Narrative review of single ventricle: where are we after 40 years?

Introduction

Background

Over the past 40 years, key medical and surgical advances have been made in the longitudinal management of patients with “functionally” single ventricle physiology, from prenatal diagnosis to interventions for failing Fontan in adulthood. Since the introduction of the Fontan procedure for tricuspid atresia (1), principles of the Fontan circulation have been applied to other complex congenital heart defects with “functionally” univentricular heart. Previously considered as inoperable, scant information was available on the natural history of children born with a single ventricle 40 years ago (2), before the advent of electronic record and large databases (3-5). prompting the publication of the article “Univentricular heart: can we alter the natural history?” (6).

Rationale and knowledge gap

The purpose of this article is to review all of the innovations that led to a change in the longitudinal management of patients born with single ventricle from fetal to adulthood care.

Objective

The purpose of our review is to emphasize that there aren’t hotspots in this longitudinal management, but the decision-making process have to be always conducted keeping in mind the best treatment for each patient in each specific point of their observation.

Methods

The literature review included all articles found published in English language on the Cochrane, MedLine, and Embase, with our research strategy summarized in Table 1. We present the following article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-22-573/rc).

Fetal diagnosis

Advancements in prenatal ultrasound technology was among the first substantial achievements for congenital heart defects, permitting accurate and early fetal echocardiographic detection. Currently, virtually almost all heart malformations are recognizable between the 16th and 18th week of pregnancy, with sensitivity greater than 96% and specificity approaching 100% (7,8). In addition to providing information on the presence of associated non-cardiac malformations (9) such as situs inversus in heterotaxy syndrome (10), prenatal echocardiography and cardiac MRI better delineates complex congenital heart defects, including “functionally” single ventricle physiology (11-15). Accurate prenatal imaging and diagnosis has been a necessary factor in conducting clinical trials for fetal interventional cardiology procedures (16-18), and have also resulted in planned, coordinated deliveries for babies with complex congenital heart defects at tertiary referral centers with the appropriate level of interventional and surgical care, resulting in improved survival outcomes (11-13,15,19-22).

Fetal brain injury

As survival rates improve for patients with complex congenital heart defects, increased rates of neurodevelopmental impairment has become better recognized in survivors. This has brought about increasing attention and efforts to optimize surgical and perioperative care, as well as improving detection and timing of neurological injury and assessing long-term outcomes (23). Children born with single ventricle physiology have the highest rates of neurodevelopmental impairment due to multiple patient and environmental factors including genetic syndromes and socioeconomic factors (24). Several studies have provided evidence suggestive of brain injury occurring during fetal development, including an alarming rate of brain lesions in the presence of cyanotic congenital heart defects before cardiac surgery (25-27). The mechanism is attributed to reduced oxygen delivery to the brain relative to fetuses with normal cardiac anatomy beginning from the completion of cardiac structural development at approximately 6 weeks of gestational age until the remainder of the gestation period (28,29). Clinical manifestations of neurologic compromise before surgery in infants with single ventricle physiology include smaller head circumference, reduced brain volume, and altered neurobehavior (25,27,30,31). Severe abnormalities in the implantation and morphology of the placenta along with higher rates of maternal pre-eclampsia and in-utero growth restriction has also been observed in the presence of pregnancies affected by congenital heart defects (32,33). Placental insufficiency suggests another cause of hemodynamic compromise to the developing brain, and potential shared developmental pathways between the placenta, heart, and brain are currently under investigation (32,33). Some institutions have introduced maternal hyperoxygenation as a potential therapeutic to improve oxygen delivery to the brain after the fetal diagnosis of cyanotic congenital heart defects (34). However, studied outcomes have included alterations in left-sided cardiac structures, cerebrovascular response, and fetal brain development (35-43). Current investigations are actively recruiting to further study safety and efficacy of the maternal hyperoxygenation.

Neonatal care

The initial neonatal treatment depends on the specific type of single ventricle physiology with main variables including ductal-dependent pulmonary or systemic circulation, reduced or increased pulmonary blood flow, obstructed pulmonary venous connections, restrictive interatrial communication, and obstructed systemic blood flow. Since the 1970s, prostaglandin E₁ infusion has been used to maintain ductal-dependent circulation in newborns (44,45) The availability of prostaglandin E₁ at hospitals have been associated with decreased neonatal morbidity by permitting the stable transfer of newborns with suspected congenital heart defects to a cardiac surgical center (46). Continuous prostaglandin E₁ infusion has also permitted more time after delivery for optimal surgical planning and even delay surgery for growth in preterm or growth-restricted neonates (47).

Post-natal diagnosis

Over the past decade, the field has also seen significant advances in the quality of postnatal diagnosis. The introduction of technological innovations such as three-dimensional echocardiography (48,49) and global longitudinal strain analysis of single ventricle physiology (50) using low radiation-dose computed tomography (51-53) can provide accurate anatomic delineation of congenital heart defects. Functional assessment of myocardial function, in addition to the echocardiographic investigations, with magnetic resonance imaging (54,55) and the introduction of techniques merging different diagnostic imaging modalities (56) facilitate operative decision-making, together with 3-D modeling and printing of the heart structures (57,58), as well as computational design of the planned surgical procedure with evaluation of the obtainable sizes of ventricular inflows/outflows and ventricular volumes (59).

Interventional cardiology procedures

In single ventricle physiology with ductal-dependent pulmonary blood flow, ductal stenting is an interventional cardiology procedure with beneficial outcomes (60-64). The presence of an intact atrial septum or highly restrictive interatrial communication in neonates with functionally single ventricle, including hypoplastic left heart syndrome, is a very high-risk situation requiring emergency catheter-based intervention and/or surgical procedure (65-68). Fortunately, for many neonates, this situation can be anticipated in the modern era with fetal echocardiography, with the fetal pulmonary venous Doppler detecting a severely restrictive interatrial communication (67). In the presence of obstructed pulmonary venous drainage, the reason for elevated mortality and morbidity has been attributed to severe hypertension in the pulmonary veins, causing either disorder of the fetal lung maturation with fibroelastosis of the alveolar septal parenchyma (68), increased medial thickness (arterialization) of the pulmonary veins and lymphangiectasis of the lung parenchyma (67-70), or underdevelopment of the small pulmonary arteries with or without associated alveolar changes (65). To control the excessive pulmonary blood flow, an interventional cardiology technique using flow restrictors was first studied in animal experimental studies (71) and have now been successfully introduced in the clinical practice (72).

Surgical procedures

As in interventional cardiology, the surgical approach depends upon the specific type of single ventricle, any associated cardiovascular malformations, and the subsequent pathophysiology. In single ventricle with reduced pulmonary blood flow, the most frequently utilized surgical option was, and still remains, a modified Blalock-Taussig shunt (73,74). In neonates with single ventricle and unrestricted pulmonary blood flow, the surgical alternative to catheter-implantable flow restrictors is still pulmonary artery banding and has advantages of reducing distal pulmonary artery pressure and maintaining the possibility for future cavo-pulmonary connections. Pulmonary artery banding can be performed using conventional techniques (75), with an adjustable system (76), and clinical successful outcome have been reported with the telemetrically adjustable FloWatch^® (77).

In hypoplastic left heart syndrome, the surgical neonatal approach is the Norwood procedure, either with a modified Blalock-Taussig shunt (78) or with a Sano right ventricle to pulmonary artery conduit (79) with recent improvement in results (80,81). The Sano conduit has utilized either a ring reinforced tubular prosthesis (82), stent-less pulmonary valved conduit (83), or valved femoral venous homograft (84). The type of Sano conduit used is still primarily based upon institutional and surgeon preferences and will require longer follow-up to determine efficacy (85).

The best timing for a Norwood procedure is still a matter of debate and will be discussed later in this review in the section on hybrid procedures.

For newborns with single ventricle physiology, ventriculo-arterial discordance and subaortic stenosis, hypoplasia of ascending aorta and aortic arch, various surgical options were introduced, classically involving early pulmonary banding and aortic arch reconstruction, with or without the enlargement of restricted bulbo-ventricular foramen, or the Damus-Kaye-Stansel procedure, associated with a new source of pulmonary blood flow, either with modified Blalock-Taussig shunt or with Sano right ventricle to pulmonary artery conduit (6,86-92). An alternative approach introduced later was a palliative arterial or ventricular switch, both procedures requiring a longer aortic cross clamp times compared to other options but preserving systolic and diastolic ventricular function and providing a superior anatomic arrangement for the subsequent surgical stages (93-96). Obstructed pulmonary venous connections is a quite rare but extremely severe complication in neonates with single ventricle physiology (97-101), but with proper pre- and post-operative imaging, recurrence can be monitored with reasonable outcomes (102).

Hybrid procedures

The “hybrid” approach, consisting of bilateral pulmonary artery banding, atrio-septostomy and ductal stent, was first introduced by a team in Giessen, Germany. In the beginning, the hybrid approach was utilized only for the high-risk patients, but eventually offered to others with satisfactory outcomes (103-109). Recently, for neonates with hypoplastic left heart structures in critical condition due to pulmonary over-circulation and insufficient systemic perfusion with subsequent multi-organ failure (110), we adopted this policy, deferring the Norwood procedure and the required cardiopulmonary bypass in neonates with depleted metabolic and functional reserves. All organs, including myocardium, brain, kidneys, liver, and lungs are allowed to recover, thus mitigating the insult of organ injury from diminished oxygen delivery (110).

Generally, the staged surgeries consist of three steps, the first being a palliative procedure in which the systemic and pulmonary circulations are usually placed in parallel; the second stage consisting of a superior cavo-pulmonary anastomosis (or bidirectional Glenn); and the final stage being conversion to a total cavo-pulmonary connection (Fontan physiology). Following the first stage palliation for single ventricle, unstable hemodynamics contributes to morbidity and mortality in the inter-stage period prior to the second stage, particularly for hypoplastic left heart syndrome (111,112). This issue has been best managed with either a lengthy hospitalization while awaiting the second stage, or discharge home through a strict continuous monitoring program (113,114).

Bidirectional Glenn

The classical Glenn procedure consisting of an end-to-side anastomosis of the divided superior vena cava to the right pulmonary artery, separated from the pulmonary artery bifurcation (115,116), despite early positive outcomes including relief of cyanosis, was later abandoned because of the high incidence of pulmonary arteriovenous malformations (117-121). The bidirectional Glenn, introduced 50 years ago (122) but popularized in more recent years (123,124), consists of the division of the superior vena cava in correspondence of the cavo-atrial junction (preserving the sinus node and its artery) and its end-to-side anastomosis to the upper aspect of the right pulmonary artery, preserving the pulmonary arteries continuity and bilateral lung perfusion. Other advantages of the bidirectional Glenn include: (I) increased effective pulmonary blood flow by deviating the most desaturated blood (the superior vena cava return) directly to the lungs; (II) preparation for later Fontan completion without any period of myocardial ischemia; (III) potential for growing, being a direct anastomosis between two native vessels. Furthermore the bidirectional Glenn avoids the single stage modified Fontan procedure where the single ventricular chamber must adapt to an abrupt reduction in ventricular filling, with subsequent reduced ventricular compliance and poor functioning of the Fontan circulation (125-128).

In patients with a persistent left superior vena cava, a bilateral bi-directional Glenn procedure is required (129,130).

The bi-directional Glenn procedure can generally be performed at 3–6 months of life, when the pulmonary vascular resistance is usually sufficiently low.

Hemi-Fontan

A surgical alternative to the bidirectional Glenn is the hemi-Fontan procedure, consisting of connection of the superior vena cava and the superior portion of the right atrium to both pulmonary arteries, augmentation of the central pulmonary arteries, occlusion of the inflow of the superior vena cava to the right atrium and elimination of the other sources of pulmonary blood flow. The hemodynamics is similar to a bi-directional Glenn procedure except all other sources of pulmonary blood flow are eliminated, avoiding ventricular volume overload. However, for patients with hypoplastic pulmonary arteries this may be a disadvantage since only 40% of the systemic venous return perfuses the pulmonary circulation until the Fontan completion. This potential disadvantage could be compensated by direct enlargement of the central pulmonary arteries, requiring cardiopulmonary bypass with aortic cross clamp, biological or prosthetic materials for central pulmonary arteries augmentation, and suturing lines in proximity to the sinus node or its artery posing a risk for supraventricular arrhythmias. Later conversion is possible to a total cavo-pulmonary connection with lateral tunnel technique, sometimes even without cardiopulmonary bypass (131-133).

Super-Glenn

Insufficient pulmonary blood flow may be increased by the addition of a small systemic-to-pulmonary artery shunt, procedure called super-Glenn (134-136). With the expanding indication for biventricular recruitment, the super-Glenn is a potential approach leaving biventricular recruitment as a future option (137).

Fontan completion

After the initial technique described for tricuspid atresia (1), the Fontan circulation has evolved in technique, beginning from the right atrial to pulmonary connection (6,138-140), to right atrial to right ventricular connection for patients with tricuspid atresia (141-144), to tricuspid valve exclusion for patients with single ventricle (6,145), to now the two surgical techniques most frequently used: the lateral tunnel (146,147), and the extra-cardiac conduit (148-150). Improvements in intra-operative techniques, as well of the available materials, has allowed accomplishment of Fontan completion while the heart continues to beat, therefore avoiding myocardial ischemia (151), or even without requiring cardiopulmonary bypass (152).

