Pulmonary Vein Stenosis—Evolving Surgical Management of a Challenging Disease

children

Review Pulmonary Vein Stenosis—Evolving Surgical Management of a Challenging Disease

Eric N. Feins 1,*, Ryan Callahan 2 and Christopher W. Baird 1

1 Department of Cardiac Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA; [email protected] 2 Department of Cardiology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA; [email protected] * Correspondence: [email protected]

Abstract: Pulmonary vein stenosis (PVS) is an extremely challenging clinical problem in congenital heart disease. It has traditionally required multimodal therapy given its complex underlying pathophysiology. As with other modalities, surgical therapy has undergone tremendous evolution since the 1950s. These evolving strategies have been based upon an improved understanding of the substrates that cause PVS and recurrent vein obstruction. More recent anatomic-based surgical strategies have focused on the pulmonary vein course, and how adjacent mediastinal structures can create a fulcrum effect on the pulmonary veins as they pass from the lung parenchyma to the left atrium. The consequent angulation of pulmonary veins creates altered wall shear stress and likely serves as a nidus for recurrent PVS. Encouraging early results suggest that eliminating pulmonary

vein angulation and shortening/straightening the pulmonary vein course may prove effective in surgically managing PVS.

Citation: Feins, E.N.; Callahan, R.; Baird, C.W. Pulmonary Vein Keywords: congenital heart defect; pulmonary vein stenosis; surgery; treatment Stenosis—Evolving Surgical Management of a Challenging Disease. Children 2021, 8, 631. https://doi.org/10.3390/ 1. Introduction children8080631 Pulmonary vein stenosis (PVS) remains one of the most challenging problems in pediatric heart disease. It is well known that effective management of PVS requires an Academic Editor: interdisciplinary team in order to implement multimodal therapy [1]. While medical and Francesca Santamaria transcatheter therapies represent two cornerstones of treatment the surgical repair of PVS remains a critical component. Operative techniques to repair PVS have evolved over Received: 29 April 2021 several decades, largely prompted by the ongoing challenges of recurrent stenosis and Accepted: 20 July 2021 mortality. Multiple large reviews have documented mortality rates ranging from 46% Published: 25 July 2021 to 58% in children with primary PVS [2–5]. Aggressive multimodal therapy including transcatheter/surgical intervention paired with tyrosine kinase receptor inhibition may Publisher’s Note: MDPI stays neutral improve patient survival to 77% but remains suboptimal [6]. Overall mortality may be with regard to jurisdictional claims in published maps and institutional afﬁl- better in patients undergoing the primary repair of total anomalous pulmonary venous iations. connection (TAPVC) with contemporary three-year survival rates approximating 85% [7]. Nonetheless, post-repair pulmonary vein obstruction occurs in up to 15–21% of these patients [8,9] and remains an ongoing challenge with survival rates of only 58–73% [10,11]. This review will discuss the evolution of PVS surgery, with a particular emphasis on the principles underlying contemporary surgical techniques and newer repair strategies. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 2. Historical Perspective This article is an open access article 2.1. Early Surgical Techniques and Outcomes distributed under the terms and conditions of the Creative Commons Kawashima was one of the ﬁrst to describe the repair of pulmonary vein stenosis Attribution (CC BY) license (https:// in 1971 [12]. The surgery was performed three years prior on a 15-year-old boy with creativecommons.org/licenses/by/ an atrial septal defect and suspected ventricular septal defect. Pulmonary vein disease 4.0/). was unexpectedly discovered upon opening the atrium. Obstruction by a membranous

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diaphragm was noted where the right upper pulmonary vein entered the left atrium with a 2 mm opening, and this was resected. Disease was also discovered on the left side, where there was localized thickening and stenosis at the junction of a common left pulmonary vein and the left atrium. This thickened tissue was incised to widen the stenotic area. More complex repair techniques were subsequently developed to address more ex- tensive disease and in younger patients. Bini and colleagues described several surgical techniques in a small series of eight patients ranging from newborn to four years of age [13]. These operations included excision of the stenotic region with direct re-implantation of the healthy pulmonary vein(s) into the left atrium, venoplasty akin to a Heinecke–Mikulicz pyloroplasty (i.e., longitudinal vein incision with transverse closure to widen the stenotic region), the use of prosthetic material (i.e., Gore-Tex®, Dacron®) to widen the vein-atrial junction, and the use of autologous atrial tissue to patch-enlarge the venous pathway. Autologous tissue reconstruction typically involved the left atrial appendage as an onlay patch onto the stenotic region of the left pulmonary veins, and the use of the interatrial septum to patch-enlarge the right-sided veins [14]. Unfortunately, early outcomes were quite sobering, particularly when the surgical repair was required early in life. Of the eight patients undergoing repair in Bini’s series, there were only ﬁve hospital survivors, all of whom developed rapid, progressive PVS recurrence and died within months of their operation [13]. So, while early surgical innovation aimed to tackle more complex pulmonary vein disease, PVS was still considered a “lethal lesion.”

