Life expectancy of patients with CHD has significantly increased over the last decades, which shifts the focus to the treatment of long-term morbidity. Reference Khairy, Ionescu-Ittu, Mackie, Abrahamowicz, Pilote and Marelli1,Reference Stuart2 In 20–82% of the patients with biventricular CHD, a reintervention is required during their life. Reference van der Palen, Blom and Kuipers3–Reference Asagai, Inai and Shinohara7 Right ventricular outflow tract obstructions are the most common cause for reinterventions of which percutaneous interventions for branch pulmonary artery stenosis account for a significant number. Reference van der Palen, Blom and Kuipers3,Reference Bacha, Scheule and Zurakowski5,Reference Sinzobahamvya, Boscheinen and Blaschczok6,Reference Santens, Van De Bruaene and De Meester8,Reference Khairy, Clair and Fernandes9 Branch pulmonary artery stenosis might result from different underlying mechanisms such as pulmonary coarctation, hypoplastic native pulmonary arteries, stenosis of anastomosis sites, iatrogenic obstruction by previous aortopulmonary shunt, compression of the pulmonary artery branch by an enlarged aorta, or the neo-pulmonary to neo-aortic geometry. Reference Elzenga, von Suylen, Frohn-Mulder, Essed, Bos and Quaegebeur10–Reference Morgan, Mertens, Grotenhuis, Yoo, Seed and Grosse-Wortmann12 Research has shown that branch pulmonary artery stenosis is associated with a reduced exercise capacity, lower peak oxygen consumption, and higher minute ventilation during exercise in patients with transposition of the great arteries and tetralogy of fallot. Reference Giardini, Khambadkone, Taylor and Derrick13,Reference Rhodes, Dave and Pulling14 This suggests that branch pulmonary artery stenosis has a significant effect on the exercise capacity in these patients. Percutaneous balloon angioplasty and stent implantation in branch pulmonary artery stenosis have been proven safe and effective in patients with CHD. Reference Baerlocher, Kretschmar, Harpes, Arbenz, Berger and Knirsch15–Reference Ko, Kim and Yu17 However, the (long-term) outcomes on exercise capacity, right ventricular function, and lung perfusion remain fairly unknown. Therefore, the aim of this review was to describe the (long-term) effects of percutaneous branch pulmonary artery interventions on exercise capacity, right ventricular function, and lung perfusion in biventricular CHD.
Methods
Prospective registration
The protocol and search string of this review were constructed by two researchers (RSJ and JPBF). The review was conducted according to the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines and was registered in PROSPERO International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42022306617).
Eligibility and exclusion criteria
Studies were included if they reported follow-up data after percutaneous interventions for branch pulmonary artery stenosis in biventricular CHD on at least one of the following outcomes: exercise capacity, right ventricular function, or lung perfusion. All age groups and type of study designs were included. Studies exclusively reporting on branch pulmonary artery stenosis in relation to pathological vessel disease (e.g. Williams or Alagille), single ventricle physiology, a systemic right ventricle, or other locations (right ventricular outflow tract, main pulmonary artery and peripheral pulmonary vessels) were beyond the scope of this review. Other exclusion criteria were studies exclusively reporting on surgical treatment, technical success, safety, efficiency and complications for branch pulmonary artery stenosis, articles that did not include at least one our outcomes of interest, experimental studies, no primary research articles (e.g. reviews, editorials, and commentaries), and articles with no full text available.
Search strategy and data extraction
A systematic search, screening, full-text review, and data extraction for articles from January 1975 to January 10, 2022, on PubMed, Embase, and Cochrane were conducted by two researchers independently (RSJ and JPBF). A date limit was set on 1975 because the arterial switch operation for dextro transposition of the great arteries first has been performed on May 4, 1975. Snowballing and back-referencing were used to ensure maximum article extraction. Deduplication was performed using Endnote (Endnote version 19.3, Clarivate analytics, London, UK), and examination of the titles, abstracts, and the remaining full texts was performed using Rayyan (rayyan.ai). A third author (JMPJB or AvdH) was consulted if initial discussion about discordance of included articles did not resolve disagreement. If the full text was not available, the first and last authors were contacted for the full text. If there was no response or the full text could not be provided, the studies were excluded. The results were presented in a narrative way and a meta-analysis could not be performed due to the heterogeneity of the patients and outcomes from the included articles.
