PART III - INTERVENTIONS FOR CONGENITAL AND ACQUIRED PULMONARY VEIN STENOSIS
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Updated on November 20, 2020
PART III

Interventions for congenital and acquired pulmonary vein stenosis

James R. Bentham, Neil Wilson

Summary

PVS is a progressive illness and unless good surgical relief can be obtained early in the course of the disease the course becomes recalcitrant to further therapeutic intervention with long-term results being generally disappointing. Published series do, however, clearly document short-term improvements from catheter approaches, not only in terms of vessel diameter, pullback gradients and right ventricular pressure or pulmonary artery resistance, but also in patient symptoms. There is clearly much room for improvement in the management of this condition though the rarity of the lesion precludes significant advances from being made. Animal models hold some promise [82, 83]. A reasoned interventional approach following exploration of surgical options and a joint institution decision would begin with a careful diagnostic catheter study followed by targeted angioplasty. In the presence of a fixed lesion, despite high inflation pressures of a non-compliant angioplasty balloon, a cutting balloon might be considered. Where there is significant recoil of a lesion and the clinical circumstances demand a good result, a stent may be placed. Interventional procedures must regrettably be regarded as palliative, with the disease being associated with an all too frequently grave overall prognosis.

Introduction

Stenosis of the pulmonary veins is a rare but serious condition and can involve single or multiple veins. The outlook is guarded and treatment options limited. Following therapy, realised clinical improvement can be disappointingly short-lived. It is against this backdrop that many catheter and surgical therapies have emerged. Results not infrequently leave the reader wondering whether the natural history has been modified at all; in most cases the progression of disease is relentless. Here we review the disease pathogenesis and the catheter-based treatment options available. Interventional techniques including angioplasty, cutting balloon angioplasty and stent placement are discussed in detail. What is known regarding risk factors for an adverse outcome is considered, along with the appropriate timing for intervention.

Definitions

Pulmonary vein stenosis (PVS) can be defined as primary or secondary depending on whether it occurs in the absence or presence of prior atrial surgery or intervention. In a paediatric population primary PVS occurs most commonly following prematurity and secondary PVS most commonly following repair of total anomalous pulmonary venous drainage (TAPVD). In an adult population, secondary PVS can follow radio-frequency ablation procedures for atrial fibrillation or atrial futter. Primary PVS can occur in isolation but is often associated with a range of other cardiac diagnoses [1, 4]. Age of presentation varies but for primary PVS it is usually in infancy, with failure to thrive, respiratory infections, dyspnoea and respiratory failure being the most frequent initial complaints [2, 4, 5]. In premature infants it can be compounded by the coexistence of chronic lung disease. There is a weak association between the number of veins involved and the degree of their obstruction with the severity of symptoms [8]. Stenosis of a single vein can, however, drive pulmonary hypertension. Pulmonary hypertension becomes increasingly severe with time and right ventricular failure evolves. If there is an associated atrial septal defect in this setting profound cyanosis can result. Periodic haemoptysis is not infrequent from the affected lobe or the collateralisation that can resut.

FOCUS BOX 1Pulmonary vein stenosis
  • PVS is a rare condition and not infrequently associated with other cardiac malformations and prematurity [1, 2]
  • PVS is a progressive illness and unless good surgical relief can be obtained early in the course of the disease the course becomes recalcitrant to further therapeutic intervention with long-term results being generally disappointing [3]
  • In this context interventional procedures must be regarded as palliative, with a primary objective of symptomatic improvement [4]

Prevalence

PVS was first described in 1951 [9] emphasising the rarity of the lesion and the difficulties with making a diagnosis. By comparison with other uncommon left heart inflow obstructive lesions (cor triatriatum, supramitral membrane and mitral stenosis), PVS is much rarer [10, 11, 12, 13, 14, 15, 16]. Searching the Pediatric Cardiac Care Consortium database over a twenty-year period, Holt reports an incidence of primary PVS of 0.03% [3]. No gender discrepancy has been described. Familial cases have rarely been reported [17, 18].

