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Circulation Research. 2004;94:1401-1402
doi: 10.1161/01.RES.0000133233.38341.17
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*Congenital Heart Defects
(Circulation Research. 2004;94:1401.)
© 2004 American Heart Association, Inc.

Editorials

Only Our Patients Know for Sure

H. Scott Baldwin

From Vanderbilt Children’s Hospital, Nashville, Tenn.

Correspondence to H. Scott Baldwin, MD, Katrina Overall Professor, Professor of Pediatrics and Cell and Developmental Biology, Vice Chair for Laboratory Sciences in Pediatrics, Vanderbilt Children’s Hospital, B3307 MCN VUMC 1161 21st St South, Nashville, TN 37232-2495. E-mail Scott.Baldwin{at}vanderbilt.edu


Key Words: congenital heart disease • coarctation • contiguous gene deletion

Although congenital heart disease (CHD) is frequently associated with syndromes that affect multiple organs, the majority of cases present as isolated CHD, and typically defects are limited to a defined structure, suggesting a unique developmental mechanism. Despite the frequent occurrence of CHD, relatively few causative genes have been clearly identified (see review1). In this issue of Circulation Research, Christiansen et al2describe the occurrence of isolated (nonsyndromic) CHD in association with the deletion of a 1.5- to 3-mB region on chromosome 1q21.1 They suggest that the cardiac defects seen represent a contiguous gene deletion syndrome and cannot be explained by the deletion of any one gene located within the region. Notably, they present patients with isolated coarctation and interrupted aortic arch (IAA) type A.

But why does a contiguous gene hypothesis have to be invoked? In the three patients presented, a spectrum of left ventricular outflow tract obstruction, including subaortic stenosis and IAA, in addition to ventricular septal defect (VSD) and aortopulmonary window, is represented. All of these abnormalities have been experimentally linked to defects in neural crest ontogeny. Likewise, deletion of connexin40 (Cx40) in mice is associated with a high incidence of conotruncal abnormalities including Tetralogy of Fallot, double outlet right ventricle, and abnormal branching of the aortic arch.3,4 These similarly implicate abnormalities of neural crest migration.5

It would be tempting to try and unify the phenotypes observed by suggesting a single gene defect altering neural crest ontogeny. However, a closer look at the specific patient phenotypes observed makes primary neural crest defects, and exclusive Cx40 alterations, a bit difficult to conjecture. Although aortic arch vessel abnormalities have been described in the Cx40-null mice,3 none of the defects seen in the patients described by Christiansen et al were seen in the Cx40 KO mice. This suggests a potential modification of the phenotype by additional genes located within the deleted region of chromosome 1q21.1. Certainly IAA type B and occasionally IAA type C with VSD is associated with experimental neural crestopathies, as observed in several experimental models affecting cardiac neural crest including Sema-3C,6,7 Foxc1 and Foxc2,8,9 and components of the endothelin signaling cascade.10–12 But rarely, if ever, is IAA type A, as seen in this cohort of patients, detected in these animal models. This may coincide with the fact that cardiac neural crest is not thought to contribute to the smooth muscle investment of the aorta distal to the origin of the left subclavian artery, which demarcates the original 4th pharyngeal arch. Even more unique is the observation of discrete coarctation of the aorta. Although frequently seen in the human population, this phenotype has yet to be recapitulated in animal models. Original identification of the gridlock gene (also known as hey2, HRT2, CHF1, HERP1, and HESR2) in zebrafish13 raised speculation that this gene might explain isolated coarctation.14 However, mutations have not been identified in human patients. Subsequent deletion-mutations in the mouse suggested a more diffuse cardiovascular phenotype without coarctation,15–17 confirming a more wide spread role for the notch signaling pathway in cardiac development.

The phenotypes presented do, however, offer a potentially more intriguing explanation. If not a primary neural crest defect, what mechanistic process(es) might explain the defects seen? One attractive hypothesis is that coarctation of the aorta, and perhaps IAA type A, are lesions that merely reflect the most severe manifestations of a more diffuse arteriopathy related to altered endothelial-endothelial or endothelial–smooth muscle cell interactions, rather than to primary neural crest development.18 Although often thought to be an isolated lesion, 10% of patients with coarctation have intracranial lesions suggestive of more diffuse arterial defects. Recently, significant extrapulmonary vascular anomalies, including coarctation of the aorta, have been described in patients with Jagged-1 mutations or Alagille syndrome, highlighting this phenotype as consistent with a more diffuse alteration in the notch signaling pathway.19 Thus, coarctation and IAA type A would perhaps not be surprising given the observation that Cx40–/– mice have been shown to have a diffuse alteration in transmission of endothelium-dependent vasodilator responses.20 Although deletion of Cx40 alone may not be sufficient to cause arch obstruction, haploinsufficiency of Cx40 associated with attenuation of other genes (perhaps located in the 1q21.1 region) might be sufficient to result in a vasculopathy phenotype. Experimentally, the vasculature appears to be particularly vulnerable to alterations in gene dosage of multiple factors required for arterial and venous differentiation, as well as vascular remodeling.21–23 Likewise, defects in Cx40 null mice have been shown to be particularly sensitive to attenuation of other members of the connexin family.4 Although Cx50 is also deleted in the contiguous region, a specific interaction between Cx40 and Cx50 has yet to be identified.

