Skip to main content
SpringerLink
Log in

Eisenmenger Syndrome in Patients with Down Syndrome

  • Chapter
  • First Online:
Pulmonary Hypertension in Adult Congenital Heart Disease

Part of the book series: Congenital Heart Disease in Adolescents and Adults ((CHDAA))

Abstract

Down syndrome (DS) is the most common autosomal chromosome abnormality with an estimated incidence of approximately 1.1 per 1000 live births, without significant differences across different races. Pulmonary hypertension (PH) can significantly affect the prognosis and quality of life of DS patients. While the most common cause of PH is congenital heart disease (CHD), DS is often associated with comorbidities that may cause or worsen PH.

In recent decades, new treatment strategies targeting pulmonary arterial hypertension (PAH) have greatly improved the clinical status of patients with PAH related to CHD (PAH-CHD). However, major clinical trials did not include DS patients, and, as a result, the efficacy of PAH-targeted therapies in this population remains largely unknown.

DS patients with PAH-CHD are a very complex population, posing major challenges in terms of diagnosis and prognosis. Tools and markers commonly used in the diagnostic workup of PAH are often difficult to apply to many DS patients, e.g. due to poor compliance to invasive or other investigations. For example, estimates of functional class and the validity of the 6-min walk test are still debated.

Given the complexity and presence of associated comorbidities, the management of DS patients with PAH-CHD requires a multidisciplinary approach and expert tertiary follow-up.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AVSD:

atrioventricular septal defect

CHD:

congenital heart disease

DS:

Down syndrome

ERA:

endothelin receptor antagonist

PAH:

pulmonary arterial hypertension

PH:

pulmonary hypertension

RHC:

right heart catheterization

VSD:

ventricular septal defect

6MWD:

six minute walk distance

6MWT:

six minute walk test

References

  1. Morris JK, Alberman E (2009) Trends in Down’s syndrome live births and antenatal diagnoses in England and Wales from 1989 to 2008: analysis of data from the National Down Syndrome Cytogenetic Register. BMJ 339:b3794

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wiseman FK, Alford KA, Tybulewic VL, Fisher EM (2009) Down syndrome—recent progress and future prospects. Hum Mol Genet 18(R1):R75–R83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Seguin E (1846) Traitement moral, hygiène et éducation des idiots et des autres enfants arriérés. Baillière, Paris

    Google Scholar 

  4. Down JL (1866) Observations on an ethnic classification of idiots. Clinical Lecture Reports: London Hospital 3:259–262

    Google Scholar 

  5. Lejeune J, Gauthier M, Turpin R (1959) Les chromosomes humains en culture de tissus. C R Hebd Seances Acad Sci 248:602–603

    CAS  PubMed  Google Scholar 

  6. Delabar JM, Theophile D, Rahmani Z, Chettouh Z, Blouin JL, Prieur M et al (1993) Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur J Hum Genet 1:114–124

    CAS  PubMed  Google Scholar 

  7. Ohira M, Ichikawa H, Suzuki E, Iwaki M, Suzuki K, Saito-Ohara F et al (1996) A 1.6-Mb P1-based physical map of the Down syndrome region on chromosome 21. Genomics 33:65–74

    Article  CAS  PubMed  Google Scholar 

  8. Korbel JO, Tirosh-Wagner T, Urban AE, Chen XN, Kasowski M, Dai L et al (2009) The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci U S A 106:12031–12036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shapiro BL (1999) The Down syndrome critical region. J Neural Transm Suppl 57:41–60

    CAS  PubMed  Google Scholar 

  10. Asim A, Kumar A, Muthuswamy S, Jain S, Agarwal S (2015) Down syndrome: an insight of the disease. J Biomed Sci 22:41

    Article  PubMed  PubMed Central  Google Scholar 

  11. Neill CA, Zuckerberg AL (1995) Syndromes and congenital heart defects. In: Nichols DG, Cameron DE, Greeley WJ et al (eds) Critical heart disease in infants and children. Mosby, St Louis, pp 987–1012

    Google Scholar 

  12. Saji T (2014) Clinical characteristics of pulmonary arterial hypertension associated with Down syndrome. Pediatr Int 56:297–303

    Article  CAS  PubMed  Google Scholar 

  13. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A et al (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62(25 Suppl):D34–D41

    Article  PubMed  Google Scholar 

  14. Jaiyesimi O, Baichoo V (2007) Cardiovascular malformations in Omani Arab children with Down’s syndrome. Cardiol Young 17:166–171

    Article  PubMed  Google Scholar 

  15. Vida VL, Barnoya J, Larrazabal LA, Gaitan G, de Maria GF, Castaneda AR (2005) Congenital cardiac disease in children with Down’s syndrome in Guatemala. Cardiol Young 15:286–290

    Article  PubMed  Google Scholar 

  16. Lin AE, Basson CT, Goldmuntz E, Magoulas PL, McDermott DA, McDonald-McGinn DM et al (2008) Adults with genetic syndromes and cardiovascular abnormalities: clinical history and management. Genet Med 10:469–494