There is no clear pattern of associated malformations occurring with PVS evident from the literature. Of 58 cases of PVS retrospectively reviewed across three European countries, isolated PVS occurred in only 10% with the remainder being associated with various cardiac anomalies (ventricular septal defect, atrioventricular septal defect, cor triatriatum, supravalvar mitral membrane, scimitar syndrome, coarctation and Ebstein’s malformation amongst others) [1]. Similar findings have been reported in other series [8, 19, 20, 21, 22]. More recently we have become increasingly aware of PVS as a long-term sequela in extremely preterm babies. Of the 26 cases reviewed by Drossner, 61% occurred in infants who were preterm [2]. Secondary or acquired PVS frequently follows repair of TAPVD (7-11%) [16, 23, 24, 25, 26, 27, 28]. It is unlikely that inadequate opening of the pulmonary venous confluence into the left atrium by the surgeon wholly explains the high incidence of PVS following TAPVD repair. A pre-existing developmental abnormality of the pulmonary veins is in many cases a more likely explanation. Secondary PVS is also seen following radio-frequency ablation in the left atrium for atrial fibrillation/flutter in adults [29, 30]. The pathology and outcome here is different and is considered separately.

The pathogenesis of PVS is poorly defined beyond the recognition that fibrous intimal thickening and medial hypertrophy occur rapidly [20, 31, 32, 33]. It may be of greater value to define the nature of the obstruction, as this may direct therapeutic approaches and be more strongly predictive of outcome following therapy. For primary PVS there is strong evidence to support rapid disease progression with stenosis eventually resulting in atresia developing through infancy or into early childhood. There are documented examples of normal pulmonary venous drainage on early imaging in individuals who have ultimately developed PVS within months [1, 2, 34, 35].

Obstruction for secondary PVS following TAPVD repair may be limited to the anastomosis or the pulmonary venous confluence. In some cases, however, the obstruction will be more extensive with a fibrous reaction extending along the course of the vein into the lung parenchyma or associated with a developmental hypoplasia or absence of the pulmonary veins. Obviously this last sub-type, with its origins most likely in utero, will be the most difficult to treat if treatable at all. It has yet to be established whether these difficult to manage patients can be identified with careful imaging, though many centres routinely perform high resolution cardiac computed tomography or magnetic resonance imaging frequently combined with diagnostic angiography with this intention. Some cases of secondary PVS are associated with mediastinal fibrosis [36, 37]. Mediastinal fibrosis is usually idiopathic and progressive but consideration should be given to infective mediastinal fibrosing disease (excluding tuberculosis and aspergillus disease especially in the setting of immunocompromised individuals, Figure 1 ).

ACQUIRED PULMONARY VEIN STENOSIS FOLLOWING RADIO-FREQUENCY ABLATION FOR ATRIAL FIBRILLATION

Acquired pulmonary vein stenosis in adults is a rare disease and until recently was most frequently caused by extrinsic disease infiltrating and surrounding the pulmonary veins (including fibrosing mediastinitis, sarcoidosis and neoplasia). Following the advent of radio-frequency ablation for atrial fibrillation a collection of adults with secondary pulmonary vein stenosis emerged. Given the rarity of this entity and the difficulties with non-invasive imaging assessment of atrial structures in the adult it is not surprising that diagnosis is frequently delayed. Presentation is usually non-specific (such as dyspnoea and lethargy), and a heightened awareness of the possibility of this diagnosis following radio-frequency procedures is essential. As ablation strategies have evolved, pulmonary vein stenosis is now an extremely uncommon complication of this treatment.

