Working towards risk stratification for ascending aortic dilatation in pediatric Turner syndrome patients: results of a longitudinal echocardiographical observation.

This study aimed to longitudinally evaluate aortic root dimensions and elasticity in pediatric Turner syndrome (TS) in relation to known cardiac implications such as coarctation of the aorta (CoA) and bicuspid aortic valves (BAV) in order to create an improved risk profile for the presumed underlying vessel pathology in childhood. We report on the longitudinal findings of our pediatric TS outpatient clinic over a period of up to 7.6 years. Forty-nine TS patients (median age at baseline 9.7 ± 5.9 years, range 0-19.8) were followed-up for on average 2.9 ± 1.1 examinations and a median time of 3.4 ± 1.6 years. Aortic root (AoR) diameters and corresponding Z-scores were determined echocardiographically, and elasticity parameters as well as annual progression rates were calculated. At baseline, 16.3% of patients showed Z-scores > 2 at one or more levels of the AoR (35.7% of patients with BAV, odds ratio of 4.2). There was net progression to be noted at all measuring levels, leading to 28.6% of patients (50% of patients with BAV) exhibiting aortic dilatation at the end of follow-up. Progression correlated with the presence of BAV, non-mosaic monosomy, and age. A levelling-off of progression was seen with the onset of adolescence. CONCLUSIONS: Marked progression of aortic diameters leading to the development of dilatation can be observed in TS patients during childhood and stresses the importance of close surveillance during childhood. Main risk factors are BAV and complete monosomy 45X0. A beneficial influence of estrogen substitution can be suspected but needs further investigation. WHAT IS KNOWN: • Patients with Turner syndrome are at an increased risk for aortic dilatation and dissection. • The presence of BAV and complete monosomy 45X are additional risk factors. WHAT IS NEW: • Aortic dilatation can be detected in pediatric patients with Turner syndrome. • Relevant progression in childhood is possible in at-risk individuals and warrants close surveillance.

Characterization of phenotypic spectrum of fetal heterotaxy syndrome by combining ultrasound and magnetic resonance imaging.

OBJECTIVE: Heterotaxy or isomerism of the atrial appendages is a congenital disorder with variable presentation, associated with both cardiac and non-cardiac anomalies, which may have a serious impact on fetal outcome. The aim of this exploratory study was to assess the value of fetal magnetic resonance imaging (MRI), as a complementary tool to ultrasound, for describing the morphological spectrum encountered in heterotaxy. METHODS: This retrospective study included 27 fetuses that underwent fetal MRI following prenatal suspicion of heterotaxy on ultrasound from 1998 to 2019 in a tertiary referral center. Heterotaxy was classified as left atrial isomerism (LAI) or right atrial isomerism (RAI) based on fetal echocardiography (FE) examination. In addition to routine prenatal ultrasound, fetal MRI was offered routinely to enhance the diagnosis of non-cardiac anomalies, which might have been missed on ultrasound. Prenatal findings on ultrasound, FE and MRI were reviewed systematically and compared with those of postnatal imaging and autopsy reports. RESULTS: Twenty-seven fetuses with heterotaxy and cardiovascular pathology, of which 19 (70%) had LAI and eight (30%) had RAI, were included. Seven (7/19 (37%)) fetuses with LAI had normal intracardiac anatomy, whereas all fetuses with RAI had a cardiac malformation. All 27 fetuses had non-cardiac anomalies on fetal MRI, including situs and splenic anomalies. In 12/19 (63%) fetuses with LAI, a specific abnormal configuration of the liver was observed on MRI. In three fetuses, fetal MRI revealed signs of total anomalous pulmonary venous connection obstruction. An abnormal bronchial tree pattern was suspected on prenatal MRI in 6/19 (32%) fetuses with LAI and 3/8 (38%) fetuses with RAI. CONCLUSIONS: Visualization on MRI of non-cardiac anomalies in fetuses with suspected heterotaxy is feasible and can assist the complex diagnosis of this condition, despite its limitations. This modality potentially enables differentiation of less severe cases from more complex ones, which may have a poorer prognosis. Fetal MRI can assist in prenatal counseling and planning postnatal management. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal diagnosis of giant cardiac rhabdomyoma in tuberous sclerosis complex: a new therapeutic option with everolimus.