And after a long period without using any valve in the Fontan circulation, the utilization of a biological valve has been reintroduced between inferior vena cava and the pulmonary circulation (153), and bioengineered conduits have also been used for the same purpose (154). Computational simulations studying the distribution of the cavo-pulmonary blood flow has led to the use of an inverted Y-graft to separate the venous return of the inferior vena cava between right and left lung (155). For patients with interruption of the inferior vena cava and systemic venous drainage of the inferior part of the body through the superior vena cava, Kawashima proposed the anastomosis of the superior vena cava end-to-side to the right pulmonary artery, exactly as in the bidirectional Glenn, creating a version of Fontan completion in one stage (156). Improvement in outcomes have resulted in expansion of indication for Fontan completion to patients previously not considered suitable candidates (157-159).

Fenestration

An issue still without generalized agreement in approach is the Fontan fenestration. An “adjustable atrial septal defect” was first introduced by Hillel Laks (160,161) to temporarily reduce excessively elevated systemic venous pressure after a Fontan procedure and reduce the immediate post-operative complications. Since then, it has been renamed “fenestration” by Nancy D. Bridges (162,163), and universally adopted to define a surgically created communication between the diverted systemic venous return and the lower pressure pulmonary atrium using both surgical techniques utilized for Fontan completion, the lateral tunnel and extracardiac conduit.

Early indications for a Fontan fenestration were limited to high-risk candidates to reduce the systemic venous pressure resulting in increased lymphatic drainage with reduction in pleural effusions, and to provide adequate preload to the systemic single ventricle which reduced the post-operative low cardiac output state (164,165). The only prospective randomized study comparing patients undergoing fenestrated versus non-fenestrated Fontan completion demonstrated a reduction in intensive care duration and hospital stay (166). The indication for fenestration was eventually extended to almost all patients, regardless the level of pre-operative risk, and became commonplace for Fontan completion. However, the early benefits of fenestration were at the expense of late complications such as lower systemic oxygenation with prolonged cyanosis and risk of long-term systemic thromboembolism. Additionally, some patients required a later intervention to close the fenestration to improve resting and exercise oxygenation, lower maximal heart rate during exercise, and increase exercise duration (167-171). As a result, fenestration became limited again to select patients facing increased risks of complications in the immediate post-operative period (172).

While two systematic literature reviews and meta-analyses on the early outcomes of a Fontan fenestration demonstrated mixed benefit in the immediate post-operative period (173,174), our meta-analyses on later outcomes showed patients required either late closure or creation/reopening of a fenestration made at the time of Fontan completion (175).

Since then, the pendulum has swung back with indications for Fontan completion now extending to different patient populations including patients with complex congenital heart defects. With the increasing complexity of patients undergoing a Fontan procedure, surgical centers have begun to reconsider the use of fenestration, and in some institutions with high-risk cases, it is used nearly universally (176). The altered hemodynamics in Fontan patients continues to be investigated using mathematical and computational fluid dynamic models comparing those with and without a fenestration (177,178), as well as quantifying the effects of different sizes of fenestration (179).

Ventricular septation

The last available option for the surgical treatment of single ventricle is the staged ventricular septation. This concept of staged surgical approach for bi-ventricular circulation is not novel: in 1984, Paul Ebert proposed “staged partitioning” for the single ventricle (180); in 1986, Roxane McKay reported “staged septation” of a double inlet left ventricle (181); and in 2022, Renee E. Margossian and colleagues reported their revised approach to surgical septation to avoid the Fontan pathway (182).

In our experience, for all newborns with borderline left heart structures, the pathway towards a bi-ventricular circulation is considered, utilizing appropriate staging of surgical procedures (183,184). For other patients on a uni-ventricular pathway, either a Norwood, bidirectional Glenn, or Fontan completion, extensive imaging and functional investigations are performed before ruling out the possibility for a bi-ventricular conversion (183-193). This decision-making process requires careful consideration of the size of inflow and outflow of the systemic ventricle, morphology and shunt direction through any interatrial and/or ventricular communication, right and left ventricular function and volumes, and morphology and flow of ascending aorta and aortic arch (183,184).

Peri-operative management

In-depth knowledge of the physiology in patients with single ventricle physiology is indispensable to achieving optimal peri-operative management of anesthesia, cardiopulmonary bypass and intensive care. Mortality rates are the highest following the first stage surgical palliation (194). In more recent years, for patients with pulmonary over-circulation and poor systemic perfusion with multi-organ failure, conservative management has been introduced, deferring the first palliative surgery to avoid cardiopulmonary bypass in neonates with already-depleted metabolic and functional reserves (110). The goal of the conservative management prior to the first palliative surgery is to maintain a QP:QS (= pulmonary-to-systemic blood flow ratio) around 1.5–2:1 with adequate utilization of mechanical ventilation with positive pressure and vasoactive medications. This ratio will become 0.5:1 after the bidirectional Glenn, and 1:1 after Fontan completion. In all these processes, a vital role is played in the use of inhaled nitric oxide (195). Better understanding of the unique hemodynamics of single ventricle physiology facilitated by many researchers over the years has resulted in better quality of life for these patients (196-201).

Fontan failure

With the intrinsic properties of the Fontan circulation, its eventual failure is not unexpected and occurs more frequently with increasing age of the patients (197,199-201), despite careful attention to the criteria for indication to this type of surgical procedure (202-204).The causes for failure of the Fontan circulation can be numerous, either anatomical and/or functional, including but not limited to obstruction or narrowing at any level from the cavo-pulmonary connections to the ventricular inlet, atrio-ventricular valve(s) regurgitation, poor systolic and/or diastolic ventricular function, systemic obstructions, elevated pulmonary vascular resistance, supra-ventricular and/or ventricular arrhythmias, etc. (200,201). Recent studies focused on the pharmacological treatment of children with single ventricle and pulmonary hypertension (205). The mechanism for late Fontan failure is multifactorial and depends upon the complex interaction between the ventricle functioning as the systemic ventricle, the ventriculo-vascular coupling, the pulmonary vascular bed, and the venous compartment (206). One of the lesser known issues after a Fontan procedure is the potential exposure of the coronary sinus to the sudden increase in systemic venous pressure with negative consequences on ventricular function (207,208). This, of course, depends entirely upon the type of surgery, lateral tunnel or extracardiac conduit, the arrangement relative to the drainage of the coronary sinus, and the presence and size of fenestration.

Treatment for recurrent protein losing enteropathy and chylothorax, well-known complications of Fontan circulation due to elevated central venous pressure affecting the thoracic duct drainage, has made recent progress by deviating the innominate venous drainage into the lower pressure common atrium. Methods include the direct innominate vein turn-down procedure, interposition of a tubular graft (209,210), or with the selective opacification followed by occlusion of the involved lymphatic vessels (211,212).

Once the reason for Fontan failure is determined, the first approach is to relief the cause of failure with either a catheter interventional or surgical procedure. When there are no identifiable causes, available interventional treatments, or prior interventions failed, alternative options must be considered. The overarching goal to prolong the state of Fontan circulation is to make the patients better candidate for heart transplantation, not at the expense of making them non-transplantable (206). If conservative measures fail, the remaining options are Fontan conversion, if the original surgery was an older arrangement; Fontan take-down, if the hemodynamics of Fontan circulation is not well-tolerated; a form of short or long-term of mechanical circulatory support; and finally, heart transplantation.

Fontan conversion

The atrio-pulmonary connection for Fontan completion has been complicated by failures caused by its non-ergonomic hemodynamics, elevated rates of energy loss rate and elevated kinetic energy maximum value, as demonstrated in computational simulations (146,213,214). In these instances of failure, the original atrio-pulmonary connection has been converted either to a lateral tunnel (215,216) or to an extracardiac conduit (217-219), with better outcomes. The most frequent reason for Fontan failure is the occurrence and recurrence of supra-ventricular or ventricular arrhythmias (220-224). The treatment has been the conversion of the previous Fontan to either a lateral tunnel or an extracardiac conduit (225,226). Resynchronization therapy was later introduced to tackle the issue of intracardiac conduction delays in these patients (227).

Fontan take-down

The decision for a Fontan take-down has to consider all of the factors related to the pre-operative diagnosis, the decision-making process that led Fontan completion, the surgical procedures performed, and the post-operative findings causing the Fontan failure. Based on all these considerations, the decision for Fontan take-down must be balanced against all the available alternatives, including the possibility of going back to the situation proceeding the Fontan completion, or to create a completely different arrangement based on the anatomical and hemodynamic characteristics of each specific patient (228).

Mechanical circulatory support

The patients with single ventricle physiology have unique anatomical configuration, etiology and mechanisms of failure, indications for mechanical circulatory support, and the type of support required, unilateral or bilateral. This makes the interpretation and the generalizability of the limited available data challenging regarding the timing and type of optimal mechanism for support (229-233).

First, the ideal management strategies much be determined by analyzing the three different stages of single ventricle management (234):

• neonatal palliation, including Norwood Stage I
• superior cavo-pulmonary shunt (bidirectional Glenn)
• completion of Fontan circulation (early and late)

Several reports are available on the indication and the type of mechanical circulatory support utilized for each stage (235-241).

Second, the pathophysiologic pattern must be determined for the specific patient. An interesting algorithm has been proposed (242) using patient weight and mechanism of failure to choose the best device for mechanical circulatory support: (I) systolic dysfunction, with elevated end-diastolic ventricular pressure and low cardiac output; (II) diastolic dysfunction, with elevated end-diastolic ventricular pressure and normal cardiac output; (III) increased pulmonary vascular resistance and Fontan failure, with elevated central venous pressure and hepatic congestion; (IV) mixed type, with elevated central venous pressure and end-diastolic ventricular pressure, pulmonary congestion and low cardiac output (242). This algorithm was generated based on these principles: differentiating between the need to improve the antegrade Fontan flow, with a “pushing” device, versus uploading the systemic ventricle with a “pulling” device (242,243).

Third, the availability of three main types of support devices must be considered: (I) veno-arterial extra-corporeal membrane oxygenation, ideal for short-term support; (II) ventricular assist device, for mid and long-term support (244), either as bridge to recovery or to transplantation; (III) total artificial heart (227-232,236-242). When planning to use a ventricular assist device, the differences among pulsatile, axial and centrifugal pumps, having different unloading abilities, must be taken in consideration (242,245). Fontan take-down and use of a temporary support device should also be considered (206,228).

Last, but not least, there are surgical issues to consider: (I) the presence of multiple previous sternotomies, complicating the chest re-entry; (II) the positioning of inflow cannulation, considering the presence of adhesions, masking the coronary arteries, the variable morphology and location of the systemic ventricular cavity, the sub-valvular apparatus of the atrio-ventricular valve; (III) the positioning of outflow cannulation, because of the ascending aorta and aortic arch reconstruction (Norwood, Damus-Kaye-Stansel).

The use of mechanical circulatory support for Fontan failure has been supported by experimental studies on animals, in vitro studies, and mathematical and computational fluid dynamic studies.

Experimental studies on animals

Investigating the acute support in a porcine model has provided interesting basic science observations that are translatable to bedside application (246-248).

In vitro studies

Two studies investigated the hemodynamic effects of a totally implantable integrated aortic-turbine venous assist device (177) with in vitro results of ventricular assist devices in right-side failing Fontan (249).

Mathematical and computational fluid dynamic studies

Investigative collaboration with bioengineers and mathematicians has opened a new horizon in the research for mechanical circulatory support even in Fontan circulation, resulting in a large number of publications on the topic (177,238,246-251).

Transplantation

Given the shortage of organ donors, it is clear that cardiac transplantation alone is not a sustainable solution to address the epidemic of heart failure associated with single ventricle pathophysiology. In addition, most patients with Fontan failure present with multi-organ failure making them poor candidates for heart transplantation. Hence, the need for alternative options, particularly mechanical circulatory support, has been increasingly recognized as a means to prolong the state of Fontan circulation and improve their candidacy heart transplantation (206). For transplantation after Fontan procedure, heart transplantation, heart and lung transplantation, and heart and liver transplantation should be discussed.

Heart transplantation

The patients with single ventricle and failing Fontan circulation present challenges, including extremely complex anatomy, multiple previous interventional procedures, unique underlying pathophysiological characteristics, and limited ability to directly assess hemodynamics. These issues complicate the decision-making process for further interventions versus heart transplantation. Consequently, patients with failing Fontan patients constitute one of the highest risk subsets of heart transplant recipients (252). Nevertheless, once only offered after failure of the Fontan circulation (252-256), indications for heart transplantation is now being offered for protein-losing enteropathy (257) and arterio-venous malformations (258). One study described the multicenter experience of heart transplantation in 514 patients with Fontan failure, reporting early mortality ranging from 15% to 23% (177). Another more recent multicenter study reported 177 children with Fontan failure listed for heart transplantation. Among the various phenotypes, abnormal lymphatics, reduced systolic function, preserved systolic function, and “normal” hearts, the group with reduced systolic function had the highest risk of waitlist mortality (21%) and post-transplantation mortality (36%) (259).

An experimental model of heterotopic heart transplantation or failing right heart, with two left ventricles arrangement, has been successful on acute tests on animals, but it has been neve implemented clinically (260).

Heart and lung transplantation

Heart and lung transplantation has historically been used as a definitive treatment for children with end-stage cardiopulmonary failure, although the number performed has steadily decreased over time. Even in patients with failing Fontan, due to the combination of shortage of donors and generally poor outcomes, the indication for heart and lung transplantation in children with single-ventricle physiology has virtually been abandoned as therapeutic option (261).