Imaging

2-D colour-flow transthoracic echocardiography remains the imaging tool of choice in affording serial assessment of right ventricular pressure as well as identifying the number of veins involved [38, 39, 40, 41] ( Figure 2 ). Pulmonary veins are potentially obstructed on echocardiography if the pulsed-wave Doppler of the pulmonary vein shows non-phasic flow or a velocity exceeding 1.6 m/s [42]. All new cases of congenital heart disease and all postoperative patients should have all pulmonary veins carefully interrogated. Chest radiographs can be difficult to interpret with single-sided pulmonary venous obstruction as some patients demonstrate ipsilateral signs of pulmonary plethora and pulmonary venous hypertension whilst others demonstrate signs in the contralateral lung because of the maldistribution of blood flow that eventually results [43, 44]. Pulmonary perfusion scans rarely help with decision making. Acoustic windows especially in older patients can limit the sensitivity of echocardiography and in the setting of clinical suspicion of pulmonary venous obstruction cardiac high resolution spiral computed tomography or magnetic resonance imaging is increasingly being employed to define the sites of obstruction with or without angiography. Computed tomography has advantages in infants, achieving greater resolution than magnetic resonance imaging and frequently obviating the need for general anaesthesia in view of the speed of image acquisition ( Figure 1 ) [45]. Magnetic resonance (MR) imaging with angiography will avoid radiation exposure and is preferred in many units performing MR scans in infants under general anaesthesia ( Figure 3 ). MR has the advantage of enabling assessment of right ventricular pressures and flow assessments for accurate quantification of pulmonary vascular resistance in combination with a transpulmonary gradient obtained with a hybrid catheter study [46, 47]. Surgical decisions may be made at this point depending on institutional preference or following diagnostic catheterisation studies. Our practice is to perform angiography as well as non-invasive imaging assessments with MR or CT. The reasons for this include an accurate assessment of pulmonary vascular resistance but more importantly an attempt at defining the exact nature of the underlying obstructive disease. Angiographic definitions of pulmonary venous obstruction can be difficult though a reduction in overall diameter to <50% of the vessel diameter, slowed return of contrast from the obstructed lung segment and a mean gradient through the stenosis >5 mmHg would be strongly supportive.

Surgical treatment options

The surgical options available to manage both primary and secondary PVS are beyond the scope of this chapter, which can only offer a brief discussion of the options against which to position the role of catheter-based intervention. Many surgical approaches have been tried including anastomotic revision for secondary PVS, intraoperative stent placement, patch venoplasty, dilation and scar excision and sutureless pericardial marsupialisation [25, 48, 49, 50]. Sutureless repair techniques involve reconstituting atrial tissue to pericardium with the intent of avoiding left atrial suture lines. There are some encouraging reports of success following these methods [25, 48, 49]. Each report is retrospective and none compares directly the efficacy of surgery versus catheter treatment and usually both treatments are used collaboratively. It is also likely that different patient populations are described since catheter treatments are often performed only when all other options have been exhausted. Nevertheless, Devaney and others report some of the most optimistic results for the management of this disease [4, 24, 25, 49, 50]. Among 11 patients with acquired PVS who underwent surtureless pericardial marsupialisation there was only one late death secondary to restenosis [4, 24, 49].

Catheter indications

Most institutions consider intervening on pulmonary veins after exhausting surgical approaches in the symptomatic child with systemic level or greater right ventricular pressures. In the asymptomatic child with single vein involvement and right ventricular pressures which are not particularly elevated, observation would seem prudent given the potential risks of intervention and the lack of evidence to support improved long-term outcome. Occasionally intervention has been performed on pulmonary veins as short-term palliation before surgery or to improve the possibility of a better surgical result, for example on obstructed descending and vertical veins in TAPVD [51, 52, 53]. Following growth, this may allow surgery on a more stable infant and is a potentially life-saving therapy.

Angioplasty might be usefully performed in a suture line anastomotic obstruction where the pulmonary venous confluence opens into the left atrium. However, it is the authors’ and others’ experience that obstruction secondary to surgical technique is rarely the cause of secondary PVS, with a more insidious developmental abnormality of the pulmonary veins being more likely and, as discussed above, less responsive to therapy. Many institutions favour further surgery using a sutureless technique as the initial approach to these patients. Stents will continue to be placed in primary and secondary PVS but generally most interventionists will place a stent only after failed angioplasty or in a high-risk situation where a good short-term result needs to be achieved, such as in a child on a ventilator with severe pulmonary hypertension. The child will, however, be committed to future procedures for in-stent stenosis.

