- Email: [email protected]
Hypoplastic Left Heart Syndrome
Journal of the American College of Cardiology © 2009 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Hypoplastic Left Heart Syndrome New Genetic Insights* Paul Grossfeld, MD,† Maoqing Ye, MD, PHD,† Richard Harvey, PHD‡§ San Diego, California; and Darlinghurst and Kensington, Australia
Hypoplastic left heart syndrome (HLHS) is a severe, uniformly fatal congenital heart defect typically characterized by hypoplasia of the left ventricular chamber and aorta in association with stenosis and/or atresia of the mitral and aortic valves (1). Since the original description of HLHS over 150 years ago (2), there has been extraordinary progress in the management of this congenital heart lesion. Surgery usually involves the 3-staged Norwood procedure, which ultimately results in a 2-chamber heart in which the right ventricle functions as the systemic ventricle. In carefully selected patients, the current 5-year survival now approaches 90% (3). However, the long-term outcome for these patients is unknown, and the surgical strategy can still only be considered palliative. See page 1065
Mechanistically, left-sided heart defects have been classified as so-called flow defects. Developmentally, chamber growth is intimately coupled to flow and/or other biophysical properties of heart function, and it is therefore likely that the final heart form is generated at least in part, by flow itself. It has been hypothesized that any lesion that compromises blood flow into or out of the developing left ventricle will cause, with graded severity, hypoplasia of the left-sided structures (4). Potentially, genetic mutations that impair normal prograde flow through the developing left ventricle could cause left-sided heart defects. As an example, clinically, there is a well-known association between the presence of ventricular septal defects and aortic arch hypoplasia (5). This has led to the hypothesis that aortic arch *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the †Division of Cardiology, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California; ‡Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and the §Faculties of Medicine and Science, University of New South Wales, Kensington, Australia.
Vol. 53, No. 12, 2009 ISSN 0735-1097/09/$36.00 doi:10.1016/j.jacc.2008.12.024
hypoplasia arises secondarily from decreased prograde blood flow to the ascending aorta, due to “steal” from the left side as a result of left-to-right shunting of blood across the ventricular septal defect. In mice, genetic and surgical interruption of blood flow through the outflow tract to the branchial arch arteries leads to abnormal branchial arch remodeling (6). Genetically engineered mice that have a large ventricular septal defect also demonstrate aortic arch hypoplasia (7), but only in some genetic backgrounds, suggesting differential genetic sensitivity to the flow effect. Therefore, identification of genes for HLHS will likely provide much needed insights into the primary mechanisms underlying the development of left-sided structures of the heart, including flow-responsive programs. There has been a growing body of evidence supporting a genetic etiology for left-sided heart defects, including HLHS. Initially, case reports described familial recurrences of HLHS, with autosomal dominant, recessive, and X-linked modes of inheritance, and variable penetrance and phenotype (4). Subsequent studies employing a systematic analysis by echocardiography demonstrated that there was likely to be a strong genetic component for HLHS (8,9). Because there was a spectrum of severity of left-sided defects occurring in affected family members (ranging from HLHS to bicuspid aortic valve [BAV]), it has been hypothesized that left-sided heart defects can be due to a common genetic etiology. More recently, statistical analyses on families with HLHS and BAV provided evidence implicating a predominantly genetic etiology (10,11). There is now strong evidence implicating multiple genetic loci for HLHS (4). Specifically, HLHS has been associated with trisomy 13, trisomy 18, chromosome X (XO, Turner syndrome), and deletion of distal 11q (Jacobsen syndrome) (12). Potential mutations in at least 4 genes—GJA1 (Connexin43, 6q22) (13), NKX2-5 (5q35) (14,15), NOTCH1 (9q34) (16), and HAND1 (5q33) (17)— have been associated with HLHS. Taken together, it is clear that HLHS and left-sided heart defects as a group are a genetically heterogeneous set of disorders. In this issue of the Journal, Hinton et al. (18) provide further evidence for genetic heterogeneity for HLHS. Specifically, they performed a genomewide nonparametric linkage analysis on 33 families with at least 1 affected member with HLHS. They identified 2 chromosomal loci implicated in disease-causation for HLHS, with another 5 loci being suggestive. Four families contributed to the identification of both loci, which is consistent with complex inheritance of HLHS. One suggestive HLHS locus was also associated with BAV in a separate group of families. Although no obvious candidate genes were identified within these loci, the analysis will hopefully lead to the identification of additional disease-causing genes for HLHS and BAV and ultimately provide important new insights into the pathogenesis of these lesions. At least 2 questions arise from the results of Hinton et al. (18). First, why were only 2 definitive loci identified, given
Grossfeld et al. Hypoplastic Left Heart Syndrome
JACC Vol. 53, No. 12, 2009 March 24, 2009:1072–4
the previous evidence implicating numerous loci? Second, why did HLHS and BAV share linkage with only 1 common locus? As described earlier, there is convincing evidence implicating as many as 8 other loci for HLHS and/or BAV, and none of these were identified by Hinton et al. (18). The most obvious explanation is that the number of families studied was insufficient to identify more loci, even though they likely exist. The careful and comprehensive phenotyping that was performed by echocardiography on over 1,000 patients demonstrates the anatomic variability of HLHS. Consequently, the anatomic subtypes could be due to the magnitude of genetic heterogeneity and could explain why more loci were not identified in this relatively small family grouping. To answer the second question, there are at least 2 possible explanations. First, in some cases, a single gene mutation may be sufficient to cause BAV and HLHS in the same family, as for the 14q23 locus identified by Hinton et al. (18), with the specific phenotype being determined ultimately by genetic or epigenetic modifiers, and/or environmental influences. In that case, then 1 possibility is that not enough families were analyzed. Second, it is noteworthy that BAV is very common (1% of the general population), is a risk factor for aortic valve disease, and is known to have a complex and heterogeneous genetic etiology. Clearly, only a small subset of BAVs in utero, possibly those that are the most restrictive, progress to HLHS. Even so, the fact that there can be isolated aortic valve atresia with a normal left ventricle suggests that there are distinct genetic factors for aortic valve defects and susceptibility to HLHS. Given the heterogeneous origins of BAV unselected for functional severity in utero, distinct loci for HLHS and BAV might be predicted to be the predominant outcome. Implications for therapies. One of the challenges in the management of some patients with left-sided heart defects is the decision to proceed with a 1- versus 2-ventricle repair for patients with mild left ventricular hypoplasia. Studies have demonstrated that in a subset of patients with left ventricle hypoplasia, the ventricle is capable of postnatal growth (19). Consequently, identification of the specific genetic cause in such patients may lead to a stratification scheme that could facilitate the selection of patients for a 1versus 2-ventricle repair. Currently, there are no medical cures for HLHS. Although the idea of treating HLHS with drug therapies in the future seems remote, the pioneering work by Brooke et al. (20) on Marfan syndrome is a case in point for how the identification of a genetic cause of a structural heart abnormality can lead to potential medical therapies that might replace current surgical approaches. Furthermore, some centers are exploring fetal intervention for HLHS. Based on the progressive nature of the defect in utero and the possibility of early diagnosis at fetal stages, correction of the obstructive lesion by ultrasound-guided balloon angioplasty may stimulate left ventricular growth (21,22). Understand-
1073
ing the genetics of HLHS may aid significantly in the decision-making processes related to this intervention. Future directions. The identification of new loci for HLHS is exciting. Nonetheless, the challenges that lie ahead to identify specific disease-causing genes for HLHS are immense. Identification of the HLHS disease-causing gene(s) among 300 potential candidates identified is a daunting task that will likely require years of further investigation. Regardless, because of the rigorous studies by Hinton et al. (18) and others, there is cause for hope for improving the outcome of this devastating congenital heart defect. Reprint requests and correspondence: Dr. Paul Grossfeld, University of California, 3020 Children’s Way, MC 5004, San Diego, California 92123. E-mail: [email protected].