Heart and liver transplantation

Fontan-associated liver disease can be one of the long-term consequences of the Fontan circulation. By adolescence, virtually 100% of these patients develop clinically silent fibrosis, demonstrated by surveillance biopsies. In the absence of a transplant option, these young patients face a poor quality of life and overall survival because of advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma (262-265). In the absence of long-term hepatic outcome data after heart transplant alone, there is a progressively increasing incidence of combined heart and liver transplantation (262-265). As experience and knowledge has improved in pre-transplant screenings and peri-operative management, better outcomes have been reported for combined heart and liver transplant in this complex group of patients (266,267).

Pregnancy

With improving rates of post-Fontan survival to adulthood, many now seek advice regarding safe pregnancy. However, little data are available and consists of mainly of anecdotal experience and small series of cases (268,269). A systematic literature review showed that the most reported cardiovascular complications during pregnancy in women with Fontan circulation were arrhythmias, heart failure and thromboembolism. Miscarriages were highly prevalent as were premature deliveries and intrauterine growth restriction, and post-partum hemorrhage was the most common obstetric complication (269). Fontan circulation may be associated with poor placental health due to the high systemic venous pressure and low cardiac output contributing to stagnation of placental blood flow and resulting in subchorionic fibrin deposition and variable villous hypoplasia. Analysis of placental pathology may help determine both candidacy for future pregnancy and long-term effects of pregnancy for women with Fontan physiology (270). As infertility and first trimester miscarriage are not uncommon in women with Fontan circulation, pregnancy may be high risk and even contraindicated. In vitro fertilization, with or without gestational surrogacy, can be an option with reports of success but poses risks during ovarian stimulation, oocyte retrieval, and the post-procedural period (271).

Exercise

In the past, several studies have shown that adult patients with Fontan circulation have reduced exercise tolerance affecting the quality of life. These patients were discouraged from any form of exercise. Initial attempts at improving the effort tolerance have been reported using intermittent external legs compression (272). More recently, several programs of cardiopulmonary training, including exercise training, fitness intervention trials, home-based long-term physical endurance and inspiratory muscle trainings, have been instituted in Fontan patients. These programs have been shown to be safe and beneficial, improving exercise capacity, cardiorespiratory performance and cardiac biomarker values, and self-reported quality of life (273-277).

Adolescents and adults without Fontan completion

Years ago, there were only case reports of individuals with single ventricle physiology surviving to adulthood. In more recent years, a number of patients have reached adulthood without any type of even palliative surgery (2,278-282), or after some form of palliation but without requiring a Fontan completion (193,283-286). Attempts should be made to identify the morphologic and pathophysiological characteristics of these patients, identify the more favorable patterns, and compare their survival and quality of life with those who underwent all conventional surgical stages.

Future studies

Experimental studies on animals

Traditionally, potential new surgical approaches were first experimented on animals, despite the difficulties of modeling single ventricle circulation and the various surgical stages in animals born with two ventricles and separate pulmonary and systemic circulations (287-291). As a result, many comparative studies focused on animals born with single ventricle physiology, such as amphibians, like axolotl salamanders (Ambystoma mexicanum) (292), frogs (Xenopus laevis) (293-295), and reptiles, who live unrestricted lifestyle for many years. In frogs and salamanders, the two circulations fuse at the level of single ventricle, splitting at the pulmonary and systemic arterial branches, and the amount of blood flow distributed between pulmonary and systemic circulations is determined by the ratio of the peripheral resistances in the two territories. The anatomic and physiologic features of the amphibian heart does not seem to be even remotely applicable to human cardiac pathophysiology, nor modifiable towards surgical options in patients born with single ventricle. However, the evolutionary origin of normal and abnormal morphogenesis of the human heart (296) has been recently demonstrated (297-299).

Computational studies

In addition animal studies, the current trend is to collaborate with bioengineers and mathematicians by providing them with three-dimensional reconstruction images obtained with computerized tomography or magnetic resonance imaging, together with the clinical information and the hemodynamic data from cardiac catheterization. With the modern computing technology, nowadays every interventional and surgical procedure can be designed and tailored for the specific patient, based on the results of computational simulations. This collaboration is now becoming a routine part of decision-making even for patients with single ventricle physiology at any stage of the surgical plan (177,178,300-302).

Genetics

Genetic studies of animal hearts with single ventricle is become increasingly important in understanding the relationship between morphology and cardiac function (295). Moreover, the underlying molecular signals responsible for the adaptive tissue responses seen in other species may be useful in our understanding of post-operative complications and the discovery of novel strategies to prevent them. Hypoplastic left heart syndrome is the type of “functionally” single ventricle most frequently requiring surgery in the first weeks of life, prompting extensive genetic investigations in these neonates (303-308).

In hypoplastic left heart syndrome of hemodynamic origin, the first mouse model showed evidence of intrinsic cardiomyocyte proliferation and differentiation defects related to left ventricular hypoplasia (306). The profound genetic heterogeneity and oligogenic etiology in hypoplastic left heart syndrome suggests that the genetic landscape is complex and should be investigated in clinical studies built on a familial study design (306). Furthermore, hypoplastic left heart syndrome can present as either isolated phenotype or as a feature of a larger genetic disorder. Specific genes have been implicated, including rare, predicted damaging MYH6 variants present in 10% of hypoplastic left heart syndrome patients, which have also been shown to be associated with decreased transplant-free survival (308).

Finally, in the most recent and large genetic study, single-nucleus RNA sequencing has been performed on 157,273 nuclei from control hearts and from patients with congenital heart disease, including hypoplastic left heart syndrome and dilated and hypertrophic cardiomyopathy (309). Specific cell states of congenital heart defects have been found in cardiomyocytes, characteristic of activated cardiac fibroblasts with an immunodeficient state and a profile suggesting deficient monocytic immunity (309). All these comprehensive phenotyping of congenital heart defects provides a roadmap towards future personalized treatments for patients with single ventricle physiology.

Stem cells

The single ventricle of right ventricular type, as in the hypoplastic left heart syndrome, is especially prone to early failure because of its vulnerability to pressure and volume overload, with a mode of failure distinct from ischemic cardiomyopathy. As these patients enter early adulthood, an emerging epidemic of ventricular failure is evident. Regenerative medicine strategies may help preserve or boost the single ventricle function in these patients by promoting angiogenesis and mitigating oxidative stress. Rescuing a single ventricle in decompensated failure may also require the creation of new, functional myocardium (310). Because of these reasons, experimental studies on animals using stem cells have been conducted in various institutions, including a few clinical trials with progenitor stem cells given via direct myocardial injection or administration in the coronary arterial blood (311-317). The preservation of single ventricular function is the key for long-term outcomes, but currently the available methods to preserve or improve the myocardial function are still limited (314). Stem cell therapy and cardiac tissue engineering present revolutionary potential in the treatments of children with single ventricle, although considerable obstacles must be overcome before their clinical translation (310).

Bioengineering

Tremendous progress have characterized the field of bioengineering and related experimental and clinical applications. Over the last years, relatively simple tasks of building biomaterials to use as patch or conduit during surgery for congenital heart defects has now evolved to bioengineering products to use in place of prosthetic materials and repair of damaged or missing myocardium (318-321). Until recently, it was unthinkable to use biomaterials to construct the systemic-to-pulmonary shunt with tunable properties to control and modulate blood flow through the shunt, thus accommodating to physiological changes as the patient grows (322). Thanks to modern technologies, now these bioengineered shunts represent a new methodology to accommodate the need for increasing pulmonary blood flow in this vulnerable patient population (322).

Nowadays tissues with three-dimensional structures can be generated using different approaches such as self-assembled organoids with tissue-engineering methods, such as bioprinting. A promising study compared heart organoids with in vivo hearts to understand the anatomical structures still lacking in the organoids, and specifically comparing the development of heart structures based on marker genes and regulatory signaling pathways (323).

Finally, we have already discussed heart transplantation as the ultimate solution for failing Fontan circulation and the limitations of human donor shortages. The waiting list for heart transplantation is higher than for any other solid organ transplantation group. Orthotopic pig heart transplantation, as a bridge to allotransplantation, could offer the prospect of long-term survival to these patients (324). In recent years, several advances in techniques of genetic engineering pigs mitigated the vigorous antibody-mediated rejection of a pig heart transplanted in nonhuman primates with extended pig cardiac graft survival (324). These experimental studies could help the progress towards clinical trials of bridging cardiac xenotransplantation for neonates and infants (178). In summary, the developing technologies investigating cell therapy, gene therapy, and tissue engineering are potential tools to regenerate hypoplastic cardiac structures and improve outcomes of neonates with single ventricle physiology.

