Innovative 2-Step Management Strategy Utilizing EXIT Procedure for a Fetus With Hypoplastic Left Heart Syndrome and Intact Atrial Septum.

Hypoplastic left heart syndrome (HLHS) with intact atrial septum (HLHS-IAS) carries a high risk of mortality and affects about 6% of all patients with HLHS. Fetal interventions, postnatal transcatheter interventions, and postnatal surgical resection have all been used, but the mortality risk continues to be high in this subgroup of patients. We describe a novel, sequential approach to manage HLHS-IAS and progressive fetal hydrops. A 28-year-old, gravida 4 para 2 mother was referred to Mayo Clinic for fetal HLHS. Fetal echocardiography at 28 weeks of gestation demonstrated HLHS-IAS with progressive fetal hydrops. The atrial septum was thick and muscular with no interatrial communication. Ultrasound-guided fetal atrial septostomy was performed with successful creation of a small atrial communication. However, fetal echocardiogram at 33 weeks of gestation showed recurrence of a pleural effusion and restriction of the atrial septum. We proceeded with an Ex uteroIntrapartum Treatment (EXIT) delivery and open atrial septectomy. This was performed successfully, and the infant was stabilized in the intensive care unit. The infant required venoarterial extracorporeal membrane oxygenator support on day of life 1. The patient later developed hemorrhagic complications, leading to his demise on day of life 9. This is the first reported case of an EXIT procedure and open atrial septectomy performed without cardiopulmonary bypass for an open-heart operation and provides a promising alternative strategy for the management of HLHS-IAS in select cases.

The neurodevelopmental implications of hypoplastic left heart syndrome in the fetus.

As survival after cardiac surgery continues to improve, an increasing number of patients with hypoplastic left heart syndrome are reaching school age and beyond, with growing recognition of the wide range of neurodevelopmental challenges many survivors face. Improvements in fetal detection rates, coupled with advances in fetal ultrasound and MRI imaging, are contributing to a growing body of evidence that abnormal brain architecture is in fact present before birth in hypoplastic left heart syndrome patients, rather than being solely attributable to postnatal factors. We present an overview of the contemporary data on neurodevelopmental outcomes in hypoplastic left heart syndrome, focussing on imaging techniques that are providing greater insight into the nature of disruptions to the fetal circulation, alterations in cerebral blood flow and substrate delivery, disordered brain development, and an increased potential for neurological injury. These susceptibilities are present before any intervention, and are almost certainly substantial contributors to adverse neurodevelopmental outcomes in later childhood. The task now is to determine which subgroups of patients with hypoplastic left heart syndrome are at particular risk of poor neurodevelopmental outcomes and how that risk might be modified. This will allow for more comprehensive counselling for carers, better-informed decision making before birth, and earlier, more tailored provision of neuroprotective strategies and developmental support in the postnatal period.

Fetal reprogramming and senescence in hypoplastic left heart syndrome and in human pluripotent stem cells during cardiac differentiation.

Hypoplastic left heart syndrome (HLHS) is a severe cardiac malformation characterized by left ventricle (LV) hypoplasia and abnormal LV perfusion and oxygenation. We studied hypoxia-associated injury in fetal HLHS and human pluripotent stem cells during cardiac differentiation to assess the effect of microenvironmental perturbations on fetal cardiac reprogramming. We studied LV myocardial samples from 32 HLHS and 17 structurally normal midgestation fetuses. Compared with controls, the LV in fetal HLHS samples had higher nuclear expression of hypoxia-inducible factor-1α but lower angiogenic growth factor expression, higher expression of oncogenes and transforming growth factor (TGF)-ß1, more DNA damage and senescence with cell cycle arrest, fewer cardiac progenitors, myocytes and endothelial lineages, and increased myofibroblast population (P < 0.05 versus controls). Smooth muscle cells (SMCs) had less DNA damage compared with endothelial cells and myocytes. We recapitulated the fetal phenotype by subjecting human pluripotent stem cells to hypoxia during cardiac differentiation. DNA damage was prevented by treatment with a TGF-ß1 inhibitor (P < 0.05 versus nonhypoxic cells). The hypoplastic LV in fetal HLHS samples demonstrates hypoxia-inducible factor-1α up-regulation, oncogene-associated cellular senescence, TGF-ß1-associated fibrosis and impaired vasculogenesis. The phenotype is recapitulated by subjecting human pluripotent stem cells to hypoxia during cardiac differentiation and rescued by inhibition of TGF-ß1. This finding suggests that hypoxia may reprogram the immature heart and affect differentiation and development.