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sarkozy A, Esposito G, Conti E, Digilio MC, Marino B, Calabrò R et al (2005) CRELD1 and GATA4 gene analysis in patients with nonsyndromic atrioventricular canal defects. Am J Med Genet 139:236–238

    Article  PubMed  Google Scholar 

  18. Thieren M, Stijns-Cailteux M, Trémouroux-Wattiez M, Jaumin P, Kestens-Servaye Y, Moulin D et al (1988) Congenital heart diseases and obstructive pulmonary vascular diseases in Down’s syndrome. A propos of 142 children with trisomy 21. Arch Mal Coeur Vaiss 81:655–661

    CAS  PubMed  Google Scholar 

  19. Hasegawa N, Oshima M, Kawakami H, Hirano H (1990) Changes in pulmonary tissue of patients with congenital heart disease and Down syndrome: a morphological and histological study. Acta Paediatr Jpn 32:60–66

    Article  CAS  PubMed  Google Scholar 

  20. Greenwood RD, Nadas AS (1976) The clinical course of cardiac disease in Down’s syndrome. Pediatrics 58:893–897

    CAS  PubMed  Google Scholar 

  21. Chi TP, Krovetz J (1975) The pulmonary vascular bed in children with Down syndrome. J Pediatr 86:533–538

    Article  Google Scholar 

  22. Irving CA, Chaudhari MP (2012) Cardiovascular abnormalities in Down’s syndrome: spectrum, management and survival over 22 years. Arch Dis Child 97:326–330

    Article  PubMed  Google Scholar 

  23. Diller GP, van Eijl S, Okonko DO, Howard LS, Ali O, Thum T et al (2008) Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 117:3020–3030

    Article  CAS  PubMed  Google Scholar 

  24. Yamaki S (2000) The diagnosis in biopsied samples from patients with VSD and PDA. The diagnosis of pulmonary vasculopathy in lung biopsy samples for clinicians, 1st edn. Medical Reviews, Osaka

    Google Scholar 

  25. Cooney TP, Thurlbeck WM (1982) Pulmonary hypoplasia in Down’s syndrome. N Engl J Med 307:1170–1173

    Article  CAS  PubMed  Google Scholar 

  26. Yamaki S, Horiuchi T, Takahashi T (1985) Pulmonary changes in congenital heart disease with Down’s syndrome: their significance as a cause of postoperative respiratory failure. Thorax 40:380–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Aurora RN, Zak RS, Karippot A, Lamm CI, Morgenthaler TI, Auerbach SH, American Academy of Sleep Medicine et al (2011) Practice parameters for the respiratory indications for polysomnography in children. Sleep 34:379–388

    Article  PubMed  PubMed Central  Google Scholar 

  28. Weijerman ME, van Furth AM, van der Mooren MD, van Weissenbruch MM, Rammeloo L, Broers CJ et al (2010) Prevalence of congenital heart defects and persistent pulmonary hypertension of the neonate with Down syndrome. Eur J Pediatr 169:1195–1199

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cua CL, Blankenship A, North AL, Hayes J, Nelin LD (2007) Increased incidence of idiopathic persistent pulmonary hypertension in Down syndrome neonates. Pediatr Cardiol 28:250–254

    Article  CAS  PubMed  Google Scholar 

  30. Shah PS, Hellmann J, Adatia I (2004) Clinical characteristics and follow up of Down syndrome infants without congenital heart disease who presented with persistent pulmonary hypertension of newborn. J Perinat Med 32:168–170

    Article  PubMed  Google Scholar 

  31. Galiè N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators et al (2006) Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 114:48–54

    Article  PubMed  Google Scholar 

  32. Gatzoulis MA, Beghetti M, Galiè N, Granton J, Berger RM, Lauer A, BREATHE-5 Investigators et al (2008) Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study. Int J Cardiol 127:27–32

    Article  PubMed  Google Scholar 

  33. Sitbon O, Beghetti M, Petit J, Iserin L, Humbert M, Gressin V et al (2006) Bosentan for the treatment of pulmonary arterial hypertension associated with congenital heart defects. Eur J Clin Investig 36(Suppl 3):25–31

    Article  CAS  Google Scholar 

  34. Benza RL, Rayburn BK, Tallaj JA, Coffey GS, Pinderski LJ, Pamoukian SV et al (2006) Efficacy of bosentan in a small cohort of adult patients with pulmonary arterial hypertension related to congenital heart disease. Chest 129:1009–1015

    Article  CAS  PubMed  Google Scholar 

  35. Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S (2007) Long-term oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 93:350–354

    Article  CAS  PubMed  Google Scholar 

  36. D’Alto M, Vizza CD, Romeo E, Badagliacca R, Santoro G, Poscia R et al (2007) Long term effects of bosentan treatment in adult patients with pulmonary arterial hypertension related to congenital heart disease (Eisenmenger physiology): safety, tolerability, clinical, and haemodynamic effect. Heart 93:621–625