2.2. TAPVC Repair Techniques and Outcomes While an exhaustive account of TAPVC repair is beyond the scope of this review, for historical context it is worth noting that the surgical correction of TAPVC dates back to the 1950s. William H. Muller, Jr. ﬁrst described the operative repair of “transposition of the pulmonary veins” in 1951 through a left thoracotomy, which involved a closed anastomosis between the left upper pulmonary vein and the left atrial appendage in a four-year-old girl [15]. Subsequent open anastomotic repair utilizing cardiopulmonary bypass was described by Denton Cooley in 1956 [16]. Reardon reported on the outcomes of TAPVC repair in 201 patients at the Texas Heart Institute spanning several decades from the 1950s to the 1980s. While survival improved dramatically with advances in surgical technique, cardiopulmonary bypass strategy, and perioperative care, younger patients, particularly those requiring surgery in the newborn period, remained at particularly high risk of mortality following TAPVC repair. In children undergoing repair at less than one month of age, mortality was 57%, and survivors were still subject to the risk of anastomotic stenosis [17]. Trans-atrial repair of TAPVC also evolved from Denton Cooley’s original technique. The goal of the trans-atrial approach to TAPVC repair was to maintain the heart in the orthotopic position when setting up and fashioning the vein-atrium anastomosis so as to avoid any distortion that might predispose to stenosis. Doty and colleagues endorsed this strategy and reported on improved outcomes (n = 20 patients) after the adoption of the trans-atrial approach in 1976, with a reduction in mortality from 57% to 8% [18]. Their ﬁndings emphasized the exquisite sensitivity to geometric distortion of the pulmonary vein-left atrial anastomosis, with subtle geometric changes causing kinking/obstruction, in addition to turbulence with subsequent intimal hyperplasia and recurrent stenosis.

3. Evolving Surgical Strategy—The Sutureless Repair 3.1. The Conceptual Basis and Early Development Given the overall sobering outcomes of primary PVS repair, as well as the significant problem of post-TAPVC repair pulmonary vein obstruction, surgical techniques continued to evolve. In particular, “sutureless” repair techniques were developed in the 1990s by multiple groups. Lacour-Gayet and colleagues in Paris first described the sutureless repair in 1996 specifically to address post-TAPVC repair pulmonary vein obstruction in a two-and- a-half-year-old child [19]. Like others, their group had experienced suboptimal outcomes Children 2021, 8, x FOR PEER REVIEW 3 of 13

by multiple groups. Lacour-Gayet and colleagues in Paris first described the sutureless repair in 1996 specifically to address post-TAPVC repair pulmonary vein obstruction in a Children 2021, 8, 631 3 of 12 two-and-a-half-year-old child [19]. Like others, their group had experienced suboptimal outcomes with conventional techniques (i.e., endarterectomy +/− patch enlargement) to address post-TAPVC repair pulmonary vein obstruction. In a review of 16 patients un- dergoingwith conventional surgery for techniques post-TAPVC (i.e., repair endarterectomy vein obstruction, +/− patchthere was enlargement) a 27% mortality to address rate [20].post-TAPVC In part inspired repair pulmonaryby the Senning vein operation obstruction. for physiologic In a review correction of 16 patients of D undergoing-transposi- tionsurgery of the for great post-TAPVC arteries, repairthe sutureless vein obstruction, technique there involved was a the 27% use mortality of an in rate situ [20 vascular-]. In part izedinspired pericardial by the Senningflap which operation was sewn for directly physiologic to the correction atrial wall of D-transpositionthereby avoiding of manipu- the great lation/suturingarteries, the sutureless directlytechnique to the pulmonary involved vein the use tissue of an (Figure in situ 1a). vascularized The virtue pericardial of this tech- ﬂap niquewhich was was based sewn upon directly the to concern the atrial that wall manipulation/suturing thereby avoiding manipulation/suturing on vein tissue served directly as a nidusto the for pulmonary inflammation, vein tissue scar (Figureformation,1A). and The recurrent virtue of thisstenosis. technique Moreover, was based suturing upon the atriumconcern to thatthe pericardiu manipulation/suturingm was felt to onallow vein for tissue a more served aggressive as a nidus resection for inﬂammation, of diseased veinscar tissue formation, since andthe surgeon recurrent would stenosis. not have Moreover, to rely suturing on unresected the atrium vein totissue the pericardiumonto which towas sew. felt to allow for a more aggressive resection of diseased vein tissue since the surgeon would not have to rely on unresected vein tissue onto which to sew.

FigureFigure 1. 1. SuturelessSutureless repair repair.. (a (A) Right) Right pulmonary pulmonary vein vein repair. repair. Veins Veins are are opened opened widely widely and and di diseasedseased tissuetissue is is resected. resected. Pericardial Pericardial flap ﬂap is is folded folded down down and and sewn sewn to to left left atrium atrium leaving leaving cut cut edge edge of of veins veins withoutwithout sutures; sutures; (b ()B Left) Left pulmonary pulmonary vein vein repair. repair. Heart Heart is retracted is retracted rightward. rightward. Left pulmonary Left pulmonary veins areveins widely are widelyopened opened and left and atrial left appendage atrial appendage is sewn istosewn pericardium to pericardium outside/around outside/around veins. (RPV veins. = right(RPV pulmonary = right pulmonary veins; LA veins; = left LA atrium; = left LPV atrium; = left LPV pulmonary = left pulmonary veins; LPA veins; = leftLPA pulmonary = left pulmonary artery; Dashedartery; lines Dashed = planned lines = suture planned line suture for left line atrial for- leftpericardial atrial-pericardial anastomosis anastomosis).). Adapted from Adapted Viola, from N.; Calderone, C.A. Surgical repair of post-repair pulmonary vein stenosis using “sutureless” tech- Viola, N.; Calderone, C.A. Surgical repair of post-repair pulmonary vein stenosis using “sutureless” niques. Op Tech Thorac Cardiovasc Surg 2011, 15, 112–121. techniques. Op Tech Thorac Cardiovasc Surg 2011, 15, 112–121.

