Advertisement
Canadian Journal of Cardiology

The Fontan Circulation: From Ideal to Failing Hemodynamics and Drug Therapies for Optimization

Published:April 22, 2022DOI:https://doi.org/10.1016/j.cjca.2022.04.014

      Abstract

      Fontan palliation results in a hemodynamically complex circulation with multisystem consequences, which in the long term adversely affect many body processes. Systemic venous hypertension, nonpulsatile low-shear pulmonary blood flow, and low cardiac output are the 3 main characteristics of a Fontan circulation, leading to unavoidable slowly progressive failure. An appreciation of how the hemodynamics of a Fontan circulation change with time and relate to the various modes of Fontan circulatory failure is important. Accurate hemodynamic assessment aid this understanding and may permit early identification of potentially treatable drivers of decline. While no evidence-based or guideline-directed pharmacologic management strategy has been established in Fontan patients, understanding the hemodynamics of Fontan circulation failure will assist in the rational selection of potentially helpful drug therapies for individual patients. In this review, we present hemodynamic concepts of the optimal Fontan physiology and Fontan circulatory failure, review practical aspects of invasive hemodynamic assessment, and discuss the role of drug therapies in increasing systemic venous blood flow return and decreasing ventricular filling pressures in Fontan circulation. Often complementary to catheter-based or surgical interventions, pharmacologic management aims at preserving patency of the circuit, adequate systolic and diastolic ventricular function, atrioventricular valve function, an unobstructed ventricular outflow tract, and pulmonary vascular integrity in order to maintain an acceptable cardiac output.

      Résumé

      L’intervention de Fontan donne lieu à une circulation complexe sur le plan hémodynamique ayant des répercussions multisystémiques qui, à long terme, nuisent à de nombreuses fonctions de l’organisme. L’hypertension veineuse systémique, le flux sanguin pulmonaire non pulsatile à faible contrainte de cisaillement et le bas débit cardiaque sont les trois principales caractéristiques d’une circulation de Fontan entrainant inévitablement une défaillance à évolution lente. Il importe de comprendre comment les caractéristiques hémodynamiques de la circulation de Fontan changent au fil du temps et de cerner leur rôle dans les différentes formes d’insuffisance circulatoire. Une évaluation hémodynamique complète peut permettre la détection précoce de facteurs de déclin qui pourraient être traitables. Aucune stratégie de prise en charge pharmacologique fondée sur des données probantes ou sur des lignes directrices n’a été établie chez les patients qui ont subi l’intervention de Fontan. Néanmoins, la compréhension des mécanismes hémodynamiques de l’insuffisance circulatoire observée après cette intervention peut guider le clinicien dans les choix de traitements médicamenteux susceptibles de répondre aux besoins de chaque patient. Dans le présent article de synthèse des données contemporaines, nous présentons les concepts hémodynamiques touchant les caractéristiques physiologiques optimales et l’insuffisance circulatoire dans le contexte de la circulation de Fontan. Nous passons aussi en revue les aspects pratiques d’une évaluation hémodynamique. Enfin, nous abordons le recours à des traitements médicamenteux visant à augmenter le retour veineux systémique et à réduire la pression de remplissage ventriculaire chez les patients ayant subi l’intervention de Fontan. Souvent instauré en complément d’une intervention chirurgicale ou par cathétérisme, le traitement médicamenteux vise à préserver la perméabilité du circuit, la fonction ventriculaire systolique et diastolique, la fonction de la valve atrioventriculaire, l’absence d’obstruction de la chambre de chasse du ventricule gauche et l’intégrité du système vasculaire pulmonaire afin de maintenir un débit cardiaque acceptable.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Fontan F.
        • Baudet E.
        Surgical repair of tricuspid atresia.
        Thorax. 1971; 26: 240-248
        • Khairy P.
        • Fernandes S.M.
        • Mayer Jr., J.E.
        • et al.
        Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery.
        Circulation. 2008; 117: 85-92
        • Gewillig M.