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by abnormal cell proliferation and tumor growth in a number of organ systems, primarily the brain, kidneys, eyes and heart. Clinical symptoms vary according to the location of the tumor. The most common disorders are seizures, neurodevelopmental disorders, renal failure and arrhythmias. TSC was found to be influenced by inhibitors of the protein kinase mammalian target of rapamycin (mTOR), which regulates abnormal cellular proliferation. mTOR inhibitors have been studied effectively in patients with subependymal giant-cell astrocytomas and renal angiolipomas in the context of TSC. We describe a prenatally diagnosed case of giant rhabdomyoma, due to right ventricular outflow tract obstruction, which presented as a duct-dependent lesion. Postnatal treatment with the mTOR inhibitor everolimus initiated significant regression of the cardiac tumor. This finding suggests that mTOR inhibitor therapy is an option for giant rhabdomyomas that develop in the neonatal period.

Detection of 15 novel mutations in 52 children from 40 families with the Marfan or Loeys-Dietz syndrome and phenotype-genotype correlations.

We report about 52 pediatric patients of 40 different families with confirmed Marfan syndrome (MFS) in 49 patients and Loeys-Dietz syndrome (LDS) in 3 patients. We found 39 different mutations, 15 of them being novel. Phenotype-genotype correlation in the 49 MFS patients showed that the majority of patients carrying mutations in exons 1-21 had ectopic lens (80%). Patients having mutations in exons 23-32 had a higher probability of aortic root dilation, in 50% even above a z score of 3. We found three children with neonatal MFS form, two of them with novel mutations. Of the three LDS patients, only one presented with the typical phenotype of LDS type 1.

Anti-activated factor II assay for monitoring unfractionated heparin in children: results of the HEARTCAT study.

Essentials Unfractionated heparin has variable effects in children and therefore, monitoring is essential. A randomized controlled trial substudy investigating an anti-IIa assay in children was conducted. Anti-IIa values are lower in younger children, an effect more pronounced at low-dose heparin. Heparin effect on Xa and IIa is not equal, particularly in infants and after high-dose heparin. SUMMARY: Background Unfractionated heparin (UFH) is used for the prophylaxis and treatment of thrombosis in children. Laboratory monitoring of UFH is needed to prevent over-anticoagulation or under-anticoagulation. Objectives To investigate the association between UFH dose and UFH effect as monitored with the anti-activated factor II (FIIa) assay, the relationship between anti-FIIa and anti-activated factor X (FXa) effects, and the influence of patient age and other factors on UFH effect. Patients and methods This was a randomized controlled trial in children during cardiac catheterization, comparing high-dose UFH (100 units kg-1 bolus) with low-dose UFH (50 units kg-1 bolus). Blood samples were drawn at baseline, and after 30 min, 60 min, and 90 min. For the purpose of this study, 49 children and 117 blood samples were evaluated. Results The anti-FIIa assay discriminated well between high-dose and low-dose UFH. Multiple regression demonstrated significant influences of UFH dose and age on anti-FIIa levels. Younger children had lower anti-FIIa levels than older children, an effect that was more pronounced with low-dose UFH. Anti-FXa/anti-FIIa ratios were equal with low-dose UFH. However, anti-FXa levels were relatively increased over anti-FIIa levels in infants and after high-dose UFH bolus administration. Conclusion The UFH effect on anti-FIIa levels is lower in infants than in older children. This influence of age appears to be dose-dependent, being more pronounced with low-dose UFH. Anti-FXa and anti-FIIa levels are not equal, particularly in infants and after high-dose UFH. Monitoring UFH solely with anti-FXa assays may not be sufficient in children, and the anti-FIIa assay may provide important complementary information.

Pulmonary flow reserve in children with idiopathic pulmonary arterial hypertension: implications for diagnosis and therapy.

AIMS: Endothelial dysfunction is likely to contribute to the pathogenesis of idiopathic Pulmonary Arterial Hypertension (iPAH). We hypothesize that there are different patterns of endothelial cell function, which we studied in 17 children with iPAH. METHODS AND RESULTS: Pulmonary flow reserve was determined by acetylcholine infusion into segmental pulmonary arteries utilizing quantitative angiography and intra-arterial Doppler flow wire. Depending on the reactivity of the pulmonary to systemic arterial pressure ratio to short-term oxygen and intravenous epoprostenol or aerosolized iloprost responders and nonresponders were classified. In 7 responders to oxygen-prostanoid administration the pressure ratio decreased from 0.9 +/- 0.2 to 0.31 +/- 0.11 (p = 0.01), the mean pulmonary flow reserve showed an excessive increase to 3.6 +/- 2.0 (p = 0.01) after infusion of acetylcholine. In 10 non-responders the pressure ratios remained unchanged during oxygen-prostanoid testing. 4 of 5 patients without any effect to acetylcholine died despite long-term epoprostenol treatment. The other 5 nonresponders to oxygen-prostanoid showed an impaired but significant increase of the pulmonary flow reserve of 1.6 +/- 1.1 (p = 0.01). 2 of these patients did not only improve clinically, but regained vascular reactivity by additional therapy with sildenafil. CONCLUSION: Endothelial reactivity in iPAH is either extensive, impaired or absent. Acetylcholine infusion casts a light on the pathogenesis and has implications for therapy.

