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Clinical outcomes after the endovascular treatments of pulmonary vein stenosis in patients with congenital heart disease

Published online by Cambridge University Press:  09 July 2019

Yoshihiko Kurita
Affiliation:
Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama-City, Okayama, Japan
Kenji Baba*
Affiliation:
Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama-City, Okayama, Japan
Maiko Kondo
Affiliation:
Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama-City, Okayama, Japan
Takahiro Eitoku
Affiliation:
Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama-City, Okayama, Japan
Shingo Kasahara
Affiliation:
Department of Cardiovascular surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama-City, Okayama, Japan
Tatsuo Iwasaki
Affiliation:
Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama-City, Okayama, Japan
Shinichi Ohtsuki
Affiliation:
Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama-City, Okayama, Japan
Hirokazu Tsukahara
Affiliation:
Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama-City, Okayama, Japan
*
Author for correspondence: K. Baba, MD, PhD, Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-Cho, Kita-Ku, Okayama-City, Okayama, 700-8558, Japan. Tel: +81-86-235-7249; Fax: +81-86-221-4745; E-mail: kenjibaba@cc.okayama-u.ac.jp
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Abstract

Background:

Pulmonary vein stenosis (PVS) is a condition with challenging treatment and leads to severe cardiac failure and pulmonary hypertension. Despite aggressive surgical or catheter-based intervention, the prognosis of PVS is unsatisfactory. This study aimed to assess the prognosis and to establish appropriate treatment strategies.

Methods:

We retrospectively reviewed endovascular treatments for PVS (2001–2017) from the clinical database at the Okayama University Hospital.

Results:

A total of 24 patients underwent PVS associated with total anomalous pulmonary venous connection and 7 patients underwent isolated congenital PVS. In total, 53 stenotic pulmonary veins were subjected to endovascular treatments; 40 of them were stented by hybrid (29) and percutaneous procedures (11) (bare-metal stent, n = 34; drug-eluting stent, n = 9). Stent size of hybrid stenting was larger than percutaneous stenting. Median follow-up duration from the onset of PVS was 24 months (4–134 months). Survival rate was 71 and 49% at 1 and 5 years, respectively. There was no statistically significant difference between stent placement and survival; however, patients who underwent bare-metal stent implantation had statistically better survival than those who underwent drug-eluting stent implantation or balloon angioplasty. Early onset of stenosis, timing of stenting, and small vessel diameter of pulmonary vein before stenting were considered as risk factors for in-stent restenosis. Freedom from re-intervention was 50 and 26% at 1 and 2 years.

Conclusions:

To improve survival and stent patency, implantation of large stent is important. However, re-intervention after stenting is also significant to obtain good outcome.

Type
Original Article
Copyright
© Cambridge University Press 2019 

Background

Pulmonary vein stenosis (PVS), which may develop following total anomalous pulmonary venous connection, and isolated congenital PVS are progressive diseases. While surgical or catheter treatments may be attempted, their effects are often temporary improvements and recurrence is common. PVS is characterised by the transformation of a local lesion into a diffuse lesion encompassing the complete pulmonary vein. It may be accompanied by pulmonary hypertension and heart failure, and the prognosis is extremely poor.Reference Seale, Webber and Uemura 1 Reference DiLorenzo, Ashley and Faerber 3 In particular, patients intending to undergo the Fontan procedure are no longer considered eligible for the procedure, and the mortality rate increases once PVS develops. Few reports are available that summarise the treatment of PVS in children.

At our treatment, PVS is treated with a combination of surgery and catheter treatment. This study aimed to evaluate the effect of endovascular therapy for PVS performed at our institution and to establish appropriate treatment strategies.

Methods

Patient selection

The study included 31 patients who underwent balloon angioplasty and/or stent implantation for PVS associated with total anomalous pulmonary venous connection or isolated congenital PVS at the Okayama University Hospital (Okayama, Japan) between January 2001 and December 2017. We retrospectively reviewed the medical records of the patients. This study was approved by the research ethics committee of Okayama University Hospital.

