Thymic Atrophy and Immune Dysregulation in Infants with Complex Congenital Heart Disease.

Congenital heart disease (CHD) is the most common birth defect, and up to 50% of infants with CHD require cardiovascular surgery early in life. Current clinical practice often involves thymus resection during cardiac surgery, detrimentally affecting T-cell immunity. However, epidemiological data indicate that CHD patients face an elevated risk for infections and immune-mediated diseases, independent of thymectomy. Hence, we examined whether the cardiac defect impacts thymus function in individuals with CHD. We investigated thymocyte development in 58 infants categorized by CHD complexity. To assess the relationship between CHD complexity and thymic function, we analyzed T-cell development, thymic output, and biomarkers linked to cardiac defects, stress, or inflammation. Patients with highly complex CHD exhibit thymic atrophy, resulting in low frequencies of recent thymic emigrants in peripheral blood, even prior to thymectomy. Elevated plasma cortisol levels were detected in all CHD patients, while high NT-proBNP and IL-6 levels were associated with thymic atrophy. Our findings reveal an association between complex CHD and thymic atrophy, resulting in reduced thymic output. Consequently, thymus preservation during cardiovascular surgery could significantly enhance immune function and the long-term health of CHD patients.

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.

The Ongoing Debate: Longevity of Biological Valves in Pulmonary Position.

BACKGROUND: In patients with tetralogy of Fallot (ToF) or ToF-like anatomy, factors possibly impacting the longevity of biological valves in the pulmonary position were investigated. METHOD: Between 1997 and 2017, 79 consecutive hospital survivors with a median age of 8.7 years (range: 0.2-56.1 years; interquartile range [IQR]: 14.8 years) with ToF or ToF-like anatomy underwent surgical implantation of Contegra (n = 34), Hancock (n = 23), Perimount (n = 9), pulmonary homograft (n = 9), and miscellaneous (n = 4) conduits. The median internal graft diameter was 19 mm (range: 11-29 mm; IQR: 8 mm) which refers to a median z-score of 0.6 standard deviation (SD) (range: -1.8 to 4.0 SD; IQR: 2.1 SD). RESULTS: The median time of follow-up was 9.4 years (range: 1.1-18.8 years; IQR: 6.0 years). Thirty-nine patients (49%) underwent surgical (n = 32) or interventional (n = 7) pulmonary valve re-replacement. Univariate Cox regression revealed patient age (p = 0.018), body surface area (p = 0.004), internal valve diameter (p = 0.005), and prosthesis z-score (p = 0.018) to impact valve longevity. Multivariate Cox regression analysis, however, did not show any significant effect (likely related to multicollinearity). Subgroup analysis showed that valve-revised patients have a higher average z-score (p = 0.003) and younger average age (p = 0.007). CONCLUSION: A decreased longevity of biological valves in the pulmonary position is related to younger age, lower valve diameter, and higher z-score. Because valve size (diameter and z-score) can be predicted by age, patient age is the crucial parameter influencing graft longevity.

Anatomic Repair of Congenitally Corrected Transposition: Reappraisal of Eligibility Criteria.

Several criteria to identify suitable candidates for anatomic repair in congenitally corrected transposition (cc-TGA) have been proposed. The purpose of this study was to critically re-evaluate adequacy of these recommendations in our patient cohort. All cc-TGA patients undergoing anatomic repair between 2010 and 2019 were reviewed. Evaluated eligibility criteria for repair included age ≤ 15 years, LV mass index ≥ 45-50 g/m2, LV mass/volume ratio > 0.9-1.5 and systolic LV to right ventricle pressure ratio > 70-90% among others. Repair failure was defined as postoperative early mortality or LV dysfunction requiring mechanical circulatory support. Twenty-five patients were included (median [interquartile range] age at surgery 1.8 years [0.7;6.6]; median postoperative follow-up 3.2 years [0.7;6.3]). Median preoperative LV ejection fraction was 60% [56;64], indexed LV mass 48.5 g/m2 [43.7;58.1] and LV mass/volume ratio 1.5 [1.1;1.6], respectively. A total of 12 patients (48%) did not meet at least one of the previously recommended criteria, however, all but two patients (92%) experienced favorable early outcome. Of 7 patients (28%) with indexed LV mass < 45 g/m2, 6 were successfully operated. There were two early repair failures (8%) with LV dysfunction: one patient died and one required mechanical circulatory support but recovered well. Surgery was performed successfully in patients with LV mass and volume Z-scores as low as - 2 and - 2.5, respectively. Anatomic correction for cc-TGA can be performed with excellent early outcome and is feasible even in patients with LV mass below previously recommended cut-offs. The use of LV mass and volume Z-scores might help to refine eligibility criteria.