TheThe area area of of diseased diseased pulmonary pulmonary vein vein on the on right the right side sidewas unroofed was unroofed,, or ideally or ideally com- pletelycompletely resected resected,, and by and sewin by sewingg the in the situ in situautologous autologous pericardial pericardial flap flap to the to theatrium, atrium, a widelya widely patulous patulous pathway pathway was was created created for forthe theright right-sided-sided pulmonary pulmonary venous venous blood blood to re- to turnreturn to the to the left left atrium. atrium. Najm Najm and and colleagues colleagues in Toronto in Toronto described described a similar a similar approach approach of usingof using an anautologous autologous peric pericardialardial flap flap to toopen open up up the the pulmonary pulmonary vein vein-atrial–atrial connection connection whilewhile avoiding avoiding a a direct direct anastomosis anastomosis to to vein vein tissue tissue in in two two patients patients [21]. [21]. In In both both reports reports,, the the pericardialpericardial flap flap was was only only applied applied on on the the right right side. side. Left Left-sided-sided PVS PVS was was addressed addressed through through thethe left left atr atriumium by by incising incising longitudinally longitudinally out out into into the the left left pulmonary pulmonary veins veins getting getting outside outside ofof the the heart. heart. Instead Instead of using of using an in an situ insitu pericardial pericardial flap flapto contain to contain the left the pulmonary left pulmonary vein flow,vein pericardial flow, pericardial adhesions adhesions from the from prior the priorTAPVC TAPVC repair repair were wererelied relied upon uponto direc tot direct pulmonarypulmonary vein vein-to-atrial-to-atrial blood blood flow flow without without hemorrhage. hemorrhage. In their review of acquired PVS management, Spray and Bridges described an alter- native for the left-sided pulmonary veins which did not rely upon previous pericardial adhesions. This involved incising into the left atrial appendage and out into the left-sided veins, carrying this incision out to the pericardial reflection. The opened left atrial appendage was then sewn down as a flap directly to the posterior pericardial reflection [22]. Analogous to the right side, described by Lacour-Gayet and Najm, this created a widely Children 2021, 8, 631 4 of 12

patulous pulmonary venous pathway into the left atrium without a direct pulmonary vein anastomosis. Because post-operative adhesions were not relied on to contain the left-sided pulmonary venous ﬂow this maneuver enabled sutureless repair to be applied for primary PVS, not just post-repair PVS (Figure1B).

3.2. Sutureless Repair Outcomes and Scope of Use Outcomes for the treatment of post-TAPVC repair PVS with the sutureless technique have generally been favorable when compared with older techniques. In a review of surgery for PVS after TAPVC repair ten years after introducing the technique, Lacour- Gayet reported an improvement in freedom from mortality or recurrent PVS from 65% to 90% [23]. Devaney and colleagues also noted improved disease-free survival in a study of 22 patients when using a sutureless pericardial marsupialization for PVS following TAPVC repair [24]. Given these encouraging results, some groups have expanded their use of the sutureless repair. Calderone and colleagues describe extending the sutureless repair to all forms of PVS, including primary repair of TAPVC [25,26]. Aside from the avoidance of direct suturing to pulmonary vein tissue (noted above), the sutureless repair is thought to simplify the anastomosis. Since the suture lines are atrio-pericardial, the anastomosis is felt to be less prone to distortion in the way that direct vein-atrium connections might be, particularly when the geometry/orientation of the pulmonary vein confluence would make direct anastomosis to the back of the left atrium challenging. In a study of 22 patients, Calderone and colleagues compared sutureless and conventional repair strategies for the primary correction of mixed-type TAPVC and found a non-significant trend toward improved survival and freedom from re-intervention in the sutureless repair group [27]. Importantly, outcomes for sutureless repair of primary PVS have been less encouraging. Kanter and colleagues found no significant difference in freedom from recurrent PVS or death when comparing 52 patients who received either a standard repair or a sutureless repair [28,29]. Similarly, Shi and colleagues saw no difference in outcomes among surgical techniques (including sutureless repairs) in 18 patients with primary PVS [27]. In a multicenter study looking at primary PVS in 30 patients, Kalfa and colleagues found no association between the use of a sutureless technique and improved outcomes [30]. Calderone’s group also found that mortality and restenosis rates remained high in a review of 23 patients despite the adoption of a sutureless repair strategy for primary PVS patients [31]. These variable outcomes largely speak to the complex, multifactorial pathophysiology underlying PVS. Sutureless repair techniques may aim to avoid direct manipulation and suturing on the pulmonary veins, however, other factors are at play that drive the over-activity of myofibroblast-like cells in the pulmonary vein subendothelium leading to PVS recurrence [32,33].

