Stenting of native right ventricular outflow tract obstructions in symptomatic infants: histological work-up of explanted specimen.

BACKGROUND: Stenting of stenotic right ventricular outflow tract is a palliative measure for severely impaired small babies with Tetralogy of Fallot or similar pathologies. Little is known about the histopathological fate of the stents in the right ventricular outflow tract. METHODS: Eight samples of surgically removed right ventricular outflow tract stents were histologically analysed according to a predefined protocol. RESULTS: The most frequent diagnosis was Tetralogy of Fallot in four patients, pulmonary atresia with ventricular septal defect in two patients, double outlet right ventricle with pulmonary obstruction in one patient, and muscular obstruction of the right ventricular outflow tract in one patient with a syndromic disease with hypertrophic cardiomyopathy. Stents mean implantation duration was 444 days ranging from 105 to 1117 days (median 305.5 days). Histology revealed a variable degree of pseudointima formation consisting of fibromuscular cells surrounded by extracellular matrix. Four of the specimen contained adjacent myocardial tissue fragments, which showed regressive changes. Neither myocardium nor pseudointima tissue or tissue parts locally related to stent struts were infiltrated by inflammatory cells. CONCLUSIONS: Histological analysis after explantation of early-in-life implanted right ventricular outflow tract stents revealed predominantly pronounced neo-intimal proliferation with a visible endothelial layer, no signs of inflammation, and no prolapse of muscular tissue through the stent struts. Thus, implantation of stents in early life seems to interfere little with the hosts' immune system and might help to open up the right ventricular outflow tract by mechanical forces and regressive changes in adjacent muscular tissue.

EGFR and MMP-9 are associated with neointimal hyperplasia in systemic-to-pulmonary shunts in children with complex cyanotic heart disease.

Systemic-to-pulmonary shunt malfunction contributes to morbidity in children with complex congenital heart disease after palliative procedure. Neointimal hyperplasia might play a role in the pathogenesis increasing risk for shunt obstruction. The aim was to evaluate the role of epidermal growth factor receptor (EGFR) and matrix-metalloproteinase 9 (MMP-9) in the formation of neointimal within shunts. Immunohistochemistry was performed with anti-EGFR and anti-MMP-9 on shunts removed at follow-up palliative or corrective procedure. Whole-genome single-nucleotide polymorphisms genotyping was performed on DNA extracted from patients´ blood samples and allele frequencies were compared between the group of patients with shunts displaying severe stenosis (≥ 40% of lumen) and the remaining group. Immunohistochemistry detected EGFR and MMP-9 in 24 of 31 shunts, located mainly in the luminal area. Cross-sectional area of EGFR and MMP-9 measured in median 0.19 mm2 (IQR 0.1-0.3 mm2) and 0.04 mm2 (IQR 0.03-0.09 mm2), respectively, and correlated positively with the area of neointimal measured on histology (r = 0.729, p < 0.001 and r = 0.0479, p = 0.018, respectively). There was a trend of inverse correlation between the dose of acetylsalicylic acid and the degree of EGFR, but not MMP-9, expression within neointima. Certain alleles in epidermal growth factor (EGF) and tissue inhibitor of metalloproteinases 1 (TIMP-1) were associated with increased stenosis and neointimal hyperplasia within shunts. EGFR and MMP-9 contribute to neointimal proliferation in SP shunts of children with complex cyanotic heart disease. SP shunts from patients carrying certain risk alleles in the genes encoding for EGF and TIMP-1 displayed increased neointima.

Transcatheter mitral valve repair using the Cardioband® system: Histopathological insights in device ingrowth and biocompatibility.

Surgical implantation of a complete or incomplete ring to reduce the valve annulus and improve leaflet coaptation is the mainstay of mitral valve surgery. The Cardioband® system (Edwards Lifesciences) was designed to address the pathophysiological mechanism of annular dilatation through a catheter-based approach. We present the histopathological workup of a Cardioband® device, which had been implanted 21 months earlier in a 34-year-old male with ischemic cardiomyopathy. Device examination demonstrate a well-positioned and securely anchored device. The described tissue reactions may have an impact on choice of device and timing in case of re-do surgery.

Nit-Occlud atrial septal defect occluder device: Histological characterisation of the healing process.

We describe the healing process following transcatheter implantation of the Nit-Occlud ASD-R occluder (PFM medical, Cologne, Germany) for atrial septal defect closure in a sheep model with histological confirmation of neotissue formation covering the device.

Surgically placed radiopaque markers: Proof-of-concept of a novel technique to facilitate percutaneous interventions in neonates and infants.

OBJECTIVES: Aim of this study was to evaluate feasibility and benefit of self-designed, radiopaque markers as a novel technique in neonates and infants with shunt- or duct-dependent lesions. BACKGROUND: Surgically placed radiopaque markers have the potential to facilitate postoperative percutaneous interventions. METHODS: All consecutive children with surgically placed radiopaque markers involving systemic-to-pulmonary artery connections or arterial ducts in the context of hybrid palliation and subsequent cardiac catheterization between January 2013 and March 2019 were included in this analysis. Our primary endpoint was our concept's feasibility, which we defined as a combination of surgical feasibility and the percutaneous intervention's success. Secondary endpoint was the rate of complications resulting from the surgical procedure or during catheterization. RESULTS: Radiopaque markers that reveal the proximal entry of a surgical shunt or the arterial duct proved to be a feasible and beneficial approach in 25 postoperative catheterizations. The markers' high accuracy enabled easy probing and proper stent positioning in 13 neonates with a median age and weight of 121 days (range 9-356) and 4.7 kg (1.6-9.4) at the intervention. No procedural complications or unanticipated events associated with the radiopaque marker occurred. The markers were never lost, never migrated, and caused no local obstructive lesion. Surgical removal was straightforward in all patients. CONCLUSIONS: Radiopaque markers are a promising and refined technique to substantially facilitate target vessel access and enabling the accurate positioning of stents during postoperative percutaneous procedures.

Double cryoenergy application (freeze-thaw-freeze) at growing myocardium: Lesion volume and effects on coronary arteries late after energy application. Implications for efficacy and safety in pediatric patients.

INTRODUCTION: Cryoenergy is accepted as an alternative to radiofrequency ablation (RFA) in childen for ablation of supraventricular tachycardia substrates. Single cryoenergy application has been shown to be inferior to RFA. Double cryoenergy application has therefore been introduced into clinical practice, but experience concerning efficacy is limited. Coronary artery stenosis has been reported as serious complication after RFA for arrhythmia substrates but not after single cryoablation. The purpose of the study was to assess lesion volume (efficacy) and risk of coronary artery damage (safety), late, that is, 6 months, after double cryoenergy application in a piglet model. METHODS: Two sequential cycles of cryoenergy were delivered at -75°C for 4 minutes at the atrioventricular groove in five piglets. Animals were restudied after 6 months by coronary angiography and intracoronary ultrasound (ICUS). Ablation lesions were examined histologically and lesion volume was determined by three-dimensional morphometric analysis. RESULTS: Cryolesion volume was 174.04 ± 67.18 mm3 for atrial and 238.69 ± 112.1 mm3 for ventricular lesions (P > .05). Ventricular lesions, 4.06 ± 1.05 mm, were significantly deeper than atrial lesions, 3.58 ± 0.78 mm, (P < .05). In two of the 29 lesions, cryoenergy induced minor coronary artery injury with mild medial and adventitial thickening as well as minimal intimal proliferation, which had neither been detected by coronary angiography nor by ICUS. CONCLUSION: Late after double cryoenergy application at growing myocardium, subclinical minor affection of the coronary artery wall could be detected with minimal intimal proliferation. As lifetime sequelae of this finding remains unknown, further studies are warranted to address safety of repeated cycles of cryoenergy application for tachycardia substrates in children.

Expectoration of bronchial casts in association with Ramipril treatment.

We report of a 26-year-old female patient who was referred to our centre with congestive heart failure (CHF). Acute myocarditis with a high Parvovirus B19 virus load was diagnosed by myocardial biopsy. CHF improved after start of ramipril 5 mg/d, metoprolol, diuretics, immunoglobins, and a 24-hour infusion of levosimendan. Soon after initiation of medical therapy, the patient started to expectorate bronchial casts with varying frequencies (three times per week to five times daily). Thorough pneumological workup, including histology of the casts, microbiology, and a CT scan of the lungs, did not reveal any cause for bronchial cast formation. Inhalative corticoids were started without any benefit. Two years later, cardiac catheterisation demonstrated normalised left ventricular function. LV end-diastolic pressure, however, was still elevated at 14 mmHg. Endomyocardial biopsies at this time were negative for virus genome. Finally, we changed afterload reduction therapy from ramipril to candesartan. Within 24 hours, expectoration of bronchial casts terminated. Four weeks later, re-exposition to ramipril prompted immediate re-appearance of cast formation, which again stopped with switching back to candesartan. Finally, we were to prove that treatment with ramipril resulted in bronchial cast formation in this patient.

Biomimetic Heparan Sulfate-Like Coated ePTFE Grafts Reduce In-graft Neointimal Hyperplasia in Ovine Carotids.

BACKGROUND: Thrombogenicity and neointimal hyperplasia are major causes for synthetic vascular graft failure. Bioactive coatings like heparin have improved patency by reducing thrombogenicity, but neointimal hyperplasia still remains an unsolved problem. Surface coatings with heparan sulfate (HS), the major component of the glycocalyx of endothelial cells, have shown reduced platelet and cell adhesion in vitro. The aim of the study was to evaluate the in vivo surface properties of expanded ePTFE vascular grafts with a semisynthetic HS-like coating (SSHS). METHODS: ePTFE vascular grafts (n = 16, diameter 3.5 mm) covalently coated with SSHS were compared with uncoated grafts (n = 16) of the same diameter in a carotid interposition model in 16 sheep. The grafts were harvested at 20 wk for histological and morphometric analysis. RESULTS: SSHS-coated grafts showed less neointima formation than uncoated grafts (P < 0.001). There was no evidence for cell or protein adhesion to SSHS-coated grafts, whereas the surface of uncoated ePTFE grafts was covered with a confluent circular layer of neointima. No difference was found concerning reactions at the anastomotic site of the genuine carotid vessel, both groups displayed neointimal hyperplasia. CONCLUSIONS: ePTFE grafts covalently coated with a semisynthetic SSHS-glycosaminoglycan successfully mimicked the endothelial glycocalyx. They displayed excellent antiadhesive properties preventing neointimal formation on the graft surface. The results indicate that a biomimetic SSHS coating may be a useful component of bioengineered grafts and an alternative to synthetic surfaces and endothelial seeding.

Late complete atrioventricular block after closure of an atrial septal defect with a gore septal occluder (GSO™).

Temporary intermittent complete heart block (CHB) occurred the day after interventional closure of an ASD with a 30 mm Gore Septal Occluder (GSO™) in a 2 years and 11-month-old female. CHB disappeared without further treatment and stable sinus rhythm recovered within 3 days. Only short episodes of 2nd degree AV-block (Wenckebach periodicity) at rare intervals were documented in Holter-monitors the following 2 months. Eleven months after device implantation the patient suffered from long lasting episodes of CHB. Surgical removal of the device resulted in incomplete recovery of AV-conduction. Histopathological work-up of the explanted GSO showed complete endothelialization of the device and regular scar formation. One year after surgery, the child had sinus rhythm during daytime but needed VVI-pacing while sleeping. Young age, inferior localization of the defect, and use of a large device have been individual risk factors for CHB in this patient. Clinical course and histologic findings indicate that mechanical compression was the only cause for CHB. The cumulative number of reports of CHB after use of different ASD-devices supports the recommendation to postpone the intervention in asymptomatic patients to preschool-age. Early removal of a pushing device may increase the chance of complete recovery from CHB.

A new breakable stent for recoarctation in early infancy: Preliminary Clinical Experience.

