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Canadian Journal of Cardiology

Hypoplastic Left Heart Syndrome Across the Lifespan: Clinical Considerations for Care of the Fetus, Child, and Adult

  • Rachel M. Wald
    Correspondence
    Corresponding author: Dr Rachel Wald, 585 University Avenue, Room 5N 517, Toronto, Ontario M5G 2N2, Canada. Tel.: +1-416-340-5502; fax: +1-416-340-5014.
    Affiliations
    Labatt Family Heart Centre, Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada

    Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada

    Peter Munk Cardiac Centre, Division of Cardiology, University Health Network, Toronto, Ontario, Canada

    Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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  • Luc L. Mertens
    Affiliations
    Labatt Family Heart Centre, Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada

    Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada

    Peter Munk Cardiac Centre, Division of Cardiology, University Health Network, Toronto, Ontario, Canada

    Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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      Abstract

      Hypoplastic left heart syndrome (HLHS) is the most common anatomic lesion in children born with single-ventricle physiology and is characterised by the presence of a dominant right ventricle and a hypoplastic left ventricle along with small left-sided heart structures. Diagnostic subgroups of HLHS reflect the extent of inflow and outflow obstruction at the aortic and mitral valves, specifically stenosis or atresia. If left unpalliated, HLHS is a uniformly fatal lesion in infancy. Following introduction of the Norwood operation, early survival has steadily improved over the past 4 decades, mirroring advances in operative and perioperative management as well as reflecting refinements in patient surveillance and interstage clinical care. Notably, survival after staged palliation has increased from 0% to a 5-year survival of 60%-65% for children in some centres. Despite the prevalence of HLHS in childhood with relatively favourable surgical outcomes in contemporary series, this cohort is only now reaching early adult life and longer-term outcomes have yet to be elucidated. In this article we focus on contemporary clinical management strategies for patients with HLHS across the lifespan, from fetal to adult life. Nomenclature and diagnostic considerations are discussed and current literature pertaining to putative genetic etiologies is reviewed. The spectrum of fetal and paediatric interventional strategies, both percutaneous and surgical, is described. Clinical, patient-reported, and neurodevelopmental outcomes of HLHS are delineated. Finally, note is made of current areas of clinical uncertainty, and suggested directions for future research are highlighted.

      Résumé

      Le syndrome d’hypoplasie du cœur gauche (SHCG) est la lésion anatomique la plus fréquente chez les enfants présentant un cœur univentriculaire. Il se caractérise par la présence d’un ventricule droit dominant, d’un ventricule gauche hypoplasique et d’un sous-développement structurel du côté gauche du cœur. Les sous-groupes diagnostiques du SHCG reflètent l’étendue de l’obstruction des voies d’admission et d’éjection au niveau des valves aortique et mitrale, en particulier une sténose ou une atrésie. Sans traitement palliatif, le SHCG provoque invariablement le décès des enfants dans leurs premières années de vie. L’avènement de l’intervention de Norwood a permis une amélioration constante de la survie aux stades initiaux durant les quatre dernières décennies. Ce constat dénote les progrès réalisés dans la prise en charge opératoire et périopératoire ainsi que les améliorations apportées à la surveillance des patients et aux soins cliniques intermédiaires. Ainsi, d’un taux de survie de 0 % après une palliation par étapes, nous sommes passés à un taux de survie de 60 % à 65 % à 5 ans chez les enfants dans certains établissements. Malgré la fréquence du SHCG chez les enfants et l’issue relativement favorable de son traitement chirurgical de nos jours, cette cohorte commence à peine à atteindre le début de l’âge adulte, et le devenir des patients à plus long terme demeure incertain. Dans le présent article, nous mettons en lumière les stratégies contemporaines de prise en charge clinique des patients atteints du SHCG tout au long de leur existence, de la vie fœtale à la vie adulte. Nous abordons aussi des considérations touchant la nomenclature et le diagnostic, et passons en revue les publications consacrées aux causes génétiques présumées. Par ailleurs, nous décrivons l’éventail des stratégies interventionnelles fœtales et pédiatriques, tant percutanées que chirurgicales. Nous caractérisons également l’issue du SHCG sur les plans clinique et neurodéveloppemental, ainsi que d’après les données d’autodéclaration des patients. Enfin, nous signalons des aspects cliniques qui restent à préciser et mettons en avant quelques avenues de recherche.

      Graphical abstract

      The management and outcomes of those born with hypoplastic left heart syndrome (HLHS) are issues of increasing relevance to the congenital cardiologist. In contemporary series, HLHS is the most common anatomic lesion in children born with single-ventricle physiology.
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      The single-ventricle patient population: a current and future concern—a population-based study in the north of England.
      Occurring in 13 to 18 per 100,000 live births, HLHS is more frequently seen in male than in female newborns, without apparent racial predilection.
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      Epidemiology of noncomplex left ventricular outflow tract obstruction malformations (aortic valve stenosis, coarctation of the aorta, hypoplastic left heart syndrome) in Texas, 1999-2001.
      The incidence of HLHS in liveborn children reflects the morphologic definition applied as well as the impact of fetal screening programs.
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      Changing epidemiology of hypoplastic left heart syndrome: results of a national Swedish cohort study.
      Variability in termination of pregnancy practices invariably affects the number of liveborn infants. A Swedish population study has demonstrated that while the numbers of children born with HLHS have decreased over time, more children have undergone surgical palliation.
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      Changing epidemiology of hypoplastic left heart syndrome: results of a national Swedish cohort study.
      As a result of advances in surgical palliation techniques for single-ventricle anatomies, the numbers of subjects alive after Fontan palliation is expected to double in number over the next 20 years, and the proportion of adult survivors with palliated HLHS will increase accordingly.
      • Schilling C.
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      • Nunn R.
      • et al.
      The Fontan epidemic: population projections from the Australia and New Zealand Fontan Registry.
      Notably, the prevalence of adults with severe congenital heart disease outnumbers children and is projected to continue to expand.
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      • Mackie A.S.
      • et al.
      Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010.
      Before the Norwood operation was introduced, HLHS was a uniformly fatal lesion with palliative (comfort) care being the mainstay therapy offered in neonatal life. Over the past 4 decades, however, the Norwood operation has translated into steady improvements in HLHS survival from 0% initially to a current 5-year survival of 60%-65%.
      • Best K.E.
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      The improved prognosis of hypoplastic left heart: a population-based register study of 343 cases in England and Wales.
      ,
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      • et al.
      Transplant-free survival and interventions at 6 years in the SVR Trial.
      In parallel with surgical refinements, novel percutaneous strategies have broadened the therapeutic options for paediatric and selected fetal subjects with HLHS. As a result of improved survival during childhood, an increasing number of palliated HLHS patients will reach early adult life; however, their long-term outcomes remain uncertain.
      • Wilson W.M.
      • Valente A.M.
      • Hickey E.J.
      • et al.
      Outcomes of patients with hypoplastic left heart syndrome reaching adulthood after fontan palliation: multicenter study.
      In this article, we review current clinical management considerations for patients with HLHS across the lifespan, from fetus to adult, and we focus on areas of uncertainty with suggested directions for future research (Fig. 1).
      Figure thumbnail gr1
      Figure 1Summary of potential interventions for hypoplastic left heart syndrome (HLHS) across the lifespan. BCPC, bidirectional cavopulmonary connection; BT, Blalock-Taussig; TCPC, total cavopulmonary connection.

      HLHS Nomenclature, Definition and Etiologies

      The term HLHS encompasses a wide spectrum of developmental abnormalities of the left ventricle (LV) that result in small left-sided heart structures. What is signified by HLHS has been controversial and even confusing as the term has been loosely used to describe a wide spectrum of disorders affecting LV size. The definition put forward by the Nomenclature Working Group of the Association for European Paediatric Cardiology is a spectrum of cardiac malformations with the following features: normally related great arteries in the absence of a common atrioventricular junction, significant LV hypoplasia, valve atresia/stenosis or hypoplasia at aortic and/or mitral valves, and hypoplasia of the ascending aorta and aortic arch.
      • Tchervenkov C.I.
      • Jacobs J.P.
      • Weinberg P.M.
      • et al.
      The nomenclature, definition and classification of hypoplastic left heart syndrome.
      It has recently been suggested that an intact ventricular septum should be included in these diagnostic criteria.
      • Anderson R.H.
      • Spicer D.E.
      • Crucean A.
      Clarification of the definition of hypoplastic left heart syndrome.
      Typically, the various structural components of the left heart are affected in subjects with HLHS including the inflow portion containing the mitral valve, the trabecular segment of the LV, the outflow component including LV outflow tract, and the aorta (including the aortic valve, the ascending aorta, and the aortic arch with the requisite presence of aortic coarctation).
      • Tchervenkov C.I.
      • Jacobs J.P.
      • Weinberg P.M.
      • et al.
      The nomenclature, definition and classification of hypoplastic left heart syndrome.
      Sometimes the term HLHS is physiologically characterised (rather than anatomically defined) as an LV incapable of supporting the systemic circulation; this approach can prove misleading as hemodynamics may evolve over time in response to variations in loading conditions and differing approaches to therapy. Nevertheless, establishing whether the LV is capable of supporting the systemic circulation will determine whether a biventricular circulation is a realistic therapeutic goal. The term “hypoplastic left heart complex” was introduced by Tchervenkov et al. to describe a heart with normally related great arteries in the absence of common atrioventricular junction, with small left heart structures but without aortic or mitral valve stenosis and typically associated with a small aorta and aortic arch.
      • Tchervenkov C.I.
      • Tahta S.A.
      • Jutras L.C.
      • Béland M.J.
      Biventricular repair in neonates with hypoplastic left heart complex.
      This variant could be considered an extreme form of aortic coarctation with associated LV hypoplasia.
      • Grossfeld P.
      • Nie S.
      • Lin L.
      • Wang L.
      • Anderson R.H.
      Hypoplastic left heart syndrome: a new paradigm for an old disease?.
      The various diagnostic subgroups of HLHS are defined by the extent of inflow and outflow obstruction present in the LV. Specific categories include mitral valve atresia with aortic valve atresia, mitral valve stenosis with aortic valve atresia, and mitral valve stenosis with aortic stenosis (Fig. 2). Atresia of the mitral valve is due to either the absence of the left atrioventricular connection (the most common form) or the presence of an imperforate mitral valve. In the context of mitral or aortic atresia, a staged univentricular approach is the only therapeutic option. In contrast, in the setting of aortic and mitral stenosis, the LV size can be deemed “borderline” and decision making between univentricular and biventricular strategies can be challenging and will be driven by interpretation of adequacy of size and function of various LV structures. In patients with mitral stenosis, the hypoplastic LV is characteristically thick-walled with an endocardial layer of fibroelastosis. In patients with mitral atresia, blood flow cannot enter the LV cavity, which is typically slit-like and diminutive in size; endocardial fibroelastosis (EFE) is usually absent in these cases. Coronary artery abnormalities can be associated with HLHS, particularly in patients with mitral stenosis and aortic atresia where cameral-coronary fistulae may be present but are not typically associated with outcomes.
      Figure thumbnail gr2
      Figure 2Morphologic subtypes of hypoplastic left heart syndrome as demonstrated on echocardiography. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
      One of the most consistent features among the spectrum of HLHS is the almost uniform compromise of the LV outflow tract with complete atresia of the aorta typifying the most severe expression of disease. This has led to speculation about the central role of aortic valve and LV outflow tract development in the pathogenesis of HLHS. Recent genetic insights pertaining to valve and ventricular morphogenesis have highlighted the potential contributions of different genes and signalling pathways to the development of HLHS (Fig. 3).
      • Hickey E.J.
      • Caldarone C.A.
      • McCrindle B.W.
      Left ventricular hypoplasia: a spectrum of disease involving the left ventricular outflow tract, aortic valve, and aorta.
      ,
      • Parker L.E.
      • Landstrom A.P.
      Genetic etiology of left-sided obstructive heart lesions: a story in development.
      Hickey et al. determined that the NOTCH1/Hey pathway could be important for the pathogenesis of HLHS because this particular pathway is involved in both endocardial cushion development required for valve development and aortic arch/isthmus development.
      • Hickey E.J.
      • Caldarone C.A.
      • McCrindle B.W.
      Left ventricular hypoplasia: a spectrum of disease involving the left ventricular outflow tract, aortic valve, and aorta.
      Although NOTCH1 variants have been observed in HLHS, they are, however, relatively uncommon abnormalities and their precise role in disease pathogenesis remains uncertain. Another gene involved in outflow tract development is the gap junction protein, named gap junction alpha-1 (GJA1)–encoded protein which encodes the connexin-43 subunit of gap junction channels.
      • Schott J.J.
      • Benson D.W.
      • Basson C.T.
      • et al.
      Congenital heart disease caused by mutations in the transcription factor NKX2-5.
      Although GJA1 is important for LV outflow tract development, its role in pathogenesis of HLHS remains inconclusive. A second group of genes of potential interest are those that encode transcription factors considered to be essential for cardiac morphogenesis. One such example is Hand1, a basic helix-loop-helix transcription factor that contributes to the balance between cardioblast proliferation and differentiation.
      • Riley P.
      • Anson-Cartwright L.
      • Cross J.C.
      The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis.
      • McFadden D.G.
      • Barbosa A.C.
      • Richardson J.A.
      • et al.
      The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage–dependent manner.
      • Srivastava D.
      Hand proteins: molecular mediators of cardiac development and congenital heart disease.
      Given its essential role in LV development, Hand1 may be considered a strong candidate gene for HLHS pathogenesis. One study identified a HAND1 frameshift mutation in 24 of 31 formalin-fixed HLHS hearts,
      • Reamon-Buettner S.M.
      • Ciribilli Y.
      • Inga A.
      • Borlak J.
      A loss-of-function mutation in the binding domain of Hand1 predicts hypoplasia of the human hearts.
      but in subsequent studies, the role of Hand1 in the pathogenesis of HLHS could not be confirmed. Sarcomeric genes have been implicated in the pathogenesis of HLHS, stemming from the observation that the genetic variants of the myosin heavy chain 6 (MYH6) gene
      • Tomita-Mitchell A.
      • Stamm K.D.
      • Mahnke D.K.
      • et al.
      Impact of MYH6 variants in hypoplastic left heart syndrome.
      have been reported to be associated with poorer HLHS outcomes.
      • Theis J.L.
      • Zimmermann M.T.
      • Evans J.M.
      • et al.
      Recessive MYH6 mutations in hypoplastic left heart with reduced ejection fraction.
      Current data suggest that MYH6 can be considered a disease-modifying rather than a disease-causing gene that contributes to the risk of development of right ventricular (RV) systolic dysfunction; importantly, this observation may signal the presence of a subset of patients genetically predisposed to development of RV dysfunction. Based on current genetic knowledge, HLHS is unlikely to be caused by single gene mutations or gene variants.
      Figure thumbnail gr3
      Figure 3Proposed genetic and physiologic etiologies that contribute to the pathogenesis of hypoplastic left heart syndrome (see text for further details). LV, left ventricle; LVOT, left ventricular outflow tract; PFO, patent foramen ovale.
      While genetics may play a role in the pathogenesis of HLHS, additional factors are likely to be equally important contributors. One such factor is the extent of flow through the LV cavity, which is recognised as a key determinant of LV development.
      • Harh J.Y.
      • Paul M.H.
      • Gallen W.J.
      • Friedberg D.Z.
      • Kaplan S.
      Experimental production of hypoplastic left heart syndrome in the chick embryo.
      Decreased flow attributable to outflow tract obstruction, reduced flow through the mitral valve related to valve dysfunction, or reduced right-left shunting through the foramen ovale may individually or cumulatively influence extent of flow through the LV cavity with consequent adverse effects on growth and development. Recently, a fetal mouse model of HLHS was created by ultrasound-guided microinjection of an embolising biomaterial contributing to occlusion of the left atrial inflow and resulting in significant hypoplasia of the LV.
      • Rahman A.
      • DeYoung T.
      • Cahill L.S.
      • et al.
      A mouse model of hypoplastic left heart syndrome demonstrating left heart hypoplasia and retrograde aortic arch flow.
      This model has the potential to facilitate study of the molecular mechanisms of flow reduction and consequent ventricular hypoplasia which could allow for a deeper understanding of the causes of, and possible novel treatments for, HLHS. Although flow is unquestionably a critical determinant of left heart development, it is unlikely to be the sole contributor to HLHS morphogenesis. Rather, HLHS is likely to be a common phenotypic expression of various underlying pathogenic mechanisms. While some forms may be primarily caused by deranged flow dynamics, other subtypes of HLHS may arise from abnormal cardiomyocyte development with intrinsic derangements at the level of genes that direct fetal ventricular development such that some HLHS variants may in fact be manifestations of a specific type of cardiomyopathy.
      • Krane M.
      • Dreßen M.
      • Santamaria G.
      • et al.
      Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome.
      This finding may explain why some forms of HLHS respond favourably to fetal aortic valvuloplasty while others do not. In addition, the development of RV systolic dysfunction in a subset of patients with HLHS points toward the presence of an intrinsic myocyte abnormality. Undoubtedly a deeper understanding of the mechanistic underpinnings of HLHS may allow for identification of subgroups of patients with distinct myogenic developmental abnormalities, which may contribute to enhanced risk stratification for late adverse outcomes, such as RV systolic dysfunction.
      Finally, it should be noted that HLHS has been described in the context of other established genetic syndromes. The most common syndrome associated with HLHS is Turner syndrome (TS). A study looking at the Texas Births Defect Registry data identified TS in about 2% of all HLHS patients and that it was associated with a significant impact on mortality.
      • Lara D.A.
      • Ethen M.K.
      • Canfield M.A.
      • Nembhard W.N.
      • Morris S.A.
      A population-based analysis of mortality in patients with Turner syndrome and hypoplastic left heart syndrome using the Texas Birth Defects Registry.
      The diagnosis of TS is important to consider in all female patients diagnosed with HLHS.