Catheterization procedure

PREPARATION AND ACCESS

The goals of the procedure are set jointly by the cardiology and surgical teams. Quantifying risks can also be problematic but they are probably similar to the risk of performing a diagnostic catheter study in a pulmonary hypertensive child. These risks have been considered in the literature and can be used as a guide [54]. General anaesthesia is indicated and appropriate planning with the anaesthetist and post-procedure intensive care team should be arranged. One unit of blood needs to be readily available. Femoral venous access improves the chances of crossing the atrial septum through a patent foramen ovale if present. Access from the inferior caval vein also improves the catheter approach to the right-sided veins which can be difficult, though not impossible, to access if approaching from the internal jugular vein. For interrupted inferior caval vein with azygous continuation or bilateral femoral vein occlusion a transhepatic approach is favoured over the internal jugular vein approach for the same reason. We routinely place a 4 French (Fr) arterial sheath for arterial pressure monitoring, confirming a normal left ventricular end-diastolic pressure and to check arterial blood gases periodically. As procedures can be prolonged and are performed on the left side of the circulation, full heparinisation is appropriate after crossing the atrial septum in case transseptal puncture is necessary (heparin sulphate 100 IU/kg iv and then to maintain an ACT >200s). Systemic emboli is a common complication either from the long sheaths and long duration of the procedure or from thrombus in partially obstructed or near atretic veins that are then openend during the procedure. Transseptal puncture in infants is potentially hazardous as the left atrium is usually small and the atrial septum hypertrophied. We prefer to use a radio-frequency wire with a coaxial catheter such as the system available from Baylis (Montreal, QC, Canada) as this affords greater control ( Figure 4 ) but standard Brockenbrough needle approaches can be used in older children. Prophylactic antibiotics are given by some to cover the procedure. A blood gas should be checked before recording haemodynamic data and the endotracheal tube position confirmed. The lung fields should be viewed on brief fluoroscopy for lobar collapse.

HAEMODYNAMICS

Right heart haemodynamic data can be obtained with a 4-5 Fr multipurpose, a 4-5 Fr Judkins right coronary or a 5-6 Fr balloon wedge catheter depending on preference. Attention should be given to the inspired oxygen content. In practice it can be difficult to keep this to less than 30% in unstable patients; blood gases will therefore need to be taken alongside haemodynamic data to calculate dissolved oxygen. The minimal set of pressures, saturations and blood gases required are inferior and superior caval veins, right atrium, pulmonary artery, left atrium and aorta. If the atrial septum cannot be crossed a pulmonary venous wedge pressure will suffice as approximating left atrial pressure.

ANGIOGRAPHY

Selective or non-selective pulmonary artery wedge angiograms can be a productive place to start following collection of haemodynamic data and are often highly informative as to the site, number and severity of stenoses. An angiogram can be performed with a balloon wedge catheter, a pigtail catheter or a multipurpose catheter either in each pulmonary artery separately or in each individual lobar branch. Layered neat non-ionic contrast media (10 mls) with either saline or aspirated blood (10 mls) can be injected rapidly by hand (20 mls leurlocked syringe) to define the course of the pulmonary venous return. These images are usually best acquired straight anteroposterior and straight lateral until the site of obstruction is defined ( Figure 1 ).

PULMONARY VEIN CANNULATION

Following wedge angiograms the atrial septum is crossed either directly or via a transseptal puncture with a Brockenbrough needle or a radio-frequency wire as already discussed. A guiding sheath can then be placed and heparin given if it has not been given already. The left-sided upper and lower veins are usually easily entered from an inferior caval vein approach. Right-sided veins can be more difficult and several catheters may need to be tried, sometimes employing the roof of the left atrium to increase the curve on the catheter. A guidewire may be useful such as a Terumo 0.035’ wire (Terumo Europe, Leuven, Belgium). Engagement should be attempted with a 5 Fr multipurpose catheter with consideration given to changing to a cobra glide catheter (Boston Scientific, Natick, MA, USA) if the former were unsuccessful. The Judkins right coronary catheter can also be gainfully employed. The pressure gradient across the target lesion should be recorded. If catheter position has been difficult to obtain then a second venous sheath will allow simultaneous left atrial and proximal vein pressure measurements to be obtained without losing position of the catheter and ultimately wire position. Selective hand angiograms should be obtained with neat contrast. The right-sided veins are often best profiled in a straight anteroposterior or right anterior oblique and lateral projection with the left-sided veins requiring some left anterior oblique and cranial angulation. Optimal profiling will require further alteration of angulation after obtaining initial angiographic images depending on the location of the stenosis [55].

Catheter intervention

ANGIOPLASTY

Angioplasty for PVS has been performed for more than two decades [56, 57, 58]. Short-term improvement is clearly documented including improvement in symptoms [6]. However, the improvement is short-lived and in most restenosis is evident by 3-6 months following the initial dilatation. It is for this reason that other methods have been tried, but due to the rarity of the lesion there are no studies directly comparing one procedure against another. In view of the fact that no procedure has proved itself superior, many operators perform angioplasty initially only proceeding to cutting balloons or stent placement if the lesion is fixed or there is marked elastic recoil respectively. If a good result is realised with angioplasty the procedure may be discontinued at this point and clinical progress observed. Drug eluting balloons can be tried but there is as yet no evidence that these yield a superior result.

FOCUS BOX 2Interventional management
  • Multiple procedures may be necessary and angioplasty is the initial technique of choice [1]
  • In the presence of a fixed lesion, despite high inflation pressures of a non-compliant angioplasty balloon, a cutting balloon might be considered [5, 6]
  • Where there is significant recoil of a lesion and the clinical circumstances demand a good result, a stent may be placed [7]

ANGIOPLASTY TECHNIQUE

The stenosed pulmonary vein should be cannulated as distally as possible to improve wire position. Several wires can be used and the choice will depend to some extent on the age of the child and the catheter position achieved. The floppy part of the wire needs to be beyond the stenosis to provide a secure scaffold for delivering and retrieving various-sized angioplasty balloons. 0.014’ coronary wires such as heavy weight or middle weight wires are particularly useful in infants (Abbott Vascular, Abbott Park, IL, USA). Two coronary wires (‘buddy wire’) can increase the amount of support and aid tracking of the angioplasty balloon ( Figure 4 ). Several coronary wires may need to be tried if it is difficult crossing a tight lesion.
Angioplasty should increase the diameter of the narrowed lesion by a factor of 3, aiming to achieve a size similar to the distal vessel diameter if possible ( Figure 5 ). This might involve using a smaller balloon followed by a larger one. The first inflation is useful in assessing the recoil of the vessel and the likelihood of achieving a good result with angioplasty alone. Again, coronary balloons are particularly useful in small infants though other non-compliant larger balloons will be required in larger patients (for example Balt Cristal [Synapse, Dublin, Ireland] and Opta® pro non-compliant balloons [Cordis, Johnson & Johnson, Warren, NJ, USA] amongst others).

CUTTING BALLOONS

Poor results from conventional balloon angioplasty led to exploration of cutting balloon angioplasty [20, 57, 59] alone or more likely in combination with angioplasty and drug euting balloons. These can be used safely in infants albeit with long procedure times [5]. As with standard balloon angioplasty, results are not sustained and repeat procedure is likely to be required within 6 months [6]. Short-term improvements in vessel calibre, right ventricular pressure and pulmonary artery resistance and improvement in patient symptoms can be expected [5]. Superiority of cutting balloon angioplasty over conventional angioplasty techniques is suggested by a number of authors but no randomised comparison has been performed [6]. Cutting balloon angioplasty has also been performed in adults with PVS following radio-frequency ablation procedures [56, 60, 61].

CUTTING BALLOON TECHNIQUE

A wire is placed in the stenosed pulmonary vein for stability as described above and a 6 Fr guiding sheath placed over the wire to protect the cardiac structures from the cutting balloon. Cutting balloons range from 2.25 mm to 8 mm in diameter (Boston Scientific, Natick, MA, USA). A manometer should be used to ensure the recommended pressures are not exceeded (8-10 atm). Care should be taken to bring the balloon back into the guiding sheath and the blades should be checked on removal from the body.

STENT PLACEMENT

Results from stent placement in PVS are difficult to evaluate by comparison with angioplasty or cutting balloon angioplasty as they are likely to be used when the initial angioplasty result is regarded by the operator as sub-optimal ( Figure 6) [7, 62, 63, 64, 65, 66, 67, 68, 69]. Although short-term results are good, significant in-stent stenosis occurs quickly and is a major problem. Further stents, intrastent sonotherapy [70], drug-eluting stents or PTFE-covered stents [71] have all been used to try to combat this but with no evidence of a superior result. Animal stent models do exist and may be useful in the future for trialling drug delivery stents to combat rapidly occurring in-stent stenosis [72]. A variety of stents are available. In infants coronary stents are commonly used as larger stents are frequently too difficult to place. Experience with coronary stents suggests that even a 4 mm stent can be dilated to 7-8 mm serially [73]. However, whilst short-term results with coronary stents are acceptable, early restenosis does occur and ultimately they are limited by the child’s growth. Whether the rate of in-stent stenosis can be slowed or delayed with drug-eluting stents or even systemic chemotherapy remains to be established [74]. Genesis stents (Cordis, Johnson & Johnson, Warren, NJ, USA) have also been used effectively; these can be delivered through a 5 or 6 Fr guiding sheath and are capable of reaching larger sizes in older children. Covered stents have also been used more recently (smallest 7 mm x 16 mm stent) [71]. Stents should generally not be used if a fixed lesion is present, though a cutting balloon might be used followed by a stent. They are of use in difficult circumstances where a good result needs to be achieved and angioplasty has been unsuccessful, for example where there is significant recoil of a lesion or a dissection flap has been raised following angioplasty.