OBJECTIVES: Transcatheter treatment of aortic coarctation (CoA) via stent implantation has become an established treatment option depending on the patient's age and CoA type. BACKGROUND: The Osypka BabyStent(®) is a low-profiled, balloon-expandable cobalt-chrome stent to treat aortic CoA in infants, which is breakable to permit unrestricted growth. We hereby evaluated our initial clinical experience to demonstrate the feasibility and efficacy of this new nonlicensed device, which we have occasionally implanted in critically ill patients or when redo-surgery would entail an excessively high risk. METHODS: Retrospective single-center analysis of all available data during and after treatment with a BabyStent implanted in infants with considerable re-CoA or reobstruction of the aortic arch after former surgery. All interventions took place under fluoroscopy and conscious sedation with local anesthesia or general anesthesia. RESULTS: Five BabyStents were implanted in four infants with technical success in all of them-median age 10 weeks (range 5-21), median bodyweight 3.8 kg (range 2.7-4.5). Aortic diameters enlarged from median 2.25 mm (range 1.5-3.3) to median 5.3 mm (range 4.6-6.0). The follow-up period lasting up to 26 months (median 8.5, range 2-26) was uneventful concerning stent-related complications. CONCLUSIONS: BabyStent(®) implantation for recoarctation was effective. However, our initial experience with the device is limited to short- and midterm follow-up only. None of the stents was subsequently overdilated with the intention to break due to our patients' limited somatic growth so far. A multicenter survey has been initiated to justify device approval.

Single center experience: Implantation failures, early, and late complications after implantation of a partially biodegradable ASD/PFO-device (BioStar®).

INTRODUCTION: In the search for a biodegradable device that leaves nothing but the tissue of the patient after complete endotheliazation and absorption, the BioSTAR® device was introduced in 2007 (CE Mark in European community and HPB in Canada) for ASD and PFO closure. It consists of a metal framework covered by a biodegradable membrane generated from a layer of porcine collagen that is broken down and absorbed over time. In a sheep model, the results were promising, showing complete closure of the defect with degradation of approximately 90% of the implanted membrane material after two years. METHODS: We report a retrospective analysis of implantation failures, early and late complications in a series of 34 patients with 30 implanted BioStar® devices in a single center with a total follow-up of more than 75 patient years. RESULTS: We report 12% of implantation failures, 9% of early and 12% of late complications. Implantation failures include one embolized device, which was interventionally retrieved. Early complications were exclusively rhythm disturbances, one patient needed electrical and pharmacological therapy. Four relevant late complications occurred. One device required explantation after 61 days because of recurrent severe fever episodes, severe headache, and malaise that subsequently subsided after device removal. One patient presented with Dressler's syndrome with pericardial effusion 5 month after implantation requiring pericardiocentesis and steroid treatment. One device showed a central residual shunt that was not clearly seen initially. Finally, one device was explanted after hemorrhagic pericardial effusion due to perforation of an arm of the frame through the right atrial roof into the pericardial fold after 19 months. CONCLUSION: We conclude that implantation of the Biostar® device is difficult in patients with deficient aortic rims and early complications are similar to those seen in other devices. Of importance, the late complications seen with the Biostar® device might be attributable to specific material and immunological properties of the partially biodegradable device. Although a biodegradable device might theoretically be more favorable more efforts for optimization of these devices have to be taken.

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) with multiple vascular complications misdiagnosed as Dubowitz syndrome.

UNLABELLED: To date, the genetic basis of Dubowitz syndrome (short stature, microcephaly, facial abnormalities, eczema) is unknown and vascular complications are not known to be associated with this syndrome. In microcephalic osteodysplastic primordial dwarfism type II (MOPD II; disproportionate short statue, microcephaly, facial abnormalities), however, cerebral aneurysms and other vascular abnormalities are frequent complications. MOPD II is a genetic disorder caused by mutations in the pericentrin (PCNT) gene (21q22). We report on a patient who came to our attention as a 22-year-old with subarachnoid bleeding due to a ruptured cranial aneurysm. Until then, the patient was thought and published to have Dubowitz syndrome; previously, he was treated with coronary bypass surgery for extensive coronary angiopathy. Consecutive genetic testing revealed MOPD II. After clinical stabilization, the patient was discharged to a specialized rehabilitation center where he died due to re-rupture of a cranial aneurysm. CONCLUSION: In patients with short stature-especially when clinical features are accompanied by vascular complications-MOPD II should be considered as a differential diagnosis leading to consecutive genetic testing. After detection of mutations in the PCNT gene, a full vascular status including cerebral imaging and cardiac evaluation needs to be determined in order to analyze vascular abnormalities and initiate prophylactic treatment.

Tissue-engineered and autologous pericardium in congenital heart surgery: comparative histopathological study of human vascular explants.

