Transcatheter Palliation With Pulmonary Artery Flow Restrictors in Neonates With Congenital Heart Disease: Feasibility, Outcomes, and Comparison With a Historical Hybrid Stage 1 Cohort.

BACKGROUND: Neonates with complex congenital heart disease and pulmonary overcirculation have been historically treated surgically. However, subcohorts may benefit from less invasive procedures. Data on transcatheter palliation are limited. METHODS: We present our experience with pulmonary flow restrictors (PFRs) for palliation of neonates with congenital heart disease, including procedural feasibility, technical details, and outcomes. We then compared our subcohort of high-risk single ventricle neonates palliated with PFRs with a similar historical cohort who underwent a hybrid Stage 1. Cox regression was used to evaluate the association between palliation strategy and 6-month mortality. RESULTS: From 2021 to 2023, 17 patients (median age, 4 days; interquartile range [IQR], 2-8; median weight, 2.5 kilograms [IQR, 2.1-3.3]) underwent a PFR procedure; 15 (88%) had single ventricle physiology; 15 (88%) were high-risk surgical candidates. All procedures were technically successful. At a median follow-up of 6.2 months (IQR, 4.0-10.8), 13 patients (76%) were successfully bridged to surgery (median time since PFR procedure, 2.6 months [IQR, 1.1-4.4]; median weight, 4.9 kilograms [IQR, 3.4-5.8]). Pulmonary arteries grew adequately for age, and devices were easily removed without complications. The all-cause mortality rate before target surgery was 24% (n=4). Compared with the historical hybrid stage 1 cohort (n=23), after adjustment for main confounding (age, weight, intact/severely restrictive atrial septum or left ventricle to coronary fistulae), the PFR procedure was associated with a significantly lower all-cause 6-month mortality risk (adjusted hazard ratio, 0.26 [95% CI, 0.08-0.82]). CONCLUSIONS: Transcatheter palliation with PFR is feasible, safe, and represents an effective strategy for bridging high-risk neonates with congenital heart disease to surgical palliation, complete repair, or transplant while allowing for clinical stabilization and somatic growth.

Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome.

BACKGROUND: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. METHODS: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. RESULTS: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. CONCLUSIONS: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.

The impact of polyethylene abrasion on the occurrence of periprosthetic proximal femoral fractures in patients with total hip arthroplasty.

INTRODUCTION: In addition to abrasion-induced osteolysis and ensuing instabilities, the polyethylene (PE) abrasion of total hip arthroplasty (THA) inlays can also cause gait instability due to the decentralization of the hip joint. The current literature yields, as yet, insufficient findings whether these two factors are linked directly or indirectly to a higher risk for periprosthetic proximal femoral fractures (PPFF). The aim of our retrospective evaluation is to analyse the impact of PE abrasion on the pathology of PPFF in patients with THA. MATERIAL AND METHODS: The retrospective evaluation comprises all PPFF in patients with THA in the period from 01/2010 up to 12/2016. The study group (SG) included 66 cases (n = 66). The control group (CG) was comprised of patients with asymptomatic THA (n = 66), who were treated by our outpatient department including routine check-ups and X-ray examinations. We used the matched-pair methodology to scale the period of postsurgical care of the CG to the lifetime of the implant up to PPFF in the SG. We included epidemiologic data, radiological femoral head decentralization, osteolysis (Gruen classification), instabilities, acetabular cup position, and implant properties in our analysis. For the SG, we also included intra-operative signs of abrasion. FINDINGS: The SG showed significantly higher numbers of decentralized THA as signs of inlay erosion with 73% compared to only 41% in the CG (p > 0.001). The SG showed 1 ± 0.68 mm hip joint decentralization as to 0.5 ± 0.59 mm in the CG (p = 0.004). We found significantly more cases of osteolysis in the SG (n = 25) than in the CG (n = 13) (p = 0.003). We found no notable differences in acetabular cup inclination or anteversion as well as cup size. However, differences were significant in femoral head size (SG 32 ± 2.3 mm, CG 36 ± 2.4 mm; p = 0.042) and head material. We found more widespread use of metal femoral heads in the SG than in the CG (SG 1:1, CG 1:21; p = 0.001). CONCLUSION: PPFF patients showed significantly higher rates of inlay erosion, resulting in femoral head decentralization and osteolysis. The higher rate of fracture is likely caused by the increasing instability of the implant fixation due to abrasion-induced osteolysis and the associated degradation of bone quality. It is conceivable that the abrasion and decentralization of the THA can also lead to gait instability, and thus, a higher proneness to falls. Gait instability can also be aggravated by increased granulation tissue and effusion due to the inlay abrasion. Although this cannot be substantiated by the investigation. In patients with decentralization of the THA and osteolysis, a radiological follow-up should be performed, and in case of gait instability (femoral head and) inlay replacements should be considered.

Mitral Valve Repair in Children Below Age 10 Years: Trouble or Success?

BACKGROUND: Mitral valve (MV) repair in children is challenging because of the broad spectrum of lesions and anticipated patient growth. The purpose of the study was to evaluate the outcome of MV repair in children below 10 years of age. METHODS: We reviewed all MV repair procedures performed in children below 10 years of age. Endpoints of the study were survival after MV repair and cumulative incidence of reoperation. RESULTS: MV repair was performed in 40 patients with congenital MV disease (MVD) and in 10 patients with acquired MVD. Median age at time of repair for congenital MVD was 1.2 years (range, 14 days to 9.8 years) and for acquired MVD 1.9 years (range, 10 days to 9.9 years). Indication for MV repair was mitral regurgitation in 31 congenital MVD patients (77.5%) and in all acquired MVD patients. In patients with congenital MVD operative mortality was 5% and late mortality was 10%. No deaths occurred in patients with acquired MVD. Patients with congenital mitral regurgitation showed a better, yet not significant, 6-year survival than patients with congenital mitral stenosis (85.3% ± 8.2% vs 60% ± 18.2%, P = .1). In patients with congenital MVD cumulative incidence of reoperation at 6 years was 38.6% ± 8.3%. CONCLUSIONS: In children below 10 years of age, MV repair is an effective treatment option for MVD. However it often just delays the time to valve replacement.

Evaluation of a biocompatible sealant for on-demand repair of vascular defects-a chronic study in a large animal model.

OBJECTIVES: Existing surgical sealants fail to combine design requirements, such as sealing performance, on-demand activation and biocompatibility. The aim of this study was to compare the effectiveness and safety of the SETALIUM™ Vascular Sealant (SVS), a novel, on-demand activatable sealant, with the commercial sealant, BioGlue®, for the repair of vascular defects. METHODS: In an in vivo porcine model, the use of SVS was compared with BioGlue, for sealing 2-mm defects of the carotid artery and jugular vein. Animals were followed for 7 days and 5 weeks (each time point and per experimental group, n = 4), respectively. The degree of stenosis and flow velocity was determined, and the local tissue response was evaluated. RESULTS: In vivo incision closure succeeded in all cases, and SVS was superior in clinical usability, enabled by its on-demand activation. Unlike BioGlue, SVS use did not induce stenosis and was associated with physiological blood flow in all cases. Moreover, closure with SVS was associated with a low inflammatory reaction and no thrombus formation or intima proliferation, in contrast to BioGlue. CONCLUSIONS: SVS demonstrated effective and rapid sealing of 2-mm vascular defects, with favourable biocompatibility compared to BioGlue. Thus, SVS seems to be an effective and safe vascular sealant.

Neonatal Mitral Valve Repair in Biventricular Repair, Single Ventricle Palliation, and Secondary Left Ventricular Recruitment: Indications, Techniques, and Mid-Term Outcomes.

OBJECTIVES: Although mitral valve repair is rarely required in neonates, this population is considered to be at high risk for adverse outcomes. The aim of this study was to review the indications for surgery, mechanisms, repair techniques, and mid-term outcomes of neonatal mitral valve repair. METHODS: The demographic, procedural, and outcome data were obtained for all neonates who underwent mitral valve repair from 2005 to 2012. The primary endpoints included mortality, transplantation, and mitral valve reoperation. RESULTS: Twenty patients were included during the study period. Median age at operation was 11 days (range: 3-25). Eleven patients (55%) presented with mitral stenosis, three had regurgitation (15%), and six had mixed mitral disease (30%). Nineteen of 20 patients had mild or less regurgitation on immediate postoperative imaging. During a median follow-up of 5 months (1 month-4.8 years), six patients died at a median of 33 months (7-41 months) from repair and one patient required orthotopic heart transplantation. Six patients required mitral valve reoperation, five for mitral valve re-repair, and one for mitral valve replacement. Freedom from death, transplantation, or mitral valve replacement was 84.2 ± 8.4% at 1 month, 71.3 ± 11% at 6 months, 64.1 ± 12% at 1 year, and 51.3 ± 15% at 2 years and was worse for patients presenting with mitral regurgitation compared to stenosis or mixed mitral valve disease. CONCLUSION: Although mitral valve repair can be performed with acceptable immediate postoperative result, this procedure carries a high burden of late death and mitral valve reoperations.

A light-reflecting balloon catheter for atraumatic tissue defect repair.

A congenital or iatrogenic tissue defect often requires closure by open surgery or metallic components that can erode tissue. Biodegradable, hydrophobic light-activated adhesives represent an attractive alternative to sutures, but lack a specifically designed minimally invasive delivery tool, which limits their clinical translation. We developed a multifunctional, catheter-based technology with no implantable rigid components that functions by unfolding an adhesive-loaded elastic patch and deploying a double-balloon design to stabilize and apply pressure to the patch against the tissue defect site. The device uses a fiber-optic system and reflective metallic coating to uniformly disperse ultraviolet light for adhesive activation. Using this device, we demonstrate closure on the distal side of a defect in porcine abdominal wall, stomach, and heart tissue ex vivo. The catheter was further evaluated as a potential tool for tissue closure in vivo in rat heart and abdomen and as a perventricular tool for closure of a challenging cardiac septal defect in a large animal (porcine) model. Patches attached to the heart and abdominal wall with the device showed similar inflammatory response as sutures, with 100% small animal survival, indicating safety. In the large animal model, a ventricular septal defect in a beating heart was reduced to <1.6 mm. This new therapeutic platform has utility in a range of clinical scenarios that warrant minimally invasive and atraumatic repair of hard-to-reach defects.

Bacterial nanocellulose as a new patch material for closure of ventricular septal defects in a pig model.

OBJECTIVES: Current materials for closure of cardiac defects such as ventricular septal defects (VSDs) are associated with compliance mismatch and a chronic inflammatory response. Bacterial nanocellulose (BNC) is a non-degradable biomaterial with promising properties such as high mechanical strength, favourable elasticity and a negligible inflammatory reaction. The aim of this study was the evaluation of a BNC patch for VSD closure and the investigation of its in vivo biocompatibility in a chronic pig model. METHODS: Young's modulus and tensile strength of BNC patches were determined before and after blood exposure. Muscular VSDs were created and closed with a BNC patch on the beating heart in an in vivo pig model. Hearts were explanted after 7, 30 or 90 days. Macropathology, histology and immunohistochemistry were performed. RESULTS: Young's modulus and tensile strength of the BNC patch decreased after blood contact from 6.3 ± 1.9 to 3.86 ± 2.2 MPa (P < 0.01) and 0.33 ± 0.06 to 0.26 ± 0.06 MPa (P < 0.01), respectively, indicating the development of higher elasticity. Muscular VSDs were closed with a BNC patch without residual shunting. After 90 days, a mild chronic inflammatory reaction was present. Moreover, there was reduced tissue overgrowth in comparison with polyester. Proceeding cellular organization characterized by fibromuscular cells, production of extracellular matrix, neoangiogenesis and complete neoendothelialization were found. There were no signs of thrombogenicity. CONCLUSIONS: BNC patches can close VSDs with good mid-term results and its biocompatibility can be considered as satisfactory. Its elasticity increases in the presence of blood, which might be advantageous. Therefore, it has potential to be used as an alternative patch material in congenital heart disease.

A blood-resistant surgical glue for minimally invasive repair of vessels and heart defects.

Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis.

Percutaneous steerable robotic tool delivery platform and metal microelectromechanical systems device for tissue manipulation and approximation: closure of patent foramen ovale in an animal model.

BACKGROUND: Beating-heart image-guided intracardiac interventions have been evolving rapidly. To extend the domain of catheter-based and transcardiac interventions into reconstructive surgery, a new robotic tool delivery platform and a tissue approximation device have been developed. Initial results using these tools to perform patent foramen ovale closure are described. METHODS AND RESULTS: A robotic tool delivery platform comprising superelastic metal tubes provides the capability of delivering and manipulating tools and devices inside the beating heart. A new device technology is also presented that uses a metal-based microelectromechanical systems-manufacturing process to produce fully assembled and fully functional millimeter-scale tools. As a demonstration of both technologies, patent foramen ovale creation and closure was performed in a swine model. In the first group of animals (n=10), a preliminary study was performed. The procedural technique was validated with a transcardiac hand-held delivery platform and epicardial echocardiography, video-assisted cardioscopy, and fluoroscopy. In the second group (n=9), the procedure was performed percutaneously using the robotic tool delivery platform under epicardial echocardiography and fluoroscopy imaging. All patent foramen ovales were completely closed in the first group. In the second group, the patent foramen ovale was not successfully created in 1 animal, and the defects were completely closed in 6 of the 8 remaining animals. CONCLUSIONS: In contrast to existing robotic catheter technologies, the robotic tool delivery platform uses a combination of stiffness and active steerability along its length to provide the positioning accuracy and force-application capability necessary for tissue manipulation. In combination with a microelectromechanical systems tool technology, it can enable reconstructive procedures inside the beating heart.

Percutaneous intracardiac beating-heart surgery using metal MEMS tissue approximation tools.

Achieving superior outcomes through the use of robots in medical applications requires an integrated approach to the design of the robot, tooling and the procedure itself. In this paper, this approach is applied to develop a robotic technique for closing abnormal communication between the atria of the heart. The goal is to achieve the efficacy of surgical closure as performed on a stopped, open heart with the reduced risk and trauma of a beating-heart catheter-based procedure. In the proposed approach, a concentric tube robot is used to percutaneously access the right atrium and deploy a tissue approximation device. The device is constructed using a metal microelectromechanical system (MEMS) fabrication process and is designed to both fit the manipulation capabilities of the robot as well as to reproduce the beneficial features of surgical closure by suture. The effectiveness of the approach is demonstrated through ex vivo and in vivo experiments.

Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age-related macular degeneration.

PURPOSE: To determine whether different complement factor H (CFH) genotypes play a role in treatment of age-related macular degeneration (AMD) with intravitreal bevacizumab. METHODS: In this prospective study, we included 197 patients with exudative AMD and treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization (CNV) was no longer active. In all patients, ophthalmological examinations, visual acuity, optical coherence tomography (OCT), fundus photography and fluorescein angiography were performed. Single nucleotide polymorphism (SNP) genotyping was performed using restriction fragment length polymorphism (RFLP) analysis of polymerase chain reaction (PCR) products. RESULTS: Age, gender and baseline mean visual acuity were similar among the three CFH genotypes. There was no significant difference in underlying lesion type of CNV, lesion size, number of injections or macula thickness. When examining the effect of genotype on post-treatment visual acuities, we observed a significant worse outcome for distance and reading visual acuity in the CFH 402HH genotype group. The number of patients who lost 3 or more lines in distance and reading visual acuity testing was significantly higher in the CFH 402HH (41%, 46%) genotype group than in patients with the CFH 402YY (28%, 26%) and CFH 402YH (26%, 24%) genotype. CONCLUSIONS: In addition to the higher risk for exudative AMD in patients with the CFH 402HH genotype that was found in previous studies, our results show that the CFH 402HH genotype also correlates with lower visual acuity outcome after treatment with bevacizumab, suggesting that pharmacogenetics of CFH plays a role in response to treatment of wet AMD.

Modification of a hybrid technique for closure of muscular ventricular septal defects in a pig model.

OBJECTIVE: Closure of muscular ventricular septal defects (mVSDs) beyond the moderator band is still a challenge for both surgeons and interventional cardiologists. We evaluated a new technique in a pig model for hybrid patch closure of mVSDs via 2 stab wound incisions in the left ventricle (LV) without cardiopulmonary bypass. METHODS: Ten pigs underwent left anterolateral thoracotomy to expose the LV. mVSDs were created via a stab wound incision of the lateral wall of the LV under epicardial echocardiographic control. The patch system was forwarded through a second puncture of the LV apex and positioned in front of the mVSD. The stapler for fixation of the patch was introduced through the same incision as used for VSD creation. Finally, the patch was attached to the septum with nitinol anchors under epicardial echocardiographic and fluoroscopic guidance. Finally, detailed echocardiographic evaluation was done. All hearts were explanted, and macroscopic evaluation was done, either immediately after patch implantation (n = 4) or after 90 days (n = 6). RESULTS: mVSD creation was successful in all pigs. Closure of mVSDs was successful in 8 of 10 pigs, as confirmed by echocardiography, hemodynamic measurements, and macroscopic examination. One patch embolized through the mVSD into the pulmonary artery because of insecure fixation, and 1 animal died during the procedure because of ventricular fibrillation. The final echocardiographic evaluation revealed good LV function and no damage to the valves. CONCLUSIONS: Closure of mVSDs can be successfully performed in a hybrid technique on the beating heart with 2 stab wound incisions; however, further modifications need to be developed before clinical application.

