Pulmonary ductal coarctation and left pulmonary artery interruption; pathology and role of neural crest and second heart field during development.

OBJECTIVES: In congenital heart malformations with pulmonary stenosis to atresia an abnormal lateral ductus arteriosus to left pulmonary artery connection can lead to a localised narrowing (pulmonary ductal coarctation) or even interruption We investigated embryonic remodelling and pathogenesis of this area. MATERIAL AND METHODS: Normal development was studied in WntCre reporter mice (E10.0-12.5) for neural crest cells and Nkx2.5 immunostaining for second heart field cells. Data were compared to stage matched human embryos and a VEGF120/120 mutant mouse strain developing pulmonary atresia. RESULTS: Normal mouse and human embryos showed that the mid-pharyngeal endothelial plexus, connected side-ways to the 6th pharyngeal arch artery. The ventral segment formed the proximal pulmonary artery. The dorsal segment (future DA) was solely surrounded by neural crest cells. The ventral segment had a dual outer lining with neural crest and second heart field cells, while the distal pulmonary artery was covered by none of these cells. The asymmetric contribution of second heart field to the future pulmonary trunk on the left side of the aortic sac (so-called pulmonary push) was evident. The ventral segment became incorporated into the pulmonary trunk leading to a separate connection of the left and right pulmonary arteries. The VEGF120/120 embryos showed a stunted pulmonary push and a variety of vascular anomalies. SUMMARY: Side-way connection of the DA to the left pulmonary artery is a congenital anomaly. The primary problem is a stunted development of the pulmonary push leading to pulmonary stenosis/atresia and a subsequent lack of proper incorporation of the ventral segment into the aortic sac. Clinically, the aberrant smooth muscle tissue of the ductus arteriosus should be addressed to prohibit development of severe pulmonary ductal coarctation or even interruption of the left pulmonary artery.

Congenital Anorectal Malformation Severity Does Not Predict Severity of Congenital Heart Defects.

OBJECTIVE: To determine the prevalence of congenital heart defects (CHDs) in patients with mild or severe congenital anorectal malformations (CARMs), and whether all patients with CARM need pediatric cardiology screening. STUDY DESIGN: We included 129 patients with CARM born between 2004 and 2013, and referred to University Medical Center Groningen. Recto-perineal and recto-vestibular fistulas were classified as mild CARMs, all others as severe. Significant patent foramen ovale, secundum atrial septal defect, and small ventricular septum defect were classified as minor CHDs, all others as major. RESULTS: Of 129 patients with CARM, 67% had mild CARM, 33% severe CARM, and 17% were additionally diagnosed with CHD. CHDs were distributed equally in patients with mild or severe CARMs. Patients with multiple congenital abnormalities were more frequently diagnosed with CHD (n = 16, 36%) than patients without multiple congenital malformations (n = 5, 9%, P = .001). Patients with CARM diagnosed with CHD using pediatric cardiac echo screening were younger than 3 months of age at diagnosis. Earlier general pediatric examinations missed 7 (50%) children with mild and 4 (50%) with severe CHDs. CONCLUSIONS: The severity of CARM could predict neither prevalence nor severity of CHD. More than one-half of CHDs were missed during the first physical examination. No new CHDs were found in patients older than 3 months of age at the time CARMs were diagnosed. We recommend screening all patients with CARM younger than 3 months of age for CHD at the time CARM is diagnosed. Preoperative echocardiography should be the rule in children younger than 3 months of age and with multiple congenital anomalies.

Echocardiography in pediatric pulmonary arterial hypertension: early study on assessing disease severity and predicting outcome.