Fetal stenting of the atrial septum: technique and initial results in cardiac lesions with left atrial hypertension.

BACKGROUND: Hypoplastic left heart syndrome with a highly restrictive or intact atrial septum (HLHS-RAS) has a very high mortality. Fetal left atrial (LA) hypertension results in abnormal lung development with lymphangiectasia and pulmonary vein muscularization. We report our initial experience with percutaneous ultrasound-guided stenting of the fetal atrial septum to decompress the LA. METHODS: Retrospective review of fetuses with HLHS-RAS or a variant that underwent active perinatal management from 2000 to 2012. RESULTS: Ten fetuses were identified. Two died in utero (33, 29 weeks). Four required the urgent creation of an atrial communication immediately after birth but died subsequently (5-54 days). Four fetuses (28-36 weeks) underwent percutaneous stenting of the atrial septum, with ultrasound guidance and intravenous maternal sedation. Elevated LA pressure, pulmonary vein dilation and MRI estimated pulmonary perfusion all improved after stenting. Three of four stented fetuses were delivered vaginally. Atrial septectomy was performed within 48 h of delivery to ensure complete LA decompression, rather than for hypoxemia. Intraoperative lung biopsy demonstrated muscularized pulmonary veins and lymphangiectasia in all four. Two fetuses developed stent stenosis in utero and died after birth, from pulmonary hypertension and sepsis respectively. Two are alive, representing an improved outcome over our previous experience (p=0.03). CONCLUSION: Fetal atrial septal stenting is feasible without maternal complications and allows vaginal delivery of a more stable neonate. Fetal LA decompression ameliorates rather than reverses lung injury, and is one component of an approach that may improve survival in HLHS-RAS.

Changing attitudes to the management of hypoplastic left heart syndrome: a European perspective.

BACKGROUND AND AIMS: Several years ago, one of us described the difference in attitude to patients with hypoplastic left heart syndrome in the United States of America and Europe as similar to that between Mars and Venus. Uncertainty remains with regard to the long-term prognosis for patients with hypoplastic left heart syndrome. This prognosis may be considered in terms of survival, functional performance, including exercise capacity and neurodevelopment, as well as psychosocial effects on the patient, family, and siblings. Counselling parents where either an antenatal or postnatal diagnosis of hypoplastic left heart syndrome has been made requires practitioners to give information on these prognostic aspects. We wanted to see how attitudes among European surgeons have changed over the last few years. METHODS: We performed a review of recent European data for hypoplastic left heart syndrome and conducted a survey among surgeons in major European centres to ascertain key aspects of their attitudes to the management of patients with hypoplastic left heart syndrome and how they counsel parents. RESULTS AND CONCLUSIONS: As of January, 2011, 2392 citations in the PubMed database were available for the search string "hypoplastic left heart". The majority of these were from the centres from the United States of America and Europe. The European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Database shows an annual increase in the number of Norwood (Stage I) operations for hypoplastic left heart syndrome from 2003 to 2009, with a corresponding reduction in mortality. European rates of antenatal detection vary widely between centres, as do the rates of termination for a prenatal diagnosis of hypoplastic left heart syndrome. We observed a wide variation in the estimates of surgeons for survival and quality of life for surgical palliation of hypoplastic left heart syndrome, as well as in their estimates for actual rates of termination of pregnancy in their centres. Further, there was marked inconsistency in the information given to parents as part of the process of counselling. These issues remain to be resolved if parents are to make a fully informed decision for their child.

Fibroblast Growth Factor-2 regulates proliferation of cardiac myocytes in normal and hypoplastic left ventricles in the developing chick.

The developing heart increases its mass predominantly by increasing the number of contained cells through proliferation. We hypothesized that addition of fibroblast growth factor-2, a factor previously shown to stimulate division of the embryonic myocytes, to the left ventricular myocardium in an experimental model of left heart hypoplasia created in the chicken would attenuate phenotypic severity by increasing cellular proliferation. We have established an effective mode of delivery of fibroblast growth factor-2 to the chick embryonic left ventricular myocardium by using adenovirus vectors, which was more efficient and better tolerated than direct injection of recombinant fibroblast growth factor-2 protein. Injection of control adenovirus expressing green fluorescent protein did not result in significant alterations in myocytic proliferation or cell death compared with intact, uninjected, controls. Co-injection of adenoviruses expressing green fluorescent protein and fibroblast growth factor-2 was used for verification of positive injection, and induction of proliferation, respectively. Treatment of both normal and hypoplastic left ventricles with fibroblast growth factor-2 expressing adenovirus resulted in to 2 to 3-fold overexpression of fibroblast growth factor-2, as verified by immunostaining. An increase by 45% in myocytic proliferation was observed following injection of normal hearts, and an increase of 39% was observed in hypoplastic hearts. There was a significant increase in anti-myosin immunostaining in the hypoplastic, but not the normal hearts. We have shown, therefore, that expression of exogenous fibroblast growth factor-2 in the late embryonic heart can exert direct effects on cardiac myocytes, inducing both their proliferation and differentiation. These data suggest potential for a novel therapeutic option in selected cases of congenital cardiac disease, such as hypoplastic left heart syndrome.