Haemodynamic and vascular assessment, cardiac catheterisation, and surgery

Evaluation and diagnosis of PVS were based on a combination of ultrasound, computed tomography (CT), and angiography. CT and angiography were used to measure pulmonary venous diameter, with the narrowest diameter set as the minimum diameter and the widest diameter in the upstream portion used as the reference diameter. If a bifurcation of the peripheral pulmonary vein was noted at this point, the reference diameter was considered as the diameter of the portion just before the bifurcation. Balloon sizes were determined based on the minimum and reference diameters. Stent size was determined on the basis of reference diameter; stent diameters were determined based on the distance between the ostium and the first bifurcation. Basically, we tried to use the stent size that is approximately 150% of the reference diameter. The difference in terms of pressure prior to and after percutaneous catheter treatment was determined by measuring the pressure in all possible cases.

Cardiac catheterisation was performed in all patients under general anaesthesia managed by anaesthesiologists. Percutaneous catheter evaluation and treatment were performed by a paediatric cardiologist in the catheterisation laboratory.

Stent implantation was performed using two methods, namely, percutaneous pulmonary vein stenting performed in the catheterisation laboratory and hybrid pulmonary vein stenting, which is an open-heart surgery and performed in the operating theatre. The indication of hybrid pulmonary vein stenting was discussed at an interdisciplinary conference. We determined a procedure assuming that anatomic problems, such as difficulty reaching the stenotic site, difficult vascular access, and multiple closely spaced ostium, required concomitant surgery. However, we have had a recent trend in which only hybrid pulmonary vein stenting was performed. Hybrid stenting is performed under cardiac arrest, and surgery is simultaneously performed at other sites if necessary.

Some patients undergo plasty of pulmonary veins prior to stent insertion into the site of PVS. All stents were directly inserted and dilated without the use of a sheath or guide wire. Following stent dilation, some veins were further dilated using a larger balloon. As shown in Figure 1, two stents were placed to perform simultaneous dilation if two sites of stenosis were in close proximity. Stent size was determined by the paediatric cardiologist based on the results of preoperative CT and angiography. In cases of hybrid stenting, the protrude part of the stent to the atrium is treated by partial resection and flaring of the proximal stent struts and then by an anchoring suture to the atrial wall. These approaches were determined by the cardiothoracic surgeon.

Figure 1. ( a ) Surgical view before hybrid pulmonary vein stenting, two orifices of pulmonary vein are very close (arrow). ( b ) After hybrid pulmonary vein stenting, two Express Vascular stents were implanted simultaneously. Both stents were of 5 mm size and 15 mm length. Cutting of extra stent strut and anchoring suture were placed to prevent migration.

In-stent restenosis following stent placement was diagnosed using CT or angiography. In this study, in-stent restenosis was defined as a 50% or higher stenosis of the stent size (≥50% luminal narrowing).

Data and statistical analysis

The patients’ backgrounds and diagnoses are shown separately based on the methods used: balloon and stent cases. As the outcomes of this comparative investigation, overall survival rate was determined for all patients and occurrence of in-stent restenosis was determined among the stent cases. The patients were divided into two groups according to the survival rate: survival and mortality groups. Further, the selected parameters were compared between these groups. Stent patency was compared between the patients that developed in-stent restenosis during follow-up and those that did not.

Statistical analysis was performed using IBM SPSS Statistics V25. Continuous variables are presented as mean ± standard deviation or median (range). Survival rates were investigated using the Kaplan–Meier curves, and the between-group comparisons were performed using the log-rank test. Cut-off values for items in the log-rank test were determined using receiver–operating characteristic curve analysis. Between-group comparisons were performed using the t-test, Mann–Whitney U-test, and chi-square test; p < 0.05 was considered statistically significant. Considering the small sample size of this study, only univariate analyses were performed.

