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Single Ventricle

Author: Joseph Heaton Editor: Daniel Heller Updated: 8/28/2023 10:09:10 PM

Introduction

A single ventricle or univentricular heart is a broad term covering various cardiac structural abnormalities in which one ventricle is severely underdeveloped, or a ventricular septal wall did not form. Through various mechanisms, the anomalous structure typically results in the mixing of oxygenated and deoxygenated blood. Occurrences are generally caused by genetic factors, though environmental factors are known to promote malformation.

Etiology

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Etiology

The origin of each condition varies by type and is influenced by multiple factors. The development process for each variation is not entirely understood.

Malformation occurs in embryogenesis, during days 30 to 56 of gestation.[1][2] Cardiac structural abnormalities are commonly associated with lateralization disorders, such as situs inversus totalis and heterotaxy.[3] In patients with primary ciliary dyskinesia (PCD), 12% of patients had evidence of heterotaxy.[4] Other genetic causes have also been identified, including Tbx5 and GATA4; the inactivation of both genes has a direct influence on the formation of the ventricular septum.[5][6] Genetic malformations without explicitly known causes have also been postulated, suggestively induced by defects in the formation of endocardial cushions and developmental influence by dynamic blood flow. These other causes are associated with extracardiac structural anomalies, as seen in DiGeorge syndrome.[7]

 Environmental factors also influence cardiac structural formation. Risk factors include:

  • Increasing parental age[8]
  • Phenylketonuria, pregestational diabetes, febrile illnesses, influenza, maternal rubella, anticonvulsants, ibuprofen, sulfasalazine, thalidomide, trimethoprim-sulfonamide, retinoids, marijuana, and organic solvents[9]
  • Lithium is associated with an increased risk of cardiac malformations, specifically at higher doses and with use during the first trimester[10][11]

 Key univentricular variations and typical features:

  • Hypoplastic left heart syndrome (HLHS): The left ventricle, mitral valve, aortic valve, and aorta are underdeveloped.
  • Tricuspid atresia: The tricuspid valve fails to develop, leading to an underdeveloped right ventricle.
  • Ebstein anomaly: Abnormal development of tricuspid valve leaflets causes right ventricular atrialization. The anomaly is associated with various cardiac structural abnormalities, including pulmonary valve pathologies, septal defects, and electrical conduction lesions.
  • Double outlet right ventricle: The aorta and the pulmonary artery exit from the right ventricle, leaving the left ventricle underdeveloped.
  • Double inlet left ventricle: Both atria connect to the left ventricle, resulting in an underdeveloped right ventricle.
  • Atrioventricular canal defect: An atrial or ventricular septal defect forms large enough to make a functionally single ventricle.

Epidemiology

The occurrence of congenital heart disease is between 6 and 13 in 1,000 live births.[12][13][14][15] Hypoplastic left heart syndrome, the most common form of univentricular heart disease, is seen in 2 to 3 per 10,000 births with a higher incidence in males.[12][16][17] Tricuspid atresia occurs in about 1 per 10,000 live births.[18][19] Ebstein anomaly occurs in about 0.5 per 10,000 live births with gender predilection.[20] However, with the maternal use of lithium, the Ebstein anomaly can increase nearly seven-fold.[21] Double outlet right ventricle occurs in 0.009 cases per 10,000 live births.[22] Double inlet left ventricle occurs in up to 0.01 per 10,000 live births.[23] Atrioventricular canal defect occurs in 0.03 to 0.04 per 10,000 live births.[24]

Pathophysiology

With a single ventricle, mixed oxygenated blood circulates throughout the body. Depending on the structural anomaly, a patent ductus arteriosus (PDA), atrial septal defect (ASD), ventricular septal defect (VSD), or communication in the great arteries may be required to maintain pulmonary and systemic circulations. More information about anatomical requirements can be found under each disease's respective chapters.

History and Physical

The presentation of a single ventricle may be identified as early as the 18th week of gestation.[25] Other structural variations may also be seen near this time, including mispositioning of the great arteries and reversal of blood flow through portions of the fetal cardiac system. Ultrasound may also reveal extracardiac structural manifestations, assisting in diagnosis.[26][27]

Post-natal presentations vary depending on underlying structural variations. Typically, a heart murmur, tachypnea, respiratory distress, cyanosis, or hypotension may be present when circulation and oxygenation are not satisfactory.[28][29] Other physical exam findings, such as hepatomegaly or dysmorphic features, may be clues to more underlying abnormalities. A neonate may not present symptoms at birth or before discharge if circulation is adequate at the time of examination.[19] Closure of the patent ductus arteriosus (PDA) or changes in flow to end organs may precipitate these symptoms after discharge.

Evaluation

Prenatal diagnosis is made through routine ultrasound techniques for gestation and fetal echocardiography. Visualization of structural abnormalities or deviations from standard flow patterns may distinguish a single ventricle in utero.

