PVS Symptom profile Venous anatomy

Treatment

Asymptomatic

1 or 2 abnormal veins, % stenosis < 50 % 1 or 2 abnormal veins, % stenosis > 50 %

Observation

1 or 2 abnormal veins, % stenosis < 50% ≥ 2 abnormal veins, % stenosis > 50%

Evaluate for other explanations for symptoms Balloon venoplasty ± stent

Symptomatic

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Symptomatic

Functional assessment, repeat CT or TEE in three months

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Asymptomatic

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Highlights: Pulmonary complications associated with pulmonary vein stenosis secondary to radiofrequency catheter ablation for atrial fibrillation: A literature review 1. Radiofrequency catheters use heat to create blocks around the pulmonary veins.

3. Damage to the pulmonary veins can cause stenosis.

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2. These lines prevent the transmission of ectopic beats from veins into the left atrium.

4. Symptoms depend on the number of stenotic veins and the degree of stenosis.

5. These patients have nonspecific signs and symptoms causing delayed diagnosis.

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6. Treatment options include venoplasty with or without stents.