    Article  PubMed  Google Scholar 

  37. Zhang ZN, Jiang X, Zhang R, Li XL, Wu BX, Zhao QH et al (2011) Oral sildenafil treatment for Eisenmenger syndrome: a prospective, open-label, multicentre study. Heart 97:1876–1881

    Article  CAS  PubMed  Google Scholar 

  38. Mukhopadhyay S, Sharma M, Ramakrishnan S, Yusuf J, Gupta MD, Bhamri N et al (2006) Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: a preliminary observational study. Circulation 114:1807–1810

    Article  CAS  PubMed  Google Scholar 

  39. Iversen K, Jensen AS, Jensen TV, Vejlstrup NG, Sondergaard L (2010) Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. Eur Heart J 31:1124–1131

    Article  CAS  PubMed  Google Scholar 

  40. D’Alto M, Romeo E, Argiento P, Sarubbi B, Santoro G, Grimaldi N et al (2012) Bosentan-sildenafil association in patients with congenital heart disease-related pulmonary arterial hypertension and Eisenmenger physiology. Int J Cardiol 155:378–382

    Article  PubMed  Google Scholar 

  41. Galiè N, Rubin LJ, Hoeper M, Jansa P, Al-Hiti H, Meyer G et al (2008) Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371:2093–2100

    Article  PubMed  Google Scholar 

  42. MAESTRO (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity). ClinicalTrials.gov identifier: NCT01743001. https://clinicaltrials.gov/ct2/show/NCT01743001?term=NCT01743001&rank=1. Accessed 28 Aug 2015

  43. Dimopoulos K, Inuzuka R, Goletto S, Giannakoulas G, Swan L, Wort SJ et al (2010) Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 121:20–25

    Article  PubMed  Google Scholar 

  44. Suzuki K, Yamaki S, Mimori S, Murakami Y, Mori K, Takahashi Y et al (2000) Pulmonary vascular disease in Down’s syndrome with complete atrioventricular septal defect. Am J Cardiol 86:434–437

    Article  CAS  PubMed  Google Scholar 

  45. Van de Bruaene A, Delcroix M, Pasquet A, De Backer J, De Pauw M, Naeije R et al (2009) The Belgian Eisenmenger syndrome registry: implications for treatment strategies? Acta Cardiol 64:447–453

    Article  PubMed  Google Scholar 

  46. Duffels MG, Vis JC, van Loon RL, Berger RM, Hoendermis ES, van Dijk AP et al (2009) Down patients with Eisenmenger syndrome: is bosentan treatment an option? Int J Cardiol 134:378–383

    Article  PubMed  Google Scholar 

  47. Duffels MG, Vis JC, van Loon RL, Nieuwkerk PT, van Dijk AP, Hoendermis ES et al (2009) Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without Down’s syndrome. Am J Cardiol 103:1309–1315

    Article  CAS  PubMed  Google Scholar 

  48. Vis JC, Thoonsen H, Duffels MG, de Bruin-Bon RA, Huisman SA, van Dijk AP et al (2009) Six-minute walk test in patients with Down syndrome: validity and reproducibility. Arch Phys Med Rehabil 90:1423–1427

    Article  PubMed  Google Scholar 

  49. D’Alto M, Romeo E, Argiento P, D’Andrea A, Sarubbi B, Correra A et al (2013) Therapy for pulmonary arterial hypertension due to congenital heart disease and Down’s syndrome. Int J Cardiol 164:323–326

    Article  PubMed  Google Scholar 

  50. D’Alto M, Diller GP (2014) Pulmonary hypertension in adults with congenital heart disease and Eisenmenger syndrome: current advanced management strategies. Heart 100:1322–1328

    Article  PubMed  Google Scholar 

  51. Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R et al (2014) Response to letters regarding article “Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)”. Circulation 130:e110–e112

    Article  PubMed  Google Scholar 

  52. Enright PL, Sherrill DL (1998) Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med 158(5 Pt 1):1384–1387

    Article  CAS  PubMed  Google Scholar 

  53. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW et al (1985) The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 132:919–923

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Second University of Naples—Monaldi Hospital, Naples, Italy

    Michele D’Alto & Giovanni Maria Di Marco

Authors
  1. Michele D’Alto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giovanni Maria Di Marco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michele D’Alto .

Editor information

Editors and Affiliations

  1. Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital and Imperial College, London, United Kingdom

    Konstantinos Dimopoulos

  2. University Hospital, Münster, Germany

    Gerhard-Paul Diller

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

D’Alto, M., Di Marco, G.M. (2017). Eisenmenger Syndrome in Patients with Down Syndrome. In: Dimopoulos, K., Diller, GP. (eds) Pulmonary Hypertension in Adult Congenital Heart Disease. Congenital Heart Disease in Adolescents and Adults. Springer, Cham. https://doi.org/10.1007/978-3-319-46028-4_18

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-46028-4_18

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-46026-0

  • Online ISBN: 978-3-319-46028-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation