Long-term function of a novel autologous transcatheter pulmonary heart valve implant in an adult animal model.

BACKGROUND: Current heart valve implants entail major disadvantages in the treatment for younger patients or those with congenital heart defects. AIM: Evaluation of novel transcatheter pulmonary valve implant made from autologous pericardium with natural crosslinking agent in an in vitro setup and in vivo animal model METHODS: Valves were tested in a pulse duplicator according to ISO-standard 5840. For in vivo studies computer tomography was performed to measure sheep's native pulmonary valve dimensions. Pericardium was harvested by thoracotomy, personalized implants were manufactured and deployed in pulmonary valve position of the same sheep. Every 3 months implant functionality was evaluated by intracardiac echocardiography, intracardiac pressure measurements and cardiac magnetic resonance imaging (cMRI). Implants were explanted for macroscopic and histological examination. RESULTS: In vitro experiments showed compliance with regulatory requirements in terms of valve opening and insufficiency. Five sheep successfully received an autologous valve implant. Two animals had to be euthanized due to trauma sustained in the stable. Long-term valve function was excellent in three out of four animals with median implant cMRI regurgitation fraction of 9% (n = 4) at 3 months, 8% (n = 3) at 6, 8% (n = 3) at 9, 12% (n = 3) at 13, 8% (n = 2) at 17% and 8% (n = 2) at 20.5 months after implantation. Despite good adherence to neighboring tissue and endothelization, histological assessment revealed some signs of degeneration. CONCLUSION: Transcatheter pulmonary valve implants showed promising function for up to 20.5 months encouraging research to further improve this approach.

Presence of reduced regional left ventricular function even in the absence of left ventricular wall scar tissue in the long term after repair of an anomalous left coronary artery from the pulmonary artery.

BACKGROUND: We sought to assess left ventricular regional function in patients with and without left ventricular wall scar tissue in the long term after repair of an anomalous origin of the left coronary artery from the pulmonary artery. METHODS: A total of 20 patients aged 12.8±7.4 years were assessed 10 (0.5-17) years after the repair of an anomalous origin of the left coronary artery from the pulmonary artery; of them, 10 (50%) patients showed left ventricular wall scar tissue on current cardiac MRI. Left ventricular regional function was assessed by two-dimensional speckle-tracking echocardiography in 10 patients with scar tissue and 10 patients without scar tissue and in 10 age-matched controls. RESULTS: In patients with scar tissue, MRI-derived left ventricular ejection fraction was significantly reduced compared with that in patients without scar tissue (51 versus 61%, p<0.05), and echocardiography-derived longitudinal strain was significantly reduced in five of six left ventricular areas compared with that in healthy controls (average relative reduction, 46%; p<0.05). In patients without scar tissue, longitudinal strain was significantly reduced in two of six left ventricular areas (average relative reduction, 23%; p<0.05) and circumferential strain was reduced in one of six left ventricular areas (relative reduction, 56%; p<0.05) compared with that in healthy controls. CONCLUSIONS: Regional left ventricular function is reduced even in patients without left ventricular wall scar tissue late after successful repair of an anomalous origin of the left coronary artery from the pulmonary artery. This highlights the need for meticulous lifelong follow-up in all patients with a repaired anomalous origin of the left coronary artery from the pulmonary artery.

Effects of incremental beta-blocker dosing on myocardial mechanics of the human left ventricle: MRI 3D-tagging insight into pharmacodynamics supports theory of inner antagonism.

