The pulmonary arterial supply in patients with pulmonary atresia when combined with a ventricular septal defect is frequently unifocal via the arterial duct. In more complex cases, it can be multifocal. This can be through bilaterally patent arterial ducts, but more typically is through major aortopulmonary collateral arteries. In patients with such major aortopulmonary collateral arteries, establishing the source and arrangement of the pulmonary arterial supply is fundamental to management and prognosis.1–3 The collateral arteries, however, show marked variability in their origin and pattern of arborisation.4
Definition and morphology of major aortopulmonary collateral arteries
Major aortopulmonary collateral arteries are large, congenital, systemic-to-pulmonary collateral arteries, representing remnants of the embryonic ventral splanchnic arteries. These vessels normally regress concomitant with the formation of the normal pulmonary arterial system in the first weeks of gestation. Major collateral arteries may persist, however, when there is early maldevelopment of the pulmonary valve or the central pulmonary arterial system, as occurs in pulmonary atresia in combination with a ventricular septal defect. In some patients with this malformation, the central pulmonary arterial system fails to develop proper continuity with the embryonic lung, and a normal pulmonary arterial tree is not formed. Instead, the systemic-to-pulmonary collateral arteries persist, and create a bewildering array of arterial connections to various segments of the lungs. The persisting arteries typically number between two and six, with the majority originating from the anterior wall of the descending thoracic aorta at the level of the carina. They can also take origin from the lower descending thoracic and abdominal aorta, or braciocephalic arteries.5, 6 They frequently run a retro-oesophageal course. Occasionally, the collateral arteries may arise from the left or right coronary artery7 (Fig. 1). In most instances, it is possible to distinguish the collateral arteries from the arterial duct on the basis of their origin, course, behaviour over the neonatal period, and histological structure.8, 9 The extent of distal pulmonary vascular bed supplied by collaterals generally varies inversely to that supplied by the true pulmonary arteries, which range from being normal in size to completely absent.10 A given lung segment may be supplied by both collateral arteries and intrapericardial pulmonary arteries, with connections between the two sources occurring centrally or peripherally, and at single or multiple sites.11 Essential collateral arteries are those that supply exclusively the arterial bed of a given portion of the lung. Redundant collateral arteries are those which overlap with the distribution of the intrapericardial pulmonary arteries.12 The collateral arteries are pre-programmed embryologically not to survive beyond early fetal life. Should they persist, there is a high incidence of significant stenosis, typically near the junction with the aorta or the pulmonary arteries at the hilums. These stenoses may progressively worsen due to ongoing turbulent flow, polycythemia, hyperviscosity, and lack of growth.13 Due to mounds of intimal tissue containing significant amounts of collagen, the stenoses may become tough and resistant to extreme high forces beyond 20 atmospheres.
Figure 1. The aortogram in a patient with a complex functionally univentricular heart, discordant ventriculo-arterial connections, and pulmonary atresia. The pulmonary arterial bed is perfused via a connection between the coronary arteries and the pulmonary arteries.
Over the past decade, surgical and interventional techniques have evolved remarkably in treating patients with complex forms of pulmonary atresia, with biventricular repair now achieved in many.14–19 This progress has been related to the better characterization of the major collateral arteries, and their distinction from the branches of the intrapericardial pulmonary arteries, together with improvements in the interventional and surgical care of small infants.20
Historical review of strategies for treatment
The collateral arteries are almost always found when the pulmonary atresia itself exists in the setting of the intracardiac anatomy of tetralogy of Fallot. In this setting, the natural history is dependent on the nature of the flow of blood to the lungs. At birth, in the presence of pulmonary arteries of adequate size, cyanosis may be minimal. In the presence of hypoplastic pulmonary arteries, the flow is dependent on the presence of the aortopulmonary collateral channels.12 Clinical presentation will depend on whether these vessels are large, moderately stenotic, or severely stenotic. A poor functional status is to be expected in those patients with excessive or inadequate pulmonary flow.