Why does this matter? Most patients with coarctation or interrupted arch are repaired in early infancy and the etiology of the defects, either primary neural crest in origin or the result of a more diffuse vasculopathy (or a mixture of both) would appear to be of secondary concern after surgical repair. However, successful surgery does not alleviate all of the pathology. In fact, vascular dysfunction of large arteries is known to persist even after early repair in many children.24 Although early surgical intervention is known to decrease the prevalence of systemic hypertension, there remains an alarming subpopulation of children who are hypertensive at rest or during exercise despite the absence of residual obstruction.25,26 In this light, it is interesting to note the hypertensive phenotype described in Cx40-null mutant mice.27 Furthermore, there is a greater incidence of noncardiac abnormalities in patients with coarctation and VSD, as opposed to isolated coarctation28 and an increased incidence of cardiac lesions (particularly left sided obstructive lesions) in 1st degree relatives of patients with coarctation.29 However, it is currently impossible to determine which patients remain at risk for hypertensive complications, which patients will display extra cardiac abnormalities, and which patients’ siblings are more likely to have CHD. These are all issues that have direct implications for patient management, potentially affecting diagnosis, surgical repair, and postoperative care. While these are all concerns that might be explained by further mechanistic understanding of the specific etiology facilitated by animal studies, animal models are likely to provide only partial information on the pathology that involves multiple gene interactions. For these conditions, we must rely on our patients to point us in the right direction as only they know for sure which gene interactions are relevant to CHD. This information will only be accessible through precise phenotypic description and detailed genetic analysis. As evidenced by the work of Christiansen et al,2 our patients may be giving us subtle hints that must be further investigated.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. Gruber PJ, Epstein JA. Development gone awry: congenital heart disease. Circ Res. 2004; 94: 273–283.[Abstract/Free Full Text]
  2. Christiansen J, Dyck JD, Elyas BG, Lilley M, Bamforth JS, Hicks M, Sprysak KA, Tomaszewski R, Haase SM, Vicen-Wyhony LM, Somerville MJ. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ Res. 2004; 94: 1429–1435.[Abstract/Free Full Text]
  3. Gu H, Smith FC, Taffet SM, Delmar M. High incidence of cardiac malformations in connexin40-deficient mice. Circ Res. 2003; 93: 201–206.[Abstract/Free Full Text]
  4. Kirchhoff S, Kim JS, Hagendorff A, Thonnissen E, Kruger O, Lamers WH, Willecke K. Abnormal cardiac conduction and morphogenesis in connexin40 and connexin43 double-deficient mice. Circ Res. 2000; 87: 399–405.[Abstract/Free Full Text]
  5. Maschhoff KL, Baldwin HS. Molecular determinants of neural crest migration. Am J Med Genet. 2000; 97: 280–288.[CrossRef][Medline] [Order article via Infotrieve]
  6. Feiner L, Webber AL, Brown CB, Lu MM, Jia L, Feinstein P, Mombaerts P, Epstein JA, Raper JA. Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development. 2001; 128: 3061–3070.[Abstract/Free Full Text]
  7. Brown CB, Feiner L, Lu MM, Li J, Ma X, Webber AL, Jia L, Raper JA, Epstein JA. PlexinA2 and semaphorin signaling during cardiac neural crest development. Development. 2001; 128: 3071–3080.[Abstract/Free Full Text]
  8. Iida K, Koseki H, Kakinuma H, Kato N, Mizutani-Koseki Y, Ohuchi H, Yoshioka H, Noji S, Kawamura K, Kataoka Y, Ueno F, Taniguchi M, Yoshida N, Sugiyama T, Miura N. Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. Development. 1997; 124: 4627–4638.[Abstract]
  9. Kume T, Jiang H, Topczewska JM, Hogan BL. The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis. Genes Dev. 2001; 15: 2470–2482.[Abstract/Free Full Text]
  10. Yanagisawa H, Hammer RE, Richardson JA, Williams SC, Clouthier DE, Yanagisawa M. Role of Endothelin-1/Endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice. J Clin Invest. 1998; 102: 22–33.[Medline] [Order article via Infotrieve]