Quality assessment
Risk of bias assessment was performed by two researchers independently (RSJ and JPBF), using the Joanna Briggs Institute critical appraisal tools. The checklist for quasi-experimental studies was used for the studies with a pre and post intervention study design and was based on 7 out of 9 criteria. Reference Tufanaru, Aromataris, Campbell, Hopp, Aromataris and Munn18 A detailed description of the quality assessment methods can be found in the supplemental material.
Results
The results were presented in a narrative way due to the heterogeneity of the patients and outcomes from the included articles. The systematic search of PubMed, Embase, and Cochrane up to January 10, 2022, resulted in 4701 hits. After removing the duplicates, 3922 potentially eligible articles remained. After screening title and abstract, 47 articles remained for full-text screening. Of those, 7 articles with in total 330 patients met the inclusion criteria (Fig. 1). Reference Hiremath, Qureshi and Prieto19–Reference Shaffer, Mullins and Grifka25
Figure 1. Flowchart.
Study characteristics
Most studies had a prospective study design (n = 6), while the remaining study was retrospective. Of those studies, 4 were single-centre and 3 were multi-centre. One study exclusively reported on patients with tetralogy of fallot, while the others reported on a heterogeneous group of patients with CHD with tetralogy of fallot as majority of the group. The majority reported on stent angioplasty as intervention for branch pulmonary artery stenosis. All interventions were percutaneous except for the study from Fogelman et al, in which 4 out of 42 patients received a stent during additional surgery (hybrid procedures). Reference Fogelman, Nykanen, Smallhorn, McCrindle, Freedom and Benson21 In most cases, the intervention was performed in the left pulmonary artery. 5 out of 7 studies specified the number of patients who underwent left pulmonary artery interventions (97 out of 160 [60%]). The remaining studies from Shaffer et al. and Sutton et al. did not distinguish between the pulmonary arteries. 3 out of 7 studies reported exclusively on interventions for unilateral branch pulmonary artery stenosis and the remaining reported on both unilateral and bilateral branch pulmonary artery stenosis. Follow-up duration differed, ranging from almost directly after the intervention to more than a decade after the intervention. The articles included reported on right ventricular function (n = 1), exercise capacity (n = 2), and lung perfusion (n = 7), which were assessed with a wide variety of parameters (Table 1).
Table 1. Baseline characteristics of the included studies.
AD = arterial duct; ALPCA = anomalous left coronary artery from pulmonary artery; DORV = double-outlet right ventricle; d-TGA = dextro transposition of the great arteries; F/u= follow-up; IVS = pulmonary atresia with intact ventricular septum; LPA = left pulmonary artery; MD = miscellaneous disorders; PA = pulmonary atresia; PAS = pulmonary artery stenosis; pPS= peripheral pulmonary stenosis; PS = pulmonary stenosis; PVR = pulmonary valve replacement; RPA = right pulmonary artery; TA = truncus arteriosus; ToF= tetralogy of fallot; VSD = ventricular septum defect.
* One patients underwent catheter closure of a patent arterial duct; the other patient had surgical ligation.
** Values are mean (range).
*** Values are median (range).
$ Aligille syndrome without distal pulmonary artery disease.
Indications for pulmonary artery interventions
Indications for pulmonary artery interventions are listed in Table 2. The studies from Hiremath et al. and Spadoni et al. described specific indications for pulmonary artery interventions while others used more general indications. Pre-interventional haemodynamic data (right ventricle pressures, gradients over stenosis, and blood flow distribution) differed between the studies ranging from mild to more severe pulmonary artery stenosis. Except for right ventricle pressures in the study from Hiremath et al. all pre-interventional haemodynamic data improved post-intervention, even in case of mild pulmonary artery stenosis (Table 2).
Table 2. Indications of percutaneous PA interventions.
BA = balloon angioplasty; MPA = mean pulmonary artery; PA = pulmonary artery; PI = pulmonary insufficiency; Psys= systolic pressure; RV = right ventricle; ToF= tetralogy of fallot.
* p<0.05 between pre- and post-intervention.
# p<0.01 between pre- and post-intervention.
** p-value unknown.
Right ventricular function
One study reported on right ventricular function measured using echocardiography and MRI (table S1). Reference Ing, Khan, Kobayashi, Hagler and Forbes24 The included study used a variety of parameters to assess right ventricular function and follow-up duration varied up to 2 years post intervention. At baseline, the majority of the patients in the study from Ing et al. showed normal right ventricular function, which remained unchanged during follow-up (p = not significant). Reference Ing, Khan, Kobayashi, Hagler and Forbes24 Therefore, the only study showed no clear information about right ventricular function or remodelling after a percutaneous intervention for branch pulmonary artery stenosis.