Treatment has evolved from palliative shunting, or interruption of the collateral arteries, in the 1970s, to unifocalization of the pulmonary arteries with connection to the right ventricle with or without closure of the ventricular septal defect.21–24 The first major advances in the understanding and treatment of these lesions came with the morphologic and physiologic characterization of the extremely variable pulmonary arterial supply.6, 11, 25 On the basis of these studies, Haworth et al.26, 27 postulated that the flow of blood to the lungs might be normalized by unifocalizing the individual arteries with the intrapericardial pulmonary arteries. Since these early reports, a number of programmes have been developed for the management of these challenging lesions. Early on, these strategies have been based on the concept of staged unifocalization, with the initial phase of management mostly designed to increase flow to the intrapericardial pulmonary arteries in order to stimulate their growth.18, 24, 28–33 Historically, there was disagreement regarding the need for surgical intervention in patients with balanced flow to the lungs. A number of those patients had survived to adulthood without surgical intervention, or with palliative shunts alone.12 Studies of the natural history of these patients, however, show that they develop left ventricular dysfunction as a result of chronic left-to-right shunting and left ventricular volume overload. Progressive aortic annular dilation commonly potentiates to aortic insufficiency, further impairing left ventricular function.30 Based on these findings, operative therapy is currently recommended for all patients whose general condition and anatomic findings are amenable to surgical repair.
Present state and clinical indications
Principles of management
The principles of management of tetralogy of Fallot with pulmonary atresia and major collateral arteries are the same, despite the wide spectrum of pulmonary vascular patterns which can be found in such patients. The ultimate goal is to normalize the circulatory physiology. The key to a satisfactory surgical result is careful selection of the patient, and if required, suitable preparation. Repair should be attempted only in patients who are predicted to have a low probability of severe postoperative right ventricular hypertension. In patients with repaired tetralogy of Fallot and pulmonary atresia, the number of segments of lung supplied by the pulmonary arterial system has been found to correlate strongly with pulmonary arterial pressure and calculated pulmonary vascular resistance.34 In patients with multifocal pulmonary arterial supply, therefore, attempts should be made to incorporate as many segments of lung as possible into the unifocalized pulmonary vascular bed.11 The lower the resistance in a given pulmonary segment, the better. This, in turn, is largely a function of the state of health of the microvasculature of the lung.
Description of pulmonary arterial supply
Detailed knowledge of the distribution of both the intrapericardial pulmonary and the collateral arteries is required in planning the surgical and interventional approach in each patient. Non-invasive techniques, including echocardiography and magnetic resonance imaging, may provide important information.12 Cardiac catheterization, nonetheless, is usually essential to obtain all the necessary information. The intrapericardial pulmonary arteries may be visualized by injection of contrast through the collateral arteries that communicate with them (Fig. 2). Pulmonary venous wedge injections may be necessary if anterograde flow is insufficient. In a neonate, the collateral arteries can best be demonstrated by a descending aortogram with distal balloon occlusion (Fig. 3). Selective injections of contrast in the individual collateral arteries can then be performed. It may also be necessary to selectively inject the right or left subclavian artery, and even the coronary arteries, to define the presence and extent of so-called indirect collateral arteries.
Figure 2. The aortogram in a patient with tetralogy of Fallot, pulmonary atresia, and ventricular septal defect. The confluent pulmonary arteries are perfused via a left-sided duct, but one segment of the right upper lobe is perfused via a collateral artery originating from the right subclavian artery.
Figure 3. Collateral arteries are demonstrated by an injection made in the descending aorta with distal balloon occlusion.
Palliative procedures
Palliative procedures may be needed initially if primary repair appears unfeasible. Palliative procedures have a dual purpose. They not only improve the management of the immediate clinical problem, but also make the patient more suitable for later definitive surgical repair.9 Palliation may be required in patients with patchy, unbalanced, excessive, or inadequate flow of blood to the lungs.
Issues relating to technique and equipment
Conventional staged surgical approach
As mentioned earlier, the ultimate goal of therapy in the setting of major collateral arteries is to construct separate pulmonary and systemic circulations that can function in series.5 The conventional approach for achieving this goal is to embark on a staged surgical reconstruction to centralize the multifocal pulmonary blood supply, recruiting as many lung segments as possible, then provide egress from the right ventricle to the unifocalized pulmonary arterial system, and close the ventricular septal defect.24, 31, 35 This generally requires, on average, three sequential steps, as outlined by Gupta et al14 in their algorithm for management.
