Inherited Structural Heart Diseases Associated with Arrhythmias: Defects in Laterality

  • Baruch S. Ticho
  • Richard Van Praagh
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 231)


The clinical presentation of patients with defects in the determination of laterality is extremely varied. Abnormalities can occur in 1) establishment of visceral and atrial situs resulting in situs inversus or heterotaxy, 2) looping of the cardiac tube resulting in ventricular inversion, and 3) positioning of the heart in the chest resulting in dextrocardia. These disorders are usually easily recognized, and can be associated with complex cardiac anomalies. Affected individuals may be completely asymptomatic or may present at any age with a broad range of severity of symptoms. Conduction defects occur most frequently in patients with heterotaxy or with “corrected” transposition of the great arteries. The clinical and conduction system manifestations of these diseases will be presented, followed by a discussion of the molecular and genetic bases for these disorders.


Ventricular Septal Defect Great Artery Situs Inversus Complete Heart Block Congenital Heart Block 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Splitt MR, Burn J, Goodship J. Defects in the determination of left-right asymmetry. J Med Genet 1996;33:498–503.PubMedCrossRefGoogle Scholar
  2. 2.
    Sapire DW, Ho SY, Anderson RH, Rigby ML. Diagnosis and significance of atrial isomerism. Am J Cardiol 1986;58:342–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Uemura H, Ho SY, Devine WA, Anderson RH. Analysis of visceral heterotaxy according to splenic status, appendage morphology, or both. Am J Cardiol 1995;76:846–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Van Praagh R. The anatomy of the heterotaxy syndromes: anomalies of right-left asymmetry with asplenia, polysplenia and a right-sided spleen. Gold, J ed., Montefiore Medical Center and the New York Society of Thoracic Surgery: State of the Art Review. 1999 (Course syllabus in press).Google Scholar
  5. 5.
    Van Praagh S, Santini F, Sanders SP. Cardiac malpositions with special emphasis on visceral heterotaxy (asplenia and polysplenia syndromes). In Fyler DC (ed): “Nadas’ Pediatric Cardiology.” Philadelphia: Hanley & Belfus, Inc., 1992, 589–608.Google Scholar
  6. 6.
    Wren C, Macartney FJ, Deanfield JE. Cardiac rhythm in atrial isomerism. Am J Cardiol 1987;59:1156–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Rossi L, Montella S, Frescura C, Thiene G. Congenital atrioventricular block in right atrial isomerism (asplenia). A case due to atrionodal discontinuity. Chest 1984;85:578–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Dickinson DF, Wilkinson JL, Anderson KR, Smith A, Ho SY, Anderson RH. The cardiac conduction system in situs ambiguus. Circulation 1979;59:879–85.PubMedCrossRefGoogle Scholar
  9. 9.
    Ih S, Fukuda K, Okada R, Saitoh S. The location and course of the atrioventricular conduction system in common atrioventricular orifice and in its related anomalies with transposition of the great arteries. Jpn Circ J 1983;47:1262–73.PubMedCrossRefGoogle Scholar
  10. 10.
    Wu MH, Wang JK, Lin JL, Lai LP, Lue HC, Young ML, Hsieh FJ. Supraventricular tachycardia in patients with right atrial isomerism. J Am Coll Cardiol 1998;32:773–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Levine JC, Walsh EP, Saul JP. Radiofrequency ablation of accessory pathways associated with congenital heart disease including heterotaxy syndrome. Am J Cardiol 1993;72:689–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Moller JH, Nakib A, Anderson RC, Edwards JE. Congenital cardiac disease associated with polysplenia, a developmental complex of bilateral ‘left-sidedness.’.Circulation 1967;36: 789–799.PubMedCrossRefGoogle Scholar
  13. 13.
    Rose V, Izukawa T, Moes CAF. Syndromes of asplenia and polysplenia: a review of cardiac and non-cardiac malformation in 60 cases with special reference to diagnosis and prognosis. Brit Heart J 1975;37:840–852.PubMedCrossRefGoogle Scholar
  14. 14.
    Momma K, Takao A, Shibata T. Characteristics and natural history of abnormal atrial rhythms in left isomerism. Am J Cardiol 1990;65:231–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Bharati S, Lev M. The course of the conduction system in dextrocardia. Circulation 1990;57:163–71.CrossRefGoogle Scholar
  16. 16.
    Garcia OL, Metha AV, Pickoff AS, Tamer DF, Ferrer PL, Wolff GS, Gelband H. Left isomerism and complete atrioventricular block: a report of six cases. Am J Cardiol 1981;48:1103–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Roguin N, Pelled B, Freundlich E, Yahalom M, Riss E. Atrioventricular block in situs ambiguus and left isomerism (polysplenia syndrome). PACE 1984;7:18–22.PubMedCrossRefGoogle Scholar
  18. 18.
    Ho SY, Fagg N, Anderson RH, Cook A, Allan L. Disposition of the atrioventricular conduction tissues in the heart with isomerism of the atrial appendages: its relation to congenital complete heart block. J Am Coll Cardiol 1992;20:904–10.PubMedCrossRefGoogle Scholar
  19. 19.
