Primary cardiac tumours in a paediatric population.

OBJECTIVE: To review the presentation, diagnosis, histology and outcome of primary cardiac tumours presenting to a paediatric cardiac unit over a 20-year period. METHODS: Hospital records and data bases were searched for the years 1980-2000. RESULTS: There were 12 patients with four histological tumour types including a predominance of rhabdomyoma, as well as myxoma, fibroma and myocardial hamartoma. Diagnosis was made in utero, by ultrasound in five cases and in the neonatal period in a further three cases. Six cases (50%) required surgical intervention and there were three tumour-related deaths. Two infants with large left ventricular tumours diagnosed in utero developed univentricular physiology, acting like hypoplastic left heart syndrome at birth. CONCLUSIONS: Despite an absence of malignant histology there was significant mortality and morbidity among the patients reviewed. The development of univentricular physiology in infants with large left ventricular tumours is rare and is a difficult management problem.

Outcome following surgical closure of secundum atrial septal defect.

OBJECTIVE: To assess the current outcome of surgical closure of secundum atrial septal defects (ASD) in an Australian paediatric population. METHODOLOGY: A retrospective chart review of 87 children, aged 2 months to 15 years, was performed for surgery between August 1995 and March 1999. RESULTS: There were no deaths in the patients studied. Approximately one in four patients (24.1%) experienced complications requiring further management. Complication rates were similar to those published previously. However, one in nine patients (11.5%) required surgical drainage of a pericardial effusion. A total of five of 87 (5.7%) patients developed post-pericardiotomy syndrome (PPS), of whom four required pericardiocentesis. The risk for developing a pericardial effusion requiring drainage or PPS was more than twice in children older than 5 years of age at the time of surgery compared to those aged under 5 years, although there was an insufficient number of subjects in the study to prove this statistically (Odds ratio 2.31). CONCLUSIONS: Most patients have an uncomplicated postoperative course following surgical closure of secundum ASD. However, a significant minority (24.1%) do develop complications requiring further management and have a correspondingly longer period of hospitalization. Patients older than 5 years of age were identified as being potentially at greater risk for the development of PPS or a pericardial effusion requiring drainage. Further research needs to be performed to clarify this.

Transcatheter embolisation of coronary artery fistulae.

BACKGROUND: Most children with coronary artery fistulae are asymptomatic, but because of associated late morbidity, early intervention is usually indicated. AIM: To assess the outcome following transcatheter embolisation of coronary artery fistulae. PATIENTS AND METHODS: Six children, with a median age of 9.5 years (range: 1.3-13.7 years), underwent transcatheter embolisation of coronary artery fistulae. Four patients had simple fistulae, which drained from the right coronary artery to the right ventricle (n = 2), the left coronary artery to the right ventricle (n = 1), or the left coronary artery to the coronary sinus (n = 1). Two patients had complex multiple fistulae arising from both coronary arteries, which communicated with either the right ventricle or the pulmonary arterial system. RESULTS: A stable position with a 5-Fr coronary catheter was obtained proximally and a 3-Fr coaxial catheter was advanced through the coronary catheter to a distal position in the coronary artery fistulae. The number of embolisation microcoils used per procedure ranged from one to 12, and the coil diameter ranged from 3 mm. Polyvinyl alcohol foam embolisation particles (1000 microm) were used to embolise small fistulae to the pulmonary arterial tree. Complete occlusion was obtained in four patients, while two children were left with insignificant residual shunts. There were no early or late cardiac complications. CONCLUSION: Transcatheter embolisation of coronary artery fistulae is a safe and effective therapy in patients with suitable anatomy.

Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells.