Beta-blockers contribute to treatment of heart failure. Their mechanism of action, however, is incompletely understood. Gradients in beta-blocker sensitivity of helically aligned cardiomyocytes compared with counteracting transversely intruding cardiomyocytes seem crucial. We hypothesize that selective blockade of transversely intruding cardiomyocytes by low-dose beta-blockade unloads ventricular performance. Cardiac magnetic resonance imaging (MRI) 3D tagging delivers parameters of myocardial performance. We studied 13 healthy volunteers by MRI 3D tagging during escalated intravenous administration of esmolol. The circumferential, longitudinal, and radial myocardial shortening was determined for each dose. The curves were analyzed for peak value, time-to-peak, upslope, and area-under-the-curve. At low doses, from 5 to 25 µg·kg(-1)·min(-1), peak contraction increased while time-to-peak decreased yielding a steeper upslope. Combining the values revealed a left shift of the curves at low doses compared with baseline without esmolol. At doses of 50 to 150 µg·kg(-1)·min(-1), a right shift with flattening occurred. In healthy volunteers we found more pronounced myocardial shortening at low compared with clinical dosage of beta-blockers. In patients with ventricular hypertrophy and higher prevalence of transversely intruding cardiomyocytes selective low-dose beta-blockade could be even more effective. MRI 3D tagging could help to determine optimal individual beta-blocker dosing avoiding undesirable side effects.

The influence of the region of interest width on two-dimensional speckle tracking-based measurements of strain and strain rate.

AIMS: There are significant variations in the published normal values of two-dimensional speckle tracking-derived strain and strain rate. These occur even when authors use the same software. To measure strain, the operator creates a region of interest (ROI) to define the myocardium to be analyzed. The purpose of this study was to test the hypothesis that measurements vary significantly with the chosen ROI width. METHODS AND RESULTS: In 20 healthy subjects (11 males, mean age 17.6 ± 6.18 years) an apical four-chamber view (4CH) and parasternal short-axis view (SAX) were analyzed. Initially ROI width was set automatically by the software. Two subsequent measurements were obtained from each cine loop by choosing the ROI width one step narrower and one step wider than the automatic ROI width. The mean differences between the measurements of narrower and automatic ROI and between automatic and wider ROI were -1.8 ± 0.7% and -0.9 ± 0.5% for global longitudinal strain (SL), -2.2 ± 0.6% and -1.7 ± 0.7% for global circumferential strain (SC), -0.10 ± 0.06/sec and -0.07 ± 0.06/sec for global longitudinal strain rate (SrL), and -0.15 ± 0.09/sec and -0.12 ± 0.07/sec for global circumferential strain rate (SrC) (all P < 0.000). This corresponds to a relative difference to the mean of both measurements of -4.4 to -11.0%. CONCLUSION: Layer-specific myocardial deformation and curvature dependency lead to an inverse correlation between the chosen ROI width and strain and strain rate measurements. Just one step of ROI-width change leads to a significant bias. Precise ROI-width definition is essential but technical factors limit its feasibility.

Feasibility of customised unipolar conversion using bipolar temporary pacing wires in patients after surgical repair of congenital heart disease.

OBJECTIVE: Temporary pacing wires play a crucial role in the diagnosis and therapy of post-operative arrhythmia after surgery for congenital heart disease. At present, bipolar pacing wires are used in most institutions. In case of functional failure of these wires, a unipolar mode of stimulation and sensing should be theoretically possible as a rescue procedure. METHODS: We tested the feasibility of the customised unipolar mode in 18 post-operative patients with congenital heart disease (age 9.2 ± 13.9 months, weight 6.3 ± 3.8 kg, and cardiopulmonary bypass time 70 ± 29 minutes). As there are two possible unipolar configurations, there are twice the number of testing parameters; of those, we compared sensing (mV) and pacing thresholds (V at 0.5 ms). RESULTS: Atrial sensing was significantly better in the unipolar modes (p < 0.001, p < 0.003). The ventricular unipolar sensing did not differ significantly in the "better" of the two possible configurations from the bipolar values (p = 0.363). For the unipolar pacing thresholds, only the "better" unipolar configuration did not differ significantly from the bipolar measurements (atrial: p = 0.058, ventricular: p = 0.138). There was no exit block or undersensing. CONCLUSION: The results demonstrate that unipolar stimulation and sensing using bipolar epicardial temporary pacing wires is feasible. In the case of failure of bipolar temporary pacing wires, this modality represents an easy rescue measure that in such cases should always be considered.

