Hypoplastic left heart syndrome: new insights.

Hypoplastic left heart syndrome (HLHS) is one of the most severe congenital heart defects, accounting for 20% to 25% of mortality in infants born with congenital heart disease. In the United States, 2000 infants are born each year with HLHS.1 To date, there is a paucity of studies that define the underlying genetic, molecular and cellular mechanisms of HLHS.2–4 Most cases of HLHS are thought to arise secondarily because of decreased flow into the developing embryonic left ventricle, although in some cases, abnormal left ventricular growth could be the primary defect. There is strong evidence for a genetic etiology for HLHS, although very little is understood about the genetic mechanisms underlying HLHS. Nineteen percent of first degree relatives of infants with HLHS have a congenital heart defect.5 In addition, there are several chromosomal disorders that are associated with HLHS. For example, 10% of all infants born with a terminal 11q deletion (Jacobsen syndrome) have HLHS.6 Mutations in at least one gene, the cardiac transcription factor NKX2.5, have been identified in patients with HLHS.7,8 Similar to many of the most severe congenital heart defects, treatment strategies for HLHS have evolved and are still changing. The two current surgical strategies include the three-stage Norwood/Fontan procedure, or, alternatively, cardiac transplantation. The Norwood procedure, which is performed optimally in the neonatal period to avoid the development of pulmonary vascular disease, entails reconstructing the aortic arch, transecting the pulmonary artery, anastamosing the pulmonary artery root to the reconstructed aorta, and placing a systemic to pulmonary artery shunt (either from aorta or more recently, from the right ventricle). Although there has been significant progress in outcomes, neither surgical approach is curative and longterm outcomes are uncertain. Consequently, there has been an ongoing effort to develop alternative strategies for the treatment of HLHS. Ideally, a two-ventricle repair, in which only the hypoplastic arch is repaired, would be preferable to preserve the left ventricle as the systemic ventricle. Although the dogma has been that hypoplasia of the left-sided structures of the heart is irreversible, (thereby making a two-ventricle approach not feasible for most patients) there is evidence that hypoplastic left-sided structures may be capable of growth under certain physiologic conditions. For example, infants with HLHS waiting for a transplant can exhibit significant postnatal growth of the left-sided structures of the heart.9 However, the mechanisms underlying postnatal growth of an HLHS heart are unknown. Currently, only a small subset of HLHS patients, those with patency (ie, not atresia) of the mitral and aortic valves and with only mild hypoplasia of the left ventricle, may be amenable to a two-ventricle repair. Even among this subset of patients, one of the ongoing challenges in the management of patients with hypoplasia of the left sided structures is to determine which patients have a left ventricle that will be capable of supporting the systemic circulation. Although there are some computer-generated models that can assist to decide between a one versus two-ventricle repair, they are far from exact and have limitations. For example, in some patients with mild hypoplasia of the left sided structures at birth, there may be insufficient postnatal growth of the left ventricle, ultimately resulting in a left ventricle that cannot sustain normal systemic cardiac output. Consequently, it may not be possible to determine, at the outset, if a hypoplastic left ventricle can grow postnatally. Thus, most clinicians opt for the “safer” (albeit tenuous) single ventricle repair when in doubt. Ideally, early identification of patients that are capable of postnatal growth of the left-sided structures would optimize the selection process of those patients that are best suited for a two-ventricle repair. In this issue of Circulation Research, deAlmeida et al,10 describe a series of experiments that begin to give possible insights into the mechanisms of HLHS. Using a chick hemodynamic model, they surgically ligated the embryonic left atrium (thereby restricting prograde blood flow into the left ventricle) which gave rise to left ventricular hypoplasia. Next, they demonstrated that the hypoplastic left ventricle can be “rescued” by subsequent clipping of the right atrium (thereby forcing more blood flow across an atrial communication, and away from the tricuspid valve, to what was destined to be a hypoplastic left ventricle). The left ventricular growth was physiologic and not a pathologic response of a failing ventricle to volume overload. Furthermore, this “hemodynamic rescue” was associated with cardiac myocyte hyperplasia. These results have important potential clinical implications. First, these studies demonstrate that at least under some The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Pediatric Cardiology, UCSD School of Medicine. Correspondence to Paul Grossfeld, MD, University of California, San Diego, Division of Pediatric Cardiology, 9500 Gilman Drive # 0831, La Jolla, CA 92093-0831. E-mail [email protected] (Circ Res. 2007;100:1246-1248.) © 2007 American Heart Association, Inc.