A Completely Biological, Tissue Engineered Valve Leaflet Suitable for TAVI

AbstractClinically available transcatheter aortic valve replacement (TAVR) technologies typically use chemically fixed bovine or equine tissues for the valve leaflets. While these fixed, xenogeneic materials have been used with success in devices placed by open surgical access, the tissue thickness (&gt;500 microns) adds significantly to the overall crossing profile of the delivery device. Complications associated with device diameter are generally reported in at least 10-20% of clinical cases, making a reduced crossing profile one of the most critical targets for second generation TAVR devices. Another limitation associated with pericardium is fatigue induced delamination. Previously we have reported clinical results with a completely autologous tissue engineered vascular graft built using a process termed sheet-based tissue engineering. Using this approach, we were able to build small diameter blood vessels with supraphysiologic burst pressures, and demonstrated clinical durability with time points out to 3 years. Importantly, this tissue engineering approach requires no chemical fixation or exogenous biomaterials. More recently, we reported initial human use with an allogeneic version of the vessel. With time points out to 1 year, the allogeneic tissue engineered material demonstrated no evidence of immune reaction. This transition to an off-the shelf, allogeneic approach enables use the material in a variety of new clinical indications, including valve reconstruction. Valve leaflets built from a single sheet, demonstrated ultimate tensile strength in excess of that for bovine valve leaflets. Of note, the thickness of the sheet was less than 200 microns, roughly 30 percent that of bovine pericardium. The tissue can also be compressed, further reducing the thickness to approximately 75 microns. This thin, durable, single layered tissue can be assembled onto commercially available TAVR devices resulting in a reduction in crossing profile of approximately 2 Fr. The valve leaflets can be sutured easily, coapt normally, and can withstand arterial backpressure. Given the non-laminated structure of the tissue engineered leaflet, the lack of synthetic materials, and the durability demonstrated in other clinical indications, this approach may provide not only a reduced crossing profile, but also improved long term clinical results.</jats:p

Antithrombotic Effects of Ionic and Non-ionic Contrast Media in Nonhuman Primates

SummaryThromboembolic complications have been attributed to the use of radiographic contrast media (CM) during interventional procedures for arterial revascularization. However, due to the low frequency of adverse events, comparisons between different CM have been difficult to perform, although it has been suggested that ionic (vs. non-ionic) CM may be associated with fewer thrombotic events. The present study was undertaken using well-characterized baboon thrombosis models in order to compare different CM under physiologically relevant and controlled conditions of blood flow, exposure time, and CM concentration. Three CM were studied: ioxaglate, iohexol, and iodixanol. CM were locally infused into the proximal segment of femoral arteriovenous shunts. Palmaz-Schatz stents (4 mm i.d.) and expanded tubular segments (9 mm i.d.), which exhibited venous-type flow recirculation and stasis, were deployed into the shunts distally. Saline was infused in identical control studies. Blood flow was maintained at 100 ml/min. Thrombosis was measured over a blood exposure period of 2 hours by gamma camera imaging of 111In-platelets and by gamma counting of deposited 125I-fibrin. CM concentrations within the flowfield were predicted using computational fluid dynamics. At infusion rates of 0.1 and 0.3 ml/min, the low-osmolar ionic CM ioxaglate reduced both platelet and fibrin deposition on the stents by 75-80% (p &lt;0.005), while both iohexol and iodixanol reduced platelet deposition by 30-50% (p &lt;0.05). In the regions of low shear flow, ioxaglate (0.3 ml/min) also reduced platelet deposition significantly (by 52% vs. control results; p &lt;0.05). Thus the three agents evaluated – ioxaglate, iohexol, and iodixanol – all produced anticoagulant and antiplatelet effects and were inherently antithrombotic in vivo. The most striking effects were seen with the low osmolarity, ionic contrast agent ioxaglate.</jats:p

Preclinical restenosis models and drug-eluting stents Still important, still much to learn

