Carol M. Cottrill

Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways

Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebsteins anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways.

Propranolol therapy during pregnancy, labor, and delivery: Evidence for transplacental drug transfer and impaired neonatal drug disposition

The administration of 160 mg of propranolol daily during pregnancy, labor, and delivery was associated with profound hypoglycemia and respiratory depression in a newborn infant. The neonates plasma propranolol level rose from 40 ng/ml at the time of birth to 90 ng/ml four hours later. This increase in plasma propranolol concentration might be due to redistribution of the drug in the neonate as well as to different elimination mechanisms than in adults. The elevated propranolol level four hours after delivery was not associated with any signs or symptoms of drug toxicity, but drug effect was apparent on the electrocardiogram. The administration of propranolol during pregnancy in doses capable of producing therapeutic maternal blood levels may be dangerous to the neonate.

Ventriculocoronary connections in hypoplastic left hearts: an autopsy microscopic study.

Serial microscopic sections of the left ventricular myocardium were examined in 12 autopsy specimens of hypoplastic left heart syndrome. Multiple ventriculocoronary arterial connections, thickwalled coronary arteries, prominent endocardial fibroelastosis, myofiber disarray and focal calcification/ scarring of the myocardium were noted in the cases with patent left ventricular inflow and obstructed outflow. The persistent embryonic microvascular pattern noted in these cases may be related to intrauterine outflow obstruction and could limit surgical attempts to produce a functional left ventricle in infants with hypoplastic left heart syndrome.

Pulmonary atresia with intact ventricular septum and ventriculocoronary communications: surgical significance.

The first stage of a repair of pulmonary atresia with intact ventricular septum (type I) was attempted in a 2-day-old infant. At surgery, decompression of the hypertensive small right ventricle was followed by a sudden loss of myocardial contractility and death. Postmortem examination revealed a fistula with a large orifice in the right ventricular infundibulum that communicated directly with the left main coronary artery. Severe hypertensive changes indicative of abnormally high perfusion pressure were noted in the distal left coronary artery branches. The clinical course suggests that the effect of relieving right ventricular outflow obstruction was a reduction of left main coronary artery blood flow, resulting in fatal intraoperative myocardial ischemia. This unusual case draws attention to the anomalous ventriculocoronary communications often present in pulmonary atresia and their potential for limiting a successful surgical repair.

Lymphocyte Subsets in Cord Blood of Preterm Infants: Effect of Antenatal Steroids

The objective of this study was to evaluate prospectively the influence of gestational age (GA) and short-term antenatal steroids on total lymphocyte count and lymphocyte subsets in cord blood from preterm infants. Two-color flow cytometric analyses of lymphocyte subsets were performed on cord blood collected from 67 infants. These infants were grouped according to GA: group I (term, n = 19); group II (GA 33–37 weeks, n = 25); group III (GA <33 weeks, n = 23). The mean absolute lymphocyte counts (ALC) in groups I, II and III were 5.6 ± 2.5 × 103/µl, 4.3 ± 1.5 × 103/µl and 3.5 ± 1.8 × 103/µl respectively. The mean values for CD4+ lymphocytes in groups I, II and III were 2.7 ± 0.8 × 103/µl, 2.0 ± 0.8 × 103/µl and 1.6 ± 0.9 × 103/µl respectively. Mean values for CD8+ lymphocytes were 0.9 ± 0.3 × 103/µl, 0.6 ± 0.3 × 103/µl and 0.5 ± 0.3 × 103/µl respectively. With decreasing GA, there was a statistically significant decrease in ALC (p = 0.0035), CD4+ lymphocytes (p = 0.0013) and CD8+ lymphocytes (p = 0.0064). We then evaluated the effect of antenatal steroids, now routinely administered to women with preterm onset of labor to facilitate fetal lung maturation, and found that after adjusting for GA, infants of women on antenatal steroids had significantly fewer ALC (p = 0.0001), CD4+ lymphocytes (p = 0.02) and CD25+ lymphocytes (p = 0.03). In this population of infants, the decreased number of lymphocytes seen at younger GAs is associated with antenatal steroid use.