In Vitro Comparison of a Closed and Semi-closed Leaflet Design for Adult and Pediatric Transcatheter Heart Valves.

Transcatheter heart valve replacements (TVR) are mostly designed in a closed position (c) with leaflets coaptating. However, recent literature suggests fabricating valves in semi-closed (sc) position to minimize pinwheeling. With about 100,000 children in need of a new pulmonary valve each year worldwide, this study evaluates both geometrical approaches in adult as well as pediatric size and condition. Three valves of each geometry were fabricated in adult (30 mm) and pediatric (15 mm) size, using porcine pericardium. To evaluate performance, the mean transvalvular pressure gradient (TPG), effective orifice area (EOA), and regurgitation fraction (RF) were determined in three different annulus geometries (circular, elliptic, and tilted). For both adult-sized valve geometries, the TPG (TPGC = 2.326 ± 0.115 mmHg; TPGSC = 1.848 ± 0.175 mmHg)* and EOA (EOAC = 3.69 ± 0.255 cm2; EOASC = 3.565 ± 0.025 cm2)* showed no significant difference. Yet the RF as well as its fluctuation was significantly higher for valves with the closed geometry (RFC = 12.657 ± 7.669 %; RFSC = 8.72 ± 0.977 %)*. Recordings showed that the increased backflow was caused by pinwheeling due to a surplus of tissue material. Hydrodynamic testing of pediatric TVRs verified the semi-closed geometry being favourable. Despite the RF (RFC = 7.721 ± 0.348 cm2; RFSC = 5.172 ± 0.679 cm2), these valves also showed an improved opening behaviour ((TPGC = 20.929 ± 0.497 cm2; TPGSC = 15.972 ± 1.158 cm2); (EOAC = 0.629 ± 0.017 cm2; EOASC = 0.731 ± 0.026 cm2)). Both adult and pediatric TVR with semi-closed geometry show better fluiddynamic functionality compared to valves with a closed design due to less pinwheeling. Besides improved short-term functionality, less pinwheeling potentially prevents early valve degeneration and improves durability. *Results are representatively shown for a circular annulus geometry.

CT-based comparison of porcine, ovine, and human pulmonary arterial morphometry.

To facilitate pre-clinical animal and in-silico clinical trials for implantable pulmonary artery pressure sensors, understanding the respective species pulmonary arteries (PA) anatomy is important. Thus, morphological parameters describing PA of pigs and sheep, which are common animal models, were compared with humans. Retrospective computed tomography data of 41 domestic pigs (82.6 ± 18.8 kg), 14 sheep (49.1 ± 6.9 kg), and 49 patients (76.8 ± 18.2 kg) were used for reconstruction of the subject-specific PA anatomy. 3D surface geometries including main, left, and right PA as well as LPA and RPA side branches were manually reconstructed. Then, specific geometric parameters (length, diameters, taper, bifurcation angle, curvature, and cross-section enlargement) affecting device implantation and post-interventional device effect and efficacy were automatically calculated. For both animal models, significant differences to the human anatomy for most geometric parameters were found, even though the respective parameters' distributions also featured relevant overlap. Out of the two animal models, sheep seem to be better suitable for a preclinical study when considering only PA morphology. Reconstructed geometries are provided as open data for future studies. These findings support planning of preclinical studies and will help to evaluate the results of animal trials.

A Glutaraldehyde-Free Crosslinking Method for the Treatment of Collagen-Based Biomaterials for Clinical Application.

Biological bioprostheses such as grafts, patches, and heart valves are often derived from biological tissue like the pericardium. These bioprostheses can be of xenogenic, allogeneic, or autologous origin. Irrespective of their origin, all types are pre-treated via crosslinking to render the tissue non-antigenic and mechanically strong or to minimize degradation. The most widely used crosslinking agent is glutaraldehyde. However, glutaraldehyde-treated tissue is prone to calcification, inflammatory degradation, and mechanical injury, and it is incapable of matrix regeneration, leading to structural degeneration over time. In this work, we are investigating an alternative crosslinking method for an intraoperative application. The treated tissue's crosslinking degree was evaluated by differential scanning calorimetry. To confirm the findings, a collagenase assay was conducted. Uniaxial tensile testing was used to assess the tissue's mechanical properties. To support the findings, the treated tissue was visualized using two-photon microscopy. Additionally, fourier transform infrared spectroscopy was performed to study the overall protein secondary structure. Finally, a crosslinking procedure was identified for intraoperative processing. The samples showed a significant increase in thermal and enzymatic stability after treatment compared to the control, with a difference of up to 22.2 °C and 100%, respectively. Also, the tissue showed similar biomechanics to glutaraldehyde-treated tissue, showing greater extensibility, a higher failure strain, and a lower ultimate tensile strength than the control. The significant difference in the structure band ratio after treatment is proof of the introduction of additional crosslinks compared to the untreated control with regard to differences in the amide-I region. The microscopic images support these findings, showing an alteration of the fiber orientation after treatment. For collagen-based biomaterials, such as pericardial tissue, the novel phenolic crosslinking agent proved to be an equivalent alternative to glutaraldehyde regarding tissue characteristics. Although long-term studies must be performed to investigate superiority in terms of longevity and calcification, our novel crosslinking agent can be applied in concentrations of 1.5% or 2.0% for the treatment of biomaterials.

Upper cavo-pulmonary anastomosis by transcatheter technique.

OBJECTIVES: The aim of this animal study was to establish a shunt connection between superior vena cava (SVC) and right pulmonary artery (RPA) by transvascular intervention solely. BACKGROUND: After initial shunt creation, the establishment of the upper cavo-pulmonary anastomosis (UCPA) is the second out of three open chest operations young infants with univentricular anatomy are subjected to. To avoid the risks of reoperation with cardiovascular bypass, we sought to replace this surgical step by an interventional technique. METHODS: After cannulation of jugular and femoral veins in four piglets (mean body weight of 12.5 kg) an UCPA was created by radiofrequency perforation from the SVC across the right atrium into the RPA and subsequent implantation of covered stents. The perforation was guided by biplane fluoroscopy and the perforation wire premounted with a coaxial catheter was advanced into the distal pulmonary artery and exchanged for a stiffer wire. A long sheath was brought into the RPA and an 80 mm long expanded poly-tetra-fluoro-ethylene (ePTFE)-covered Cheatham Platinum stent was then implanted connecting the SVC with the RPA. RESULTS: Immediate angiography showed antegrade flow from SVC to RPA. Angiographic re-evaluation after a median period of 4 weeks showed partial in-stent stenosis but patent lumina. Additionally, veno-venous collaterals from the SVC to the right atrium had developed. Histology of the explanted stents revealed parietal thrombi and mild to moderate pseudo intima proliferation inside the lumina. CONCLUSIONS: The transvascular creation of an upper unidirectional cavo-pulmonary anastomosis in piglets is technically feasible using standard catheterization equipment.

Transcatheter Pulmonary Valve Replacement from Autologous Pericardium with a Self-Expandable Nitinol Stent in an Adult Sheep Model.

Transcatheter pulmonary valve replacement has been established as a viable alternative approach for patients suffering from right ventricular outflow tract or bioprosthetic valve dysfunction, with excellent early and late clinical outcomes. However, clinical challenges such as stented heart valve deterioration, coronary occlusion, endocarditis, and other complications must be addressed for lifetime application, particularly in pediatric patients. To facilitate the development of a lifelong solution for patients, transcatheter autologous pulmonary valve replacement was performed in an adult sheep model. The autologous pericardium was harvested from the sheep via left anterolateral minithoracotomy under general anesthesia with ventilation. The pericardium was placed on a 3D shaping heart valve model for non-toxic cross-linking for 2 days and 21 h. Intracardiac echocardiography (ICE) and angiography were performed to assess the position, morphology, function, and dimensions of the native pulmonary valve (NPV). After trimming, the crosslinked pericardium was sewn onto a self-expandable Nitinol stent and crimped into a self-designed delivery system. The autologous pulmonary valve (APV) was implanted at the NPV position via left jugular vein catheterization. ICE and angiography were repeated to evaluate the position, morphology, function, and dimensions of the APV. An APV was successfully implanted in sheep J. In this paper, sheep J was selected to obtain representative results. A 30 mm APV with a Nitinol stent was accurately implanted at the NPV position without any significant hemodynamic change. There was no paravalvular leak, no new pulmonary valve insufficiency, or stented pulmonary valve migration. This study demonstrated the feasibility and safety, in a long-time follow-up, of developing an APV for implantation at the NPV position with a self-expandable Nitinol stent via jugular vein catheterization in an adult sheep model.

Four-Dimensional Computed Tomography-Guided Valve Sizing for Transcatheter Pulmonary Valve Replacement.

The measurements of the right ventricle (RV) and pulmonary artery (PA), for selecting the optimal prosthesis size for transcatheter pulmonary valve replacement (TPVR), vary considerably. Three-dimensional (3D) computed tomography (CT) imaging for device size prediction is insufficient to assess the displacement of the right ventricular outflow tract (RVOT) and PA, which could increase the risk of stent misplacement and paravalvular leak. The aim of this study is to provide a dynamic model to visualize and quantify the anatomy of the RVOT to PA over the entire cardiac cycle by four-dimensional (4D) cardiac CT reconstruction to obtain an accurate quantitative evaluation of the required valve size. In this pilot study, cardiac CT from sheep J was chosen to illustrate the procedures. 3D cardiac CT was imported into 3D reconstruction software to build a 4D sequence which was divided into eleven frames over the cardiac cycle to visualize the deformation of the heart. Diameter, cross-sectional area, and circumference of five imaging planes at the main PA, sinotubular junction, sinus, basal plane of the pulmonary valve (BPV), and RVOT were measured at each frame in 4D straightened models prior to valve implantation to predict the valve size. Meanwhile, dynamic changes in the RV volume were also measured to evaluate right ventricular ejection fraction (RVEF). 3D measurements at the end of the diastole were obtained for comparison with the 4D measurements. In sheep J, 4D CT measurements from the straightened model resulted in the same choice of valve size for TPVR (30 mm) as 3D measurements. The RVEF of sheep J from pre-CT was 62.1 %. In contrast with 3D CT, the straightened 4D reconstruction model not only enabled accurate prediction for valve size selection for TPVR but also provided an ideal virtual reality, thus presenting a promising method for TPVR and the innovation of TPVR devices.

Transcatheter creation of an aortopulmonary shunt in an animal model.

BACKGROUND: The surgical creation of an aortopulmonary shunt is an important tool in the therapy of complex congenital heart defects. We report on a transcatheter approach to establish an aortopulmonary shunt in piglets. MATERIAL, METHODS AND RESULTS: In 10 piglets with a median body weight of 10.5 kg (8-12 kg), a central aortopulmonary shunt was created by radiofrequency perforation from the aorta to the pulmonary trunk, followed by stent implantation. The procedures were performed via the femoral vessels through 5F sheaths under biplane fluoroscopy guidance. A total of six bare metal coronary stents and five polytetrafluoroethylene-covered coronary stents of 3-4 mm diameter were deployed. Four animals were sacrificed immediately after intervention; six pigs were reevaluated 4-5 weeks later for stent patency and measurement of shunt volume. The procedure was successful in all pigs. Median shunt volume was Qp:Qs = 2.4:1. At re-evaluation median body weight had increased to 18 kg (15.5-27.5 kg) P < 0.028. Four of six stents were completely obstructed due to tissue ingrowth in the bare metal stents (two cases) and thrombus formation in the covered stents (two cases). A third bare metal stent had a residual lumen, and a third covered stent was fully open without any thrombus formation or tissue ingrowth. CONCLUSIONS: Transcatheter creation of an aortopulmonary shunt by radiofrequency perforation and stent implantation is feasible. The use of appropriate covered stents and an effective anticoagulatory regimen seem to be crucial to keep the shunts open.