    Bjarke BB, Kidd BS. Proceedings: Congenitally corrected transposition of the great arteries: a clinical study of 101 cases. Br Heart J 1976;38:535.PubMedGoogle Scholar
  20. 20.
    Van Praagh R, Papagiannis J, Grunenfelder J, Bartram U, Martanovic P. Pathologic anatomy of corrected transposition of the great arteries: medical and surgical implications. Am Heart J 1998;135:772–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Connelly MS, Liu PP, Williams WG, Webb GD, Robertson P, McLaughlin PR. Congenitally corrected transposition of the great arteries in the adult: functional status and complications. J Am Coll Cardiol 1996;27:1238–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Presbitero P, Somerville J, Rabajoli F, Stone S, Conte MR. Corrected transposition of the great arteries without associated defects in adult patients: clinical profile and follow up. Br Heart J 1995;74:51–9.CrossRefGoogle Scholar
  23. 23.
    Bharati S, Rosen K, Steinfield L, Miller RA, Lev M. The anatomic substrate for preexcitation in corrected transposition. Circulation 1980;62:831–42.PubMedCrossRefGoogle Scholar
  24. 24.
    Benson DW Jr, Gallagher JJ, Oldham HN, Sealy WC, Sterba R, Spach MS. Corrected transposition with severe intracardiac deformities with Wolff-Parkinson-White syndrome in a child. Electrophysiologic investigation and surgical correction. Circulation 1980;61:1256–61.PubMedCrossRefGoogle Scholar
  25. 25.
    Daliento L, Corrado D, Buja G, John N, Nava A, Thiene G. Rhythm and conduction disturbances in isolated, congenitally corrected transposition of the great arteries. Am J Cardio 1986;58:314–8.CrossRefGoogle Scholar
  26. 26.
    Huhta JC, Maloney JD, Ritter DG, Ilstrup DM, Feldt RH. Complete atrioventricular block in patients with atrioventricular discordance. Circulation 1983;67:1374–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Gillette PC, Busch U, Mullins CE, McNamara DG. Electrophysiologic studies in patients with ventricular inversion and “corrected transposition”. Circulation 1979;60:939–45.PubMedCrossRefGoogle Scholar
  28. 28.
    Anderson RH, Becker AE, Arnold R, Wilkinson JL.The conducting tissues in congenitally corrected transposition. Circulation 50:911–23.Google Scholar
  29. 29.
    Smeenk RJ. Immunological aspects of congenital atrioventricular block. 1997. PACE 1974;20:2093–7.CrossRefGoogle Scholar
  30. 30.
    Yost HJ. Left-right development in Xenopus and zebrafish. Semin Cell Dev 1998;9:61–66.CrossRefGoogle Scholar
  31. 31.
    Levin M, Johnson RL, Stern CD, Kuehn M, Tabin C. A molecular pathway determining left-right asymmetry in chick embyogenesis. Cell 1995;82:803–814.PubMedCrossRefGoogle Scholar
  32. 32.
    Meno C, Shimono A, Saijoh Y, et al. Lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 1998;94:287–97.PubMedCrossRefGoogle Scholar
  33. 33.
    Hyatt BA, Lohr JL, Yost H.J. Initiation of verebrate left-right axis formation by maternal Vgl. Nature 1996;384:62–65.PubMedCrossRefGoogle Scholar
  34. 34.
    Isaac A, Sargent MG, Cooke J. Control of vertebrate left-right asymmetry by a Snail-related zinc finger gene. Science 1997;275:1301–1304.PubMedCrossRefGoogle Scholar
  35. 35.
    Supp DM, Brueckner M, Potter SS. Handed asymmetry in the mouse: understanding how things go right (or left) by studying how they go wrong. Semin Cell Dev Biol 1998;9:77–87.PubMedCrossRefGoogle Scholar
  36. 36.
    Supp DM, Witte DP, Potter SS, Brueckner M. Mutation of an axonemal dynein in the left-right asymmetry mouse mutant inversus viscerum. Nature 1997;389:963–966.PubMedCrossRefGoogle Scholar
  37. 37.
    Mochizuki T, Saijoh Y, Tsuchiya K, et al. Cloning of inv, a gene that controls left/right asymmetry and kidney development. Nature 1998;395:177–81.PubMedCrossRefGoogle Scholar
  38. 38.
    Morgan D, Turnpenny L, Goodship J, et al. Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse. Nat Genet 1998;20:149–56.PubMedCrossRefGoogle Scholar
  39. 39.
    Yokoyama T, Copeland NG, Jenkins NA, Montgomery CA, Elder FFB, Overbeek PA. Reversal of left-right asymetry: a situs inversus mutation. Science 1993;260:679–682.PubMedCrossRefGoogle Scholar
  40. 40.
    Oh SP, Li E. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 1997;11:1812–1826.PubMedCrossRefGoogle Scholar
  41. 41.
    Chang C, Wilson PA, Mathews LS, Hemmati-Brivanlou A. A Xenopus type I activin receptor mediates mesodermal but not neural specification during embryogenesis. Development 1997;124:827–837.PubMedGoogle Scholar
  42. 42.