4. New PVS Repair Concepts and Strategies—The Fulcrum Effect and the Anatomic-Based Repair 4.1. External Anatomy—The Impact on Pulmonary Veins While much of the focus on PVS has been on the pulmonary veins themselves, little attention has been paid to the surrounding intrathoracic structures that can impact the pulmonary vein course. At our institution, we have increasingly recognized, through pre-operative imaging, and intraoperatively, a fulcrum effect on the pulmonary veins of our PVS patients. We have observed that as the pulmonary veins pass from the lung parenchyma they must pivot over/pass neighboring mediastinal structures and across the pericardial reﬂection before reaching the back of the left atrium more medially. This creates a long, angulated, and tortuous pulmonary vein course from the lung parenchyma to the heart. It is well known that vessel angulation leads to variations in wall shear stress, a phenomenon well described by Han [34]. Importantly, changes to vessel wall shear stress contribute to vascular remodeling, intimal hyperplasia, and stenosis [35]. Children 2021, 8, x FOR PEER REVIEW 5 of 13

PVS patients. We have observed that as the pulmonary veins pass from the lung parenchyma they must pivot over/pass neighboring mediastinal structures and across the pericardial reflection before reaching the back of the left atrium more medially. This creates a long, angulated, and tortuous pulmonary vein course from the lung parenchyma to the heart. It is well known that vessel angulation leads to variations in wall shear stress, a Children 2021, 8, 631 phenomenon well described by Han [34]. Importantly, changes to vessel wall shear 5stress of 12 contribute to vascular remodeling, intimal hyperplasia, and stenosis [35]. The specific mediastinal structures that impact the pulmonary vein course vary with location.The specificThe left mediastinalupper pulmonary structures vein that must impact pass anteriorly the pulmonary over the vein left course mainstem vary bron- with location.chus and Thethen leftpass upper across pulmonary the pericardial vein reflection must pass before anteriorly entering over the the left left atrium mainstem more bronchusmedially and and posteriorly. then pass across Enlargement the pericardial of the bronchus reflection in before the setting entering of chronic the left lung atrium dis- moreease with medially elevated and airway posteriorly. pressures Enlargement can exacerbate of the pulmonary bronchus invein the angulation setting of chronic lung(Figure disease 2a). The with left elevated lower pulmonary airway pressures vein must can pass exacerbate anteriorly pulmonary over the veindescending angulation tho- (Figureracic aorta2A). andThe then left cross lower the pulmonary pericardial vein reflection must pass before anteriorly reaching over the l theeft atrium descending more thoracicmedially aorta (Figure and 2b then,c). crossIn their the analysis pericardial of left reflection-sided PVS before in reachingsingle-ventricle the left atriumpatients, more Ko- mediallytani and (Figurecolleagues2B,C). described In their analysis this relationship of left-sided of PVS the inleft single-ventricle pulmonary veins patients, and Kotanithe de- andscending colleagues thoracic described aorta [36]. this relationshipUsing MRI data of the they left pulmonarydemonstrated veins that and an the anterolaterally descending thoracicdisplaced aorta descending [36]. Using thoracic MRI dataaorta they in combination demonstrated with that cardiomegaly an anterolaterally predisposed displaced sin- descendinggle-ventricle thoracic patients aorta to left in combination lower pulmonary with cardiomegaly vein stenosis. predisposed We have single-ventricleanecdotally ob- patientsserved thatto left left lower lower pulmonary lobe atelectasis vein stenosis. is a common We have anecdotallyfinding in PVS observed patients that who left lower have lobechronic atelectasis lung disease, is a common and this finding can pull in PVSthe left patients lower who vein have more chronic posteriorly, lung disease,thus exacer- and thisbating can this pull vessel the left angulation. lower vein more posteriorly, thus exacerbating this vessel angulation.

FigureFigure 2.2. Left pulmonary veins veins (CT (CT images). images). (a ()A Left) Left upper upper pulmonary pulmonary vein vein takes takes long, long, angulated angulated course course as it aspasses it passes from fromlung lungparenchyma parenchyma over overleft mainstem left mainstem bronchus, bronchus, across across pericardial pericardial reflection reflection into intoleft atrium left atrium medially; medially; (b) Left (B) Leftlower lower pul- pulmonarymonary vein vein courses courses anteriorly anteriorly over over the the descending descending thoracic thoracic aorta aorta taking taking an angulated course;course; ((Cc) Left lowerlower pulmonarypulmonary veinvein crossingcrossing thethe pericardialpericardial reflectionreflection andand entering enteringfar far medially medially into into left left atrium. atrium. (LA(LA == leftleft atrium;atrium; LUPVLUPV == leftleft upperupper pulmonary vein; LMSB = left mainstem bronchus; LLPV = left lower pulmonary vein; Asterisk = descending thoracic pulmonary vein; LMSB = left mainstem bronchus; LLPV = left lower pulmonary vein; Asterisk = descending thoracic aorta). aorta). The right upper pulmonary vein angulates over the right pulmonary artery and then mustThe pass right across upper the pericardialpulmonary reflectionvein angulates before over entering the right the pulmonary left atrium moreartery medially and then (Figuremust pass3A). across Importantly, the pericardial when pulmonary reflection hypertension before entering exists, the aleft common atrium condition more medially with PVS, the pulmonary arteries are enlarged and hypertensive, which accentuates their impact on the pulmonary vein course. The right lower pulmonary vein is the least commonly involved vessel in PVS, a finding noted in an analysis by Callahan and colleagues of the disease patterns and outcomes for the specific pulmonary veins [37]. When right lower PVS does occur there is angulation as the vein passes across the pericardial reflection and into the left atrium. This is typically seen with a more posteriorly directed right lower pulmonary vein (Figure3B), in contrast to the more typical orientation that has a straight pathway to the left atrium (Figure3C). Children 2021, 8, x FOR PEER REVIEW 6 of 13

(Figure 3a). Importantly, when pulmonary hypertension exists, a common condition with PVS, the pulmonary arteries are enlarged and hypertensive, which accentuates their impact on the pulmonary vein course. The right lower pulmonary vein is the least commonly involved vessel in PVS, a finding noted in an analysis by Callahan and colleagues of the disease patterns and outcomes for the specific pulmonary veins [37]. When right lower PVS does occur there is angulation as the vein passes across the pericardial reflection and Children 2021, 8, 631 into the left atrium. This is typically seen with a more posteriorly directed right lower 6 of 12 pulmonary vein (Figure 3b), in contrast to the more typical orientation that has a straight pathway to the left atrium (Figure 3c).