Distribution of type I and type II collagen gene expression during the development of human long bones.

The temporal and spatial gene expression of collagen type I and type II during the development of the human long bones was studied by the technique of in situ hybridization covering the period from the cartilagenous bone anlage to the formation of a regular growth plate in the newborn. Analysis of the early stages around the seventh week of gestation revealed for type II collagen a strong hybridization signal limited to the chondrogenic tissue. The surrounding connective tissue and the perichondrium showed weak type I collagen expression, while the zones of desmal ossification like the clavicle gave a strong signal. Beginning with the eighth week of gestation, type I collagen mRNA was detectable in newly formed osteoblasts at the diaphysis and appeared along with the formation bone marrow, in the areas of enchondral ossification. Parallel to the development of the different zones of cartilage differentiation, a specific pattern of type II expression could be observed: type II was mainly found in the chondrocytes of the hypertrophic zone and to a lesser degree in the zone of proliferation, while the resting zone and the zone of provisional calcification showed little activity. This segregation of type II expression was most pronounced in the early stages of cartilage calcification and in the growth plate of the newborn.

Percutaneous closure of secundum atrial septal defect with a new self centering device ("angel wings").

OBJECTIVE: To investigate the safety, efficacy, and clinical application of a new self centering device ("angel wings") for closure of secundum atrial septal defects (ASD II) and persistent foramen ovale in all age groups. DESIGN: Multicentre, prospective, nonrandomised study. INCLUSION CRITERIA: defects with an occlusive diameter of < or = 20 mm and a surrounding rim of > 4 mm; body weight > 10 kg; and an indication for surgical closure of secundum atrial septal defect. Additionally, there were compassionate indications for closure in patients with persistent foramen ovale. INTERVENTIONS: Defects were closed by a transcatheter device consisting of two square frames made of superelastic nitinol wire. The frames are covered by elastic polyester fabric, which is sewn together at a central circle. All procedures, except for three interventions that were carried out under sedation, were performed under general anaesthesia using transoesophageal echocardiography and fluoroscopy to monitor intervention. RESULTS: Closure was attempted in 75 (71%) of 105 patients. An ASD II was present in 35 children and 15 adults. A persistent foramen ovale was present in 25 adults with suspected paradoxical embolism. Transcatheter closure was unsuccessful in three children and crossover to surgery was required. Residual shunts were found in 20 patients (27%) immediately after the procedure. A transient atrioventricular third degree block occurred in three patients (4%) and the right atrial disk was not fully deployed in three. A minor shunt (< 3 mm) was present in only three (4%) of 72 patients during follow up of 1-17 months. Blood clots on the right atrial disks in two patients (one required lysis) were seen during follow up transoesophageal echocardiography. Serious complications demanding surgical removal of the device occurred in three patients. One patient had haemopericardial tamponade because of an aortic lesion. Left atrial thrombus formation due to an unfolded right atrial disk was found in a second patient and dislodgement of the left atrial disk resulted in a large residual shunt in a third. CONCLUSIONS: Percutaneous closure of a central ASD with a diameter < or = 20 mm in paediatric and adult patients is feasible and effective with this new device. It is a promising alternative to surgical closure. Modifications of the design, however, seem to be mandatory as 4% of patients developed serious complications.

Norepinephrine, enoximone, and nitric oxide for treatment of myocardial stunning and pulmonary hypertension in a newborn with diaphragmatic hernia.

A newborn with right diaphragmatic hernia suffered myocardial stunning and suprasystemic pulmonary hypertension secondary to postpartal asphyxia. In addition to conventional therapy, norepinephrine, enoximone, and inhalational nitric oxide were successfully used. Norepinephrine improved myocardial perfusion pressure; the addition of enoximone, a phosphodiesterase-inhibitor, to beta-adrenergic agents increased cardiac performance. with decreasing concentrations of inhalational nitric oxide, severe pulmonary hypertension resolved after a few days, suggesting that transient endothelial dysfunction was partially responsible for pulmonary vasoconstriction in the newborn with congenital diaphragmatic hernia.

Incidence of thrombotic and bleeding complications during cardiac catheterization in children: comparison of high-dose vs. low-dose heparin protocols.