Conclusions

These last 40 years have certainly changed the course of natural history for children born with any form of “functionally” single ventricle, thanks to the improvement in diagnostic and treatment techniques, and particularly to the increased knowledge of the morphology and function of these complex hearts, from fetal to adult life. There is still much left unexplored and room for improvement, and all efforts should be concentrated in collaborations among different institutions and specialties, focused on the same matter.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics for the series “The Impact of the Progresses of Knowledge and Technologies in Pediatrics”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-22-573/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-573/coif). The series “The Impact of the Progresses of Knowledge and Technologies in Pediatrics” was commissioned by the editorial office without any funding or sponsorship. AFC served as the unpaid Guest Editor of the series and serves as an unpaid Deputy Editor-in-Chief of Translational Pediatrics from April 2022 to June 2024. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax 1971;26:240-8. [Crossref] [PubMed]
2. Moodie DS, Ritter DG, Tajik AJ, et al. Long-term follow-up in the unoperated univentricular heart. Am J Cardiol 1984;53:1124-8. [Crossref] [PubMed]
3. Hager A, Kaemmerer H, Eicken A, et al. Long-term survival of patients with univentricular heart not treated surgically. J Thorac Cardiovasc Surg 2002;123:1214-7. [Crossref] [PubMed]
4. Pradat P, Francannet C, Harris JA, et al. The epidemiology of cardiovascular defects, part 1: a study based on data from three large registries of congenital malformations. Pediatr Cardiol 2003;24:195-221. [Crossref] [PubMed]
5. Harris JA, Francannet C, Pradat P, et al. The epidemiology of cardiovascular defects, part 2: a study based on data from three large registries of congenital malformations. Pediatr Cardiol 2003;24:222-35. [Crossref] [PubMed]
6. Corno A, Becker AE, Bulterijs AH, et al. Univentricular heart: can we alter the natural history? Ann Thorac Surg 1982;34:716-27. [Crossref] [PubMed]
7. Allan LD, Crawford DC, Chita SK, et al. Prenatal screening for congenital heart disease. Br Med J (Clin Res Ed) 1986;292:1717-9. [Crossref] [PubMed]
8. Bull C. Current and potential impact of fetal diagnosis on prevalence and spectrum of serious congenital heart disease at term in the UK. British Paediatric Cardiac Association. Lancet 1999;354:1242-7 ik.
9. Axt-Fliedner R, Enzensberger C, Fass N, et al. Fetal diagnosis of hypoplastic left heart, associations and outcomes in the current era. Ultraschall Med 2012;33:E51-6. [Crossref] [PubMed]
10. Beaton AZ, Pike JI, Stallings C, et al. Predictors of repair and outcome in prenatally diagnosed atrioventricular septal defects. J Am Soc Echocardiogr 2013;26:208-16. [Crossref] [PubMed]
11. Tworetzky W, McElhinney DB, Reddy VM, et al. Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation 2001;103:1269-73. [Crossref] [PubMed]
12. Levey A, Glickstein JS, Kleinman CS, et al. The impact of prenatal diagnosis of complex congenital heart disease on neonatal outcomes. Pediatr Cardiol 2010;31:587-97. [Crossref] [PubMed]
13. Trivedi N, Levy D, Tarsa M, et al. Congenital cardiac anomalies: prenatal readings versus neonatal outcomes. J Ultrasound Med 2012;31:389-99. [Crossref] [PubMed]
14. Marini D, van Amerom J, Saini BS, et al. MR imaging of the fetal heart. J Magn Reson Imaging 2020;51:1030-44. [Crossref] [PubMed]
15. Pedra SRFF. Imaging for Hypoplastic Left Heart Syndrome. World J Pediatr Congenit Heart Surg 2022;13:571-5. [Crossref] [PubMed]
16. Van Aerschot I, Rosenblatt J, Boudjemline Y. Fetal cardiac interventions: myths and facts. Arch Cardiovasc Dis 2012;105:366-72. [Crossref] [PubMed]
17. Quartermain MD, Glatz AC, Goldberg DJ, et al. Pulmonary outflow tract obstruction in fetuses with complex congenital heart disease: predicting the need for neonatal intervention. Ultrasound Obstet Gynecol 2013;41:47-53. [Crossref] [PubMed]
18. Marini D, Xu J, Sun L, et al. Current and future role of fetal cardiovascular MRI in the setting of fetal cardiac interventions. Prenat Diagn 2020;40:71-83. [Crossref] [PubMed]
19. Rychik J, Szwast A, Natarajan S, et al. Perinatal and early surgical outcome for the fetus with hypoplastic left heart syndrome; a 5-year single institutional experience. Ultrasound Obstet Gynecol 2010;36:465-70. [Crossref] [PubMed]
20. Weber RW, Ayala-Arnez R, Atiyah M, et al. Foetal echocardiographic assessment of borderline small left ventricles can predict the need for postnatal intervention. Cardiol Young 2013;23:99-107. [Crossref] [PubMed]
21. Sun HY. Prenatal diagnosis of congenital heart defects: echocardiography. Transl Pediatr 2021;10:2210-24. [Crossref] [PubMed]
22. Bonnet D. Impacts of prenatal diagnosis of congenital heart diseases on outcomes. Transl Pediatr 2021;10:2241-9. [Crossref] [PubMed]
23. Marino BS, Lipkin PH, Newburger JW, et al. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management a scientific statement from the American Heart Association. Circulation 2012;126:1143-72. [Crossref] [PubMed]
24. Gaynor JW, Stopp C, Wypij D, et al. Neurodevelopmental outcomes after cardiac surgery in infancy. Pediatrics 2015;135:816-25. [Crossref] [PubMed]
25. Miller SP, McQuillen PS, Hamrick S, et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007;357:1928-38. [Crossref] [PubMed]
26. Khalil A, Suff N, Thilaganathan B, et al. Brain abnormalities and neurodevelopmental delay in congenital heart disease: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2014;43:14-24. [Crossref] [PubMed]
27. Owen M, Shevell M, Donofrio M, et al. Brain volume and neurobehavior in newborns with complex congenital heart defects. J Pediatr 2014;164:1121-1127.e1. [Crossref] [PubMed]
28. Kobayashi K, Liu C, Jonas RA, et al. The Current Status of Neuroprotection in Congenital Heart Disease. Children (Basel) 2021;8:1116. [Crossref] [PubMed]
29. Claessens NHP, Chau V, de Vries LS, et al. Brain Injury in Infants with Critical Congenital Heart Disease: Insights from Two Clinical Cohorts with Different Practice Approaches. J Pediatr 2019;215:75-82.e2. [Crossref] [PubMed]
30. Clouchoux C, du Plessis AJ, Bouyssi-Kobar M, et al. Delayed cortical development in fetuses with complex congenital heart disease. Cereb Cortex 2013;23:2932-43. [Crossref] [PubMed]
31. Sun L, Macgowan CK, Sled JG, et al. Reduced fetal cerebral oxygen consumption is associated with smaller brain size in fetuses with congenital heart disease. Circulation 2015;131:1313-23. [Crossref] [PubMed]
32. Rychik J, Goff D, McKay E, et al. Characterization of the placenta in the newborn with congenital heart disease: distinction based on type of cardiac malformation. Pediatr Cardiol 2018;39:1165-71. [Crossref] [PubMed]
33. Leon RL, Mir IN, Herrera CL, et al. Neuroplacentology in congenital heart disease: placental connections to neurodevelopmental outcomes. Pediatr Res 2022;91:787-94. [Crossref] [PubMed]
34. Lee FT, Marini D, Seed M, et al. Maternal hyperoxygenation in congenital heart disease. Transl Pediatr 2021;10:2197-209. [Crossref] [PubMed]
35. Kohl T. Chronic intermittent materno-fetal hyperoxygenation in late gestation may improve on hypoplastic cardiovascular structures associated with cardiac malformations in human fetuses. Pediatr Cardiol 2010;31:250-63. [Crossref] [PubMed]
36. Kohl T. Effects of maternal-fetal hyperoxygenation on aortic arch flow in a late-gestation human fetus with closed oval foramen at risk for coarctation. J Thorac Cardiovasc Surg 2011;142:e67-9. [Crossref] [PubMed]
37. Channing A, Szwast A, Natarajan S, et al. Maternal hyperoxygenation improves left heart filling in fetuses with atrial septal aneurysm causing impediment to left ventricular inflow. Ultrasound Obstet Gynecol 2015;45:664-9. [Crossref] [PubMed]
38. Borik S, Macgowan CK, Seed M. Maternal hyperoxygenation and foetal cardiac MRI in the assessment of the borderline left ventricle. Cardiol Young 2015;25:1214-7. [Crossref] [PubMed]
39. Lara DA, Morris SA, Maskatia SA, et al. Pilot study of chronic maternal hyperoxygenation and effect on aortic and mitral valve annular dimensions in fetuses with left heart hypoplasia. Ultrasound Obstet Gynecol 2016;48:365-72. [Crossref] [PubMed]
40. Zeng S, Zhou J, Peng Q, et al. Sustained Chronic Maternal Hyperoxygenation Increases Myocardial Deformation in Fetuses with a Small Aortic Isthmus at Risk for Coarctation. J Am Soc Echocardiogr 2017;30:992-1000. [Crossref] [PubMed]
41. Szwast A, Putt M, Gaynor JW, et al. Cerebrovascular response to maternal hyperoxygenation in fetuses with hypoplastic left heart syndrome depends on gestational age and baseline cerebrovascular resistance. Ultrasound Obstet Gynecol 2018;52:473-8. [Crossref] [PubMed]
42. Edwards LA, Lara DA, Sanz Cortes M, et al. Chronic Maternal Hyperoxygenation and Effect on Cerebral and Placental Vasoregulation and Neurodevelopment in Fetuses with Left Heart Hypoplasia. Fetal Diagn Ther 2019;46:45-57. [Crossref] [PubMed]
43. Hogan WJ, Moon-Grady AJ, Zhao Y, et al. Fetal cerebrovascular response to maternal hyperoxygenation in congenital heart disease: effects of cardiac physiology. Ultrasound Obstet Gynecol 2021;57:769-75. [Crossref] [PubMed]
44. Olley PM, Coceani F, Bodach E. E-type prostaglandins: a new emergency therapy for certain cyanotic congenital heart malformations. Circulation 1976;53:728-31. [Crossref]
45. Heymann MA. Pharmacologic use of prostaglandin E1 in infant with congenital heart disease. Am Heart J 1981;101:837-43. [Crossref] [PubMed]
46. Moffett BS, Garrison JM, Hang A, et al. Prostaglandin Availability and Association with Outcomes for Infants with Congenital Heart Disease. Pediatr Cardiol 2016;37:338-44. [Crossref] [PubMed]
47. Mustafa HJ, Cross SN, Jacobs KM, et al. Preterm birth of infants prenatally diagnosed with congenital heart disease: characteristics, associations, and outcomes. Pediatr Cardiol 2020;41:972-8. [Crossref] [PubMed]
48. Mah K, Khoo NS, Martin BJ, et al. Insights from 3D Echocardiography in Hypoplastic Left Heart Syndrome Patients Undergoing TV Repair. Pediatr Cardiol 2022;43:735-43. [Crossref] [PubMed]
49. Wang L, Fang L, Li Y, et al. Real-time 3D transoesophageal echocardiography visualization of congenital double orifice mitral valve. Eur Heart J Cardiovasc Imaging 2022;23:e263. [Crossref] [PubMed]
50. Wilkinson JC, Colquitt JL, Doan TT, et al. Global Longitudinal Strain Analysis of the Single Right Ventricle: Leveling the Playing Field. J Am Soc Echocardiogr 2022;35:657-63. [Crossref] [PubMed]
51. Dodge-Khatami J, Adebo DA. Evaluation of complex congenital heart disease in infants using low dose cardiac computed tomography. Int J Cardiovasc Imaging 2021;37:1455-60. [Crossref] [PubMed]
52. Corno AF, Salazar JD. Role of cardiac CT in the pre-operative and post-operative evaluation of congenital heart defects in children. Chapter for the book: “Pediatric cardiac CT in congenital heart disease”. Editor: Adebo D, Springer Nature, 2021, pp.219-268.
53. John S, Schoeneberg L, Greenleaf CE, et al. Pre- and post-operative cardiovascular CT in Stage I single ventricle palliation. J Card Surg 2022;37:322-8. [Crossref] [PubMed]
54. Pizzuto A, Ait-Ali L, Marrone C, et al. Role of cardiac MRI in the prediction of pre-Fontan end-diastolic ventricular pressure. Cardiol Young 2022;32:1930-7. [Crossref] [PubMed]
55. Kanngiesser LM, Freitag-Wolf S, Boroni Grazioli S, et al. Serial Assessment of Right Ventricular Deformation in Patients With Hypoplastic Left Heart Syndrome: A Cardiovascular Magnetic Resonance Feature Tracking Study. J Am Heart Assoc 2022;11:e025332. [Crossref] [PubMed]
56. Fournier E, Batteux C, Mostefa-Kara M, et al. Cardiac tomography-echocardiography imaging fusion: a new approach to congenital heart disease. Rev Esp Cardiol (Engl Ed) 2023;76:10-8. [Crossref] [PubMed]
57. Yoo SJ, Hussein N, Peel B, et al. 3D Modeling and Printing in Congenital Heart Surgery: Entering the Stage of Maturation. Front Pediatr 2021;9:621672. [Crossref] [PubMed]
58. Liang J, Zhao X, Pan G, et al. Comparison of blood pool and myocardial 3D printing in the diagnosis of types of congenital heart disease. Sci Rep 2022;12:7136. [Crossref] [PubMed]
59. Corno AF, Durairaj S, Skinner GJ. Narrative review of assessing the surgical options for double outlet right ventricle. Transl Pediatr 2021;10:165-76. [Crossref] [PubMed]
60. Ratnayaka K, Nageotte SJ, Moore JW, et al. Patent Ductus Arteriosus Stenting for All Ductal-Dependent Cyanotic Infants: Waning Use of Blalock-Taussig Shunts. Circ Cardiovasc Interv 2021;14:e009520. [Crossref] [PubMed]
