Attributable mortality benefit of digoxin treatment in hypoplastic left heart syndrome after the Norwood operation: An instrumental variable-based analysis using data from the Pediatric Health Information Systems Database.

BACKGROUND: Observational studies have demonstrated an association between the use of digoxin and reduced interstage mortality after Norwood operation for hypoplastic left heart syndrome (HLHS). Digoxin use has increased significantly but remains variable between different hospitals, independent of case-mix. Instrumental variable analyses have the potential to overcome unmeasured confounding, the major limitation of previous observational studies and to generate an estimate of the attributable benefit of treatment with digoxin. METHODS: A cohort of neonates with HLHS born from January 1, 2007 to December 31, 2021 who underwent Norwood operation at Pediatric Health Information Systems Database hospitals and survived >14 days after operation were studied. Using hospital-specific, 6-month likelihood of administering digoxin as an instrumental variable, analyses adjusting for both unmeasured confounding (using the instrumental variable) and measured confounders with multivariable logistic regression were performed. RESULTS: The study population included 5,148 subjects treated at 47 hospitals of which 63% were male and 46% non-Hispanic white. Of these, 44% (n = 2,184) were prescribed digoxin. Treatment with digoxin was associated with superior 1-year transplant-free survival in unadjusted analyses (85% vs 82%, P = .02). This survival benefit persisted in an instrumental-variable analysis (OR: 0.71, 95% CI: 0.54-0.94, P = .01), which can be converted to an absolute risk reduction of 5% (number needed to treat of 20). CONCLUSIONS: In this observational study of patients with HLHS after Norwood using instrumental variable techniques, a significant benefit in 1-year transplant-free survival attributable to digoxin was demonstrated. In the absence of clinical trial data, this should encourage the use of digoxin in this vulnerable population.

Association of Digoxin With Preserved Echocardiographic Indices in the Interstage Period: A Possible Mechanism to Explain Improved Survival?

Background For patients with hypoplastic left heart syndrome, digoxin has been associated with reduced interstage mortality after the Norwood operation, but the mechanism of this benefit remains unclear. Preservation of right ventricular (RV) echocardiographic indices has been associated with better outcomes in hypoplastic left heart syndrome. Therefore, we sought to determine whether digoxin use is associated with preservation of the RV indices in the interstage period. Methods and Results We conducted a retrospective cohort study of prospectively collected data using the public use data set from the Pediatric Heart Network Single Ventricle Reconstruction trial, conducted in 15 North American centers between 2005 and 2008. We included all patients who survived the interstage period and had echocardiographic data post-Norwood and pre-Glenn operations. We used multivariable linear regression to compare changes in RV parameters, adjusting for relevant covariates. Of 289 patients, 94 received digoxin at discharge post-Norwood. There were no significant differences in baseline clinical characteristics or post-Norwood echocardiographic RV indices (RV end-diastolic volume indexed, RV end-systolic volume indexed, ejection fraction) in the digoxin versus no-digoxin groups. At the end of the interstage period and after adjustment for relevant covariates, patients on digoxin had better preserved RV indices compared with those not on digoxin for the ΔRV end-diastolic volume (11 versus 15 mL, P=0.026) and the ΔRV end-systolic volume (6 versus 9 mL, P=0.009) with the indexed ΔRV end-systolic volume (11 versus 20 mL/BSA1.3, P=0.034). The change in the RV ejection fraction during the interstage period between the 2 groups did not meet statistical significance (-2 versus -5, P=0.056); however, the trend continued to be favorable for the digoxin group. Conclusions Digoxin use during the interstage period is associated with better preservation of the RV volume and tricuspid valve measurements leading to less adverse remodeling of the single ventricle. These findings suggest a possible mechanism of action explaining digoxin's survival benefit during the interstage period.

Hypoplastic left heart syndrome (HLHS): molecular pathogenesis and emerging drug targets for cardiac repair and regeneration.

INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is a severe developmental defect characterized by the underdevelopment of the left ventricle along with aortic and valvular defects. Multiple palliative surgeries are required for survival. Emerging studies have identified potential mechanisms for the disease onset, including genetic and hemodynamic causes. Genetic variants associated with HLHS include transcription factors, chromatin remodelers, structural proteins, and signaling proteins necessary for normal heart development. Nonetheless, current therapies are being tested clinically and have shown promising results at improving cardiac function in patients who have undergone palliative surgeries. AREAS COVERED: We searched PubMed and clinicaltrials.gov to review most of the mechanistic research and clinical trials involving HLHS. This review discusses the anatomy and pathology of HLHS hearts. We highlight some of the identified genetic variants that underly the molecular pathogenesis of HLHS. Additionally, we discuss some of the emerging therapies and their limitations for HLHS. EXPERT OPINION: While HLHS etiology is largely obscure, palliative therapies remain the most viable option for the patients. It is necessary to generate animal and stem cell models to understand the underlying genetic causes directly leading to HLHS and facilitate the use of gene-based therapies to improve cardiac development and regeneration.

A word on netting of angiotensin-converting enzyme inhibitor therapy in hypoplastic left heart syndrome following stage-I.

NPC-QIC Registry data showed that angiotensin-converting enzyme inhibitors were described in almost 38% for patients with single ventricle physiology after stage-I Norwood palliation. However, mortality and ventricular dysfunction or atrioventricular valve insufficiency seems to be not improved by oral application of angiotensin-converting enzyme inhibitors. The final conclusion was that despite limited evidence of benefit for patients with hypoplastic left heart syndrome, prescription of angiotensin-converting enzyme inhibitors during interstage is still common. Taking into account of the predominant cardiovascular regulation in newborns and young infants by circulating catecholamines, no real improvement is to be expected from angiotensin-converting enzyme inhibitor monotherapy. The goals of drug therapy after stage-I Norwood palliation in hypoplastic left heart syndrome are prevention of systemic right ventricle failure, balancing pulmonary and systemic blood flow, and reduction of oxygen consumption with regard to limitations of oxygen supply by the single ventricle, furthermore, avoiding harmful effects of endogenous catecholamine production in the long term on somatic and cognitive development. In this light of knowledge, we want to recommend the use of a long-acting and highly specific ß1-adrenoreceptor blocker for almost all patients after stage-I Norwood palliation and a combination with angiotensin-converting enzyme inhibitors only by indication after exclusion of potential side effects.

Trends in Discharge Prescription of Digoxin After Norwood Operation: An Analysis of Data from the Pediatric Health Information System (PHIS) Database.

Quality improvement efforts have focused on reducing interstage mortality for infants with hypoplastic left heart syndrome (HLHS). In 1/2016, two publications reported that use of digoxin was associated with reduced interstage mortality. The degree to which these findings have affected real world practice has not been evaluated. The discharge medications of neonates with HLHS undergoing Norwood operation between 1/2007 and 12/2018 at Pediatric Health Information Systems Database hospitals were studied. Mixed effects models were calculated to evaluate the hypothesis that the likelihood of digoxin prescription increased after 1/2016, adjusting for measurable confounders with furosemide and aspirin prescription measured as falsification tests. Interhospital practice variation was measured using the median odds ratio. Over the study period, 6091 subjects from 45 hospitals were included. After adjusting for measurable covariates, discharge after 1/2016 was associated with increased odds of receiving digoxin (OR 3.9, p < 0.001). No association was seen between date of discharge and furosemide (p = 0.26) or aspirin (p = 0.12). Prior to 1/2016, the likelihood of receiving digoxin was decreasing (OR 0.9 per year, p < 0.001), while after 1/2016 the rate has increased (OR 1.4 per year, p < 0.001). However, there remains significant interhospital variation in the likelihood of receiving digoxin even after adjusting for known confounders (median odds ratio = 3.5, p < 0.0001). Following publication of studies describing an association between digoxin and improved interstage survival, the likelihood of receiving digoxin at discharge increased without similar changes for furosemide or aspirin. Despite concerted efforts to standardize interstage care, interhospital variation in pharmacotherapy in this vulnerable population persists.

Angiotensin-Converting Enzyme Inhibitor Prescription for Patients With Single Ventricle Physiology Enrolled in the NPC-QIC Registry.