Figure 3. Right pulmonary veins (CT images). (a) Right upper pulmonary vein crosses over right pulmonary artery caus- Figure 3. Right pulmonary veins (CT images). (A) Right upper pulmonary vein crosses over right pulmonary artery causing ing angulation as it passes across pericardial reflection into left atrium; (b) Right lower pulmonary vein stenosis involves moreangulation posteriorly as directed it passes pulmonary across pericardial vein that reflection angulates into when left atrium;crossing ( Bpericardial) Right lower reflection; pulmonary (c) Right vein lower stenosis pulmonar involvesy more veinposteriorly without stenosis directed has pulmonary straight, less vein angulated that angulates course when into left crossing atrium. pericardial (RUPV = reflection;right upper (C pulmonary) Right lower vein; pulmonary RPA = vein rightwithout pulmonary stenosis artery; has RLPV straight, = right less lower angulated pulmonary course vein; into LA left = atrium. left atrium (RUPV). = right upper pulmonary vein; RPA = right pulmonary artery; RLPV = right lower pulmonary vein; LA = left atrium). 4.2. The Anatomic-Based Repair 4.2. The Anatomic-Based Repair Given the recognition of the long, angulated course that the pulmonary veins can take as theyGiven pass the from recognition the lungof parenchyma the long, angulated to the left course atrium, that we the now pulmonary place greater veins em- can take phasisas theyon the pass extrinsic from the anatomy lung parenchyma when repairing to the PVS left atrium,of all forms we now [38]. placeThe goal greater of the emphasis an- on atomicthe- extrinsicbased PVS anatomy repair stra whentegy repairing is to remove PVS the of allfulcrum forms effect [38]. Thethat goaladjacent of the mediastinal anatomic-based structuresPVS repair and the strategy pericardial is toremove reflection the can fulcrum have on effect the thatpulmonary adjacent veins, mediastinal and create structures a shorterand and the straighter pericardial course reflection of the can veins have into on the the left pulmonary atrium. veins, and create a shorter and straighter course of the veins into the left atrium. 4.2.1. Pre-operative Evaluation 4.2.1. Pre-Operative Evaluation Pre-operatively, this involves having a clear understanding of both the extent/location of thePre-operatively, pulmonary vein this disease involves as well having as the a clear actual understanding course of the ofveins both in the the extent/location mediastinum.of the Cardiac pulmonary catheterization vein disease remains as well the as gold the actualstandard course for assessing of the veins pulmonary in the mediastinum. vein diseaCardiacse severity catheterization and includes remains hemodynamics, the gold standardangiography, for assessing pressure pulmonaryassessment, veinintra- disease vascularseverity ultrasound and includes, and balloon hemodynamics, compliance angiography, testing. In addition, pressure we assessment, are increasingly intravascular using ultrasound,pre-operative and computed balloon tomography compliance (CT) testing. for surgical In addition, planning we in are order increasingly to get a more using pre- operative computed tomography (CT) for surgical planning in order to get a more global sense of the pulmonary veins, the adjacent mediastinal structures, and the degree of vessel angulation/tortuosity (Figures2 and3).

4.2.2. Operative Technique The primary components of the anatomic-based PVS repair strategy are: 1. Thorough takedown of the pericardial reﬂection and aggressive mobilization of the pulmonary veins as they enter the pericardial space, in order to eliminate any angulation as the veins cross the pericardium; 2. Resection of any stenotic or thickened pulmonary vein tissue; Children 2021, 8, x FOR PEER REVIEW 7 of 13

global sense of the pulmonary veins, the adjacent mediastinal structures, and the degree of vessel angulation/tortuosity (Figures 2 and 3).