61. Prabhu NK, Zhu A, Meza JM, et al. Transition to Ductal Stenting for Single Ventricle Patients Led to Improved Survival: An Institutional Case Series. World J Pediatr Congenit Heart Surg 2021;12:518-26. [Crossref] [PubMed]
62. Schranz D, Esmaeii A, Akintuerk H. Hypoplastic left heart: stage-I will be performed interventionally soon. Pediatr Cardiol 2021;42:727-35. [Crossref] [PubMed]
63. Gil-Jaurena JM, Zunzunegui JL, Pérez-Caballero R, et al. Hybrid Procedures. Opening Doors for Surgeon and Cardiologist Close Collaboration. Front Pediatr 2021;9:687909. [Crossref] [PubMed]
64. Maeda K, Yamaki S, Kado H, et al. Hypoplasia of the small pulmonary arteries in hypoplastic left heart syndrome with restrictive atrial septal defect. Circulation 2004;110:II139-46. [Crossref] [PubMed]
65. Photiadis J, Urban AE, Sinzobahamvya N, et al. Restrictive left atrial outflow adversely affects outcome after the modified Norwood procedure. Eur J Cardiothorac Surg 2005;27:962-7. [Crossref] [PubMed]
66. Divanovic A, Hor K, Cnota J, et al. Prediction and perinatal management of severely restrictive atrial septum in fetuses with critical left heart obstruction; clinical experience using pulmonary venous Doppler analysis. J Thorac Cardiovasc Surg 2011;141:988-94. [Crossref] [PubMed]
67. Goltz D, Lunkenheimer JM, Abedini M, et al. Left ventricular obstruction with restrictive inter-atrial communication leads to retardation in fetal lung maturation. Prenat Diagn 2015;35:463-70. [Crossref] [PubMed]
68. Luciani GB, Pessotto R, Mombello A, et al. Hypoplastic left heart syndrome with restrictive atrial septal defect and congenital pulmonary lymphangiectasis. Cardiovasc Pathol 1999;8:49-51. [Crossref] [PubMed]
69. Rychik J, Rome JJ, Collins MH, et al. The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome. J Am Coll Cardiol 1999;34:554-60. [Crossref] [PubMed]
70. Graziano JN, Heidelberger KP, Ensing GJ, et al. The influence of a restrictive atrial septal defect on pulmonary vascular morphology in patients with hypoplastic left heart syndrome. Pediatr Cardiol 2002;23:146-51. [Crossref] [PubMed]
71. Khan AH, Hoskoppal D, Kumar TKS, et al. Utility of the Medtronic microvascular plug™ as a transcatheter implantable and explantable pulmonary artery flow restrictor in a swine model. Catheter Cardiovasc Interv 2019;93:1320-8. [Crossref] [PubMed]
72. Kurtz JD, Alsoufi B, Wilkens SJ, et al. Modified Microvascular Plug as a Flow Restrictor in Hypoplastic Left Heart Syndrome with Dysplastic Tricuspid and Pulmonary Valves. Pediatr Cardiol 2021;42:1653-7. [Crossref] [PubMed]
73. Alsagheir A, Koziarz A, Makhdoum A, et al. Duct stenting versus modified Blalock-Taussig shunt in neonates and infants with duct-dependent pulmonary blood flow: A systematic review and meta-analysis. J Thorac Cardiovasc Surg 2021;161:379-390.e8. [Crossref] [PubMed]
74. Lehenbauer DG, Morales DLS. Shunts versus stents? Collaboration better than competition. J Thorac Cardiovasc Surg 2021;161:394-5. [Crossref] [PubMed]
75. Ramakrishnan K, Alfares FA, Hammond-Jack K, et al. Optimal Timing of Pulmonary Banding for Newborns with Single Ventricle Physiology and Unrestricted Pulmonary Blood Flow. Pediatr Cardiol 2016;37:606-9. [Crossref] [PubMed]
76. Lan YT, Chang RK, Laks H. Outcome of patients with double-inlet left ventricle or tricuspid atresia with transposed great arteries. J Am Coll Cardiol 2004;43:113-9.
77. Corno AF, Ladusans EJ, Pozzi M, et al. FloWatch® versus conventional pulmonary artery banding. J Thorac Cardiovasc Surg 2007;134:1413-9. [Crossref] [PubMed]
78. Juaneda I, Chiostri B, Kreutzer C. Technical aspects and common pitfalls of Norwood with modified Blalock-Taussig shunt. World J Pediat Congenit Heart Surg 2022;13:576-80. [Crossref] [PubMed]
79. Reemtsen BL, Pike NA, Starnes VA. Stage I palliation for hypoplastic left heart syndrome: Norwood versus Sano modification. Curr Opin Cardiol 2007;22:60-5. [Crossref] [PubMed]
80. Kanazawa T, Shimizu K, Iwasaki T, et al. Perioperative Milrinone Infusion Improves One-Year Survival After the Norwood-Sano Procedure. J Cardiothorac Vasc Anesth 2021;35:2073-8. [Crossref] [PubMed]
81. Sano S, Sano T, Kobayashi Y, et al. Journey Toward Improved Long-Term Outcomes After Norwood-Sano Procedure: Focus on the Aortic Arch Reconstruction. World J Pediatr Congenit Heart Surg 2022;13:581-7. [Crossref] [PubMed]
82. Myers PO, Emani SM, Baird CW. Ring-reinforced Sano right ventricular to pulmonary artery conduit at Norwood stage I. Multimed Man Cardiothorac Surg 2016;2016:mmv038. [Crossref] [PubMed]
83. Ginestar AC, Martinez FS, Argudo JA, et al. Norwood-sano operation using a stentless pulmonary valved conduit. World J Pediatr Congenit Heart Surg 2011;2:133-5. [Crossref] [PubMed]
84. Briceno-Medina M, Kumar TKS, Sathanandam S, et al. Femoral vein homograft as Sano shunt results in improved pulmonary artery growth after Norwood operation. Cardiol Young 2018;28:118-25. [Crossref] [PubMed]
85. Said SM, Dearani JA. Norwood valved Sano shunt: Early reward versus late penalty? J Thorac Cardiovasc Surg 2018;155:1756-7. [Crossref] [PubMed]
86. Jonas RA, Castaneda AR, Lang P. Single ventricle (single- or double-inlet) complicated by subaortic stenosis: surgical options in infancy. Ann Thorac Surg 1985;39:361-6. [Crossref] [PubMed]
87. Lin AE, Laks H, Barber G, et al. Subaortic obstruction in complex congenital heart disease: management by proximal pulmonary artery to ascending aorta end-to-side anastomosis. J Am Coll Cardiol 1986;7:617-24. [Crossref] [PubMed]
88. Trusler GA, Freedom RM. Management of subaortic stenosis in the univentricular heart. Ann Thorac Surg 1989;47:643-4. [Crossref] [PubMed]
89. Cheung HC, Lincoln C, Anderson RH, et al. Options for surgical repair in hearts with univentricular atrioventricular connection and subaortic stenosis. J Thorac Cardiovasc Surg 1990;100:672-81.
90. Karl TR, Watterson KG, Sano S, et al. Operations for subaortic stenosis in univentricular hearts. Ann Thorac Surg 1991;52:420-7; discussion 427-8. [Crossref] [PubMed]
91. Kido T, Steringer MT, Vodiskar J, et al. Improved Long-term Outcome of Damus-Kaye-Stansel Procedure Without Previous Pulmonary Artery Banding. Ann Thorac Surg 2022;114:545-51. [Crossref] [PubMed]
92. Elmahrouk AF, Ismail MF, Arafat AA, et al. Combined Norwood and cavopulmonary shunt as the first palliation in late presenters with hypoplastic left heart syndrome and single ventricle lesions. J Thorac Cardiovasc Surg 2022;163:1592-600. [Crossref] [PubMed]
93. Freedom RM, Trusler GA. Arterial switch for palliation of subaortic stenosis in single ventricle and transposition: no mean feat! Ann Thorac Surg 1991;52:415-6. [Crossref] [PubMed]
94. Mee RB. Neonatal palliative switch for complex univentricular heart. Semin Thorac Cardiovasc Surg 1994;6:39-40.
95. Yurdakok O, Cicek M, Korun O, et al. The choice of palliative arterial switch operation as an alternative for selected cases in a single center: experience and mid-term results. J Card Surg 2021;36:1979-94. [Crossref] [PubMed]
96. Najim HK, Oh NA. The ventricular switch: an alternative strategy toward biventricular repair in moderately hypoplastic left ventricle complex connections. World J Pediat Congenit Heart Surg 2022;13:650-4. [Crossref] [PubMed]
97. Kaneko Y, Hirata Y, Yagyu K, et al. Pulmonary-to-systemic blood flow ratio-oriented management after repair of obstructive total anomalous pulmonary venous connection in neonates with single ventricle. Ann Thorac Surg 2003;75:1010-2. [Crossref] [PubMed]
98. Lodge AJ, Rychik J, Nicolson SC, et al. Improving outcomes in functional single ventricle and total anomalous pulmonary venous connection. Ann Thorac Surg 2004;78:1688-95. [Crossref] [PubMed]
99. Kelle AM, Backer CL, Gossett JG, et al. Total anomalous pulmonary venous connection: results of surgical repair of 100 patients at a single institution. J Thorac Cardiovasc Surg 2010;139:1387-1394.e3. [Crossref] [PubMed]
100. Nakayama Y, Hiramatsu T, Iwata Y, et al. Surgical results for functional univentricular heart with total anomalous pulmonary venous connection over a 25-year experience. Ann Thorac Surg 2012;93:606-13. [Crossref] [PubMed]
101. Sugano M, Murata M, Ide Y, et al. Midterm results and risk factors of functional single ventricles with extracardiac total anomalous pulmonary venous connection. Gen Thorac Cardiovasc Surg 2019;67:941-8. [Crossref] [PubMed]
102. Vasquez Choy AL, Adebo DA, John S, et al. Essential role of cardiac computed tomography for surgical decision making in children with total anomalous pulmonary venous connection and single ventricle. J Card Surg 2022;37:1544-9. [Crossref] [PubMed]
103. Yerebakan C, Murray J, Valeske K, et al. Long-term results of biventricular repair after initial Giessen hybrid approach for hypoplastic left heart variants. J Thorac Cardiovasc Surg 2015;149:1112-20; discussion 1120-2.e2. [Crossref] [PubMed]
104. Fuchigami T, Nishioka M, Akashige T, et al. Growing potential of small aortic valve with aortic coarctation or interrupted aortic arch after bilateral pulmonary artery banding. Interact Cardiovasc Thorac Surg 2016;23:688-93. [Crossref] [PubMed]
105. Higashida A, Hoashi T, Kitano M, et al. Application of hybrid Stage I palliation for patients with two ventricular cavities and hypoplastic left heart structures. Interact Cardiovasc Thorac Surg 2018;26:906-11. [Crossref] [PubMed]
106. Erek E, Suzan D, Aydin S, et al. Staged Biventricular Repair After Hybrid Procedure in High-Risk Neonates and Infants. World J Pediatr Congenit Heart Surg 2019;10:426-32. [Crossref] [PubMed]
107. Ceneri NM, Desai MH, Tongut A, et al. Hybrid strategy in neonates with ductal-dependent systemic circulation and multiple risk factors. J Thorac Cardiovasc Surg 2022;164:1291-1303.e6. [Crossref] [PubMed]
108. Hoashi T, Imai K, Okuda N, et al. Intermediate-term outcomes of deferred Norwood strategy. Eur J Cardiothorac Surg 2022;62:ezac099. [Crossref] [PubMed]
109. Akintürk H, Yörüker U, Schranz D. Hypoplastic Left Heart Syndrome Palliation: Technical Aspects and Common Pitfalls of the Hybrid Approach. World J Pediatr Congenit Heart Surg 2022;13:588-92. [Crossref] [PubMed]
110. Eckersley LG, Mills L, Hirose A, et al. The Perinatal Transition and Early Neonatal Period in Hypoplastic Left Heart Syndrome Is Associated With Reduced Systemic and Cerebral Perfusion. Can J Cardiol 2021;37:1923-33. [Crossref] [PubMed]
111. Baker-Smith CM, Goldberg SW, Rosenthal GL. Predictors of Prolonged Hospital Length of Stay Following Stage II Palliation of Hypoplastic Left Heart Syndrome (and Variants): Analysis of the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) Database. Pediatr Cardiol 2015;36:1630-41. [Crossref] [PubMed]
112. Ono M, Kido T, Wallner M, et al. Preoperative risk factors influencing inter-stage mortality after the Norwood procedure. Interact Cardiovasc Thorac Surg 2021;33:218-26. [Crossref] [PubMed]
113. Klausner RE, Parra D, Kohl K, et al. Impact of Digoxin use on interstage outcomes of single ventricle heart disease (from a NPC-QIC registry Database). Am J Cardiol 2021;154:99-105. [Crossref] [PubMed]
114. Matthews CR, Hartman D, Farrell AG, et al. Impact of Home Monitoring Program and Early Gastrostomy Tube on Interstage Outcomes following Stage 1 Norwood Palliation. Pediatr Cardiol 2023;44:124-31. [Crossref] [PubMed]
115. Carlon CA, Mondini PG, De Marchi R. A new vascular anastomosis for the surgical therapy of various cardiovascular defects. G Ital Chir 1950;6:760-74.
116. Glenn WWL. Circulatory bypass of the right side of the heart. II. Shunt between superior vena cava and distal right pulmonary artery: report of clinical application. N Engl J Med 1958;259:117-20. [Crossref] [PubMed]
117. di Carlo D, Williams WG, Freedom RM, et al. The role of cava-pulmonary (Glenn) anastomosis in the palliative treatment of congenital heart disease. J Thorac Cardiovasc Surg 1982;83:437-42.
118. Kopf GS, Laks H, Stansel HC, et al. Thirty year follow up of superior vena cava-pulmonary artery (Glenn) shunts. J Thorac Cardiovasc Surg 1990;100:662-71.
119. Srivastava D, Preminger T, Lock JE, et al. Hepatic venous blood and the development of pulmonary arteriovenous malformations in congenital heart disease. Circulation 1995;92:1217-22. [Crossref] [PubMed]
120. Shah MJ, Rychik J, Fogel MA, et al. Pulmonary arteriovenous malformations after superior cavopulmonary connection: resolution after inclusion of hepatic veins in the pulmonary circulation. Ann Thorac Surg 1997;63:960-3. [Crossref] [PubMed]
121. Magee AG, McCrindle BW, Mawson J, et al. Systemic venous collateral development after the bi-directional cavopulmonary anastomosis. J Am Coll Cardiol 1998;32:505-8. [Crossref] [PubMed]
