Lower Extremity Revascularization Using Optical Coherence Tomography-Guided Directional Atherectomy: Final Results of the EValuatIon of the PantheriS OptIcal COherence Tomography ImagiNg Atherectomy System for Use in the Peripheral Vasculature (VISION) Study.

PURPOSE: To evaluate the safety and efficacy of a novel optical coherence tomography (OCT)-guided atherectomy catheter in treating patients with symptomatic femoropopliteal disease. METHODS: The VISION trial ( ClinicalTrials.gov identifier NCT01937351) was a single-arm, multicenter, global investigational device exemption study enrolling 158 subjects (mean age 67.2±10.5 years; 87 men) across 20 participating sites. In this cohort, 198 lesions were treated with an average length of 53±40 mm using the Pantheris catheter alone or Pantheris + adjunctive therapy. The primary safety endpoint was the composite of major adverse events (MAEs) through 6 months (objective performance goal 43.2%). Technical success (primary efficacy outcome) was defined as the percent of target lesions with a residual diameter stenosis ≤50% after treatment with the Pantheris device alone (objective performance goal 87.0%). Procedural success was defined as reduction in stenosis to ≤30% after Pantheris ± adjunctive therapy. Tissue specimens retrieved from each treated lesion were histologically analyzed to evaluate the accuracy and precision of OCT image guidance. RESULTS: The primary efficacy outcome was achieved in 192 (97.0%) of the 198 lesions treated with the Pantheris catheter. Across all lesions, mean diameter stenosis was reduced from 78.7%±15.1% at baseline to 30.3%±11.8% after Pantheris alone (p<0.001) and to 22.4%±9.9% after Pantheris ± adjunctive therapy (p<0.001). Of the 198 target lesions, 104 (52.5%) were treated with the Pantheris alone, 84 (42.4%) were treated with Pantheris + adjunctive angioplasty, and 10 (5.1%) with Pantheris + angioplasty + stenting. The composite MAE outcome through 6 months occurred in 25 (16.6%) of 151 subjects. There were no clinically significant perforations, 1 (0.5%) catheter-related dissection, 4 (2%) embolic events, and a 6.4% clinically driven target lesion revascularization rate at 6 months. The 40-lesion chronic total occlusion (CTO) subset (mean lesion length 82±38 mm) achieved a similar significant reduction in stenosis to 35.5%±13.6% after Pantheris alone (p<0.001). Histological analysis of atherectomy specimens confirmed <1% adventitia in 82.1% of the samples, highlighting the precision of OCT guidance. Characterization of the OCT-guided lesions revealed evidence of an underestimation of disease burden when using fluoroscopy. CONCLUSION: OCT-guided atherectomy for femoropopliteal disease is safe and effective. Additionally, the precision afforded by OCT guidance leads to greater removal of plaque during atherectomy while sparing the adventitia.

Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms.

BACKGROUND: Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease. METHODOLOGY/PRINCIPAL FINDINGS: AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE(-/-) mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE(-/-) mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion. CONCLUSION/SIGNIFICANCE: Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.

Novel high-throughput polymer biocompatibility screening designed for SAR (structure-activity relationship): application for evaluating polymer coatings for cardiovascular drug-eluting stents.

The development of stents has been a major advancement over balloon angioplasty, improving vessel revascularization in obstructive coronary artery disease. The development of drug-eluting stents (DES) was the next breakthrough, designed to prevent the development of neointimal hyperplasia (restenosis) following percutaneous coronary interventions (PCI). Several DES are currently in various stages of clinical development; these DES use different stent platforms, different antiproliferative drugs and different polymeric coatings that carry the drugs and control their delivery kinetics. Following DES implantation, when the entire drug is released, the polymeric coating is still retained on the stent and can influence subsequent tissue response and vascular healing. Therefore, the biocompatibility of the polymeric coatings is an important component of DES safety and needs to be thoroughly evaluated. Here we describe the development of a high-throughput screening platform for the evaluation of polymer biocompatibility, assaying whether a polymeric coating triggers inflammation in vascular cells. The data generated by these assays provides a structure-activity relationship (SAR) that can guide polymer chemists in polymer design. We have also applied this methodology to evaluate the components of a novel polymer system (BioLinx polymer system) designed in-house. In addition, we assayed other polymeric coatings similar to those currently used on various DES. The results of this evaluation reveal a remarkable correlation between polymer hydrophobicity and its ability to provoke inflammatory response.

Impact of polymer hydrophilicity on biocompatibility: implication for DES polymer design.

Polymer coatings are essential for local delivery of drug from the stent platform. In designing a DES, it is critical to balance the hydrophilic and hydrophobic components of the polymer system to obtain optimal biocompatibility, while maintaining controlled drug elution. This study investigates the impact of polymer composition of the BioLinx polymer blend on in vitro biocompatibility, as measured by monocytic adhesion. Comparable evaluation was performed with polymers similar to those utilized in various DES that are currently being marketed. Relative hydrophilicities of polymer surfaces were determined through contact angle measurements and surface analyses. Polymer biocompatibility was evaluated in a novel in vitro assay system in which activated monocyte cells were exposed to polymer coated on 96-well plates. Enhanced monocyte adhesion was observed with polymers of a more hydrophobic nature, whereas those which were more hydrophilic did not induce activated monocyte adhesion. Our data supports the hypothesis that polymer composition is a feature that dictates in vitro biocompatibility as measured by monocyte driven inflammation. Monocyte adhesion has been shown to induce local inflammation as well as promote vascular cell proliferation factors contributing to in stent restenosis (Rogers et al., Arterioscler Thromb Vasc Biol 1996;16:1312-1318). Observed results suggest hydrophobic but not hydrophilic polymer surfaces support adhesion of activated monocytes to the polymer scaffold. The proprietary DES polymer blend BioLinx has a hydrophilic surface architecture and does not induce an inflammatory response as measured by these in vitro assays.

Synergistic induction of tissue factor by coagulation factor Xa and TNF: evidence for involvement of negative regulatory signaling cascades.

Enzymes of the blood coagulation pathway enhance the inflammatory response leading to endothelial dysfunction, accounting, in part, for the vascular complications occurring in sepsis and cardiovascular disease. The responses of endothelial cell activation include induction of the expression of tissue factor (TF), a membrane glycoprotein that promotes thrombosis, and of E-selectin, a cell adhesion molecule that promotes inflammation. In this report, we demonstrate synergistic interactions between the coagulation factor Xa (fXa) and the proinflammatory cytokines TNF, IL-1beta, and CD40L, leading to enhanced expression of TF and E-selectin in endothelial cells. A detailed analysis of the molecular pathways that could account for this activity of fXa showed that fXa inhibited the cytokine-induced expression of dual specificity phosphatases, MAP kinase phosphatase-L, -4, -5, and -7, blocking a negative regulatory effect on c-Jun N-terminal kinase. The synergistic interaction between fXa and TNF was also involved in the inhibition of A20 and IkappaBalpha expression in the IkappaB kinase-NF-kappaB pathway. The data indicate that inhibition of negative regulatory signaling accounts for the amplification of cytokine-induced endothelial cell activation by fXa.