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The Palliated Univentricular Heart

  • Rafael Alonso-Gonzalez
Chapter
Part of the Congenital Heart Disease in Adolescents and Adults book series (CHDAA)

Abstract

The most significant area of growth in adult congenital cardiac practice is in relation to patients with complex univentricular hearts. These patients represent the extreme end of the ACHD spectrum and demonstrate unique manifestations of heart failure. This chapter describes, in detail, the underlying pathophysiology of these changes focusing on patients who have undergone Fontan or cavopulmonary operations. The possible therapeutic options for these patients are explained in terms of their specific impact on the abnormal haemodynamics. The multisystem impact of heart failure and the importance of other end-organ involvement are discussed particularly in the context of timely referral for transplant assessment.

Keywords

Univentricular heart Fontan failure Liver disease Protein-losing enteropathy Transplantation 

References

  1. 1.
    Gewillig M, Goldberg DJ. Failure of the fontan circulation. Heart Fail Clin. 2014;10:105–16.CrossRefPubMedGoogle Scholar
  2. 2.
    Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax. 1971;26:240–8.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bjork VO, Olin CL, Bjarke BB, Thoren CA. Right atrial-right ventricular anastomosis for correction of tricuspid atresia. J Thorac Cardiovasc Surg. 1979;77:452–8.PubMedGoogle Scholar
  4. 4.
    de Leval MR, Kilner P, Gewillig M, Bull C. Total cavopulmonary connection: a logical alternative to atriopulmonary connection for complex Fontan operations. Experimental studies and early clinical experience. J Thorac Cardiovasc Surg. 1988;96:682–95.PubMedGoogle Scholar
  5. 5.
    Kreutzer G, Galindez E, Bono H, De Palma C, Laura JP. An operation for the correction of tricuspid atresia. J Thorac Cardiovasc Surg. 1973;66:613–21.PubMedGoogle Scholar
  6. 6.
    Marcelletti C, Corno A, Giannico S, Marino B. Inferior vena cava-pulmonary artery extracardiac conduit. A new form of right heart bypass. J Thorac Cardiovasc Surg. 1990;100:228–32.PubMedGoogle Scholar
  7. 7.
    Gewillig M, Brown SC. The Fontan circulation after 45 years: update in physiology. Heart. 2016;102:1081–6.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lastinger L, Zaidi AN. The adult with a Fontan: a panacea without a cure? Circ J. 2013;77:2672–81.CrossRefPubMedGoogle Scholar
  9. 9.
    Norozi K, Wessel A, Alpers V, Arnhold JO, Geyer S, Zoege M, Buchhorn R. Incidence and risk distribution of heart failure in adolescents and adults with congenital heart disease after cardiac surgery. Am J Cardiol. 2006;97:1238–43.CrossRefPubMedGoogle Scholar
  10. 10.
    Piran S, Veldtman G, Siu S, Webb GD, Liu PP. Heart failure and ventricular dysfunction in patients with single or systemic right ventricles. Circulation. 2002;105:1189–94.CrossRefPubMedGoogle Scholar
  11. 11.
    Goldberg DJ, Shaddy RE, Ravishankar C, Rychik J. The failing Fontan: etiology, diagnosis and management. Expert Rev Cardiovasc Ther. 2011;9:785–93.CrossRefPubMedGoogle Scholar
  12. 12.
    Mondesert B, Marcotte F, Mongeon FP, Dore A, Mercier LA, Ibrahim R, Asgar A, Miro J, Poirier N, Khairy P. Fontan circulation: success or failure? Can J Cardiol. 2013;29:811–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Nakamura Y, Yagihara T, Kagisaki K, Hagino I, Kobayashi J. Ventricular performance in long-term survivors after Fontan operation. Ann Thorac Surg. 2011;91:172–80.CrossRefPubMedGoogle Scholar
  14. 14.
    Saiki H, Eidem BW, Ohtani T, Grogan MA, Redfield MM. Ventricular-arterial function and coupling in the adult Fontan circulation. J Am Heart Assoc. 2016;5:e003887.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sluysmans T, Sanders SP, van der Velde M, Matitiau A, Parness IA, Spevak PJ, Mayer JE Jr, Colan SD. Natural history and patterns of recovery of contractile function in single left ventricle after Fontan operation. Circulation. 1992;86:1753–61.CrossRefPubMedGoogle Scholar
  16. 16.