Background The routine use of angiotensin-converting enzyme inhibitors (ACEI) during palliation of hypoplastic left heart syndrome is controversial. We sought to describe ACEI prescription in the interstage between stage 1 palliation (stage I Norwood procedure) discharge and stage 2 palliation (stage II superior cavopulmonary anastomosis procedure) admission using the NPC-QIC (National Pediatric Cardiology Quality Improvement Collaborative) registry. Methods and Results Analysis of all patients (n=2180) enrolled in NPC-QIC from 2008 to 2016 included preoperative anatomy, risk factors, and echocardiographic data. ACEI were prescribed at stage I Norwood procedure discharge in 38% of patients. ACEI prescription declined from 2011 to 2016 compared with pre-2010 (36.8% versus 45%; P=0.005) with significant variation across centers (range 7-100%; P<0.001) and decreased prescribing rates associated with increased center volume (P=0.004). There was no difference in interstage mortality (P=0.662), change in atrioventricular valve regurgitation (P=0.101), or change in ventricular dysfunction (P=0.134) between groups. In multivariable analysis of all patients, atrioventricular septal defect (odds ratio [OR], 1.84; 95% CI, 1.28-2.65) or double outlet right ventricle (OR, 1.47; CI, 1.02-2.11), and preoperative mechanical ventilation (OR, 1.37; 95% CI, 1.12-1.68) were associated with increased ACEI prescription. In multivariable analysis of patients with complete echocardiographic data (n=812), ACEI prescription was more common with at least moderate atrioventricular valve regurgitation (OR, 1.88; 95% CI, 1.22-2.31). Conclusions ACEI prescription remains common in the interstage despite limited evidence of benefit. ACEI prescription is associated with preoperative mechanical ventilation, double outlet right ventricle, and atrioventricular valve regurgitation with marked inter-center variation. ACEI prescription is not associated with reduction in mortality, ventricular dysfunction, or atrioventricular valve regurgitation during the interstage.

The effect of prenatal diagnosis on antibiotic therapy in neonates with hypoplastic left heart syndrome. Antibiotics in prenatally diagnosed patients with HLHS.

INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is a congenital heart anomaly that is diagnosed prenatally or postnatally. The prenatal diagnosis leads to limiting the rate of systemic complications in the preoperative period due to optimization of the early therapeutic management. OBJECTIVE: The objective of the study is to determine the effect of prenatal diagnostic management of HLHS on the condition of newborns and the frequency of antibiotherapy employment prior to the first stage of surgical treatment. METHODOLOGY: The study included 95 children with HLHS operated on in the years 2014-2016. The cohort was divided into two groups: newborns with a prenatally diagnosed heart defect (50 children - 52.6%) and neonates with the defect diagnosed after birth (45 children - 47.4%). The data of the patients were analyzed based on their medical records. RESULTS: The mean age of the children upon admission was 3.86 days in the group of patients with the prenatally diagnosed heart defect (PreHLHS) and 7.41 days in the group of newborns without the prenatal diagnosis (PostHLHS) (p = 0.001). In 60% of the PreHLHS group patients (30/50), at least one antibiotic was administered, while in the PostHLHS group, antibiotherapy was employed in 93.3% (42/45) cases (p = 0.001). Bacteriological tests demonstrated pathogen growth in 33 children (36% and 33.3%, respectively), what accounted for 34.7% of the entire cohort. On the average, the first antibiotic was introduced on the 6.55th day of life in the PreHLHS group and on the 2.73th day in the PostHLHS group (p = 0.005). The most profound differences in antibiotic employment involved aminoglycosides. The aforementioned type of antibiotic medications was administered to 6% of the children with the prenatal diagnosis and to 17.8% of the children diagnosed postnatally (p = 0.042). CONCLUSIONS: Preoperative antibiotherapy in children with HLHS was employed more frequently than it would be indicated by microbiology tests results. Antibiotics were observed to be introduced more commonly and earlier in the newborns with the postnatally diagnosed congenital heart defect.

Changing trends in IVIG use in pediatric patients: A retrospective review of practices in a network of major USA pediatric hospitals.

The use of immunoglobulins is gradually increasing. Intravenous immunoglobulins (IVIG) are used as replacement therapy for primary and secondary immune deficiencies, and as an anti-inflammatory and immunomodulatory medication for the treatment of neurologic, dermatologic, and rheumatologic diseases. The objective of this study was to analyze trends in the IVIG use in pediatric patients hospitalized to 47 US-based children's hospitals from 2007 to 2014. IVIG was used for the treatment of >2300 primary diagnoses in 53,648 unique patients. The number of IVIG admissions increased by 30.2% during the study period, while the mean rate of IVIG admissions/100,000 admissions increased only 5.8%. Most patients receiving IVIG were children and adolescents. IVIG was frequently used off-label or for the treatment of FDA-approved indications in children under two years of age and BMT patients <20 years of age. Primary immune deficiencies represented only 1.2% of all IVIG admissions. Pediatric patients with mucocutaneous lymph node syndrome (Kawasaki disease, KD) and idiopathic thrombocytopenic purpura (ITP) were two primary consumers of the IVIG. Another top-ranked indications were acute infectious polyneuritis (Guillain-Barré syndrome, GBS) and prophylaxis of infections in patients receiving antineoplastic chemotherapy. IVIG usage is a dynamic process guided by emerging evidence and FDA approval for new indications. IVIG was mostly prescribed for treatment of diseases with pathologic immune responses to foreign of self-antigens. These indications usually, require higher amounts of IVIG per admission. More studies are needed to understand whether IVIG treatments of off-label indications are effective and cost-efficient.

Successful use of oral prostaglandin E1 derivative for maintaining ductus-dependent systemic circulation in a neonate with trisomy 18.

A Japanese female infant with trisomy 18 was diagnosed with hypoplastic left heart syndrome variant. She was administered oral prostaglandin E1 every 6 hours through a feeding tube as an alternative drug for lipo-prostaglandin E1. Oral prostaglandin E1 was effective for maintenance of the ductus arteriosus and may serve as a palliative treatment approach.

Digoxin Use in Infants with Single Ventricle Physiology: Secondary Analysis of the Pediatric Heart Network Infant Single Ventricle Trial Public Use Dataset.

Digoxin has been associated with reduced interstage mortality after Norwood procedure. We sought to determine its association with survival and change in weight-for-age Z-score (WAZ) before the superior cavopulmonary connection (SCPC) surgery and at 14 months in a heterogeneous group of single ventricle infants. We performed a post-hoc analysis of the Pediatric Heart Network Infant Single Ventricle public use dataset to determine associations between digoxin and survival, transplant-free survival, and change in WAZ pre-SCPC and at 14 months. Sub-analyses of survival and transplant-free survival were performed for subjects who underwent Damus-Kaye-Stansel (DKS)/Norwood. Propensity score weighting was used in Cox hazard-proportion models. Of 229 subjects, 82 (36%) received digoxin and 147 (64%) received no digoxin. Pre-SCPC and 14-month survival and transplant-free survival were not significantly different between the digoxin and no digoxin groups for the main cohort and DKS/Norwood sub-group. However, in DKS/Norwood subjects there was a trend towards improved interstage transplant-free survival in the digoxin group (95.7 vs. 89.6%, p = 0.08). Digoxin was associated with a greater decrease in WAZ from birth to pre-SCPC (- 1.96 ± 0.19 vs. - 1.31 ± 0.18, p < 0.001) and birth to 14 months (- 0.64 ± 0.15 vs. - 0.19 ± 0.15, p = 0.03). Digoxin was not associated with improved survival during the interstage or at 14 months in a mixed single ventricle cohort, but there was a trend towards improved interstage transplant-free survival in post-Norwood infants. As digoxin was associated with poorer weight gain, further research is needed to identify the risks/benefits for anatomic subtypes of infants with single ventricles.

Variability of antithrombotics use in patients with hypoplastic left heart syndrome and its variants following first- and second-stage palliation surgery: a national report using the National Pediatric Cardiology Quality Improvement Collaborative registry.

Purpose Patients with hypoplastic left heart syndrome and its variants following palliation surgery are at risk for thrombosis. This study examines variability of antithrombotic practice, the incidence of interstage shunt thrombosis, and other adverse events following Stage I and Stage II palliation within the National Pediatric Cardiology Quality Improvement Collaborative registry. METHODS: We carried out a multicentre, retrospective review using the National Pediatric Cardiology Quality Improvement Collaborative registry including patients from 2008 to 2013 across 52 surgical sites. Antithrombotic medications used at Stage I and Stage II discharge were evaluated. Variability of antithrombotics use at the individual patient level and intersite variability, incidence of shunt thrombosis, and other adverse events such as cardiac arrest, seizure, stroke, and need for cardiac catheterisation intervention in the interstage period were identified. Antithrombotic strategies for hybrid Stage I patients were evaluated but they were excluded from the variability and outcomes analysis. RESULTS: A total of 932 Stage I and 923 Stage II patients were included in the study: 93.8% of Stage I patients were discharged on aspirin and 4% were discharged on no antithrombotics, and 77% of Stage II patients were discharged on aspirin and 17.5% were discharged on no antithrombotics. Only three patients (0.2%) presented with interstage shunt thrombosis. The majority of patients who died during interstage or required shunt dilation and/or stenting were discharged home on aspirin. CONCLUSION: Aspirin is the most commonly used antithrombotic following Stage I and Stage II palliation. There is more variability in the choice of antithrombotics following Stage II compared with Stage I. The incidence of interstage shunt thrombosis and associated adverse events was rare.

Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery.

OBJECTIVES: To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. DESIGN: Prospective, dose escalation trial. SETTING: Single-center, pediatric catheterization laboratory. PATIENTS: Twelve children poststage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range, 0.8, 4.0), weight 11 kg (8, 13), nine females, and 10 with a single right ventricle. INTERVENTIONS: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 min). MEASUREMENTS: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. MAIN RESULTS: Maximum sildenafil concentrations ranged from 92 to 775 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type 5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index in all 12 subjects (median pulmonary vascular resistance index 2.2 [range, 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU × m; p < 0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p = 0.04) and saturations (+2% [0, 16], p = 0.04) in those with baseline pulmonary vascular resistance index ≥ 2 WU × m (n = 7). Change in saturations correlated inversely with change in pulmonary vascular resistance index (r = 0.74, p < 0.01). Sildenafil also lowered mean blood pressure (-12% [-20, +10]; p = 0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. CONCLUSIONS: Sildenafil demonstrated nonlinear exposure with high interindividual variability but was well tolerated and effectively lowered pulmonary vascular resistance index in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.

Preoperative management in patients with single-ventricle physiology.

OBJECTIVE: Advancements in the preoperative management of patients with single-ventricle physiology continue to evolve. Previous reports have questioned the benefit of using inhaled nitrogen in single-ventricle patients, suggesting that this therapeutic modality may not provide adequate systemic cardiac output. The objective of this study was to review our institutional experience managing preoperative patients with single-ventricle physiology using a combination of afterload reduction and inhaled hypoxemic therapy. DESIGN, SETTING, AND PATIENTS: This is a retrospective review of 49 consecutive single-ventricle patients admitted preoperatively between July 2004 and January 2009, to the cardiac intensive care unit at Children's Hospital of Pittsburgh who underwent single-ventricle palliation, and treated preoperatively with milrinone and inhaled nitrogen. Therapeutic interventions and indirect indicators of cardiac output were collected on day of admission (time 0) and compared with those collected on the morning of surgery (time 1); data included clinical assessment, hemodynamic measurements, and laboratory values. RESULTS: When comparing time 0 to time 1, there was a statistically significant decrease in lactate (from 2.2 to 1.8 mEq/L [P < 0.001]) and an increase in pH (from 7.36 to 7.41 [P < 0.001]), serum bicarbonate (from 24.16 to 27.55 mmol/L [P < 0.001]) and arterial PaO2 (from 38.10 to 41.82 mm Hg [P = 0.027]). Preoperatively, there were no deaths, and only two patients had an evidence of multiorgan dysfunction on day of surgery (time 1). CONCLUSION: Our results suggest that a combination of afterload reduction and hypoxemic therapy was able to maintain an appropriate distribution of the cardiac output in the majority of preoperative patients with single-ventricle physiology. An adequate balance of systemic and pulmonary blood flow was successfully achieved with an increase in arterial PaO2 values.

Impact of pharmacotherapy on interstage outcomes in single ventricle infants.

OBJECTIVE: To characterize the pharmacotherapeutic regimens used in infants with single ventricle heart disease and determine the influence of outpatient medications on interstage weight gain. DESIGN: Retrospective review. SETTING: Tertiary care pediatric hospital. PATIENTS: All patients discharged from our institution with single ventricle heart disease that underwent neonatal first stage surgical palliation between 2002 and 2009 were included. Patients who died prior to second stage palliation or underwent orthotopic heart transplantation were excluded. OUTCOME MEASURES: Outpatient medication regimens during the interstage period were reviewed. Medication regimens were compared between surgical eras and between patient groups experiencing different outcomes. A logistic regression model was developed to determine independent factors for an interstage increase in weight-for-age z-score (WAZ) and a linear regression model to determine medications significant for an increase in weight gain per day. RESULTS: The study cohort consisted of 161 patients (58% male). Most patients in this cohort had either hypoplastic left heart syndrome (51%) or unbalanced complete atrioventricular canal (29%). Patients were placed on a median of four medications (range 1-9) at discharge from first surgical palliation, with aspirin (79%), furosemide (79%), and angiotensin converting enzyme inhibitors (ACE-I) (73%) most commonly prescribed. A median of six medication doses per day (range 2-18) were prescribed at discharge. Most patients (71%) had a decrease in WAZ during the interstage period. Use of digoxin (P < 0.01) and high-dose furosemide (P = .02) were associated with a decrease in WAZ score during the interstage period. Additionally, the use of ACE-I, ranitidine, proton-pump inhibitors, or promotility agents was not associated with improved somatic growth during the interstage period. CONCLUSIONS: Infants with single ventricle heart disease have a high-medication burden during the interstage period. Despite the focused and intensified use of medications to improve feeding tolerance and somatic growth, current pharmacotherapeutic regimens appear to have little effect on interstage weight gain.

Two-year follow-up of the pharmacokinetics of immunosuppressive drugs in a neonate who underwent heart transplantation.

The pharmacokinetic properties of immunosuppressive drugs are quite different in newborns than in adults and few studies describe the pharmacokinetics of these drugs in pediatric heart transplant recipients. We report on the two-year follow up of a neonate who underwent heart transplantation for Hypoplastic Left Heart Syndrome on day of life 9. Two different immunosuppressive regimens were used: cyclosporine, azathioprine and prednisone in the early postoperative period, followed by the routine tacrolimus and mycophenolate mofetil combination plus prednisone from post-transplant day 22. Our findings demonstrate marked variability in immunosuppressive pharmacokinetic profiles early post-transplant. Frequent monitoring of drug levels is required to ensure that they remain within the therapeutic range. After the first 2-3 months post-transplant, changes in immunosuppressive drug levels are less marked and correlate more with the administered dosage.

Early results of bilateral pulmonary artery banding for hypoplastic left heart syndrome.

OBJECTIVE: To compare the haemodynamics and perioperative course of initial palliation with bilateral pulmonary artery banding (PAB) and the Norwood procedure. METHODS: Between April 2004 and December 2007, 43 consecutive children with hypoplastic left heart syndrome (HLHS) or a variant underwent initial palliation (PAB, n=18; Norwood, n=25). Clinical perioperative data were analysed. In the PAB group, lipo-prostaglandin E1 administration was continued with hospitalisation until stage 2 palliation with a bi-directional Glenn shunt and the Norwood procedure. RESULTS: There were no significant differences in the age and operative weight of patients who received stage 1 palliation (PAB, 12+/-9 days, 2.7+/-0.6 kg; Norwood, 12+/-8 days, 2.8+/-0.4 kg). The PAB group had more high-risk patients than the Norwood group (PAB, 83%; Norwood, 48%, p=0.04). Increased early and inter-stage mortality were observed in patients who underwent the Norwood procedure (early mortality with PAB, 6% vs Norwood, 12%; inter-stage mortality, 6% vs 27%, respectively). Mortality between stages 1 and 2 was 11% for the PAB group and 36% for the Norwood group. The Kaplan-Meier survival estimate at 1 year did not differ between groups (77% for the PAB group, 64% for the Norwood group). Ductal stenosis was found in one patient in the PAB group during the follow-up period. Twenty-eight patients underwent stage 2 reconstruction, and the patients in the PAB group were younger at the time of surgery (PAB, 116 days; Norwood, 224 days). There were no significant differences between groups in pulmonary artery index regarding body surface area (BSA) (PAB, 179 mm(2)BSA(-1); Norwood, 194 mm(2)BSA(-1)) and the incidence of ventricular dysfunction after stage 2 construction (PAB, 21%; Norwood, 21%). CONCLUSIONS: Bilateral PAB with continuous lipo-prostaglandin E1 administration may improve early and intermediate mortality in infants with HLHS. Intimate care with hospitalisation may contribute to the results.

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.