First stage: shunt or conduit from the right ventricle-to-pulmonary arteries or outflow patch
The first stage involves interventions, either surgical or by cardiac catheterization, to promote growth of the intrapericardial pulmonary arteries when present, and to control excessive flow of blood to the lungs. In the simplest cases, the intrapericardial pulmonary arteries will be of adequate size and distribution, and the collateral vessels are redundant. Palliation by means of construction of a systemic-to-pulmonary shunt was traditionally performed in the neonatal period to maintain arterial oxygen saturation in an acceptable range, usually from 80 to 85% in room air. Currently, such patients would be considered for primary repair.
If the intrapericardial pulmonary arteries are hypoplastic, as is seen in up to one-third of patients, the options are to place a conduit from the right ventricle to the pulmonary arteries, or patch the pulmonary outflow tract without closing the ventricular septal defect15 (Fig. 4). Some surgeons may prefer other types of shunts, such as a modified Blalock-Taussig shunt, a central shunt, or an end-to-side anastomosis of the hypoplastic pulmonary trunk to the ascending aorta. Redundant collateral arteries may be ligated surgically at the time of surgery, or embolized during cardiac catheterization before or after the surgery. In some patients, maintaining flow through redundant collateral arteries may be desirable to maintain an adequate arterial saturation.12
Figure 4. The aortogram in a neonate with severely hypoplastic intrapericardial pulmonary arteries, tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collaterals. In this patient, a conduit was placed from the right ventricle to the pulmonary arteries to promote growth of the intrapericardial pulmonary arteries.
Second stage: unifocalization
The second stage involves unifocalization of the major collateral arteries in both lungs. This refers broadly to procedures that join the multifocal sources of arterial supply, be they intrapericardial arteries or one or more collateral arteries, into a single source. Unifocalization should be undertaken at an age when the collateral arteries are large enough to permit construction of an anastomosis of sufficient size that is less likely to become stenotic with growth. Staged procedures may be required for bilateral and multiple collateral arteries. Many different types of procedures have been reported. These include direct anastomosis of the collateral arteries to the supply derived from intrapericardial pulmonary arteries,24, 31, 36 or placement of interposition grafts between collateral arteries and the branches of the intrapericardial pulmonary arteries. These interposition grafts can be synthetic,16, 24 autologous artery or vein,24, 36 xenograft pericardium,35 or autologous pericardium.36
An ideal unifocalization procedure should, first, allow incorporation of all nonredundant collateral arteries and the supply from the intrapericardial arteries to each lung without distortion. Second, conduits should be used that will either grow, or be large enough to supply adequate flow in adulthood without replacement. Third, the risk of thrombosis must be minimized, and finally, the focalized segment should be easily accessible from the mediastinum at the time of definitive repair. Unifocalization techniques using pericardial tubes are held to fulfil these criterions.12
Third stage: definitive repair
The third stage involves completion of the anatomic repair, with closure of the ventricular septal defect and establishment of continuity between the right ventricle and the reconstructed pulmonary vasculature. All systemic-to-pulmonary shunts, including redundant collateral arteries and surgically created shunts, should have been previously occluded, or else be retrievable from a median sternotomy incision to allow occlusion at the time of complete repair.12 As mentioned before; successful definitive repair is dependent on the adequacy of the pulmonary vascular bed. There is now strong evidence that definitive repair is possible if 15 out of the 20 bronchopulmonary segments are connected to confluent pulmonary arteries.9 Repair can also be achieved if 11 to 14 segments are connected to the intrapericardial pulmonary arteries, but at an increased risk of a high postoperative pressure ratio and an increased surgical mortality.34
Prediction of outcome after definitive repair
A number of methods have been developed to predict the outcome preoperatively based on the size of the pulmonary arteries and estimations of the pulmonary vascular resistance.37, 38 These predictive indexes are valuable as guidelines for definitive repair, but they are not without shortcomings. Should there be reduced flow to the lungs, then the size of the pulmonary arteries may be underestimated. Measurement of distal pulmonary arterial pressure may be difficult and, as flow cannot be measured accurately, the pulmonary vascular resistance may be difficult to determine. To make acceptable the early and late morbidity and mortality for definitive repair, the predicted right ventricular pressure should be no higher than two-thirds the systemic pressure.12
Definitive single-stage repair in early infancy
The natural history of major collateral arteries often follows a course of progressive stenosis and occlusion. Iatrogenic occlusion can also occur when these vessels are unifocalized in stages using nonviable conduits, sometimes resulting in loss of segments.11 Because some aortopulmonary collateral arteries do not have major stenoses, segments may be perfused by such collaterals at or near systemic pressure. This unrestricted flow can lead to early pulmonary vascular obstructive disease, which also effectively raises resistance. Injuries to the distal pulmonary vasculature due to both hypoperfusion and perfusion at systemic pressure are progressive and time-related processes. Recent publications, therefore, have advocated the normalization of the pulmonary circulation as early in life as possible, removing the pulmonary vascular bed from exposure to the inevitable haemodynamic vagaries associated with major collateral arteries.5, 11, 39
According to McElhinney et al.,11 complete repair in early infancy allows for early normalization of cardiovascular physiology, with preservation of the pulmonary vascular bed, recruitment of all lung segments, alleviation of cyanosis, and prevention of other cardiac sequels. By performing the repair in a single stage, the number of operations required can be minimized, and the number of patients who can be completely repaired is likely to be enhanced.
Principles of one-stage unifocalization
The approach to one-stage unifocalization and complete repair follows several basic principles. Surgery is performed through a generous midline incision and median sternotomy,5, 11, 39 although some investigators have described the use of a bilateral transsternal thoracotomy, also providing good exposure.40 A variety of approaches are used to identify and dissect the collateral arteries. Both pleural spaces are opened widely just beneath the sternum and well anterior to the phrenic nerve. It is essential to control all collateral arteries before commencing cardiopulmonary bypass, and to perform reconstruction between native tissues whenever possible. Important concepts in achieving this type of unifocalization are flexibility regarding reconstruction, aggressive mobilization, maximizing the length of the major collateral arteries, and creative rerouting.11 Avenues for rerouting the collateral arteries are developed by opening the pleura on both sides posterior to the phrenic nerves in the hilar regions, and by opening the subcarinal space through the transverse sinus.
In order to meet the objective of complete unifocalization without use of peripheral conduits, and to maximize the anastomosis of native tissues, it is possible to make side-to-side or oblique end-to-side anastomoses between collateral arteries, or between collateral arteries and the peripheral branches of intrapericardial pulmonary arteries. Alternatively, the intrapericardial pulmonary arteries can be anastomosed to an aortic button giving off multiple unobstructed collateral arteries, or a long onlay or side-to-side anastomosis made between the collateral arteries and the intrapericardial pulmonary arteries. Other options are to make an end-to-end or end-to-side anastomosis of collateral arteries to a central conduit, to augment the stenotic distal collateral arteries with an allograft patch, or to use such patches for augmentation of the reconstructed intrapericardial pulmonary arteries. In rare cases, it is possible to use allograft conduits to reconstruct the intrapericardial pulmonary arteries.11 These techniques are used as necessary in the individual patient, and frequently combined, depending on the particular anatomy. In most patients, flow of blood to the unifocalized pulmonary arteries is provided via a valved conduit, which can be a homograft or allograft, placed from the right ventricle to the intrapericardial pulmonary arteries.
Whether or not to close the ventricular septal defect?
