Evidence for extrathymic T cell maturation after thymectomy in infancy.

Our previous study showed that children who had been partially or completely thymectomized during heart surgery as infants had lower proportions and numbers of total lymphocytes and reduced proportions of T cells (CD3(+)), helper T cells (CD4(+)) and naive T cells (CD3(+) CD4(+) CD45RA(+)), but normal proportion of cytotoxic T cells (CD8(+)). In this study T lymphocytes from a selected group of eight of these children and age- and gender-matched controls were characterized further using flow cytometry to determine phenotypes of T cells and T cell subsets related to T cell regulation and phenotypes suggestive of extrathymic maturation. Immune function was assessed by measuring autoantibodies and antibodies against vaccines. The study group had significantly lower numbers of all the main subsets of T lymphocytes and the composition was different. Thus, the proportions of lymphocytes with the following phenotypes: CD3(+), CD2(+), CD7(+), CD4(+), CD62L(+), CD4(+) CD62L(+) and CD4(+) CD69(-) were significantly reduced in the study group compared with the control group, but significantly higher proportions were seen of lymphocytes expressing CD8alpha(+) CD8beta(-) and TCRgammadelta(+) CD8alpha(+) CD8beta(-). The absolute number and proportion of CD4(+) CD25(+) cells were reduced but the proportions of the subgroup of naive regulatory T cells (CD4(+) CD25(+) CD62L(+)) and non-activated regulatory T cells (CD4(+) CD25(+) CD69(-)) were not reduced in the thymectomized children. We conclude that the phenotypic characteristics of T lymphocytes of children who have lost their thymus in infancy are indicative of extrathymic maturation. T regulatory cells appear to be less affected than other subsets by the general reduction in T cell numbers.

Pulmonary artery growth fails to match the increase in body surface area after the Fontan operation.

OBJECTIVE: To evaluate the growth of the pulmonary arteries after a Fontan procedure. DESIGN: Retrospective review. SETTING: Two paediatric cardiology tertiary care centres. PATIENTS: 61 children who underwent a modified Fontan operation and had angiography suitable for assessment of pulmonary artery size before the Fontan procedure and during long term follow up. An atriopulmonary connection (APC) was present in 23 patients (37.7%) and a total cavopulmonary connection (TCPC) was present in 38 (62.3%). Postoperative angiograms were performed 0.5-121 months (median 19 months) after the Fontan operation. MAIN OUTCOME MEASURE: Growth of each pulmonary artery measured just before the first branching point. The diameter was expressed as a z score with established nomograms used to standardise for body surface area. RESULTS: The mean change in the preoperative to postoperative z scores of the right pulmonary artery was -1.06 (p = 0.004). The mean change in the preoperative to postoperative z scores of the left pulmonary artery was -0.88 (p = 0.003). Changes in the preoperative to postoperative z scores were more pronounced in the patients undergoing APC than TCPC, especially for the right pulmonary artery. CONCLUSION: After the Fontan operation, growth of the pulmonary arteries often fails to match the increase in body surface area.

[Prenatal diagnosis of heart disease.].

Fetal echocardiography is a detailed examination of the fetal heart, its anatomy and function, performed with high frequency, high-resolution ultrasound probes. Advancements in echocardiographic technology have made possible accurate diagnosis of complex cardiac defects from a transabdominal approach, as early as 14-18 weeks of gestation, although optimal images are usually acquired at 20 weeks of gestation. Indications for fetal echocardiogram are maternal or fetal factors that place the fetus at increased risk for having heart defect but suspected cardiac abnormality on a level 1 scan is the most frequent referral indication and the one indication with the highest yield of positive fetal echocardiogram. Diagnosis of fetal heart disease can have major influences on the prenatnal and postnatal management and enables parents to prepare and plan for the birth of a child with a cardiac defect.

[Heart transplantation.].

Heart transplantation has been established as an accepted treatment for end-stage heart disease, in both adults and children. Survival following heart transplantation today is good, one year actuarial survival is 85% and approximately 65% after five years. Chronic rejection presenting as an post-transplant coronary artery disease is the main limiting factor for long term survival. Complications from immunosuppression are troublesome, but quality of life is generally very good.

Complications of endomyocardial biopsy in children.