    Menon S, Chennapragada M, Ugaki S, Sholler GF, Ayer J, Winlaw DS. The lymphatic circulation in adaptations to the Fontan circulation. Pediatr Cardiol. 2017;38:886–92.CrossRefPubMedGoogle Scholar
  17. 17.
    Anderson PA, Sleeper LA, Mahony L, Colan SD, Atz AM, Breitbart RE, Gersony WM, Gallagher D, Geva T, Margossian R, McCrindle BW, Paridon S, Schwartz M, Stylianou M, Williams RV, Clark BJ III, Pediatric Heart Network I. Contemporary outcomes after the Fontan procedure: a Pediatric Heart Network Multicenter study. J Am Coll Cardiol. 2008;52:85–98.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Khairy P, Fernandes SM, Mayer JE Jr, Triedman JK, Walsh EP, Lock JE, Landzberg MJ. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation. 2008;117:85–92.CrossRefPubMedGoogle Scholar
  19. 19.
    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. J Am Coll Cardiol. 2012;59:1178–85.CrossRefPubMedGoogle Scholar
  20. 20.
    d'Udekem Y, Iyengar AJ, Galati JC, Forsdick V, Weintraub RG, Wheaton GR, Bullock A, Justo RN, Grigg LE, Sholler GF, Hope S, Radford DJ, Gentles TL, Celermajer DS, Winlaw DS. 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. Circulation. 2014;130:S32–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Elder RW, Wu FM. Clinical approaches to the patient with a failing Fontan procedure. Curr Cardiol Rep. 2016;18:44.CrossRefPubMedGoogle Scholar
  22. 22.
    Yap SC, Harris L, Silversides CK, Downar E, Chauhan VS. Outcome of intra-atrial re-entrant tachycardia catheter ablation in adults with congenital heart disease: negative impact of age and complex atrial surgery. J Am Coll Cardiol. 2010;56:1589–96.CrossRefPubMedGoogle Scholar
  23. 23.
    Ueda A, Suman-Horduna I, Mantziari L, Gujic M, Marchese P, Ho SY, Babu-Narayan SV, Ernst S. Contemporary outcomes of supraventricular tachycardia ablation in congenital heart disease: a single-center experience in 116 patients. Circ Arrhythm Electrophysiol. 2013;6:606–13.CrossRefPubMedGoogle Scholar
  24. 24.
    Diller GP, Giardini A, Dimopoulos K, Gargiulo G, Muller J, Derrick G, Giannakoulas G, Khambadkone S, Lammers AE, Picchio FM, Gatzoulis MA, Hager A. Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J. 2010;31:3073–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Diller GP, Dimopoulos K, Okonko D, Uebing A, Broberg CS, Babu-Narayan S, Bayne S, Poole-Wilson PA, Sutton R, Francis DP, Gatzoulis MA. Heart rate response during exercise predicts survival in adults with congenital heart disease. J Am Coll Cardiol. 2006;48(6):1250.CrossRefPubMedGoogle Scholar
  26. 26.
    Diller GP, Okonko DO, Uebing A, Dimopoulos K, Bayne S, Sutton R, Francis DP, Gatzoulis MA. Impaired heart rate response to exercise in adult patients with a systemic right ventricle or univentricular circulation: prevalence, relation to exercise, and potential therapeutic implications. Int J Cardiol. 2009;134:59–66.CrossRefPubMedGoogle Scholar
  27. 27.
    Deal BJ, Jacobs ML. Management of the failing Fontan circulation. Heart. 2012;98:1098–104.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Goldberg DJ, Surrey LF, Glatz AC, Dodds K, O'Byrne ML, Lin HC, Fogel M, Rome JJ, Rand EB, Russo P, Rychik J. Hepatic fibrosis is universal following Fontan operation, and severity is associated with time from surgery: a liver biopsy and hemodynamic study. J Am Heart Assoc. 2017;6:e004809.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wu FM, Kogon B, Earing MG, Aboulhosn JA, Broberg CS, John AS, Harmon A, Sainani NI, Hill AJ, Odze RD, Johncilla ME, Ukomadu C, Gauvreau K, Valente AM, Landzberg MJ, Alliance for Adult Research in Congenital Cardiology I. Liver health in adults with Fontan circulation: a multicenter cross-sectional study. J Thorac Cardiovasc Surg. 2017;153:656–64.CrossRefPubMedGoogle Scholar
  30. 30.