BACKGROUND: During cardiac catheterization (CC) in children, unfractionated heparin (UFH) is used for primary prophylaxis of thrombotic events (TE). However, the optimal UFH dose to minimize TE and bleeding in children has yet to be established. OBJECTIVES: To (i) objectively assess the incidence of TE and bleeding during pediatric CC using clinical assessment and ultrasound; and (ii) compare a high-dose vs. low-dose UFH protocol for thromboprophylaxis. METHODS: A randomized controlled trial (RCT) comparing high-dose UFH (100 units kg(-1) bolus, followed by 20 units kg h(-1) continuous infusion) vs. low-dose UFH (50 units kg(-1) bolus) during CC. Outcome assessment was by clinical examination and vascular ultrasound, performed by blinded examiners before and within 48 h after CC. Children with no consent for randomization were followed in a cohort receiving standard-of-care UFH (parallel-cohort RCT). RESULTS: A total of 227 children were included; 137 were randomized and 90 followed in the cohort study. The overall incidence of TE was 4.6% and bleeding 6.6%. The RCT was stopped early for futility as there were no differences between the high-dose and the low-dose UFH in TE (5% vs. 3%; risk ratios [RR] 1.5, 95% confidence interval [CI] 0.3; 9) and bleeding (7% vs. 12%, RR 0.6, 95% CI 0.2; 2). There were also no differences when RCT and cohort study populations were combined. CONCLUSIONS: The incidences of TE and bleeding during CC in children were low. There were no differences between the high-dose and the low-dose UFH protocols studied. Although Heparin Anticoagulation Randomized Trial in Cardiac Catheterization (HEARTCAT) was not designed as non-inferiority trial, low-dose UFH (50 units kg(-1) bolus) appears sufficient for thromboprophylaxis during CC.

Balloon valvuloplasty in the treatment of congenital aortic valve stenosis--a retrospective multicenter survey of more than 1000 patients.

BACKGROUND: The value of balloon valvuloplasty of the aortic valve in childhood is still under debate. OBJECTIVE: To evaluate the results of the procedure in a retrospective multicenter survey of a large cohort over a long time interval. METHODS: Retrospective analysis of 1004 patients with balloon valvuloplasty of the aortic valve performed between 9/1985 and 10/2006 at 20 centers in Germany, Austria and Switzerland. Amongst others, the following parameters were evaluated before and after the procedure as well as at the end of follow-up or before surgery: clinical status, left ventricular function, transaortic pressure gradient, degree of aortic regurgitation, freedom from re-intervention or surgery. PATIENTS: Patients from 1 day to 18 years of age with aortic valve stenosis were divided into four groups: 334 newborns (1-28 days); 249 infants (29-365 days); 211 children (1-10 years), and 210 adolescents (10-18 years). RESULTS: Median follow-up was 32 months (0 days to 17.5 years). After dilatation the pressure gradient decreased from 65 (± 24)mm Hg to 26 (± 16)mm Hg and remained stable during follow-up. The newborns were the most affected patients. Approximately 60% of them had clinical symptoms and impaired left ventricular function before intervention. Complication rate was 15% in newborns, 11% in infants and 6% in older children. Independently of age, 50% of all patients were free from surgery 10 years after intervention. CONCLUSIONS: In this retrospective multicenter study, balloon valvuloplasty of the aortic valve has effectively postponed the need for surgery in infants, children and adolescents up to 18 years of age.

Fenestration in extracardiac conduits in children after modified Fontan operation by implantation of stent grafts.

Three patients (ages 3, 5, and 8 years) with various forms of functionally univentricular heart lesions received a total cavopulmonary connection with an extracardiac conduit as a final reconstructive procedure. Failure of the Fontan circulation occurred immediately after surgery because of spontaneous closure of surgical fenestrations in two children and absent fenestration in one. As an emergency procedure, in all patients the conduit was perforated by transcatheter intervention in order to create a connection to the anatomical right atrium. Following balloon dilatation of the perforated conduit, in all three patients covered stent grafts were placed in the newly created defect to attain a reliable communication. Patency of the fenestration was demonstrated by angiogram and any leakage was ruled out. Cardiac output improved and severe pleural effusion and ascites subsided. Right-to-left shunt could be demonstrated by echocardiography at follow-up after 7 months (median) in all three patients. Oxygen saturation remained stable between 85 and 90%. These preliminary results suggest that stent graft fenestration can serve as a valuable tool in failing Fontan circulation, particularly in patients with an extracardiac conduit. Covered stents have the potential to reduce the acute risk of bleeding and they help to prevent early spontaneous closure of the newly created fenestration.

Perioperative management in pediatric heart transplantation.