Result

Patient demographics

Details of patient demographics are summarised in Table 1. In total, 31 patients (11 females) who underwent endovascular treatments were included in this study. PVS developed in 53 veins. A total of 40 stents were placed in 38 veins of 21 patients, and balloon angioplasty alone was performed 29 times in 15 veins of 10 patients. PVS developed at a median of 7 months (3–20 months) from birth, and multiple stenosis developed in 17 cases. Further, PVS associated with total anomalous pulmonary venous connection occurred in 24 cases, whereas isolated congenital PVS occurred in 7 cases. An intra-cardiac diagnosis of functionally univentricular heart was made in 23 cases, 8 of which were candidates for biventricular repair, including total anomalous pulmonary venous connection. The following surgical approaches were done: repair of total anomalous pulmonary venous connection (24 cases), modified Blalock–Taussig shunt (10 cases), pulmonary artery banding (13 cases), bidirectional Glenn shunt (6 cases), Fontan procedure (2 cases), modified Norwood procedure (4 cases), atrioventricular valve plasty (7 cases), and release of PVS (25 cases). The median interval to the first intra-cardiac repair was 1 month (0.1–7 months) from birth.

Table 1. Patient demographics and diagnostic data of pulmonary vein stenosis

BAP = balloon angioplasty; IUGR = intra uterine growth retardation; TAPVC = total anomalous pulmonary vein connection; iCPVS = isolated congenital pulmonary vein stenosis; CAVSD = complete atrioventricular septum defect; DORV = double outlet right ventricle

Patients of only balloon angioplasty and haemodynamic change

Among cases that underwent balloon angioplasty alone, the median follow-up period from PVS onset was 17 months (11–104 months). Balloon angioplasty was performed 29 times in 15 pulmonary veins of 10 patients, and 7 patients underwent treatment within 6 months following the onset of PVS. Details of the procedures are summarised in Table 2. Significant improvements were observed in terms of the stenosis site (2.0 ± 0.5 to 3.8 ± 1.0 mm, p = 0.02) and pressure difference (11.8 ± 3.5 to 5.7 ± 1.9 mmHg) following balloon angioplasty. In this group, eight veins (53%) presented complete vascular occlusion at the end of the follow-up.

Table 2. Details about balloon angioplasty (BAP) of pulmonary vein stenosis

BAP = balloon angioplasty.

Patients and details of stenting

Table 3 presents a comparison of hybrid pulmonary vein stenting and percutaneous pulmonary vein stenting performed in the operating theatre. Significant differences were found in terms of stent size, vascular diameter after stenting, stent size/minimum diameter ratio, and stent size/reference diameter ratio. Two types of stents were used: bare-metal stent designed for peripheral arteries and drug-eluting stent designed for coronary arteries. Thirty-four bare-metal stents were placed in 28 cases and 6 drug-eluting stents in 5 cases. Three types of bare-metal stents measuring 5–10 mm were used: Palmaz (Cordis, Miami Lakes, FL, United States of America), Express-Vascular (Boston Scientific, Natick, MA, United States of America), and Omnilink Elite (Abbott Vascular, Abbot Park, IL, United States of America). Two types of drug-eluting stents measuring 3.5 mm were used: Cypher sirolimus-eluting stent (Cordis) and Nobori biolimus-eluting stent (Terumo Corporation, Tokyo, Japan). Significant differences were observed between the bare-metal stent and drug-eluting stent groups in terms of the minimum and reference diameters of PVS prior to stent insertion and in terms of vascular diameter following stent insertion (Table 4).

Table 3. Difference between hybrid pulmonary vein stenting (HPVS) and percutaneous pulmonary vein stenting (PPVS)

Table 4. Stent types and characteristics, comparison between bare-metal stents (BMS) and drug-eluting stent (DES)

Among the 29 stents placed by hybrid procedure, 18 were subjected to anchoring suture to the atrial wall following stent insertion. Post-dilatation was performed in five stent cases. Simultaneous hybrid stenting at two stent sites in close proximity was performed in three cases.