Exercise capacity
Exercise capacity was assessed in two articles using treadmill and bicycle exercise tests (Table 3). Reference Hiremath, Qureshi and Prieto19,Reference Sutton, Peng and Lock20 The follow-up duration was approximately the same. In both studies, known or suspected residual pulmonary artery stenosis was considered as indication for right heart catheterisation (Table 2). In general, exercise capacity showed improvement after a percutaneous intervention for branch pulmonary artery stenosis. Sutton and Hiremath et al. both showed a significant increase in peak O2 pulse (% predicted), VO2 max (% predicted) and the VE/VCO2 slope (Sutton et al: peak O2 pulse = 87.3 ± 20.1 versus 105 ± 23, VO2max = 66.3 ± 14.4 versus 80.6 ± 12.8, VE/VCO2 slope = 33.4 ± 7.8 versus 28.6 ± 5.4; Hiremath: peak O2 pulse = 82 (51–100) versus 93.5 (53–134), VO2max = 70 (45–96) versus 83 (47–121), and VE/VCO2 slope = 32.5 (26–42) versus 29.3 (20–37), all p < 0.05). Reference Hiremath, Qureshi and Prieto19,Reference Sutton, Peng and Lock20 Both studies also showed that successful stenting ≥ 5% improvement in pulmonary blood flow to the stenosed lung (Sutton et al.) and ≥ 20% improvement in pulmonary blood flow to the stenosed lung (Hiremath et al.) significantly improved the exercise capacity, whereas unsuccessful stenting did not. Therefore, both studies that reported on exercise capacity after a percutaneous treatment for branch pulmonary artery stenosis showed a significant improvement.
Table 3. Outcomes on exercise capacity.
AD = arterial duct; ALPCA = anomalous left coronary artery from pulmonary artery; BAP = balloon angioplasty procedure; DORV = double-outlet right ventricle; d–TGA = dextro transposition of the great arteries; F/u= follow–up; IVS = intact ventricular septum; LPA = left pulmonary artery; MD = miscellaneous disorders; Ns= not significant; PA = pulmonary atresia; PAS = pulmonary artery stenosis; pPS= peripheral pulmonary stenosis; PS = pulmonary stenosis; PVR = pulmonary valve replacement ; RPA = right pulmonary artery; TA = truncus arteriosus; ToF= tetralogy of fallot; VSD = ventricular septum defect.
$ Aligille syndrome without distal pulmonary artery disease.
# Borg score is a measure of subjective perceived exertion.
& Peak work and Borg score became significant with imputed data (n = 14) (p = 0.03 and p = 0.02). Descriptive statistics were similar.
* Values are median (range).
** ≥5% improvement in pulmonary blood flow to the stenosed lung.
Lung perfusion
Lung perfusion was reported by seven studies using nuclear lung perfusion scans, MRI, or both (Table 4). Reference Hiremath, Qureshi and Prieto19–Reference Shaffer, Mullins and Grifka25 The follow-up duration varied from shortly after to 2 year after the procedure. All studies included patients with known or suspected pulmonary artery stenosis. Hiremath and Spadoni et al. reported indications based on a number of criteria, while the other studies used the presence of pulmonary artery stenosis in general (Table 2). Overall, the lung perfusion to the affected lung is improved after a percutaneous intervention for branch pulmonary artery stenosis. All studies that assessed mean flow to the affected lung reported improvement, ranging from 20 to 32% before the intervention and 36–47% during follow-up (all p < 0.05). Reference Hiremath, Qureshi and Prieto19–Reference Shaffer, Mullins and Grifka25 Fogelman reported, in addition to improved flow after percutaneous treatment for the left pulmonary artery, no significant improvement for the right PA. Reference Fogelman, Nykanen, Smallhorn, McCrindle, Freedom and Benson21 Sutton and Hiremath et al. both showed significant reduction in blood flow maldistribution measured as the percentage of discrepancy from the normal blood flow distribution (55 right lung/45% left lung). Reference Hiremath, Qureshi and Prieto19,Reference Sutton, Peng and Lock20 Therefore, the majority of the studies show an improvement in lung perfusion after a percutaneous intervention for branch pulmonary artery stenosis.
Table 4. Outcomes on lung perfusion.