      Fetal Diagnosis of HLHS and the Role of Fetal Interventions

      The diagnosis of HLHS can be made relatively easily during fetal life after identification of a small LV cavity on the fetal 4-chamber view in the presence of normally related great arteries, absence of a common atrioventricular junction, and no ventricular septal defect, reflecting the key morphologic components that define HLHS. The mitral valve atresia subtype is typically associated with a diminutive LV with concomitant aortic atresia. The mitral stenosis variant invariably includes the presence of a hypertrophic LV with either aortic stenosis or atresia. The ascending aorta is typically small, and retrograde flow is seen in the context of aortic atresia. Common associations include arch hypoplasia and the substrate for coarctation of the aorta. Flow in the aortic arch is retrograde or bidirectional in the presence of aortic stenosis (which can include some antegrade flow across the aortic valve). The diagnosis of HLHS should be reserved for only those lesions with left-heart valve atresia or stenosis and a hypoplastic LV cavity. Other lesions, such as coarctation of the aorta, can present in fetal life with smaller left-heart structures, including small mitral and aortic valves, but are lacking stenoses at the level of the mitral and aortic valves. “Hypoplastic left heart complex” can be considered the more extreme form of this entity. Because the prognosis of differing lesions is distinct, it is important to accurately distinguish between disease variations.
      A unique subgroup of patients is defined by the presence of severe aortic stenosis with associated mitral stenosis or hypoplasia. Severe aortic stenosis can present with LV hypertrophy, EFE, and a small LV cavity or, alternatively, with a dilated LV with reduced LV systolic function. The fetal natural history of aortic valve stenosis diagnosed at midgestation suggests the presence of a process in evolution, whereby LV dilation and dysfunction are initially seen to grow, with progressive loss of LV capacity, over subsequent weeks, resulting in hypoplasia of the LV at the time of birth.
      • Allan L.D.
      • Sharland G.
      • Tynan M.J.
      The natural history of the hypoplastic left heart syndrome.
      • Simpson J.M.
      • Sharland G.K.
      Natural history and outcome of aortic stenosis diagnosed prenatally.
      • Danford D.A.
      • Cronican P.
      Hypoplastic left heart syndrome: progression of left ventricular dilation and dysfunction to left ventricular hypoplasia in utero.
      It is therefore a logical assumption that treatment of aortic valve stenosis early in fetal life may facilitate later LV growth as a result of reduced pressure loading and increased flow through the LV, thus preventing downstream development of LV hypoplasia. Consequently, fetal aortic valvuloplasty was introduced as a preemptive interventional strategy to prevent later development of HLHS and to increase the chances of successful biventricular repair. While initial procedural success was reported in the 1990s, there were ongoing challenges pertaining to optimal technique and appropriate selection of patients.
      • Maxwell D.
      • Allan L.
      • Tynan M.J.
      Balloon dilatation of the aortic valve in the fetus: a report of two cases.
      Further study of the natural progression of disease has resulted in a refined approach to patient selection for fetal intervention.
      • Mäkikallio K.
      • McElhinney D.B.
      • Levine J.C.
      • et al.
      Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention.
      Despite the procedural risk, which remains significant with risk of fetal demise approximately 10% in expert centres, outcome data suggest that up to 43% of liveborn fetuses could successfully undergo biventricular repair as a result of fetal intervention.
      • Freud L.R.
      • McElhinney D.B.
      • Marshall A.C.
      • et al.
      Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome: postnatal outcomes of the first 100 patients.
      However, these data require comparison with similar fetuses not undergoing fetal aortic valvuloplasty to ascertain the incremental value of intervention compared with natural evolution of the underlying congenital heart disease. Notably, data from a European registry on fetal aortic stenosis revealed that up to 33% of fetuses with aortic stenosis and emerging HLHS successfully underwent biventricular repair without preceding fetal intervention, suggesting that the therapeutic benefit of fetal intervention on the aortic valve may be relatively modest.
      • Gardiner H.M.
      • Kovacevic A.
      • Tulzer G.
      • et al.
      Natural history of 107 cases of fetal aortic stenosis from a European multicenter retrospective study.
      Subsequent data from the same registry, however, demonstrated improved survival in the fetal intervention group, independently from the type of circulation ultimately achieved.
      • Kovacevic A.
      • Öhman A.
      • Tulzer G.
      • et al.
      Fetal hemodynamic response to aortic valvuloplasty and postnatal outcome: a European multicenter study.
      Adequacy of the atrial septal shunt has been another intuitive area of focus for the fetal interventionalist. Patients with HLHS and a restrictive atrial septum have long been recognised as a high-risk subgroup of patients who can present with severe hypoxemia and marked pulmonary congestion after birth, because sufficiency of the atrial communication is essential for adequate mixing of blood as well as decompression of the left atrium in the context of small left-side structures. Moreover, fetal atrial restriction may result in developmental abnormalities of the lungs (including pulmonary venous wall thickening or arterialisation, lymphatic dilation in the lungs, or pulmonary lymphangiectasia), further complicating management of the single-ventricle patient and contributing to elevated mortality and morbidity in this subgroup despite successful neonatal decompression.
      • Glatz J.A.
      • Tabbutt S.
      • Gaynor J.W.
      • et al.
      Hypoplastic left heart syndrome with atrial level restriction in the era of prenatal diagnosis.
      ,
      • Vlahos A.P.
      • Lock J.E.
      • McElhinney D.B.
      • van der Velde M.E.
      Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: outcome after neonatal transcatheter atrial septostomy.
      Fetal intervention including septoplasty and/or stent placement is geared toward acute amelioration of hemodynamics in this very high-risk population; however, the impact on outcomes remains uncertain.
      • Vida V.L.
      • Bacha E.A.
      • Larrazabal A.
      • et al.
      Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: surgical experience from a single center.
      ,
      • Chaturvedi R.R.
      • Ryan G.
      • Seed M.
      • van Arsdell G.
      • Jaeggi E.T.
      Fetal stenting of the atrial septum: technique and initial results in cardiac lesions with left atrial hypertension.
      The International Fetal Cardiac Intervention Registry published the results of 47 fetal interventions on the atrial septum.
      • Chaturvedi R.R.
      • Ryan G.
      • Seed M.
      • van Arsdell G.
      • Jaeggi E.T.
      Fetal stenting of the atrial septum: technique and initial results in cardiac lesions with left atrial hypertension.
      Despite procedural success in 77% of the interventions, fetal demise was observed in 13%, with no difference in postnatal survival in those with compared with without fetal intervention. Overall survival to hospital discharge was extremely low, 35%, indicating that despite achievement of a technically successful fetal intervention, HLHS patients with a restrictive atrial septum remain a very high-risk group. Identification of patients with potential for atrial restriction during fetal life can be enhanced through the application of acute maternal hyperoxygenation, which contributes to increased pulmonary blood flow by reducing pulmonary vascular resistance. In patients with HLHS, this manoeuvre can be used to gauge pulmonary vasodilatory capacity, which is significantly reduced in patients with atrial septal restriction and thus can identify patients with abnormal pulmonary vascularity who may prove to be poor candidates for fetal intervention.
      • Enzensberger C.
      • Axt-Fliedner R.
      • Degenhardt J.
      • et al.
      Pulmonary vasoreactivity to materno-fetal hyperoxygenation testing in fetuses with hypoplastic left heart.
      • Lee F.T.
      • Marini D.
      • Seed M.
      • Sun L.
      Maternal hyperoxygenation in congenital heart disease.
      • Szwast A.
      • Tian Z.
      • McCann M.
      • Donaghue D.
      • Rychik J.
      Vasoreactive response to maternal hyperoxygenation in the fetus with hypoplastic left heart syndrome.
      In addition, acute maternal hyperoxygenation may facilitate identification of fetuses who may need urgent atrial septostomy after birth. A logical extension would be to determine whether chronic maternal hyperoxygenation could potentially affect left heart growth by increasing flow though the left-side structures. An initial study by Kohl suggested a potential impact of maternal hyperoxygenation on the growth of fetal left-side structures,
      • Kohl T.
      Chronic intermittent materno-fetal hyperoxygenation in late gestation may improve on hypoplastic cardiovascular structures associated with cardiac malformations in human fetuses.
      but a pilot study by Lara et al. demonstrated that the effect of chronic oxygen exposure on growth of left-side structures is likely modest.
      • Lara D.A.
      • Morris S.A.
      • Maskatia S.A.
      • et al.
      Pilot study of chronic maternal hyperoxygenation and effect on aortic and mitral valve annular dimensions in fetuses with left heart hypoplasia.
      In a small study on chronic maternal hyperoxygenation, Edwards et al. observed slower fetal head circumference growth in the treatment group compared with the control group, with no effect on neurodevelopmental outcomes at 6 and 12 months after birth.
      • Edwards L.A.
      • Lara D.A.
      • Sanz Cortes M.
      • et al.
      Chronic maternal hyperoxygenation and effect on cerebral and placental vasoregulation and neurodevelopment in fetuses with left heart hypoplasia.
      These data indicate that further studies are necessary to elucidate the potential risks and benefits associated with this approach.
      • McHugh A.
      • El-Khuffash A.
      • Franklin O.
      • Breathnach F.M.
      Calling into question the future of hyperoxygenation in pregnancy.
      Fetal diagnosis has undoubtedly changed the management and outcomes of patients with HLHS and has improved the understanding of the natural history of the development of HLHS, paving the way for the introduction of novel interventional therapies, albeit with a somewhat limited impact on longer-term outcomes. Most importantly, fetal diagnosis has allowed for extensive discussions with the parents about therapeutic options in the near term and outcomes in the longer term. In the event that the decision is made to continue on with pregnancy, perinatal care planning can occur, which typically includes delivery at an expert centre, initiation of prostaglandins after delivery and performance of timely balloon atrial septostomy in those with significant atrial restriction.
      • Bonnet D.
      Impacts of prenatal diagnosis of congenital heart diseases on outcomes.
      ,
      • Słodki M.
      • Respondek-Liberska M.
      • Pruetz J.D.
      • Donofrio M.T.
      Fetal cardiology: changing the definition of critical heart disease in the newborn.