Three-dimensional alignment of the aggregated myocytes in the normal and hypertrophic murine heart.

Several observations suggest that the transmission of myocardial forces is influenced in part by the spatial arrangement of the myocytes aggregated together within ventricular mass. Our aim was to assess, using diffusion tensor magnetic resonance imaging (DT-MRI), any differences in the three-dimensional arrangement of these myocytes in the normal heart compared with the hypertrophic murine myocardium. We induced ventricular hypertrophy in seven mice by infusion of angiotensin II through a subcutaneous pump, with seven other mice serving as controls. DT-MRI of explanted hearts was performed at 3.0 Tesla. We used the primary eigenvector in each voxel to determine the three-dimensional orientation of aggregated myocytes in respect to their helical angles and their transmural courses (intruding angles). Compared with controls, the hypertrophic hearts showed significant increases in myocardial mass and the outer radius of the left ventricular chamber (P < 0.05). In both groups, a significant change was noted from positive intruding angles at the base to negative angles at the ventricular apex (P < 0.01). Compared with controls, the hypertrophied hearts had significantly larger intruding angles of the aggregated myocytes, notably in the apical and basal slices (P < 0.001). In both groups, the helical angles were greatest in midventricular sections, albeit with significantly smaller angles in the mice with hypertrophied myocardium (P < 0.01). The use of DT-MRI revealed significant differences in helix and intruding angles of the myocytes in the mice with hypertrophied myocardium.

Partial anomalous pulmonary venous drainage in young pediatric patients: the role of magnetic resonance imaging.

Studies of larger patient groups for systematic assessment of the anatomical accuracy of magnetic resonance imaging (MRI) for partial anomalous pulmonary venous drainage (PAPVD) have been performed so far only in adults. This study was undertaken to evaluate whether MRI can precisely depict pulmonary venous anatomy in infants and young children. Data on 26 children under 10 years old that underwent MRI over the past 2 years for suspected PAPVD were assessed. The MRI protocol included shunt quantification by velocity-encoded cine as well as morphological and functional assessment by multislice multiphase and contrast-enhanced MR techniques. MRI was performed in the compliant patient in breath-hold (n = 8; age range, 4.6-9.5 years) and in the noncompliant patient in conscious-sedation free breathing (n = 18; age range, 0.4 to 7.5 years). In 22 patients, PAPVD was diagnosed with MRI and confirmed during surgery. In four patients with large atrial septal defects not accessible to percutaneous closure, normal pulmonary venous return was demonstrated by MRI and confirmed during surgery. MRI under conscious sedation accurately specifies the anatomy of pulmonary veins in infants and small children. Therefore, we suggest performing MRI in patients with inconclusive transthoracic echocardiographic results in the preoperative assessment of PAPVD.

Retraction: Bruder, L. et al. Transcatheter Decellularized Tissue-Engineered Heart Valve (dTEHV) Grown on Polyglycolic Acid (PGA) Scaffold Coated with P4HB Shows Improved Functionality over 52 Weeks due to Polyether-Ether-Ketone (PEEK) Insert. J. Funct. Biomater. 2018, 9(4), 64.

Due to human error, the authors included some of the experimental data in this article [...].

RIKADA Study Reveals Risk Factors in Pediatric Primary Cardiomyopathy.