Congenital aortic valve repair using CorMatrix® : A histologic evaluation.

BACKGROUND: The reconstruction of heart valves provides substantial benefits, particularly in the pediatric population. We present our experience using decellularized extracellular matrix (dECM, CorMatrix® ) for aortic valve procedures. METHODS: We retrospectively reviewed the case histories of 6 patients (aged from 2 months - 14 years) who underwent surgery for severe aortic valve stenosis (n = 4) or regurgitation (n = 2). Aortic valve repair was performed on all patients using dECM as a leaflet replacement or leaflet extension. Follow-ups were performed using echocardiography. Reoperation was necessary in 4 cases, and the dECM was explanted and examined histologically and immunohistochemically. RESULTS: The early post-operative period was uneventful, and the scaffold fulfilled the mechanical requirements. Significant valve insufficiency developed in 5 patients during the post-operative period (119-441 days postoperatively). In all specimens, only a migration of inflammatory cells was identified, which induced structural and functional changes caused by the chronic inflammatory response. CONCLUSIONS: Our results suggest a mixed immunological response of remodeling and inflammation following the implantation. The expected process of seeding/migration and remodeling of the bioscaffold into the typical 3-layered architecture were not observed in our explanted specimens.

Cardiac transplantation in a neonate-First case in Switzerland and European overview.

Twenty-four percent of pediatric heart transplantations (pHTx) are carried out in infants. Neonatal heart transplantation is both rarely performed and challenging. We report on a newborn baby girl suffering from cardiac failure due to a huge tumor (24×52 mm) within the free wall of the left ventricle (LV) and subtotal obstruction of the main left bronchus. Following a surgical tumor resection, a Berlin Heart EXCOR left ventricular assist device was implanted as the bridge to the transplantation. In spite of an organ donor/recipient mismatch of >200%, both heart transplantation and the postoperative course were successful. In addition to this case report, the authors also present data from a survey on performed infant and neonatal transplantations in Western Europe. As neonatal heart transplantation is a rare event in Europe, the authors think it is of crucial importance to share this limited experience. We discuss an alternative strategy-namely, palliative surgical correction using the Fontan pathway. The challenges of donor/recipient weight mismatch and the possibilities of overcoming infant donor organ shortage as a postoperative immunosuppressive regimen are discussed as well.

Effectiveness of Balloon Angioplasty in Children With Recurrent Aortic Coarctation Depends on the Type of Aortic Arch Pathology.

OBJECTIVES: The aim of this study was to evaluate the effectiveness of balloon angioplasty (BAP) for recurrent aortic coarctation (ReCoA) in infants comparing simple and complex type of aortic arch pathology (Norwood I procedure). BACKGROUND: ReCoA is a known complication after cardiovascular surgery for coarctation of the aortic arch. METHODS AND RESULTS: In a single center case study, we analyzed 20 infants undergoing BAP for ReCoA comparing simple (n = 10) and complex type of aortic arch pathology (n = 10). At catherization diameter of ReCoA stenosis was 3.2 ± 0.7 mm (mean ± SD) with short localized (11/20) or long hypoplastic stenosis (9/20) before and 4.8 ± 1.2 mm after BAP (P < 0.001). Invasive systolic pressure gradient was reduced from 27.5 ± 16.2 mmHg before to 5.1 ± 6.6 mmHg after BAP (P < 0.001), comparable in simple and complex type of ReCoA. At day 1 after catherization noninvasive systolic arterial blood pressure gradient was reduced from 20.2 ± 23.1 to 6.7 ± 9.9 mmHg (P < 0.001), respectively, calculated continuous wave Doppler echo gradient from 36.3 ± 22 to 16.8 ± 9.6 mmHg (P < 0.01). Complications were aortic arch dissection (1/20), discrete aortic arch aneurysm formation (1/20), pericardial effusion (1/20), and peripheral arterial thrombosis (4/20). At a mid-term follow up of 9.5 months (1-40) after BAP, 3 infants needed early surgical reintervention due to secondary ReCoA, all with long hypoplastic aortic arch segments, but simple type of aortic arch pathology. CONCLUSIONS: At mid-term follow up, BAP remains an effective catheter intervention for ReCoA for infants with localized ReCoA, but not with long hypoplastic aortic arch segments, even in simple type of aortic arch pathology.

Age-related reoperation rate after the Ross procedure: a report from the German Ross Registry.