[Recent developments in fetal surgery. Technical, organizational and ethical considerations]. / Développements récents de la chirurgie foetale. Aspects techniques, organisationnels et éthiques.

Progress in prenatal diagnosis has led to more frequent detection of fetal abnormalities which, if left untreated, would be fatal or cause severe disabilities despite optimal postnatal care. Intrauterine surgery is possible in selected cases. Most procedures involve microendoscopy with local or regional analgesia. Fetal analgesia is indicated for procedures that are directly invasive for the fetus. Surgical treatment of twin-to-twin transfusion is so far the only example of successful fetal therapy, as demonstrated in a randomized controlled trial. The most severe forms of congenital diaphragmatic hernia may also benefit from temporary occlusion of the fetal trachea in order to allow lung growth and prevent pulmonary hypoplasia. The future of open fetal surgery will depend partly on the results of the ongoing MOM study of intrauterine coverage of myelomeningocele. These developments also raise ethical questions, including the competence of the surgical team, and the borderline between therapeutic innovation, experimental surgery, and standard of care. The possibility of therapeutic termination should not be overlooked.

Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: surgical experience from a single center.

BACKGROUND: The presence of an intact or highly restrictive atrial septum (I/HRAS) has long been recognized as a predictor of poor outcome among patients with hypoplastic left heart syndrome (HLHS), although the rarity of this condition has precluded conclusive study. The purpose of this review is to summarize recent surgical outcomes for these patients at our center and to identify predictors. METHODS: We retrospectively identified all neonates with a diagnosis of HLHS and I/HRAS who underwent stage I palliation at Children's Hospital Boston between January 2001 and December 2006. Chart review enabled analysis of patient and procedural variables. RESULTS: All 32 patients underwent left atrial decompression in utero or postnatally before surgery. Fourteen patients (44%) underwent fetal intervention, either atrial septoplasty (n = 9) or aortic valvuloplasty (n = 5). Twenty-nine of the 32 patients had postnatal left atrial hypertension and underwent transcatheter atrial septoplasty as neonates before surgery; 3 did not require postnatal atrial septoplasty after successful fetal atrial septoplasty. After stage I, hospital survival was 69% (22 of 32). Need for shunt revision (p = 0.02) and for extracorporeal membrane oxygenation use (p < 0.001) were associated with hospital mortality. Survival at 6 months was 69% for patients who had fetal intervention, and 38% for those who were treated only postnatally (p = 0.2). CONCLUSIONS: Surgical outcome for patients with HLHS and I/HRAS continues to improve. Prenatal decompression of the left atrium may be associated with greater hospital survival. Proposed effects of fetal intervention on lung pathology and longer-term survival are subjects for future study in this unique group of patients.

Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: outcome after neonatal transcatheter atrial septostomy.

BACKGROUND: Hypoplastic left heart syndrome (HLHS) with intact or very restrictive atrial septum is a highly lethal combination. We review our 13-year institutional experience treating this high-risk subgroup of patients with emergent catheter therapy. METHODS AND RESULTS: Infants with HLHS requiring catheter septostomy within the first 2 days of life were compared with a matched control group with adequate interatrial communication. Preoperative, early postoperative, and medium-term survival were evaluated. Earlier experience was compared with recent results to assess the effect of changes in catheterization and surgical and intensive care unit management strategies over the study period. From 1990 to 2002, 33 newborns with HLHS (11% of newborns with HLHS managed during this period) underwent urgent/semiurgent catheterization to create or enlarge an interatrial communication before surgical palliation. Preoperative and early postoperative mortality were high (48%) compared with control HLHS patients, regardless of prenatal diagnosis and despite successful catheter-based atrial septostomy with clinical stabilization. Mortality trended down during the later part of the study period. Those who survived the neonatal period had late survival, pulmonary artery pressure, and resistance similar to those of control subjects. CONCLUSIONS: Neonatal mortality in the subgroup of HLHS patients with intact or highly restrictive atrial septum remains high despite successful urgent septostomy. Persistently poor outcomes for these patients have prompted efforts at our center to develop techniques for fetal intervention for this condition, in the hope that prenatal relief of left atrial and pulmonary venous hypertension may promote normal pulmonary vascular and parenchymal development and improve both short- and long-term outcomes.

