Herbert E. Ulmer

Perinatal Outcome of Fetal Complete Atrioventricular Block: A Multicenter Experience

The clinical course and outcome of 55 fetuses with complete atrioventricular (AV) block detected prenatally were studied to identify factors that affect the natural history of this lesion. In 29 fetuses (53%) complete AV block was associated with complex structural heart defects, usually left atrial isomerism (n = 17) or discordant AV connection (n = 7). The other 26 fetuses had normal cardiac anatomy; in 19 cases the mother had connective tissue disease or tested positive for antinuclear antibodies. Six fetuses showed progression from sinus rhythm or second degree block to complete AV block. Of the 55 pregnancies, 5 were terminated and 24 fetuses or neonates died; at the end of the neonatal period 26 fetuses were still alive. Fetal or neonatal death correlated significantly with the presence of structural heart defects (4 of 29 surviving, p less than 0.001), hydrops (0 of 22 surviving, p less than 0.001), an atrial rate less than or equal to 120 beats/min (1 of 12 surviving, p less than 0.005) or a ventricular rate less than or equal to 55 beats/min (3 of 21 surviving, p less than 0.001). Mean atrial and ventricular rates were higher in surviving than in nonsurviving fetuses (142 +/- 8 vs. 127 +/- 21 beats/min, p less than 0.002; 64 +/- 8 vs. 52 +/- 8 beats/min, p less than 0.001, respectively). A slow atrial rate, however, was frequently associated with left atrial isomerism.(ABSTRACT TRUNCATED AT 250 WORDS)

Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study

BACKGROUND Serum thyroid hormone concentrations decline transiently during critical illness and after surgical procedures. We investigated prospectively the endocrine and haemodynamic effects of tri-iodothyronine treatment after cardiopulmonary bypass operations in children with congenital cardiac malformations. METHODS We did a randomised, double-blind, placebo-controlled trial, in which 40 children (median age 0.6 years; range 2 days to 10.4 years) were randomly assigned placebo (saline) or one daily infusion of tri-iodothyronine (2 microg/kg bodyweight on day 1 after surgery and 1 microg/kg bodyweight on subsequent postoperative days up to 12 days after surgery. Before and 2 h, 24 h, and 72 h after the first infusion, plasma concentrations of thyroid hormones were measured by RIA, and systolic cardiac function was evaluated by echocardiography. During the postoperative course intensive-care measures were assessed by use of the therapeutic intervention scoring system. FINDINGS In all patients, postoperative plasma concentrations of thyrotropin, thyroxine, free thyroxine, tri-iodothyronine were abnormally low and plasma concentrations of reverse tri-iodothyronine were raised. After start of treatment, tri-iodothyronine was significantly higher in patients given tri-iodothyronine than in those receiving placebo, whereas thyrotropin, thyroxine, free thyroxine, and reverse tri-iodothyronine remained similar in the two groups. At discharge, thyroid hormones of all patients were within the normal range, but thyrotropin secretion increased to plasma concentrations higher than those seen before treatment. The mean change of cardiac index was significantly higher in children given tri-iodothyronine (20.4% [SD 19.6] vs 10.0% [15.2]; p=0.004). Systolic cardiac function improved most in patients given tri-iodothyronine after longer cardiopulmonary bypass operations. Overall, patients given tri-iodothyronine had significantly lower mean treatment scores. INTERPRETATION Treatment of children with tri-iodothyronine after cardiopulmonary bypass operations raises tri-iodothyronine plasma concentrations and improves myocardial function especially in patients with low postoperative cardiac output without adverse events, and without delaying postoperative recovery of thyroid function. Furthermore, tri-iodothyronine reduces the need for postoperative intensive care.

Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension.

Asymmetrical dimethyl-l-arginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. We hypothesized that plasma levels of ADMA could be increased in patients with congenital heart disease and pulmonary hypertension. Cardiac catheterization was performed in 20 children and young adults with congenital heart disease with a median age of 10 years (range, 4 months to 33 years). The patients were assigned to group I (high flow, low pressure; n = 14) when Qp/Qs was 1.5 or greater and the mean PAP was less than 25 mm Hg or to group II (high pressure, high resistance; n = 6) when the mean PAP was greater than 25 mm Hg and Rp/Rs was greater than 0.3. Blood samples were taken from pulmonary vein or left ventricle. ADMA was measured by high-performance liquid chromatography. In addition, levels of ADMA were measured in peripheral venous blood obtained from eight control patients. Levels of ADMA in control patients (median, 0.21 &mgr;M/l; range, 0.08–0.27 &mgr;M/l) did not differ from levels obtained in group I (median, 0.30 &mgr;M/l; range, 0.06–0.49) &mgr;M/l). Patients in group II showed increased plasma levels of ADMA (median, 0.55; range, 0.25–0.79) (p < 0.01). Inhibition of nitric oxide synthase by increased levels of ADMA might contribute to pulmonary hypertension in patients with congenital heart disease.