Post-natal diagnosis is made through a variety of techniques. Echocardiography is the best modality for the diagnosis of a single ventricle. Other techniques may aid in the diagnosis of a single ventricle, including electrocardiography, plain chest films, and pulse oximetry.[30][31] Physical exam findings may also support the diagnosis. Computed tomography (CT), cardiac catheterization, magnetic resonance imaging (MRI), and cardiac magnetic resonance imaging might also reveal a single ventricle but are typically reserved for indeterminant investigations or treatment.

Treatment / Management

Treatment options of the univentricular variants depend on the time of discovery, prognosis, and goals of care. Prognosis must be discussed in depth before proceeding with treatment, as an intervention may be futile in some instances.

Univentricular heart syndrome medical management is targeted to the underlying pathology. Supplemental oxygen will help alleviate hypoxemia, and acid-base or metabolic disturbances should have correctable factors mended.[32] Inhaled nitric oxide is beneficial to reduce resistance in the pulmonary vasculature, allowing more blood to be oxygenated by the lungs.[33] In strained hearts, inotropes may assist contraction force, but catecholamines should be avoided due to arrhythmogenesis.[34] When a patent ductus arteriosus (PDA) is needed to maintain collateral flow, prostaglandin E1 prolongs the opening of the ductus arteriosus, providing a bridge to permanent interventions.[32] Non-steroidal anti-inflammatory medications should be avoided to maintain a patent ductus arteriosus.(A1)

Catheter-based management is also based on underlying etiology, time of discovery, and prognosis. When discovered in utero, catheter-based structural interventions and valvuloplasty can mitigate sequala by correcting anomalies during the developmental process.[35][36][37] Many interventions can also be performed after delivery, though further development is less influenced. In Ebstein anomaly, associated pulmonary arteriovenous malformations can be occluded using a transcatheter approach.[38](B2)

Surgical intervention can also correct any of the abovementioned anatomical variations, though technique varies by condition. The Fontan procedure, a popular choice for intervention, works by delivering blood to the lungs utilizing central venous pressure, and reduced intrathoracic pressure.[39] Optimal pressure dynamics with low pulmonary flow resistance allows for anterograde circulation.[40] Though reliably successful, the Fontan procedure should not be the only option considered. 

In patients with severe disease, palliative surgery may be the best option and is typically preferred over choosing strict comfort measures.[41] Data is unclear if the Fontan procedure is superior to palliative options.[42] Patients should be referred to tertiary care centers for specialized evaluation and treatment.[42] Cardiac transplantation may be considered, albeit associated with suboptimal outcomes due to comorbidities.[43][44] Cardiac transplantation may also be required despite previous alternative procedures.(B2)

Differential Diagnosis

The neonatal presentation may be seen emergently after birth or develop within a few days of delivery, as collateral circulations diminish. Emergent presentations after delivery should consider sepsis, infantile respiratory distress syndrome (IRDS), independent aortic and pulmonary disorders, and transposition of the great arteries.[45]

Less severe cases may present after a few months or years when growth rates are affected; infection, failure to thrive, and malnutrition etiologies should be considered.

Prognosis

Hypoplastic left heart syndrome is almost universally fatal if untreated but improves to 60% to 70% survival with partial revisions.[46][47][48] Patients alive beyond one year of age after surgical correction have a 90% chance of living to 18 years of age.[49] While survival is optimistic, regardless of the intervention performed, there is an increased risk of suboptimal neurodevelopment.[50][51] Consequently, the American Heart Association recommends developmental evaluation for patients, which may be caused by poor nutrition delivery.[52][53]

Patients with tricuspid atresia are typically better with intervention, noting 90% survival at one year of age and 80% survival at ten years.[54][55] Ebstein anomaly has high perinatal mortality, with up to 32% of live births expiring before discharge.[56] One-year and ten-year survival rates are 67% and 59%, respectively.[57] Limited prognostic data is available after ten years.

The prognosis for other causes of single ventricles vary by etiology; nevertheless, more than half survive two years with the average length of up to 30 to 40 years.[58]

Complications

Single ventricle heart syndromes are typically corrected through direct intervention, obfuscating the origin of certain complications. Expected complications of corrected single ventricle hearts are listed below:

  • Arrhythmias[59][60][61]
  • Esophageal varices[61]
  • Heart failure with thrombus formation and increased risk of bleeding from treatment[62][63]
  • Increased risk for decompensation with anesthesia[64]
  • Long-term cyanosis[65]
  • Restrictive and diffusion-limited lung disease.[66][67] Pulmonary diseases may be due in part to subclinical plastic bronchitis and subclinical pulmonary embolisms[68]
  • Protein-losing enteropathy[69][70]
  • Recurrent laryngeal nerve injury[71]
  • Reduced height and somatic development[72]
  • Renal dysfunction[65]
  • Systemic venous-to-pulmonary venous and systemic artery-to-pulmonary artery collaterals[61]

Consultations

Consultations with interventional specialists and thoracic surgeons should be made when the anomaly is discovered. Prompt referral allows for earlier intervention with optimal informed consent.