The decision to close the ventricular septal defect at the time of unifocalization is critical to successful repair. In contrast to staged repair, catheterization and angiographic data are not available following unifocalization. Angiographic measurements of the collateral and pulmonary arteries preoperatively can be used to estimate an index for the newly constructed pulmonary arteries, which is the sum of the indexed cross-sectional areas of all vessels unifocalized.23 All patients with an index above 200 millimetres squared per metre squared can safely have their ventricular septal defect closed, but the index is apparently of little benefit in predicting suitability for closure in patients below this level.11 Reddy et al.23 therefore, developed an intraoperative technique to estimate the resistance of the unifocalized pulmonary arterial bed, showing the method to be reliable in predicting the mean pulmonary arterial pressure when the ventricular septal defect is closed. If the mean pulmonary arterial pressure is estimated to be more than 25 millimetres of mercury in infants, the defect is typically left open.11 Should the defect be closed, a small atrial septal defect is usually created, or else a patent oval foramen left open, to function as a “pop-off” valve for systemic venous blood in the event of right ventricular dysfunction or elevated right-sided pressures.11, 39
Percutaneous balloon dilation of major collaterals, with or without subsequent implantation of stents
Although the current trend is towards early unifocalization or repair, some lesions are not amenable to surgical procedures. In these settings, transcatheter interventions may offer a valuable alternative or additive prior to or after surgical therapy.41 Moreover, some patients who have previously not been considered for surgical intervention may now have reached their teens being severely cyanotic, and can be palliated by interventional techniques. Over the past ten years, increasing experience has been gained in the percutaneous treatment of major collateral arteries, improving patients clinically and facilitating further surgical procedures.42
Conventional balloon dilation
Some lesions can be treated with conventional balloon dilation, albeit that discrete segments are often resistant to high pressures or large balloons, with increased risk of complications such as dissection, aneurysmal formation, disruption of the adjacent vessel wall, or loss of segmental lung perfusion (Fig. 5). The choice of the size of the balloon is made according to the severity of the stenosis and the size of the vessel, but generally a non-compliant balloon not larger than one and a half times the size of the nearest normal vessel should be selected.
Figure 5. Two consecutive stenoses in a collateral artery resistant to balloon dilation up to 20 atmospheres.
Dilation using cutting balloons
Cutting balloons were developed and approved for angioplasty of resistant coronary arterial obstructions.43, 44 These balloon catheters are equipped with three or four metal blades mounted on the surface of the balloon. Angioplasty produces sharp, longitudinal, incisions directed radially into the media. These microsurgical incisions result in smoother dilation, with less injury to the media or adventitia. Expansion occurs at multiple sites, and not in one tear. Elastic recoil is reduced, and there is less subsequent intimal proliferation. Despite the significant experience with such balloons for coronary angioplasty, there is limited data for their use in children. Several groups have begun to explore their safety and effectiveness in dilating peripheral pulmonary arterial stenoses resistant to conventional techniques.45–47
The balloons are currently available in sizes from 2 to 8 millimetres. Using these balloons, pressure-resistant stenoses, and even filiform or long segment lesions, can be dilated successfully and safely42 (Fig. 6). A balloon sized approximately 1.1 times larger than the diameter of the artery is recommended. Control angiography after dilation often reveals evidence of intimal damage. This finding was described in the series of Bergersen et al.47 in up to two-fifths of the vessels dilated. It is described as a “cobblestone” appearance, or “intimal” flap, without extravasation of contrast outside the lumen. This type of intravascular disruption is expected, and indeed is necessary for successful angioplasty.48
Figure 6. A selective injection (a) in a major aortopulmonary collateral artery of an 11-year-old patient with tetralogy of Fallot, pulmonary atre-sia, and major collateral arteries. He had become severely cyanotic due to progressive stenoses of the collateral vessels. In panel (b), we show the results after dilation using a cutting balloon and implantation of a stent. Arterial saturation improved from 65 to 82%.