Missense Mutations and Gene Interruption in PROSIT240, a Novel TRAP240-Like Gene, in Patients With Congenital Heart Defect (Transposition of the Great Arteries)

Background—Congenital heart disease represents the most common severe birth defect, affecting 0.7% to 1% of all neonates, among whom 5% to 7% display transposition of the great arteries (TGA). TGA represents a septation defect of the common outflow tract of the heart, manifesting around the fifth week during embryonic development. Despite its high prevalence, very little is known about the pathogenesis of this disease. Methods and Results—Using a positional cloning approach, we isolated a novel gene, PROSIT240 (also termed THRAP2), that is interrupted in a patient with a chromosomal translocation and who displays TGA and mental retardation. High expression of PROSIT240 within the heart (aorta) and brain (cerebellum) was well correlated with the malformations observed in the patient and prompted further analyses. PROSIT240 shows significant homology to the nuclear receptor coactivator TRAP240, suggesting it to be a new component of the thyroid hormone receptor-associated protein (TRAP) complex. Interestingly, several TRAP components have been previously shown to be important in early embryonic development in various organisms, making PROSIT240 an excellent candidate gene to be correlated to the patient’s phenotype. Subsequent mutational screening of 97 patients with isolated dextro-looped TGA revealed 3 missense mutations in PROSIT240, which were not detected in 400 control chromosomes. Conclusions—Together, these genetic data suggest that PROSIT240 is involved in early heart and brain development.

Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation

AIMS Left ventricular non-compaction (LVNC) is caused by mutations in multiple genes. It is still unclear whether LVNC is the primary determinant of cardiomyopathy or rather a secondary phenomenon with intrinsic cardiomyocyte dysfunction being the actual cause of the disease. Here, we describe a family with LVNC due to a novel missense mutation, pE96K, in the cardiac troponin T gene (TNNT2). METHODS AND RESULTS The novel mutation was identified in the index patient and all affected relatives, but not in 430 healthy control individuals. Mutations in known LVNC-associated genes were excluded. To investigate the pathophysiological implications of the mutation, we generated transgenic mice expressing human wild-type cTNT (hcTNT) or a human troponin T harbouring the pE96K mutation (mut cTNT). Animals were characterized by echocardiography, histology, and gene expression analysis. Mut cTNT mice displayed an impaired left ventricular function and induction of marker genes of heart failure. Remarkably, left ventricular non-compaction was not observed. CONCLUSION Familial co-segregation and the cardiomyopathy phenotype of mut cTNT mice strongly support a causal relationship of the pE96K mutation and disease in our index patient. In addition, our data suggest that a non-compaction phenotype is not required for the development of cardiomyopathy in this specific TNNT2 mutation leading to LVNC.

External Stabilization of Long-Segment Tracheobronchomalacia Guided by Intraoperative Bronchoscopy

BACKGROUND Symptomatic obstruction of long-segment tracheal or bronchial portions either related to congenital instability or secondary to vascular compression are rare malformations, which remain difficult to manage. A method of external tracheal or bronchial stabilization is described. METHODS From July 1992 to April 1995, 7 children (age range, 4 months to 4 years; mean age, 19 months) and 1 adult (age, 46 years) were operated on for severe respiratory insufficiency. In 4 cases of congenital tracheal instability, 2 children had associated type IIIb esophageal atresia. Both children with esophageal atresia had previous operations (two and three times, respectively): 1 child had aortopexy and division of a patent ductus arteriosus and another child had distal tracheal resection elsewhere, both without relief of malacia. All children were intubated and ventilated since birth for 11 to 15 months. Secondary tracheobronchomalacia due to vascular compression was seen in 4 patients caused by double aortic arch (n = 2) and persisting ligamentum arteriosum after previous ligation of a patent ductus arteriosus (n = 2), with 1 child ventilated thereafter for 5 months. Operation was performed with the aid of extracorporeal circulation in all patients but 1, and consisted of transection of vascular rings and persistent ligamentum Botalli (n = 5), closure of multiple ventricular septal defects (n = 1) and extensive mobilization of the tracheobronchial tree as well as the great arteries. External stabilization of the severely dysplastic distal trachea (n = 6) or left main bronchus (n = 2) was achieved by suspending the malacic segment within an oversized and longitudinally opened ring-reinforced polytetrafluoroethylene prosthesis. Multiple plegeted sutures were placed extramucosally to the dysplastic tracheal wall and the dyskinetic pars membranacea, as well as to the polytetrafluoroethylene prosthesis in a radial orientation. Guided by simultaneous video-assisted bronchoscopy, reexpansion of the collapsed segments was achieved by gentle traction on the sutures while tying. RESULTS Stenosis-free tracheobronchial reexpansion was achieved in all patients, as seen on repeated bronchoscopies during hospitalization and thereafter. All patients were extubated within 1 to 12 days after the operation. There was one late death, unrelated to the procedure, in a 31-month-old child 20 months after the operation. All other patients are free of stridor and in excellent clinical condition 21 to 54 months (mean, 38 months) thereafter. CONCLUSIONS The presented method of bronchoscopically guided external tracheobronchial suspension within a ring-reinforced polytetrafluoroethylene prosthesis immediately relieves severe malacia of the trachea or main bronchi in infants as well as adults without necessitating resection. Midterm preliminary data suggest that growth potential of the affected segment exists within the oversized polytetrafluoroethylene prosthesis.