Background Cardiomyopathies are heterogeneous diseases with clinical presentations varying from asymptomatic to life-threatening events, including severe heart failure and sudden cardiac death. The role of underlying genetic and disease-modulating factors in children and adolescents is relatively unknown. In this prospective study, in-depth phenotypic and genetic characterization of pediatric patients with primary cardiomyopathy and their first-degree family members (FMs) was performed. Outcome was assessed to identify clinical risk factors. Methods and Results Sixty index patients with primary cardiomyopathy (median age: 7.8 years) and 124 FMs were enrolled in the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study. Family screening included cardiac workup and genetic testing. Using cardiologic screening, we identified 17 FMs with cardiomyopathies and 30 FMs with suspected cardiomyopathies. Adverse events appeared in 32% of index patients and were more common in those with lower body surface area (P=0.019), increased NT-proBNP (N-terminal pro-brain natriuretic peptide; P<0.001), and left ventricular dysfunction (P<0.001) and dilatation (P=0.005). The worst prognosis was observed in dilated and restrictive cardiomyopathies. Genetic variants of interest were detected in patients (79%) and FMs (67%). In all 15 families with at least 1 FM with cardiomyopathy, we found a variant of interest in the index patient. Increased number of variants of interest per patient was associated with adverse events (P=0.021). Late gadolinium enhancement was related to positive genotypes in patients (P=0.041). Conclusions Lower body surface area, increased NT-proBNP, left ventricular dysfunction or dilatation, late gadolinium enhancement, and increased number of variants of interest were associated with adverse outcome and should be considered for risk assessment in pediatric primary cardiomyopathies. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03572569.

Carag bioresorbable septal occluder (CBSO): histopathology of experimental implants.

AIMS: The aim of this study was to evaluate local biological responses to the partially bioresorbable nonmetal frame Carag bioresorbable septal occluder system in an experimental setting. METHODS AND RESULTS: A Good Laboratory Practices (GLP) study was performed with implantation of the device into the interatrial septum of 24 German Landrace pigs with follow-up periods of 3, 5, 8 and 15 months (six animals in each group). One non-implant-related death occurred one month after implantation. Histology was obtained by sawing and grinding of the hard-resin embedded specimen after formalin fixation. All occlusion devices were found correctly positioned without any residual shunt at the end of the experiments. Complete endothelialisation could be confirmed histologically in all specimens independent of implantation period. There were only a few lymphocytic infiltrations locally related to the implant materials. Sporadic macrophages and foreign body giant cells were found adjacent to the textile fabric. Resorption of the biodegradable frame material was seen to proceed with implantation time. CONCLUSIONS: This is the first report on histopathology of a septal defect occluder with a bioresorbable filament structure in vivo which is already in clinical use. Good biocompatibility was demonstrated with documentation of timely degradation and substitution of the polymer material by fibromuscular cells and extracellular matrix components.

Transcatheter Decellularized Tissue-Engineered Heart Valve (dTEHV) Grown on Polyglycolic Acid (PGA) Scaffold Coated with P4HB Shows Improved Functionality over 52 Weeks due to Polyether-Ether-Ketone (PEEK) Insert.

Many congenital heart defects and degenerative valve diseases require replacement of heart valves in children and young adults. Transcatheter xenografts degenerate over time. Tissue engineering might help to overcome this limitation by providing valves with ability for self-repair. A transcatheter decellularized tissue-engineered heart valve (dTEHV) was developed using a polyglycolic acid (PGA) scaffold. A first prototype showed progressive regurgitation after 6 months in-vivo due to a suboptimal design and misguided remodeling process. A new geometry was developed accordingly with computational fluid dynamics (CFD) simulations and implemented by adding a polyether-ether-ketone (PEEK) insert to the bioreactor during cultivation. This lead to more belly-shaped leaflets with higher coaptation areas for this second generation dTEHV. Valve functionality assessed via angiography, intracardiac echocardiography, and MRI proved to be much better when compared the first generation dTEHV, with preserved functionality up to 52 weeks after implantation. Macroscopic findings showed no thrombi or signs of acute inflammation. For the second generation dTEHV, belly-shaped leaflets with soft and agile tissue-formation were seen after explantation. No excessive leaflet shortening occurred in the second generation dTEHV. Histological analysis showed complete engraftment of the dTEHV, with endothelialization of the leaflets and the graft wall. Leaflets consisted of collagenous tissue and some elastic fibers. Adaptive leaflet remodeling was visible in all implanted second generation dTEHV, and most importantly no fusion between leaflet and wall was found. Very few remnants of the PGA scaffold were detected even 52 weeks after implantation, with no influence on functionality. By adding a polyether-ether-ketone (PEEK) insert to the bioreactor construct, a new geometry of PGA-scaffold based dTEHV could be implemented. This resulted in very good valve function of the implanted dTEHV over a period of 52 weeks.

Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model.

Valvular heart disease is a major cause of morbidity and mortality worldwide. Current heart valve prostheses have considerable clinical limitations due to their artificial, nonliving nature without regenerative capacity. To overcome these limitations, heart valve tissue engineering (TE) aiming to develop living, native-like heart valves with self-repair, remodeling, and regeneration capacity has been suggested as next-generation technology. A major roadblock to clinically relevant, safe, and robust TE solutions has been the high complexity and variability inherent to bioengineering approaches that rely on cell-driven tissue remodeling. For heart valve TE, this has limited long-term performance in vivo because of uncontrolled tissue remodeling phenomena, such as valve leaflet shortening, which often translates into valve failure regardless of the bioengineering methodology used to develop the implant. We tested the hypothesis that integration of a computationally inspired heart valve design into our TE methodologies could guide tissue remodeling toward long-term functionality in tissue-engineered heart valves (TEHVs). In a clinically and regulatory relevant sheep model, TEHVs implanted as pulmonary valve replacements using minimally invasive techniques were monitored for 1 year via multimodal in vivo imaging and comprehensive tissue remodeling assessments. TEHVs exhibited good preserved long-term in vivo performance and remodeling comparable to native heart valves, as predicted by and consistent with computational modeling. TEHV failure could be predicted for nonphysiological pressure loading. Beyond previous studies, this work suggests the relevance of an integrated in silico, in vitro, and in vivo bioengineering approach as a basis for the safe and efficient clinical translation of TEHVs.

Usage of the T1 effect of an iron oxide contrast agent in an animal model to quantify myocardial blood flow by MRI.

BACKGROUND: To present a new method for fully quantitative analysis of myocardial blood flow (MBF) using magnetic resonance imaging. The first pass of an intravascular iron oxide contrast medium can be used to quantify myocardial perfusion. The technique was validated in an animal model using colored microspheres. MATERIALS AND METHODS: In six pigs, a tracking catheter was positioned in the left anterior descending artery (LAD). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed on a 1.5-T scanner using a hybrid gradient-echo/echoplanar imaging (GRE-EPI) sequence. Regional myocardial blood flow (rMBF) was altered by either inducing vasodilatation with adenosine or creating coronary artery obstruction. The T(1) effect of a superparamagnetic iron oxide-based contrast medium (Resovist) administered at a dose of 8 micromol/kg was used. Upslope, time-to-peak and peak intensity were calculated from the signal intensity-time curves and absolute rMBF using the Kety-Schmidt equation; results were compared to those obtained using colored microspheres. RESULTS: The mean rMBF calculated by MRI was 1.49 (+/-6.91, quartile width) ml/min/g versus 3.21 (+/-1.61) ml/min/g measured by means of microspheres under resting conditions. rMBF increased to a mean of 6.21 (+/-2.83) ml/min/g versus 4.22 (+/-1.70) ml/min/g under adenosine and was reduced to zero flow in total occlusion. Linear regression showed the best correlation for upslope (R=0.714), time-to-peak (R=0.626) and the Kety-Schmidt equation (R=0.584). CONCLUSIONS: The T(1) effect of an iron oxide-based contrast medium allows determination of rMBF when using the Kety-Schmidt equation. The results are similar to those obtained with the standard of reference, colored micropheres, but not better than the results of the semiquantitative approach.