Hypoplastic left heart syndrome: new developments and current controversies.

Prior to 1980, the diagnosis of hypoplastic left heart syndrome (HLHS) was almost uniformly lethal. Over the past 25 years, the development of operative options, including staged surgical palliation and infant heart transplant, have resulted in major improvements in survival and quality-of-life outcomes. Throughout this period, the optimal treatment strategy for children with HLHS has continued to be controversial. Current advances include fetal diagnosis, medical management, catheter intervention and operative techniques, and hold great promise for further improvements. However, as new techniques continue to evolve, controversies will continue to arise. This article will explore the treatment strategies for children with HLHS and review current controversies surrounding this complex congenital cardiac disease.

Pattern of pulmonary venous blood flow in the hypoplastic left heart syndrome in the fetus.

OBJECTIVE: To determine whether restriction at the atrial septum in the newborn with hypoplastic left heart syndrome can be predicted accurately by examining the pattern of pulmonary venous flow in the fetus. A restrictive atrial septum can contribute to haemodynamic instability before surgery for this lesion and has been associated with an increased mortality. DESIGN: Pulmonary venous pulsed Doppler tracings were compared between fetuses with hypoplastic left heart syndrome and controls. The size of the atrial septal defect on the postnatal echocardiogram was graded according to the degree of restriction. Pulsed Doppler tracings of pulmonary venous blood flow were obtained in 18 fetuses with left atrial outflow atresia and compared with 77 controls, adjusted for gestational age. Postnatal echocardiograms were available for analysis in 13 of 18 neonates. SETTING: A tertiary referral centre for fetal cardiology and paediatric cardiac surgery. RESULTS: Fetuses with hypoplastic left heart syndrome were different from controls in all pulmonary vein indices measured. As assessed from the postnatal echocardiogram, there were seven fetuses with a restrictive atrial septum. In these fetuses, the systolic flow velocity (p < 0.01), S/D ratio (p < 0.01), and peak reversal wave (p < 0.001) in the pulmonary vein tracing showed a good correlation with the degree of restriction. CONCLUSIONS: The Doppler pattern of pulmonary venous flow in the fetus with hypoplastic left heart syndrome appears to be a reliable predictor of restriction of the atrial septum in the neonate. This may help in the immediate post-delivery management of these infants before surgery.

Fetal diaphragmatic hernia: echocardiography and clinical outcome.

It is difficult to predict survival of fetuses diagnosed prenatally with congenital diaphragmatic hernia. Some studies suggest that left heart underdevelopment is associated with poor outcome, but fetal echocardiographic variables have not been conclusively proven to be good predictors of postnatal survival. The authors reviewed detailed fetal echocardiographic studies in twelve fetuses with congenital diaphragmatic hernia. Ten echocardiographic variables, including left and right ventricular width, left ventricular volume, and left ventricular mass, were examined from a four-chamber view, corrected for gestational age, and compared with normal data. The results of this study showed no significant differences between survivors and nonsurvivors in the ten variables analyzed. Although left heart dimensions and left ventricular volume in fetuses with congenital diaphragmatic hernia were below the expected normal range, these results did not predict postnatal outcome.

Risk factors for hypoplastic left heart syndrome.

A case-control study was performed in Finland to investigate the etiology of the lethal heart malformation, hypoplastic left heart syndrome (HLHS). The cases represented all verified HLHS (n = 34) in Finland during 1982-1983, and controls (n = 756) were randomly selected from all babies born during the same period. Both case and control mothers were interviewed by midwives approximately 3 mo after delivery. Maternal upper respiratory infection during the first trimester of pregnancy was a significant risk factor for HLHS (OR = 2.5, Cl95 = 1.2-5.4). Maternal exposures at work to factors such as disinfectants, pesticides, dyes, lacquers or paints, and anesthetic gases were rare and failed to indicate any risk for HLHS. Maternal use of deodorants or hairsprays during the first trimester of pregnancy was not a significant risk factor for HLHS (OR = 1.8, Cl95 = 0.9-3.6). The risk of HLHS was not associated with seasonal variation, maternal smoking, alcohol or coffee consumption, or use of acetosalicylic acid. Because the study material is limited in size, the power of this investigation is weak for testing the teratogenicity of specific chemicals on the risk of HLHS. Thus, conclusions from the negative findings of this study should be drawn very carefully.