Peri- and early postoperative mortality significantly influences the probability of survival following heart transplantation in children. Main causes of death early after transplantation are rejection, non specific graft failure and RV failure due to pulmonary hypertension. Optimal therapy of pulmonary hypertension and aggressive use of assist devices as a bridge to recovery will substantially improve survival in the early period after transplantation. Furthermore, the use of marginal donor organs will be more acceptable because transient myocardial insufficiency may recover during extracorporeal life support.

Transcatheter radiofrequency perforation and stent implantation for palliation of pulmonary atresia in a 3060-g infant.

In a 3060-g infant with fibromuscular pulmonary atresia an open right ventricular outflow tract was created by means of interventional cardiological methods. Following two inadvertent perforations without sequelae or clinical symptoms, radiofrequency perforation and subsequent balloon dilatation were successfully performed. The implantation of a Palmaz iliac stent led to a predictable communication between the right ventricle and pulmonary artery.

[Reopening of a persistent left superior vena cava in the early postoperative period following bidirectional cavopulmonary anastomosis--treatment by coil embolization]. / Frühpostoperative Eröffnung einer linkspersistierenden oberen Hohlvene nach bidirektionaler cavopulmonaler Konnektion - Coilembolisation als Therapie der Wahl.

Diagnosis of systemic venous drainage is mandatory for patients with congenital heart disease planned for cavopulmonary anastomosis or any Fontan-type palliation. Preexisting venous channels as the persistent left superior vena cava are common in cardiac anomalies and may lead to postoperative deterioration and cyanosis. We describe a 6 month old boy with a complex imbalanced atrioventricular septal defect who developed cyanosis in the very early postoperative period, following bidirectional cavopulmonary anastomosis. It was caused by ineffective lung perfusion due to a reopened persistent left superior vena cava with drainage to the coronary sinus.He underwent coil embolization of the persistent left superior vena cava with retrievable coils and cyanosis improved. Coil embolization is an effective alternative to secondary surgery, especially for hemodynamically compromised patients in the postoperative period.

Gradual angioplasty and stent implantation to treat complete superior vena cava occlusion after Mustard procedure.

A 16-year-old male was admitted with complete occlusion of the superior vena cava pathway 14 years after Mustard procedure for transposition of the great arteries. From a left subclavian vein approach, the atretic vein segment was perforated using a straight guidewire, and was followed by sequential balloon dilation. Implantation of a 30 mm Palmaz-stent through a femoral vein approach resulted in a widely patent channel of the vena cava superior into the systemic venous atrium.

[Intravascular stents for treatment of systemic venous obstructions]. / Intravaskuläre Stents zur Behandlung systemvenöser Obstruktionen.

Two young adults, 16 and 18 years of age were admitted with complete occlusion of the superior vena cava pathway following previous Mustard procedure. In both patients, perforation of complete occluded vein segment using a straight guidewire and subsequent sequential enlargement by balloon dilation were successfully performed by a left subclavian vein approach. Implantation of a 30 mm Palmaz-stent resulted in a widely patent channel of the vena cava superior into the systemic venous atrium. In short-term follow-up of 3 months both stents remained patent. Repeat dilation of the stents was performed after 3 months. A third patient with systemic venous obstruction was a 3-year old child who suffered low cardiac output following modified Fontan operation caused by a narrowing of the superior vena cava to right pulmonary artery connection and stenosis of distal left pulmonary artery. The severe hemodynamic problem was resolved by implantation of Palmaz-stents in the two separate obstructions. At recatheterization 6 months later, both stents were patent without any residual pressure gradient.

Superior caval venous syndrome after atrial switch procedure: relief of complete venous obstruction by gradual angioplasty and placement of stents.

Superior caval venous syndrome is one of the late problems known to occur after Mustard repair of complete transposition. Reoperation may leave residual stenosis, and carries substantial risk for the patient. It is now feasible to use intravascular stents to overcome systemic venous baffle obstructions, and such an approach is probably more effective. The purpose of our study therefore, was to assess immediate and medium term results of inserting stents subsequent to gradual balloon enlargement of acquired atresia of the intraatrial baffle in patients who had undergone an atrial switch operation. We investigated five patients with complete obstruction of the superior caval venous pathway at perforation of the atretic segment was achieved using a guide wire technique. The procedure was successful in all patients. Gradual angioplasty was performed and intravascular stents were implanted. The pressure in the superior caval vein dropped to normal values, symptoms improved, and the patency of the newly created venoatrial communication was proven at mid-term follow-up. Thus critical obstructions at the superior caval venous pathway after the Mustard procedure can be reopened by interventional catheterization. Implantation of balloon-expandable intravascular stents is safe and effective in the acute relief of the obstructions, but careful long-term follow-up is mandatory.