Abstract Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous ...donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control – representing currently used homografts – dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs.
Percutaneous mitral valve repair (MVR) using the MitraClip system has become a valid alternative for patients with severe mitral regurgitation (MR) and high operative risk.
To identify clinical and ...periprocedural factors that may have an impact on clinical outcome.
Multi-centre longitudinal cohort study.
Tertiary referral centres.
Here we report on the first 100 consecutive patients treated with percutaneous MVR in Switzerland between March 2009 and April 2011. All of them had moderate-severe (3+) or severe (4+) MR, and 62% had functional MR. 82% of the patients were in New York Heart Association (NYHA) class III/IV, mean left ventricular ejection fraction was 48% and the median European System for Cardiac Operative Risk Evaluation was 16.9%.
MitraClip implantation performed under echocardiographic and fluoroscopic guidance in general anaesthesia.
Clinical, echocardiographic and procedural data were prospectively collected.
Acute procedural success (APS, defined as successful clip implantation with residual MR grade ≤2+) was achieved in 85% of patients. Overall survival at 6 and 12 months was 89.9% (95% CI 81.8 to 94.6) and 84.6% (95% CI 74.7 to 91.0), respectively. Univariate Cox regression analysis identified APS (p=0.0069) and discharge MR grade (p=0.03) as significant predictors of survival.
In our consecutive cohort of patients, APS was achieved in 85%. APS and residual discharge MR grade are important predictors of mid-term survival after percutaneous MVR.
Rheumatic heart disease (RHD) still affects more patients globally than degenerative valve disease. The vast majority of these patients live in low- to middle-income countries. Once symptomatic, they ...will need heart valve surgery. Unfortunately, prosthetic valves perform poorly in these patients given their young age, the high incidence of multi-valve disease, late diagnoses and often challenging socio-economic circumstances.
Notwithstanding the fact that better valve designs would ideally be available, ill-informed decision making processes between bioprosthetic and mechanical valves are contributing to the poor results. In the absence of multicentred, randomised clinical trials, comparing the current generations of bioprostheses with mechanical valves across all age groups Western guidelines tend to be uncritically applied. As a consequence, mechanical valves are being implanted into patients who are often not able to deal with anticoagulation while bioprosthetic valves may be overly shunned for fear of reoperations.
Almost sixty years after the advent of cardiac surgery heart valve prostheses have eventually undergone improvements and several potentially disruptive developments are on the horizon. Until they materialise, however, choices between contemporary valve prostheses need to be made on the basis of individual risk and life-expectancy rather than an uncritical implementation of guidelines that were derived for very different patients and under distinctly different conditions.
Given the fast expansion of cardiac surgery in middle-income countries and a growing number of independently operating centres in low-income countries a critical appraisal of facts underlying the choice of heart valve prostheses for patients with RHD seems opportune.
•RHD affects more patients globally than degenerative valve disease.•Heart valve replacement is often required in these young patients.•Western guidelines and available HV-prostheses are often ill-suited.•For the time being mechanical valves may be detrimentally over-prescribed.•Head-to-head studies of tissue valves versus mechanical valves are overdue.
Abstract Stem cells have been repeatedly suggested for cardiac regeneration after myocardial infarction (MI). However, the low retention rate of single cell suspensions limits the efficacy of current ...therapy concepts so far. Taking advantage of three dimensional (3D) cellular self-assembly prior to transplantation may be beneficial to overcome these limitations. In this pilot study we investigate the principal feasibility of intramyocardial delivery of in-vitro generated stem cell-based 3D microtissues (3D-MTs) in a porcine model. 3D-MTs were generated from iron-oxide (MPIO) labeled human adipose-tissue derived mesenchymal stem cells (ATMSCs) using a modified hanging-drop method. Nine pigs (33 ± 2 kg) comprising seven healthy ones and two with chronic MI in the left ventricle (LV) anterior wall were included. The pigs underwent intramyocardial transplantation of 16 × 103 3D-MTs (1250 cells/MT; accounting for 2 × 10 7 single ATMSCs) into the anterior wall of the healthy pigs ( n = 7)/the MI border zone of the infarcted ( n = 2) of the LV using a 3D NOGA electromechanical mapping guided, transcatheter based approach. Clinical follow-up (FU) was performed for up to five weeks and in-vivo cell-tracking was performed using serial magnet resonance imaging (MRI). Thereafter, the hearts were harvested and assessed by PCR and immunohistochemistry. Intramyocardial transplantation of human ATMSC based 3D-MTs was successful in eight animals (88.8%) while one pig (without MI) died during the electromechanical mapping due to sudden cardiac-arrest. During FU, no arrhythmogenic, embolic or neurological events occurred in the treated pigs. Serial MRI confirmed the intramyocardial presence of the 3D-MTs by detection of the intracellular iron-oxide MPIOs during FU. Intramyocardial retention of 3D-MTs was confirmed by PCR analysis and was further verified on histology and immunohistochemical analysis. The 3D-MTs appeared to be viable, integrated and showed an intact micro architecture. We demonstrate the principal feasibility and safety of intramyocardial transplantation of in-vitro generated stem cell-based 3D-MTs. Multimodal cell-tracking strategies comprising advanced imaging and in-vitro tools allow for in-vivo monitoring and post-mortem analysis of transplanted 3D-MTs. The concept of 3D cellular self-assembly represents a promising application format as a next generation technology for cell-based myocardial regeneration.