122. Azzolina G, Eufrate S, Pensa P. Tricuspid atresia: experience in surgical management with a modified cavopulmonary anastomosis. Thorax 1972;27:111-5. [Crossref] [PubMed]
123. Mazzera E, Corno A, Picardo S, et al. Bidirectional cavopulmonary shunts: clinical applications as staged or definitive palliation. Ann Thorac Surg 1989;47:415-20. [Crossref] [PubMed]
124. Gatzoulis MA, Munk MD, Williams WG, et al. Definitive palliation with cavopulmonary or aortopulmonary shunts for adults with single ventricle physiology. Heart 2000;83:51-7. [Crossref] [PubMed]
125. Norwood WI, Jacobs ML. Fontan’s procedure in two stages. Am J Surg 1993;166:548-51. [Crossref] [PubMed]
126. Donofrio MT, Jacobs ML, Norwood WI, et al. Early changes in ventricular septal defect size and ventricular geometry in the single left ventricle after volume-unloading surgery. J Am Coll Cardiol 1995;26:1008-15. [Crossref] [PubMed]
127. Freedom RM, Nykanen D, Benson LN. The physiology of the bidirectional cavopulmonary connection. Ann Thorac Surg 1998;66:664-7. [Crossref] [PubMed]
128. Tanoue Y, Sese A, Ueno Y, et al. Bidirectional Glenn procedure improves the mechanical efficiency of a total cavopulmonary connection in high-risk fontan candidates. Circulation 2001;103:2176-80. [Crossref] [PubMed]
129. Keizman E, Tejman-Yarden S, Mishali D, et al. The Bilateral Bidirectional Glenn Operation as a Risk Factor Prior to Fontan Completion in Complex Congenital Heart Disease Patients. World J Pediatr Congenit Heart Surg 2019;10:174-81. [Crossref] [PubMed]
130. Imai K, Hoashi T, Okuda N, et al. Impact of bilateral bidirectional Glenn anastomosis on staged Fontan strategy and Fontan circulation. Eur J Cardiothorac Surg 2021;60:930-8. [Crossref] [PubMed]
131. Douville EC, Sade RM, Fyfe DA. Hemi-Fontan operation in surgery for single ventricle: a preliminary report. Ann Thorac Surg 1991;51:893-9; discussion 900. [Crossref] [PubMed]
132. Jacobs ML, Rychik J, Rome JJ, et al. Early reduction of the volume work of the single ventricle: the hemi-Fontan operation. Ann Thorac Surg 1996;62:456-61; discussion 461-2.
133. Jacobs ML, Pourmoghadam KK. The hemi-Fontan operation. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2003;6:90-7. [Crossref] [PubMed]
134. van de Wal HJ, Ouknine R, Tamisier D, et al. Bi-directional cavopulmonary shunt: is accessory pulsatile flow, good or bad? Eur J Cardiothorac Surg 1999;16:104-10. [Crossref] [PubMed]
135. Mosca RS. Super-Glenn: able to defeat recalcitrant pulmonary vascular adversaries? Semin Thorac Cardiovasc Surg 2018;30:189-90. [Crossref] [PubMed]
136. Chen X, Yuan H, Liu J, et al. Hemodynamic Effects of Additional Pulmonary Blood Flow on Glenn and Fontan Circulation. Cardiovasc Eng Technol 2020;11:268-82. [Crossref] [PubMed]
137. Marathe SP, Piekarski B, Beroukhim RS, et al. Super-Glenn for staged biventricular repair: impact on left ventricular growth? Eur J Cardiothorac Surg 2021;60:534-41. [Crossref] [PubMed]
138. Yacoub MH, Radle-Smith R. Use of a valved conduit from right atrium to pulmonary artery for “correction” of a single ventricle. Circulation 1976;54:III63.
139. Driscoll DJ, Offord KP, Feldt RH, et al. Five- to fifteen-year follow-up after Fontan operation. Circulation 1992;85:469-96. [Crossref] [PubMed]
140. Burkhart HM, Dearani JA, Mair DD, et al. The modified Fontan procedure: early and late results in 132 adult patients. J Thorac Cardiovasc Surg 2003;125:1252-9. [Crossref] [PubMed]
141. Kreutzer G, Galíndez E, Bono H, et al. An operation for the correction of tricuspid atresia. J Thorac Cardiovasc Surg 1973;66:613-21.
142. Björk VO, Olin CL, Bjarke BB, et al. Right atrial-right ventricular anastomosis for correction of tricuspid atresia. J Thorac Cardiovasc Surg 1979;77:452-8.
143. Coles JG, Leung M, Kielmanowicz S, et al. Repair of tricuspid atresia: utility of right ventricular incorporation. Ann Thorac Surg 1988;45:384-9. [Crossref] [PubMed]
144. Lee CN, Schaff HV, Danielson GK, et al. Comparison of atriopulmonary versus atrioventricular connections for modified Fontan/Kreutzer repair of tricuspid valve atresia. J Thorac Cardiovasc Surg 1986;92:1038-43.
145. Lamberti JJ, Thilenius O, de la Fuente D, et al. Right atrial partition and right ventricular exclusion. J Thorac Cardiovasc Surg 1976;71:386-91.
146. de Leval MR, Kilner P, Gewillig M, et al. Total cavopulmonary connection: a logical alternative to atriopulmonary connection for complex Fontan operations. J Thorac Cardiovasc Surg 1988;96:682-95.
147. Jonas RA, Castaneda AR. Total cavo-pulmonary connection. J Thorac Cardiovasc Surg 1988;96:830.
148. Marcelletti C, Corno AF, Giannico S, et al. Inferior vena cava to pulmonary artery extracardiac conduit: a new form of right heart bypass. J Thorac Cardiovasc Surg 1990;100:228-32.
149. Mavroudis C, Backer CL, Deal BJ. The total cavopulmonary artery Fontan connection using lateral tunnel and extracardiac techniques. Oper Tech Card Thorac Surg 1997;2:180.
150. Giannico S, Trezzi M, Cantarutti N, et al. Late outcome of extracardiac Fontan patients: 32 years of follow-up. Eur J Cardiothorac Surg 2022;62:ezac301. [Crossref] [PubMed]
151. Corno AF, Horisberger J, David J, et al. Right atrial surgery with unsnared inferior vena cava. Eur J Cardiothorac Surg 2004;26:219-20. [Crossref] [PubMed]
152. Burke RP, Jacobs JP, Ashraf MH, et al. Extracardiac Fontan operation without cardiopulmonary bypass. Ann Thorac Surg 1997;63:1175-7. [Crossref] [PubMed]
153. Baslaim G, Hussain A, Kouatli A, et al. Bovine valved xenograft in the extracardiac Fontan procedure. J Thorac Cardiovasc Surg 2003;126:586-8. [Crossref] [PubMed]
154. Isomatsu Y, Shin'oka T, Matsumura G, et al. Extracardiac total cavopulmonary connection using a tissue-engineered graft. J Thorac Cardiovasc Surg 2003;126:1958-62. [Crossref] [PubMed]
155. Trusty PM, Wei Z, Sales M, et al. Y-graft modification to the Fontan procedure: Increasingly balanced flow over time. J Thorac Cardiovasc Surg 2020;159:652-61. [Crossref] [PubMed]
156. Kawashima Y, Kitamura S, Matsuda H, et al. Total cavopulmonary shunt operation in complex cardiac anomalies: a new operation. J Thorac Cardiovasc Surg 1984;87:74-81.
157. Zachary CH, Jacobs ML, Apostolopoulou S, et al. One-lung Fontan operation: hemodynamics and surgical outcome. Ann Thorac Surg 1998;65:171-5. [Crossref] [PubMed]
158. Tchervenkov CI, Chedrawy EG, Korkola SJ. Fontan operation for patients with severe distal pulmonary artery stenosis, atresia, or a single lung. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002;5:68-75. [Crossref] [PubMed]
159. Schmauss D, Kaczmarek I, Sachweh J, et al. Successful single lung fontan operation in 2 children: case reports. Heart Surg Forum 2007;10:E331-3. [Crossref] [PubMed]
160. Laks H, Haas GS, Pearl JM, et al. The use of an adjustable intraatrial communication in patients undergoing the Fontan and other definitive heart procedures. Circulation 1988;78:II357.
161. Laks H, Pearl JM, Haas GS, et al. Partial Fontan: advantages of an adjustable interatrial communication. Ann Thorac Surg 1991;52:1084-94; discussion 1094-5. [Crossref] [PubMed]
162. Bridges ND, Lock JE, Castaneda AR. Baffle fenestration with subsequent catheter closure: modification of the Fontan operation for patients with increased risk. Circulation 1990;82:1681-9. [Crossref] [PubMed]
163. Bridges ND, Mayer JE Jr, Lock JE, et al. Effect of baffle fenestration on outcome of the modified Fontan operation. Circulation 1992;86:1762-9. [Crossref] [PubMed]
164. Kopf GS, Kleinman CS, Hijazi Z, et al. Fenestrated Fontan with delayed transcatheter ASD closure: improved results in high-risk patients. J Thorac Cardiovasc Surg 1992;103:1039-47.
165. Kuhn MA, Jarmakani JM, Laks H, et al. Effect of late postoperative atrial septal defect closure on hemodynamic function in patients with lateral tunnel Fontan procedure. J Am Coll Cardiol 1995;26:259-65. [Crossref] [PubMed]
166. Lemler MS, Scott WA, Leonard SR, et al. Fenestration improves clinical outcome of the Fontan procedure: a prospective randomized study. Circulation 2002;105:207-12. [Crossref] [PubMed]
167. Goff DA, Blume ED, Gauvreau K, et al. Clinical outcome of fenestrated Fontan patients after closure. The first 10 years. Circulation 2000;102:2094-9. [Crossref] [PubMed]
168. Mays WA, Border WL, Knecht SK, et al. Exercise capacity improves after transcatheter closure of the Fontan fenestration in children. Congenit Heart Dis 2008;3:254-61. [Crossref] [PubMed]
169. Meadows J, Lang P, Marx G, et al. Fontan fenestration closure has no acute effect on exercise capacity but improves ventilatory response to exercise. J Am Coll Cardiol 2008;52:108-13. [Crossref] [PubMed]
170. Momenah TS, Eltayb H, El Oakley R, et al. Effects of transcatheter closure of Fontan fenestration on exercise tolerance. Pediatr Cardiol 2008;29:585-8. [Crossref] [PubMed]
171. Boshoff DE, Brown SC, De Giovanni J, et al. Percutaneous management of a Fontan fenestration: in search of the ideal restriction/occlusion device. Cath Cardiovasc Interv 2010;75:60-5. [Crossref] [PubMed]
172. Salazar JD, Zafar F, Siddiqui K, et al. Fenestration during Fontan palliation: now the exception instead of the rule. J Thorac Cardiovasc Surg 2010;140:129-36. [Crossref] [PubMed]
173. Li D, Li M, Zhou X, An Q. Comparison of the fenestrated and non-fenestrated Fontan procedures: A meta-analysis. Medicine (Baltimore) 2019;98:e16554. [Crossref] [PubMed]
174. Bouhout I, Ben-Ali W, Khalaf D, et al. Effect of Fenestration on Fontan Procedure Outcomes: A Meta-Analysis and Review. Ann Thorac Surg 2020;109:1467-74. [Crossref] [PubMed]
175. Greenleaf CE, Lim ZN, Li W, et al. Impact on clinical outcomes from transcatheter closure of the Fontan fenestration: A systematic review and meta-analysis. Front Pediatr 2022;10:915045. [Crossref] [PubMed]
176. Corno AF, Koerner TS, Salazar JD. The pendulum of Fontan fenestration. Translational Pediatric 2022; In press.
177. Rijnberg FM, Hazekamp MG, Wentzel JJ, et al. Energetics of blood flow in cardiovascular disease concept and clinical implications of adverse energetics in patients with a Fontan circulation. Circulation 2018;137:2393-407. [Crossref] [PubMed]
178. Hsia TY, Conover T, Figliola R, et al. Computational Modeling to Support Surgical Decision Making in Single Ventricle Physiology. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2020;23:2-10. [Crossref] [PubMed]
179. Ahmad Z, Jin LH, Penny DJ, et al. Optimal Fenestration of the Fontan Circulation. Front Physiol 2022;13:867995. [Crossref] [PubMed]
180. Ebert PA. Staged partitioning of single ventricle. J Thorac Cardiovasc Surg 1984;88:908-13.
181. McKay R, Bini RM, Wright JP. Staged septation of double inlet left ventricle. Br Heart J 1986;56:563-6. [Crossref] [PubMed]
182. Margossian RE, Solowiejczyk D, Bourlon F, et al. Septation of the single ventricle: revisited. J Thorac Cardiovasc Surg 2002;124:442-7. [Crossref] [PubMed]
183. Greenleaf C, Sinha R, Cerra Z, et al. Development of a biventricular conversion program: A new paradigm. J Card Surg 2021;36:2013-20. [Crossref] [PubMed]
184. Greenleaf CE, Salazar JD. Biventricular Conversion for Hypoplastic Left Heart Variants: An Update. Children (Basel) 2022;9:690. [Crossref] [PubMed]
185. Bacha E. Borderline left ventricle: Trying to see the forest for the trees. J Thorac Cardiovasc Surg 2017;154:570-1. [Crossref] [PubMed]
186. Chen Q, Li S, Hua Z, et al. Anatomical Repair Conversion After Bidirectional Cavopulmonary Shunt for Complex Cardiac Anomalies: Palliation is Not a One-Way Path. Pediatr Cardiol 2018;39:604-9. [Crossref] [PubMed]
187. Oladunjoye OO, Piekarski B, Banka P, et al. Staged ventricular recruitment in patients with borderline ventricles and large ventricular septal defects. J Thorac Cardiovasc Surg 2018;156:254-64. [Crossref] [PubMed]
188. Andersen ND, Scherba JC, Turek JW. Biventricular Conversion in the Borderline Hypoplastic Heart. Curr Cardiol Rep 2020;22:115. [Crossref] [PubMed]
189. Haberer K, Fruitman D, Power A, Hornberger LK, Eckersley L. Fetal echocardiographic predictors of biventricular circulation in hypoplastic left heart complex. Ultrasound Obstet Gynecol 2021;58:405-10. [Crossref] [PubMed]
190. Houeijeh A, Godart F, Pagniez J, et al. From Fontan to Anatomical Repair 16 Years Later. Ann Thorac Surg 2021;111:e15-7. [Crossref] [PubMed]
191. Sunil GS, Srimurugan B, Kottayil BP, et al. Conversion of prior univentricular repairs to septated circulation: Case selection, challenges, and outcomes. Indian J Thorac Cardiovasc Surg 2021;37:91-103. [Crossref] [PubMed]
192. Sojak V, Bokenkamp R, Kuipers I, et al. Left heart growth and biventricular repair after hybrid palliation. Interact Cardiovasc Thorac Surg 2021;32:792-9. [Crossref] [PubMed]