4.2.2. Operative Technique The primary components of the anatomic-based PVS repair strategy are: Children 2021, 8, 631 7 of 12 1. Thorough takedown of the pericardial reflection and aggressive mobilization of the pulmonary veins as they enter the pericardial space, in order to eliminate any angulation as the veins cross the pericardium; 3.2. ResectionLateralizing of any and stenotic enlargement or thickened of the pulmonary pulmonary vein vein-left tissue; atrial junction, such that 3. Laterathe courselizing of and the enlargement pulmonary of veins the pulmonary into the left vein atrium–left atrial is shorter, junction, less such angulated, that the and coursetherefore of lessthe pulmonary prone to disturbed veins into flow. the left atrium is shorter, less angulated, and Figuretherefore4 depicts less prone operative to disturbed repair flow. of right-sided pulmonary vein disease. Figure4A demonstratesFigure 4 depicts the right operative pulmonary repair veins of right prior-sided to repair. pulmonary They course vein disease. across the Figure pericardial 4a reflection,demonstrates as depicted the right inpulmonary the figure, veins and prior then to enter repair. the They left atriumcourse across quite medially.the pericardial The first operativereflection, stepas depicted involves in the complete figure, and takedown then enter of the left pericardial atrium quite reflection, medially. during The first which theoperative pulmonary step involves veins are complete freed up taked completelyown of the out pericardial into the reflection, lung parenchyma during which (Figure the4 B). Importantly,pulmonary veins the regionare freed of up stenosis completely typically out into correlates the lung with parenchyma where the (Figure veins crossed4b). Im- the pericardialportantly, the reflection, region of asstenosis denoted typically in the correlates figure (yellow with where arrow). the Theveins veins crossed are the opened per- up inicardial this region reflection, to createas denot aed wide, in the patulous figure (yellow pathway arrow). from The the veins lung are parenchyma opened up in into this the region to create a wide, patulous pathway from the lung parenchyma into the left atrium, left atrium, depicted by the white outline in Figure4C. The pulmonary vein-left atrial depicted by the white outline in Figure 4c. The pulmonary vein–left atrial connection is connection is then patched, which enlarges the pathway and helps move the vein-atrial then patched, which enlarges the pathway and helps move the vein–atrial connection connection more laterally (Figure4D). Various patch materials have been used for this part more laterally (Figure 4d). Various patch materials have been used for this part of the of the repair. A thin-patch pulmonary homograft is often used given its compliant tissue repair. A thin-patch pulmonary homograft is often used given its compliant tissue char- characteristics. Importantly, we have a preference for using a decellularized homograft acteristics. Importantly, we have a preference for using a decellularized homograft given given its decreased immunogenicity, an important consideration for a patient population its decreased immunogenicity, an important consideration for a patient population that thatmay mayrequire require lung lungtransplantation transplantation [39]. Alternatively, [39]. Alternatively, we have we used have autologous used autologous atrial flaps atrial flapsto lateralize to lateralize and augment and augment the pulmonary the pulmonary vein–left vein-left atrial pathway, atrial pathway, thereby thereby using only using na- only nativetive tissue tissue on onthe the pulmonary pulmonary veins veins themselves. themselves.

FigureFigure 4. Right pulmonary pulmonary vein vein repair. repair. (a ()A Right) Right-sided-sided pulmonary pulmonary veins veins crossing crossing pericardial pericardial reflec- reﬂec- tion before entering left atrium more medially; (b) Complete mobilization of pericardial reflection tion before entering left atrium more medially; (B) Complete mobilization of pericardial reﬂection and right pulmonary veins with stenotic region denoted (yellow arrow); (c) Right pulmonary veins C andwidely right opened pulmonary up and veins diseased with tissue stenotic resected region creating denoted patulous (yellow pulmonary arrow); ( )vein Right–le pulmonaryft atrial path- veins widely opened up and diseased tissue resected creating patulous pulmonary vein-left atrial pathway (white outline); (D) Patch augmentation moves pulmonary vein-left atrial connection out laterally to shorten/straighten pulmonary vein course. (RUPV = right upper pulmonary vein; RPA = right pulmonary artery; PV-LA = pulmonary vein-left atrium). Children 2021, 8, x FOR PEER REVIEW 8 of 13

Children 2021, 8, 631 way (white outline); (d) Patch augmentation moves pulmonary vein–left atrial connection out8 of lat- 12 erally to shorten/straighten pulmonary vein course. (RUPV = right upper pulmonary vein; RPA = right pulmonary artery; PV–LA = pulmonary vein–left atrium).

FigureFigure 55aA demonstrates demonstrates the the medial medial entrance entrance of of the the left left pulmonary pulmonary veins veins into into the theleft atriumleft atrium as they as theycross crossthe pericardial the pericardial reflection. reflection. Akin to Akin the right to the-sided right-sided veins, the veins, pericar- the dialpericardial reflection reflection is aggressively is aggressively taken down taken downand the and veins the are veins mobilized are mobilized out into out the into lung the parenchyma.lung parenchyma. The veins The veins are opened are opened out beyond out beyond the thestenosed stenosed region region and and diseased diseased tissue tissue is resected.is resected. The The venotomy venotomy is extended is extended into intothe base the base of the of left the atrial left atrial appendage appendage and the and vein the- atrialvein-atrial connection connection is patch is patch-augmented-augmented to lateralize to lateralize the the vein vein-atrial–atrial confluence. confluence. FigureFigure 55bB demonstratesdemonstrates the the repaired repaired veins, veins, where where the the left left atrium atrium has has been been effectively effectively lateralized lateralized by theby thepatch, patch, and andthe thepericardium pericardium is well is well away away from from the veins, the veins, thereby thereby alleviating alleviating the ful- the crumfulcrum effect. effect.

Figure 5. LeftLeft pulmonary pulmonary vein vein repair. repair. (a (A) Pre) Pre-repair—Left-repair—Left pulmonary pulmonary veins veins cross cross pericardial pericardial reflection reflection and and enter enter back back of leftofleft atrium atrium more more medially; medially; (b) ( B Post) Post-repair—Pericardial-repair—Pericardial reflection reflection has has been been taken taken down down and and PV PV-LA–LA confluence confluence is straighter/lateralized. (PV–LA = pulmonary vein–left atrium). straighter/lateralized. (PV-LA = pulmonary vein-left atrium).