        • Brown S.C.
        The Fontan circulation after 45 years: update in physiology.
        Heart. 2016; 102: 1081-1086
        • Gewillig M.
        • Brown S.C.
        • van de Bruaene A.
        • Rychik J.
        Providing a framework of principles for conceptualising the Fontan circulation.
        Acta Paediatr. 2020; 109: 651-658
        • Alsaied T.
        • Bokma J.P.
        • Engel M.E.
        • et al.
        Factors associated with long-term mortality after Fontan procedures: a systematic review.
        Heart. 2017; 103: 104-110
        • Alsaied T.
        • Rathod R.H.
        • Aboulhosn J.A.
        • et al.
        Reaching consensus for unified medical language in Fontan care.
        ESC Heart Fail. 2021; 8: 3894-3905
        • Baumgartner H.
        • de Backer J.
        • Babu-Narayan S.V.
        • et al.
        2020 ESC guidelines for the management of adult congenital heart disease.
        Eur Heart J. 2021; 42: 563-645
        • Stout K.K.
        • Daniels C.J.
        • Aboulhosn J.A.
        • et al.
        2018 AHA/ACC guideline for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        J Am Coll Cardiol. 2019; 73: e81-e192
        • Hsia T.Y.
        • Khambadkone S.
        • Redington A.N.
        • Migliavacca F.
        • Deanfield J.E.
        • de Leval M.R.
        Effects of respiration and gravity on infradiaphragmatic venous flow in normal and Fontan patients.
        Circulation. 2000; 102: III148-III153
        • Korperich H.
        • Barth P.
        • Gieseke J.
        • et al.
        Impact of respiration on stroke volumes in paediatric controls and in patients after Fontan procedure assessed by MR real-time phase-velocity mapping.
        Eur Heart J Cardiovasc Imaging. 2015; 16: 198-209
        • Wei Z.
        • Whitehead K.K.
        • Khiabani R.H.
        • et al.
        Respiratory effects on fontan circulation during rest and exercise using real-time cardiac magnetic resonance imaging.
        Ann Thorac Surg. 2016; 101: 1818-1825
        • La Gerche A.
        • Gewillig M.
        What limits cardiac performance during exercise in normal subjects and in healthy Fontan patients?.
        Int J Pediatr. 2010; 2010
        • Ohuchi H.
        Cardiopulmonary response to exercise in patients with the Fontan circulation.
        Cardiol Young. 2005; 15: 39-44
        • Tran D.
        • d’Ambrosio P.
        • Verrall C.E.
        • et al.
        Body composition in young adults living with a Fontan circulation: the myopenic profile.
        J Am Heart Assoc. 2020; 9e015639
        • Wittekind S.
        • Mays W.
        • Gerdes Y.
        • et al.
        A novel mechanism for improved exercise performance in pediatric Fontan patients after cardiac rehabilitation.
        Pediatr Cardiol. 2018; 39: 1023-1030
        • Sutherland N.
        • Jones B.
        • Westcamp Aguero S.
        • et al.
        Home- and hospital-based exercise training programme after Fontan surgery.
        Cardiol Young. 2018; 28: 1299-1305
        • Cunningham J.W.
        • Nathan A.S.
        • Rhodes J.
        • Shafer K.
        • Landzberg M.J.
        • Opotowsky A.R.
        Decline in peak oxygen consumption over time predicts death or transplantation in adults with a Fontan circulation.
        Am Heart J. 2017; 189: 184-192
        • Ohuchi H.
        • Negishi J.
        • Miike H.
        • et al.
        Positive pediatric exercise capacity trajectory predicts better adult Fontan physiology rationale for early establishment of exercise habits.
        Int J Cardiol. 2019; 274: 80-87
        • Senzaki H.
        • Masutani S.
        • Ishido H.
        • et al.
        Cardiac rest and reserve function in patients with Fontan circulation.
        J Am Coll Cardiol. 2006; 47: 2528-2535
        • 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.