    Schwartz MC, Sullivan L, Cohen MS, Russo P, John AS, Guo R, Guttenberg M, Rand EB. Hepatic pathology may develop before the Fontan operation in children with functional single ventricle: an autopsy study. J Thorac Cardiovasc Surg. 2012;143:904–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Schwartz MC, Sullivan LM, Glatz AC, Rand E, Russo P, Goldberg DJ, Rome JJ, Cohen MS. Portal and sinusoidal fibrosis are common on liver biopsy after Fontan surgery. Pediatr Cardiol. 2013;34:135–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Wu FM, Jonas MM, Opotowsky AR, Harmon A, Raza R, Ukomadu C, Landzberg MJ, Singh MN, Valente AM, Egidy Assenza G, Perez-Atayde AR. Portal and centrilobular hepatic fibrosis in Fontan circulation and clinical outcomes. J Heart Lung Transplant. 2015;34:883–91.CrossRefPubMedGoogle Scholar
  33. 33.
    Alonso-Gonzalez R. Liver dysfunction and congenital heart disease: are we ready for the epidemic? Int J Cardiol. 2017;249:169–70.CrossRefPubMedGoogle Scholar
  34. 34.
    Asrani SK, Asrani NS, Freese DK, Phillips SD, Warnes CA, Heimbach J, Kamath PS. Congenital heart disease and the liver. Hepatology. 2012;56:1160–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Hilscher MB, Johnson JN, Cetta F, Driscoll DJ, Poterucha JJ, Sanchez W, Connolly HM, Kamath PS. Surveillance for liver complications after the Fontan procedure. Congenit Heart Dis. 2017;12:124–32.CrossRefPubMedGoogle Scholar
  36. 36.
    Wu FM, Earing MG, Aboulhosn JA, Johncilla ME, Singh MN, Odze RD, Ukomadu C, Gauvreau K, Landzberg MJ, Valente AM, Alliance for Adult Research in Congenital Cardiology I. Predictive value of biomarkers of hepatic fibrosis in adult Fontan patients. J Heart Lung Transplant. 2017;36:211–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Wegria R, Zekert H, Walter KE, Entrup RW, De Schryver C, Kennedy W, Paiewonsky D. Effect of systemic venous pressure on drainage of lymph from thoracic duct. Am J Phys. 1963;204:284–8.Google Scholar
  38. 38.
    Dori Y, Keller MS, Fogel MA, Rome JJ, Whitehead KK, Harris MA, Itkin M. MRI of lymphatic abnormalities after functional single-ventricle palliation surgery. Am J Roentgenol. 2014;203:426–31.CrossRefGoogle Scholar
  39. 39.
    Dori Y, Keller MS, Rychik J, Itkin M. Successful treatment of plastic bronchitis by selective lymphatic embolization in a Fontan patient. Pediatrics. 2014;134:e590–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Connor FL, Angelides S, Gibson M, Larden DW, Roman MR, Jones O, Currie BG, Day AS, Bohane TD. Successful resection of localized intestinal lymphangiectasia post-Fontan: role of (99m)technetium-dextran scintigraphy. Pediatrics. 2003;112:e242–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Parikh K, Witte MH, Samson R, Teodori M, Carpenter JB, Lowe MC, Morgan W, Hardin C, Brown M, Naughton Y, Sinha S, Barber BJ. Successful treatment of plastic bronchitis with low fat diet and subsequent thoracic duct ligation in child with fontan physiology. Lymphology. 2012;45:47–52.PubMedGoogle Scholar
  42. 42.
    Dori Y, Keller MS, Rome JJ, Gillespie MJ, Glatz AC, Dodds K, Goldberg DJ, Goldfarb S, Rychik J, Itkin M. Percutaneous lymphatic embolization of abnormal pulmonary lymphatic flow as treatment of plastic bronchitis in patients with congenital heart disease. Circulation. 2016;133:1160–70.CrossRefPubMedGoogle Scholar
  43. 43.
    Hraska V. Decompression of thoracic duct: new approach for the treatment of failing Fontan. Ann Thorac Surg. 2013;96:709–11.CrossRefPubMedGoogle Scholar
  44. 44.
    Mertens L, Hagler DJ, Sauer U, Somerville J, Gewillig M. Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group. J Thorac Cardiovasc Surg. 1998;115:1063–73.CrossRefPubMedGoogle Scholar
  45. 45.
    John AS, Johnson JA, Khan M, Driscoll DJ, Warnes CA, Cetta F. Clinical outcomes and improved survival in patients with protein-losing enteropathy after the Fontan operation. J Am Coll Cardiol. 2014;64:54–62.CrossRefPubMedGoogle Scholar
  46. 46.
