Drug-Coated Balloon Venoplasty for In-Stent Restenosis in a Patient With Recurrent Pulmonary Vein Stenosis Post Ablation for Atrial Fibrillation: Initial Experience With a New Treatment Technique

Abstract: Pulmonary vein stenosis (PVS) is an uncommon but serious complication following radiofrequency ablation for atrial fibrillation. Occurrence of this complication has risen with increased rates of ablation procedures, with >50,000 AF ablation procedures performed per year, and can occur within weeks to months post procedure. Currently, the main therapies for PVS include percutaneous interventions with balloon angioplasty and stenting, but these treatments are complicated by a high rate of restenosis. The optimal treatment for recurrent pulmonary vein in-stent restenosis has not been determined. We describe the novel use of a paclitaxel drug-coated balloon for the treatment of in-stent restenosis of the pulmonary veins.

J INVASIVE CARDIOL 2016;28(5):E44-E48

Key words: pulmonary vein stenosis, radiofrequency ablation

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Pulmonary vein stenosis (PVS) is an uncommon but serious complication following radiofrequency ablation for atrial fibrillation (AF). The incidence of this complication has increased with the rising rate of ablation procedures performed yearly. The mainstays of therapy for PVS consist of percutaneous interventions with balloon angioplasty and stenting, but these treatments are complicated by a high rate of restenosis.^1-3 The optimal treatment for recurrent pulmonary vein in-stent restenosis has yet to be determined. We describe the novel use of a paclitaxel drug-coated balloon (DCB) for the treatment of in-stent restenosis of the pulmonary veins.

Case Presentation

Clinical patient description. A 28-year-old male underwent AF ablation at an outside hospital for persistent AF in April 2014. Three months later, he presented to our hospital with hemoptysis and was found to have left lower pulmonary vein (LLPV) stenosis that was successfully treated with an 8.0 x 17 mm Express stent. Three months after this intervention, he presented to an outside institution where he was found to have left upper pulmonary vein (LUPV) stenosis for which he received a 6.0 x 20 mm Cook 418 Formula Biliary stent. He was also noted to have right upper pulmonary vein (RUPV) occlusion for which he underwent sternotomy and left atriotomy for repair with a CorMatrix patch at the same outside institution. Six weeks later, he was found to have a restenosed RUPV and received a 6.0 x 29 mm Abbott Omnilink stent, which was postdilated with an 8 mm Armada balloon, again at the same outside institution. Two months later, he presented to the same outside institution with recurrent chest pain, dyspnea, and hemoptysis and underwent right heart catheterization with contrast injection and levophase left atrialgram, which showed patent pulmonary veins. In addition, cardiac magnetic resonance imaging was performed 1 month later for persistent symptoms, which revealed patent stents with likely intimal hyperplasia, as well as a left lower-lung lobe consolidation and effusion. Two weeks later, he sought a second opinion at our institution and underwent transesophageal echocardiography (TEE), which showed severe stenosis of the RUPV and LUPV, with mean gradients of 19 mm Hg for each, as well as mild-moderate stenosis of the LLPV with a mean gradient of 7.6 mm Hg. Stent external diameter in the RUPV was 6 mm with an internal lumen diameter of 3-4 mm, and stent external diameter in the LUPV was 8 mm with an internal lumen diameter of 5-6 mm (Figure 1). By way of providing perspective, in an early Mayo Clinic series of 23 patients felt to have clinically significant PVS, computed tomography (CT) demonstrated a minimal lumen diameter of 3 ± 2 mm and a catheter-obtained trans-stenotic gradient of 12 ± 5 mm Hg.³ Based on our patient’s clinical presentation and the anatomic and physiologic TEE data, he was referred for cardiac catheterization for further evaluation, lesion characterization, and intervention.

