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than 28 weeks gestation. Arch Dis Child Fetal Neonatal Ed 2001; 84:F106-F110.

SUPPORT Study Group of the Eunice Kennedy Shriver NICHD 4. Neonatal Research Network. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010;362:1959-69.

Idem.5. Early CPAP versus surfactant in extremely preterm in-fants. N Engl J Med 2010;362:1970-9.

Walsh MC, Yao Q, Gettner P, et al. Impact of a physiologic 6. definition on bronchopulmonary dysplasia rates. Pediatrics 2004; 114:1305-11.

Clucas L, Doyle LW, Dawson J, Donath S, Davis PG. Compli-7. ance with alarm limits for pulse oximetry in very preterm in-fants. Pediatrics 2007;119:1056-60.

Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of the 8.

National Institutes of Health consensus definition of broncho-pulmonary dysplasia. Pediatrics 2005;116:1353-60.

Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxy-9. gen-saturation targets and outcomes in extremely preterm in-fants. N Engl J Med 2003;349:959-67.

Sterne JA, Davey Smith G. Sifting the evidence whats 10. wrong with significance tests? BMJ 2001;322:226-31.

Bolton DP, Cross KW. Further observations on cost of pre-11. venting retrolental fibroplasia. Lancet 1974;1:445-8.

Chow LC, Wright KW, Sola A. Can changes in clinical 12. practice decrease the incidence of severe retinopathy of prema-turity in very low birth weight infants? Pediatrics 2003;111:339-45.Copyright 2010 Massachusetts Medical Society.

Hypoplastic Left Heart SyndromeCarolyn A. Bondy, M.D.

Just 30 years ago, the newborn with hypoplastic left heart syndrome faced certain death. This con-genital defect involves a rudimentary mitral valve and left ventricle, coupled with a hypoplastic aor-tic valve and ascending aorta.1 Multistage surgical remediation of hypoplastic left heart syndrome, introduced in the 1980s, has led to survival rates that exceed 60%, and in this issue of the Journal, Ohye et al. report a further survival benefit with the use of a newly developed shunt.2

The fetus with hypoplastic left heart is able to survive until birth because of the unique fetal circulatory pattern. In the fetus with hypoplas-tic left heart syndrome, since fetal blood is oxy-genated by the placenta, the right-heart and pul-monary circulation is usually sidetracked before birth, so the right heart may pinch hit for the left to serve the systemic circulation. Oxygenat-ed blood entering the left atrium crosses the fo-ramen ovale to the right heart and is pumped into the pulmonary artery. This blood then by-passes the defective ascending aorta and reaches the systemic circulation via a dilated ductus arte-riosus (see Fig. 1 of the article by Ohye et al.2). Birth is a catastrophic event in hypoplastic left heart syndrome. Under normal circumstances, the foramen ovale and ductus close at birth to allow the newborns blood to be oxygenated by means of the pulmonary circulation. In newborns with hypoplastic left heart syndrome, however, these changes effectively shut down the systemic circulation, causing right heart failure and death within a few days.

Hypoplastic left heart syndrome is a genetically heterogeneous disorder that affects 1 in 5000 live

births.3 About one third of cases occur in the context of a recognized genetic disorder such as Turners syndrome (in which all or major parts of one sex chromosome are deleted) or Jacobsens syndrome (in which the terminal part of 11q is deleted) or in the context of a monogenic disor-der such as Noonans or HoltOrams syndrome. Screening studies involving family members of nonsyndromic probands with hypoplastic left heart syndrome suggest that heritability is com-plex, encompassing various left ventricular out-flow tract defects, and no single disease-causing gene or pathway has as yet been identified.4

In the early 1980s, Norwood and colleagues at the Childrens Hospital of Philadelphia pio-neered a three-stage surgical intervention for hy-poplastic left heart syndrome.5 Their goal was to establish a right-heartbased systemic circulation, using the Fontan procedure to create a separate pulmonary circulation, in which venous blood returns passively to the lungs. The first stage, known as the Norwood procedure, is the most difficult to perform and is associated with a high risk of death; it must be undertaken soon after birth to save the infants life and prevent dam-age to the right heart and pulmonary vasculature. The procedure involves excising the atrial sep-tum, so that oxygenated blood entering the left atrium crosses to the right heart; remodeling the ascending aorta, which is then patched into the proximal pulmonary artery, allowing the right ventricle to drive the systemic circulation; and establishing a separate conduit to deliver blood from the right ventricle to the pulmonary circu-lation.

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editorials

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In the original Norwood procedure (stage I), a systemicpulmonary shunt (the modified Bla lockTaussig [MBT] shunt) connected the bra chio ce-phal ic artery to the pulmonary artery (see Fig. 2 of the article by Ohye et al.2). Stage II (performed when the infant is 4 to 6 months old) and stage III (at 2 to 4 years of age) complete the separa-tion of the pulmonary from the systemic circu-lation by switching the connections of the supe-rior and inferior vena cavae from the right heart to the pulmonary arteries (with removal of the Norwood shunt). Mortality is much lower with the stage II and III operations than with the stage I procedure.

Few infants survived this perilous surgery in the 1980s, but by the year 2000, steady improve-ments in surgical technique and medical care had led to survival rates of 65 to 75% with perfor-mance of the three-stage reconstruction at lead-ing pediatric centers.6 Follow-up data on the quality of life of children who have undergone this surgery are limited, but it appears that about 75% of school-age survivors have reduced exer-cise capacity and about 25% have some degree of cognitive or neurologic impairment.6 Most of these older children underwent surgery before the recent adoption of regional cerebral perfusion dur-ing aortic reconstruction, however, and the hope is that neurologic outcomes will be better for patients who have undergone the modified sur-gery and been spared cerebral anoxia. Improve-ment in survival rates with the three-stage re-construction has been so great that neonatal cardiac transplantation the only alternative therapeutic approach for children with hypoplas-tic left heart syndrome has been largely rele-gated to a rescue intervention for patients in whom surgical reconstruction is not successful.

Even with this remarkable progress, it has been difficult or impossible to identify which of many refinements in surgical and medical care were crucial for improving outcomes in infants with hypoplastic left heart syndrome, since dif-ferent centers used different criteria to select sur-gical candidates as well as locally preferred treat-ment strategies. A case in point involves the controversy over the relative benefits of the sys-temicpulmonary (MBT) shunt used in the orig-inal Norwood procedure as compared with the recently introduced right ventriclepulmonary ar-tery (RVPA) shunt,7 which connects the right ven-tricle directly to the pulmonary circulation through

a right ventriculotomy (see Fig. 2 of the article by Ohye et al.2). The RVPA shunt appears to im-prove perfusion of the coronary arteries and vi-tal organs, owing to higher diastolic pressures, and to achieve a better balance of pulmonary and systemic circulation; however, there has been con-cern that the ventriculotomy might impair myo-cardial and tricuspid-valve function and increase the risk of ventricular arrhythmias. In a few small studies involving historical controls, hemodynam-ic variables and early survival improved with the use of the RVPA shunt for the Norwood proce-dure, but the results have been inconsistent and follow-up was often inadequate.8

To effectively compare the two procedures, a randomized, controlled trial was designed and implemented by the Pediatric Heart Network, with 15 participating centers providing a more than adequate sample of over 500 infants.9 The major outcome of the study was transplantation-free survival at 1 year, and the results, reported by Ohye et al.,2 show a significant advantage of the RVPA shunt over the MBT shunt (transplantation-free survival rate, 74% vs. 64%; P = 0.01). More-over, major concerns about the potential for harm-ful effects of the right ventriculotomy proved to be unwarranted, although additional, unplanned interventions were performed in the RVPA shunt group to maintain shunt patency. The major ben-efit of the RVPA shunt, as compared with the MBT shunt, seems to be an increased survival rate in the early period after the procedure, but longer-term follow-up will be required to assess effects beyond the 12-month period assessed in this trial.

The surgical, cardiologic, and intensivist teams involved in this heroic work deserve enormous credit for providing the best that modern medi-cine has to offer. The Pediatric Heart Network investigators have made a remarkable contribu-tion with this well-designed and expeditiously im-plemented clinical trial. Their work is just begin-ning, however, since the goal line keeps moving with the frequent introduction of new and po-tentially better treatments. For example, there is now a hybrid approach to remediation of the hy-poplastic left heart syndrome, which uses a com-bination of surgical banding of the pulmonary-artery branches and endovascular stenting of the ductus with balloon atrial septostomy, in place of the Norwood stage I procedure.10 More-over, now that substantial numbers of children with this syndrome are surviving, we must de-

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velop the knowledge and resources to provide essential long-term follow-up and support for these children and their families.11

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

From the Program in Developmental Endocrinology and Genetics, National Institute of Child Health and Development, Bethesda, MD.

Noonan JA, Nadas AS. The hypoplastic left heart syndrome: 1. an analysis of 101 cases. Pediatr Clin North Am 1958;5:1029-56.

Ohye RG, Sleeper LA, Mahony L, et al. Comparison of shunt 2. types in the Norwood procedure for single-ventricle lesions. N Engl J Med 2010;362:1980-92.

Gordon BM, Rodriguez S, Lee M, Chang R-K. Decreasing 3. number of deaths of infants with hypoplastic left heart syn-drome. J Pediatr 2008;153:354-8.

Grossfeld P, Ye M, Harvey R. Hypoplastic left heart syn-4. drome: new genetic insights. J Am Coll Cardiol 2009;53:1072-4.

Norwood WI, Lang P, Hansen DD. Physiologic repair of aor-5.

tic atresiahypoplastic left heart syndrome. N Engl J Med 1983;308:23-6.

Wernovsky G. The paradigm shift toward surgical interven-6. tion for neonates with hypoplastic left heart syndrome. Arch Pediatr Adolesc Med 2008;162:849-54.

Sano S, Ishino K, Kawada M, et al. Right ventricle-pulmo-7. nary artery shunt in first-stage palliation of hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 2003;126:504-9.

Reemtsen BL, Pike N, Starnes V. Stage I palliation for hy-8. poplastic left heart syndrome: Norwood versus Sano modifica-tion. Curr Opin Cardiol 2007;22:60-5.

Ohye RG, Gaynor JW, Ghanayem NS, et al. Design and ra-9. tionale of a randomized trial comparing the Blalock-Taussig and right ventricle-pulmonary artery shunts in the Norwood proce-dure. J Thorac Cardiovasc Surg 2008;136:968-75.

Galantowicz M, Cheatham JP, Phillips A, et al. Hybrid ap-10. proach for hypoplastic left heart syndrome: intermediate results after the learning curve. Ann Thorac Surg 2008;85:2063-71.

McCrindle BW, Williams RV, Mitchell PD, et al. Relationship 11. of patient and medical characteristics to health status in chil-dren and adolescents after the Fontan procedure. Circulation 2006;113:1123-9.Copyright 2010 Massachusetts Medical Society.

Ten Years On The Human Genome and MedicineHarold Varmus, M.D.

On a June day nearly 10 years ago, the leaders of the United States and the United Kingdom, accom-panied by the leaders of the public and private teams deciphering the human genome, announced that a draft sequence had been completed. That occasion was rich with promises of new and more powerful ways to understand, diagnose, prevent, and treat disease. Two years later, the Journal pub-lished a series of articles that reviewed the status of medical genetics and the prospects for a new era of genomic medicine. The tone was cautionary, if hopeful. An editorial (full disclosure: written by me) that accompanied the launch of the series re-minded readers that the full potential of a DNA-based transformation of medicine will be realized only gradually, over the course of decades.1

Now, after the first decade of a postgenome world, only a handful of major changes some gene-specific treatments for a few cancers, some novel therapies for a few mendelian traits, and some strong genetic markers for assessing drug responsiveness, risk of disease, or risk of disease progression have entered routine medical prac-tice. And most of these can be traced to discover-ies that preceded the unveiling of the human ge-nome. As Francis Collins, formerly the leader of the publicly funded sequencing efforts, recently commented: the consequences for clinical medi-cine . . . have thus far been modest . . . the

Human Genome Project has not yet directly af-fected the health care of most individuals.2

In this issue, the Journal begins another series of articles on genomic medicine.3 Is it appropri-ate for the Journal to be taking stock so soon? It is, and for the following reasons.

First, readers will want to know the state of play about the dramatic expansion of the knowledge of human genes and proteins and about the extent to which such knowledge is af-fecting the prevention and treatment of diseases especially for the more common disorders in which inherited risk has long been implicated but rarely defined. As several articles in this se-ries will describe, detailed maps of genetic markers of human variation, mostly single-nucle-otide polymorphisms (SNPs), have facilitated many remarkable genomewide efforts to associ-ate known SNPs with disease predisposition. But this approach has usually failed to reveal strongly influential haplotypes, and in general, other im-plicated susceptibility haplotypes collectively ac-count for only a small fraction of the apparent heritable risk. Clearly, more than one decade of genomics will be required to understand the inborn risks of most common disorders, such as diabetes and hypertension.

Second, readers will enjoy learning from these articles how rapidly the engines of genomics and

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