OBJECTIVE: Recruitment of neutrophils to sites of inflammation requires coordinated regulation of their capture, activation, and migration on vascular endothelium. This study examines whether exposure of neutrophils to antineutrophil cytoplasmic antibodies (ANCAs) can disrupt this sequence of events. METHODS: Isolated human neutrophils were perfused in the presence or absence of ANCA-positive IgG over endothelial cells that had been activated with either 2 units/ml or 100 units/ml of tumor necrosis factor alpha (TNFalpha) for 4 hours. RESULTS: When endothelial cells were activated with 100 units/ml of TNFalpha, neutrophils were captured from flow, a small proportion of adherent cells rolled, and the majority transmigrated through the endothelial cell monolayer. When neutrophils were treated with ANCA IgG immediately before, 5 minutes before, or 15 minutes before perfusion, none rolled on contact with the endothelium, but the majority still transmigrated. When endothelial cells were activated with 2 units/ml of TNFalpha, the majority of untreated adherent neutrophils rolled, a few transmigrated, and the number that attached decreased with time during washout. In contrast, when neutrophils were pretreated with ANCA IgG just before perfusion, adhesion was stabilized, and the number of neutrophils that transmigrated was increased 10-fold. Priming of the neutrophils with TNFalpha before the addition of ANCA further increased the stability of neutrophil binding, but did not significantly increase transmigration. CONCLUSION: Rather than frustrating the transmigration process, ANCAs promoted the migration of neutrophils through the endothelium. That the effect was evident at a relatively low level of endothelial activation suggests that ANCAs may potentiate the early vasculitic lesion and promote tissue damage and recruitment of other proinflammatory cells.

The middle aortic syndrome: an important feature of Williams' syndrome.

The middle aortic syndrome, with diffuse narrowing of the thoracic and abdominal aorta, was present in 10 of 18 patients with Williams' syndrome (55%). There were 3 thoracic coarctations, and 2 abdominal coarctations, with gradients greater than 20 mmHg across the zone of narrowing. Seven patients had mild renal arterial stenosis, and 6 had visceral arterial stenoses. Ten were hypertensive. Measured dimensions of the aortic lumen failed to increase with age in 3 males who had serial angiographic studies. One developed mesenteric arterial stenosis, with mild bilateral renal arterial stenoses, between the ages of 9 and 19 years. Aortic intravascular ultrasound performed in 2 patients confirmed abnormally thick vessel walls with small lumens. Diffusely narrowed and thick-walled stiff arteries, lacking elastin, are a feature of Williams' syndrome. The arteriopathy tends to progress with age, and systemic hypertension is common in teenagers and beyond. The middle aortic syndrome was present in more than half our patients, and does not necessarily reflect a bias because of cardiologic referral. Aortography with measurement of aortic diameters and delineation of the visceral branches is an important requirement for complete evaluation of patients with Williams' syndrome.

Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin-mediated adhesion.

OBJECTIVE: The vascular lesions associated with autoimmune small-vessel vasculitis may arise from activation of circulating neutrophils by antineutrophil cytoplasmic antibodies (ANCA), resulting in increased adhesion of these neutrophils to the vessel wall. The present study examined the effects of ANCA-positive IgG (ANCA IgG), derived from patients with small-vessel vasculitis, on neutrophil adhesion. METHODS: An in vitro, flow-based adhesion assay was used to determine the effects of ANCA IgG on neutrophils rolling on P-selectin presented by a monolayer of activated platelets. The platelets act as a surrogate vessel wall and can also support beta2 integrin-mediated immobilization of neutrophils if they are purposefully activated (e.g., by FMLP). RESULTS: In the absence of any added agents, neutrophils rolled continuously over the platelet monolayer. Superfusion of ANCA IgG over rolling cells resulted in conversion to stationary adhesion accompanied by shape change. The ANCA-mediated response was transient, peaking at 5-6 minutes and returning to baseline by 15 minutes, even in the continued presence of ANCA. In contrast, normal (ANCA-negative) IgG and ANCA F(ab')2 fragments caused minimal conversion to stationary adhesion. Pretreatment of neutrophils with blocking antibodies directed toward Fc gamma receptor type IIA or the integrin chain CD11b completely inhibited the ANCA-mediated conversion, confirming that ANCA-mediated activation occurred through Fc gamma receptors and that neutrophil immobilization was mediated by the activated beta2 integrin (CD11b/CD18). CONCLUSION: These findings support the concept that ANCA can directly activate neutrophils to become firmly adherent to vessel walls, where they may obstruct flow, initiate tissue damage, and contribute to pathogenesis of vasculitis.

The activation of the neutrophil respiratory burst by anti-neutrophil cytoplasm autoantibody (ANCA) from patients with systemic vasculitis requires tyrosine kinases and protein kinase C activation.