Deterrence and Patient Education

Intervention is not always sensible or the best option. In-depth discussions about prognosis and outcomes should be discussed with family members. A specific expression that staged procedures may not be curative should be given, mentioning the possible need for cardiac transplantation in the future. If found in utero, elective termination may be necessary for the discussion of available options. Living conditions should also be discussed with patients. Families residing at altitudes higher than 1700 meters above sea level may impair long-term survival benefits.[73]

Enhancing Healthcare Team Outcomes

The identification of a single ventricle can be made in utero or after birth. When made in utero, healthcare teams must report this finding and begin goal discussions with the mother as soon as possible. When found emergently after delivery, healthcare employees need to work as an interprofessional team to provide an urgent resolution quickly. Overall, general practitioners should understand the severity of single ventricles and the suboptimal prognoses to guide decision-making better.

References

[1]

Dhanantwari P, Lee E, Krishnan A, Samtani R, Yamada S, Anderson S, Lockett E, Donofrio M, Shiota K, Leatherbury L, Lo CW. Human cardiac development in the first trimester: a high-resolution magnetic resonance imaging and episcopic fluorescence image capture atlas. Circulation. 2009 Jul 28:120(4):343-51. doi: 10.1161/CIRCULATIONAHA.108.796698. Epub     [PubMed PMID: 19635979]

[2]

Sizarov A, Ya J, de Boer BA, Lamers WH, Christoffels VM, Moorman AF. Formation of the building plan of the human heart: morphogenesis, growth, and differentiation. Circulation. 2011 Mar 15:123(10):1125-35. doi: 10.1161/CIRCULATIONAHA.110.980607. Epub     [PubMed PMID: 21403123]

Level 3 (low-level) evidence

[3]

Kennedy MP, Omran H, Leigh MW, Dell S, Morgan L, Molina PL, Robinson BV, Minnix SL, Olbrich H, Severin T, Ahrens P, Lange L, Morillas HN, Noone PG, Zariwala MA, Knowles MR. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation. 2007 Jun 5:115(22):2814-21     [PubMed PMID: 17515466]

Level 2 (mid-level) evidence

[4]

Shapiro AJ, Davis SD, Ferkol T, Dell SD, Rosenfeld M, Olivier KN, Sagel SD, Milla C, Zariwala MA, Wolf W, Carson JL, Hazucha MJ, Burns K, Robinson B, Knowles MR, Leigh MW, Genetic Disorders of Mucociliary Clearance Consortium. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest. 2014 Nov:146(5):1176-1186. doi: 10.1378/chest.13-1704. Epub     [PubMed PMID: 24577564]

[5]

Bruneau BG, Logan M, Davis N, Levi T, Tabin CJ, Seidman JG, Seidman CE. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Developmental biology. 1999 Jul 1:211(1):100-8     [PubMed PMID: 10373308]

Level 3 (low-level) evidence

[6]

Zeisberg EM, Ma Q, Juraszek AL, Moses K, Schwartz RJ, Izumo S, Pu WT. Morphogenesis of the right ventricle requires myocardial expression of Gata4. The Journal of clinical investigation. 2005 Jun:115(6):1522-31     [PubMed PMID: 15902305]

Level 3 (low-level) evidence

[7]

Towbin JA, Belmont J. Molecular determinants of left and right outflow tract obstruction. American journal of medical genetics. 2000 Winter:97(4):297-303     [PubMed PMID: 11376441]

Level 3 (low-level) evidence

[8]

Materna-Kiryluk A, Wiśniewska K, Badura-Stronka M, Mejnartowicz J, Wieckowska B, Balcar-Boroń A, Czerwionka-Szaflarska M, Gajewska E, Godula-Stuglik U, Krawczyński M, Limon J, Rusin J, Sawulicka-Oleszczuk H, Szwalkiewicz-Warowicka E, Walczak M, Latos-Bieleńska A. Parental age as a risk factor for isolated congenital malformations in a Polish population. Paediatric and perinatal epidemiology. 2009 Jan:23(1):29-40. doi: 10.1111/j.1365-3016.2008.00979.x. Epub     [PubMed PMID: 19228312]

[9]

Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR, Elixson M, Warnes CA, Webb CL, American Heart Association Council on Cardiovascular Disease in the Young. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007 Jun 12:115(23):2995-3014     [PubMed PMID: 17519397]

[10]

Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. The New England journal of medicine. 2017 Jun 8:376(23):2245-2254. doi: 10.1056/NEJMoa1612222. Epub     [PubMed PMID: 28591541]

[11]

Fornaro M, Maritan E, Ferranti R, Zaninotto L, Miola A, Anastasia A, Murru A, Solé E, Stubbs B, Carvalho AF, Serretti A, Vieta E, Fusar-Poli P, McGuire P, Young AH, Dazzan P, Vigod SN, Correll CU, Solmi M. Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis of Safety and Efficacy Outcomes. The American journal of psychiatry. 2020 Jan 1:177(1):76-92. doi: 10.1176/appi.ajp.2019.19030228. Epub 2019 Oct 18     [PubMed PMID: 31623458]

Level 1 (high-level) evidence

[12]

Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. The Journal of pediatrics. 2008 Dec:153(6):807-13. doi: 10.1016/j.jpeds.2008.05.059. Epub 2008 Jul 26     [PubMed PMID: 18657826]

[13]