BACKGROUND: The value of echocardiography in assessing disease severity and predicting outcome in pediatric pulmonary arterial hypertension (PAH) is insufficiently defined. The aim of this study was to describe correlations between echocardiography and disease severity and outcome in pediatric PAH. METHODS AND RESULTS: Forty-three consecutive children (median age, 8.0 years; range, 0.4-21.5) with idiopathic/hereditary PAH (n=25) or PAH associated with congenital heart disease (n=18) were enrolled in a prospective single-center observational study. Anatomic and right ventricular-functional variables were obtained by two-dimensional echocardiography and Doppler-echocardiography at presentation and at standardized follow-up and were correlated with measures of disease severity (World Health Organization functional class [WHO-FC], N-terminal-pro-B-type natriuretic peptide, hemodynamics) and lung-transplantation-free survival. Right atrial and right ventricular dimensions correlated with WHO-FC and hemodynamics (P<0.05), whereas left ventricular dimensions correlated with hemodynamics and survival (P<0.05). Right-to-left ventricular dimension ratiocorrelated with WHO-FC, hemodynamics and survival (P<0.05). Right ventricular ejection time correlated with hemodynamics and survival (P<0.05) and tended to correlate with WHO-FC (P=0.071). Tricuspid annular plane systolic excursion correlated with WHO-FC, mean right atrial pressure and survival (P<0.05). CONCLUSIONS: This early descriptive study shows that echocardiographic chararacteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The preliminary data from this study support the potential value of echocardiography as a tool in guiding management in children with PAH.

Quantification of ventricular volume load in the context of a bidirectional cavopulmonary shunt: a theoretical treatise.

BACKGROUND: Functional univentricular hearts are currently palliated by a staged procedure of which the bidirectional cavopulmonary shunt is usually the second stage. In addition to this stage, a calibrated amount of additional pulmonary blood flow may be preserved to promote pulmonary artery growth and increase the length of the interval preceding the total cavopulmonary connection. However, additional pulmonary blood flow can be deleterious for ventricular functioning and development as it increases functional ventricular volume load. METHODS: Using the Fick principle we devised a theoretic framework to estimate the ventricular volume loading caused by additional pulmonary and collateral aortopulmonary flow. To use this framework, blood samples need to be taken intraoperatively from the aorta, pulmonary veins, and inferior caval vein to determine oxygen saturations. The oxygen saturation samples have to be taken sequentially with and without additional pulmonary blood flow. RESULTS: The objective of this paper is to provide a theoretic framework to estimate the ventricular volume loading caused by collateral aortopulmonary flow and additional pulmonary blood flow in the context of a bidirectional cavopulmonary shunt in the staged palliation of univentricular hemodynamics. The formulas have not yet systematically been applied in vivo. CONCLUSIONS: The added volume loading of the ventricle caused by additional pulmonary blood flow can theoretically be estimated using the newly devised formulas so as to calibrate ventricular volume loading to a desired level intraoperatively.

The effect of additional pulmonary blood flow on timing of the total cavopulmonary connection.

BACKGROUND: The staged Fontan procedure is used to palliate functionally univentricular hearts. The effect of additional pulmonary blood flow combined with a bidirectional cavopulmonary shunt in these patients remains a controversial subject. METHODS: This retrospective study included all 82 patients with a unilateral or bilateral bidirectional cavopulmonary shunt at our institution between April 1990 and July 2010. Patients with hypoplastic left heart syndrome were excluded. Two groups, based on the presence (n=57) or absence (n=25) of additional pulmonary blood flow after the bidirectional cavopulmonary shunt, were compared. RESULTS: Patients with a bidirectional cavopulmonary shunt combined with additional pulmonary blood flow had higher arterial oxygen saturations postoperatively (86% [interquartile range, 85% to 90%] vs 82% [80% to 85%]; p=0.001) and had a longer median interval before the total cavopulmonary connection (3.42 [2.43 to 4.89] years vs 2.90 [2.08 to 3.32] years; p=0.06). At the total cavopulmonary connection, they were older (4.59 [3.88 to 6.49] years vs 3.94 [3.10 to 4.57] years; p=0.03) and had a larger median body surface area (0.73 [0.65 to 0.87] m2 vs 0.68 [0.59 to 0.73] m2; p=0.04). CONCLUSIONS: Patients with a bidirectional cavopulmonary shunt and additional pulmonary blood flow have a longer interval before the total cavopulmonary connection without evident untoward effects. This may theoretically be advantageous for the pulmonary artery growth needed for a successful Fontan circulation. Furthermore, postponement of the final Fontan may ensure the insertion of a larger extracardiac conduit to avoid prosthesis-patient mismatch.