Mortality and outcomes

The median overall follow-up period from PVS onset was 24 months (4–134 months). Fifteen patients died during the observation period owing to cardiac failure, pulmonary hypertension, or respiratory failure accompanying PVS. Figure 2 shows the Kaplan–Meier curve of survival rate. The overall survival rate was 71% at 1 year and 49% at 5 years. As shown in Table 5, there were no significant differences except for the use of bare-metal stent between the survival and mortality groups. Although no significant differences were found between the cases of stent treatment and those of balloon angioplasty alone, the survival rate significantly differed between cases undergoing bare-metal stent and those undergoing other procedures (drug-eluting stent alone or balloon angioplasty alone). After initiating the treatment of PVS, biventricular repair, bidirectional Glenn shunt, and Fontan procedure were performed in two cases each. Takedown from bidirectional Glenn shunt to modified Blalock–Taussig shunt was performed in one case.

Figure 2. ( a ) Kaplan-Meier analysis of patients treated for pulmonary vein stenosis. In overall, estimated survival is 71% and 49% at 1 years and 5 years. There is no significant difference between stent group and balloon angioplasty (BAP) group. ( b )Kaplan-Meier comparing survival of patients who received bare-metal stent (BMS) implantation and patients who received only drug-eluting stent (DES) or only balloon angioplasty (BAP).

Table 5. Association with mortality of patients for pulmonary vein stenosis

IUGR = intra uterine growth retardation; TAPVC = total anomalous of pulmonary venous connection.

In-stent restenosis

During the observation period, in-stent restenosis occurred in 27 stents (68%). The in-stent restenosis onset rate was 34% at 1 year and 70% at 5 years from stent implantation. Table 6 presents the comparison between the no in-stent restenosis and the in-stent restenosis groups. The timing of PVS onset and stent implantation were significantly earlier and the stent size was smaller in the in-stent restenosis group than in the no in-stent restenosis group. Regarding PVS before stent implantation, no significant difference was observed in terms of the minimum diameter, whereas the reference diameter before stent implantation and vascular diameter after stent implantation was larger in the no in-stent restenosis group. Moreover, we found that stents placed by hybrid procedure were associated with freedom from significant in-stent stenosis compared to stents placed by percutaneous procedure. As shown in Figure 3, the in-stent restenosis onset rate during the observation period was significantly lower in the cases in which a stent of ≥8mm was used.

Table 6. Comparison of pulmonary vein stent with intra-stent restenosis (ISR) or not

HPVS = hybrid pulmonary vein stenting; PPVS = percutaneous pulmonary vein stenting.

Figure 3. Kaplan-Meier analysis showing vascular outcome. Stent implanted with diameter ≥8 mm had a longer freedom from in-stent restenosis (ISR) (p = 0.04).

Re-intervention of stents

Re-intervention following stent implantation was performed for 24 stents (60%) in 16 cases, and the procedure was performed 48 times. Balloon dilation was performed 43 times. Stent-in-stent was performed in one case, whereas surgical dilation was performed in one case. Significant improvements were noted in terms of the narrowest diameter (2.2 ± 1.2 to 4.4 ± 1.7 mm, p = 0.01) and stenosis site pressure difference (10.2 ± 3.1 to 4.1 ± 1.7 mmHg, p = 0.02) following balloon dilation. As shown in Figure 4, re-intervention is commonly required following stent implantation. The median time of the first re-intervention was 5 months (1–43 months) from stent implantation. Re-intervention was performed 31 times (65%) in the first year following stent insertion and 11 times (23%) in the following year. In 10 stents, multiple balloon dilations of stent were required. Figure 5 shows the progress of a patient with isolated congenital PVS who received balloon angioplasty six times after stenting.

Figure 4. Kaplan-Meier analysis of re-intervention for pulmonary vein stents. Free from re-intervention of pulmonary vein stent is 50 and 26% at 1 and 2 years, respectively.