Khoshnood B, Lelong N, Houyel L, Thieulin AC, Jouannic JM, Magnier S, Delezoide AL, Magny JF, Rambaud C, Bonnet D, Goffinet F, EPICARD Study Group. Prevalence, timing of diagnosis and mortality of newborns with congenital heart defects: a population-based study. Heart (British Cardiac Society). 2012 Nov:98(22):1667-73. doi: 10.1136/heartjnl-2012-302543. Epub 2012 Aug 11     [PubMed PMID: 22888161]

Level 2 (mid-level) evidence

[14]

Liu S, Joseph KS, Lisonkova S, Rouleau J, Van den Hof M, Sauve R, Kramer MS, Canadian Perinatal Surveillance System (Public Health Agency of Canada). Association between maternal chronic conditions and congenital heart defects: a population-based cohort study. Circulation. 2013 Aug 6:128(6):583-9. doi: 10.1161/CIRCULATIONAHA.112.001054. Epub 2013 Jun 28     [PubMed PMID: 23812182]

Level 2 (mid-level) evidence

[15]

Ferencz C, Rubin JD, McCarter RJ, Brenner JI, Neill CA, Perry LW, Hepner SI, Downing JW. Congenital heart disease: prevalence at livebirth. The Baltimore-Washington Infant Study. American journal of epidemiology. 1985 Jan:121(1):31-6     [PubMed PMID: 3964990]

Level 2 (mid-level) evidence

[16]

Fixler DE, Nembhard WN, Salemi JL, Ethen MK, Canfield MA. Mortality in first 5 years in infants with functional single ventricle born in Texas, 1996 to 2003. Circulation. 2010 Feb 9:121(5):644-50. doi: 10.1161/CIRCULATIONAHA.109.881904. Epub 2010 Jan 25     [PubMed PMID: 20100974]

Level 2 (mid-level) evidence

[17]

Karamlou T, Diggs BS, Ungerleider RM, Welke KF. Evolution of treatment options and outcomes for hypoplastic left heart syndrome over an 18-year period. The Journal of thoracic and cardiovascular surgery. 2010 Jan:139(1):119-26; discussion 126-7. doi: 10.1016/j.jtcvs.2009.04.061. Epub 2009 Nov 11     [PubMed PMID: 19909991]

[18]

Hoffman JI, Kaplan S. The incidence of congenital heart disease. Journal of the American College of Cardiology. 2002 Jun 19:39(12):1890-900     [PubMed PMID: 12084585]

[19]

Rao PS. Tricuspid Atresia. Current treatment options in cardiovascular medicine. 2000 Dec:2(6):507-520     [PubMed PMID: 11096554]

[20]

Pradat P, Francannet C, Harris JA, Robert E. The epidemiology of cardiovascular defects, part I: a study based on data from three large registries of congenital malformations. Pediatric cardiology. 2003 May-Jun:24(3):195-221     [PubMed PMID: 12632215]

[21]

Diav-Citrin O, Shechtman S, Tahover E, Finkel-Pekarsky V, Arnon J, Kennedy D, Erebara A, Einarson A, Ornoy A. Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study. The American journal of psychiatry. 2014 Jul:171(7):785-94. doi: 10.1176/appi.ajp.2014.12111402. Epub     [PubMed PMID: 24781368]

Level 2 (mid-level) evidence

[22]

Demir MT, Amasyall Y, Kopuz C, Aydln ME, Corumlu U. The double outlet right ventricle with additional cardiac malformations: an anatomic and echocardiographic study. Folia morphologica. 2009 May:68(2):104-8     [PubMed PMID: 19449298]

Level 3 (low-level) evidence

[23]

Gidvani M, Ramin K, Gessford E, Aguilera M, Giacobbe L, Sivanandam S. Prenatal diagnosis and outcome of fetuses with double-inlet left ventricle. AJP reports. 2011 Dec:1(2):123-8. doi: 10.1055/s-0031-1293515. Epub 2011 Nov 7     [PubMed PMID: 23705101]

Level 3 (low-level) evidence

[24]

Hoffman JI. Incidence of congenital heart disease: I. Postnatal incidence. Pediatric cardiology. 1995 May-Jun:16(3):103-13     [PubMed PMID: 7617503]

[25]

Tongsong T, Sittiwangkul R, Wanapirak C, Chanprapaph P. Prenatal diagnosis of isolated tricuspid valve atresia: report of 4 cases and review of the literature. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. 2004 Jul:23(7):945-50     [PubMed PMID: 15292563]

Level 3 (low-level) evidence

[26]

Berg C, Lachmann R, Kaiser C, Kozlowski P, Stressig R, Schneider M, Asfour B, Herberg U, Breuer J, Gembruch U, Geipel A. Prenatal diagnosis of tricuspid atresia: intrauterine course and outcome. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2010 Feb:35(2):183-90. doi: 10.1002/uog.7499. Epub     [PubMed PMID: 20101636]

Level 2 (mid-level) evidence

[27]

Galindo A, Comas C, Martínez JM, Gutiérrez-Larraya F, Carrera JM, Puerto B, Borrell A, Mortera C, de la Fuente P. Cardiac defects in chromosomally normal fetuses with increased nuchal translucency at 10-14 weeks of gestation. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2003 Mar:13(3):163-70     [PubMed PMID: 12820838]