Preoperative assessment and follow-up of congenital abnormalities of the pulmonary arteries using CT and MRI

Congenital heart disease (CHD), including complex anomalies of the pulmonary arteries, are now earlier diagnosed and treated. Due to improvements in interventional and surgical therapy, the number of patients with the need for follow-up examinations is increasing. Pre- and postinterventional imaging should be done as gently as possible, avoiding invasive techniques if possible. With the technical improvement of multidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI), both techniques are increasingly used for noninvasive assessment of the pulmonary vasculature in children with CHD. Knowledge of the most common diseases affecting the pulmonary vasculature and the kind of surgical and interventional procedures is essential for optimal imaging planning. This is especially important because interventions can be positively influenced by high-quality imaging. Therefore, the most common diseases and procedures are described and imaging modality of choice and important image findings are discussed.

Primary Pulmonary Hypertension in Children May Have a Different Genetic Background Than in Adults

Mutations of the bone morphogenetic protein receptor II (BMPR2) gene on chromosome 2q33 can cause familial primary pulmonary hypertension (PPH) and may occur in 26% adult patients with sporadic disease. Other disease-related genes have been localized to chromosomes 2q31 (PPH2) and 12q13 (ALK1). The genetic background in affected children remains unclear. Thirteen children (age at diagnosis, 6 mo to 13 y; mean, 5.6 ± 3.9 y) with invasively confirmed PPH were screened for BMPR2 mutations using denaturing HPLC and sequence analysis. In addition, all children were scanned for BMPR2 deletions by Southern blot analysis. Pulmonary artery pressure was assessed using echocardiography at rest and during exercise in 57 family members of six infants. The six families were subjected to linkage analysis. None of the 13 children had a BMPR2 mutation or deletion. Linkage to chromosome 2 or 12 could not be confirmed in any of the families investigated. In all assessed families, both parents of the index patient and/or members of both branches revealed an abnormal pulmonary artery systolic pressure (PASP)-response to exercise. PPH in children may have a different genetic background than in adults. We postulate a recessive mode of inheritance in a proportion of infantile cases.

Rings, slings and other vascular abnormalities. Ultrafast computed tomography and magnetic resonance angiography in pediatric cardiology.

Die neuen Methoden der ultraschnellen CTund MR-Angiographien sind nicht-invasive, qualitativ hochwertige und aussagekräftige Methoden zur präoperativen Diagnostik und Planung angeborener Herzfehler und Anomalien der großen herznahen Gefäße bei Kindern und Jugendlichen. Sie zeigen sich in der Diagnostik der Gefäßanomalien der konventionellen Katheterangiographie gleichwertig. In der prognostischen Beurteilung potenziell bedeutsamer Komplikationen wie der Kompression der Trachea, der Bronchien oder des Ösophagus bieten sie sogar Vorteile. Die Möglichkeiten der ultraschnellen CT- und MR-Angiographie werden am Beispiel 22 pädiatrischer Patienten mit obstruktiven Gefäßanomalien aufgezeigt. Ultrafast CT and MR angiography are noninvasive, accurate and robust techniques for preoperative diagnosis and planning of congenital heart disease and vascular abnormalities in pediatric patients. While they seem to be equivalent to conventional catheter angiocardiography for detecting vascular abnormalities, they are more accurate for the diagnosis of potentially life-threatening complications, such as tracheal, bronchial or esophageal compression. The value of ultrafast CT and MR angiography is demonstrated in 22 pediatric patients with vascular rings, slings and other vascular abnormalities.

Rings, slings and other vascular abnormalities

Die neuen Methoden der ultraschnellen CTund MR-Angiographien sind nicht-invasive, qualitativ hochwertige und aussagekräftige Methoden zur präoperativen Diagnostik und Planung angeborener Herzfehler und Anomalien der großen herznahen Gefäße bei Kindern und Jugendlichen. Sie zeigen sich in der Diagnostik der Gefäßanomalien der konventionellen Katheterangiographie gleichwertig. In der prognostischen Beurteilung potenziell bedeutsamer Komplikationen wie der Kompression der Trachea, der Bronchien oder des Ösophagus bieten sie sogar Vorteile. Die Möglichkeiten der ultraschnellen CT- und MR-Angiographie werden am Beispiel 22 pädiatrischer Patienten mit obstruktiven Gefäßanomalien aufgezeigt. Ultrafast CT and MR angiography are noninvasive, accurate and robust techniques for preoperative diagnosis and planning of congenital heart disease and vascular abnormalities in pediatric patients. While they seem to be equivalent to conventional catheter angiocardiography for detecting vascular abnormalities, they are more accurate for the diagnosis of potentially life-threatening complications, such as tracheal, bronchial or esophageal compression. The value of ultrafast CT and MR angiography is demonstrated in 22 pediatric patients with vascular rings, slings and other vascular abnormalities.