REFERENCES
1. Lev M. Pathologic anatomy and interrelationship of hypoplasia of the aortic tract complexes. Lab Invest 1952;1:61–7. 2. Gehrmann J, Krasemann T, Kehl HG, Vogt J. Hypoplastic left-heart syndrome: the first description of the pathophysiology in 1851; translation of a publication by Dr. Bardeleben from Giessen, Germany. Chest 2001;120:1368 –71. 3. Pigula FA, Vida V, Del Nido P, Bacha E. Contemporary results and current strategies in the management of hypoplastic left heart syndrome. Semin Thorac Cardiovasc Surg 2007;19:238 – 44. 4. Grossfeld PD. The genetics of hypoplastic left heart syndrome. Cardiol Young 1999;9:627– 63. 5. Anderson RH, Lenox CC, Zuberbuhler JR. Morphology of ventricular septal defect associated with coarctation of aorta. Br Heart J 1983;50:176 – 81. 6. Yashiro K, Shiratori H, Hamada H. Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 2007;450:285– 8. 7. High FA, Zhang M, Proweller A, et al. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. J Clin Invest 2007;117:353– 63. 8. Loffredo CA. Epidemiology of cardiovascular malformations: prevalence and risk factors. Am J Med Genet 2000;97:319 –25. 9. Lewin MB, McBride KL, Pignatelli R, et al. Echocardiographic evaluation of asymptomatic parental and sibling cardiovascular anomalies associated with congenital left ventricular outflow tract lesions. Pediatrics 2004;114:691– 6. 10. Hinton RB Jr., Martin LJ, Tabangin ME, Mazwi ML, Cripe LH, Benson DW. Hypoplastic left heart syndrome is heritable. J Am Coll Cardiol 2007;50:1590 –5. 11. Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. Bicuspid aortic valve is heritable. J Am Coll Cardiol 2004;44:138 – 43. 12. Grossfeld PD, Mattina T, Lai Z, et al. The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Genet A 2004;129:51– 61. 13. Dasgupta C, Martinez AM, Zuppan CW, Shah MM, Bailey LL, Fletcher WH. Identification of connexin43 (alpha1) gap junction gene mutations in patients with hypoplastic left heart syndrome by denaturing gradient gel electrophoresis (DGGE). Mutat Res 2001;479: 173– 86. 14. Elliott DA, Kirk EP, Yeoh T, et al. Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Cardiol 2003;41:2072– 6. 15. McElhinney DB, Geiger E, Blinder J, Benson DW, Goldmuntz E. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 2003;42:1650 –5. 16. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005;437:270 – 4.
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Grossfeld et al. Hypoplastic Left Heart Syndrome
17. Reamon-Buettner SM, Ciribilli Y, Inga A, Borlak J. A loss-offunction mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts. Hum Mol Genet 2008;17:1397– 405. 18. Hinton RB, Martin LJ, Rame-Gowda S, Tabangin ME, Cripe LH, Benson DW. Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. J Am Coll Cardiol 2009;53:1065–71. 19. Minich LL, Tani LY, Hawkins JA, Shaddy RE. Possibility of postnatal left ventricular growth in selected infants with non-apexforming left ventricles. Am Heart J 1997;133:570 – 4.
JACC Vol. 53, No. 12, 2009 March 24, 2009:1072–4 20. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med 2008;358:2787–9. 21. Kohl T, Sharland G, Allan LD, et al. World experience of percutaneous ultrasound-guided balloon valvuloplasty in human fetuses with severe aortic valve obstruction. Am J Cardiol 2000;85:1230 –3. 22. Makikallio K, McElhinney DB, Levine JC, et al. Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention. Circulation 2006;113:1401–5. Key Words: genetics y heart valves y cardiovascular malformation.
EDITORIAL COMMENT
Hypoplastic Left Heart Syndrome New Genetic Insights* Paul Grossfeld, MD,† Maoqing Ye, MD, PHD,† Richard Harvey, PHD‡§ San Diego, California; and Darlinghurst and Kensington, Australia
Hypoplastic left heart syndrome (HLHS) is a severe, uniformly fatal congenital heart defect typically characterized by hypoplasia of the left ventricular chamber and aorta in association with stenosis and/or atresia of the mitral and aortic valves (1). Since the original description of HLHS over 150 years ago (2), there has been extraordinary progress in the management of this congenital heart lesion. Surgery usually involves the 3-staged Norwood procedure, which ultimately results in a 2-chamber heart in which the right ventricle functions as the systemic ventricle. In carefully selected patients, the current 5-year survival now approaches 90% (3). However, the long-term outcome for these patients is unknown, and the surgical strategy can still only be considered palliative. See page 1065
Mechanistically, left-sided heart defects have been classified as so-called flow defects. Developmentally, chamber growth is intimately coupled to flow and/or other biophysical properties of heart function, and it is therefore likely that the final heart form is generated at least in part, by flow itself. It has been hypothesized that any lesion that compromises blood flow into or out of the developing left ventricle will cause, with graded severity, hypoplasia of the left-sided structures (4). Potentially, genetic mutations that impair normal prograde flow through the developing left ventricle could cause left-sided heart defects. As an example, clinically, there is a well-known association between the presence of ventricular septal defects and aortic arch hypoplasia (5). This has led to the hypothesis that aortic arch *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the †Division of Cardiology, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California; ‡Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and the §Faculties of Medicine and Science, University of New South Wales, Kensington, Australia.
Vol. 53, No. 12, 2009 ISSN 0735-1097/09/$36.00 doi:10.1016/j.jacc.2008.12.024
hypoplasia arises secondarily from decreased prograde blood flow to the ascending aorta, due to “steal” from the left side as a result of left-to-right shunting of blood across the ventricular septal defect. In mice, genetic and surgical interruption of blood flow through the outflow tract to the branchial arch arteries leads to abnormal branchial arch remodeling (6). Genetically engineered mice that have a large ventricular septal defect also demonstrate aortic arch hypoplasia (7), but only in some genetic backgrounds, suggesting differential genetic sensitivity to the flow effect. Therefore, identification of genes for HLHS will likely provide much needed insights into the primary mechanisms underlying the development of left-sided structures of the heart, including flow-responsive programs. There has been a growing body of evidence supporting a genetic etiology for left-sided heart defects, including HLHS. Initially, case reports described familial recurrences of HLHS, with autosomal dominant, recessive, and X-linked modes of inheritance, and variable penetrance and phenotype (4). Subsequent studies employing a systematic analysis by echocardiography demonstrated that there was likely to be a strong genetic component for HLHS (8,9). Because there was a spectrum of severity of left-sided defects occurring in affected family members (ranging from HLHS to bicuspid aortic valve [BAV]), it has been hypothesized that left-sided heart defects can be due to a common genetic etiology. More recently, statistical analyses on families with HLHS and BAV provided evidence implicating a predominantly genetic etiology (10,11). There is now strong evidence implicating multiple genetic loci for HLHS (4). Specifically, HLHS has been associated with trisomy 13, trisomy 18, chromosome X (XO, Turner syndrome), and deletion of distal 11q (Jacobsen syndrome) (12). Potential mutations in at least 4 genes—GJA1 (Connexin43, 6q22) (13), NKX2-5 (5q35) (14,15), NOTCH1 (9q34) (16), and HAND1 (5q33) (17)— have been associated with HLHS. Taken together, it is clear that HLHS and left-sided heart defects as a group are a genetically heterogeneous set of disorders. In this issue of the Journal, Hinton et al. (18) provide further evidence for genetic heterogeneity for HLHS. Specifically, they performed a genomewide nonparametric linkage analysis on 33 families with at least 1 affected member with HLHS. They identified 2 chromosomal loci implicated in disease-causation for HLHS, with another 5 loci being suggestive. Four families contributed to the identification of both loci, which is consistent with complex inheritance of HLHS. One suggestive HLHS locus was also associated with BAV in a separate group of families. Although no obvious candidate genes were identified within these loci, the analysis will hopefully lead to the identification of additional disease-causing genes for HLHS and BAV and ultimately provide important new insights into the pathogenesis of these lesions. At least 2 questions arise from the results of Hinton et al. (18). First, why were only 2 definitive loci identified, given