Percutaneous coronary intervention continues to revolutionize the treatment of coronary atherosclerosis. Restenosis remains a significant problem but may at last be yielding to technologic advances. The examination of neointimal hyperplasia in injured animal artery models has helped in our understanding of angioplasty and stenting mechanisms, and as drug-eluting stent (DES) technologies have arrived, they too have been advanced through the study of animal models.These models are useful for predicting adverse clinical outcomes in patients with DESs because suboptimal animal model studies typically lead to problematic human trials. Similarly, stent thrombosis in animal models suggests stent thrombogenicity in human patients. Equivocal animal model results at six or nine months occasionally have been mirrored by excellent clinical outcomes in patients. The causes of such disparities are unclear but may result from differing methods, including less injury severity than originally described in the models. Ongoing research into animal models will reconcile apparent differences with clinical trials and advance our understanding of how to apply animal models to clinical stenting in the era of DESs

Cerivastatin represses atherogenic gene expression through the induction of KLF2 via isoprenoid metabolic pathways

AbstractEarlier clinical studies have reported that cerivastatin has an antiatherosclerotic effect that is unique among the statins. In our study, human THP-1 macrophage cells were used to study the effects of various statins on the expressions of the atherosclerotic genes and Kruppel-like factor 2 (KLF2). Cerivastatin significantly inhibited the two atherosclerotic genes, monocyte chemoattractant protein-1 (MCP-1) and C-C chemokine receptor type 2 (CCR2) at both the mRNA and protein levels, while the other statins did not. Accordingly, cerivastatin was also the most potent inducer of KLF2 transcription in the macrophages. An siRNA-induced reduction in KLF2 expression blocked the inhibition of MCP-1 and CCR2 by cerivastatin. When the cells were further treated with mevalonate, farnesylpyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP), the effects of cerivastatin on KLF2, MCP-1 and CCR2 were obviously reversed. Thus, the results showed that cerivastatin was a potent inhibitor of the inflammation genes MCP-1 and CCR2 through the induction of KLF2. The regulation of MCP-1, CCR2 and KLF2 by cerivastatin was isoprenoid pathway dependent. Our studies suggest that the effect of cerivastatin on atherosclerotic genes and KLF2 expression may contribute to the cardioprotection observed in reported clinical studies.</jats:p

Evaluation of a Novel Slow-Release Paclitaxel-Eluting Stent With a Bioabsorbable Polymeric Surface Coating

ObjectivesWe sought to evaluate a new second-generation drug-eluting stent (DES), comprising a slow-release biodegradable polylactide coglycolide (PLGA) polymer and low-dose paclitaxel on a thin-strut cobalt chromium stent platform, in a clinically relevant animal model.BackgroundOur previous work demonstrated subacute vascular toxicity and necrosis triggering late excess neointima in pig coronaries, with a moderate paclitaxel dose eluted from an erodible polymer. The use of slower-releasing absorbable polymers with lower doses of paclitaxel is expected to minimize such adverse outcomes.MethodsThree types of stents were implanted in pig coronary arteries using quantitative coronary angiography to optimize stent apposition: bare-metal stents (BMS); absorbable, slow-release polymer-coated-only stents (POLY); and absorbable polymer-based paclitaxel-eluting stents (PACL). The dose density of paclitaxel was 0.15 μg/mm2 with in vitro studies demonstrating a gradual elution over the course of 12 to 16 weeks. Animals underwent angiographic restudy and were terminated at 1 and 3 months for complete histopathologic and histomorphometric analyses.ResultsAt 1 month, intimal thickness varied significantly according to stent type, with the lowest level for the PACL group compared with the BMS and POLY groups (0.06 ± 0.02 mm vs. 0.17 ± 0.07 mm, 0.17 ± 0.08 mm, respectively, p &lt; 0.001); histological percent area stenosis was 18 ± 4% for PACL compared with 27 ± 7% for BMS and 30 ± 12% for POLY, respectively (p = 0.001). At 3 months, PACL showed similar neointimal thickness as BMS and POLY (0.09 ± 0.05 mm vs. 0.13 ± 0.10 mm and 0.11 ± 0.03 mm respectively, p = 0.582). Histological percent area stenosis was 23 ± 8% for PACL versus 23 ± 11% for BMS and 23 ± 2% for POLY, respectively (p = 1.000).ConclusionsThis study shows favorable vascular compatibility and efficacy for a novel DES that elutes paclitaxel in porcine coronary arteries. These results support the notion that slowing the release rate and lowering the dose of paclitaxel favorably influences the vascular biological response to DES implant, decreasing early toxicity and promoting stable healing while still suppressing neointima formation