Differential responses of the right ventricle to abnormal loading conditions in mice: pressure vs. volume load.

AIMS: Right ventricular (RV) dysfunction is a major determinant of long-term morbidity and mortality in congenital heart disease. The right ventricle (RV) is genetically different from the left ventricle (LV), but it is unknown as to whether this has consequences for the cellular responses to abnormal loading conditions. In the LV, calcineurin-activation is a major determinant of pathological hypertrophy and an important target for therapeutic strategies. We studied the functional and molecular adaptation of the RV in mouse models of pressure and volume load, focusing on calcineurin-activation. METHODS AND RESULTS: Mice were subjected to pulmonary artery banding (PAB), aorto-caval shunt (Shunt), or sham surgery (Control). Four weeks later, mice were functionally evaluated with cardiac magnetic resonance imaging, pressure measurements, and voluntary cage wheel exercise. Right ventricular hypertrophy and calcineurin-activation were assessed after sacrifice. Mice with increased pressure load (PAB) or volume load (Shunt) of the RV developed similar degrees of hypertrophy, yet revealed different functional and molecular adaptation. Pulmonary artery banding increased expression of Modulatory-Calcineurin-Interacting-Protein 1 (MCIP1), indicating calcineurin-activation, and the ratio of beta/alpha-Myosin Heavy Chain (MHC). In addition, PAB reduced exercise capacity and induced moderate RV dilatation with normal RV output at rest. In contrast, Shunt did not increase MCIP1 expression, and only moderately increased beta/alpha-MHC ratio. Shunt did not affect exercise capacity, but increased RV volumes and output at rest. CONCLUSIONS: Pressure and volume load induced different functional and molecular adaptations in the RV. These results may have important consequences for therapeutic strategies to prevent RV failure in the growing population of adults with congenital heart disease.

Neonatal myocardial infarction or myocarditis?

We report a 29 week-gestation preterm infant who presented during his second week of life with cardiogenic shock. Clinical presentation and first diagnostics suggested myocardial infarction, but echocardiographic features during follow-up pointed to a diagnosis of enteroviral myocarditis. The child died of chronic heart failure at 9 months of age. Autopsy showed passed myocardial infarction. No signs for active myocarditis were found. We discuss the difficulties in differentiating between neonatal myocardial infarction and myocarditis. Recognizing enteroviral myocarditis as cause for cardiogenic shock is of importance because of the therapeutic options.

Continuous indomethacin infusion may be less effective than bolus infusions for ductal closure in very low birth weight infants.

The effectiveness of continuous indomethacin (INDO) infusion versus bolus infusions for closure of patent ductus arteriosus (PDA) was investigated. The study design was an open-label case series (continuous INDO) with historic controls matched for gestational age (bolus INDO). Ductal closure rates were determined in two groups: 16 preterm infants with PDA treated with continuous INDO infusion (CONTIN group) and 16 control patients, matched for gestational age, who received bolus INDO infusions (BOLUS group). The total dosage was the same for both groups. PDA closed in seven of 16 preterm infants in the CONTIN group and in 13 of 16 in the BOLUS group ( p = 0.033, Fisher's exact test). In infants < 1000 g it was two of eight in the CONTIN group and 10 of 10 in the BOLUS group ( p = 0.002). Continuous INDO infusion was more likely than bolus infusion to be associated with failure of ductal closure (odds ratio, 19; 95% CI, 1.5 to 247; p = 0.023). This indicates that continuous infusion of INDO may be less effective in closing PDA than bolus infusions, especially in extremely low birth weight infants.