The ability of antineutrophil cytoplasm autoantibodies (ANCA) from patients with systemic vasculitis to stimulate protein kinase C (PKC) and tyrosine kinases was examined in human neutrophils. Using the superoxide dismutase-inhibitable reduction of ferricytochrome C, the kinetics of ANCA-induced superoxide (O2-) production were characterized and subsequently manipulated by specific inhibitors of PKC and tyrosine kinases. With this approach, ANCA IgG, but not normal IgG or ANCA F(ab')2 fragments caused a time and dose dependent release of O2- from TNF-alpha primed neutrophils. The kinetics of ANCA-induced O2- production showed an initial 10-15 min lag phase compared to the N-formyl-L-methionyl-L-leucyl-L-phenylalanine response, suggesting differences in the signalling pathways recruited by these two stimuli. Inhibitor studies revealed that ANCA-activation involved members of both the Ca2+-dependent and -independent PKC isoforms and also tyrosine kinases. ANCA IgG resulted in the translocation of the betaII isoform of PKC at a time corresponding to the end of the lag phase of O2- production, suggesting that PKC activity may be instrumental in processes regulating the activity of the NADPH oxidase in response to ANCA. Tyrosine phosphorylation of numerous proteins also peaked 10-15 min after stimulation with ANCA but not normal IgG. These data suggest that PKC and tyrosine kinases regulate O2- production from neutrophils stimulated with autoantibodies from patients with systemic vasculitis.

Percutaneous transluminal coronary angioplasty in a 30-month-old child with embolic long segment occlusion of the left anterior descending artery.

A 30-mo-old girl developed occlusion of her left anterior descending coronary artery following mitral valve replacement. She presented with refractory angina pectoris. Successful percutaneous transluminal coronary angioplasty of the left anterior descending artery was performed, resulting in restoration of flow, resolution of anginal symptoms, and early improvement in left ventricular function.

IL-1 beta production by human polymorphonuclear leucocytes stimulated by anti-neutrophil cytoplasmic autoantibodies: relevance to systemic vasculitis.

Neutrophils accumulate in the acute blood vessel lesions of patients with autoimmune systemic vasculitis. They have been shown previously to produce the cytokine IL-1 beta in response to stimulation with TNF. This study demonstrates that neutrophils can be stimulated by anti-neutrophil cytoplasmic antibodies (ANCA), which are present in patients with systemic vasculitis, to express mRNA and protein for IL-1 beta. Both human ANCA and MoAbs to a variety of autoantigens recognized by ANCA, including proteinase 3, myeloperoxidase, bactericidal/permeability increasing protein and elastase, are effective. This response can be inhibited by actinomycin and cycloheximide, suggesting a requirement for de novo protein synthesis. IL-1 beta production can be inhibited by pooled human intravenous immunoglobulins but not by FK506 or cyclosporin A. These data suggest that ANCA in patients with active vasculitis may stimulate neutrophils to produce cytokines. It is hypothesized that cytokine production from neutrophils that accumulate in significant numbers in vasculitic lesions contribute to and augment the local inflammatory response by the activation of vascular endothelial cells and infiltrating leucocytes.

Endothelial cells and renal epithelial cells do not express the Wegener's autoantigen, proteinase 3.

Proteinase 3 (PR3) is the major antigen for autoantibodies (C-ANCA) against cytoplasmic components of neutrophils which are strongly associated with Wegener's granulomatosis (WG). Recent data that PR3 may be expressed by renal tubular epithelial cells and endothelial cells suggest potential for a direct pathogenic effect against these cells by C-ANCA or cytoxic T lymphocytes. Using a semi-quantitative polymerase chain reaction (PCR), ELISA and indirect immunofluorescence staining we studied endothelial and epithelial cell PR3 expression. By PCR, no PR3 expression was found in human umbilical vein endothelial cells (HUVEC) either untreated, or when treated with interferon-gamma (IFN-gamma) (200 U/ml, 6 h, 24 h), IL-1 (20 U/ml, 6 h), tumour necrosis factor-alpha, (TNF-alpha) (200 U/ml, 0, 1, 2, 4, 6 h) or IFN-gamma + TNF-alpha (6 h); iliac vein and artery endothelial cells did not express PR3 either. In contrast, PR3 was detected in HL60 cells and neutrophils by PCR, expression being confirmed by sequence analysis. Three PR3 MoAbs showed no binding to unstimulated or TNF-alpha-stimulated HUVEC either by ELISA or by indirect immunofluorescence staining. The epithelial cell line A549 expressed PR3 when assayed by PCR. However, three renal epithelial cell lines (two tubular and one glomerular) showed little or no PR3 expression by PCR or ELISA. These studies fail to demonstrate evidence for PR3 expression by endothelial cells, even when using the highly sensitive PCR assay. Whilst PR3 expression by A549 cells is intriguing, the relevance of this in the pathology of WG is doubtful considering the negligible expression by renal epithelial cell lines.

