Nanospheres encapsulated everolimus delivery into arterial wall-the tissue pharmacokinetics and vascular response experimental study.

OBJECTIVE: This study aimed to evaluate the pharmacokinetic profile and tissue effects of everolimus delivered into arterial wall using biodegradable nanospheres. BACKGROUND: Delivery of everolimus into the arterial wall is challenging due to its low-lipophilic profile. METHODS: A pharmacokinetic study included 28 porcine coronary arterial segments initially injured with balloon angioplasty followed by the local delivery of everolimus encapsulated in nanospheres (EEN) via injection through a microporous delivery catheter. The animals were sacrificed at 1 hour, 1,7,28, and 90-day follow-up. In the tissue effects study 16 coronary bare metal stent (BMS) were implanted following EEN delivery, 15 BMS following nanospheres delivery without the drug (reference group) and 16 implanted BMS served as a control. Angiographic and histology follow-up was scheduled at 28 and 90-day. RESULTS: The study showed high-everolimus concentrations in arterial tissue early after nanoparticles delivery followed by its gradual decrease to 1.15 ± 0.40 ng/mg at 90 days. Histology analysis showed favorable biocompatibility and healing profile with comparable area stenosis between groups at both time-points. CONCLUSIONS: The present study demonstrates for the first time the safety, biocompatibility, and long-term retention of everolimus in arterial tissue after single local delivery of biodegradable nanospheres.

Safety of catheter-based radiofrequency renal denervation on branch renal arteries in a porcine model.

OBJECTIVES: We aimed to investigate the safety of radiofrequency (RF)-renal denervation (RDN) on branch renal arteries (RAs) in a porcine model. BACKGROUND: The efficacy of RF-RDN was enhanced by treatment of the branch RA, in addition to the main RA. However, there are concerns regarding the safety of RF-RDN on branch RA because of their smaller diameter and proximity to the kidney. METHODS: RF was delivered to 24 RA from 12 swine. A total of 8 RA from 4 swine were untreated. Treated RA were examined by angiography and histopathology at 7, 30, and 90 days. Serum creatinine concentration, biophysical parameters during RF delivery, and renal norepinephrine concentration were also assessed. RESULTS: Angiography revealed minimal late lumen loss and diameter stenosis in the main and branch RA at any time point. There was no change in serum creatinine after RF-RDN. Histopathologically, no augmentation of medial damage or neointimal formation was found in branch RA compared with main RA. No or minimal damage to surrounding tissues including the kidneys, ureters, lymph nodes, and muscles was observed at any time point in both the main and branch RA. Equivalent electrode temperature in the main and branch RA was achieved by automatic adjustment of output power by the generator. The renal norepinephrine concentration was significantly lower in the treated group compared with the untreated group. CONCLUSIONS: RF-RDN on branch RA was safe in a porcine model, with stenosis-free healing of treated arteries and negligible kidney damage at 7, 30, and 90 days.

Translational Research: The Cornerstone for Medical Technology Advancement.

Significant improvements in quality of life and mortality have occurred over the last century due to the giant advancements in medical innovation. Medical innovation continues to move forward, and it is expanding to areas never explored before. In particular, the advancement in big data analytics is now enabling the rapid progress in the understanding of gene influence in human diseases. The progress in medical innovation achieved until today is significant; however, the potential that future technologies have to modify patterns of disease thought to be incurable is mind-boggling. In the present issue of Toxicologic Pathology, a wide variety of devices and validation platforms are presented as a clear evidence of the multidisciplinary approach that is necessary for the progress of this field. As a clinician, scientist, and medical device innovator, I am confident that this special issue dedicated to the "Pathology of Medical Devices" will be of great value to the scientific and medical device innovation community.

Histology Strategies for Medical Implants and Interventional Device Studies.

Histology of medical devices poses a variety of unique challenges. Comprehensive histologic assessment of medical devices often requires spatial context and high-quality retention of the device-tissue interface. However, the composition of many medical devices is often not amenable to traditional paraffin embedding and thus alternative specialized methodologies such as hard resin embedding must be used. Hard resin embedding requires specialized laboratory technical expertise and equipment, and the fixation techniques and resin composition used markedly impact the feasibility of immunohistochemistry. For the continuity of spatial context during histologic evaluation, additional imaging methods such as macrophotography, radiography, micro-Computerized Tomography (microCT), or magnetic resonance imaging (MRI) can be used to guide sectioning and to complement histologic findings. Although standardized approaches are scarce for medical devices, important considerations specific to medical device histology are discussed, including general specimen preparation, special considerations for devices by organ system, and the challenges of immunohistochemistry. Histologic preparation of medical devices must be thoughtful, thorough, and tailored to achieve optimal histologic outcomes for complex, valuable, and often limited implant specimens.

Different Vascular Responses to a Bare Nitinol Stent in Porcine Femoral and Femoropopliteal Arteries.

Nitinol stents are widely used for the treatment of peripheral arterial diseases in lower extremity arteries and have shown different clinical outcomes depending on implanted arterial segments. We aimed to compare histopathological responses to nitinol stents in femoral artery (FA) with those in femoropopliteal artery (FPA), which is markedly bended during knee flexion. A single nitinol stent was implanted in FA and FPA of 21 domestic swine. The stented vessels were angiographically assessed and then harvested for histopathology at 1 and 3 months after implantation. Angiographic late lumen loss was significantly greater in FPA than in FA at 3 months. Neointimal area decreased in FA and increased in FPA from 1 to 3 months. Compared with FA, peri-strut area of FPA showed more pronounced hemorrhage and fibrin deposition at 1 month and angiogenesis and inflammation at 1 and 3 months. Injury to internal elastic lamina or media was minimal in both FA and FPA at both time points. In conclusion, vascular responses to nitinol stents were different between FA and FPA with respect to time course of neointimal formation and progress of healing, suggesting that repetitive interaction between stent and vessel wall during dynamic vessel motion affected vascular responses.

Comprehensive Preclinical Postmortem Evaluation of Valvular Prosthesis.

Transcatheter prosthetic valves are heralding a new era in interventional cardiology and affording real therapeutic options to categories of patients currently medically disqualified, namely the elderly and higher risk individuals. An increasing variety of novel artificial valve designs and delivery systems are being tested preclinically. Cardiologists and surgeons are generally well-equipped to assess deliverability and function; however, methods for pathological evaluation of animals enrolled in transcatheter valve implant testing are scant, often vague, and far from consensual. Through this manuscript, we present and discuss a comprehensive evaluation platform that is proving reliable, reproducible, effective, and applicable to most, if not all, types and locations of valvular prostheses.

Biological effect on drug distribution and vascular healing via paclitaxel-coated balloon technology in drug eluting stent restenosis swine model.

OBJECTIVES: To evaluate the biological effect of a paclitaxel-coated balloon (PCB) technology on vascular drug distribution and healing in drug eluting stent restenosis (DES-ISR) swine model. BACKGROUND: The mechanism of action and healing response via PCB technology in DES-ISR is not completely understood. METHODS: A total of 27 bare metal stents were implanted in coronary arteries and 30 days later the in-stent restenosis was treated with PCB. Treated segments were harvested at 1 hr, 14 days and 30 days post treatment for the pharmacokinetic analysis. In addition, 24 DES were implanted in coronary arteries for 30 days, then all DES-ISRs were treated with either PCB (n = 12) or uncoated balloon (n = 12). At day 60, vessels were harvested for histology following angiography and optical coherence tomography (OCT). RESULTS: The paclitaxel level in neointimal tissue was about 18 times higher (P = 0.0004) at 1 hr Cmax , and retained about five times higher (P = 0.008) at day 60 than that in vessel wall. A homogenous distribution of paclitaxel in ISR was demonstrated by using fluorescently labeled paclitaxel. Notably, in DES-ISR, both termination OCT and quantitative coronary angioplasty showed a significant neointimal reduction and less late lumen loss (P = 0.05 and P = 0.03, respectively) post PCB versus post uncoated balloon. The PES-ISR + PCB group displayed higher levels of peri-strut inflammation and fibrin scores compared to the -limus DES-ISR + PCB group. CONCLUSIONS: In ISR, paclitaxel is primarily deposited in neointimal tissue and effectively retained over time following PCB use. Despite the presence of metallic struts, a uniform distribution was characterized. PCB demonstrated an equivalent biological effect in DES-ISR without significantly increasing inflammation. © 2015 Wiley Periodicals, Inc.

