PATHFINDER-CHD: prospective registry on adults with congenital heart disease, abnormal ventricular function, and/or heart failure as a foundation for establishing rehabilitative, prehabilitative, preventive, and health-promoting measures: rationale, aims, design and methods.

BACKGROUND: Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. AIMS: The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). METHODS: This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. DESIGN: The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. PROCESSES: Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. ASSESSMENTS: Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. DISCUSSION OF THE DESIGN: The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. CONCLUSION: The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.

Off-pump direct hepatic veins-to-hemiazygos vein anastomosis after primary Kawashima operation: long-term result.

Direct hepatic veins-to-hemiazygos connection offers the balanced distribution of hepatic venous blood to both lungs, not requiring anticoagulation. We report a 13-year follow-up after this type of off-pump Fontan completion. Patient's hepatic veins-to-hemiazygos confluence increased with growth to allow for unobstructed flow. This unique technique can be recommended in heterotaxy patients, if atrial hepatic venous drainage and hemiazygos vein are in close proximity.

Portal vein thrombosis in Fontan-associated liver disease.

A 25-year-old patient with signs of cirrhosis on ultrasound and CT presented with portal vein thrombosis on routine follow-up examinations; retrograde hepatic wedge angiography demonstrated only the right-sided portal vein branch. Development of a portosystemic collateral vessel to the left-sided renal vein prevented signs of hypersplenism. This unique complication of portal vein thrombosis should be considered during long-term surveillance.

Predictors of health-related quality of life in children with chronic heart disease.

OBJECTIVE: Chronic paediatric heart disease is often associated with residual symptoms, persisting functional restrictions, and late sequelae for psychosocial development. It is, therefore, increasingly important to evaluate the health-related quality of life of children and adolescents with chronic heart disease. The aim of this study was to determine medical and socio-demographic variables affecting health-related quality of life in school-aged children and adolescents with chronic heart disease. Patients and methods The Pediatric Cardiac Quality of Life Inventory was administered to 375 children and adolescents and 386 parental caregivers. Medical information was obtained from the charts. The socio-demographic information was provided by the patients and caregivers. RESULTS: Greater disease severity, low school attendance, current cardiac medication, current parental employment, uncertain or limited prognosis, history of connection to a heart-lung machine, number of nights spent in a hospital, and need for treatment in a paediatric aftercare clinic independently contributed to lower health-related quality of life (self-report: R2=0.41; proxy-report: R2=0.46). High correlations between self-reports and parent-proxy reports indicated concordance regarding the evaluation of a child's health-related quality of life. CONCLUSIONS: Beyond medical treatment, integration into school is important to increase health-related quality of life in children and adolescents surviving with chronic heart disease. Regular screening of health-related quality of life is recommended to identify patients with special needs.

Neonatal aortic arch obstruction due to pedunculated left ventricular foetal myxoma.

Myxoma in neonatal life are extremely rare. We report a case of a neonate with a pedunculated cardiac tumour arising from the anterolateral left ventricular wall protruding across the left ventricular outflow tract and continuously extending into the distal aortic arch. Surgical removal at 14 days of age via combined transaortic approach and apical ventriculotomy was indicated because of the risk of further compromise of aortic valve function and aortic arch obstruction. Histopathologic examination was consistent with a myxoma.

Thoracic lymphatic anomalies in patients with univentricular hearts: correlation of morphologic findings in isotropic T2-weighted MRI with the outcome after fontan palliation.