Immunological detection of cardiac glycosides in plants.

Australian native and introduced plants were examined, using digoxin immunoassays, to detect the presence of cross-reacting cardiac glycosides. These compounds were found in 27 species from 20 genera. The assay technique can also be used on serum samples to confirm cardiac glycoside ingestion.

Pulmonary veno-occlusive disease: diagnosis during life in four patients.

Pulmonary veno-occlusive disease is a rare form of primary pulmonary hypertension of unknown aetiology. Four cases were diagnosed in young patients. The diagnosis was suspected on the basis of clinical, radiological, echocardiographic, and catheter evidence and confirmed by taking a lung biopsy sample. In all patients the histology showed obstruction of the pulmonary veins by intimal fibrosis. The clinical course of all patients has been one of progressive deterioration. Although there is no specific treatment for this disease, to establish the diagnosis during life is of great importance in overall clinical management, including counselling the patient and family.

Oral health of children with congenital cardiac diseases: a controlled study.

Congenital cardiac disease (CCD) is one of the most common developmental anomalies in children. Affected children require special care in dentistry because of their susceptibility to infective endocarditis from oral infections, yet little information is available on the oral health of children with CCD. The present study, which investigated 39 children with CCD and 33 healthy control siblings, showed that CCD children generally suffered poorer oral health. In patients with primary dentitions, 52% of CCD children had enamel hypoplasia, compared with only 23% in the control group. In addition, CCD children had significantly more teeth with untreated dental decay (mean dmft 4.2 vs. 2.3), and more endodontically treated teeth. Children with CCD also had less than optimal professional and home dental care. Only 31% had professional advice regarding increased preventive dental health behavior, and only 15% used fluoride supplements, although the children resided in a nonfluoridated area. Furthermore, significantly fewer CCD children had parental help with tooth brushing compared to control children. This study shows that children with CCD should be targeted for vigorous preventive dental care.

Pregnancy outcome and Ebstein's anomaly.

BACKGROUND: Ebstein's anomaly is an uncommon congenital cardiac abnormality that may be associated with cyanosis and arrhythmias. For those female patients with the anomaly who survive to adult life there is little information available about pregnancy, maternal complications, and fetal outcome. This study was designed to address this issue so that these patients can receive appropriate advice and management. METHODS AND RESULTS: Forty two pregnancies in 12 women with Ebstein's anomaly were studied. The mothers' cardiac lesions were assessed on the basis of symptoms, the presence of cyanosis or arrhythmia, and by echocardiographic grading of severity. In the absence of important maternal cyanosis or arrhythmia, pregnancy was well tolerated. Neonatal outcome was good though there was an increased risk of prematurity and dysmaturity in the babies born to mothers with cyanosis. CONCLUSIONS: This study indicates that women with Ebstein's anomaly who reach child-bearing age can be advised that pregnancy is likely to be well tolerated with good fetal outcome. Maternal arrhythmia or cyanosis are indications for closer maternal and fetal observation.

Fetal echocardiography in the diagnosis of congenital heart disease.