      Postnatal Diagnosis and Postnatal Management

      After birth, the diagnosis of HLHS is established by means of echocardiography, which is the first-line imaging technique and, for the majority of patients, the only modality necessary to establish a diagnosis and to guide further management. A full segmental anatomic approach allows for clear delineation of the anatomic features, including subtyping, assessment of the aorta and aortic arch, evaluation of ductal patency and shunting, and interrogation of sufficiency of the atrial communication. In the context of aortic and mitral atresia, the LV cavity is typically severely hypoplastic. Surgical decision making requires assessment of RV systolic function and severity of tricuspid valve regurgitation; tricuspid valve abnormalities are common in HLHS, and significant tricuspid regurgitation has been associated with poorer outcomes.
      • Honjo O.
      • Atlin C.R.
      • Mertens L.
      • et al.
      Atrioventricular valve repair in patients with functional single-ventricle physiology: impact of ventricular and valve function and morphology on survival and reintervention.
      In the majority of patients with HLHS, decision making and surgical planning is based on echocardiographic data only. One notable exception is for subjects with aortic stenosis and mitral stenosis where the presence of a borderline LV may allow for successful biventricular repair. This patient subset is generally considered to be a challenging one to manage because candidate selection for a biventricular vs a univentricular approach can be nuanced and therefore difficult to establish with confidence. An erroneous decision to pursue a biventricular strategy can result in high operative mortality.
      • Hickey E.J.
      • Caldarone C.A.
      • Blackstone E.H.
      • et al.
      Biventricular strategies for neonatal critical aortic stenosis: high mortality associated with early reintervention.
      Careful selection of patients for either strategy requires thoughtful integration of morphologic and physiologic data sets. Based on retrospective analysis of outcome data, different multivariable equations have been proposed to aid with decision making in patients with left outflow obstruction. Scoring systems, such as the Rhodes score
      • Rhodes L.A.
      • Colan S.D.
      • Perry S.B.
      • Jonas R.A.
      • Sanders S.P.
      Predictors of survival in neonates with critical aortic stenosis.
      or the Congenital Heart Surgeons Society calculator,
      • Lofland G.K.
      • McCrindle B.W.
      • Williams W.G.
      • et al.
      Critical aortic stenosis in the neonate: a multi-institutional study of management, outcomes, and risk factors. Congenital Heart Surgeons Society.
      have been proposed for patients with critical aortic stenosis, using echocardiographic dimensions such aortic valve diameter and LV length corrected for patient size. These, however, rely on morphologic information alone without incorporation of dynamic parameters such as valve integrity, ventricular function (systolic or diastolic), or flows. With the advent of cardiovascular magnetic resonance imaging (CMR), it has become possible to add higher-fidelity volumetric information along with detailed flow measurements, which can further facilitate clinical decision making.
      • Grosse-Wortmann L.
      • Yun T.J.
      • Al-Radi O.
      • et al.
      Borderline hypoplasia of the left ventricle in neonates: insights for decision-making from functional assessment with magnetic resonance imaging.
      Of note, CMR data have demonstrated that echocardiography significantly underestimates LV volumes and that flow data do not necessarily correlate with size of aortic and mitral valves.
      • Grosse-Wortmann L.
      • Yun T.J.
      • Al-Radi O.
      • et al.
      Borderline hypoplasia of the left ventricle in neonates: insights for decision-making from functional assessment with magnetic resonance imaging.
      In addition, CMR allows for superior delineation of the extent of EFE. The criteria used at The Hospital for Sick Children in Toronto are based on the integration of echocardiographic and CMR data. Biventricular repair is considered to be a viable option in patients with aortic and mitral valve z scores > −3. In those with z scores < −3, CMR is performed, and biventricular repair is typically offered to subjects with an indexed LV end-diastolic volume (LVEDVi) > 25 mL/m2 along with ascending aortic flow > 2 L/min/m2 if in the absence of major aortic or mitral valve disease or significant EFE. Patients with LVEDVi < 18 mL/m2 are referred for univentricular palliation. As discussed in more detail below, the hybrid procedure is a temporising approach which enables postponement of the ultimate decision to commit to univentricular vs biventricular approach by allowing time for the LV to grow.
      • Haller C.
      • Caldarone C.A.
      The evolution of therapeutic strategies: niche apportionment for hybrid palliation.
      This approach is typically applied to “intermediate” patients with LVEDVi of 18-25 mL/m2. After application of bilateral pulmonary arterial bands and stenting at ductal level (± atrial septostomy) patients are reassessed after 2 to 3 months, and if there is sufficient growth of the LV with improvement in LV output, a biventricular strategy can be offered at that time. The approach adopted at Children’s Hospital Boston for LV recruitment allows for a longer period for LV adaptation and delays the decision to convert from a univentricular to a biventricular strategy to 2-3 years of age; guidance is provided from morphologic and physiologic data sets, including cardiac catheterisation and CMR with measurement of LVEDVi.
      • Banka P.
      • Schaetzle B.
      • Komarlu R.
      • et al.
      Cardiovascular magnetic resonance parameters associated with early transplant-free survival in children with small left hearts following conversion from a univentricular to biventricular circulation.