BACKGROUND AND AIM OF THE STUDY: An increasing number of young adult patients are choosing bioprostheses for aortic valve replacement (AVR). In this context, the Ross operation deserves renewed consideration as an alternative biological substitute. After both the Ross procedure and bioprosthetic AVR, reoperation rates remain a concern and may be related to age at surgery. Herein are reported details of freedom from reoperation after the Ross procedure for different age groups. METHODS: The reoperation rates of 1,925 patients (1,444 males, 481 females; mean age 41.2 ± 15.3 years) from the German Ross registry with a mean follow up of 7.4 ± 4.7 years (range: 0.00-18.51 years; total 12,866.6 patient-years) were allocated to three age groups: group I < 40 years; group II 40-60 years; and group III > 60 years. RESULTS: At 10 years (respectively 15 years) of follow up, freedom from reoperation was 86% (76%) in group I, 93% (85%) in group II, and 89% (83%) in group III. CONCLUSION: There is some evidence that, at least during the first 10 and 15 years after AVR, the Ross procedure provides a significantly lower reoperation rate in young adult and middle-aged patients aged < 60 years. This information may be of interest to the patients' or physicians' decision-making for aortic valve surgery.

One-Year Outcome of an Ongoing Pre-Clinical Growing Animal Model for a Tissue-Engineered Valved Pulmonary Conduit.

Objectives: A self-constructed valved pulmonary conduit made out of a de-cellularized porcine small intestinal submucosal extracellular matrix biological scaffold was tested in a chronic growing lamb model. Methods: The conduit was implanted in pulmonary valve position in 19 lambs. We monitored clinical, laboratory, and echocardiographic findings until 12 months after surgery. In two animals, euthanasia was planned at nine and twelve months. Pre-mortem chest computed tomography and post-mortem pathologic work up were performed. Data are presented as frequency and percentage, median and range, or mean and standard deviation. Results: Twelve (63.2%) animals survived the perioperative period. Three unexpected deaths occurred during the follow-up period: one due to aspiration pneumonia at 23 days after surgery, and two due to early and late infective endocarditis of the conduit at 18 and 256 days. In the two animals with planned scarification, the pre-mortem CT scan revealed mild or no calcification within the conduit or valve leaflets. In the echocardiographic examination at 12 months, peak and mean systolic pressure gradients across the conduit valve were 6.5 (3-21) mmHg and 3 (2-12) mmHg, while valve regurgitation was none (n = 2), trivial (n = 5), moderate (n = 1), or severe (n = 1). No clinical or laboratory signs of hemolysis were seen. After 12 months of follow-up, the animals' body weights had increased from 33 (27-38) kg to 53 (38-66) kg (p = 0.010). Conclusions: Implantation of a valved pulmonary conduit in our growing lamb model was feasible. Infective endocarditis of the implanted valved conduit remained a significant complication.

Multiobjective Optimization of Rotodynamic Blood Pumps: The Use Case of a Cavopulmonary Assist Device.

Comprehensive optimization of rotodynamic blood pumps (RBPs) requires the consideration of three partially conflicting objectives: size, hemocompatibility, and motor efficiency. Optimizing these individual objectives independently, the potential of multiobjective optimizations often remains untapped. This study aimed at the multiobjective optimization of an RBP for cavopulmonary support accounting for all three objectives simultaneously. Hydraulic and electromagnetic design spaces were characterized using computational fluid dynamics and computational electromagnetics, respectively. Design variables included secondary flow gap widths, impeller diameters, and stator heights. The size objective encompassed the RBP widths and heights, the hemocompatibility objective was a weighted composite measure of well-established metrics, and the motor objective was determined by motor losses. Multiobjective optimization was performed through Pareto analysis. 81 designs were considered, and 21 Pareto-optimal designs were identified. The Pareto analysis indicated that hemocompatibility performance could be improved by 72.4% with a concomitant 1.5% reduction in the baseline pump volume. This, however, entailed an increase in motor losses by 0.2 W, while still meeting design requirements, with maximum local temperature rises remaining below 0.4 K. The multiobjective optimization led to a Pareto front, demonstrating the feasibility to improve hemocompatibility at reduced pump volume, however, at the cost of a diminished yet still acceptable motor performance.

Anatomical Compliance of Cavopulmonary Assist Device Designs: A Virtual Fitting Study in Fontan Patients.