    Ostrow AM, Freeze H, Rychik J. Protein-losing enteropathy after fontan operation: investigations into possible pathophysiologic mechanisms. Ann Thorac Surg. 2006;82:695–700.CrossRefPubMedGoogle Scholar
  47. 47.
    Bode L, Eklund EA, Murch S, Freeze HH. Heparan sulfate depletion amplifies TNF-alpha-induced protein leakage in an in vitro model of protein-losing enteropathy. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1015–23.CrossRefPubMedGoogle Scholar
  48. 48.
    Bode L, Salvestrini C, Park PW, Li JP, Esko JD, Yamaguchi Y, Murch S, Freeze HH. Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. J Clin Invest. 2008;118:229–38.CrossRefPubMedGoogle Scholar
  49. 49.
    Wilkinson P, Pinto B, Senior JR. Reversible protein-losing enteropathy with intestinal lymphangiectasia secondary to chronic constrictive pericarditis. N Engl J Med. 1965;273:1178–81.CrossRefPubMedGoogle Scholar
  50. 50.
    Levitt DG, Levitt MD. Protein losing enteropathy: comprehensive review of the mechanistic association with clinical and subclinical disease states. Clin Exp Gastroenterol. 2017;10:147–68.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ohuchi H, Yasuda K, Miyazaki A, Kitano M, Sakaguchi H, Yazaki S, Tsuda E, Yamada O. Haemodynamic characteristics before and after the onset of protein losing enteropathy in patients after the Fontan operation. Eur J Cardiothorac Surg. 2013;43:e49–57.CrossRefPubMedGoogle Scholar
  52. 52.
    Ringel RE, Peddy SB. Effect of high-dose spironolactone on protein-losing enteropathy in patients with Fontan palliation of complex congenital heart disease. Am J Cardiol. 2003;91:1031–2. A9.CrossRefPubMedGoogle Scholar
  53. 53.
    Ryerson L, Goldberg C, Rosenthal A, Armstrong A. Usefulness of heparin therapy in protein-losing enteropathy associated with single ventricle palliation. Am J Cardiol. 2008;101:248–51.CrossRefPubMedGoogle Scholar
  54. 54.
    Schumacher KR, Cools M, Goldstein BH, Ioffe-Dahan V, King K, Gaffney D, Russell MW. Oral budesonide treatment for protein-losing enteropathy in Fontan-palliated patients. Pediatr Cardiol. 2011;32:966–71.CrossRefPubMedGoogle Scholar
  55. 55.
    Turner Z, Lanford L, Webber S. Oral budesonide as a therapy for protein-losing enteropathy in patients having undergone Fontan palliation. Congenit Heart Dis. 2012;7:24–30.CrossRefPubMedGoogle Scholar
  56. 56.
    Heinemann M, Breuer J, Steger V, Steil E, Sieverding L, Ziemer G. Incidence and impact of systemic venous collateral development after Glenn and Fontan procedures. Thorac Cardiovasc Surg. 2001;49:172–8.CrossRefPubMedGoogle Scholar
  57. 57.
    McMullan DM, Reddy VM, Gottliebson WM, Silverman NH, Perry SB, Chan F, Hanley FL, Riemer RK. Morphological studies of pulmonary arteriovenous shunting in a lamb model of superior cavopulmonary anastomosis. Pediatr Cardiol. 2008;29:706–12.CrossRefPubMedGoogle Scholar
  58. 58.
    Kavarana MN, Jones JA, Stroud RE, Bradley SM, Ikonomidis JS, Mukherjee R. Pulmonary arteriovenous malformations after the superior cavopulmonary shunt: mechanisms and clinical implications. Expert Rev Cardiovasc Ther. 2014;12:703–13.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Jahangiri M, Kreutzer J, Zurakowski D, Bacha E, Jonas RA. Evaluation of hemostatic and coagulation factor abnormalities in patients undergoing the Fontan operation. J Thorac Cardiovasc Surg. 2000;120:778–82.CrossRefPubMedGoogle Scholar
  60. 60.
    Odegard KC, McGowan FX Jr, Zurakowski D, Dinardo JA, Castro RA, del Nido PJ, Laussen PC. Procoagulant and anticoagulant factor abnormalities following the Fontan procedure: increased factor VIII may predispose to thrombosis. J Thorac Cardiovasc Surg. 2003;125:1260–7.CrossRefPubMedGoogle Scholar
  61. 61.