Miniature Swine for Preclinical Modeling of Complexities of Human Disease for Translational Scientific Discovery and Accelerated Development of Therapies and Medical Devices.

Noncommunicable diseases, including cardiovascular disease, diabetes, chronic respiratory disease, and cancer, are the leading cause of death in the world. The cost, both monetary and time, of developing therapies to prevent, treat, or manage these diseases has become unsustainable. A contributing factor is inefficient and ineffective preclinical research, in which the animal models utilized do not replicate the complex physiology that influences disease. An ideal preclinical animal model is one that responds similarly to intrinsic and extrinsic influences, providing high translatability and concordance of preclinical findings to humans. The overwhelming genetic, anatomical, physiological, and pathophysiological similarities to humans make miniature swine an ideal model for preclinical studies of human disease. Additionally, recent development of precision gene-editing tools for creation of novel genetic swine models allows the modeling of highly complex pathophysiology and comorbidities. As such, the utilization of swine models in early research allows for the evaluation of novel drug and technology efficacy while encouraging redesign and refinement before committing to clinical testing. This review highlights the appropriateness of the miniature swine for modeling complex physiologic systems, presenting it as a highly translational preclinical platform to validate efficacy and safety of therapies and devices.

First in vivo evaluation of a flexible self-apposing left atrial appendage closure device in the canine model.

OBJECTIVES: Aimed to evaluate the feasibility of deployment and healing response of a novel transcatheter left atrial appendage (LAA) occlusion device in the canine model BACKGROUND: LAA occlusion is proposed to reduce the risk of stroke in atrial fibrillation patients METHODS: Transseptal puncture and device deployment was guided under fluoroscopy and transesophageal echocardiography (TEE) in five dogs. First, a distal cylindrical bulb occluder was released and secured to the appendage wall with hooks. Subsequently, a proximal sail was unfolded, covering the LAA ostium. Rotational angiography, TEE, and histology outcomes were assessed 30 days following implantation RESULTS: Pre-operative TEE revealed the mean diameter of the LAA ostium to be 17.2 ± 1.6 mm with a depth of 18.5 ± 1.7 mm. The landing zone for the distal bulb was measured to be 12.8 ± 1.3 mm. The mean bulb diameter at implant was 16.8 ± 1.8 mm. Post-operative TEE showed adequate positioning and successful LAA occlusion with all implanted devices. Pericardial effusion requiring pericardiocentesis was seen in one animal following device implantation. At 30 days, TEE revealed full occlusion of all LAA ostia with the exception of a minimal peri-device leak (<3 mm) observed in one animal. No pericardial effusion or device-related thrombus formation was found at termination. Histological analysis confirmed circumferential occlusion of all appendages and complete neointimal coverage on the luminal aspect of the occluder CONCLUSION: The percutaneous delivery of a novel self-positioning LAA occlusion device is feasible and safe in a canine model. At 30 days, all devices displayed complete healing and occlusion of the LAA without any device related adverse events.

Acute, subacute, and long-term evaluation of a novel endovascular occlusion system in a large animal model.

OBJECTIVES: Endovascular occlusion of blood vessels represents a key component of interventional therapy. While coils are most commonly used, vessel occlusion is generally not achieved immediately and may necessitate a large number of devices. It has been suggested that endovascular plugs may overcome these limitations; however, immediate and durable occlusion remains a challenge with plugs as well. This study evaluates a newly designed endovascular occlusion system (EOS) METHODS: The EOS combines a nitinol coil with an impermeable membranous cap made of expanded polytetrafluoroethylene. The coil offers sufficient radial force to expand the membrane and minimize post-deployment migration. Fifteen test devices were deployed in the iliac (external and internal) and femoral arteries of five miniature swine, while two commercially available devices (platinum coils and a vascular plug) were used as controls in one miniswine. Angiography was performed 1, 5, and 10 minutes after device implantation. Follow-up angiography was obtained either on day 29 or day 61, prior to devices harvesting for histological evaluation and biocompatibility assessment. RESULTS: No clinical complications were observed in the animals throughout the study course. All test devices were deployed as intended, and produced complete and immediate vessel-occlusion. No recanalization or acute migration was observed within 10 minutes of deployment, whereas five test devices had migrated between 5 and 15 mm at follow-up angiography. Complete and durable vessel-occlusion without any sign of recanalization was observed in all EOS devices during the follow-up period. CONCLUSION: The EOS is a safe and reliable device resulting in immediate and durable vessel occlusion in the peripheral arterial circulation. While no device migration was observed in the pelvic area, it was observed with five test and one control devices in the vicinity of highly mobile articulations, leading to the conclusion that occlusion devices should not be placed within hypermobile areas such as the hip joint.