        Circulation. 2019; 140: e234-e284
        • Claessen G.
        • La Gerche A.
        • van de Bruaene A.
        • et al.
        Heart rate reserve in Fontan patients: chronotropic incompetence or hemodynamic limitation?.
        J Am Heart Assoc. 2019; 8e012008
        • Ridderbos F.J.
        • Wolff D.
        • Timmer A.
        • et al.
        Adverse pulmonary vascular remodeling in the Fontan circulation.
        J Heart Lung Transplant. 2015; 34: 404-413
        • Hays B.S.
        • Baker M.
        • Laib A.
        • et al.
        Histopathological abnormalities in the central arteries and veins of Fontan subjects.
        Heart. 2018; 104: 324-331
        • Adachi I.
        • Ueno T.
        • Hori Y.
        • Sawa Y.
        Alterations in the medial layer of the main pulmonary artery in a patient with longstanding Fontan circulation.
        Interact Cardiovasc Thorac Surg. 2010; 11: 682-683
        • Egbe A.C.
        • Miranda W.R.
        • Anderson J.H.
        • Borlaug B.A.
        Hemodynamic and clinical implications of impaired pulmonary vascular reserve in the Fontan circulation.
        J Am Coll Cardiol. 2020; 76: 2755-2763
        • Gewillig M.
        • Cools B.
        • van de Bruaene A.
        Pulmonary vascular reserve in fontan patients: looking upstream for the true heart of the matter.
        J Am Coll Cardiol. 2020; 76: 2764-2767
        • van Melle J.P.
        • Wolff D.
        • Horer J.
        • et al.
        Surgical options after Fontan failure.
        Heart. 2016; 102: 1127-1133
        • Simpson K.E.
        • Pruitt E.
        • Kirklin J.K.
        • et al.
        Fontan patient survival after pediatric heart transplantation has improved in the current era.
        Ann Thorac Surg. 2017; 103: 1315-1320
        • Mitchell M.B.
        • Campbell D.N.
        • Ivy D.
        • et al.
        Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure.
        J Thorac Cardiovasc Surg. 2004; 128: 693-702
        • Heath L.
        • Ling S.
        • Racz J.
        • et al.
        Prospective, longitudinal study of plastic bronchitis cast pathology and responsiveness to tissue plasminogen activator.
        Pediatr Cardiol. 2011; 32: 1182-1189
        • Penny D.J.
        • Redington A.N.
        Diastolic ventricular function after the Fontan operation.
        Am J Cardiol. 1992; 69: 974-975
        • Kutty S.
        • Rathod R.H.
        • Danford D.A.
        • Celermajer D.S.
        Role of imaging in the evaluation of single ventricle with the Fontan palliation.
        Heart. 2016; 102: 174-183
        • Margossian R.
        • Sleeper L.A.
        • Pearson G.D.
        • et al.
        Assessment of diastolic function in single-ventricle patients after the Fontan procedure.
        J Am Soc Echocardiogr. 2016; 29: 1066-1073
        • Michel M.
        • Logoteta J.
        • Entenmann A.
        • et al.
        Decline of systolic and diastolic 2D strain rate during follow-up of HLHS patients after Fontan palliation.
        Pediatr Cardiol. 2016; 37: 1250-1257
        • Steflik D.
        • Butts R.J.
        • Baker G.H.
        • et al.
        A preliminary comparison of two-dimensional speckle tracking echocardiography and pressure-volume loop analysis in patients with Fontan physiology: the role of ventricular morphology.
        Echocardiography. 2017; 34: 1353-1359
        • Razzouk A.J.
        • Freedom R.M.
        • Cohen A.J.
        • et al.
        The recognition, identification of morphologic substrate, and treatment of subaortic stenosis after a Fontan operation. An analysis of twelve patients.
        J Thorac Cardiovasc Surg. 1992; 104: 938-944
        • Tseng S.Y.
        • Siddiqui S.
        • di Maria M.V.
        • et al.
        Atrioventricular valve regurgitation in single ventricle heart disease: a common problem associated with progressive deterioration and mortality.