Stents can also be placed in obstructed descending or vertical veins in TAPVD before surgical correction. Angioplasty has been effectively performed for this indication though stent placement may be more appropriate since the cause is usually fixed compression [75, 76]. This may be particularly useful to ameliorate the preoperative condition of the collapsed neonate presenting with pulmonary venous obstruction [77, 78]. In the setting of a univentricular circulation this may be sufficient to enable growth and delay surgery through to bicaval bidirectional anastomosis [51, 52, 53, 67, 68].

Intraoperative stent placement

Stents can be placed intraoperatively [7, 62] although this is a very rare procedure since access can generally be obtained with perseverance using transcatheter techniques

Post-intervention assessment

Intensive care or high dependency support following these procedures is prudent as the patient is at a significant risk of a pulmonary hypertensive crisis. The usual monitoring procedures of access sites should be followed as per local institution preference. Close surveillance is necessary for follow-up and children are usually reviewed within 4 weeks following the procedure. Echocardiography is often sufficient to monitor progress.

Outcome analysis

Regardless of aetiology the prognosis for paediatric patients with PVS remains poor. There is a suggestion from published series that early surgical intervention in suitable cases with sutureless techniques may be associated with better outcomes, but this is far from proven and remains hotly debated. The difficulty lies in identifying those cases likely to benefit. Diagnosis in infancy, markedly elevated mean pulmonary artery pressure, multiple vein involvement and congenital rather than acquired disease may be associated with a worse outcome [3]. In those cases not deemed suitable for surgical intervention two-year survivals of 40-50% are consistently reported across case series [1, 2, 6, 79, 80]. It is particularly problematic comparing outcomes between different techniques as published series are small, retrospective and not randomised. Given that it is likely that more severe cases would undergo a catheter rather than a surgical procedure it is not possible to compare the two approaches. Rapid restenosis is well documented with all catheter interventions [3, 7, 62]. The concerning lack of evidence that an intervention alters the natural progression of the disease means that therapy needs to be directed towards achieving symptomatic improvement.

Predictors of poor outcome or rapid progression of disease that might guide the timing of intervention and the type of intervention performed are lacking. Earlier age of onset particularly in infancy, multiple involved veins, associated cardiac malformation and higher initial pulmonary artery pressure are identified variables but are not especially helpful in the day-to-day management of an individual case [3]. Primary PVS may also be a worse prognostic variable than secondary or acquired PVS following repair of TAPVD [27, 28, 50, 81].

Personal perspective - Neil Wilson

Pulmonary vein stenosis is an extremely rare condition such that most interventionists will only manage a small number of cases during their careers. The rarity of the lesion precludes objective direct comparison of differing techniques because case series are small. As we mention in the text, the emergence of cutting balloons, stent angioplasty and drug-eluting stent use are symptoms of the progressive disease which one is dealing with in most cases. Despite the progression of this disease surgery is favoured initially by most institutions. Ultimately, therefore, catheter-based procedures are performed late on very sick infants. Over the last two decades we have moved from a more aggressive approach to a more balanced position as the hoped-for improvements have not been realised. Thorough multimodal diagnostic assessment is essential if we are to understand the nature of the condition. Timely angioplasty, usually on a repeated basis followed by close follow-up, is our procedure of choice. More aggressive approaches with stent placement are adopted when there is significant recoil of a lesion and the clinical situation affords no other option. These infants are often ventilator dependent and have severe pulmonary hypertension. This is a condition for which a national register of data may prove useful and dialogue with international colleagues of emerging techniques is likely to be of more use than review of the literature. Objectives need to be realistic with an overall aim of improving quality of life. Education and counselling of the parents should honestly reflect this.

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