Long term impact of balloon post-dilatation on neointimal formation: an experimental comparative study between second-generation self-expanding versus balloon-expandable stent technologies.

Background: Self-expanding stents (SES) are reemerging as therapeutic alternatives to treat coronary artery disease. It has been proposed that SES can improve clinical outcomes by inducing less injury at implantation and achieving better vessel wall apposition.To date, little data exists comparing the vascular response to both methods of deployment in a controlled experimental setting. Objective: To quantify differences in vascular injury and healing between second-generation SES and balloon-expandable stents (BES) and the effects of balloon post-dilatation in a porcine coronary model. Methods: Seventy-five bare SES (AXXESS or vProtect) and 42 BES (Vision) were implanted in porcine coronaries. A subset of these received balloon post-dilatation(SES 1 D 5 22, BES 1 D 5 20). Follow-up was scheduled at 30 (BES 5 10, BES 1 D 56, SES 5 19, SES 1 D 5 8), 90 (BES 5 6, BES 1 D 5 8, SES 5 19, SES 1 D 5 8), and 180 days (BES 5 6, BES 1 D 5 6, SES 5 15, SES 1 D 5 6). Results: In vivo imaging and histological analysis showed that neointimal formation peaks early (30 days) in BES. Conversely, for SES, the peak occurred later (90 days). However, the neointimal formation achieved in either group equalized at 180 days. For SES, post-dilatation shortened the peak of neointimal formation to 30 days. Conversely, for BES, post-dilatation delayed the peak of neointimal formation to 90 days. At 30 days, histology showed that SES had significantly less injury. However, at 90 days, injury scores tended to be higher for SES. By 180 days, injury scores were comparable between both groups. Conclusions: The mechanism of stent expansion influences the degree of vascular injury and healing. The synergistic use of balloon post dilatation changes the dynamics of healing and may impact the potential beneficial effects inherent to SES technologies.

Experimental evaluation of pharmacokinetic profile and biological effect of a novel paclitaxel microcrystalline balloon coating in the iliofemoral territory of swine.

BACKGROUND: New paclitaxel coated balloons (PCB) developments have been proposed to maintain therapeutic levels of drug in the tissue while decreasing particle release. In this series of studies, we evaluated the pharmacokinetic profile and biological effects after paclitaxel delivery via novel microcrystalline PCB coating (mcPCB, Pax®, Balton) in porcine iliofemoral arteries. METHODS: Ten domestic swine were enrolled yielding 24 iliofemoral segments for evaluation. In the pharmacokinetic study, nine mcPCBs were dilated for 60 sec and animals sacrificed after 1 hr, 3 and 7 days. Studied segments were harvested and tissue paclitaxel concentration was analyzed utilizing HPLC. In the biological response evaluation, self-expandable stents were implanted followed by post dilation with either mcPCB (n = 10) or POBA (n = 5). After 28 days, angiography was performed, animals were sacrificed and stented segments harvested for histopathological evaluation. RESULTS: The 1-hr, 3 and 7 days vessel paclitaxel concentrations were 152.9 ± 154.5, 36.5 ± 49.5, and 0.9 ± 0.7 ng/mg respectively. In the biological response study, stents in the mcPCB group presented lower angiographic measures of neointimal hyperplasia as expressed by late loss when compared to POBA (-0.43 ± 0.9 vs. 0.23 ± 1.2; P = 0.24) at 28 days. In the histopathological evaluation, percent area of stenosis (%AS) was reduced by 42% in the mcPCB group (P < 0.05). The healing process in mcPCB group was comparable to POBA with regard to fibrin deposition (0.7 vs. 0.7; P = ns), neointimal maturity (1.97 vs. 1.93; P = ns), inflammation score (0.92 vs. 1; P = ns) and endothelialization score (1.77 vs. 1.73; P = ns). The mcPCB group did however display a greater tendency of medial cell loss and mineralization (60% vs. 0; P = 0.08). CONCLUSIONS: Delivery of paclitaxel via a novel mcPCB resulted in low long-term tissue retention of paclitaxel. However, this technological approach displayed reduced neointimal proliferation and favorable healing profile.