    Marrone C, Galasso G, Piccolo R, de Leva F, Paladini R, Piscione F, Santoro G. Antiplatelet versus anticoagulation therapy after extracardiac conduit Fontan: a systematic review and meta-analysis. Pediatr Cardiol. 2011;32:32–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Kempny A, Dimopoulos K, Uebing A, Moceri P, Swan L, Gatzoulis MA, Diller GP. Reference values for exercise limitations among adults with congenital heart disease. Relation to activities of daily life—single centre experience and review of published data. Eur Heart J. 2012;33:1386–96.CrossRefPubMedGoogle Scholar
  63. 63.
    Paridon SM, Mitchell PD, Colan SD, Williams RV, Blaufox A, Li JS, Margossian R, Mital S, Russell J, Rhodes J, Pediatric Heart Network I. A cross-sectional study of exercise performance during the first 2 decades of life after the Fontan operation. J Am Coll Cardiol. 2008;52:99–107.CrossRefPubMedGoogle Scholar
  64. 64.
    Giardini A, Hager A, Pace Napoleone C, Picchio FM. Natural history of exercise capacity after the Fontan operation: a longitudinal study. Ann Thorac Surg. 2008;85:818–21.CrossRefPubMedGoogle Scholar
  65. 65.
    Cunningham JW, Nathan AS, Rhodes J, Shafer K, Landzberg MJ, Opotowsky AR. Decline in peak oxygen consumption over time predicts death or transplantation in adults with a Fontan circulation. Am Heart J. 2017;189:184–92.CrossRefPubMedGoogle Scholar
  66. 66.
    Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M, Picchio FM. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 2008;29:1681–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM, Rychik J. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation. 2011;123:1185–93.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Schuuring MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG, Sieswerda GT, de Bruin-Bon RH, Mulder BJ, Bouma BJ. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Fail. 2013;15:690–8.CrossRefPubMedGoogle Scholar
  69. 69.
    Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, Hanseus K, Sorensen KE, Sondergaard L. 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;130:2021–30.CrossRefPubMedGoogle Scholar
  70. 70.
    Cohen MI, Rhodes LA, Wernovsky G, Gaynor JW, Spray TL, Rychik J. Atrial pacing: an alternative treatment for protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg. 2001;121(3):582.CrossRefPubMedGoogle Scholar
  71. 71.
    Barber G, Di Sessa T, Child JS, Perloff JK, Laks H, George BL, Williams RG. Hemodynamic responses to isolated increments in heart rate by atrial pacing after a Fontan procedure. Am Heart J. 1988;115:837–41.CrossRefPubMedGoogle Scholar
  72. 72.
    Kouatli AA, Garcia JA, Zellers TM, Weinstein EM, Mahony L. Enalapril does not enhance exercise capacity in patients after Fontan procedure. Circulation. 1997;96:1507–12.CrossRefPubMedGoogle Scholar
  73. 73.
    Menachem JN, Golbus JR, Molina M, Mazurek JA, Hornsby N, Atluri P, Fuller S, Birati EY, Kim YY, Goldberg LR, Wald JW. Successful cardiac transplantation outcomes in patients with adult congenital heart disease. Heart. 2017;103:1449–54.CrossRefPubMedGoogle Scholar
  74. 74.
    Ross HJ, Law Y, Book WM, Broberg CS, Burchill L, Cecchin F, Chen JM, Delgado D, Dimopoulos K, Everitt MD, Gatzoulis M, Harris L, Hsu DT, Kuvin JT, Martin CM, Murphy AM, Singh G, Spray TL, Stout KK, American Heart Association Adults With Congenital Heart Disease Committee of the Council on Clinical C, Council on Cardiovascular Disease in the Young tCoCR, Intervention, the Council on Functional G and Translational B. Transplantation and mechanical circulatory support in congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2016;133:802–20.PubMedGoogle Scholar
  75. 75.
    VanderPluym CJ, Cedars A, Eghtesady P, Maxwell BG, Gelow JM, Burchill LJ, Maltais S, Koehl DA, Cantor RS, Blume ED. Outcomes following implantation of mechanical circulatory support in adults with congenital heart disease: an analysis of the interagency registry for mechanically assisted circulatory support (INTERMACS). J Heart Lung Transplant. 2018;37:89–99.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Rafael Alonso-Gonzalez
    • 1
  1. 1.Royal Brompton Hospital and the National Heart and Lung Institute, Imperial CollegeLondonUK

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