  11. Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, de Wit D, Emoto N, Hammer RE. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development. 1998; 125: 825–836.[Abstract]
  12. Clouthier DE, Hosoda K, Richardson JA, Williams SC, Yanagisawa H, Kuwaki T, Kumada M, Hammer RE, Yanagisawa M. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development. 1998; 125: 813–824.[Abstract]
  13. Weinstein BM, Stemple DL, Driever W, Fishman MC. Gridlock, a localized heritable vascular patterning defect in the zebrafish. Nat Med. 1995; 1: 1143–1147.[CrossRef][Medline] [Order article via Infotrieve]
  14. Towbin JA, McQuinn TC. Gridlock: a model for coarctation of the aorta? Nat Med. 1995; 1: 1141–1142.[CrossRef][Medline] [Order article via Infotrieve]
  15. Gessler M, Knobeloch KP, Helisch A, Amann K, Schumacher N, Rohde E, Fische r A, Leimeister C. Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2–/– mice. Curr Biol. 2002; 12: 1601–1604.[CrossRef][Medline] [Order article via Infotrieve]
  16. Donovan J, Kordylewska A, Jan YN, Utset MF. Tetralogy of Fallot and other congenital heart defects in Hey2 mutant mice. Curr Biol. 2002; 12: 1605–1610.[CrossRef][Medline] [Order article via Infotrieve]
  17. Sakata Y, Kamei CN, Nakagami H, Bronson R, Liao JK, Chin MT. Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Proc Natl Acad Sci U S A. 2002; 99: 16197–16202.[Abstract/Free Full Text]
  18. Warnes CA. Bicuspid aortic valve and coarctation: two villains part of a diffuse problem. Heart. 2003; 89: 965–966.[Free Full Text]
  19. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, Krantz ID. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation. 2004; 109: 1354–1358.[Abstract/Free Full Text]
  20. de Wit C, Roos F, Bolz SS, Kirchhoff S, Kruger O, Willecke K, Pohl U. Impaired conduction of vasodilation along arterioles in connexin40-deficient mice. Circ Res. 2000; 86: 649–655.[Abstract/Free Full Text]
  21. Zhong TP, Childs S, Leu JP, Fishman MC. Gridlock signalling pathway fashions the first embryonic artery. Nature. 2001; 414: 216–220.[CrossRef][Medline] [Order article via Infotrieve]
  22. Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC. Gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science. 2000; 287: 1820–1824.[Abstract/Free Full Text]
  23. Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev. 2004; 18: 901–911.[Abstract/Free Full Text]
  24. de Divitiis M, Pilla C, Kattenhorn M, Zadinello M, Donald A, Leeson P, Wallace S, Redington A, Deanfield JE. Vascular dysfunction after repair of coarctation of the aorta: impact of early surgery. Circulation. 2001; 104: I165–I170.[Medline] [Order article via Infotrieve]
  25. de Divitiis M, Pilla C, Kattenhorn M, Donald A, Zadinello M, Wallace S, Redington A, Deanfield J. Ambulatory blood pressure, left ventricular mass, and conduit artery function late after successful repair of coarctation of the aorta. J Am Coll Cardiol. 2003; 41: 259–265.
  26. O’Sullivan JJ, Derrick G, Darnell R. Prevalence of hypertension in children after early repair of coarctation of the aorta: a cohort study using casual and 24 hour blood pressure measurement. Heart. 2002; 88: 163–166.[Abstract/Free Full Text]
  27. de Wit C, Roos F, Bolz SS, Pohl U. Lack of vascular connexin 40 is associated with hypertension and irregular arteriolar vasomotion. Physiol Genomics. 2003; 13: 169–177.[Abstract/Free Full Text]
  28. Wollins DS, Ferencz C, Boughman JA, Loffredo CA. A population-based study of coarctation of the aorta: comparisons of infants with and without associated ventricular septal defect. Teratology. 2001; 64: 229–236.[CrossRef][Medline] [Order article via Infotrieve]
  29. Loffredo CA, Chokkalingam A, Sill AM, Boughman JA, Clark EB, Scheel J, Brenner JI. Prevalence of congenital cardiovascular malformations among relatives of infants with hypoplastic left heart, coarctation of the aorta, and d-transposition of the great arteries. Am J Med Genet. 2004; 24A: 225–230.[CrossRef]




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*Congenital Heart Defects

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