Implantation of stents
Indications for implantation of stents after dilation with either conventional or cutting balloons are significant recoil of the dilated artery, severe intimal damage with aneurysmal formation, dissection and risk of subsequent loss of patency, and critical filiform long segment narrowing. The choice of the stent will vary according to the shape, size, and length of the stenotic segment, and whether there are acute angles proximal to the stenosis. The risk for thrombosis seems to be higher in curved or long stents.42
Transcatheter embolization of redundant collateral arteries
Patients may occasionally present with multiple, large, unobstructed aortopulmonary collateral arteries producing excessive flow of blood to the lungs, and necessitating intervention. Redundant collateral arteries may also sometimes need to be embolized before or after surgery to promote growth of the intrapericardial pulmonary arteries. A number of embolic materials have been used to occlude such collateral arteries, including tissue adhesives, detachable silicone balloons, and Gianturco coils.49 Currently, coils are most commonly used for this purpose. The technique of embolization is similar to that used in other vessels. An alternative source of arterial supply to the lung segment supplied by the target vessel must be ensured before the collateral artery is occluded. A peculiar origin, or tortuosity of the collateral artery, may cause difficulty in positioning properly the tip of the catheter, but various guide wires and catheters, including the 3 French Target catheters are available, and may help achieve an ideal position of the catheter to ensure safe implantation of the coil.49 A coil that is from one-third to half larger than the diameter of the target artery is recommended because of possible distention of the artery following implantation.49 A study by Verma et al.50 has revealed complete occlusion in nine-tenths of vessels, also demonstrating endothelialization of coils protruding into the aortic lumen. Furthermore, no episodes of stroke, embolic events, endarteritis or migration were observed. Transcatheter embolization of major aortopulmonary collateral arteries with coils, therefore, can be considered feasible, safe, and effective. The technique is of significant value in the overall management of this subset of patients.49
Acute and long term outcomes
Analysis of the results of surgical repair of congenital cardiac malformations associated with major collateral arteries is difficult, due to the extreme variability of the supply through the intrapericardial pulmonary arteries as opposed to the collateral arteries. Griselli et al.,20 however, devised a classification of the pulmonary arterial supply to determine the influence of the arterial morphology on the results of surgery. Current classifications are usually based on the presence and size of the intrapericardial pulmonary arteries. Patients without intrapericardial pulmonary arteries, but with confluent intrapulmonary arteries, have a better outcome than those with nonconfluent pulmonary arteries.
The surgical techniques have evolved over the last two decades. Reddy et al.51 reported their experience in 85 patients. Early one-stage complete unifocalization could be performed in more than nine-tenths of patients, even in those lacking intrapericardial pulmonary arteries, and yielded good functional results. Complete repair in a single stage was achieved in two-thirds of patients. Sequential unifocalization procedures are reserved for patients with multiple significant distal collateral stenoses, or those with significant co-morbid factors that contraindicate cardiopulmonary bypass. The outcome with these strategies has been good, with early mortality of 10 percent, and 80 percent actuarial survival at 3 years. The need for reintervention, either by catheterization or surgery, to dilate or occlude vessels and to enlarge pulmonary arteries, or to change valved conduits, continues to be a problem, but as can be anticipated, patients with pulmonary arteries of small size have a 6-fold greater risk of reintervention when compared with patients having adequate-sized vasculature.20 Actuarial survival free from reintervention was 42 percent at 5 years.51 The natural history of this condition for purposes of comparison is difficult to elucidate. Bull et al.,52 nonetheless, noted a mortality of 50 percent at 1 year of age in such patients. We can reasonably conclude, therefore, that a considerable improvement has been achieved for these patients.
Future outlook
Over the last decade, considerable progress has been made in the surgical and interventional treatment of patients with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries. Despite these advances in treatment, inadequate growth of the pulmonary vasculature is seen in a fraction of patients even after optimal surgical and interventional treatment. Recent studies have implicated the Notch signalling pathway in human cardiac development by demonstrating mutations or deletions of the JAG 1 gene as the basis for Alagille syndrome and some cases of isolated tetralogy of Fallot or pulmonary stenosis.53 McElhinney et al.53 demonstrated an apparently poor outcome among individuals with a JAG 1 mutation and tetralogy of Fallot with pulmonary atresia. This observation certainly warrants additional investigation, because it may have implications for clinical decision-making in this subset of patients. The association of tetralogy of Fallot with 22q11 microdeletion is now well recognized, and is also more common in tetralogy of Fallot associated with pulmonary atresia and major collateral arteries than in tetralogy of Fallot with pulmonary stenosis. Chessa et al.54 compared the morphology of the pulmonary arteries, and the origin, course, and connections of the major aortopulmonary collateral arteries, in patients with or without chromosome 22q11 deletion. A specific phenotype could be defined in patients with deletion. The collateral arteries mostly showed complex morphology, and the intrapericardial pulmonary arteries were smaller. Differences in the morphology of the pulmonary vessels may indicate a different timing of the faulty developmental pathway in patients with and without 22q11 deletion. Genetic information, therefore, may open the way for therapeutic strategies to enhance distal pulmonary angiogenesis, and help in planning the best surgical strategy.