Figure 5. Angiogram and computed tomography of a patients who has isolated congenital pulmonary vein stenosis and common atrioventricular valve defect. Four pulmonary veins developed severe stenosis at early infantile period. ( a ) Right lower pulmonary vein stenosis of orifice before hybrid stenting at 11 months from birth. Two left stents were placed by percutaneous procedure. ( b ) Computed tomography of right upper and lower pulmonary vein stenosis. Two orifices of pulmonary vein were very close. ( c ) In-stent stenosis 10 months after placement of 5 mm bare-metal stent by hybrid procedure. ( d ) Follow-up catheter evaluation showed good patency except the occluded right upper pulmonary vein. This is the recent angiogram 5 years after stenting. This patient underwent trans-catheter re-interventions by balloon six times.

Complication, obstruction, and malposition of stents

In our patients, we did not find any complications related to stent implantation other than a minor haemorrhage from the lung after a percutaneous procedure. During follow-up, stent occlusion was noted in five stent cases (13%), among which four were recanalised with catheter intervention. Further, one stent migrated to the descending aorta and was retrieved with a percutaneous catheter.

Discussion

In this study, we present the results of balloon and stent treatment of PVS performed at our institution. The restenosis rate following surgery for the total anomalous pulmonary venous connection was reported as 10–15%,Reference Seale, Uemura and Webber 2 , Reference Mendelsohn, Bove and Lupinetti 4 , Reference Hancock Friesen, Zurakowski and Thiagarajan 5 and the reported risk factors include a small preoperative pulmonary veins,Reference Jenkins, Sanders, Orav, Coleman, Mayer and Colan 6 preoperative stenotic lesions of pulmonary veins, and infra-cardiac total anomalous pulmonary venous connection.Reference Shi, Zhu and Chen 7 Several studies have reported various effects of sutureless marsupialisation on prognosis.Reference Shi, Zhu and Chen 7 , Reference Kanter, Kirshbom and Kogon 8 Isolated congenital PVS is a rare disease with a poor prognosis, despite the existence of several treatments. The reported 3-year survival rate is 49% and risk factors for mortality include bilateral lesion, progression of diffuse stenosis, onset during early infancy, and restenosis following surgical treatment.Reference Seale, Webber and Uemura 1 , Reference Song, Bae and Jeong 9

Regarding the PVS post pulmonary vein isolation for adult patients, the use of stents rather than balloon treatment alone has been reported to result in a lower risk of restenosis,Reference Fender, Widmer and Hodge 10 , Reference Buiatti, von Olshausen and Martens 11 and stents of ≥10 mm have demonstrated good patency.Reference Prieto, Schoenhagen, Arruda, Natale and Worley 12