      Management Strategies for Patients With HLHS and Early Outcomes

      The treatment of HLHS was revolutionised by the introduction of the Norwood operation in the early 1980s.
      • Norwood W.I.
      • Kirklin J.K.
      • Sanders S.P.
      Hypoplastic left heart syndrome: experience with palliative surgery.
      ,
      • Norwood W.I.
      • Lang P.
      • Hansen D.D.
      Physiologic repair of aortic atresia-hypoplastic left heart syndrome.
      The intrinsic concept of the Norwood approach is to designate the RV as the systemic ventricle by connecting the main pulmonary artery to the reconstructed aorta, disconnecting the pulmonary circulation, and redirecting pulmonary blood flow, which is accomplished in 3 distinct stages of surgical palliation (Fig. 4). Stage 1 of the Norwood palliation includes a Damus-Kaye-Stansel connection between the hypoplastic ascending aorta and the main pulmonary artery. This is achieved by dividing the main pulmonary artery proximal to the bifurcation and closing the distal pulmonary artery with a patch. The proximal pulmonary artery is then sewn to the aorta, often using a patch for augmentation. The pulmonary blood flow is delivered via a modified Blalock-Taussig shunt or by an RV–to–pulmonary artery conduit (referred to as the Sano modification).
      • Sano S.
      • Ishino K.
      • Kawada M.
      • Honjo O.
      Right ventricle–pulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome.
      The initial neonatal operation requires cardiopulmonary bypass with circulatory arrest and deep hypothermia or with selective cerebral perfusion and results in parallel systemic and pulmonary circulations. An optimal shunt fraction (pulmonary/systemic blood flow, or Qp/Qs) can be difficult to maintain at the time of transitional circulation and is further associated with significant mortality and morbidity in the early postoperative period and in the interstage time between stages 1 and 2. As pulmonary vascular resistance changes significantly over the first weeks of life, there can be important shifts in flow from the systemic to the pulmonary circulation that can be influenced by shunt size, pulmonary vascular resistance, and/or systemic vascular resistance. Too much pulmonary blood flow can affect systemic perfusion and can result in volume loading of the RV which can then lead to a cascade of progressive RV dilation, worsening tricuspid regurgitation, and ultimately RV systolic failure. Conversely, insufficient pulmonary blood flow can cause cyanosis and may reflect shunt stenosis, pulmonary branch stenosis, or increased pulmonary vascular resistance. Management strategies should target optimisation of the factors determining a balance of pulmonary and systemic perfusion, which requires active management in the first months of life both during the hospital stay and after discharge. Introduction of a home monitoring programs based on daily reporting of oxygen saturations (target 75%-90%), weight gain, and oral intake have translated into a reduction in interstage mortality.
      • Hansen J.H.
      • Furck A.K.
      • Petko C.
      • et al.
      Use of surveillance criteria reduces interstage mortality after the Norwood operation for hypoplastic left heart syndrome.
      • Rudd N.A.
      • Frommelt M.A.
      • Tweddell J.S.
      • et al.
      Improving interstage survival after Norwood operation: outcomes from 10 years of home monitoring.
      • Siehr S.L.
      • Norris J.K.
      • Bushnell J.A.
      • et al.
      Home monitoring program reduces interstage mortality after the modified Norwood procedure.
      Stage 2 is generally performed at the age of 6 months and consists of a bidirectional superior cavopulmonary connection (BCPC). Typically, the pulmonary vascular resistance can be expected to be low and the superior vena cava (SVC) can provide enough blood flow to sustain the pulmonary circulation. Preoperative SVC flow has been demonstrated to be predictive of postoperative BCPC saturations; specifically preoperative flow < 1.6 L/min/m2 or < 0.5 L/min has been associated with post-BCPC mortality.
      • Luo S.
      • Haranal M.
      • Deng M.X.
      • et al.
      Low preoperative superior vena cava blood flow predicts bidirectional cavopulmonary shunt failure.
      This again underscores the importance of incorporating physiologic information into surgical decision making and demonstrates how detailed flow information can contribute to risk stratification and prediction of outcomes. Following BCPC insertion, patients can be expected to have more hemodynamic stability along with baseline saturations of 80%-85%. At 5 to 6 months of age, SVC flow will generally contribute to 40%-50% of total cardiac output, but as children grow the contribution of inferior vena cava (IVC) flow increases and the proportional enlargement of the lower body exceeds that of the upper body. This results in progressive desaturation and exercise restriction when children are 2 to 3 years old. At this stage of life, the third and final surgical procedure is performed to achieve redirection of the IVC flow to the pulmonary circulation (a total cavopulmonary connection or TCPC) by either a lateral tunnel or an extracardiac conduit (modified Fontan operation). This approach redirects the entire systemic venous circulation to the pulmonary circulation, bypassing the heart entirely. Often a fenestration is created at the time of stage 3 to facilitate the transition to the Fontan circulation. The fenestration allows systemic venous decompression, and right-to-left shunting contributes to cardiac output at the expense of arterial desaturation. A fenestration can be closed in the catheterisation laboratory (if not spontaneously closed), typically 6 to 12 months after the surgical procedure, thereby achieving Fontan completion.
      Figure thumbnail gr4
      Figure 4Staged palliation for hypoplastic left heart syndrome. Stage 1: Norwood or hybrid approach; stage 2: bidirectional cavopulmonary connection (BCPC) or Glenn shunt; stage 3: total cavopulmonary connection (TCPC) or Fontan circulation. Ao, aorta; BT, Blalock-Taussig; IVC, inferior vena cava; LPA, left pulmonary artery; PA, pulmonary artery; PV, pulmonary valve; RPA, right pulmonary artery; RV, right ventricle; SVC, superior vena cava; TV, tricuspid valve.
      Reproduced from Barron et al.
      • Barron D.J.
      • Kilby M.D.
      • Davies B.
      • et al.
      Hypoplastic left heart syndrome.
      with permission from Elsevier.
      The mortality and morbidity associated with this staged palliative approach can be formidable, with the most robust data currently available provided by the Pediatric Heart Network single-ventricle reconstruction study.
      • Ohye R.G.
      • Sleeper L.A.
      • Mahony L.
      • et al.
      Comparison of shunt types in the Norwood procedure for single-ventricle lesions.
      This randomised trial was originally designed to compare the surgical outcomes of the Norwood approach with the more recent modification using an RV–pulmonary artery conduit as proposed by Sano. Although the modified Blalock-Taussig shunt can be more difficult to manage in the early postoperative stage owing to challenges achieving a stable balance between systemic and pulmonary circulations, the Sano modification, although more stable postoperatively, can contribute to pulmonary artery distortion resulting in the need for additional interventions to rehabilitate the RV–pulmonary artery conduit or the pulmonary arteries. A main conclusion from the Pediatric Heart Network trial was that transplant-free survival after 12 months was 74% for the RV–pulmonary artery conduit vs 64% for the modified Blalock-Taussig shunt, which was statistically significant, although a lasting survival benefit of the Sano modification could not be demonstrated after 3 and 6 years.
      • Newburger J.W.
      • Sleeper L.A.
      • Gaynor J.W.
      • et al.
      Transplant-free survival and interventions at 6 years in the SVR Trial.
      ,
      • Newburger J.W.
      • Sleeper L.A.
      • Frommelt P.C.
      • et al.
      Transplantation-free survival and interventions at 3 years in the single ventricle reconstruction trial.
      As expected, subjects with RV–pulmonary artery conduits went on to require additional interventions for pulmonary artery stenosis. These data report an overall medium-term transplant-free survival of approximately 60% for the Norwood strategy, independently from shunt type. The Pediatric Heart Network trial was a pivotal study that allowed for comparison of surgical outcomes between 2 techniques in expert centres across North America. Risk factors for increased mortality after stage 1 included prematurity, low birth weight, systemic ventricular dysfunction, tricuspid regurgitation, restrictive/intact atrial septum, and presence of other congenital abnormalities. The introduction of multidisciplinary teams with interstage home monitoring techniques and referral to high-volume centres with expertise in more nuanced clinical care have translated into better outcomes.
      • Coyan G.N.
      • Diaz-Castrillon C.
      • Castro-Medina M.
      • et al.
      High risk status for stage I palliation increases mortality after stage II but not stage III [e-pub ahead of print].
      Multicentre data have highlighted the importance of centre experience as an important determinant of outcome and that all procedures should be centralised within centres of excellence.
      • Pasquali S.K.
      • Thibault D.
      • O’Brien S.M.
      • et al.
      National variation in congenital heart surgery outcomes.
      Alternative interventional strategies have been proposed to delay the extensive aortic reconstruction completed as part of the stage 1 palliation in the neonate which could be beneficial in the early management of particularly high risk patients, such as those born prematurely or with low birth weights. The hybrid approach was initially proposed by the Leeds group in the United Kingdom but was ultimately abandoned owing to problems with ductal stent adequacy (Fig. 4).
      • Gibbs J.L.
      • Wren C.
      • Watterson K.G.
      • Hunter S.
      • Hamilton J.R.
      Stenting of the arterial duct combined with banding of the pulmonary arteries and atrial septectomy or septostomy: a new approach to palliation for the hypoplastic left heart syndrome.
      The hybrid procedure was reintroduced and further optimised by the Giessen group in Germany with subsequent adoption by centres worldwide.
      • Akintuerk H.
      • Michel-Behnke I.
      • Valeske K.
      • et al.
      Stenting of the arterial duct and banding of the pulmonary arteries: basis for combined Norwood stage I and II repair in hypoplastic left heart.
      Cardiopulmonary bypass is avoided in the neonatal period with the use of a combined surgical-interventional approach. The initial step of the hybrid approach consists of bilateral pulmonary artery banding with stenting of the ductus arteriosus ± atrial balloon septostomy. This creates a parallel circulation with the systemic RV providing blood supply to the banded (protected) pulmonary circulation and to the systemic circulation through the stented ductus arteriosus. If the atrial communication is restrictive, an atrial septostomy is performed at the time of the hybrid procedure or in later follow-up. The aortic arch continues to be perfused in a retrograde fashion if there is insufficient antegrade flow. Of note, retrograde perfusion can be compromised by arch obstruction after ductal stenting and needs to be monitored carefully. In addition, coronary perfusion is dependent on adequate retrograde flow. A stage 2 approach is completed around 6 months of life and combines aortic arch reconstruction, ductal stent removal, and a BCPC. The Giessen group reported a 15-year survival rate of 77% with the use of this approach in their centre, which included higher-risk patents.
      • Schranz D.
      • Bauer A.
      • Reich B.
      • et al.
      Fifteen-year single center experience with the “Giessen hybrid” approach for hypoplastic left heart and variants: current strategies and outcomes.
      Modifications to the hybrid procedure have been proposed at different centres.
      • Galantowicz M.
      • Cheatham J.P.
      • Phillips A.
      • et al.
      Hybrid approach for hypoplastic left heart syndrome: intermediate results after the learning curve.
      These include the use of a reverse shunt between the main pulmonary artery and the aorta to avoid problems with retrograde flow in the aortic arch after ductal stenting as well as variations in the timing of atrial septal interventions.
      • Baba K.
      • Honjo O.
      • Chaturvedi R.
      • et al.
      “Reverse Blalock-Taussig shunt”: application in single ventricle hybrid palliation.
      One of the ongoing concerns after the hybrid procedure is the need for subsequent pulmonary artery interventions,
      • Davies R.R.
      • Radtke W.A.
      • Klenk D.
      • Pizarro C.
      Bilateral pulmonary arterial banding results in an increased need for subsequent pulmonary artery interventions.
      which places these patients at elevated risk of complications at the time of Fontan completion. In most centres, the hybrid approach is reserved for those patients who are at high risk and considered to be poor candidates for the Norwood procedure, as a bridge either to Norwood stage 1 or to stage 2.
      Medical and surgical management choices are directed by multiple factors, including allocation of resources, centre experience, and practitioner preference. Although the Pediatric Heart Network trial could not identify a survival difference between stage 1 procedures utilizing a Blalock-Taussig shunt vs an RV–pulmonary artery conduit, the Congenital Heart Surgeons Society observational cohort study, including 454 propensity-matched newborns with HLHS, demonstrated a 6-year survival benefit in patients undergoing the RV–pulmonary artery conduit modification.
      • Wilder T.J.
      • McCrindle B.W.
      • Phillips A.B.
      • et al.
      Survival and right ventricular performance for matched children after stage-1 Norwood: modified Blalock-Taussig shunt versus right-ventricle–to–pulmonary-artery conduit.
      These data have largely resulted in more centres favouring the Sano modification, though it should be noted that decision making regarding surgical approach should ultimately be tailored to patient-specific characteristics.
      • Barron D.J.
      The Norwood procedure: in favour of the RV-PA conduit.
      Because practices between centres remain varied and continue to evolve, it is difficult to determine percentages of each type of stage I procedure currently performed globally.
      A matter of considerable ongoing debate relates to whether care for complex heart disease should be centralised within specialised centres where significant expertise in treatment can be amassed and multidisciplinary teams providing streamlined patient management can be assembled. Both centre experience and centre volume have been flagged as possible determinants of patient outcome, which may explain the significant variability in survival observed following the Norwood palliation.
      • Pasquali S.K.
      • Jacobs J.P.
      • He X.
      • et al.
      The complex relationship between center volume and outcome in patients undergoing the Norwood operation.
      A study looking at the impact of the number Norwood operations performed per year in 53 centres in the United States has suggested that approximately 14% of the between-centre mortality variation can be explained by the relative volumes within a centre; however, additional important between-centre differences persist despite adjustment for in-centre volumes. These observations suggest that volume is not the sole determinant of outcome and, in fact, desirable outcomes can also be achieved in lower-volume centres. Further study is required to elucidate additional factors that can further determine between-centre variability in outcomes.
      An important factor to consider is the cost associated with management of HLHS patients undergoing the Norwood operation. Data from centres in the United States reveal that costs are high although varied across surgical centres performing the stage I Norwood operation (ranging from US$50,559 to US$230,851).
      • McHugh K.E.
      • Pasquali S.K.
      • Hall M.A.
      • Scheurer M.A.
      Cost variation across centers for the Norwood operation.
      Differences in cost can be attributed, at least in part, to variations in complication rates and lengths of hospital stay. In high-cost centres, complications were more often seen, including pleural effusions, seizures, wound infections, thrombus, liver dysfunction, sepsis, and necrotising enterocolitis, which contributed to longer hospital admissions. Apart from the expense of the initial Norwood operation, the costs associated with life-long care for these patients are considerable, though as yet not well studied.
      • Hansen J.E.
      • Madsen N.L.
      • Bishop L.
      • Morales D.L.S.
      • Anderson J.B.
      Longitudinal health care cost in hypoplastic left heart syndrome palliation.
      ,
      • Dean P.N.
      • Hillman D.G.
      • McHugh K.E.
      • Gutgesell H.P.
      Inpatient costs and charges for surgical treatment of hypoplastic left heart syndrome.
      Contemporary data defining the financial burden imposed on the health care system by the HLHS population are necessary but lacking. Adequate resources for management of these patients may not be readily available in all health care systems, leading to important disparities in health care; in extreme cases, compassionate care may be the only option in an under-resourced environment.
      • Iyer K.S.
      Treating hypoplastic left heart syndrome in emerging economies: heading the wrong way?.
      To better understand minimum care required for acceptable outcomes, health care systems beyond the United States (which delivers relatively costly care) should be scrutinised to promote active HLHS management in lower-resourced environments.