OBJECTIVES: To evaluate the incidence of, and risk factors for, complications of endomyocardial biopsy in children. BACKGROUND: Endomyocardial biopsy (EMB) is a low risk procedure in adults, but there is a paucity of data with regard to performing this procedure in children. METHODS: Retrospective review of the morbidity and mortality of 1,000 consecutive EMB procedures. RESULTS: One thousand EMB procedures (right ventricle 986, left ventricle 14) were performed on 194 patients from July 1987 through March 1996. Indications for EMB included heart transplant rejection surveillance (846) and the evaluation of cardiomyopathy or arrhythmia for possible myocarditis (154). Thirty-seven (4%) procedures were performed on patients receiving intravenous inotropic support. There was one biopsy related death, secondary to cardiac perforation, in a two-week-old infant with dilated cardiomyopathy. There were nine perforations of the right ventricle, eight occurring in patients with dilated cardiomyopathy and one in a transplant recipient. The transplant patient did not require immediate intervention; two patients required pericardiocentesis alone, and six underwent pericardiocentesis and surgical intervention. All nine perforations were from the femoral venous approach (p < 0.01). Multivariate analysis demonstrated that the greatest risk of perforation occurred in children being evaluated for possible myocarditis (p = 0.01) and in those requiring inotropic support (p < 0.01). Other complications included arrhythmia (5) and single cases of coronary-cardiac fistula, flail tricuspid leaflet, pneumothorax, hemothorax, endocardial stripping and seizure. CONCLUSIONS: Risk of endomyocardial biopsy is highest in sick children with suspected myocarditis on inotropic support. However, EMB can be performed safely with very low morbidity in pediatric heart transplant recipients.

Potential role of mechanical stress in the etiology of pediatric heart disease: septal shear stress in subaortic stenosis.

OBJECTIVES: The objective of this study was to show elevations in septal shear stress in response to morphologic abnormalities that have been associated with discrete subaortic stenosis (SAS) in children. Combined with the published data, this critical connection supports a four-stage etiology of SAS that is advanced in this report. BACKGROUND: Subaortic stenosis constitutes up to 20% of left ventricular outflow obstruction in children and frequently requires surgical removal, and the lesions may reappear unpredictably after the operation. The etiology of SAS is unknown. This study proposes a four-stage etiology for SAS that I) combines morphologic abnormalities, II) elevation of septal shear stress, III) genetic predisposition and IV) cellular proliferation in response to shear stress. METHODS: Morphologic structures of a left ventricular outflow tract were modeled based on measurements in patients with and without SAS. Septal shear stress was studied in response to changes in aortoseptal angle (AoSA) (120 degrees to 150 degrees), outflow tract convergence angle (45 degrees, 22.5 degrees and 0 degree), presence/location of a ventricular septal defect (VSD) (3-mm VSD; 2 and 6 mm from annulus) and shunt velocity (3 and 5 m/s). RESULTS: Variations in AoSA produced marked elevations in septal shear stress (from 103 dynes/cm2 for 150 degrees angle to 150 dynes/cm2 for 120 degrees angle for baseline conditions). This effect was not dependent on the convergence angle in the outflow tract (150 to 132 dynes/cm2 over full range of angles including extreme case of 0 degree). A VSD enhanced this effect (150 to 220 dynes/cm2 at steep angle of 120 degrees and 3 m/s shunt velocity), consistent with the high incidence of VSDs in patients with SAS. The position of the VSD was also important, with a reduction of the distance between the VSD and the aortic annulus causing further increases in septal shear stress (220 and 266 dynes/cm2 for distances of 6 and 2 mm from the annulus, respectively). CONCLUSIONS: Small changes in AoSA produce important changes in septal shear stress. The levels of stress increase are consistent with cellular flow studies showing stimulation of growth factors and cellular proliferation. Steepened AoSA may be a risk factor for the development of SAS. Evidence exists for all four stages of the proposed etiology of SAS.

Abnormalities of the left ventricular outflow tract associated with discrete subaortic stenosis in children: an echocardiographic study.

