For peripheral endovascular intervention, self-expanding (SE) stents are commonly oversized in relation to target arteries to assure optimal wall apposition and prevent migration. However, the consequences of oversizing have not been well studied. The purpose of this study was to examine the effects of SE stent oversizing (OS) with respect to the kinetics of late stent expansion and the long-term histological effects of OS. Pairs of overlapped 8 x 28-mm Nitinol SE stents were implanted into the iliofemoral arteries of 14 Yucatan swine. Due to variations in target artery size, the stent-to-artery ratio ranged from 1.2:1 to 1.9:1. Lumen and stent diameters were assessed by quantitative angiography at the time of implantation. Following angiographic assessment at 6 months, stented arteries were perfusion-fixed, sectioned, and stained for histological analysis. Immediately following implantation, the stents were found to be expanded to a range of 4.7-7.1 mm, largely conforming to the diameter of the recipient target artery. The stents continued to expand over time, however, and all stents had enlarged to nearly their 8-mm nominal diameter by 6 months. The histological effects of OS were profound, with marked increases in injury and luminal area stenosis, including a statistically significant linear correlation between stent-to-artery ratio and area stenosis. In this experimental model of peripheral endovascular intervention, oversized Nitinol SE stents are constrained by their target artery diameter upon implantation but expand to their nominal diameter within 6 months. Severe OS (stent-to-artery ratio >1.4:1) results in a profound long-term histological response including exuberant neointimal proliferation and luminal stenosis.

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.

Background-Atrial fibrillation is associated with a high risk for cardioembolic stroke. The left atrial appendage (LAA) is the source of the vast majority of these thromboemboli. A novel implanted device for percutaneous LAA transcatheter occlusion (PLAATO) has been designed to seal the LAA. The purpose of this study was to test the feasibility and safety of transcatheter LAA occlusion in dogs. Methods and Results-A PLAATO implant was delivered to the LAA through a 12F transseptal catheter in 25 dogs. The PLAATO device was repositioned until occlusion was seen, or it was recaptured and replaced with a different size. LAA sealing was confirmed by intracardiac echocardiography and contrast fluoroscopy. Follow-up was performed 2 days to 6 months after implantation. After imaging assessment, dogs were euthanized and LAA was examined for device healing, migration, perforation, and any thrombosis, both grossly and histologically. The LAA was occluded in all cases.No mobile thrombi associated with the implantation were seen. Healing on the atrial-facing surface was 90% at 1 month and was complete by 3 months, which was confirmed by gross and histological examination. Light microscopic examination of brain, kidney, and spleen showed no evidence of emboli or infarct. Conclusions-Transcatheter LAA occlusion is simple and feasible. At the follow-up study, the device remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. This new strategy may provide an alternative treatment for patients with nonvalvular atrial fibrillation who are less than optimal candidates for warfarin.

The lower-hoop-strength, higher-profile tantalum Strecker stent is affected by vascular wall recoil and evokes a greater degree of neointima formation than the lower-profile, higher-hoop-strength Palmaz stent and Wallstent. Medial atrophy is pronounced outside the latter two stents. The rigid Palmaz stent can penetrate through the vascular wall in flexing arteries.

There are differences in conformation of LAA surrounding structures with variable healing response between WM and ACP after LAA closure in the canine model. WM does not obstruct or impact the LAA adjacent structures, resulting in a favorable surface recovery. In comparison, the disk of ACP could potentially jeopardize LAA neighboring structures and leads to delayed healing.

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This intracardiac device integration study delineated healing stages of early thrombus deposition, thrombus organization, inflammation and granulation tissue, final healing by connective tissue, and endocardialization without inflammation. These observations may yield insight into cellular healing processes in other cardiac devices.