Three types of stenosis may develop following surgical repair of total anomalous pulmonary venous stenosis: stenosis of the atrial orifice following surgery, discrete stenosis in each inflow site of pulmonary vein, and long-segment stenosis from the inflow site to the upstream pulmonary vein. Our basic strategy is to perform rapid stenosis release, thus inhibiting the progression of the lesion to the upstream pulmonary vein.Reference Kato, Fu and Zhu 13 While surgical release of the atrial orifice stenosis is effective, surgical and balloon angioplasty and/or stent implantations are considered for other types of stenosis. Although balloon angioplasty can be used to achieve stenosis release, the improvement is only temporary with a high likelihood of restenosis and many cases undergo the procedure multiple times. Among our cases, following balloon angioplasty alone, 8 (53%) of 15 blood vessels became completely occluded during the follow-up period. Previous studies report the use of a cutting balloon for PVS, though only short-term improvement has been noted with a poor long-term prognosis.Reference Seale, Daubeney, Magee and Rigby 14 , Reference McMahon, McDermott and Walsh 15 Reported methods for stent implantation include bare-metal stent, drug-eluting stent, and covered stent. Balasubramanian et al reported a significant difference in terms of the re-intervention rate for stents of ≥7 mm,Reference Balasubramanian, Marshall and Gauvreau 16 whereas Cory et al found that although no difference was found in the survival rate of drug-eluting stent and other types of stent, stent patency was superior in the group of drug-eluting stent.Reference Cory, Ooi, Kelleman, Vincent, Kim and Petit 17 As shown in Figure 2, our investigation revealed no significant differences in the survival rate between the group undergoing balloon angioplasty alone and that undergoing stent implantation. However, we did find a significant difference in terms of the survival rate between the bare-metal stent group and other groups. The investigation based on the stent type revealed that stent size, minimum diameter, reference diameter, and vascular diameter following stent implantation were all significantly larger in the bare-metal stent group than in the other groups (Table 4). Therefore, we hypothesise that the placement of a large stent to secure a larger vascular diameter contributes to improved survival rates. On the other hand, our result shows that it is difficult to place a large stent in an area where pulmonary stenosis is severe and progressive to upstream veins. Tomita et al found that good patency was achieved in the blood vessels of patients who underwent dilatation with a stent of ≥5.6 mm and that repeated post-dilatation was required to maintain patency.Reference Tomita, Watanabe and Yazaki 18 While the implantation of a large stent could contribute to prognosis and patency improvement, oversized stents could also contribute to in-stent restenosis development. Aggressive stent implantation using a high-pressure or an oversized balloon is reportedly associated with the risk of in-stent restenosis, and damage to the intima could contribute to stenosis development.Reference Klues, Radke, Hoffmann and vom Dahl 19 Zamora et al investigated in-stent restenosis in miniature pigs that underwent oversized stent insertion into the iliac artery and reported that the use of an oversized stent of 152% or greater resulted in a higher incidence of in-stent restenosis compared to smaller sized stents.Reference Zamora, Sugimoto, Yamaguchi and Sugimura 20 Although we use stents of 150% or below the reference diameter, we have also inserted oversized stents larger than 150% into eight vessels for cases of hybrid pulmonary vein stenting.

According to a previous report by Furukawa et al on the use and effectiveness of drug-eluting stent for PVS, comparison of similar sized drug-eluting stent and bare-metal stent in pigs indicated that bare-metal stent was associated with more severe internal proliferation and stent stenosis and a significantly larger amount of granuloma formation than drug-eluting stent.Reference Furukawa, Kishiro and Fukunaga 21 Drug-eluting stents used in our study were all of the size 3.5 mm. A drug-eluting stent has an advantage of pharmacological benefits; however, we selected a bare-metal stent because the larger stent is believed to be more important for good outcomes. Several reports have focused on the use of covered stent,Reference Balasubramanian, Marshall and Gauvreau 16 with Gordon and Moore indicating that atrium expanded polytetrafluoroethylene-covered stents are more effective for PVS than bare-metal stent.Reference Gordon and Moore 22

Several reports have focused on hybrid stenting.Reference Mendelsohn, Bove and Lupinetti 4 , Reference Ungerleider, Johnston, O’Laughlin, Jaggers and Gaskin 23 Reference Yoon, Kim and Song 26 We found that hybrid stenting resulted in no significant difference in terms of the minimum diameter of the stenosis site before stent implantation compared with percutaneous stenting; however, it did result in significantly larger stents being used and post-stent vascular diameter being significantly larger. Possible advantages of hybrid pulmonary vein stenting include the fact that it can be performed in cases with limited vascular access; stent insertion can be performed under direct vision; while the location must be predetermined, it can be easily adjusted; severe stenosis can be surgically dilatated prior to stent insertion; a larger stent can be inserted; stent implantation is possible following plasty even for nearly occluded stenosis sites; any excessive stent length protruding to the atrium can be trimmed, flared, and adjusted for future catheter treatment; and malposition can be prevented by an anchoring suture connecting the stent tip to the atrial wall. Since 2010, our hospital has adopted the strategy of proactively performing only hybrid pulmonary vein stenting in patients. Although the physical burden associated with the use of a cardiopulmonary bypass (on-pump) and open-heart surgery is naturally greater than that associated with catheter treatment, it has several advantages. It has also been indicated that suturing of the atrial wall to prevent malposition can cause stent stenosis.Reference Shell, Ebeid, Salazar, Dodge-Khatami and Batlivala 25 However, our strategy is to use stent suturing to prevent malposition. When suturing, the stent edge is slightly flared and sutured to the atrial wall, while ensuring that the thread of suturing does not contact the inside of stent. Sullivan et al introduced the techniques of tailoring stents to fit the unique-shaped anatomical vessels.Reference Sullivan, Liou and Takao 27 It may be possible to deploy trimmed stents to stenotic pulmonary vein using percutaneous procedure. However, advantages of hybrid pulmonary vein stenting are not only trimming but also flaring and suturing of stents. These advantages are the primary reason why we selected hybrid stenting over percutaneous stenting in our hospital. Alternatively, avoiding cardiac surgery is an absolute merit for patients; hence, in the future, the feasibility of percutaneous stenting should be considered.