OBJECTIVES: The purpose of this study was to examine the echocardiographic abnormalities of the left ventricular outflow tract associated with subaortic stenosis in children. BACKGROUND: Considerable evidence suggests that subaortic stenosis is an acquired and progressive lesion, but the etiology remains unknown. We have proposed a four-stage etiologic process for the development of subaortic stenosis. This report addresses the first stage by defining the morphologic abnormalities of the left ventricular outflow tract present in patients who develop subaortic stenosis. METHODS: Two study groups were evaluated-33 patients with isolated subaortic stenosis and 12 patients with perimembranous ventricular septal defect and subaortic stenosis-and were compared with a size- and lesion-matched control group. Subjects ranged in age from 0.05 to 23 years, and body surface area ranged from 0.17 to 2.3 m2. Two independent observers measured aortoseptal angle, aortic annulus diameter and mitral-aortic separation from previously recorded echocardiographic studies. RESULTS: The aortoseptal angle was steeper in patients with isolated subaortic stenosis than in control subjects (p < 0.001). This pattern was also true for patients with ventricular septal defect and subaortic stenosis compared with control subjects (p < 0.001). Neither age nor body surface area was correlated with aortoseptal angle. A trend toward smaller aortic annulus diameter indexed to patient size was seen between patients and control subjects but failed to achieve statistical significance (p = 0.08). There was an excellent interrater correlation in aortoseptal angle and aortic annulus measurement. The mitral-aortic separation measurement was unreliable. Our results, specifically relating steep aortoseptal angle to subaortic stenosis, confirm the results of other investigators. CONCLUSIONS: This study demonstrates that subaortic stenosis is associated with a steepened aortoseptal angle, as defined by two-dimensional echocardiography, and this association holds in patients with and without a ventricular septal defect. A steepened aortoseptal angle may be a risk factor for the development of subaortic stenosis.

Long-term survivors of pediatric heart transplantation: a multicenter report of sixty-eight children who have survived longer than five years.

OBJECTIVE: Short-term survival after pediatric heart transplantation is now excellent, but ultimately the efficacy of this procedure will depend on duration and quality of survival. We sought to evaluate the clinical course of long-term survivors of heart transplantation in childhood. METHODS: Patients who had undergone heart transplantation at the university hospitals of Stanford, Columbia, and Pittsburgh between 1975 and 1989 and survived longer than 5 years from transplantation were identified and their clinical courses retrospectively reviewed. RESULTS: Sixty eight children have survived more than 5 years from transplantation, and 60 (88%) are currently alive with a median follow-up of 6.8 years (5 to 17.9 years). Thirteen have survived more than 10 years from transplantation. Renal dysfunction caused by immunosuppressive agents was common, and two patients required late renal transplantation. Lymphoproliferative disease or other neoplasm occurred in 12 patients, but none resulted in death. Coronary artery disease was diagnosed in 13 patients (19%), leading to retransplantation in eight. Death after 5 years was related to acute or chronic rejection in 5 of 8 cases. Two of the deaths were directly related to noncompliance with immunosuppressive medication. All survivors are in New York Heart Association class 1. CONCLUSIONS: Long-term survival with good quality of life can be achieved after heart transplantation in childhood, though complications of immunosuppression remain common. Posttransplantation coronary artery disease is emerging as the main factor limiting long term graft and patient survival.

Intrapericardial left atrial aneurysm: noninvasive diagnosis.

Intrapericardial aneurysm of the left atrium is a rare cardiac anomaly. We present a 10-year-old girl in whom the diagnosis was made following referral for an abnormal configuration of the left heart border seen on chest radiography. Diagnosis was made by echocardiography, but magnetic resonance imaging defined the exact morphology and the relation to adjacent structures. Surgical removal of this aneurysm is recommended because of potentially serious complications.

[Congenital heart defects in Icelandic twins.].