    Schulte-Merker S, Smith JC, Dale L. Effects of truncated activin and FGF receptors and of follistatin on the inducing activities of Bvgl and activin: does activin play a role in mesoderm induction? EMBO J 1994; 13:3533–3541.PubMedGoogle Scholar
  43. 43.
    Nomura M, Li E. Roles for Smad2 in mesoderm formation, left-right patterning and craniofacial development in mice. Nature 1998;393:786–90.PubMedCrossRefGoogle Scholar
  44. 44.
    Lin AE,Ticho BS, Houde KK, Westgate MN, Holmes LB. Heterotaxy: Etiology and prevalence in a newborn population. Am J Human Genet 1998;63:A112.Google Scholar
  45. 45.
    Simpson J, Zellweger H. Familial occurrence of Ivemark syndrome with splenic hypoplasia and asplenia in sibs. J Med Genet 1973; 10:303–304.PubMedCrossRefGoogle Scholar
  46. 46.
    Hurwitz RC, Caskey, CT. Ivemark syndrome in siblings. Clin Genet 1982;22:7–11.PubMedCrossRefGoogle Scholar
  47. 47.
    Ruttenberg HD, Neufeld HN, Lucas RV, Carey LS, Adams P, Anderson RC, Edwards JE. Syndrome of congenital cardiac disease with asplenia. Am J Cardiol 1964;13:387–406.PubMedCrossRefGoogle Scholar
  48. 48.
    Chen SC, Monteleone PL. Familial splenic anomaly syndrome. J Pediat 1977;91:160–161.PubMedCrossRefGoogle Scholar
  49. 49.
    Hallett JJ, Gang DL, Holmes LB. Familial polysplenia and cardiovascular defects. Pediatr Res 1979; 13:344.Google Scholar
  50. 50.
    de la Monte SM, Hutchins GM. Sisters with polysplenia. Am J Med Genet 1985;21:171–173.PubMedCrossRefGoogle Scholar
  51. 51.
    Kawagoe K, Hara K, Jimbo T, Mizuno M, Sakamoto S. Occurrence of Ivemark syndrome with polysplenia in sibs of a family. Proc Jpn Acad 1980; 56 633–637.CrossRefGoogle Scholar
  52. 52.
    Niikawa N, Kohsaka S, Mizumoto M, Hamada I, Kajii T. Familial clustering of situs inversus totalis, and asplenia and polysplenia syndromes. Am J Med Genet 1983; 16:43–47.PubMedCrossRefGoogle Scholar
  53. 53.
    Arnold GL, Bixler D, Girod D. Probable autosomal recessive inheritance of polysplenia, situs inversus and cardiac defects in an Amish family. Am J Med Genet 1983;16:35–42.PubMedCrossRefGoogle Scholar
  54. 54.
    Polhemus DW, Schafer WB. Congenital absence of spleen; syndrome withatrioventricularis and situs inversus. Pediatrics 1952;9:696–708.PubMedGoogle Scholar
  55. 55.
    Zlotogora J, Elian E. Asplenia and polysplenia syndromes with abnormalities of lateralization in a sibship. J Med Genet 1981;301–302.Google Scholar
  56. 56.
    Kosaki R, Gebbia M, Kosaki K, Lewin M, Bowers P, Towbin JA, Casey B. Left-Right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet 1999;82:70–76.PubMedCrossRefGoogle Scholar
  57. 57.
    Casey B, Devoto M, Jones KL, Ballabio A. Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27.1. Nat Genet 1993;5:403–407.PubMedCrossRefGoogle Scholar
  58. 58.
    Gebbia M, Ferrero GB, Pilia G, et al B. X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 1997;17:305–308.PubMedCrossRefGoogle Scholar
  59. 59.
    Bassi MT, Kosaki K, Belmont J, Casey B. NODAL, LEFTY and HNF-3b nucleotide changes associated with complex heart defects and other features of left-right axis malformations. Am J Hum Genet 1997;61: A4.Google Scholar
  60. 60.
    Kosaki K, Casey B. Genetics of human left-right axis malformations. Semin Cell Dev Biol 1998;9:89–99.PubMedCrossRefGoogle Scholar
  61. 61.
    Kosaki K, Bassi MT, Kosaki R, Lewin M, Belmont J, Schauer G, Casey B. Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am J Hum Genet 1999;64:712–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Vogel G. Developmental biology. How to get a heart in the right place. Science 1999;285:23.PubMedCrossRefGoogle Scholar
  63. 63.
    Becker TA, Van Amber R, Moller JH, Pierpont ME. Occurrence of cardiac malformations in relatives of children with transposition of the great arteries. Am J Med Genet 1996;66:28–32.PubMedCrossRefGoogle Scholar
  64. 64.
    Rose V, Gold RJ, Lindsay G, Allen M. A possible increase in the incidence of congenital heart defects among the offspring of affected parents. J Am Coll Cardiol 1985;6:376–82.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Baruch S. Ticho
    • 1
  • Richard Van Praagh
    • 2
  1. 1.Massachusetts General HospitalBostonUSA
  2. 2.Children’s HospitalBostonUSA

Personalised recommendations