        J Am Heart Assoc. 2020; 9e015737
        • King G.
        • Ayer J.
        • Celermajer D.
        • et al.
        Atrioventricular valve failure in Fontan palliation.
        J Am Coll Cardiol. 2019; 73: 810-822
        • d’Udekem Y.
        • Xu M.Y.
        • Galati J.C.
        • et al.
        Predictors of survival after single-ventricle palliation: the impact of right ventricular dominance.
        J Am Coll Cardiol. 2012; 59: 1178-1185
        • Grewal J.
        • Al Hussein M.
        • Feldstein J.
        • et al.
        Evaluation of silent thrombus after the Fontan operation.
        Congenit Heart Dis. 2013; 8: 40-47
        • Sughimoto K.
        • Okauchi K.
        • Zannino D.
        • et al.
        Total cavopulmonary connection is superior to atriopulmonary connection fontan in preventing thrombus formation: computer simulation of flow-related blood coagulation.
        Pediatr Cardiol. 2015; 36: 1436-1441
        • Tsang W.
        • Johansson B.
        • Salehian O.
        • et al.
        Intracardiac thrombus in adults with the Fontan circulation.
        Cardiol Young. 2007; 17: 646-651
        • Coon P.D.
        • Rychik J.
        • Novello R.T.
        • Ro P.S.
        • Gaynor J.W.
        • Spray T.L.
        Thrombus formation after the Fontan operation.
        Ann Thorac Surg. 2001; 71: 1990-1994
        • Balling G.
        • Vogt M.
        • Kaemmerer H.
        • Eicken A.
        • Meisner H.
        • Hess J.
        Intracardiac thrombus formation after the Fontan operation.
        J Thorac Cardiovasc Surg. 2000; 119: 745-752
        • Sathananthan G.
        • Johal N.
        • Verma T.
        • et al.
        Clinical importance of fontan circuit thrombus in the adult population: significant association with increased risk of cardiovascular events.
        Can J Cardiol. 2019; 35: 1807-1814
        • Cromme-Dijkhuis A.H.
        • Henkens C.M.
        • Bijleveld C.M.
        • Hillege H.L.
        • Bom V.J.
        • van der Meer J.
        Coagulation factor abnormalities as possible thrombotic risk factors after Fontan operations.
        Lancet. 1990; 336: 1087-1090
        • Jahangiri M.
        • Shore D.
        • Kakkar V.
        • Lincoln C.
        • Shinebourne E.
        Coagulation factor abnormalities after the Fontan procedure and its modifications.
        J Thorac Cardiovasc Surg. 1997; 113 (discussion: 992-3): 989-992
        • van Nieuwenhuizen R.C.
        • Peters M.
        • Lubbers L.J.
        • Trip M.D.
        • Tijssen J.G.
        • Mulder B.J.
        Abnormalities in liver function and coagulation profile following the Fontan procedure.
        Heart. 1999; 82: 40-46
        • RocheRodriguez M.
        • DiNardo J.A.
        The lymphatic system in the Fontan patient—pathophysiology, imaging, and interventions: what the anesthesiologist should know.
        J Cardiothorac Vasc Anesth. 2021; S1053-0770: 00631-00635
        • Mertens L.
        • Hagler D.J.
        • Sauer U.
        • Somerville J.
        • Gewillig M.
        • PLE Study Group
        Protein-losing enteropathy after the Fontan operation: an international multicenter study.
        J Thorac Cardiovasc Surg. 1998; 115: 1063-1073
        • Mackie A.S.
        • Veldtman G.R.
        • Torup L.
        • Hjortdal V.E.
        • Dori Y.
        Plastic bronchitis and protein-losing enteropathy in the fontan patient: evolving understanding and emerging therapies.
        Can J Cardiol. 2022; 38: 988-1001
        • Emamaullee J.
        • Zaidi A.N.
        • Schiano T.
        • et al.
        Fontan-associated liver disease: screening, management, and transplant considerations.