Technique description. The procedure was performed in the cardiac catheterization laboratory under general anesthesia. An 8 Fr Mullins sheath (Medtronic Vascular) was introduced into the right femoral vein and a trans-septal needle was used to cross the interatrial septum under TEE guidance. Heparin was administered to maintain therapeutic activated clotting times. The Mullins sheath was then exchanged for an 8.5 Fr Agilis steerable deflectable sheath (St. Jude Medical). Next, the LUPV was cannulated using a 4 Fr multipurpose catheter over a Versacore wire (Abbott Vascular) where hemodynamic evaluation revealed a mean gradient of 16 mm Hg with pulmonary arterial configuration of the pulmonary venous waveform upstream to the stent (Figure 2). The stenosis was predilated with a Mustang 6.0 x 40 mm balloon (Boston Scientific) at 8 atm. Next, a Lutonix 6.0 x 40 mm DCB (Bard Peripheral Vascular) was advanced over an Amplatzer 0.035˝ guidewire (St. Jude Medical) and inflated in the LUPV for 60 seconds at 6 atm, followed by postdilation with a 7.0 x 40 mm Mustang balloon (Boston Scientific). Residual gradient across the LUPV was measured to be 5 mm Hg with a left atrial configuration of the pulmonary venous waveform upstream to the stent. Attention was then given to the RUPV, which was cannulated using a 4 Fr multipurpose catheter over a Versacore wire where hemodynamic evaluation revealed a mean gradient of 23 mm Hg with pulmonary arterial configuration of the pulmonary venous waveform upstream to the stent. Since a 40 mm balloon was not available, a 6.0 x 60 mm Lutonix DCB was advanced over the Amplatzer 0.035˝ guidewire and inflated in the LUPV for 60 seconds at 12 atm, followed by postdilation with an 8.0 x 40 mm Mustang balloon (Figure 3). Residual gradient across the LUPV was measured to be 1 mm Hg with a left atrial configuration of the pulmonary venous waveform upstream to the stent. The procedure was well tolerated and the patient was discharged on warfarin as required for anticoagulation 1 year post AF ablation, as well as aspirin 81 mg and clopidogrel 75 mg daily for at least 6-12 months.

Follow-up. One month post procedure, the patient presented again with what appeared to be hemoptysis while on aspirin, clopidogrel, and therapeutic coumadin. Otolaryngology evaluation revealed right anterior nasal septum bleeding. Anticoagulation was modified to coumadin and low-dose aspirin. To definitively rule out pulmonary vein restenosis, a CT angiogram and a TEE were performed. CT angiography revealed the stent in the RUPV to be widely patent and the stent in the LUPV to have a “very mild peripheral low density which could represent a very mild degree of intimal hyperplasia.” TEE demonstrated a RUPV mean gradient of 8 mm Hg and a LUPV mean gradient of 6 mm Hg, consistent with mild stenosis. He remained free of symptoms at 6-month follow-up exam.

Discussion

Percutaneous intervention with balloons and stents has become the standard of care for this uncommon, yet serious complication. While the results of stenting make this the procedure of choice, there remains a significant incidence of symptomatic restenosis associated with this intervention. In addition, stenting has been associated with complications including hemoptysis, intimal flap, pulmonary vein tear resulting in tamponade, and pulmonary vein dissection.^4,5 The optimal treatment strategy for managing in-stent restenosis of the pulmonary veins has yet to be established, as there is a dearth of both experience and literature currently available. We describe our experience with what we believe to be the first reported use of a paclitaxel DCB for the treatment of pulmonary vein in-stent restenosis post AF ablation in an adult. 