Objectives: In this study we examined the correlation between the extent of thoracic lymphatic anomalies in patients after surgical palliation by total cavopulmonary connection (TCPC) and their outcome in terms of clinical and laboratory parameters. Materials and methods: We prospectively examined 33 patients after TCPC with an isotropic heavily T2-weighted MRI sequence on a 3.0 T scanner. Examinations were performed after a solid meal, slice thickness of 0.6 mm, TR of 2400 ms, TE of 692 ms, FoV of 460 mm, covering thoracic and abdominal regions. Findings of the lymphatic system were correlated with clinical and laboratory parameters obtained at the annual routine check-up. Results: Eight patients (group 1) showed type 4 lymphatic abnormalities. Twentyfive patients (group 2) presented less severe anomalies (type 1-3). In the treadmill CPET, group 2 reached step 7.0;6.0/8.0 vs. 6.0;3.5/6.8 in group 1 (p = 0.006*) and a distance of 775;638/854 m vs. 513;315/661 m (p = 0.006*). In the laboratory examinations, group 2 showed significantly lower levels of AST, ALT and stool calprotectin as compared to group 1. There were no significant differences in NT-pro-BNP, total protein, IgG, lymphocytes or platelets, but trends. A history of ascites showed 5/8 patients in group 1 vs. 4/25 patients in group 2 (p = 0.02*), PLE occurred in 4/8 patient in group 1 vs. 1/25 patients in group 2 (p = 0.008*). Conclusion: In the long-term follow-up after TCPC, patients with severe thoracic and cervical lymphatic abnormalities showed restrictions in exercise capacity, higher liver enzymes and an increased rate of symptoms of imminent Fontan-failure such as ascites and PLE.

Health and quality of life in adults with Noonan syndrome.

OBJECTIVE: To obtain information on health and quality of life in adults with Noonan syndrome. STUDY DESIGN: From a cohort of 144 children with the diagnosis of Noonan syndrome whose height data had been published 23 years ago, 103 pediatric files providing adequate data were identified. Participants were sent questionnaires and asked to provide saliva for DNA analysis and to return for physical examination. RESULTS: Ten of 103 individuals had died, 3 of them suddenly (standardized mortality ratio, 3.00; 95% CI, 1.44-5.52). Eighty-one individuals could be contacted by mail, with a positive response from 45. Genotyping in 36 of 45 participants revealed characteristic mutations in 61%. Median age at follow-up was 42.8 years. Mean adult heights were 169.2 cm (men) and 154.4 cm (women). In comparison with the general population, participants had lower educational status and lived more frequently without any partner. According to the response to the Short Form-36 questionnaire, quality of life was not impaired. CONCLUSIONS: Individuals with Noonan syndrome have higher mortality, lower education, and rarely partnership. Quality of life according to self-reported Short Form-36 was good. Men grew taller than previously reported from this cohort.

Fetal magnetocardiography (fMCG): moving forward in the establishment of clinical reference data by advanced biomagnetic instrumentation and analysis.

Cardiotocography and echocardiography are currently standard for fetal heart monitoring. However, both do not provide adequate temporal resolution to measure fetal cardiac time intervals and detect arrhythmias, which can occur during normal sinus rhythm. Fetal magnetocardiography (fMCG) is a non-invasive technique measuring magnetic signals generated by fetal heart activity. Most fMCG devices are installed in research institutions limiting the implementation of this method in a clinical setting. Several institutions made a step forward by installing devices, in particular for fetal investigations, in hospital sites to evaluate the clinical benefit. Based on instrumentation differences which can affect signal quality, there is still no established reference database for fetal cardiac time intervals. A new magnetograph dedicated to fetal recordings was implemented with improved patient comfort. The setting was optimized to establish a standard. A total of 103 healthy fetuses starting as early as possible after the first trimester were recorded and fMCG values of cardiac time intervals were compared to former studies. Data allowed high and reliable detection for all fMCG components starting at 17 weeks. The data were comparable to fMCG multicenter studies, fetal electrocardiography and neonatal ECG results and could serve as a database of norm values for further investigation of fetal arrhythmias.

Noninvasive cardiac output measurement at rest and during exercise in pediatric patients after interventional or surgical atrial septal defect closure.

In the majority of patients, secundum atrial septal defects (ASDs) are treated interventionally or surgically, before the onset of clinical symptoms, between 3 and 6 years of age. Because right-ventricular dimensions usually normalize after ASD closure, it has been assumed that cardiac function and exercise performance also normalize at long-term follow-up. The aim of our study was to determine cardiac index (CI) at rest and during exercise at medium-term follow-up of children who had undergone surgical or interventional closure of ASD because no such reports have been published thus far. Seventeen patients (age range 8.8-17.3 years) who underwent surgical correction were included together with 17 subjects who received an interventional procedure with Amplatzer and Helex occluders (age range 12.2-17.3 years). The study was performed after a median interval of 8.6 years (range 6.5-11.6) after the procedure. Twelve healthy children of comparable age served as controls. CI measurements were performed based on the inert gas-rebreathing method with the Innocor system. For exercise testing, the standard treadmill protocol of the German Society of Pediatric Cardiology was used. CI, stroke volume (SV), and heart rate (HR) were determined at rest and at two standardized submaximal exercise levels (levels 3 and 6). CI increased in all subjects under exercise conditions. Neither SV nor HR displayed significant differences between the three groups either at rest or under exercise conditions. Although HR increased continuously, no increase of indexed SV occurred beyond level 3. Noninvasive determination of CI at rest and during exercise with the IGR method is feasible in the pediatric age group. At medium-term follow-up, we found no significant differences between patients who underwent surgical or interventional ASD closure compared with normal controls.

Ice-free cryopreservation of heart valve allografts: better extracellular matrix preservation in vivo and preclinical results.

The purpose of this study was evaluation of an ice-free cryopreservation method for heart valves in an allogeneic juvenile pulmonary sheep implant model and comparison with traditionally frozen cryopreserved valves. Hearts of 15 crossbred Whiteface sheep were procured in Minnesota. The valves were processed in South Carolina and the pulmonary valves implanted orthotopically in 12 black faced Heidschnucke sheep in Germany. The ice-free cryopreserved valves were cryopreserved in 12.6 mol/l cryoprotectant (4.65, 4.65, and 3.31 mol/l of dimethylsulfoxide, formamide and 1,2-propanediol) and stored at -80°C. Frozen valves were cryopreserved by controlled slow rate freezing in 1.4 mol/l dimethylsulfoxide and stored in vapor-phase nitrogen. Aortic valve tissues were used to evaluate the impact of preservation without implantation. Multiphoton microscopy revealed reduced but not significantly damaged extracellular matrix before implantation in frozen valves compared with ice-free tissues. Viability assessment revealed significantly less metabolic activity in the ice-free valve leaflets and artery samples compared with frozen tissues (P < 0.05). After 3 and 6 months in vivo valve function was determined by two-dimensional echo-Doppler and at 7 months the valves were explanted. Severe valvular stenosis with right heart failure was observed in recipients of frozen valves, the echo data revealed increased velocity and pressure gradients compared to ice-free valve recipients (P = 0.0403, P = 0.0591). Histo-pathology showed significantly thickened leaflets in the frozen valves (P < 0.05) and infiltrating CD3+ T-cells (P < 0.05) compared with ice-free valve leaflets. Multiphoton microscopy at explant revealed reduced inducible autofluorescence and extracellular matrix damage in the frozen explants and well preserved structures in the ice-free explant leaflets. In conclusion, ice-free cryopreservation of heart valve transplants at -80°C avoids ice formation, tissue-glass cracking and preserves extracellular matrix integrity resulting in minimal inflammation and improved hemodynamics in allogeneic juvenile sheep.

Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.

BACKGROUND: Tetralogy of Fallot (ToF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra- and extracardiac phenotypes. In order to get further insight into genotype-phenotype correlation, a large cohort of 230 unselected patients with ToF was comprehensively investigated. METHODS AND RESULTS: 230 patients with ToF were studied by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. Pathogenic genetic aberrations were found in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic ToF (0.9%). One patient showed a recurrent polyalanine stretch elongation within TBX1 which represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation. CONCLUSION: This study shows that 22q11.2 deletion represents the most common known cause of ToF, and that the associated cardiac phenotype is distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with ToF is very suggestive of trisomy 21 and almost excludes 22q11.2 deletion. We report a further patient with a recurrent polyalanine stretch elongation within TBX1 and for the first time link TBX1 cytoplasmatic protein aggregation to congenital heart defects.

Prophylaxis of thromboembolic complications after the Fontan operation (total cavopulmonary anastomosis).

OBJECTIVES: Thrombotic events have been reported as a major cause of morbidity after the Fontan procedure. There is no consensus concerning the postoperative mode and duration of anticoagulation prophylaxis. In a retrospective study, we evaluated the results of a prophylactic regimen on the basis of the surgical technique, potentially predisposing risk factors, and specific sequelae. METHODS: We evaluated 142 surviving patients after total cavopulmonary anastomosis (mean follow-up was 91.1 +/- 43.9 months). Prophylactic antithrombotic treatment was initiated in 86 patients with partial prosthetic venous pathway with acetylsalicylic acid; 45 patients with complete autologous tissue venous pathway or partial prosthetic venous pathway received no anticoagulation, and 11 patients received warfarin sodium (Coumadin). During long-term follow-up, 22 patients (12 after acetylsalicylic acid medication) crossed over to warfarin. RESULTS: Thrombotic events occurred in 10 patients (7%), with systemic venous thrombus formation in 8 (5.6%), stroke in 2 (1.4%), and a peak incidence during the first postoperative year. Eight of 10 patients were receiving heparin therapy mainly for prolonged postoperative immobilization. During follow-up, none of the 74 patients receiving acetylsalicylic acid and 1 of 40 patients without medication presented with thrombus formation. Under warfarin medication, 1 of 28 patients had an asymptomatic thrombus. Expected freedom from a thromboembolic event was 92% at 5 years and 79% at 10 years. There was no association with coagulation factor abnormalities. Protein-losing enteropathy was present in 4 of 10 patients. CONCLUSION: A prophylactic anticoagulation strategy that considers the surgical technique and potential predisposing circumstances proved effective in the prevention of late thrombotic complications after total cavopulmonary anastomosis. There is no need for routine anticoagulation during long-term follow-up after Fontan-type surgery in pediatric patients.

Fontan-type procedures: residual lesions and late interventions.

BACKGROUND: The purpose of this study was to determine the type and incidence of hemodynamic and electrophysiological abnormalities requiring surgical or catheter-based interventions in a single-center long-term experience. METHODS: Eighty-eight patients with a follow-up of at least 5 years (mean follow-up, 9.6 +/- 2.6 years) after Fontan-type procedures were included. All patients had undergone cardiac catheterization either as part of the regular postoperative protocol or because of symptomatic atrial tachycardia or increasing cyanosis. RESULTS: Freedom from reoperation for up to 5 years was documented for 82% of patients and decreased to 76% after 8 years. Late reoperations included conversion of an atriopulmonary anastomosis to a total cavopulmonary anastomosis in 2 patients with atrial dysrhythmia and implantation of an extracardiac conduit in 1 patient with left atrial isomerism and intrapulmonary arteriovenous malformations after a Kawashima operation. Decline in sinus node function with symptomatic bradycardia required pacemaker therapy in 10 patients (11%). Transcatheter interventions included fenestration occlusion in 5 of the 11 patients with initial baffle fenestration. In 6 of 17 patients with aortopulmonary collaterals, coil occlusion was indicated to reduce future systemic ventricular volume load. Various systemic venous collaterals were documented in 11 patients and required coil occlusion in 2. One patient with symptomatic protein-losing enteropathy underwent transcatheter fenestration creation without sustained relief of symptoms. Freedom from transcatheter interventions decreased from 94% to 82% after 5 and 10 years, respectively. CONCLUSIONS: During long-term follow-up, reoperations are rare and mainly involve Fontan conversion to either a lateral-tunnel or extracardiac-conduit procedure. Detailed angiographic evaluation on a routine basis allows identification of the vascular sites of origin of aortopulmonary collateral vessels and systemic venous collaterals potentially developing during long-term follow-up. Transcatheter interventions including fenestration occlusion and occlusion of venous collaterals and aortopulmonary collaterals were performed to maintain and improve the Fontan circulation in clinically symptomatic and asymptomatic patients. During long-term follow-up after Fontan-type operations, a regular postoperative cardiac catheterization protocol is recommended.

Restrictive ventricular septal defect and critical subaortic stenosis in tetralogy of Fallot.