      Neurodevelopmental Outcomes in the HLHS Population

      The paediatric literature identifies those with HLHS as a vulnerable population with increased risk of morbidity and mortality, distinguishing these individuals among the wider spectrum of patients with single-ventricle physiology.
      • Feinstein J.A.
      • Benson D.W.
      • Dubin A.M.
      • et al.
      Hypoplastic left heart syndrome: current considerations and expectations.
      Concomitant with decreasing surgical mortality has been an increasing awareness of the quality of life (QOL) of survivors, with recent emphasis placed on neurodevelopmental and psychosocial outcomes. Children with palliated HLHS have been noted to have deficiencies in cognitive function, gross and fine motor development, and speech and language achievement.
      • Hansen J.H.
      • Rotermann I.
      • Logoteta J.
      • et al.
      Neurodevelopmental outcome in hypoplastic left heart syndrome: Impact of perioperative cerebral tissue oxygenation of the Norwood procedure.
      • Newburger J.W.
      • Sleeper L.A.
      • Bellinger D.C.
      • et al.
      Early developmental outcome in children with hypoplastic left heart syndrome and related anomalies: the single ventricle reconstruction trial.
      • Sananes R.
      • Goldberg C.S.
      • Newburger J.W.
      • et al.
      Six-year neurodevelopmental outcomes for children with single-ventricle physiology.
      • Mahle W.T.
      • Clancy R.R.
      • Moss E.M.
      • et al.
      Neurodevelopmental outcome and lifestyle assessment in school-aged and adolescent children with hypoplastic left heart syndrome.
      Additional impairments have been documented for QOL, functional status, and behavioural adaptation in school-age children with HLHS.
      • Goldberg C.S.
      • Hu C.
      • Brosig C.
      • et al.
      Behaviour and quality of life at 6 years for children with hypoplastic left heart syndrome.
      Neurodevelopmental deficits are now recognised at the most frequent paediatric morbidity in the HLHS population, and contemporary trials include neurodevelopmental outcomes as a robust study end point alongside traditional outcomes such death and transplant-free survival.
      • Newburger J.W.
      • Sleeper L.A.
      • Bellinger D.C.
      • et al.
      Early developmental outcome in children with hypoplastic left heart syndrome and related anomalies: the single ventricle reconstruction trial.
      ,
      • Sananes R.
      • Goldberg C.S.
      • Newburger J.W.
      • et al.
      Six-year neurodevelopmental outcomes for children with single-ventricle physiology.
      Compromise in neurodevelopmental outcomes in the HLHS population is likely multifactorial and the culmination of a variety of etiologies, including prenatal hemodynamics, fetal development, genetic determinants, neonatal characteristics, perioperative management, interstage complications, and age at Fontan completion.
      • Sugimoto A.
      • Ota N.
      • Ibuki K.
      • et al.
      Risk factors for adverse neurocognitive outcomes in school-aged patients after the Fontan operation.
      • Mahle W.T.
      • Visconti K.J.
      • Freier M.C.
      • et al.
      Relationship of surgical approach to neurodevelopmental outcomes in hypoplastic left heart syndrome.
      • Atallah J.
      • Garcia Guerra G.
      • Joffe A.R.
      • et al.
      Survival, neurocognitive, and functional outcomes after completion of staged surgical palliation in a cohort of patients with hypoplastic left heart syndrome.
      Although surgical strategy selected for the first palliative stage has not emerged as a feature associated with later neurocognitive outcome, current evidence is pointing toward the association of intrinsic patient factors and general medical morbidity in the first year as factors most highly associated with impaired neurodevelopment in those born with HLHS.
      • Newburger J.W.
      • Sleeper L.A.
      • Bellinger D.C.
      • et al.
      Early developmental outcome in children with hypoplastic left heart syndrome and related anomalies: the single ventricle reconstruction trial.
      ,
      • Mahle W.T.
      • Visconti K.J.
      • Freier M.C.
      • et al.
      Relationship of surgical approach to neurodevelopmental outcomes in hypoplastic left heart syndrome.
      ,
      • Laraja K.
      • Sadhwani A.
      • Tworetzky W.
      • et al.
      Neurodevelopmental outcome in children after fetal cardiac intervention for aortic stenosis with evolving hypoplastic left heart syndrome.
      ,
      • Knirsch W.
      • Liamlahi R.
      • Dave H.
      • Kretschmar O.
      • Latal B.
      Neurodevelopmental outcome of children with hypoplastic left heart syndrome at one and four years of age comparing hybrid and Norwood procedure.
      Recognition of the association between pathogenic copy number variants in a subset of single-ventricle patients and inferior neurocognitive and growth outcomes may allow for early identification of patients at risk.
      • Carey A.S.
      • Liang L.
      • Edwards J.
      • et al.
      Effect of copy number variants on outcomes for infants with single ventricle heart defects.
      Whereas the majority of publications describe neurodevelopmental outcomes exclusively in children, a recent study sought to describe neurodevelopmental outcomes in the adolescent and adult after Fontan palliation. In that study, 107 single-ventricle patients (55% male) after Fontan palliation were studied at a mean age of 23 ± 8 years and were compared with control groups of patients with biventricular circulations (consisting of transposition of the great arteries [n = 50] and normal hearts [n = 41]). Although patients with HLHS were not identified per se, 31% of the population had predominantly RV morphology presumably inclusive of HLHS. Mean z scores were lower in all neurocognitive domains in the Fontan subjects compared with control subjects, and impairment was more pronounced in adults compared with adolescents. Cerebral lesions were a universal finding in the Fontan population, and all global brain volumetric measures were smaller in the Fontan subjects. Notably, global brain volumes were found to be associated with neurocognitive outcomes.
      • Verrall C.E.
      • Yang J.Y.M.
      • Chen J.
      • et al.
      Neurocognitive dysfunction and smaller brain volumes in adolescents and adults with a Fontan circulation.