[28]

Forbess JM, Cook N, Roth SJ, Serraf A, Mayer JE Jr, Jonas RA. Ten-year institutional experience with palliative surgery for hypoplastic left heart syndrome. Risk factors related to stage I mortality. Circulation. 1995 Nov 1:92(9 Suppl):II262-6     [PubMed PMID: 7586421]

[29]

Vlahos AP, Lock JE, McElhinney DB, van der Velde ME. Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: outcome after neonatal transcatheter atrial septostomy. Circulation. 2004 May 18:109(19):2326-30     [PubMed PMID: 15136496]

Level 2 (mid-level) evidence

[30]

de-Wahl Granelli A, Wennergren M, Sandberg K, Mellander M, Bejlum C, Inganäs L, Eriksson M, Segerdahl N, Agren A, Ekman-Joelsson BM, Sunnegårdh J, Verdicchio M, Ostman-Smith I. Impact of pulse oximetry screening on the detection of duct dependent congenital heart disease: a Swedish prospective screening study in 39,821 newborns. BMJ (Clinical research ed.). 2009 Jan 8:338():a3037. doi: 10.1136/bmj.a3037. Epub 2009 Jan 8     [PubMed PMID: 19131383]

Level 3 (low-level) evidence

[31]

Monaco MA, Liberman L, Starc TJ, Silver ES. Defining the electrocardiogram in the neonate with hypoplastic left heart syndrome. Pediatric cardiology. 2015 Jun:36(5):1014-8. doi: 10.1007/s00246-015-1112-x. Epub 2015 Jan 21     [PubMed PMID: 25605039]

Level 2 (mid-level) evidence

[32]

Donofrio MT, Moon-Grady AJ, Hornberger LK, Copel JA, Sklansky MS, Abuhamad A, Cuneo BF, Huhta JC, Jonas RA, Krishnan A, Lacey S, Lee W, Michelfelder EC Sr, Rempel GR, Silverman NH, Spray TL, Strasburger JF, Tworetzky W, Rychik J, American Heart Association Adults With Congenital Heart Disease Joint Committee of the Council on Cardiovascular Disease in the Young and Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Council on Cardiovascular and Stroke Nursing. Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American Heart Association. Circulation. 2014 May 27:129(21):2183-242. doi: 10.1161/01.cir.0000437597.44550.5d. Epub 2014 Apr 24     [PubMed PMID: 24763516]

[33]

Atz AM, Munoz RA, Adatia I, Wessel DL. Diagnostic and therapeutic uses of inhaled nitric oxide in neonatal Ebstein's anomaly. The American journal of cardiology. 2003 Apr 1:91(7):906-8     [PubMed PMID: 12667588]

[34]

Cai J, Su Z, Shi Z, Zhou Y, Xu Z, Xu Z, Yang Y. Nitric oxide and milrinone: combined effect on pulmonary circulation after Fontan-type procedure: a prospective, randomized study. The Annals of thoracic surgery. 2008 Sep:86(3):882-8; discussion 882-8. doi: 10.1016/j.athoracsur.2008.05.014. Epub     [PubMed PMID: 18721577]

Level 1 (high-level) evidence

[35]

Mäkikallio K, McElhinney DB, Levine JC, Marx GR, Colan SD, Marshall AC, Lock JE, Marcus EN, Tworetzky W. Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention. Circulation. 2006 Mar 21:113(11):1401-5     [PubMed PMID: 16534003]

Level 2 (mid-level) evidence

[36]

Tworetzky W, Wilkins-Haug L, Jennings RW, van der Velde ME, Marshall AC, Marx GR, Colan SD, Benson CB, Lock JE, Perry SB. Balloon dilation of severe aortic stenosis in the fetus: potential for prevention of hypoplastic left heart syndrome: candidate selection, technique, and results of successful intervention. Circulation. 2004 Oct 12:110(15):2125-31     [PubMed PMID: 15466631]

Level 3 (low-level) evidence

[37]

Freud LR, McElhinney DB, Marshall AC, Marx GR, Friedman KG, del Nido PJ, Emani SM, Lafranchi T, Silva V, Wilkins-Haug LE, Benson CB, Lock JE, Tworetzky W. Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome: postnatal outcomes of the first 100 patients. Circulation. 2014 Aug 19:130(8):638-45. doi: 10.1161/CIRCULATIONAHA.114.009032. Epub 2014 Jul 22     [PubMed PMID: 25052401]

[38]

Fletcher SE, Cheatham JP, Bolam DL. Primary transcatheter treatment of congenital pulmonary arteriovenous malformation causing cyanosis of the newborn. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2000 May:50(1):48-51     [PubMed PMID: 10816279]

Level 3 (low-level) evidence

[39]

Shafer KM, Garcia JA, Babb TG, Fixler DE, Ayers CR, Levine BD. The importance of the muscle and ventilatory blood pumps during exercise in patients without a subpulmonary ventricle (Fontan operation). Journal of the American College of Cardiology. 2012 Nov 13:60(20):2115-21. doi: 10.1016/j.jacc.2012.08.970. Epub 2012 Oct 17     [PubMed PMID: 23083785]