Several device designs for cavopulmonary mechanical circulatory support (MCS) are under investigation, however, challenged by the Fontan population's heterogeneity in size, cardiovascular and thoracic anatomy. This study aimed to preclinically assess the anatomical compliance of proposed device designs in silico. Representative double- and single-outlet cavopulmonary assist device (CPAD) designs were virtually implanted into CT imaging data of 10 patients previously palliated with total cavopulmonary connection (TCPC) for functionally univentricular hearts. Anatomical device compatibility was characterized concerning pump proximity to cardiovascular, respiratory and thoracic structures, as well as pump in- and outflow graft configuration. In 10 Fontan patients with a median age of 10.4 years (interquartile range [IQR] 5.0-15.3 years) and a median body surface area of 1.09 m2 (IQR 0.76-1.28 m2), implantation of a double-outlet CPAD was feasible in 1 patient (10%). In all other, adverse device intersection with the trachea and (neo-)aorta, or posterior pulmonary artery outflow graft kinking were observed. A single-outlet design permitted enhanced device mobilization adapting to individual anatomical conditions, resulting in device fit in nine of 10 patients (90%). Despite vast anatomical variations among single ventricle patients, a single-outlet device design may provide intracorporeal cavopulmonary MCS to a broad spectrum of failing Fontan patients.

Feasibility of an Animal Model for Cavopulmonary Support With a Double-Outflow Pump.

Both single- and double-outflow cavopulmonary assist devices (CPADs) were recently proposed for the Fontan population, whereas single-outflow configurations were evaluated in large animal trials and double-outflow concepts are lacking an equivalent in vivo assessment. The aim of this study was to test the hemodynamic properties of a double-outflow CPAD device in an acute sheep model. The two inflow cannulae of a CPAD were anastomosed to the caval veins. Outflow graft connection was performed via end-to-side anastomosis to the right (RPA) and main pulmonary artery (MPA). Speed ramp protocols were conducted, and hemodynamic effects were monitored in terms of caval flows, cardiac output (CO), central venous pressure (CVP), pulmonary artery pressure (PAP), and left atrial pressure (LAP). Six experiments were conducted (53.35 ± 5.1 kg). In three experiments, the animal model was established, the CPAD was examined, and restoration of biventricular equivalency in terms of venous return was achieved. Venous pressures (CVP) declined linearly with increasing pump speed (r > 0.879), whereas caval flow (r > 0.973), CO (r > 0.993), PAP (r > 0.973), and LAP (r > 0.408) increased. Despite the considerable complexity of the sheep model caused by the sheep pulmonary arterial anatomy that requires substantial graft bending, the CPAD was evaluated in three acute experiments and showed the potential to completely substitute a subpulmonary ventricle.

Mid-aortic syndrome: computed tomography angiography depicting extensive collateral circulation in an 11-year-old patient with thoracoabdominal aortic coarctation.

The mid-aortic syndrome is an uncommon clinical condition characterized by severe narrowing of the descending aorta, usually with involvement of its renal and visceral branches, presenting with uncontrollably elevated blood pressures of the upper body, renal and cardiac failure, intestinal ischemia, encephalopathy symptoms and claudication of the lower limbs, although clinical presentation is variable. In this article we report the case of an eleven-year-old patient with the initial diagnosis of a mid-aortic syndrome and present the computed tomography angiography pictures and reconstructions before and after surgical therapy.

Using three-dimensional visualization as an optimal tool to plan and validate an aortopexy in a congenital heart disease patient with severe tracheal stenosis.

We present a patient with severe tracheal stenosis resulting from a compression by the innominate artery 6 months after an arterial switch operation in a dextro-transposition of the great arteries. Segmentation and three-dimensional (3D) visualization were derived from a contrast-enhanced dual-source computed tomography and post-processing was performed using a dedicated open-source platform (3D Slicer). Post-processing allowed a comprehensible visualization of the relationship of the innominate artery to the trachea when compared to standard computer tomography reformations. Finally, the surgical approach to move the innominate artery anteriorly in order to relieve the tracheal obstruction was emphasized based on the improved 3D visualization of the actual pathology. An effective aortopexy could be performed and the postoperative result was confirmed by a second 3D visualization. About 3 months of follow-up, the patient is completely asymptomatic. Three-dimensional visualization offers excellent opportunities for diagnosis, treatment planning and follow-up in patients with a vascular-related tracheal stenosis in the context of congenital heart disease.

Antimicrobial effects of inhaled sphingosine against Pseudomonas aeruginosa in isolated ventilated and perfused pig lungs.