Fetal echocardiography provides an opportunity to diagnose congenital heart disease as early as the midtrimester of pregnancy, allowing for proper planning of perinatal care and counselling of the parents. This paper reviews the accuracy and outcomes of fetal cardiac ultrasound studies at The Prince Charles Hospital over the past 4 years. A total of 43 fetuses, of gestational ages 16-39 weeks, were studied. The indications for these were: previous sibling with cardiac anomaly (16 cases); abnormal heart on obstetric ultrasound scan (USS) (13 cases); abnormalities found on obstetric USS with normal appearing heart (one case); fetal bradycardia (seven cases); fetal tachycardia (four cases); irregular fetal heart beat (two cases). At birth all fetuses assessed because of a previously affected sibling were normal. Of the 13 referred because of structural heart lesions suspected on obstetric USS, eight were abnormal, four were normal and one was terminated without autopsy. Important rhythm disturbances occurred in nine of the 11 referred because of abnormal heart rates. One false positive diagnosis of a possible coarctation was made, and in four cases an abnormality was noted on USS but the diagnosis was not completely correct. Nine of the 19 infants with abnormalities detected have died. Fetal echocardiography is an accurate and useful method of diagnosing congenital heart disease in utero. Although the mortality of affected fetuses is high, antenatal diagnosis allows planning of medical care and offers the greatest chance of a successful outcome.

Fetal and neonatal congenital complete heart block.

Fifteen cases of congenital complete heart block were diagnosed in utero or at birth, over a nine-year period. Six cases were confirmed by fetal echocardiography between 22 and 36 weeks of gestation. Two cases were treated in utero for cardiac failure, and serial ultrasonography was used to monitor the progress. Structural heart disease was present in seven (47%) infants; in four of these infants the defect was a corrected transposition of the great arteries. Ventricular pacing was required in seven patients--four infants with anatomically-normal hearts and three infants with associated structural heart disease. Eight children did not require permanent pacing, and remained well after a mean follow-up period of 23 months (range, one to 72 months). The mortality was highest in those patients with structural heart disease, three of whom died as neonates. Only one baby died with an anatomically-normal heart. Antinuclear antibodies were present in the mothers of seven of the eight infants who were born with a structurally-normal heart. Four mothers either had pre-existing connective-tissue disease or had developed manifestations of such disease subsequent to pregnancy. Of this group, all the women were antibody-seropositive to the nuclear antigen SS-A during pregnancy. Mothers of three infants had antinuclear antibodies in low titres, were seronegative for antibody to SS-A and remained free of the manifestations of connective-tissue disease. Six of the seven most-recent cases have been diagnosed in utero, which confirms a trend towards the more-frequent prenatal diagnosis of congenital heart disease as a result of the increased use of fetal monitoring and ultrasonography.

Facial and immunological anomalies associated with tetralogy of Fallot.

Dysmorphic facial features were present in 9 of 31 children with tetralogy of Fallot anatomy (29%). These anomalies included hypertelorism, low-set ears, small mouth, short philtrum, and micrognathia. Ten children had pulmonary atresia, 13 (42%) had a right aortic arch, and 13 had extracardiac congenital anomalies. There were 16 children in the series (52%) who had hospital admissions for important or recurrent infections, and 18 who had immune deficiency: low levels of T lymphocytes were found in 9, low levels of complement in 8, and low immunoglobulins in 3. Embryologically, the cardiac outflow tracts, the aortic arch, the face, and the thymus develop at the same time, and all receive migrating cells from the neural crest. Teratogenic factors possibly produce this constellation of anomalies, which is in the spectrum of the Di George syndrome (third and fourth pharyngeal pouch syndrome). It is of importance for the management of such children, that their immune deficiency be recognized and treated appropriately.

Spectrum of Di George syndrome in patients with truncus arteriosus: expanded Di George syndrome.

A study of 26 patients with truncus arteriosus showed a high prevalence of facial dysmorphism, aortic arch abnormalities, extracardiac malformations, and significant prenatal risk factors. There was little evidence of parathyroid or thymic abnormalities. However, there was laboratory evidence of immune deficiency, especially T-helper lymphocytes, and clinical evidence of predilection to infection. These findings suggest that patients with truncus arteriosus belong to the spectrum of the Di George syndrome.

The association between immunodeficiency and congenital heart disease.

The predilection of children with congenital heart disease (CHD) to infection may be explained in part by an underlying immunodeficiency disorder. Some 13 syndromes in which immunodeficiency and CHD may coexist have been reported in the medical literature. In addition, immunoglobulin and T-cell deficiencies have been found in nonsyndromal patients with CHD. The diagnosis of immunodeficiency should be entertained in such children, as early recognition of an immunodeficiency disorder can result in improved antimicrobial and immunological management.