InIn select select cases cases,, we we have have opted opted to to place place a a short short stent stent at at the the pulmonary pulmonary vein vein-left–left atrial connectionconnection asas partpart of of the the repair. repair. This This is typicallyis typically reserved reserved for casesfor cases with with severely severely hypoplastic hypo- plasticor atretic or pulmonaryatretic pulmonary veins (i.e., veins less (i.e. than, less 2 mm than in luminal2 mm in diameter), luminal diameter), where there where is concern there isabout concern the pulmonaryabout the pulmonary vein-left atrial vein connection–left atrial gettingconnection compressed getting compressed and narrowing and down nar- rowingdespite down patch enlargement.despite patch Toenlargement. date, we have To placedate, stentswe have in sixplace patients stents at in the six time patients of PVS at therepair. time Figure of PVS6A repair. shows Figure small 6a left shows upper small and left lower upper pulmonary and lower veins pulmonary despite veins opening de- spiteout into opening them out with into resection them with of diseased resection tissue. of diseased A note tissue. is made A note of theis made mobilization of the mobi- and lizationtakedown and of takedown the pericardial of the reﬂection.pericardial After reflection. patch After augmenting patch augmenting and lateralizing and lateraliz- the vein- ingatrial the connection vein–atrial (Figure connec6B),tion a stent(Figure is trimmed6b), a stent to ~3is mmtrimmed and pre-dilatedto ~3 mm and with pre particular-dilated withattention particular paid toattention not over-dilate paid to not the over stent-dilate (Figure the6C). stent Separate (Figure stents 6c). Separate are placed stents at theare placedostia of at the the left ostia lower of (Figurethe left6 D)lower and (Figure left upper 6d) pulmonary and left upper veins pulmonary (Figure6E). veins These (Figure stents 6e).are meantThese s totents maintain are meant the to luminal maintain size the of luminal the reconstructed size of the veinsreconstructed (Figure6 veinsF). A critical(Figure 6f).operative A critical step operative is to secure step theis to stents secure in the place stents with in multipleplace with 7-0 multiple polypropylene 7-0 polypropylene sutures to suturesprevent to dislodgement. prevent dislodgement. Importantly, Importantly, the stents act the as stents a substrate act as for a substratefuture transcatheter for future transcatheterdilation in these dilation cases in of these hypoplastic cases of pulmonary hypoplastic veins. pulmonary veins.

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FigureFigure 6. IntraoperativeIntraoperative stent stent placement. placement. (a) Hypoplastic (A) Hypoplastic left upper left and upper lower and pulmonary lower pulmonaryveins; (b) veins; Patch enlargement and lateralization of vein–atrial connection; (c) Stent trimmed to ~3 mm and pre- (B) Patch enlargement and lateralization of vein-atrial connection; (C) Stent trimmed to ~3 mm and dilated over balloon; (d) Placement of left lower pulmonary vein stent; (e) Placement of left upper predilatedpulmonary overvein stent; balloon; (f) Final (D) Placementposition of stents of left in lower left veins pulmonary to maintain vein luminal stent; caliber (E) Placement and prevent of left upper pulmonarycompression. vein (LUPV stent; = left (F) uppe Finalr pulmonary position of vein; stents LLPV in left = left veins lower to maintainpulmonary luminal vein). caliber and prevent compression. (LUPV = left upper pulmonary vein; LLPV = left lower pulmonary vein). 4.2.3. Post-operative Evaluation and Management 4.2.3.Patients Post-Operative are maintained Evaluation on therapeutic and Management anticoagulation with unfractionated heparin that isPatients transitioned are maintained to low-molecular on therapeutic-weight heparin, anticoagulation along with aspirin with unfractionated. Standard post- heparin thatoperative is transitioned surveillance to involves low-molecular-weight echocardiography heparin, paired withalong nuclear with aspirin. lung perfusion Standard post- operativescans. These surveillance studies are performed involves monthly echocardiography for three months, paired and with then nuclearless frequently lung perfusionif scans.there is These no evidence studies of are PVS performed recurrence. monthly Post-operative for three axial months, imaging andis being then performed less frequently if theremore frequently is no evidence to assess of PVSthe anatomic recurrence. result Post-operative of this repair strategy, axial imaging although is there being is not performed currently a formalized protocol for the timing/frequency of post-operative axial imaging. more frequently to assess the anatomic result of this repair strategy, although there is not We have observed effective lateralization of the pulmonary vein–atrial connection to currentlyshorten the a course formalized of the veins protocol as they for pass the timing/frequencyinto the left atrium. Figure of post-operative 7 demonstrates axial this imaging. Weeffect have on observedthe left upper effective and lower lateralization veins. Pre of-operatively, the pulmonary the left vein-atrial upper vein connection passes over to shorten thethe coursebronchus of and the across veins asthe they pericardial pass into reflection the left before atrium. entering Figure the7 leftdemonstrates atrium medial this effect onto the the descending left upper aorta and (Figure lower 7a). veins. After Pre-operatively, repair, the left upper the vein left takes upper a shorter vein passes course, over the bronchusaway from andthe airway, across and the enters pericardial the left reflectionatrium more before laterally entering (Figure the7b). leftSimilarly, atrium pre medial- to theoperative descending imaging aorta of the (Figure left lower7A). vein After shows repair, its more the left medial upper entry vein into takes the left a shorter atrium course, awayafter coursing from the over airway, the descending and enters aorta the (Figure left atrium 7c). Following more laterally repair, (Figure the left7 lowerB). Similarly, vein pre- operativenow enters imaging more laterally of the and left has lower a shorter/straighter vein shows its course more into medial the left entry atrium into without the left atrium afterpivoting coursing over the over aorta the (Figure descending 7d). aorta (Figure7C). Following repair, the left lower vein now enters more laterally and has a shorter/straighter course into the left atrium without pivoting over the aorta (Figure7D). Post-operative chemotherapy is reserved for patients with intraluminal PVS (presence of fibromyxoid proliferation) confirmed by a pre-operative biopsy or by angiography and intravascular ultrasound. Excluded patients are those with single-vessel PVS and those with pulmonary venous obstruction isolated to a surgical anastomosis or confluence without individual vessel involvement as determined by cardiac catheterization. Eligible patients are started on imatinib for targeted anti-proliferative therapy 7–10 days after surgery to allow for adequate wound healing.