OBJECTIVE: Several investigations have been published on the incidence of congenital heart defects (CHD), showing the incidence to be 0.8-1.1%. Few studies have dealt with the incidence of CHD in twins, but they indicate higher incidence of CHD among twins compared to singletons. The purpose of this study was to investigate the incidence of CHD and the different types of defects among twins born in Iceland over a 10 year period and compare the data to the incidence of CHD in the Icelandic population. MATERIAL AND METHODS: Information was obtained on all twins born alive in Iceland from 1986-1995 at the Icelandic Statistical Bureau. That list was compared to a list of all children born in Iceland over the same period and diagnosed with CHD, thus finding all twins with diagnosed CHD. The incidence of CHD for the period of 1986-1990 and 1991-1995 was studied separately. Causes of death, whether the patients needed treatment or not, and the results of treatment were studied. Chi-squared test for statistical analysis was used when appropriate. RESULTS: Incidence: Of 1089 liveborn twins 35 had CHD or 3.21% compared to an incidence rate of 1.0% among singletons, which is a statistically significant difference (p<0.001). The incidence was 2.13% in the years 1986-1990 and 3.78% in the years 1991-1995 (p<0.005). Types of defects: Of 35 twins with CHD 20 had minor defects (no treatment needed) whereas 15 had major defects. Ventricular septal defects were the most common defects encountered, or 40%, atrial septal defects were 20%, patent ductus arteriosus 9%, complex defects 9% and tetralogy of Fallot 6%. Other defects were less common. Sex ratio: The male/female ratio was 0.591, whereas the ratio in the control population was 1.1. However, this did not reach statistical difference (p>0.05). Twin types: Of the twins with CHD 34% were male-female pairs, 26% were male-male pairs and 40% were female-female pairs. Age at diagnosis: Thirteen patients were diagnosed in the first week of life and 20 from one week to five months of age. After six months of age only two patients have been diag notnosed with CHD. TREATMENT: Twelve patients have been operated for CHD, one patient was treated in an interventional cardiac catheterization and 10 patients received medical treatment. Mortality: Six twins died as a consequence of their heart defect (17%). The mortality rate was significantly higher among twins with major CHD compared to the control population (p<0.005). CONCLUSION: Congenital heart defects are more common among twins compared to the control group. They were also more common in the latter half of the investigation period. The mortality rate is also higher among the twins. In 1991 in titero fertilization was started in Iceland resulting in increased number of twins and at the same time increase in incidence of CHD is seen. Further studies are required to clarify this.

[Heart Transplantation: Treatment for children and adolescents with end-stage heart disease.].

Heart transplantation, which is the recently accepted treatment for children and adolescents with end stage heart disease, is the subject of this review article. Issues such as selection of patients, follow up and management post transplant are discussed, as well as the surgical procedure and the immediate postoperative management. Results from recent studies of long term survival following pediatric heart transplantation are discussed. Short term survival following heart transplantation is now excellent but limited long term follow-up data is available as this operation has only been performed for about two decades. One year survival is now over 90% and five year survival is estimated to be close to 70% in major transplant centers around the world. Post transplant coronary artery disease is mainly responsible for the decreased long term survival. Complications of immunosuppression such as infections, lymphoprolifrative disorders and depressed renal function are still common but usually not life threatening. Non-compliance with medication was observed amongst teenage recipients and can have lethal consequences. Despite this, it has been shown that heart transplantation can provide good quality of life and prolong survival in pediatric patients with end-stage heart disease.

[Cardiac surgery of the neonate and children in Iceland 1990-1995.].

Over the past three decades Icelandic children with congenital heart defects have been operated abroad. In 1990 the first infant with congenital heart defect underwent surgical correction here in Iceland that otherwise would have been transported to a foreign country. This paper summarizes our experience with children with congenital defects who have been operated in Iceland. There were 26 patients who underwent 28 surgical procedures, the ages were from three days to 18 years, median 10 months. Fourteen patients had coarctation of the aorta, four patients with complex defects underwent shunt operations, four patients had atrial septal defects and four patients underwent other operations. The 30 day mortality rate was 3.8% (one patient with complex defect died after shunt placement). There was one late death from progressive heart failure in spite of successful initial surgical palliation. Cost analysis is presented in the paper. In conclusion the overall results are encouraging and acceptable for correcting congenital heart defects here in Iceland and is cost effective.

Is a cleft in the anterior leaflet of an otherwise normal mitral valve an atrioventricular canal malformation?

OBJECTIVES: This study sought to ascertain the surgical anatomy of a cleft in the left atrioventricular (AV) valve. BACKGROUND: Important morphologic differences exist between hearts with a cleft in the anterior leaflet of an otherwise normal mitral valve and those with a so-called cleft in the left AV valve when there is an AV septal defect, but it has been customary to link the lesions together on developmental grounds. METHODS: Eight autopsied specimens with a cleft in the aortic (or anterior) leaflet of the mitral valve were studied in detail, and echocardiograms from 21 patients with such a cleft were compared with the specimens and with findings typical of the so-called partial AV canal and other forms of AV septal defect. RESULTS: The structure and direction of the cleft, location of the papillary muscles within the left ventricle and AV junctional morphology of hearts with an otherwise normally structured mitral valve were significantly different from typical findings in hearts with AV septal defects. CONCLUSIONS: It is necessary to distinguish morphologically a cleft in an otherwise normally structured mitral valve in hearts with separate right and left AV junctions from the trifoliate left component of a common AV valve in hearts with an AV septal defect and a common AV junction because the disposition of the AV conduction tissues varies markedly between the lesions.