AD = arterial duct; ALPCA = anomalous left coronary artery from pulmonary artery; DORV = double-outlet right ventricle; d–TGA = dextro transposition of the great arteries; F/u= follow–up; IVS = intact ventricular septum; LPA = left pulmonary artery; LPS = lung perfusion scans (nuclear); Ns= not significant; MRI = magnetic resonance imaging; PA = pulmonary atresia; PAs= pulmonary arteries; PAS = pulmonary artery stenosis; PS = pulmonary stenosis; RPA = right pulmonary artery; TA = truncus arteriosus; ToF= tetralogy of fallot; VSD = ventricular septum defect.
* One patients underwent catheter closure of a patent arterial duct; the other patient had surgical ligation.
** Values are median (range).
*** Maldistribution refers to the percentage point deviation from the normal 55%/45% right/left pulmonary blood flow distribution.
$ Aligille syndrome without distal pulmonary artery disease.
& p–value between lung perfusion post intervention and follow–up (both 6 months and 1 year) not significant (p > 0.05).
# p–value between lung perfusion pre intervention and post intervention significant (p < 0.001).
Quality assessment
Two out of 7 studies were considered low risk of bias and 5 were considered moderate risk of bias. An overview of the quality assessment is given in table S2.
Discussion
This study systematically reviewed literature on (long-term) outcomes for right ventricular function, exercise capacity, and lung perfusion after percutaneous interventions for branch pulmonary artery stenosis in biventricular CHD. In general, lung perfusion and exercise capacity seem to improve after percutaneous treatment for branch pulmonary artery stenosis. No conclusions about right ventricular function or remodelling could be made given that only one study discussed right ventricular function. All results and conclusions discussed in this review should be interpreted with caution because study numbers were low, study populations of the included articles were very heterogeneous, no individual results were reported and conclusions of the articles are based on the group as a whole. This remains a large issue in CHD but cannot be avoided since none of the CHD patients are similar in their anatomy, haemodynamics, and function.
Right ventricular function
A variation of parameters was used to measure right ventricular function with echocardiography and MRI, where MRI is considered the gold standard to assess right ventricular function. Reference Pennell26 The only study reporting on right ventricular function during follow-up showed no clear changes in right ventricular function after a percutaneous intervention for branch pulmonary artery stenosis. Reference Ing, Khan, Kobayashi, Hagler and Forbes24 However, p-values of echocardiographic right ventricle pressures during follow-up were lacking. In addition, only 17 patients (29%) underwent MRI prior to the intervention and 5 patients (9%) during follow-up. Moreover, right ventricular ejection fraction was already in the normal range in the majority of these limited number of patients, which might explain the lack of a clear improvement after the intervention. Given that only one article reported on right ventricular function without statistical support, it is difficult to discuss any conclusions. This shows the urgency for future research about right ventricular function in the (long-term) follow-up of these patients.
Exercise capacity
Two studies were included for exercise capacity with similarities in parameters that increases the generalisability of the results. Reference Hiremath, Qureshi and Prieto19,Reference Sutton, Peng and Lock20 Both studies showed a significant increase in the exercise capacity despite different study populations (age, type of CHD, severity of pulmonary artery stenosis, and unilateral versus bilateral) and a relatively short follow-up duration. This is supported by other studies, which reported a negative effect of pulmonary artery stenosis on exercise capacity by limiting the pulmonary blood flow. Reference Giardini, Khambadkone, Taylor and Derrick13,Reference Rhodes, Dave and Pulling14 Long-term data about exercise capacity after percutaneous interventions for branch pulmonary artery stenosis are limited, but current data suggest that exercise capacity increases, even in case of mild pulmonary artery stenosis. Nevertheless, further research is needed.
Lung perfusion
Lung perfusion was reported by seven studies, which made it the most reported outcome . Reference Hiremath, Qureshi and Prieto19–Reference Shaffer, Mullins and Grifka25 All studies assessed lung perfusion to the affected lung using the gold standard nuclear lung perfusion scans and MRI, which improves the generalisability of the results. Reference Dessy, Hermus, van den Heuvel, Oei, Krenning and Hess27,Reference Pruckmayer, Zacherl, Salzer-Muhar, Schlemmer and Leitha28 In general, stent or balloon angioplasty improved lung perfusion and reduced the maldistribution of the pulmonary blood flow, despite differences in study populations and pulmonary artery stenosis severity. This might be explained by the increase in blood vessel diameter and is substantiated by studies that show the effectiveness of interventions for branch pulmonary artery stenosis on dilating the blood vessel. Reference Baerlocher, Kretschmar, Harpes, Arbenz, Berger and Knirsch15–Reference Ko, Kim and Yu17 Fogelman et al. found no significant improvement for right pulmonary artery flow after the percutaneous intervention, which might be a result of the small sample size (n = 4). Overall, there is a general trend towards improved lung perfusion after a percutaneous intervention in the branch pulmonary arteries, even in case of less severe pulmonary artery stenosis.