      Clinical and Patient-Reported Outcomes Late After Fontan Palliation for HLHS

      Despite early successes following Fontan surgery in childhood, complications become increasingly common in later life. Chronically elevated Fontan circuit pressures along with decreased output from the heart contribute to the extreme fragility of the Fontan circulation. For the population of Fontan patients as a whole, life expectancy is truncated compared with the average population; when expressed in terms of standardised mortality ratio, the hypothetical risk of death of a 40-year-old with congenital heart disease is similar to that of a 75-year-old without congenital heart disease.
      • Diller G.P.
      • Kempny A.
      • Alonso-Gonzalez R.
      • et al.
      Survival prospects and circumstances of death in contemporary adult congenital heart disease patients under follow-up at a large tertiary centre.
      As Fontan survivorship continues to expand, our understanding of the development of late complications continues to evolve in general, although much remains unknown, specifically for those born with HLHS.
      • Ohye R.G.
      • Schranz D.
      • D’Udekem Y.
      Current therapy for hypoplastic left heart syndrome and related single ventricle lesions.
      The first survivors of surgical palliation for HLHS are only now entering early adult life and reflect the pioneering days of surgical intervention and evolving perioperative management strategies. While RV dominance has been identified as a strong predictor of poor survival particularly at the pre-BCPC phase, improvement in outcome has been observed over time.
      • d’Udekem Y.
      • Xu M.Y.
      • Galati J.C.
      • et al.
      Predictors of survival after single-ventricle palliation: the impact of right ventricular dominance.
      The era effect on survivorship is underscored by data from a large binational cohort study from the same authors who observed a striking difference in HLHS survivorship according to decade of birth: before 1990 the proportion was 1% (1/173) and after 2000 it increased to 16% (80/500).
      • d’Udekem Y.
      • Iyengar A.J.
      • Galati J.C.
      • et al.
      Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand.
      Contemporary estimates suggest that nearly two-thirds of subjects with HLHS operated on in the best centres today can be expected to reach adulthood.
      • Best K.E.
      • Miller N.
      • Draper E.
      • et al.
      The improved prognosis of hypoplastic left heart: a population-based register study of 343 cases in England and Wales.
      ,
      • Newburger J.W.
      • Sleeper L.A.
      • Gaynor J.W.
      • et al.
      Transplant-free survival and interventions at 6 years in the SVR Trial.
      ,
      • d’Udekem Y.
      • Iyengar A.J.
      • Galati J.C.
      • et al.
      Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand.
      Based on existing paediatric data, it is clear that when compared with other forms of congenital heart disease, HLHS is a relative outlier and survival is substantially lower compared with other anatomic lesions resulting in single-ventricle physiology.
      • Moons P.
      • Bovijn L.
      • Budts W.
      • Belmans A.
      • Gewillig M.
      Temporal trends in survival to adulthood among patients born with congenital heart disease from 1970 to 1992 in Belgium.
      Data from the Australia and New Zealand Fontan Registry of more than 1000 Fontan cases demonstrated a striking difference in 10-year freedom from Fontan failure (defined as death, transplantation, reoperation, or poor functional status) in the HLHS group compared with other morphologies in the registry (79% vs 92%; P < 0.001), and HLHS anatomy was identified as the primary predictor of Fontan failure (hazard ratio 3.8, 95% confidence interval 2.0-7.1; P < 0.001).
      • d’Udekem Y.
      • Iyengar A.J.
      • Galati J.C.
      • et al.
      Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand.
      In a study focused on patients with extracardiac Fontan connections only, with a mean follow-up of 6.7 ± 3.5 years, HLHS was predictive not only of late Fontan failure (defined as late death, transplantation, New York Heart Association functional class III or IV, or protein-losing enteropathy), but also of prolonged hospital stay (prolonged effusions) and adverse events (including late failure, reoperation, percutaneous intervention, pacemaker implantation, thromboembolic event, or supraventricular tachycardia).
      • Iyengar A.J.
      • Winlaw D.S.
      • Galati J.C.
      • et al.
      Trends in Fontan surgery and risk factors for early adverse outcomes after Fontan surgery: the Australia and New Zealand Fontan Registry experience.
      While underlying HLHS morphologic subtype has not been clearly associated with survival, the presence of aortic atresia has been recently observed to be independently associated with adverse events in the HLHS population at a mean follow-up of 6.4 ± 4.7 years.
      • Newland D.P.
      • Poh C.L.
      • Zannino D.
      • et al.
      The impact of morphological characteristics on late outcomes in patients born with hypoplastic left heart syndromedagger.
      Given the young age of the cohort of HLHS survivors entering adulthood, mid- and long-term outcomes remain incompletely undefined but likely include a myriad of intracardiac and extracardiac complications that are likely to increase with time (Figs. 5 and 6). A recent study focused exclusively on outcomes of adults with HLHS surviving to > 18 years of age.
      • Wilson W.M.
      • Valente A.M.
      • Hickey E.J.
      • et al.
      Outcomes of patients with hypoplastic left heart syndrome reaching adulthood after fontan palliation: multicenter study.
      That multinational study reported on the outcomes of 59 patients at 7 centres (median age 21 years, oldest survivor 28 years). Despite a relative short period of follow-up in adult life (median 3.9 years) a Fontan-specific major adverse cardiovascular event was evident in 24% of the population studied (defined as death, end-stage heart failure with transplant listing, hospitalisation for heart failure requiring intravenous medications, sustained ventricular tachycardia, protein-losing enteropathy, or major thromboembolic event) (Fig. 5). This strikingly high adverse event rate appears to differentiate patients with a Fontan circulation for underlying HLHS compared with those referred for Fontan palliation for other underlying lesions. Although scant, existing data point toward a relatively guarded prognosis for adult survivors with HLHS. Type and frequency of surveillance testing as outlined for the general Fontan population cardiovascular system is likely applicable to the HLHS population (Table 1), with the caveat that some complications, such as protein-losing enteropathy and plastic bronchitis, may occur more frequently in HLHS subjects and a higher level of vigilance for these sequelae is therefore necessary.
      • Ait Ali L.
      • Lurz P.
      • Ripoli A.
      • et al.
      Implications of atrial volumes in surgical corrected tetralogy of Fallot on clinical adverse events.
      When Fontan failure is suspected, a full diagnostic work-up for Fontan failure is indicated and management will be driven by etiology and clinical status.
      • Goldberg D.J.
      • Shaddy R.E.
      • Ravishankar C.
      • Rychik J.
      The failing Fontan: etiology, diagnosis and management.
      Figure thumbnail gr5
      Figure 5Cardiovascular magnetic resonance imaging to rule out anatomic Fontan obstruction in a 25-year-old woman with a new diagnosis of protein-losing enteropathy. Fontan circuit (asterisks) is unobstructed in (left) axial imaging and (right) coronal magnetic resonance angiogram.
      Figure thumbnail gr6
      Figure 6Cardiovascular magnetic resonance image demonstrating hepatocellular carcinoma (arrow) in a 29-year-old man with palliated hypoplastic left heart syndrome after a lapse of care of 10 years.
      Table 1Surveillance testing for cardiac and extracardiac complications in the HLHS population after the Fontan operation
      Source: American Heart Association, Inc.
      • Rychik J.
      • Atz A.M.
      • Celermajer D.S.
      • et al.
      Evaluation and management of the child and adult with Fontan circulation: a scientific statement from the American Heart Association.
      TestChildhoodAdolescenceAdulthood
      Outpatient visit with physical examinationEvery 6-12 monthsEvery 6-12 monthsEvery 6-12 months
      ElectrocardiographyEvery 6-12 monthsEvery 12 monthsEvery 6-12 months
      EchocardiographyEvery 12 monthsEvery 12 monthsEvery 12 months
      HolterDirected by symptomsDirected by symptomsAs directed by symptoms
      Lab work (BNP, liver function, renal function)Every 3 yearsEvery 12 monthsEvery 12 months
      Cardiopulmonary exercise studyFirst test around age 8 yearsEvery 2 yearsEvery 1-3 years
      Cardiac magnetic resonanceAge > 8 yearsEvery 3 yearsEvery 2-3 years
      Cardiac computed tomographyAs neededAs neededAs needed
      Abdominal ultrasoundAge > 8 yearsEvery 3 yearsEvery 1-2 years
      Cardiac catheterisationAs directed by symptomsAs directed by symptomsAs directed by symptoms
      BNP, B-type natriuretic peptide; HLHS, hypoplastic left heart syndrome.
      As an adjunct to clinical outcomes, patient-reported outcomes pertaining to health-related QOL (HR-QOL) provide valuable metrics related to health status that are of interest to subjects and their health care providers. A recent meta-analysis reviewed 50 publications that addressed HR-QOL in children, adolescents, and adults with a Fontan circulation. In total, data from 2793 individuals were available for review and the authors determined that, compared with reference patients, those with a Fontan circulation had lower scores across all domains. Older age at assessment was associated with poorer total HR-QOL as well as compromised emotional and social functioning. The diagnosis of HLHS was specifically associated with inferior social functioning.
      • Marshall K.H.
      • d’Udekem Y.
      • Sholler G.F.
      • et al.
      Health-related quality of life in children, adolescents, and adults with a Fontan circulation: a meta-analysis.
      Recent data indicate that individuals with congenital heart disease are at increased risk of deficits in executive function and that this is particularly problematic in patients with single-ventricle physiology.
      • Cassidy A.R.
      • White M.T.
      • DeMaso D.R.
      • Newburger J.W.
      • Bellinger D.C.
      Executive function in children and adolescents with critical cyanotic congenital heart disease.
      In addition, sexual dysfunction appears to be more prevalent in this population.
      • Rubenis I.
      • Tran D.
      • Bullock A.
      • et al.
      Sexual function in men living with a Fontan circulation.
      Whether patients with HLHS differ from an HR-QOL perspective compared with their peers within the wider cohort of Fontan patients is a topic worthy of further exploration. Specifically designed studies are necessary to explore HR-QOL and should include validated scoring systems such as those developed by the Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart Disease-International Study (APPROACH-IS)
      • Moons P.
      • Kovacs A.H.
      • Luyckx K.
      • et al.
      Patient-reported outcomes in adults with congenital heart disease: inter-country variation, standard of living and healthcare system factors.
      and the International Consortium for Health Outcomes Measurement.
      • Hummel K.
      • Whittaker S.
      • Sillett N.
      • et al.
      Development of an international standard set of clinical and patient-reported outcomes for children and adults with congenital heart disease: a report from the International Consortium for Health Outcomes Measurement Congenital Heart Disease Working Group.
      Such data will be important for guidance of management strategies for this at-risk patient population.