PVS is an uncommon but serious complication following radiofrequency ablation for AF. While acquired PVS can occur due to extrinsic compression such as neoplasm, sarcoidosis, or mediastinitis, it is most frequently associated with ablation for AF.¹ The occurrence of this complication has risen with increased rates of ablation procedures, with >50,000 AF ablation procedures performed per year, and can occur within weeks to months post procedure.³ The mechanism is unknown, but is hypothesized to be due to periadventitial inflammation or collagen deposition causing reactive hyperplasia and fibrosis.^3,6 In early reports, PVS incidence was as high as 42.4% post AF ablation.⁷ With advances in technique, the incidence of PVS has decreased to 1%-3% in a series of case reports, and to as little as 0.3% in a worldwide study of 188 centers’ experience with AF ablation updated in 2010.⁸ Post-AF ablation rates may be further decreasing with the expansion of cryotherapy techniques. Determination of the frequency of this complication is difficult to quantify due to the difficulty in diagnosis. Symptoms are often vague, and include dyspnea, chest pain, cough, hemoptysis, and pneumonia or bronchitis. Clinicians must be astute to recognize these symptoms as a sign of PVS post AF ablation. Diagnosis can be made with TEE demonstrating increased gradient across the pulmonary veins,² or with magnetic resonance imaging or CT,³ as well as with radionuclide quantitative pulmonary flow imaging.¹ 

Treatment of PVS has evolved such that percutaneous interventions with balloon angioplasty and stenting are the mainstays of therapy, but all of these treatments are complicated by a high rate of restenosis. In a 2008 study, Pietro et al demonstrated a 42% acute success rate of balloon dilation compared with a 95% acute successful stenting rate, with success defined as postdilation stenosis <30%. However, the rate of significant restenosis was 72% after balloon dilation and 33% after stent (P<.001).⁵ Traditionally, bare-metal stents have been the device of choice, as drug-eluting stents have not been commercially available in sizes adequate to treat the pulmonary veins. One case series of 5 patients with a total of 7 pulmonary veins treated with drug-eluting stents revealed only one occurrence of in-stent restenosis, but the authors also noted that at least two of the stents were undersized for the pulmonary veins treated.² Another case report describes the use of a covered stent for the treatment of PVS with a successful result.⁹ While stents have been successful in treating PVS, there remains a significant rate of in-stent restenosis, with recurrence rates of at least 30%-50%.³ The optimal method for treating in-stent restenosis in the pulmonary veins has yet to be delineated in the literature.

Given this patient’s highly symptomatic in-stent restenosis, we chose to treat him with drug-coated Lutonix peripheral balloons in the hope of preserving pulmonary vein patency and limiting recurrent stenosis. Due to size constraints of the largest DCB, postdilation following application of the DCB was necessary as described in the device’s instructions for use when the device is used in large peripheral arteries. There were no acute complications with this therapy. At 1-month follow-up exam, Doppler evaluation did not demonstrate significant restenosis. At 6-month follow-up exam, he remained free of symptoms. Since submitting this manuscript, we now have 12-month TEE follow-up demonstrating continued patency without significant restenosis.

In addition to reporting our initially favorable experience with the Lutonix DCB to improve long-term patency rates of PV stents, we also demonstrated the use of TEE as a minimally invasive technique for hemodynamic assessment of pulmonary vein gradients, with good correlation in the catheterization laboratory. In previous studies, CT and magnetic resonance imaging have been the diagnostic and surveillance techniques of choice; however, CT is limited by the heavy dose of ionizing radiation, presence of arrhythmias, as well as artifact in the presence of stents. Magnetic resonance imaging is limited by long acquisition times, sensitivity to motion artifacts and arrhythmias, potential artifact in the presence of stents, and somewhat limited spatial resolution. 

Conclusion

Advances in treatment of AF have decreased the rate of PVS post ablation; however, this remains a serious and life-threatening complication. Percutaneous treatment options are available, including balloon venoplasty and stenting, but restenosis remains a common and significant sequela, and there is currently no definitive treatment for in-stent restenosis in the pulmonary veins. For pulmonary vein in-stent restenosis, the use of a DCB is feasible and may provide good long-term results. Further strategies to prevent and treat pulmonary vein restenosis, including DCB use during initial PVS treatment, should continue to be explored.

References 

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