Grossfeld et al. Hypoplastic Left Heart Syndrome
JACC Vol. 53, No. 12, 2009 March 24, 2009:1072–4
the previous evidence implicating numerous loci? Second, why did HLHS and BAV share linkage with only 1 common locus? As described earlier, there is convincing evidence implicating as many as 8 other loci for HLHS and/or BAV, and none of these were identified by Hinton et al. (18). The most obvious explanation is that the number of families studied was insufficient to identify more loci, even though they likely exist. The careful and comprehensive phenotyping that was performed by echocardiography on over 1,000 patients demonstrates the anatomic variability of HLHS. Consequently, the anatomic subtypes could be due to the magnitude of genetic heterogeneity and could explain why more loci were not identified in this relatively small family grouping. To answer the second question, there are at least 2 possible explanations. First, in some cases, a single gene mutation may be sufficient to cause BAV and HLHS in the same family, as for the 14q23 locus identified by Hinton et al. (18), with the specific phenotype being determined ultimately by genetic or epigenetic modifiers, and/or environmental influences. In that case, then 1 possibility is that not enough families were analyzed. Second, it is noteworthy that BAV is very common (1% of the general population), is a risk factor for aortic valve disease, and is known to have a complex and heterogeneous genetic etiology. Clearly, only a small subset of BAVs in utero, possibly those that are the most restrictive, progress to HLHS. Even so, the fact that there can be isolated aortic valve atresia with a normal left ventricle suggests that there are distinct genetic factors for aortic valve defects and susceptibility to HLHS. Given the heterogeneous origins of BAV unselected for functional severity in utero, distinct loci for HLHS and BAV might be predicted to be the predominant outcome. Implications for therapies. One of the challenges in the management of some patients with left-sided heart defects is the decision to proceed with a 1- versus 2-ventricle repair for patients with mild left ventricular hypoplasia. Studies have demonstrated that in a subset of patients with left ventricle hypoplasia, the ventricle is capable of postnatal growth (19). Consequently, identification of the specific genetic cause in such patients may lead to a stratification scheme that could facilitate the selection of patients for a 1versus 2-ventricle repair. Currently, there are no medical cures for HLHS. Although the idea of treating HLHS with drug therapies in the future seems remote, the pioneering work by Brooke et al. (20) on Marfan syndrome is a case in point for how the identification of a genetic cause of a structural heart abnormality can lead to potential medical therapies that might replace current surgical approaches. Furthermore, some centers are exploring fetal intervention for HLHS. Based on the progressive nature of the defect in utero and the possibility of early diagnosis at fetal stages, correction of the obstructive lesion by ultrasound-guided balloon angioplasty may stimulate left ventricular growth (21,22). Understand-
1073
ing the genetics of HLHS may aid significantly in the decision-making processes related to this intervention. Future directions. The identification of new loci for HLHS is exciting. Nonetheless, the challenges that lie ahead to identify specific disease-causing genes for HLHS are immense. Identification of the HLHS disease-causing gene(s) among 300 potential candidates identified is a daunting task that will likely require years of further investigation. Regardless, because of the rigorous studies by Hinton et al. (18) and others, there is cause for hope for improving the outcome of this devastating congenital heart defect. Reprint requests and correspondence: Dr. Paul Grossfeld, University of California, 3020 Children’s Way, MC 5004, San Diego, California 92123. E-mail: [email protected].