193. Zheng WC, Lee MGY, d'Udekem Y. Fate of Patients With Single Ventricles Who Do Not Undergo the Fontan Procedure. Ann Thorac Surg 2022;114:25-33. [Crossref] [PubMed]
194. Alsoufi B, McCracken C, Kochilas LK, et al. Factors Associated With Interstage Mortality Following Neonatal Single Ventricle Palliation. World J Pediatr Congenit Heart Surg 2018;9:616-23. [Crossref] [PubMed]
195. Reddy VM, Liddicoat JR, Fineman JR, et al. Fetal model of single ventricle physiology: hemodynamic effects of oxygen, nitric oxide, carbon dioxide, and hypoxia in the early postnatal period. J Thorac Cardiovasc Surg 1996;112:437-49. [Crossref] [PubMed]
196. Somerville J. Changing form and function in one ventricle hearts. Herz 1979;4:206-12.
197. Fontan F, Kirklin JW, Fernandez G, et al. Outcome after a “perfect” Fontan operation. Circulation 1990;81:1520-36. [Crossref] [PubMed]
198. Penny DJ, Hayek Z, Redington AN. The effects of positive and negative extrathoracic pressure on pulmonary blood flow after total cavopulmonary connection. Int J Cardiol 1991;30:128-30. [Crossref] [PubMed]
199. Castaneda AR. From Glenn to Fontan. A continuing evolution. Circulation. 1992;86:II80-II84.
200. de Leval MR, Deanfield JE. Four decades of Fontan palliation. Nat Rev Cardiol 2010;7:520-7. [Crossref] [PubMed]
201. Gewillig M, Brown SC. The Fontan circulation after 45 years: update in physiology. Heart 2016;102:1081-6. [Crossref] [PubMed]
202. Choussat A, Fontan F, Besse P, et al. Selection criteria for Fontan’s procedure. In: Anderson RH, Shinebourne EA (eds): Paediatric Cardiology. Churchill Livingstone, Edinburgh. 1977:559-66.
203. Marcelletti C, Mazzera E, Olthof H, et al. Fontan’s operation: an expanded horizon. J Thorac Cardiovasc Surg 1980;80:764-9.
204. Hosein RB, Clarke AJ, McGuirk SP, et al. Factors influencing early and late outcome following the Fontan procedure in the current era. The “Two Commandments”? Eur J Cardiothorac Surg 2007;31:344-52. [Crossref] [PubMed]
205. Chen X, Cai XM, Xu JH, et al. Pharmacokinetics of treprostinil in children with functional single-ventricle pulmonary arterial hypertension: a randomized controlled trial. Ann Transl Med 2021;9:1163. [Crossref] [PubMed]
206. De Rita F, Crossland D, Griselli M, et al. Management of the failing Fontan. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2015;18:2-6. [Crossref] [PubMed]
207. Ilbawi MN, Idriss FS, Muster AJ, et al. Effects of elevated coronary sinus pressure on left ventricular function after the Fontan operation. An experimental and clinical correlation. J Thorac Cardiovasc Surg 1986;92:231-7.
208. Miura T, Hiramatsu T, Forbess JM, et al. Effects of elevated coronary sinus pressure on coronary blood flow and left ventricular function. Implications after the Fontan operation. Circulation 1995;92:II298-II303. [Crossref] [PubMed]
209. Hraska V, Mitchell ME, Woods RK, et al. Innominate Vein Turn-down Procedure for Failing Fontan Circulation. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2020;23:34-40. [Crossref] [PubMed]
210. Hraska V, Hjortdal VE, Dori Y, et al. Innominate vein turn-down procedure: Killing two birds with one stone. JTCVS Tech 2021;7:253-60. [Crossref] [PubMed]
211. Maleux G, Storme E, Cools B, et al. Percutaneous embolization of lymphatic fistulae as treatment for protein-losing enteropathy and plastic bronchitis in patients with failing Fontan circulation. Catheter Cardiovasc Interv 2019;94:996-1002. [Crossref] [PubMed]
212. Mackie AS, Veldtman GR, Thorup L, et al. Plastic bronchitis and protein-losing enteropathy in the Fontan patients: evolving understanding and emerging therapies. Can J Cardiol 2022;38:988-1001. [Crossref] [PubMed]
213. Van Haesdonck JM, Mertens L, Sizaire R, et al. Comparison by computerized numeric modeling of energy losses in different Fontan connections. Circulation 1995;92:II322-6. [Crossref] [PubMed]
214. Cavalcanti S, Gnudi G, Masetti P, et al. Analysis by mathematical model of haemodynamic data in the failing Fontan circulation. Physiol Meas 2001;22:209-22. [Crossref] [PubMed]
215. Kreutzer CJ, Keane JF, Lock JE, et al. Conversion of modified Fontan procedure to lateral atrial cavopulmonary anastomosis. J Thorac Cardiovasc Surg 1996;111:1169-76. [Crossref] [PubMed]
216. Scholl FG, Alejos JC, Laks H. Revision of the traditional atriopulmonary Fontan connection. Adv Card Surg 1997;9:217-27.
217. Marcelletti CF, Hanley FL, Mavroudis C, et al. Revision of previous Fontan connections to total extracardiac cavopulmonary anastomosis: A multicenter experience. J Thorac Cardiovasc Surg 2000;119:340-6. [Crossref] [PubMed]
218. Tatewaki H, Fujita S, Kimura S, et al. Modification of Glenn anastomosis for total cavopulmonary connection conversion after atriopulmonary Fontan. Gen Thorac Cardiovasc Surg 2020;68:1357-9. [Crossref] [PubMed]
219. Hoashi T, Shimada M, Imai K, et al. Long-term therapeutic effect of Fontan conversion with an extracardiac conduit. Eur J Cardiothorac Surg 2020;57:951-7. [Crossref] [PubMed]
220. Peters NS, Somerville J. Arrhytmias after the Fontan procedure. Br Heart J 1992;68:199-204. [Crossref] [PubMed]
221. Cecchin F, Johnsrude CL, Perry JC, et al. Effect of age and surgical technique on symptomatic arrhythmias after the Fontan operation. Am J Cardiol 1995;76:386-91. [Crossref] [PubMed]
222. Durongpisitkul K, Porter CJ, Cetta F, et al. Predictors of early- and late-onset supraventricular tachyarrhythmias after Fontan operation. Circulation 1998;98:1099-107. [Crossref] [PubMed]
223. Ghai A, Harris L, Harrison DA, et al. Outcomes of late atrial tachyarrhytmias in adults after the Fontan operation. J Am Coll Cardiol 2001;37:585-92. [Crossref] [PubMed]
224. Rijnberg FM, Blom NA, Sojak V, et al. A 45-year experience with the Fontant procedure: tachyarrhythmia, an important sign for adverse outcome. Interact Cardiovasc Thorac Surg 2019;29:461-8. [Crossref] [PubMed]
225. Mavroudis C, Deal BJ, Backer CL. The beneficial effects of total cavopulmonary conversion and arrhythmia surgery for the failed Fontan. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002;5:12-24. [Crossref] [PubMed]
226. Deal BJ, Mavroudis C, Backer CL. Beyond Fontan conversion: Surgical therapy of arrhythmias including patients with associated complex congenital heart disease. Ann Thorac Surg 2003;76:542-53; discussion 553-4. [Crossref] [PubMed]
227. Senzaki H, Kyo S, Matsumoto K, et al. Cardiac resynchronization therapy in a patient with single ventricle and intracardiac conduction delay. J Thorac Cardiovasc Surg 2004;127:287-8. [Crossref] [PubMed]
228. Knott-Craig CJ, Danielson GK, Schaff HV, et al. The modified Fontan operation: an analysis of risk factors for early postoperative death or takedown in 702 consecutive patients from one institution. J Thorac Cardiovasc Surg 1995;109:1237-43. [Crossref] [PubMed]
229. Miller JR, Lancaster TS, Callahan C, et al. An overview of mechanical circulatory support in single ventricle patients. Transl Pediatr 2018;7:151-61. [Crossref] [PubMed]
230. Griselli M, Sinha R, Jang S, et al. Mechanical Circulatory Support for Single Ventricle Failure. Front Cardiovasc Med 2018;5:115. [Crossref] [PubMed]
231. Merritt T, Gazit AZ, Carvajal H, et al. Evolution of Ventricular Assist Device Support Strategy in Children With Univentricular Physiology. Ann Thorac Surg 2022;114:1739-44. [Crossref] [PubMed]
232. Villa CR, Greenberg JW, Morales DLS. Mechanical support for the failing single ventricle. J Thorac Cardiovasc Surg Tech 2022;13:174-81. [Crossref] [PubMed]
233. Reid CS, Kaiser HA, Heinisch PP, et al. Ventricular assist device for Fontan: who, when and why? Curr Opin Anaesthesiol 2022;35:12-7. [Crossref] [PubMed]
234. Rossano JW, Woods RK, Berger S, et al. Mechanical support as failure intervention in patients with cavo-pulmonary shunts (MFICS): rationale and aims of a new registry of mechanical circulatory support in single ventricle patients. Congenit Heart Dis 2013;8:182-6. [Crossref] [PubMed]
235. Puri K, Adachi I. Mechanical Support for The Failing Single Ventricle at Pre-Fontan Stage: Current State of The Field and Future Directions. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2021;24:10-8. [Crossref] [PubMed]
236. Niebler RA, Ghanayem NS, Shah TK, et al. Use of HeartWare ventricular assit device in a patient with failed Fontan circulation. Ann Thorac Surg 2014;97:e115-6. [Crossref] [PubMed]
237. Rossano JW, Goldberg DJ, Fuller S, et al. Successful use of the total artificial heart in the failing Fontan circulation. Ann Thorac Surg 2014;97:1438-40. [Crossref] [PubMed]
238. Corno AF, Vergara C, Subramanian C, et al. Assisted Fontan procedure: animal and in vitro models and computational fluid dynamics study. Interact Cardiovasc Thorac Surg 2010;10:679-84. [Crossref] [PubMed]
239. Sinha P, Deutsch N, Ratnayaka K, et al. Effect of mechanical assistance of the systemic ventricle in single ventricle circulation with cavopulmonary connection. J Thorac Cardiovasc Surg 2014;147:1271-5. [Crossref] [PubMed]
240. Peer SM, Deatrick KB, Johnson TJ, et al. Mechanical Circulatory Support for the Failing Fontan: Conversion to Assisted Single Ventricle Circulation-Preliminary Observations. World J Pediatr Congenit Heart Surg 2018;9:31-7. [Crossref] [PubMed]
241. Bedzra EKS, Adachi I, Peng DM, et al. Systemic ventricular assist device support of the Fontan circulation yields promising outcomes: An analysis of The Society of Thoracic Surgeons Pedimacs and Intermacs Databases. J Thorac Cardiovasc Surg 2022;164:353-64. [Crossref] [PubMed]
242. Horne D, Conway J, Rebeyka IM, et al. Mechanical circulatory support in univentricular hearts: current management. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2015;18:17-24. [Crossref] [PubMed]
243. Rodefeld MD, Marsden A, Figliola R, et al. Cavopulmonary assist: Long-term reversal of the Fontan paradox. J Thorac Cardiovasc Surg 2019;158:1627-36. [Crossref] [PubMed]
244. Escher A, Strauch C, Hubmann EJ, et al. A Cavopulmonary Assist Device for Long-Term Therapy of Fontan Patients. Semin Thorac Cardiovasc Surg 2022;34:238-48. [Crossref] [PubMed]
245. Davies RR, Lantz Apn JL, Mullowney SK, et al. Heart Failure After Cavopulmonary Connection: Conversion to Biventricular Circulatory Support. Ann Thorac Surg 2021;112:e185-8. [Crossref] [PubMed]
246. Pekkan K, Aka IB, Tutsak E, et al. In vitro validation of a self-driving aortic-turbine venous-assist device for Fontan patients. J Thorac Cardiovasc Surg 2018;156:292-301.e7. [Crossref] [PubMed]
247. Trusty PM, Tree M, Maher K, et al. An in vitro analysis of the PediMag and CentriMag for right-sided failing Fontan support. J Thorac Cardiovasc Surg 2019;158:1413-21. [Crossref] [PubMed]
248. Durham LA 3rd, Dearani JA, Burkhart HM, et al. Application of Computer Modeling in Systemic VAD Support of Failing Fontan Physiology. World J Pediatr Congenit Heart Surg 2011;2:243-8. [Crossref] [PubMed]
249. Lin WCP, Doyle MG, Roche SL, et al. Computational fluid dynamic simulations of a cavopulmonary assist device for failing Fontan circulation. J Thorac Cardiovasc Surg 2019;158:1424-1433.e5. [Crossref] [PubMed]
250. Good BC, Ponnaluri SV, Weiss WJ, Manning KB. Computational Modeling of the Penn State Fontan Circulation Assist Device. ASAIO J 2022;68:1513-22. [Crossref] [PubMed]
251. Prather R, Das A, Farias M, et al. Parametric investigation of an injection-jet self-powered Fontan circulation. Sci Rep 2022;12:2161. [Crossref] [PubMed]
252. Mauchley DC, Mitchell MB. Transplantation in the Fontan patient. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2015;18:7-16. [Crossref] [PubMed]
253. Macoviak JA, Baldwin JC, Ginsburg R, et al. Orthotopic cardiac transplantation for univentricular heart. Ann Thorac Surg 1988;45:85-6. [Crossref] [PubMed]
254. Carey JA, Hamilton JR, Hilton CJ, et al. Orthotopic cardiac transplantation for the failing Fontan circulation. Eur J Cardiothorac Surg 1998;14:7-13; discussion 13-4. [Crossref] [PubMed]
255. Michielon G, Parisi F, Di Carlo D, et al. Orthotopic heart transplantation for failing single ventricle physiology. Eur J Cardiothorac Surg 2003;24:502-10; discussion 510. [Crossref] [PubMed]
256. Cardoso B, Kelecsenyi A, Smith J, et al. Improving outcomes for transplantation in failing Fontan: what is the next target? J Thorac Cardiovasc Surg Open 2021;8:565-73. [Crossref] [PubMed]
257. Sierra C, Calleja F, Picazo B, et al. Protein-losing enteropathy secondary to Fontan procedure resolved after cardiac transplantation. J Pediatr Gastroenterol Nutr 1997;24:229-30. [Crossref] [PubMed]
258. Graham K, Sondheimer H, Schaffer M. Resolution of cavopulmonary shunt-associated pulmonary arteriovenous malformations after heart transplantation. J Heart Lung Transplant 1997;16:1271-4.
259. Dykes JC, Rosenthal DN, Bernstein D, et al. Clinical and hemodynamic characteristics of the pediatric failing Fontan. J Heart Lung Transplant 2021;40:1529-39. [Crossref] [PubMed]
260. Corno AF, Laks H, Davtyan H, et al. The Heterotopic right heart assist transplant. J Heart Transplant 1988;7:183-90.
261. Carvajal HG, Costello JP, Miller JR, et al. Pediatric heart-lung transplantation: Technique and special considerations. J Heart Lung Transplant 2022;41:271-8. [Crossref] [PubMed]
262. Reardon LC, DePasquale EC, Tarabay J, et al. Heart and heart-liver transplantation in adults with failing Fontan physiology. Clin Transplant 2018;32:e13329. [Crossref] [PubMed]
263. Emamaullee J, Zaidi AN, Schiano T, et al. Fontan-associated liver disease: screening, management and transplant considerations. Circulation 2020;142:591-604. [Crossref] [PubMed]
264. Sganga D, Hollander SA, Vaikunth S, et al. Comparison of combined heart-liver vs heart-only transplantation in pediatric and adult Fontan recipients. J Heart Lung Transplant 2021;40:298-306. [Crossref] [PubMed]
265. Amdani S. Failing Fontan. Heart or heart-liver transplant: the jury is (still) out? J Heart Lung Transplant 2021;40:1020.
266. Duong P, Coats L, O'Sullivan J, et al. Combined heart-liver transplantation for failing Fontan circulation in a late survivor with single-ventricle physiology. ESC Heart Fail 2017;4:675-8. [Crossref] [PubMed]
267. Vaikunth SS, Concepcion W, Daugherty T, et al. Short-term outcomes of en bloc combined heart and liver transplantation in the failing Fontan. Clin Transplant 2019;33:e13540. [Crossref] [PubMed]
268. Davis MB, Rogers IS. Pregnancy After Fontan Palliation: Caution When Details Are Lost in Translation. Circ Cardiovasc Qual Outcomes 2018;11:e004734. [Crossref] [PubMed]
269. Garcia Ropero A, Baskar S, Roos Hesselink JW, et al. Pregnancy in Women With a Fontan Circulation: A Systematic Review of the Literature. Circ Cardiovasc Qual Outcomes 2018;11:e004575. [Crossref] [PubMed]
270. Phillips AL, Cetta F, Kerr SE, et al. The placenta: A site of end-organ damage after Fontan operation. A case series. Int J Cardiol 2019;289:52-5. [Crossref] [PubMed]
271. Kim YY, Levine LD, Partington SL, et al. Successful in vitro fertilization in women with Fontan physiology. J Assist Reprod Genet 2020;37:3017-23. [Crossref] [PubMed]
272. Hernandez J, Chopski SG, Lee S, et al. Externally applied compression therapy for Fontan patients. Transl Pediatr 2018;7:14-22. [Crossref] [PubMed]
273. Sutherland N, Jones B, Westcamp Aguero S, et al. Home- and hospital-based exercise training programme after Fontan surgery. Cardiol Young 2018;28:1299-305. [Crossref] [PubMed]
274. Tran DL, Gibson H, Maiorana AJ, et al. Exercise Intolerance, Benefits, and Prescription for People Living With a Fontan Circulation: The Fontan Fitness Intervention Trial (F-FIT)-Rationale and Design. Front Pediatr 2022;9:799125. [Crossref] [PubMed]
275. Dirks S, Kramer P, Schleiger A, et al. Home-Based Long-Term Physical Endurance and Inspiratory Muscle Training for Children and Adults With Fontan Circulation-Initial Results From a Prospective Study. Front Cardiovasc Med 2022;8:784648. [Crossref] [PubMed]
276. Pyykkönen H, Rahkonen O, Ratia N, et al. Exercise Prescription Enhances Maximal Oxygen Uptake and Anaerobic Threshold in Young Single Ventricle Patients with Fontan Circulation. Pediatr Cardiol 2022;43:969-76. [Crossref] [PubMed]
277. Perrone MA, Pomiato E, Palmieri R, et al. The Effects of Exercise Training on Cardiopulmonary Exercise Testing and Cardiac Biomarkers in Adult Patients with Hypoplastic Left Heart Syndrome and Fontan Circulation. J Cardiovasc Dev Dis 2022;9:171. [Crossref] [PubMed]
278. Fesslova V, Hunter S, Stark J, et al. Long-term clinical outcome of patients with tricuspid atresia: “natural history”. J Cardiovasc Surg (Torino) 1989;30:262-72.
279. Ammash NM, Warnes CA. Survival into adulthood of patients with unoperated single ventricle. Am J Cardiol 1996;77:542-4. [Crossref] [PubMed]
280. Saliba Z, Butera G, Bonnet D, et al. Quality of life and perceived health status in surviving adults with univentricular heart. Heart 2001;86:69-73. [Crossref] [PubMed]
281. Restaino G, Dirksen MS, de Roos A. Long-term survival in a case of unoperated single ventricle. Int J Cardiovasc Imaging 2004;20:221-5. [Crossref] [PubMed]
282. Poterucha JT, Anavekar NS, Egbe AC, et al. Survival and outcomes of patients with unoperated single ventricle. Heart 2016;102:216-22.
283. Moodie DS, Ritter DG, Tajik AH, et al. Long-term follow-up after palliative operation for univentricular heart. Am J Cardiol 1984;53:1648-51. [Crossref] [PubMed]
284. Franklin RC, Spiegelhalter DJ, Anderson RH, et al. Double-inlet ventricle presenting in infancy. I. Survival without definitive repair. J Thorac Cardiovasc Surg 1991;101:767-76.
285. Franklin RC, Spiegelhalter DJ, Anderson RH, et al. Double-inlet ventricle presenting in infancy. II. Results of palliative operations. J Thorac Cardiovasc Surg 1991;101:917-23.
286. Buendía-Fuentes F, Gordon-Ramírez B, Dos Subirà L, et al. Long-term Outcomes of Adults With Single Ventricle Physiology Not Undergoing Fontan Repair: A Multicentre Experience. Can J Cardiol 2022;38:1111-20. [Crossref] [PubMed]
287. Macé L, Dervanian P, Weiss M, et al. Hemodynamics of different degrees of right heart bypass: experimental assessment. Ann Thorac Surg 1995;60:1230-7. [Crossref] [PubMed]
288. Randsbaek F, Riordan CJ, Storey JH, et al. Animal model of the univentricular heart and single ventricular physiology. J Invest Surg 1996;9:375-84. [Crossref] [PubMed]
289. Myers CD, Mattix K, Presson RG Jr, et al. Twenty-four hour cardiopulmonary stability in a model of assisted newborn Fontan circulation. Ann Thorac Surg 2006;81:264-70; discussion 270-1. [Crossref] [PubMed]
290. McMullan DM, Reddy VM, Gottliebson WM, et al. Morphological studies of pulmonary arteriovenous shunting in a lamb model of superior cavopulmonary anastomosis. Pediatr Cardiol 2008;29:706-12. [Crossref] [PubMed]
291. Granegger M, Valencia A, Quandt D, et al. Approaches to Establish Extracardiac Total Cavopulmonary Connections in Animal Models-A Review. World J Pediatr Congenit Heart Surg 2019;10:81-9. [Crossref] [PubMed]
292. MeyerSLLauridsenHPedersenKStreaming of disparate blood flows in single ventricles as a possible mechanism for survival in amphibians and human. Opportunities and shortcomings of the axolotl salamander heart as model.Research Square 2022. doi: .
293. Corno AF, Zhou Z, Uppu SC, et al. The Secrets of the Frogs Heart. Pediatr Cardiol 2022;43:1471-80. [Crossref] [PubMed]
294. Corno AF, Flores NE, Li W, et al. Anesthesia for Echocardiography and Magnetic Resonance Imaging in the African Clawed Frog (Xenopus laevis). Comp Med 2022;72:243-7. [Crossref] [PubMed]
295. Angelini P, Marino B, Corno AF. Single ventricle: amphibians and human beings. World J Pediatr 2022;18:643-6. [Crossref] [PubMed]
296. Taussig HB. Evolutionary origin of cardiac malformations. J Am Coll Cardiol 1988;12:1079-86. [Crossref] [PubMed]
297. Koshiba-Takeuchi K, Mori AD, Kaynak BL, et al. Reptilian heart development and the molecular basis of cardiac chamber evolution. Nature 2009;461:95-8. [Crossref] [PubMed]
298. Oliverio M, Digilio MC, Versacci P, et al. Shells and heart: are human laterality and chirality of snails controlled by the same maternal genes? Am J Med Genet A 2010;152A:2419-25. [Crossref] [PubMed]
299. Poelmann RE, Gittenberger-de Groot AC, Vicente-Steijn R, et al. Evolution and development of ventricular septation in the amniote heart. PLoS One 2014;9:e106569. [Crossref] [PubMed]
300. Rydberg A, Teien DE, Krus P. Computer simulation of circulation in patient with total cavo-pulmonary connection: inter-relationship of cardiac and vascular pressure, flow, resistance and capacitance. Med Biol Eng Comput 1997;35:722-8. [Crossref] [PubMed]
301. Bove EL, de Leval MR, Migliavacca F, et al. Computational fluid dynamics in the evaluation of hemodynamic performance of cavopulmonary connections after the Norwood procedure for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 2003;126:1040-7. [Crossref] [PubMed]
302. Hong H, Menon PG, Zhang H, et al. Postsurgical comparison of pulsatile hemodynamics in five unique total cavopulmonary connections: identifying ideal connection strategies. Ann Thorac Surg 2013;96:1398-404. [Crossref] [PubMed]
303. Natowicz M, Chatten J, Clancy R, et al. Genetic disorders and major extracardiac anomalies associated with the hypoplastic left heart syndrome. Pediatrics 1988;82:698-706.
304. Bohlmeyer TJ, Helmke S, Ge S, et al. Hypoplastic left heart syndrome myocytes are differentiated but possess a unique phenotype. Cardiovasc Pathol 2003;12:23-31. [Crossref] [PubMed]
305. Tomita-Mitchell A, Stamm KD, Mahnke DK, et al. Impact of MYH6 variants in hypoplastic left heart syndrome. Physiol Genomics 2016;48:912-21. [Crossref] [PubMed]
306. Yagi H, Liu X, Gabriel GC, et al. The Genetic Landscape of Hypoplastic Left Heart Syndrome. Pediatr Cardiol 2018;39:1069-81. [Crossref] [PubMed]
307. Findley TO, Crain AK, Mahajan S, et al. Congenital heart defects and copy number variants associated with neurodevelopmental impairment. Am J Med Genet A 2022;188:13-23. [Crossref] [PubMed]
308. Anfinson M, Fitts RH, Lough JW, et al. Significance of α-Myosin Heavy Chain (MYH6) Variants in Hypoplastic Left Heart Syndrome and Related Cardiovascular Diseases. J Cardiovasc Dev Dis 2022;9:144. [Crossref] [PubMed]
309. Hill MC, Kadow ZA, Long H, et al. Integrated multi-omic characterization of congenital heart disease. Nature 2022;608:181-91. [Crossref] [PubMed]
310. Chery J, Wong J, Huang S, et al. Regenerative Medicine Strategies for Hypoplastic Left Heart Syndrome. Tissue Eng Part B Rev 2016;22:459-69. [Crossref] [PubMed]
311. Ishigami S, Ohtsuki S, Tarui S, et al. Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial. Circ Res 2015;116:653-64. [Crossref] [PubMed]
312. Burkhart HM, Qureshi MY, Rossano JW, et al. Autologous stem cell therapy for hypoplastic left heart syndrome: Safety and feasibility of intraoperative intramyocardial injections. J Thorac Cardiovasc Surg 2019;158:1614-23. [Crossref] [PubMed]
313. Saraf A, Book WM, Nelson TJ, et al. Hypoplastic left heart syndrome: From bedside to bench and back. J Mol Cell Cardiol 2019;135:109-18. [Crossref] [PubMed]
314. Vincenti M, O'Leary PW, Qureshi MY, et al. Clinical Impact of Autologous Cell Therapy on Hypoplastic Left Heart Syndrome After Bidirectional Cavopulmonary Anastomosis. Semin Thorac Cardiovasc Surg 2021;33:791-801. [Crossref] [PubMed]
315. Hall B, Alonzo M, Texter K, et al. Probing single ventricle heart defects with patient-derived induced pluripotent stem cells and emerging technologies. Birth Defects Res 2022;114:959-71. [Crossref] [PubMed]
316. Kaushal S, Hare JM, Shah AM, et al. Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome (CHILD Study). Pediatr Cardiol 2022;43:1481-93. [Crossref] [PubMed]
317. Kobayashi K, Higgins T, Liu C, et al. Defining the optimal historical control group for a phase 1 trial of mesenchymal stromal cell delivery through cardiopulmonary bypass in neonates and infants. Cardiol Young 2022; Epub ahead of print. [Crossref]
318. Bejleri D, Streeter BW, Nachlas ALY, et al. A Bioprinted Cardiac Patch Composed of Cardiac-Specific Extracellular Matrix and Progenitor Cells for Heart Repair. Adv Healthc Mater 2018;7:e1800672. [Crossref] [PubMed]
319. Lewis-Israeli YR, Wasserman AH, Gabalski MA, et al. Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease. Nat Commun 2021;12:5142. [Crossref] [PubMed]
320. Gao L, Li X, Tan R, et al. Human-derived decellularized extracellular matrix scaffold incorporating autologous bone marrow stem cells from patients with congenital heart disease for cardiac tissue engineering. Biomed Mater Eng 2022;33:407-21. [Crossref] [PubMed]
321. Bejleri D, Robeson MJ, Brown ME, et al. In vivo evaluation of bioprinted cardiac patches composed of cardiac-specific extracellular matrix and progenitor cells in a model of pediatric heart failure. Biomater Sci 2022;10:444-56. [Crossref] [PubMed]
322. Garven E, Rodell CB, Shema K, et al. Tunable Blood Shunt for Neonates With Complex Congenital Heart Defects. Front Bioeng Biotechnol 2021;9:734310. [Crossref] [PubMed]
323. Jiang S, Feng W, Chang C, et al. Modeling Human Heart Development and Congenital Defects Using Organoids: How Close Are We? J Cardiovasc Dev Dis 2022;9:125. [Crossref] [PubMed]
324. Raza SS, Hara H, Cleveland DC, et al. The potential of genetically engineered pig heart transplantation in infants with complex congenital heart disease. Pediatr Transplant 2022;26:e14260. [Crossref] [PubMed]