        Circulation. 2020; 142: 591-604
        • Munsterman I.D.
        • Duijnhouwer A.L.
        • Kendall T.J.
        • et al.
        The clinical spectrum of Fontan-associated liver disease: results from a prospective multimodality screening cohort.
        Eur Heart J. 2019; 40: 1057-1068
        • Baumgartner H.
        • De Backer J.
        The ESC clinical practice guidelines for the management of adult congenital heart disease 2020.
        Eur Heart J. 2020; 41: 4153-4154
        • Sorajja P.
        • Borlaug B.A.
        • Dimas V.V.
        • et al.
        SCAI/HFSA clinical expert consensus document on the use of invasive hemodynamics for the diagnosis and management of cardiovascular disease.
        Catheter Cardiovasc Interv. 2017; 89: E233-E247
        • Miranda W.R.
        • Borlaug B.A.
        • Hagler D.J.
        • Connolly H.M.
        • Egbe A.C.
        Haemodynamic profiles in adult Fontan patients: associated haemodynamics and prognosis.
        Eur J Heart Fail. 2019; 21: 803-809
        • Stumper O.
        • Penford G.
        Catheter hemodynamic assessment of the univentricular circulation.
        Ann Pediatr Cardiol. 2017; 10: 167-174
        • Egbe A.C.
        • Connolly H.M.
        • Miranda W.R.
        • et al.
        Hemodynamics of Fontan failure: the role of pulmonary vascular disease. 10. Circ Heart Fail, 2017
        • Ferrante G.
        • Rao S.V.
        • Juni P.
        • et al.
        Radial versus femoral access for coronary interventions across the entire spectrum of patients with coronary artery disease: a meta-analysis of randomized trials.
        JACC Cardiovasc Interv. 2016; 9: 1419-1434
        • Egbe A.C.
        • Miranda W.R.
        • Veldtman G.R.
        • Graham R.P.
        • Kamath P.S.
        Hepatic venous pressure gradient in fontan physiology has limited diagnostic and prognostic significance.
        CJC Open. 2020; 2: 360-364
        • Kiesewetter C.H.
        • Sheron N.
        • Vettukattill J.J.
        • et al.
        Hepatic changes in the failing Fontan circulation.
        Heart. 2007; 93: 579-584
        • Townsley M.I.
        Structure and composition of pulmonary arteries, capillaries, and veins.
        Compr Physiol. 2012; 2: 675-709
        • Asante-Korang A.
        • Sreeram N.
        • McKay R.
        • Arnold R.
        Thrombolysis with tissue-type plasminogen activator following cardiac surgery in children.
        Int J Cardiol. 1992; 35: 317-322
        • Rosenthal D.N.
        • Friedman A.H.
        • Kleinman C.S.
        • Kopf G.S.
        • Rosenfeld L.E.
        • Hellenbrand W.E.
        Thromboembolic complications after Fontan operations.
        Circulation. 1995; 92: II287-II293
        • Diab Y.A.
        • Ramakrishnan K.
        • Alfares F.A.
        • et al.
        Transcatheter treatment of thrombosis in the single ventricle pathway: an institutional experience.
        Congenit Heart Dis. 2016; 11: 39-44
        • Mongeon F.P.
        • Macle L.
        • Beauchesne L.M.
        • et al.
        Non–vitamin K antagonist oral anticoagulants in adult congenital heart disease.
        Can J Cardiol. 2019; 35: 1686-1697
        • Alsaied T.
        • Alsidawi S.
        • Allen C.C.
        • Faircloth J.
        • Palumbo J.S.
        • Veldtman G.R.
        Strategies for thromboprophylaxis in Fontan circulation: a meta-analysis.
        Heart. 2015; 101: 1731-1737
        • Khairy P.
        • Van Hare G.F.
        • Balaji S.
        • et al.
        PACES/HRS expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology (ACC), the American Heart Association (AHA), the European Heart Rhythm Association (EHRA), the Canadian Heart Rhythm Society (CHRS), and the International Society for Adult Congenital Heart Disease (ISACHD).
        Can J Cardiol. 2014; 30: e1-e63
        • Yang H.
        • Veldtman G.R.
        • Bouma B.J.
        • et al.
        Non–vitamin K antagonist oral anticoagulants in adults with a Fontan circulation: are they safe.
        Open Heart. 2019; 6e000985
        • Georgekutty J.
        • Kazerouninia A.
        • Wang Y.
        • et al.
        Novel oral anticoagulant use in adult Fontan patients: a single center experience.
        Congenit Heart Dis. 2018; 13: 541-547
        • McCrindle B.W.
        • Michelson A.D.
        • van Bergen A.H.
        • et al.
        Thromboprophylaxis for children post–Fontan procedure: insights from the UNIVERSE study.
        J Am Heart Assoc. 2021; 10e021765
        • Budts W.
        • Ravekes W.J.
        • Danford D.A.
        • Kutty S.
        Diastolic heart failure in patients with the Fontan circulation: a review.
        JAMA Cardiol. 2020; 5: 590-597
        • Budts W.
        • Roos-Hesselink J.
        • Radle-Hurst T.
        • et al.
        Treatment of heart failure in adult congenital heart disease: a position paper of the Working Group of Grown-Up Congenital Heart Disease and the Heart Failure Association of the European Society of Cardiology.
        Eur Heart J. 2016; 37: 1419-1427
        • McDonagh T.A.
        • Metra M.
        • Adamo M.
        • et al.
        2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.
        Eur Heart J. 2021; 42: 3599-3726
        • Ishibashi N.
        • Park I.S.
        • Waragai T.
        • et al.
        Effect of carvedilol on heart failure in patients with a functionally univentricular heart.
        Circ J. 2011; 75: 1394-1399
        • Butts R.
        • Atz A.M.
        • BaezHernandez N.
        • Sutcliffe D.
        • Reisch J.
        • Mahony L.
        Carvedilol does not improve exercise performance in Fontan patients: results of a crossover trial.
        Pediatr Cardiol. 2021; 42: 934-941
        • Wilson T.G.
        • Iyengar A.J.
        • Winlaw D.S.
        • et al.
        Use of ACE inhibitors in Fontan: rational or irrational?.
        Int J Cardiol. 2016; 210: 95-99
        • Kouatli A.A.
        • Garcia J.A.
        • Zellers T.M.
        • Weinstein E.M.
        • Mahony L.
        Enalapril does not enhance exercise capacity in patients after Fontan procedure.
        Circulation. 1997; 96: 1507-1512
        • Yim D.L.
        • Jones B.O.
        • Alexander P.M.
        • d’Udekem Y.
        • Cheung M.M.
        Effect of antiheart failure therapy on diastolic function in children with single-ventricle circulations.
        Cardiol Young. 2015; 25: 1293-1299
        • Hsu D.T.
        • Zak V.
        • Mahony L.
        • et al.
        Enalapril in infants with single ventricle: results of a multicenter randomized trial.
        Circulation. 2010; 122: 333-340
        • Burchill L.J.
        • Redington A.N.
        • Silversides C.K.
        • et al.
        Renin-angiotensin-aldosterone system genotype and serum BNP in a contemporary cohort of adults late after Fontan palliation.
        Int J Cardiol. 2015; 197: 209-215
        • Maurer S.J.
        • Pujol Salvador C.
        • Schiele S.
        • Hager A.
        • Ewert P.
        • Tutarel O.
        Sacubitril/valsartan for heart failure in adults with complex congenital heart disease.
        Int J Cardiol. 2020; 300: 137-140
        • Lluri G.
        • Lin J.
        • Reardon L.
        • Miner P.
        • Whalen K.
        • Aboulhosn J.
        Early experience with sacubitril/valsartan in adult patients with congenital heart disease.
        World J Pediatr Congenit Heart Surg. 2019; 10: 292-295
        • Appadurai V.