Objective Constrictive external mesh support of vein grafts was shown to mitigate intimal hyperplasia in animal experiments. To determine the degree of constriction required for the elimination of ...dimensional irregularities in clinically used vein grafts, a detailed anatomic study of human saphenous veins was conducted. Methods In 200 consecutive patients having coronary artery bypass grafting, harvested saphenous veins (length 34.4 ± 10.8 cm) were analyzed regarding diameter irregularities, side branch distribution, and microstructure. Results The mean outer diameter of surgically distended saphenous veins was 4.2 ± 0.6 mm (men, 4.3 ± 0.6 mm vs women, 3.9 ± 0.5 mm; P < .0001). Although the outer diameter significantly decreased over the initial 18 cm (−7.6%; P < .0001), the overall increase between malleolus and thigh was not significant (+11.2%). Smaller-diameter veins (<3.5 mm) had more pronounced diameter fluctuations than larger veins (31.8% ± 11.0% vs 21.2% ± 8.8%; P < .0001), with more than 71% of all veins showing caliber changes of more than 20%. There was 1 side branch every 5.4 ± 4.3 cm, with a significantly higher incidence between 20 and 32 cm from the malleolus ( P < .0001 to distal, P < .0004 to proximal). Generally, women had more side branches than men (0.30 ± 0.15 cm−1 vs 0.25 ± 0.12 cm−1 ; P = .0190). Thick-walled veins (565.7 ± 138.4 μm) had a significantly higher number of large side branches ( P < .0001), and thin-walled veins (398.7 ± 123.2 μm) had significantly more small side branches ( P < .0001). Pronounced intimal thickening (“cushions”) was found in 28% of vessels (119.8 ± 28.0 μm vs 40.1 ± 18.2 μm; P < .0001). Conclusion Although the preferential location of side branches may be addressed by the deliberate discarding of infragenicular vein segments, a diameter constriction of 27% on average would eliminate diameter irregularities in 98% of vein grafts.
Leaflet durability and costs restrict contemporary trans-catheter aortic valve replacement (TAVR) largely to elderly patients in affluent countries. TAVR that are easily deployable, avoid secondary ...procedures and are also suitable for younger patients and non-calcific aortic regurgitation (AR) would significantly expand their global reach. Recognizing the reduced need for post-implantation pacemakers in balloon-expandable (BE) TAVR and the recent advances with potentially superior leaflet materials, a trans-catheter BE-system was developed that allows tactile, non-occlusive deployment without rapid pacing, direct attachment of both bioprosthetic and polymer leaflets onto a shape-stabilized scallop and anchorage achieved by plastic deformation even in the absence of calcification. Three sizes were developed from nickel-cobalt-chromium MP35N alloy tubes: Small/23 mm, Medium/26 mm and Large/29 mm. Crimp-diameters of valves with both bioprosthetic (sandwich-crosslinked decellularized pericardium) and polymer leaflets (triblock polyurethane combining siloxane and carbonate segments) match those of modern clinically used BE TAVR. Balloon expansion favors the wing-structures of the stent thereby creating supra-annular anchors whose diameter exceeds the outer diameter at the waist level by a quarter. In the pulse duplicator, polymer and bioprosthetic TAVR showed equivalent fluid dynamics with excellent EOA, pressure gradients and regurgitation volumes. Post-deployment fatigue resistance surpassed ISO requirements. The radial force of the helical deployment balloon at different filling pressures resulted in a fully developed anchorage profile of the valves from two thirds of their maximum deployment diameter onwards. By combining a unique balloon-expandable TAVR system that also caters for non-calcific AR with polymer leaflets, a powerful, potentially disruptive technology for heart valve disease has been incorporated into a TAVR that addresses global needs. While fulfilling key prerequisites for expanding the scope of TAVR to the vast number of patients of low- to middle income countries living with rheumatic heart disease the system may eventually also bring hope to patients of high-income countries presently excluded from TAVR for being too young.