Evaluation of a new hybrid technique for closure of muscular ventricular septal defects in a long-term setting.

OBJECTIVE: Therapy for muscular ventricular septal defects beyond the moderator band, especially in neonates and infants, has always been challenging for both surgeons and cardiologists. Recently, we established a patch closure hybrid therapy for muscular ventricular septal defects. In this study, we evaluated it in a long-term porcine model. METHODS: Thirteen minipigs underwent anterolateral thoracotomy to expose the left ventricle. Muscular ventricular septal defects were created under 2- and 3-dimensional echocardiographic guidance with a 7.5-mm sharp punch instrument. Closure of the defects was undertaken with our new patch system in hybrid technique. Animals were observed for 3 months. Echocardiographic evaluation and pathologic examination, including immunohistochemical staining, were undertaken. RESULTS: Defects were successfully created in 12 pigs and closed in 10 pigs. Seven survived for 3 months. Residual shunting was noticed in 1 animal. Neither left ventricular dysfunction nor relevant damage to the valves could be detected. Pathologic examination showed complete endothelialization of the patch and the nitinol anchors without protruding parts of the system. Cellular organization was proceeding. Immunohistochemical staining demonstrated endothelial cells on the surface of the patch and fibromuscular cells around the patch. CONCLUSION: Our hybrid therapy was efficacious in closing muscular ventricular septal defects without impairment of cardiac function. The patch system and nitinol anchors demonstrated good integration into the septum. Further development of the system for human application is already being undertaken.

Off-pump extraanatomic bypass from the ascending to the descending aorta for re-operation of interrupted aortic arch in an adolescent.

The appearance of re-stenosis after repair of an interrupted aortic arch may be a surgical challenge due to adhesions. Here, we describe an approach using off-pump coronary artery bypass grafting techniques to reach the descending aorta through a median sternotomy in a patient with aortic arch stenosis after conduit repair. The 17-year-old patient with diagnoses of interrupted aortic arch and ventricular septal defect presented after two previous operations (one left lateral thoracotomy and one median sternotomy) with a stenosed vascular graft between ascending and descending aorta. Surgery was done via re-sternotomy without cardio-pulmonary bypass. An extraanatomic graft was used to connect ascending and descending aorta. When performing the distal anastomosis, the heart was exposed using a standard suction device. This case demonstrates that the use of modern techniques may facilitate surgical approaches dramatically. In our opinion the above-described technique is the first choice for all patients requiring arch repair following multiple previous operations, performed via sternotomy and thoracotomy.

Quality of life after replacement of the ascending aorta in patients with true aneurysms.

True aneurysms of the ascending aorta often remain undetected, yet their sequelae carry a high rate of mortality and morbidity. The operative risk of nonemergent replacement of the ascending aorta is low. It is important to consider quality of life in determining the most appropriate treatment for patients who have aneurysms but have not yet experienced major complications.From January 1999 to December 2003, 134 consecutive patients underwent replacement of a dilated ascending aorta at our center. Another 124 patients with acute or chronic aortic dissections, aortic rupture, or intramural hematoma were excluded. Standard SF-36 and general health questionnaires were sent to all 124 survivors who could be traced. Follow-up was 98.4% complete. The mean age of the survivors was 61.7 +/- 11 years, and 63.4% were men. Operative procedures consisted of supracoronary replacement of the ascending aorta in 35.9%, the Wheat procedure in 44%, the David procedure in 11.2%, the Bentall-DeBono procedure in 9%, and the Cabrol procedure in 2.2%. Patients were monitored until May 2005.Thirty-day and midterm mortality rates were 3.7% and 3.9%, respectively. Morbidity due to stroke was 6%, to bleeding 6%, and to myocardial infarction 4.4%. Postoperative quality-of-life evaluation revealed many subscales of SF-36 that were below the norm when compared with a standard population in physically dominated categories.Replacement of the dilated ascending aorta carries acceptable risk in regard to operative death and postoperative quality of life, although this last showed some decline in comparison with quality of life in a normal, healthy population.