        • Thoreau J.
        • Malpas T.
        • Nicolae M.
        Sacubitril/valsartan in adult congenital heart disease patients with chronic heart failure—a single centre case series and call for an international registry.
        Heart Lung Circ. 2020; 29: 137-141
        • Packer M.
        • Anker S.D.
        • Butler J.
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Stephens E.H.
        • Dearani J.A.
        Management of the bad atrioventricular valve in Fontan … time for a change.
        J Thorac Cardiovasc Surg. 2019; 158: 1643-1648
        • Wang W.
        • Hu X.
        • Liao W.
        • et al.
        The efficacy and safety of pulmonary vasodilators in patients with Fontan circulation: a meta-analysis of randomized controlled trials.
        Pulm Circ. 2019; 9 (2045894018790450)
        • Hebert A.
        • Jensen A.S.
        • Idorn L.
        • Sorensen K.E.
        • Sondergaard L.
        The effect of bosentan on exercise capacity in Fontan patients; rationale and design for the TEMPO study.
        BMC Cardiovasc Disord. 2013; 13: 36
        • Goldberg D.J.
        • Zak V.
        • Goldstein B.H.
        • et al.
        Results of the FUEL trial.
        Circulation. 2020; 141: 641-651
        • van de Bruaene A.
        • La Gerche A.
        • Claessen G.
        • et al.
        Sildenafil improves exercise hemodynamics in Fontan patients.
        Circ Cardiovasc Imaging. 2014; 7: 265-273
        • Cedars A.M.
        • Saef J.
        • Peterson L.R.
        • et al.
        Effect of ambrisentan on exercise capacity in adult patients after the Fontan procedure.
        Am J Cardiol. 2016; 117: 1524-1532
        • Giardini A.
        • Balducci A.
        • Specchia S.
        • Gargiulo G.
        • Bonvicini M.
        • Picchio F.M.
        Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients.
        Eur Heart J. 2008; 29: 1681-1687
        • Goldberg D.J.
        • French B.
        • Szwast A.L.
        • et al.
        Impact of sildenafil on echocardiographic indices of myocardial performance after the Fontan operation.
        Pediatr Cardiol. 2012; 33: 689-696
        • Giordano R.
        • Palma G.
        • Poli V.
        • et al.
        First experience with sildenafil after Fontan operation: short-term outcomes.
        J Cardiovasc Med (Hagerstown). 2015; 16: 552-555
        • Mendoza A.
        • Albert L.
        • Belda S.
        • et al.
        Pulmonary vasodilator therapy and early postoperative outcome after modified Fontan operation.
        Cardiol Young. 2015; 25: 1136-1140
        • Shang X.K.
        • Lu R.
        • Zhang X.
        • et al.
        Efficacy of bosentan in patients after Fontan procedures: a double-blind, randomized controlled trial.
        J Huazhong Univ Sci Technolog Med Sci. 2016; 36: 534-540
        • 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 Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study.
        Circulation. 2014; 130: 2021-2030
        • Reinhardt Z.
        • Uzun O.
        • Bhole V.
        • et al.
        Sildenafil in the management of the failing Fontan circulation.
        Cardiol Young. 2010; 20: 522-525
        • Morchi G.S.
        • Ivy D.D.
        • Duster M.C.
        • Claussen L.
        • Chan K.C.
        • Kay J.
        Sildenafil increases systemic saturation and reduces pulmonary artery pressure in patients with failing Fontan physiology.
        Congenit Heart Dis. 2009; 4: 107-111
        • Agnoletti G.
        • Gala S.
        • Ferroni F.
        • et al.
        Endothelin inhibitors lower pulmonary vascular resistance and improve functional capacity in patients with Fontan circulation.
        J Thorac Cardiovasc Surg. 2017; 153: 1468-1475
        • Ovaert C.
        • Thijs D.
        • Dewolf D.
        • et al.
        The effect of bosentan in patients with a failing Fontan circulation.
        Cardiol Young. 2009; 19: 331-339