INTRODUCTION: Tetralogy of Fallot is characterized by a non-restrictive malalignment ventricular septal defect (VSD), an overriding aorta and right ventricular outflow tract obstruction resulting from anterior deviation of the infundibular septum. Due to the large VSD, systolic pressures are equal in both ventricles. In rare cases, redundant tricuspid valve tissue may prolapse into the VSD resulting in restriction of the defect size and causing suprasystemic pressure in the right ventricle. Subaortic obstruction by prolapse of the redundant tricuspid tissue into the left ventricular outflow tract, although theoretically possible in this situation, has not been described yet in the literature. CASE REPORT: We report on a newborn with tetralogy of Fallot presenting with cyanosis and severe arterial hypotension a few hours after birth. Echocardiography revealed redundant hammock-like accessory tricuspid valve tissue almost completely occluding the originally large VSD. Suprasystemic pressure in the right ventricle resulted in protrusion of tricuspid valve tissue across the VSD and thereby caused severe left ventricular outflow tract obstruction. Emergency pulmonary balloon valvuloplasty performed for decompression of the right ventricle, reduced prolapse of tricuspid tissue into the left ventricular outflow tract and resulted in significant improvement of pulmonary and systemic blood flow. CONCLUSION: In tetralogy of Fallot, accessory tricuspid valve tissue may obstruct the VSD as well as the left ventricular outflow tract resulting in a life threatening condition in newborns shortly after birth.

The performance of ice-free cryopreserved heart valve allografts in an orthotopic pulmonary sheep model.

Transplantation of cryopreserved heart valves (allografts) is limited by immune responses, inflammation, subsequent structural deterioration and an expensive infrastructure. In previous studies we demonstrated that conventional frozen cryopreservation (FC) is accompanied by serious alterations of extracellular matrix (ECM) structures. As the main culprit of the observed damages ice crystal formation was identified. Objective of this study was the application principles of cryoprotection as observed in nature, occurring in animals or plants, for ice-free cryopreservation (IFC) of heart valves. Using IFC, valves were processed and stored above the glass transition temperature of the cryoprotectant formulation (-124 degrees C) at -80 degrees C to avoid any ice formation, tissue-glass cracking and preserving ECM. After implantation in the orthotopic pulmonary position in sheep, we demonstrate that IFC resulted in cell free matrices, while maintaining crucial ECM-components such as elastin and collagen, translating into superior hemodynamics. In contrast, we reveal that FC valves showed ECM damage that was not restored in vivo, and T-cell inflammation of the stroma with significant leaflet thickening. Compared to currently applied FC practice IFC also reduced infrastructural needs for preservation, storage and shipping. These results have important implications for clinical valve transplantation including the promise of better long-term function and lower costs.

Severe left ventricular hypoplasia in patients with unbalanced incomplete atrioventricular septal defect and pulmonary hypertension: feasibility of biventricular repair.

We report three patients with partial atrioventricular septal defect who presented in the neonatal period with excessive left to right shunting and progressive pulmonary hypertension. Successful biventricular repair was accomplished despite the fact that left ventricular area and left sided structures did not meet the criteria established previously for biventricular management in children with critical aortic stenosis or complete atrioventricular septal defect. Indication for biventricular management was based on the fact that none of our patients had morphological mitral or aortic stenosis and that the hypoplastic left ventricle proved capable to maintain the systemic circulation following closure of the arterial duct. Fenestrated closure of the atrial septum and an individualized approach regarding the closure of the cleft in the left sided atrioventricular valve appear to be important surgical options to reduce postoperative left atrial pressure and to allow the ventricles to adapt to the new loading conditions.

Severe pulmonary valve incompetence late after debanding: repair by bicuspidization.

We report a simple valve repair for severe pulmonary incompetence in a 25-year-old patient. The patient had been operated on twice before for ventricular septal defect and coarctation of the aorta. The first operation consisted of pulmonary artery banding and coarctectomy and end-to-end anastomosis at 4 months, followed by debanding and transinfundibular ventricular septal defect closure at 6 years of age. Massive pulmonary incompetence was due to destruction of one valve cusp with the right ventricular outflow tract and pulmonary artery dilated secondarily. Repair consisted of pulmonary valve bicuspidization and right ventricular remodelling.