Ventriculocoronary connections in hypoplastic right heart syndrome: Autopsy serial section study of six cases

Myocardial sinusoids communicating with the coronary systems occur in pulmonary atresia with intact ventricular septum. To test the hypothesis that the extent of ventriculocoronary connections correlates with the degree of right ventricular outflow obstruction as evidenced by clinical, angiographic and gross anatomic findings, a serial section study of six human autopsy hearts representing a spectrum of hypoplastic right heart was undertaken. Slides were evaluated for the presence and extent of ventriculocoronary connections, associated developmental abnormalities and secondary changes in the ventricular walls. Whereas extensive blind-ended deep sinusoids were a feature of all five cases with unrelieved obstruction, ventriculocoronary connections were identified in three. Changes that suggested ongoing remodeling provide new evidence for the postnatal temporal evolution of these anomalous communications. The regional distribution of myofiber disarray in hypoplastic right heart supports the concept that vascularization parallels myocardial organization in the developing human heart.

Tetralogy of Fallot with Absent Pulmonary Valve and Bronchial Compression: Treatment with Endobronchial Stents

Abstract. Absent pulmonary valve syndrome (APVS) is a rare congenital cardiac lesion. The lesion includes ventricular septal defect, overriding aorta, and absence of the pulmonary valve, with resultant pulmonary incompetence. It has been suggested that the pulmonary incompetence induces intrauterine dilatation of the pulmonary artery, which leads to tracheobronchial compression. One of the presenting features in infants with APVS is severe airway obstruction, which may be difficult to manage. We report an infant who benefited from bilateral endobronchial endoscopic stent placement.

Sternal defects associated with congenital pericardial and cardiac defects

We describe three cases of sternal defects of varying severity associated with other congenital anomalies. In the most severe case, both anterior and posterior defects were seen, with near-absence of the sternum and pericardium continuous with a large omphalocele. This resulted in external location of organs usually confined within the thoracic and abdominal cavities. A ventricular septal defect was present, and the arterial duct was absent. The course of the ascending aorta was anomalous. The baby had anencephaly and rachischisis. In the intermediate case, a proximal sternal cleft was associated with shortening of the sternum, and absence of the manubrium. Anterior pericardial and diaphragmatic defects were seen, while a scalp defect and an encephalocele were present on the posterior aspect of the head. This baby had tricuspid atresia. The remaining case had only an anterior defect with a shortened sternum. A supra-umbilical omphalocele contained a left ventricular diverticulum without interposing pericardium or diaphragm. Ventricular and atrial septal defects were present. The first two cases can be considered as representing failure of development of both an anterior and a posterior midline field. The third case, much milder than the other two, represents failure of development of an anterior field.

Primary Cardiac Lipoblastoma

Lipoblastoma is a benign adipose tumor in children that has been described in various anatomic locations, most commonly the extremities. We describe the case of a 17-month-old boy diagnosed with cardiac lipoblastoma, a previously unreported primary cardiac tumor in children. Our patient presented with symptoms of coughing, wheezing, and hoarseness and was found to have a large mediastinal mass, which narrowed the left mainstem bronchus and compressed the right atrium and superior vena cava, causing superior vena cava syndrome. Surgical exploration revealed an intrapericardial soft tissue mass arising from the area of the posterior interatrial septum. Grossly, the resected mass was lobulated, pale yellow, and fatty with focal areas of gray myxoid tissue. Microscopically, the tumor consisted of both immature and mature adipocytes, with focal vascular myxoid areas containing lipoblasts, diagnostic of lipoblastoma. Two months after surgery, the patient was in good health without evidence of recurrence.

Echocardiography in hypoxemic neonatal pulmonary disease

Sixteen newborn infants with severe pulmonary parenchymal disease and profound hypoxemia were treated with mechanical ventilation, alkalinization, and intravenous tolazoline. Eight infants responded within two hours of initiation of tolazoline therapy with a rise in Pao2 by at least 100% of pretreatment values (mean = 188%, range = 103 to 427%). Eight infants showed little or no change in Pao2 with administration of tolazoline. Echocardiographic evaluation prior to therapy demonstrated marked elevation in both left (LPEP/LVET = 0.52 +/- 0.13) and right (RPEP/RVET = 0.56 +/- 0.08) ventricular systolic time intervals in the eight infants who subsequently responded to tolazoline. Systolic time intervals in nonresponders were within the normal range (LPEP/LVET = 0.37 +/- 0.03, RPEP/RVET = 0.33 +/- 0.04) and were not significantly different from those observed in a control group of 15 infants with pulmonary disease requiring mechanical ventilation but without hypoxemia. Following tolazoline therapy, systolic time intervals in all eight responders fell to normal values. Echocardiography can provide a safe, noninvasive method for identifying those infants with primary pulmonary disease and severe hypoxemia who could be expected to benefit from tolazoline therapy, thereby avoiding tolazoline side effects in infants for whom tolazoline therapy can be predicted to be of little benefit.