      Knowledge Gaps and Future Directions

      Despite the dramatic improvement in childhood survival achieved over recent decades, the HLHS population remains a challenging group of patients to manage and as such consumes a substantial proportion of the resources in paediatric cardiac centres. There are important gaps in knowledge that require further study before improvements in short- and long-term outcomes can be realistically achieved. Various studies have cited development of RV dysfunction, at any stage, as one of the critical determinants of poor clinical outcomes.
      • Wilder T.J.
      • McCrindle B.W.
      • Phillips A.B.
      • et al.
      Survival and right ventricular performance for matched children after stage-1 Norwood: modified Blalock-Taussig shunt versus right-ventricle–to–pulmonary-artery conduit.
      ,
      • Chetan D.
      • Kotani Y.
      • Jacques F.
      • et al.
      Surgical palliation strategy does not affect interstage ventricular dysfunction or atrioventricular valve regurgitation in children with hypoplastic left heart syndrome and variants.
      • Jean-St-Michel E.
      • Meza J.M.
      • Maguire J.
      • Coles J.
      • McCrindle B.W.
      Survival to stage II with ventricular dysfunction: secondary analysis of the Single Ventricle Reconstruction Trial.
      • Lin L.Q.
      • Conway J.
      • Alvarez S.
      • et al.
      Reduced right ventricular fractional area change, strain, and strain rate before bidirectional cavopulmonary anastomosis is associated with medium-term mortality for children with hypoplastic left heart syndrome.
      Research focused on various aspects of RV systolic dysfunction, including pathophysiology, early identification, prevention, and treatment, may translate into improvement in long-term outcomes. Identification of patients at risk for developing RV dysfunction by imaging and/or genetics could help to identify patients who are poor candidates for the Norwood strategy.
      • Altit G.
      • Bhombal S.
      • Chock V.Y.
      • Tacy T.A.
      Immediate postnatal ventricular performance is associated with mortality in hypoplastic left heart syndrome.
      Serial monitoring of RV function with the use of echocardiography measures such as fractional area change, RV strain, and tricuspid annular plane systolic excursion can help in early detection and risk stratification.
      • Lin L.Q.
      • Conway J.
      • Alvarez S.
      • et al.
      Reduced right ventricular fractional area change, strain, and strain rate before bidirectional cavopulmonary anastomosis is associated with medium-term mortality for children with hypoplastic left heart syndrome.
      ,
      • Balasubramanian S.
      • Smith S.N.
      • Srinivasan P.
      • et al.
      Longitudinal assessment of right ventricular function in hypoplastic left heart syndrome.
      • Borrelli N.
      • Di Salvo G.
      • Sabatino J.
      • et al.
      Serial changes in longitudinal strain are associated with outcome in children with hypoplastic left heart syndrome.
      • Colquitt J.L.
      • Loar R.W.
      • Morris S.A.
      • et al.
      Serial strain analysis identifies hypoplastic left heart syndrome infants at risk for cardiac morbidity and mortality: a pilot study.
      • Kim A.S.
      • Witzenburg C.M.
      • Conaway M.
      • et al.
      Trajectory of right ventricular indices is an early predictor of outcomes in hypoplastic left heart syndrome.
      • mercer-rosa l
      • goldberg dj
      prognostic value of serial echocardiography in hypoplastic left heart syndrome: smaller hearts, better results.
      Although the initial selection of surgical strategy does not seem to have important impact on RV systolic function,
      • Chetan D.
      • Kotani Y.
      • Jacques F.
      • et al.
      Surgical palliation strategy does not affect interstage ventricular dysfunction or atrioventricular valve regurgitation in children with hypoplastic left heart syndrome and variants.
      ,
      • Frommelt P.C.
      • Gerstenberger E.
      • Cnota J.F.
      • et al.
      Impact of initial shunt type on cardiac size and function in children with single right ventricle anomalies before the Fontan procedure: the single ventricle reconstruction extension trial.
      • Frommelt P.C.
      • Hu C.
      • Trachtenberg F.
      • et al.
      Impact of initial shunt type on echocardiographic indices in children after single right ventricle palliations.
      • Grotenhuis H.B.
      • Ruijsink B.
      • Chetan D.
      • et al.
      Impact of Norwood versus hybrid palliation on cardiac size and function in hypoplastic left heart syndrome.
      • Hill G.D.
      • Frommelt P.C.
      • Stelter J.
      • et al.
      Impact of initial Norwood shunt type on right ventricular deformation: the Single Ventricle Reconstruction Trial.
      • Latus H.
      • Nassar M.S.
      • Wong J.
      • et al.
      Ventricular function and vascular dimensions after Norwood and hybrid palliation of hypoplastic left heart syndrome.
      • Mah K.
      • Serrano Lomelin J.
      • Colen T.
      • et al.
      Right ventricular remodelling in hypoplastic left heart syndrome is minimally impacted by cardiopulmonary bypass: a comparison of Norwood vs hybrid.
      strategies for medical preservation of the RV may be a promising avenue of future study. Recent data suggest that digoxin use in the interstage is associated with better survival, likely related to an effect of RV remodelling,
      • Batsis M.
      • Kochilas L.
      • Chin A.J.
      • et al.
      Association of digoxin with preserved echocardiographic indices in the interstage period: a possible mechanism to explain improved survival?.
      but other potential medical therapies deserve similar exploration. This will require a more refined understanding of potential for RV remodelling as well as of the impact of HLHS on RV function. Preliminary data indicating that there is potential benefit from transcoronary intramyocardial injection of stem cells during surgical palliation
      • 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.
      • Saraf A.
      • Book W.M.
      • Nelson T.J.
      • Xu C.
      Hypoplastic left heart syndrome: from bedside to bench and back.
      • Tarui S.
      • Ishigami S.
      • Ousaka D.
      • et al.
      Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single-Ventricle Physiology (TICAP) trial.
      have resulted in prospective trials designed to study the potential use of stem cell therapy during surgical palliation. Other techniques for managing failing Fontan physiology are emerging as new technologies for mechanical circulatory support are becoming available, and results with ventricular assist devices are encouraging at both pre- and post-Fontan stages.
      • Bedzra E.K.S.
      • Adachi I.
      • Peng D.M.
      • 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 [e-pub ahead of print].
      • Puri K.
      • Adachi I.
      Mechanical support for the failing single ventricle at pre-Fontan stage: current state of the field and future directions.
      • Trusty P.M.
      • Tree M.
      • Maher K.
      • et al.
      An in vitro analysis of the PediMag and CentriMag for right-sided failing Fontan support.
      Recent advances in computational flow dynamics and 4-dimensional magnetic resonance imaging have contributed to a deeper understanding of factors that contribute to energy losses in the Fontan circuit, and the translation of this technology is enabling optimised patient-specific Fontan design.
      • Cibis M.
      • Jarvis K.
      • Markl M.
      • et al.
      The effect of resolution on viscous dissipation measured with 4D flow MRI in patients with Fontan circulation: evaluation using computational fluid dynamics.
      • Mercer-Rosa L.
      • Fogel M.A.
      • Wei Z.A.
      • et al.
      Fontan geometry and hemodynamics are associated with quality of life in adolescents and young adults [e-pub ahead of print].
      • Rijnberg F.M.
      • Westenberg J.J.M.
      • van Assen H.C.
      • et al.
      4D flow cardiovascular magnetic resonance derived energetics in the Fontan circulation correlate with exercise capacity and CMR-derived liver fibrosis/congestion.
      • Siallagan D.
      • Loke Y.H.
      • Olivieri L.
      • et al.
      Virtual surgical planning, flow simulation, and 3-dimensional electrospinning of patient-specific grafts to optimise Fontan hemodynamics.
      Insights from these technologies have also enabled design of more “futuristic” models of a Fontan circulation, including the possible incorporation of a pulsatile subpulmonary “neoventricle” from engineered heart tissue, thus providing additional energy to drive pulmonary blood flow as well as other devices designed to propel blood through the Fontan circuit.
      • Prather R.
      • Das A.
      • Farias M.
      • et al.
      Parametric investigation of an injection-jet self-powered Fontan circulation.
      ,
      • Köhne M.
      • Behrens C.S.
      • Stüdemann T.
      • et al.
      A potential future Fontan modification: preliminary in vitro data of a pressure-generating tube from engineered heart tissue [e-pub ahead of print].
      As tricuspid valve regurgitation is another important determinant of long-term outcomes, research directed toward a deeper understanding of the mechanisms of progressive tricuspid valve dysfunction in HLHS could result in optimisation of surgical techniques and strategies for repair.
      • Bautista-Hernandez V.
      • Brown D.W.
      • Loyola H.
      • et al.
      Mechanisms of tricuspid regurgitation in patients with hypoplastic left heart syndrome undergoing tricuspid valvuloplasty.
      • Bharucha T.
      • Honjo O.
      • Seller N.
      • et al.
      Mechanisms of tricuspid valve regurgitation in hypoplastic left heart syndrome: a case-matched echocardiographic-surgical comparison study.
      • Mah K.
      • Khoo N.S.
      • Tham E.
      • et al.
      Tricuspid regurgitation in hypoplastic left heart syndrome: three-dimensional echocardiography provides additional information in describing jet location.
      • Shigemitsu S.
      • Mah K.
      • Thompson R.B.
      • et al.
      Tricuspid valve tethering is associated with residual regurgitation after valve repair in hypoplastic left heart syndrome: a three-dimensional echocardiographic study.
      As neurologic outcomes remain uncertain, further study into factors that contribute to poor neurologic outcomes are required before development of preventive strategies can occur.
      Coupled with the knowledge that the number of subjects alive following Fontan palliation is projected to double in the next 2 decades and that the HLHS subset can be expected to have poorer outcomes compared with the larger Fontan population, considerations pertaining to delivery of end-of-life care will become increasingly relevant for this high-risk population. Therapeutic options for those with a failing Fontan physiology are extremely limited. Medical therapies can provide only temporary symptomatic relief. Completed and ongoing trials have been designed to explore the potential benefit of pulmonary vasodilators in the larger Fontan population with some beneficial effect noted on exercise capacity in recent studies.
      • Goldberg D.J.
      • Zak V.
      • Goldstein B.H.
      • et al.
      Results of the FUEL Trial.
      • Goldberg D.J.
      • French B.
      • McBride M.G.
      • et al.
      Impact of oral sildenafil on exercise performance in children and young adults after the Fontan operation: a randomised, double-blind, placebo-controlled, crossover trial.
      • Hebert A.
      • Mikkelsen U.R.
      • Thilen U.
      • et al.
      Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomised, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study.
      • Sabri M.R.
      • Zolfi-Gol A.
      • Ahmadi A.
      • Haghjooy-Javanmard S.
      Effect of tadalafil on myocardial and endothelial function and exercise performance after modified Fontan operation.
      • Schuuring M.J.
      • Vis J.C.
      • van Dijk A.P.
      • et al.
      Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomised controlled trial.
      • Cedars A.M.
      • Saef J.
      • Peterson L.R.
      • et al.
      Effect of ambrisentan on exercise capacity in adult patients after the Fontan procedure.
      Surgical strategies such as Fontan conversion or heart transplantation are relatively high-risk and are applicable only to a minority of patients, and are therefore rarely undertaken. A 2019 analysis of all adults who underwent heart transplantation in United States hospitals from 2004 to 2014 included 93 Fontan patients and found their in-hospital post-transplantation mortality to be 5 times that of non-Fontan recipients (26% vs 5%; P < 0.001).
      • Hernandez L.E.
      • Chrisant M.K.
      • Valdes-Cruz L.M.
      Global left ventricular relaxation: a useful echocardiographic marker of heart transplant rejection and recovery in children.
      Emerging data are pointing toward potential benefit in lymphatic drainage interventions or external ventilation strategies, although further study is required before these options can be more widely applied in clinical practice.
      • Charla P.
      • Karur G.R.
      • Yamamura K.
      • et al.
      Augmentation of pulmonary blood flow and cardiac output by non-invasive external ventilation late after Fontan palliation.
      ,
      • Rychik J.
      • Atz A.M.
      • Celermajer D.S.
      • et al.
      Evaluation and management of the child and adult with Fontan circulation: a scientific statement from the American Heart Association.

      Conclusion

      Advances in care for patients with HLHS across the lifespan have resulted in current survival rates of approximately 60% to 65% for children who have undergone staged palliation. This reflects the investment of significant resources over recent decades. Important morbidities continue to be associated with the various treatment strategies. With an expanding cohort of HLHS reaching adulthood following Fontan completion, there is a growing concern that this is a population at particular risk for early Fontan failure. Future therapeutic innovations would ideally target novel therapies for preservation of RV systolic function as well as maintenance of tricuspid valve integrity, optimisation of Fontan hemodynamics, and improvement of neurocognitive outcomes.

      Funding Sources

      The authors have no funding sources to declare.

      Disclosures

      The authors have no conflicts of interest to disclose.

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