[40]

Goldberg DJ, Dodds K, Rychik J. Rare problems associated with the Fontan circulation. Cardiology in the young. 2010 Dec:20 Suppl 3():113-9. doi: 10.1017/S1047951110001162. Epub     [PubMed PMID: 21087567]

[41]

Prsa M, Holly CD, Carnevale FA, Justino H, Rohlicek CV. Attitudes and practices of cardiologists and surgeons who manage HLHS. Pediatrics. 2010 Mar:125(3):e625-30. doi: 10.1542/peds.2009-1678. Epub 2010 Feb 15     [PubMed PMID: 20156891]

[42]

Uzark K, Zak V, Shrader P, McCrindle BW, Radojewski E, Varni JW, Daniels K, Handisides J, Hill KD, Lambert LM, Margossian R, Pemberton VL, Lai WW, Atz AM, Pediatric Heart Network Investigators. Assessment of Quality of Life in Young Patients with Single Ventricle after the Fontan Operation. The Journal of pediatrics. 2016 Mar:170():166-72.e1. doi: 10.1016/j.jpeds.2015.11.016. Epub 2015 Dec 10     [PubMed PMID: 26685073]

Level 2 (mid-level) evidence

[43]

Alsoufi B, Deshpande S, McCracken C, Kogon B, Vincent R, Mahle W, Kanter K. Results of heart transplantation following failed staged palliation of hypoplastic left heart syndrome and related single ventricle anomalies. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2015 Nov:48(5):792-8; discussion 798-9. doi: 10.1093/ejcts/ezu547. Epub 2015 Jan 18     [PubMed PMID: 25602055]

Level 2 (mid-level) evidence

[44]

Alsoufi B, Mahle WT, Manlhiot C, Deshpande S, Kogon B, McCrindle BW, Kanter K. Outcomes of heart transplantation in children with hypoplastic left heart syndrome previously palliated with the Norwood procedure. The Journal of thoracic and cardiovascular surgery. 2016 Jan:151(1):167-74, 175.e1-2. doi: 10.1016/j.jtcvs.2015.09.081. Epub 2015 Sep 28     [PubMed PMID: 26520008]

[45]

Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. The New England journal of medicine. 1967 Feb 16:276(7):357-68     [PubMed PMID: 5334613]

Level 2 (mid-level) evidence

[46]

Newburger JW, Sleeper LA, Gaynor JW, Hollenbeck-Pringle D, Frommelt PC, Li JS, Mahle WT, Williams IA, Atz AM, Burns KM, Chen S, Cnota J, Dunbar-Masterson C, Ghanayem NS, Goldberg CS, Jacobs JP, Lewis AB, Mital S, Pizarro C, Eckhauser A, Stark P, Ohye RG, Pediatric Heart Network Investigators. Transplant-Free Survival and Interventions at 6 Years in the SVR Trial. Circulation. 2018 May 22:137(21):2246-2253. doi: 10.1161/CIRCULATIONAHA.117.029375. Epub 2018 Feb 1     [PubMed PMID: 29437119]

[47]

Scheurer MA, Salvin JW, Vida VL, Fynn-Thompson F, Bacha EA, Pigula FA, Mayer JE Jr, del Nido PJ, Wessel DL, Laussen PC, Thiagarajan RR. Survival and clinical course at Fontan after stage one palliation with either a modified Blalock-Taussig shunt or a right ventricle to pulmonary artery conduit. Journal of the American College of Cardiology. 2008 Jul 1:52(1):52-9. doi: 10.1016/j.jacc.2008.03.034. Epub     [PubMed PMID: 18582635]

Level 2 (mid-level) evidence

[48]

d'Udekem Y, Xu MY, Galati JC, Lu S, Iyengar AJ, Konstantinov IE, Wheaton GR, Ramsay JM, Grigg LE, Millar J, Cheung MM, Brizard CP. Predictors of survival after single-ventricle palliation: the impact of right ventricular dominance. Journal of the American College of Cardiology. 2012 Mar 27:59(13):1178-85. doi: 10.1016/j.jacc.2011.11.049. Epub     [PubMed PMID: 22440217]

Level 2 (mid-level) evidence

[49]

Siffel C, Riehle-Colarusso T, Oster ME, Correa A. Survival of Children With Hypoplastic Left Heart Syndrome. Pediatrics. 2015 Oct:136(4):e864-70. doi: 10.1542/peds.2014-1427. Epub 2015 Sep 21     [PubMed PMID: 26391936]

[50]

Laraja K, Sadhwani A, Tworetzky W, Marshall AC, Gauvreau K, Freud L, Hass C, Dunbar-Masterson C, Ware J, Lafranchi T, Wilkins-Haug L, Newburger JW. Neurodevelopmental Outcome in Children after Fetal Cardiac Intervention for Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome. The Journal of pediatrics. 2017 May:184():130-136.e4. doi: 10.1016/j.jpeds.2017.01.034. Epub 2017 Feb 21     [PubMed PMID: 28233547]