Although stem-cell therapies have been suggested for cardiac-regeneration after myocardial-infarction (MI), key-questions regarding the in-vivo cell-fate remain unknown. While most available ...animal-models require immunosuppressive-therapy when applying human cells, the fetal-sheep being pre-immune until day 75 of gestation has been proposed for the in-vivo tracking of human cells after intra-peritoneal transplantation. We introduce a novel intra-uterine myocardial-infarction model to track human mesenchymal stem cells after direct intra-myocardial transplantation into the pre-immune fetal-sheep. Thirteen fetal-sheep (gestation age: 70-75 days) were included. Ten animals either received an intra-uterine induction of MI only (n = 4) or MI+intra-myocardial injection (IMI;n = 6) using micron-sized, iron-oxide (MPIO) labeled human mesenchymal stem cells either derived from the adipose-tissue (ATMSCs;n = 3) or the bone-marrow (BMMSCs;n = 3). Three animals received an intra-peritoneal injection (IPI;n = 3; ATMSCs;n = 2/BMMSCs;n = 1). All procedures were performed successfully and follow-up was 7-9 days. To assess human cell-fate, multimodal cell-tracking was performed via MRI and/or Micro-CT, Flow-Cytometry, PCR and immunohistochemistry. After IMI, MRI displayed an estimated amount of 1×10(5)-5×10(5) human cells within ventricular-wall corresponding to the injection-sites which was further confirmed on Micro-CT. PCR and IHC verified intra-myocardial presence via detection of human-specific β-2-microglobulin, MHC-1, ALU-Sequence and anti-FITC targeting the fluorochrome-labeled part of the MPIOs. The cells appeared viable, integrated and were found in clusters or in the interstitial-spaces. Flow-Cytometry confirmed intra-myocardial presence, and showed further distribution within the spleen, lungs, kidneys and brain. Following IPI, MRI indicated the cells within the intra-peritoneal-cavity involving the liver and kidneys. Flow-Cytometry detected the cells within spleen, lungs, kidneys, thymus, bone-marrow and intra-peritoneal lavage, but not within the heart. For the first time we demonstrate the feasibility of intra-uterine, intra-myocardial stem-cell transplantation into the pre-immune fetal-sheep after MI. Utilizing cell-tracking strategies comprising advanced imaging-technologies and in-vitro tracking-tools, this novel model may serve as a unique platform to assess human cell-fate after intra-myocardial transplantation without the necessity of immunosuppressive-therapy.
Background Flow patterns and shear forces in native coronary arteries are more protective against neointimal hyperplasia than those in femoral arteries. Yet, the caliber mismatch with their target ...arteries makes coronary artery bypass grafts more likely to encounter intimal hyperplasia than their infrainguinal counterparts due to the resultant slow flow velocity and decreased wall stress. To allow a site-specific, flow-related comparison of remodeling behavior, saphenous vein bypass grafts were simultaneously implanted in femoral and coronary positions. Methods Saphenous vein grafts were concomitantly implanted as coronary and femoral bypass grafts using a senescent nonhuman primate model. Duplex ultrasound-based blood flow velocity profiles and vein graft and target artery dimensions were correlated with dimensional and histomorphologic graft remodeling in large, senescent Chacma baboons (n = 8; 28.1 ± 4.9 kg) during a 24-week period. Results At implantation, the cross-sectional quotient (Qc ) between target arteries and vein grafts was 0.62 ± 0.10 for femoral grafts vs 0.17 ± 0.06 for coronary grafts, resulting in a dimensional graft-to-artery mismatch 3.6 times higher ( P < .0001) in coronary grafts. Together with different velocity profiles, these site-specific dimensional discrepancies resulted in a 57.9% ± 19.4% lower maximum flow velocity ( P = .0048), 48.1% ± 23.6% lower maximal cycling wall shear stress ( P = .012), and 62.2% ± 21.2% lower mean velocity ( P = .007) in coronary grafts. After 24 weeks, the luminal diameter of all coronary grafts had contracted by 63%, from an inner diameter of 4.49 ± 0.60 to 1.68 ± 0.63 mm ( P < .0001; subintimal diameter: −41.5%; P = .002), whereas 57% of the femoral interposition grafts had dilated by 31%, from 4.21 ± 0.25 to 5.53 ±1.30 mm ( P = .020). Neointimal tissue was 2.3 times thicker in coronary than in femoral grafts (561 ± 73 vs 240 ± 149 μm; P = .001). Overall, the luminal area of coronary grafts was an average of 4.1 times smaller than that of femoral grafts. Conclusions Although coronary and infrainguinal bypass surgery uses saphenous veins as conduits, they undergo significantly different remodeling processes in these two anatomic positions.
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