Mitochondrial Ca2+ Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.

The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.

Gene expression differences during the heterogeneous progression of peripheral atherosclerosis in familial hypercholesterolemic swine.

BACKGROUND: The heterogeneous progression of atherosclerotic disease in the peripheral arteries is currently not well understood. In humans, artery specific disease progression is partly attributed to the local hemodynamic environments. However, despite similar hemodynamic environments, porcine brachial arteries are protected while femoral arteries are highly susceptible to advanced lesion formation. The aim of this investigation was to determine whether artery specific gene expression patterns contribute to the uneven distribution of peripheral arterial disease (PAD) in Rapacz Familial-Hypercholesterolemic (FHC) swine. RESULTS: Histological results confirmed rapid atherosclerotic disease progression in femoral but not brachial arteries. A total of 18,922 probe sets had sufficient signal abundance. A main effect for age and artery was observed for 1784 and 1256 probe sets, respectively. A significant age x artery interaction was found for 184 probe sets. Furthermore, comparison between arteries found a decrease from 714 to 370 differentially expressed transcripts from nine months to two years of age. Gene ontology analysis of the 56 genes with a main effect for artery and an age x artery interaction identified vascular smooth muscle contraction as enhanced biological signaling pathway. CONCLUSION: This is the first investigation to report that the total number of differential genes decreases with diverging atherosclerotic disease pattern between porcine brachial and femoral arteries.

Low-dose sirolimus-eluting hydroxyapatite coating on stents does not increase platelet activation and adhesion ex vivo.

We previously found paclitaxel-eluting polymer-coated stents causing more human platelet-monocyte complex formation than bare metal stents in vitro. Presently, we examined patterns of platelet activation and adhesion after exposure to 6 nanofilm HAp-coated (HAp-nano) stents, 6 HAp-microporous-coated (HAp-micro) stents, 5 HAp sirolimus-eluting microporous-coated (HAp-SES) stents and 5 cobalt-chromium stents (BMS) deployed in an in vitro flow system. Blood obtained from healthy volunteers was circulated and sampled at 0, 10, 30 and 60 min. By flow cytometry, there were no significant differences in P-Selectin expression between the 4 stent types (HAp-nano = 32.5%; HAp-micro = 42.5%, HAp-SES = 10.23%, BMS = 7% change from baseline at 60 min, p = NS); PAC-1 antibody binding (HAp-nano = 11.8%; HAp-micro = 2.9%, HAp-SES = 18%, BMS = 6.4% change from baseline at 60 min, p = NS) or PMC formation (HAp-nano = 21.6%; HAp-micro = 4%, HAp-SES = 6.6%, BMS = 17.4% change from baseline at 60 min, p = NS). The 4 stent types did not differ in the average number of platelet clusters >10 µm in diameter by SEM (HAp-nano = 2.39 ± 5.75; HAp-micro = 2.26 ± 3.43; HAp-SES = 1.93 ± 3.24; BMS = 1.94 ± 2.41, p = NS). The majority of the struts in each stent group were only mildly covered by platelets, (HAp-nano = 80%, HAp-micro = 61%, HAp-SES = 78% and BMS = 52.1%, p = NS). The HAp-microporous-coated stents (ECD) attracted slightly more proteinaceous material than bare metal stents (HAp-micro = 35% struts with complete protein coverage, P < 0.0001 vs. other 3 stent types). In conclusion, biomimetic stent coating with nanofilm or microporous hydroxyapatite, even when eluting low-dose sirolimus, does not increase the platelet activation in circulating human blood, or platelet adhesion to stent surface when compared to bare metal stents in vitro.