Our investigation of in-stent restenosis occurrence during the follow-up period indicated that the in-stent restenosis group had earlier onset of PVS and stent insertion timing and that the stent size tended to be smaller. As previously reported, early onset of PVS is a sign of poor prognosis, which may be due to severe disease and stenosis in the upstream pulmonary vein, making it impossible to insert a larger stent.Reference Song, Bae and Jeong 9 , Reference Quinonez, Gauvreau and Borisuk 28 The tendency for stents of ≥8 mm to maintain patency was similar to those reported in previous studies.

During the observation period, stent re-intervention was performed 48 times. Quinonez LG investigated catheter treatment following stent insertion and reported that re-intervention became less common as the time since stent insertion increased. They hypothesised that disease progression might burnout.Reference Quinonez, Gauvreau and Borisuk 28 In this study, the re-intervention-free rate was 50% at 1 year and 26% at 2 years, indicating that re-intervention was required by most stents. However, improvement was achieved in terms of vascular diameter and pressure difference in in-stent balloon dilation cases. Therefore, this procedure seems to be useful to maintain stent patency and is, therefore, strongly recommended. We believe that performing pulmonary vein stent implantation according to a long-term treatment plan, including balloon dilation of stent following insertion, can achieve better results. Cory et al reported that for in-stent balloon dilation, frequent re-intervention improved survival rates and vascular patency, suggesting that repeated performance of in-stent treatment to maintain patency contributes to achieving better outcomes.Reference Cory, Ooi, Kelleman, Vincent, Kim and Petit 17 Habara et al reported that the use of a drug-coated balloon achieved a better clinical and vascular prognosis compared to a conventional balloon. However, they reported a maximum balloon size of 4 mm.Reference Habara, Iwabuchi and Inoue 29 In the future, we hope to consider the use of drug-coated balloon also for the treatment of PVS and in-stent restenosis.

To date, we have not implemented chemotherapy to prevent stenosis nor have we conducted histological evaluation. The pathological mechanism of PVS is believed to be the occlusion of the pulmonary venous intima due to de novo intimal hyperplasia by myofibroblast proliferation.Reference Sadr, Tan, Kieran and Jenkins 30 Riedlinger et al previously demonstrated that various types of receptor tyrosine kinase and ligands are expressed in the intima where stenosis has occurred.Reference Riedlinger, Juraszek and Jenkins 31 Rehman et al found that the use of vincristine and methotrexate for inhibiting myofibroblast proliferation led to limited improvement.Reference Rehman, Jenkins and Juraszek 32 Callahan et al reported that chemotherapy with imatinib mesylate and bevacizumab combination achieved a certain level of efficacy with few adverse events.Reference Callahan, Kieran and Baird 33 We believe that further investigation of such possibilities for the development of novel treatment of PVS needs to be conducted.