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FigureFigure 7.7. Pre-Pre- and post post-repair-repair pulmonary pulmonary vein vein CT CT imaging. imaging. (a) ( APre) Pre-operative-operative left leftupper upper pulmonary pulmonary veinvein takingtaking long course over over left left bronchus bronchus before before entering entering medially medially into into left leftatrium; atrium; (b) Post (B) Post-repair-repair left upper vein course is shorter and more lateral—minimizing angulation; (c) Pre-operative left left upper vein course is shorter and more lateral—minimizing angulation; (C) Pre-operative left lower vein entering left atrium very medially after coursing over descending aorta; (d) Post-repair lowerleft lower vein vein entering takes leftshorter/straighter atrium very medially course as after it e coursingnters atrium over more descending laterally. aorta;(LUPV (D–LA) Post-repair = left leftupper lower pulmonary vein takes vein shorter/straighter–left atrium; LMSB course= left mainstem as it enters bronchus; atrium LLPV more– laterally.LA = left lower (LUPV-LA pulmo- = left uppernary vein pulmonary–left atrium; vein-left Asterisk atrium; = descending LMSB = left thoracic mainstem aorta bronchus;). LLPV-LA = left lower pulmonary vein-left atrium; Asterisk = descending thoracic aorta). Post-operative chemotherapy is reserved for patients with intraluminal PVS (pres- 4.2.4.ence of Preliminary fibromyxoid Outcomes proliferation) confirmed by a pre-operative biopsy or by angiography and This intravascular newer anatomic-focused ultrasound. Excluded approach patients hasyielded are those encouraging with single results-vessel to PVS date. and While onlythose implemented with pulmonary in the venous last several obstruction years, isolated we have to a observed surgical anastomosis an improvement or confluence in mortality whenwithout compared individual to vessel more involvement conventional as PVS determined repair techniques, by cardiac catheterization. with a two-year Eligible survival ofpatients 82.1% are versus started 61.8% on imatinib for conventional for targeted repair anti-proliferative (p = 0.03) [40 therapy]. Importantly, 7–10 days this after mortality sur- beneﬁtgery to wasallow observed for adequate after wound controlling healing. for potential confounding factors, including age, number of vessels involved, surgical era, and use of adjuvant chemotherapy. Nonetheless, ongoing4.2.4. Preliminary surveillance Outcomes is crucial to better understand the longer-term durability of this repair strategy.This We newer have anatomic not observed-focused a signiﬁcant approach changehas yielded in the encouraging re-intervention results rate, to however, date. re-intervention,While only implemented especially in transcatheter,the last several should years, we not have be considered observed an a improvement “failure”. PVS in is a challengingmortality when and compared chronic disease,to more andconventional the expectations PVS repair should techniques, be that with despite a two evolving-year surgicalsurvival techniques,of 82.1% versus re-intervention 61.8% for conventional is a likely and repair even (p expected = 0.03) [40]. management Importantly, strategy. this mortality benefit was observed after controlling for potential confounding factors, includ- 5.ing Conclusions age, number of vessels involved, surgical era, and use of adjuvant chemotherapy. Nonetheless,The multimodal ongoing surveillance treatment of is PVScrucial has to evolvedbetter understand tremendously the longer over-term the past durabil- several decades,ity of thiswith repair advances strategy. inWe medical, have not transcatheter, observed a significant and operative change therapies. in the re-intervention Surgical repair ofrate PVS, however, remains re a- centralintervention component, especially of treatment, transcatheter and, techniquesshould not ofbe repairconsidered have developeda “failure”. PVS is a challenging and chronic disease, and the expectations should be that despite with our increasing understanding of the underlying pathophysiology of PVS. While conventional venoplasty techniques initially rendered poor outcomes, sutureless techniques sought to eliminate the risk of geometric distortion and scar formation related to direct

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pulmonary vein manipulation. The sutureless techniques proved to be effective in certain circumstances, however, they have not been the panacea for PVS. The more recent focus on the pulmonary vein course, angulation, and the fulcrum effect has expanded our conception of how best to correct the anatomic substrates leading to PVS. Newer anatomic- based techniques aimed at eliminating the fulcrum/angulation have rendered promising outcomes thus far. As with every novel therapy for PVS, it will be critical to follow these patients closely to understand whether this new approach has a lasting impact. Importantly, given the heterogeneity of PVS, it is unlikely that one operative strategy will work for all forms of the disease. In that regard, continued surgical evolution will be important to further enhance our operative “toolkit” for the treatment of this challenging disease.

Author Contributions: Conceptualization, E.N.F., R.C. and C.W.B.; writing—Original draft prepara- tion, E.N.F.; writing—Review and editing, E.N.F., R.C. and C.W.B. All authors have read and agreed to the published version of the manuscript. Funding: This review received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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