6-Month Evaluation of a Transcatheter Aortic Valve (Myval) in a Novel Ovine, Supra-Aortic Banding Model.

The aim of the study was to evaluate a balloon expandable transcatheter heart valve (THV) system (Myval) at 6-month follow-up in ovine banding model. Eleven THV systems were implanted via carotid approach. There were 2 procedure-related deaths and 2 premature deaths. At 6 months all valves that completed follow-up (n = 7) were functional, with no significant regurgitation, calcification, thrombi, or vegetation. Mean pressure gradient was 21.9 ± 11 mm Hg, maximum velocity = 3.3 ± 1 m/s, and ejection fraction was 53.3 ± 6%. Myval THV showed optimal hemodynamic performance and biocompatibility.

Gene expression differences in healthy brachial and femoral arteries of Rapacz familial hypercholesterolemic swine.

The mechanisms underlying the unequal distribution of atherosclerotic disease in the peripheral arteries are currently unclear. Gene expression differences in healthy arteries may influence the heterogeneous distribution of atherosclerosis. Therefore, this investigation compares gene expression in healthy atheroprotected brachial and atherosusceptible femoral arteries of young and disease free Rapacz familial hypercholesterolemic (FHC) swine. We hypothesized that transcripts related to atherosusceptibility would be differentially expressed between these arteries prior to the onset of disease. Femoral and brachial arteries were harvested from four 13-day-old Rapacz FHC swine. No atherosclerotic disease was detected using Sudan IV, Verhoeff-van Gieson, and hematoxylin-eosin staining. Gene expression was quantified using Affymetrix GeneChip Porcine Genome Arrays. An average of 15,552 probe sets had detectable transcripts, while 430 probe sets showed a significant differential expression between arteries (false discovery rate < 0.05). The human orthologs of 63 probe sets with differential expression and a 1.5-fold or greater transcript abundance between arteries are associated with Wnt/ß-catenin, lysophospholipid, and Ca-signaling, as well as apoptosis. This is the first investigation reporting that differences in relative abundance of gene expression exist between brachial and femoral arteries in young Rapacz FHC swine prior to the development of atherosclerotic lesions.

A percutaneous aortic device for cerebral embolic protection during cardiovascular intervention.

BACKGROUND: Embolic stroke is a major cause of morbidity in aortic and cardiac interventional procedures. Although cerebral embolic protection devices have been developed for carotid interventions and for open heart surgery, a percutaneous device for cerebral embolic protection during aortic and cardiac interventions would be desirable. METHODS: The Embrella Embolic Deflector (Embrella Cardiovascular Inc, Wayne, Pa) is a percutaneously placed embolic protection device, inserted by a 6F access in the pig's right forelimb, and deployed in the aorta, covering the brachiocephalic vessel origins. The device functions by deflecting embolic debris downstream in the aortic circulation. A swine model (n = 3) was developed for testing the deployment, retrieval, and efficacy of the device using a carotid filtration circuit for collection of emboli. Human atheromatous material was prepared as embolization particles with diameters between 150 and 600 µm. Deflection efficiency of the device was calculated by comparing numbers of embolic particles in the carotid circulation during protected and unprotected injections. RESULTS: The device was reliably deployed, positioned, and retrieved (n = 24). There was no significant drop in blood pressure across the membrane of the device to suggest reduction of cerebral blood flow. The device did not become occluded by embolic debris despite an embolic load many times that encountered in the clinical situation. Particles entering the carotid circulation after aortic injection of emboli were reduced from 19% of total (unprotected) to 1.3% (protected, P < .0001), with 98.7% of all injected particles being deflected downstream. There was no evidence of arterial injury related to the device found at necropsy. CONCLUSION: The Embrella Embolic Deflector performs safely and reliably in the swine model of human atheroembolism. It effectively deflects almost all emboli downstream, away from the carotid circulation. The deflector shows promise as an aortic embolic protection device and merits further investigation.