REFERENCES
1. Lev M. Pathologic anatomy and interrelationship of hypoplasia of the aortic tract complexes. Lab Invest 1952;1:61–7. 2. Gehrmann J, Krasemann T, Kehl HG, Vogt J. Hypoplastic left-heart syndrome: the first description of the pathophysiology in 1851; translation of a publication by Dr. Bardeleben from Giessen, Germany. Chest 2001;120:1368 –71. 3. Pigula FA, Vida V, Del Nido P, Bacha E. Contemporary results and current strategies in the management of hypoplastic left heart syndrome. Semin Thorac Cardiovasc Surg 2007;19:238 – 44. 4. Grossfeld PD. The genetics of hypoplastic left heart syndrome. Cardiol Young 1999;9:627– 63. 5. Anderson RH, Lenox CC, Zuberbuhler JR. Morphology of ventricular septal defect associated with coarctation of aorta. Br Heart J 1983;50:176 – 81. 6. Yashiro K, Shiratori H, Hamada H. Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 2007;450:285– 8. 7. High FA, Zhang M, Proweller A, et al. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. J Clin Invest 2007;117:353– 63. 8. Loffredo CA. Epidemiology of cardiovascular malformations: prevalence and risk factors. Am J Med Genet 2000;97:319 –25. 9. Lewin MB, McBride KL, Pignatelli R, et al. Echocardiographic evaluation of asymptomatic parental and sibling cardiovascular anomalies associated with congenital left ventricular outflow tract lesions. Pediatrics 2004;114:691– 6. 10. Hinton RB Jr., Martin LJ, Tabangin ME, Mazwi ML, Cripe LH, Benson DW. Hypoplastic left heart syndrome is heritable. J Am Coll Cardiol 2007;50:1590 –5. 11. Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. Bicuspid aortic valve is heritable. J Am Coll Cardiol 2004;44:138 – 43. 12. Grossfeld PD, Mattina T, Lai Z, et al. The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Genet A 2004;129:51– 61. 13. Dasgupta C, Martinez AM, Zuppan CW, Shah MM, Bailey LL, Fletcher WH. Identification of connexin43 (alpha1) gap junction gene mutations in patients with hypoplastic left heart syndrome by denaturing gradient gel electrophoresis (DGGE). Mutat Res 2001;479: 173– 86. 14. Elliott DA, Kirk EP, Yeoh T, et al. Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Cardiol 2003;41:2072– 6. 15. McElhinney DB, Geiger E, Blinder J, Benson DW, Goldmuntz E. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 2003;42:1650 –5. 16. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005;437:270 – 4.
1074
Grossfeld et al. Hypoplastic Left Heart Syndrome
17. Reamon-Buettner SM, Ciribilli Y, Inga A, Borlak J. A loss-offunction mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts. Hum Mol Genet 2008;17:1397– 405. 18. Hinton RB, Martin LJ, Rame-Gowda S, Tabangin ME, Cripe LH, Benson DW. Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. J Am Coll Cardiol 2009;53:1065–71. 19. Minich LL, Tani LY, Hawkins JA, Shaddy RE. Possibility of postnatal left ventricular growth in selected infants with non-apexforming left ventricles. Am Heart J 1997;133:570 – 4.
JACC Vol. 53, No. 12, 2009 March 24, 2009:1072–4 20. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med 2008;358:2787–9. 21. Kohl T, Sharland G, Allan LD, et al. World experience of percutaneous ultrasound-guided balloon valvuloplasty in human fetuses with severe aortic valve obstruction. Am J Cardiol 2000;85:1230 –3. 22. Makikallio K, McElhinney DB, Levine JC, et al. Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention. Circulation 2006;113:1401–5. Key Words: genetics y heart valves y cardiovascular malformation.