[51]

Goldberg CS, Lu M, Sleeper LA, Mahle WT, Gaynor JW, Williams IA, Mussatto KA, Ohye RG, Graham EM, Frank DU, Jacobs JP, Krawczeski C, Lambert L, Lewis A, Pemberton VL, Sananes R, Sood E, Wechsler SB, Bellinger DC, Newburger JW, Pediatric Heart Network Investigators. Factors associated with neurodevelopment for children with single ventricle lesions. The Journal of pediatrics. 2014 Sep:165(3):490-496.e8. doi: 10.1016/j.jpeds.2014.05.019. Epub 2014 Jun 19     [PubMed PMID: 24952712]

Level 1 (high-level) evidence

[52]

Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, Gaynor JW, Mussatto KA, Uzark K, Goldberg CS, Johnson WH Jr, Li J, Smith SE, Bellinger DC, Mahle WT, American Heart Association Congenital Heart Defects Committee, Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, and Stroke Council. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association. Circulation. 2012 Aug 28:126(9):1143-72     [PubMed PMID: 22851541]

[53]

Ravishankar C, Zak V, Williams IA, Bellinger DC, Gaynor JW, Ghanayem NS, Krawczeski CD, Licht DJ, Mahony L, Newburger JW, Pemberton VL, Williams RV, Sananes R, Cook AL, Atz T, Khaikin S, Hsu DT, Pediatric Heart Network Investigators. Association of impaired linear growth and worse neurodevelopmental outcome in infants with single ventricle physiology: a report from the pediatric heart network infant single ventricle trial. The Journal of pediatrics. 2013 Feb:162(2):250-6.e2. doi: 10.1016/j.jpeds.2012.07.048. Epub 2012 Aug 30     [PubMed PMID: 22939929]

Level 1 (high-level) evidence

[54]

Alsoufi B, Schlosser B, Mori M, McCracken C, Slesnick T, Kogon B, Petit C, Sachdeva R, Kanter K. Influence of Morphology and Initial Surgical Strategy on Survival of Infants With Tricuspid Atresia. The Annals of thoracic surgery. 2015 Oct:100(4):1403-9; discussion 1409-10. doi: 10.1016/j.athoracsur.2015.05.037. Epub 2015 Jul 30     [PubMed PMID: 26233275]

[55]

Mair DD, Puga FJ, Danielson GK. The Fontan procedure for tricuspid atresia: early and late results of a 25-year experience with 216 patients. Journal of the American College of Cardiology. 2001 Mar 1:37(3):933-9     [PubMed PMID: 11693773]

Level 2 (mid-level) evidence

[56]

Freud LR, Escobar-Diaz MC, Kalish BT, Komarlu R, Puchalski MD, Jaeggi ET, Szwast AL, Freire G, Levasseur SM, Kavanaugh-McHugh A, Michelfelder EC, Moon-Grady AJ, Donofrio MT, Howley LW, Tierney ES, Cuneo BF, Morris SA, Pruetz JD, van der Velde ME, Kovalchin JP, Ikemba CM, Vernon MM, Samai C, Satou GM, Gotteiner NL, Phoon CK, Silverman NH, McElhinney DB, Tworetzky W. Outcomes and Predictors of Perinatal Mortality in Fetuses With Ebstein Anomaly or Tricuspid Valve Dysplasia in the Current Era: A Multicenter Study. Circulation. 2015 Aug 11:132(6):481-9. doi: 10.1161/CIRCULATIONAHA.115.015839. Epub 2015 Jun 9     [PubMed PMID: 26059011]

Level 2 (mid-level) evidence

[57]

Celermajer DS, Bull C, Till JA, Cullen S, Vassillikos VP, Sullivan ID, Allan L, Nihoyannopoulos P, Somerville J, Deanfield JE. Ebstein's anomaly: presentation and outcome from fetus to adult. Journal of the American College of Cardiology. 1994 Jan:23(1):170-6     [PubMed PMID: 8277076]

Level 2 (mid-level) evidence

[58]

Yeh T Jr, Williams WG, McCrindle BW, Benson LN, Coles JG, Van Arsdell GS, Webb GG, Freedom RM. Equivalent survival following cavopulmonary shunt: with or without the Fontan procedure. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 1999 Aug:16(2):111-6     [PubMed PMID: 10485406]

Level 2 (mid-level) evidence

[59]

Lasa JJ, Glatz AC, Daga A, Shah M. Prevalence of arrhythmias late after the Fontan operation. The American journal of cardiology. 2014 Apr 1:113(7):1184-8. doi: 10.1016/j.amjcard.2013.12.025. Epub 2014 Jan 14     [PubMed PMID: 24513470]

Level 2 (mid-level) evidence

[60]

Durongpisitkul K, Porter CJ, Cetta F, Offord KP, Slezak JM, Puga FJ, Schaff HV, Danielson GK, Driscoll DJ. Predictors of early- and late-onset supraventricular tachyarrhythmias after Fontan operation. Circulation. 1998 Sep 15:98(11):1099-107     [PubMed PMID: 9736597]