Balloon angioplasty versus stent implantation
The majority of studies performed percutaneous stent placement as treatment for pulmonary artery stenosis. Reference Hiremath, Qureshi and Prieto19,Reference Fogelman, Nykanen, Smallhorn, McCrindle, Freedom and Benson21–Reference Shaffer, Mullins and Grifka25 Sutton et al. were the only study that reported on balloon angioplasty. Reference Sutton, Peng and Lock20 Even in this study, almost all balloon angioplasty ended in stent placement, and results of balloon angioplasty were not presented separately. Therefore, no comparison can be made between the effects of balloon angioplasty and stent implantation.
Differences in underlying CHD
From the included articles, one exclusively reported on tetralogy of fallot, whereas the others reported on an heterogeneous study population. Reference Oyen, van Oort, Tanke, van Mill, Aengevaeren and Corstens22 In all heterogeneous study populations, tetralogy of fallot resembled the majority of the group. Reference Hiremath, Qureshi and Prieto19–Reference Fogelman, Nykanen, Smallhorn, McCrindle, Freedom and Benson21,Reference Spadoni, Giusti, Bertolaccini, Maneschi, Kraft and Carminati23–Reference Shaffer, Mullins and Grifka25 The difference in aetiology of pulmonary artery stenosis makes it difficult to generalise the reported results, primarily for tetralogy of fallot, to other CHD such as transposition of the great arteries. In tetralogy of fallot, pulmonary artery stenosis might be caused by pulmonary coarctation, hypoplastic native pulmonary arteries, stenosis of anastomosis sites, or iatrogenic obstruction by previous aortopulmonary shunt, whereas in transposition of the great arteries, it is mainly caused by compression of the pulmonary artery branch by an enlarged aorta or the neo-pulmonary to neo-aortic geometry. Reference Elzenga, von Suylen, Frohn-Mulder, Essed, Bos and Quaegebeur10–Reference Morgan, Mertens, Grotenhuis, Yoo, Seed and Grosse-Wortmann12 Therefore, balloon angioplasty might be less effective in increasing the branch pulmonary artery diameter in transposition of the great arteries compared to tetralogy of Fallot and percutaneous stent placement might have a more favourable effect. Reference Formigari, Santoro and Guccione29 Currently, the data are very limited for transposition of the great arteries, and this review cannot draw any conclusions for this group separately because of the limited number of transposition of the great arteries patients in the included articles (16 out of 330 patients in all studies combined). In addition, no conclusions could be made for other types of biventricular CHD due to low patient numbers.
Limitations
This review has several limitations with the low number of included studies as the most striking one. This small retrieval might partly result from extensive inclusion and exclusion criteria for our specific outcomes of interest in biventricular CHD. As a result, no significant or statistically analysable and practical conclusions can be made from the results. In addition, patient populations of the included articles were very heterogenous, which made it impossible to derive population specific conclusions. Finally, effects between stent and balloon angioplasty could not be compared due to a lack of articles reporting on our outcomes of interest after balloon angioplasty interventions. These limitations show that there is need for larger prospective studies about right ventricular function, exercise capacity, and lung perfusion after pulmonary artery interventions in biventricular CHD. Therefore, we started a multicentre randomised controlled trial about the effects of percutaneous pulmonary artery interventions on exercise capacity and right ventricular function in patients with biventricular CHD in the Netherlands (ClinicalTials.gov ID: NCT05809310).
Conclusion
Although pulmonary artery interventions are frequently performed in biventricular CHD, data on relevant outcome parameters such as exercise capacity, lung perfusion, and right ventricular function are largely lacking. An increase in exercise capacity and improvement of lung perfusion to the affected lung has been described in case of mild to more severe pulmonary artery stenosis during relatively short follow-up. However, there is an urgent need for future studies to evaluate the effect of pulmonary artery interventions in various CHD populations including transposition of the great arteries.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S1047951124000015.
Acknowledgements
We thank Drs. Paulien H. Wiersma for her assistance and contribution as librarian from the University Utrecht to the search string of this review.
Financial support
We acknowledge the support from the Netherlands Cardiovascular Research Initiative to this review as funding source for R.S. Joosen her PhD project as part of the OUTREACH consortium: an initiative with support of the Dutch Heart Foundation and Hartekind, CVON2019-002 OUTREACH.
Competing interests
None.
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