OBJECTIVES: The goal of this histological study was to assess the biocompatibility of vascular patches used in the repair of congenital heart defects. METHODS: We examined tissue-engineered bovine (n = 7) and equine (n = 7) patches and autologous human pericardium (n = 7), all explanted due to functional issues or follow-up procedures. Techniques like Movat-Verhoeff, von Kossa and immunohistochemical staining were used to analyse tissue composition, detect calcifications and identify immune cells. A semi-quantitative scoring system was implemented to evaluate the biocompatibility aspects, thrombus formation, extent of pannus, inflammation of pannus, cellular response to patch material, patch degradation, calcification and neoadventitial inflammation. RESULTS: We observed distinct material degradation patterns among types of patches. Bovine patches showed collagen disintegration and exudate accumulation, whereas equine patches displayed edematous swelling and material dissolution. Biocompatibility scores were lower in terms of cellular response, degradation and overall score for human autologous pericardial patches compared to tissue-engineered types. The extent of pannus formation was not influenced by the type of patch. Bovine patches had notable calcifications causing tissue hardening, and foreign body giant cells were more frequently seen in equine patches. Plasma cells were frequently detected in the neointimal tissue of engineered patches. CONCLUSIONS: Our results confirm the superior biocompatibility of human autologous patches and highlight discernible variations in the changes of patch material and the cellular response to patch material between bovine and equine patches. Our approach implements the semi-quantitative scoring of various aspects of biocompatibility, facilitating a comparative quantitative analysis across all types of patches, despite their inherent differences.

Therapeutic apheresis in pediatric patients with acute CNS inflammatory demyelinating disease.

BACKGROUND/AIMS: In adults, plasma exchange (PE) has been shown to be an efficient treatment for severe relapses of acute inflammatory CNS demyelinating diseases. The aim of this study was to evaluate the safety and efficacy of this treatment in pediatric patients. METHODS: We retrospectively analyzed a single-center cohort of pediatric patients with inflammatory CNS demyelinating disorders who underwent apheresis between 2007 and 2011. RESULTS: Ten patients (mean age: 11.6 ± 3.4 years) with an acute relapse of multiple sclerosis (n = 5), neuromyelitis optica (n = 2) or acute disseminated encephalomyelitis were included. All received methylprednisolone prior to treatment with either PE (n = 5) or immunoadsorption (n = 5). Apheresis-related side effects were either self-limiting or easily managed. EDSS (Expanded Disability Status Scale) improved in 7 of 8 patients during apheresis and in all patients within 30 days from a median of 7.5 to 1 (p < 0.01). The visual acuity initially worsened during the procedure in 3 of 7 affected eyes (mean 0.09), but improved in all at follow-up (mean: 0.5; p = 0.008). CONCLUSIONS: Apheresis was well tolerated and associated with a favorable outcome in all pediatric patients similar to reports in adults.

Assessment of Nit-Occlud atrial septal defect occluder device healing process using micro-computed tomography imaging.

After percutaneous implantation of a cardiac occluder, a complex healing process leads to the device coverage within several months. An incomplete device coverage increases the risk of device related complications such as thrombosis or endocarditis. We aimed to assess the device coverage process of atrial septal defect (ASD) occluders in a chronic sheep model using micro-computed tomography (micro-CT). After percutaneous creation of an ASD, 8 ewes were implanted with a 16-mm Nit-Occlud ASD-R occluder (PFM medical, Cologne, Germany) and were followed for 1 month (N = 3) and 3 months (N = 5). After heart explant, the device coverage was assessed using micro-CT (resolution of 41.7 µm) and was compared to histological analysis. The micro-CT image reconstruction was performed in 2D and 3D allowing measurement of the coverage thickness and surface for each device. Macroscopic assessment of devices showed that the coverage was complete for the left-side disk in all cases. Yet incomplete coverage of the right-side disk was observed in 5 of the 8 cases. 2D and 3D micro-CT analysis allowed an accurate evaluation of device coverage of each disk and was overall well correlated to histology sections. Surface calculation from micro-CT images of the 8 cases showed that the median surface of coverage was 93±8% for the left-side disk and 55±31% for the right-side disk. The assessment of tissue reactions, including endothelialisation, after implantation of an ASD occluder can rely on in vitro micro-CT analysis. The translation to clinical practice is challenging but the potential for individual follow-up is shown, to avoid thrombotic or infective complications.