[61]

Chin AJ, Whitehead KK, Watrous RL. Insights after 40 years of the fontan operation. World journal for pediatric & congenital heart surgery. 2010 Oct:1(3):328-43. doi: 10.1177/2150135110379623. Epub     [PubMed PMID: 23804889]

[62]

Egbe AC, Connolly HM, Niaz T, Yogeswaran V, Taggart NW, Qureshi MY, Poterucha JT, Khan AR, Driscoll DJ. Prevalence and outcome of thrombotic and embolic complications in adults after Fontan operation. American heart journal. 2017 Jan:183():10-17. doi: 10.1016/j.ahj.2016.09.014. Epub 2016 Oct 4     [PubMed PMID: 27979032]

[63]

Mahnke CB, Boyle GJ, Janosky JE, Siewers RD, Pigula FA. Anticoagulation and incidence of late cerebrovascular accidents following the Fontan procedure. Pediatric cardiology. 2005 Jan-Feb:26(1):56-61     [PubMed PMID: 14994183]

[64]

Eagle SS, Daves SM. The adult with Fontan physiology: systematic approach to perioperative management for noncardiac surgery. Journal of cardiothoracic and vascular anesthesia. 2011 Apr:25(2):320-34. doi: 10.1053/j.jvca.2010.12.003. Epub     [PubMed PMID: 21477759]

Level 1 (high-level) evidence

[65]

Rychik J, Atz AM, Celermajer DS, Deal BJ, Gatzoulis MA, Gewillig MH, Hsia TY, Hsu DT, Kovacs AH, McCrindle BW, Newburger JW, Pike NA, Rodefeld M, Rosenthal DN, Schumacher KR, Marino BS, Stout K, Veldtman G, Younoszai AK, d'Udekem Y, American Heart Association Council on Cardiovascular Disease in the Young and Council on Cardiovascular and Stroke Nursing. Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association. Circulation. 2019 Aug 6:140(6):e234-e284. doi: 10.1161/CIR.0000000000000696. Epub 2019 Jul 1     [PubMed PMID: 31256636]

[66]

Matthews IL, Fredriksen PM, Bjørnstad PG, Thaulow E, Gronn M. Reduced pulmonary function in children with the Fontan circulation affects their exercise capacity. Cardiology in the young. 2006 Jun:16(3):261-7     [PubMed PMID: 16725065]

Level 2 (mid-level) evidence

[67]

Idorn L, Hanel B, Jensen AS, Juul K, Reimers JI, Nielsen KG, Søndergaard L. New insights into the aspects of pulmonary diffusing capacity in Fontan patients. Cardiology in the young. 2014 Apr:24(2):311-20. doi: 10.1017/S1047951113000358. Epub 2013 Apr 3     [PubMed PMID: 23552344]

Level 2 (mid-level) evidence

[68]

Liptzin DR, Di Maria MV, Younoszai A, Narkewicz MR, Kelly SL, Wolfe KR, Veress LA. Pulmonary Screening in Subjects after the Fontan Procedure. The Journal of pediatrics. 2018 Aug:199():140-143. doi: 10.1016/j.jpeds.2018.03.050. Epub 2018 May 7     [PubMed PMID: 29747936]

[69]

Rychik J. Protein-losing enteropathy after Fontan operation. Congenital heart disease. 2007 Sep-Oct:2(5):288-300. doi: 10.1111/j.1747-0803.2007.00116.x. Epub     [PubMed PMID: 18377444]

[70]

Feldt RH, Driscoll DJ, Offord KP, Cha RH, Perrault J, Schaff HV, Puga FJ, Danielson GK. Protein-losing enteropathy after the Fontan operation. The Journal of thoracic and cardiovascular surgery. 1996 Sep:112(3):672-80     [PubMed PMID: 8800155]

[71]

Ting J, Roy S, Navuluri S, Hanfland R, Mulcahy L, Yuksel S, Huang Z, Jiang ZY. Airway evaluation in children with single ventricle cardiac physiology. International journal of pediatric otorhinolaryngology. 2018 Aug:111():115-118. doi: 10.1016/j.ijporl.2018.06.004. Epub 2018 Jun 5     [PubMed PMID: 29958593]

[72]

Cohen MS, Zak V, Atz AM, Printz BF, Pinto N, Lambert L, Pemberton V, Li JS, Margossian R, Dunbar-Masterson C, McCrindle BW. Anthropometric measures after Fontan procedure: implications for suboptimal functional outcome. American heart journal. 2010 Dec:160(6):1092-8, 1098.e1. doi: 10.1016/j.ahj.2010.07.039. Epub     [PubMed PMID: 21146663]

Level 2 (mid-level) evidence

[73]

Johnson JT, Lindsay I, Day RW, Van Dorn CS, Hoffman J, Everitt MD, Yetman AT. Living at altitude adversely affects survival among patients with a Fontan procedure. Journal of the American College of Cardiology. 2013 Mar 26:61(12):1283-9. doi: 10.1016/j.jacc.2013.01.008. Epub 2013 Feb 13     [PubMed PMID: 23414794]

Level 2 (mid-level) evidence