Contrast-enhanced ultrasound for imaging vasa vasorum: comparison with histopathology in a swine model of atherosclerosis.

AIM: To evaluate the agreement between contrast-enhanced ultrasound imaging and histopathology in an animal model of atherosclerosis. METHODS AND RESULTS: Atherosclerosis was studied in both femoral arteries of four Rapacz familial hypercholesterolaemia (RFH) swine. Contrast-enhanced ultrasound imaging of the eight femoral arteries was performed at baseline and at 5, 12, 26, and 43 weeks follow-up after percutaneous transluminal stimulation of atherosclerosis to assess the progression of intima-media thickness (IMT) and the density and extent of the vasa vasorum network. Contrast-enhanced ultrasound imaging allowed an early detection of atherosclerosis and showed a significant gradual progression of atherosclerosis over time. IMT increased from 0.22 +/- 0.05 mm at baseline to 0.45 +/- 0.06 mm (P < 0.001) at follow-up. The density of the vasa vasorum network increased during follow-up and was significantly higher in advanced than in early atherosclerosis. The findings with contrast-enhanced ultrasound were confirmed by histopathological specimens of the arterial wall. CONCLUSION: Contrast-enhanced ultrasound is effective for in vivo detection of vasa vasorum in atherosclerotic plaques in the RFH swine model. After stimulation of atherosclerosis, contrast-enhanced ultrasound demonstrated a significantly increased IMT and significantly increased density of the vasa vasorum network in the developing atherosclerotic plaque, which was validated by histology.

Patterns of activation and deposition of platelets exposed to the polymeric surface of the paclitaxel eluting stent.

The interaction of platelets with the polymeric surface of drug eluting stents has not been fully described in the literature. Our aim was to analyze the patterns of activation and deposition of platelets exposed to two different stent platforms; (a) the polymeric surface of the paclitaxel eluting stent (Taxus((R)) stent, PES,) and (b) the metallic surface of a stent with identical structural design (Express((R)) stent, BMS). Platelet activation was tested by deploying stents in an in vitro flow chamber model. Anticoagulated blood of 25 healthy volunteers was circulated (flow rate 10 ml/min for 60 min) into the flow chamber system. P-selectin expression, glycoprotein IIb/IIIa activation (PAC-1 binding) and platelet-monocyte complexes (PMC) formation were evaluated at 0, 10, 30 and 60 min. Surface platelet deposition was assessed by surface electron microscopy in stents implanted in the in vitro system for 60 min and in stents implanted in normal porcine coronary arteries for 24 h. Platelet activation evaluation showed a higher P-Selectin expression (92.9% of baseline in PES versus 68.3 % in BMS, P = 0.01) and higher PMC formation (125.7 % of baseline in PES versus 75.6% in BMS, P < 0.01) in the PES compared to the BMS control group. PAC-1 binding levels did not differ among groups. In the in vitro study, SEM analysis of the stent surface showed no statistical differences on platelet deposition between the groups. In addition, presence of proteinaceous material was more frequently seen on the BMS group (moderate to complete coverage = 80% in BMS versus 26% in PES, P < 0.01). In the in vivo study, complete platelet coverage was similar between groups (PES = 7% versus BMS = 8%, P = NS). However, there was an overall trend towards less platelet deposition on the BMS surface (mild and moderate coverage = 83%, 9% in BMS versus 49%, 44% in PES, P < 0.001 for both) but thrombus formation was not observed in either group. The polymeric surface of the PES appears to induce a higher degree of platelet activation and deposition compared to the BMS surface. The biological implications of these findings on the patterns of vascular healing need to be further studied in vivo. Condensed Abstract The interaction of human platelets with the surface of drug eluting stents has not been fully characterized. Patterns of platelet activation and adhesion were evaluated in vitro and in vivo after exposing platelets to the surface of the paclitaxel-eluting stent and identical bare metal stent. The degree of PMC formation and P-selectin expression was increased in PES compared to BMS. In the in vivo study, complete platelet coverage was similar between groups. There was an overall trend towards less platelet deposition on the BMS surface, however, thrombus formation was not observed on either surface. The polymeric surface of the PES appears to induce a higher degree of platelet activation and deposition compared to the BMS surface.