BACKGROUND: Ex-vivo lung perfusion (EVLP) is a save way to verify performance of donor lungs prior to implantation. A major problem of lung transplantation is a donor-to-recipient-transmission of bacterial cultures. Thus, a broadspectrum anti-infective treatment with sphingosine in EVLP might be a novel way to prevent such infections. Sphingosine inhalation might provide a reliable anti-infective treatment option in EVLP. Here, antimicrobial potency of inhalative sphingosine in an infection EVLP model was tested. METHODS: A 3-hour EVLP run using pig lungs was performed. Bacterial infection was initiated 1-hour before sphingosine inhalation. Biopsies were obtained 60 and 120 min after infection with Pseudomonas aeruginosa. Aliquots of broncho-alveolar lavage (BAL) before and after inhalation of sphingosine were plated and counted, tissue samples were fixed in paraformaldehyde, embedded in paraffin and sectioned. Immunostainings were performed. RESULTS: Sphingosine inhalation in the setting of EVLP rapidly resulted in a 6-fold decrease of P. aeruginosa CFU in the lung (p = 0.016). We did not observe any negative side effects of sphingosine. CONCLUSION: Inhalation of sphingosine induced a significant decrease of Pseudomonas aeruginosa at the epithelial layer of tracheal and bronchial cells. The inhalation has no local side effects in ex-vivo perfused and ventilated pig lungs.

A potential future Fontan modification: preliminary in vitro data of a pressure-generating tube from engineered heart tissue.

OBJECTIVES: Univentricular malformations are severe cardiac lesions with limited therapeutic options and a poor long-term outcome. The staged surgical palliation (Fontan principle) results in a circulation in which venous return is conducted to the pulmonary arteries via passive laminar flow. We aimed to generate a contractile subpulmonary neo-ventricle from engineered heart tissue (EHT) to drive pulmonary flow actively. METHODS: A three-dimensional tubular EHT (1.8-cm length, 6-mm inner diameter, ca. 1-mm wall thickness) was created by casting human-induced pluripotent stem cell-derived cardiomyocytes (0.9 ml, 18 mio/ml) embedded in a fibrin-based hydrogel around a silicone tube. EHTs were cultured under continuous, pulsatile flow through the silicone tube for 23 days. RESULTS: The constructs started to beat macroscopically at days 8-14 and remained stable in size and shape over the whole culture period. Tubular EHTs showed a coherent beating pattern after 23 days in culture, and isovolumetric pressure measurements demonstrated a coherent pulsatile wave formation with an average frequency of 77 ± 5 beats/min and an average pressure of 0.2 mmHg. Histological analysis revealed cardiomyocytes mainly localized along the inner and outer curvature of the tubular wall with mainly longitudinal alignment. Cell density in the center of the tubular wall was lower. CONCLUSIONS: A simple tube-shaped contractile EHT was generated from human-induced pluripotent stem cells and developed a synchronous beating pattern. Further steps need to focus on optimizing support materials, flow rates and geometry to obtain a construct that creates sufficient pressures to support a directed and pulsatile blood flow.

A Cavopulmonary Assist Device for Long-Term Therapy of Fontan Patients.

Treatment of univentricular hearts remains restricted to palliative surgical corrections (Fontan pathway). The established Fontan circulation lacks a subpulmonary pressure source and is commonly accompanied by progressively declining hemodynamics. A novel cavopulmonary assist device (CPAD) may hold the potential for improved therapeutic management of Fontan patients by chronic restoration of biventricular equivalency. This study aimed at translating clinical objectives toward a functional CPAD with preclinical proof regarding hydraulic performance, hemocompatibility and electric power consumption. A prototype composed of hemocompatible titanium components, ceramic bearings, electric motors, and corresponding drive unit was manufactured for preclinical benchtop analysis: hydraulic performance in general and hemocompatibility characteristics in particular were analyzed in-silico (computational fluid dynamics) and validated in-vitro. The CPAD's power consumption was recorded across the entire operational range. The CPAD delivered pressure step-ups across a comprehensive operational range (0-10 L/min, 0-50 mm Hg) with electric power consumption below 1.5 W within the main operating range. In-vitro hemolysis experiments (N = 3) indicated a normalized index of hemolysis of 3.8 ± 1.6 mg/100 L during design point operation (2500 rpm, 4 L/min). Preclinical investigations revealed the CPAD's potential for low traumatic and thrombogenic support of a heterogeneous Fontan population (pediatric and adult) with potentially accompanying secondary disorders (e.g., elevated pulmonary vascular resistance or systemic ventricular insufficiency) at distinct physical activities. The low power consumption implied adequate settings for a small, fully implantable system with transcutaneous energy transfer. The successful preclinical proof provides the rationale for acute and chronic in-vivo trials aiming at the confirmation of laboratory findings and verification of hemodynamic benefit.