Study limitations

This was a single-institution, retrospective study with a small sample size. It included the cases of PVS following surgery of total anomalous pulmonary venous connection and isolated congenital PVS with varying severity. While rare, there were some cases in which patients withdrew from the treatment prior to completion. Treatment approaches and devices that we use have changed from 2001 to 2017. Our patients underwent balloon and stent treatments as well as various types of surgery; therefore, it was impossible to evaluate the effects of balloon and stent treatment alone as well as each method’s issues. Further, it was impossible to investigate the effects of chemotherapy. Because PVS is a rare but often severe disease, comparison of different treatment selection is difficult. The conclusions derived from the present study are consistent with those of previous studies, indicating that insertion of a larger stent contributes to good vascular patency. However, we believe that to improve prognosis, proactive treatment is also required following stent implantation. Additional data are required to comprehensively evaluate surgical treatment, endovascular therapy, and chemotherapy, and further investigation is required regarding prevention of PVS.

Conclusion

We used balloon and stent treatments to aggressively treat PVS. The overall survival rates of 71% at 1 year and 49% at 5 years are not superior to those reported previously. The results suggest that the use of larger stents improves survival and vascular patency and that hybrid pulmonary vein stenting is suitable for the placement of larger stents. Treatment plans should consider post-stent re-interventions.

Acknowledgment

We would like to thank Dr Shunji Sano, Professor of surgery, Division of Pediatric Cardiothoracic Surgery of University of California San Francisco for the surgery of congenital heart disease in this research.

Financial Support

This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.

Conflicts of Interest

None.

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Figure 0

Figure 1. (a) Surgical view before hybrid pulmonary vein stenting, two orifices of pulmonary vein are very close (arrow). (b) After hybrid pulmonary vein stenting, two Express Vascular stents were implanted simultaneously. Both stents were of 5 mm size and 15 mm length. Cutting of extra stent strut and anchoring suture were placed to prevent migration.

Figure 1

Table 1. Patient demographics and diagnostic data of pulmonary vein stenosis

Figure 2

Table 2. Details about balloon angioplasty (BAP) of pulmonary vein stenosis

Figure 3

Table 3. Difference between hybrid pulmonary vein stenting (HPVS) and percutaneous pulmonary vein stenting (PPVS)

Figure 4

Table 4. Stent types and characteristics, comparison between bare-metal stents (BMS) and drug-eluting stent (DES)

Figure 5

Figure 2. (a) Kaplan-Meier analysis of patients treated for pulmonary vein stenosis. In overall, estimated survival is 71% and 49% at 1 years and 5 years. There is no significant difference between stent group and balloon angioplasty (BAP) group. (b)Kaplan-Meier comparing survival of patients who received bare-metal stent (BMS) implantation and patients who received only drug-eluting stent (DES) or only balloon angioplasty (BAP).

Figure 6

Table 5. Association with mortality of patients for pulmonary vein stenosis

Figure 7

Table 6. Comparison of pulmonary vein stent with intra-stent restenosis (ISR) or not

Figure 8

Figure 3. Kaplan-Meier analysis showing vascular outcome. Stent implanted with diameter ≥8 mm had a longer freedom from in-stent restenosis (ISR) (p = 0.04).

Figure 9

Figure 4. Kaplan-Meier analysis of re-intervention for pulmonary vein stents. Free from re-intervention of pulmonary vein stent is 50 and 26% at 1 and 2 years, respectively.

Figure 10

Figure 5. Angiogram and computed tomography of a patients who has isolated congenital pulmonary vein stenosis and common atrioventricular valve defect. Four pulmonary veins developed severe stenosis at early infantile period. (a) Right lower pulmonary vein stenosis of orifice before hybrid stenting at 11 months from birth. Two left stents were placed by percutaneous procedure. (b) Computed tomography of right upper and lower pulmonary vein stenosis. Two orifices of pulmonary vein were very close. (c) In-stent stenosis 10 months after placement of 5 mm bare-metal stent by hybrid procedure. (d) Follow-up catheter evaluation showed good patency except the occluded right upper pulmonary vein. This is the recent angiogram 5 years after stenting. This patient underwent trans-catheter re-interventions by balloon six times.