Endovascular Venous Stenosis and Thrombosis Large Animal Model: Angiographic, Histological, and Biomechanical Characterizations.

PURPOSE: To characterize an ovine endovascular radiofrequency (RF) ablation-based venous stenosis and thrombosis model for studying venous biomechanics and response to intervention. MATERIALS AND METHODS: Unilateral short-segment (n = 2) or long-segment (n = 6) iliac vein stenoses were created in 8 adult sheep using an endovenous RF ablation technique. Angiographic assessment was performed at baseline, immediately after venous stenosis creation, and after 2-week (n = 6) or 3-month (n = 2) survival. Stenosed iliac veins and the contralateral healthy controls were harvested for histological and biomechanical assessment. RESULTS: At follow-up, the short-segment RF ablation group showed stable stenosis without occlusion. The long-segment group showed complete venous occlusion/thrombosis with the formation of collateral veins. Stenosed veins showed significant wall thickening (0.28 vs 0.16 mm, P = .0175) and confluent collagen deposition compared with the healthy controls. Subacute nonadherent thrombi were apparent at 2 weeks, which were replaced by fibrous luminal obliteration with channels of recanalization at 3 months. Stenosed veins demonstrated increased longitudinal stiffness (448.5 ± 5.4 vs 314.6 ± 1.5 kPa, P < .0001) and decreased circumferential stiffness (140.8 ± 2.6 vs 246.0 ± 1.6 kPa, P < .0001) compared with the healthy controls. CONCLUSION: Endovenous RF ablation is a reliable technique for creating venous stenosis and thrombosis in a large animal model with histological and biomechanical attributes similar to those seen in humans. This platform can facilitate understanding of venous biomechanics and testing of venous-specific devices and interventions.

Impact of Postthrombotic Vein Wall Biomechanics on Luminal Flow during Venous Angioplasty and Stent Placement: Computational Modeling Results.

This study characterized the impact of vein wall biomechanics on inflow diameter and luminal flow during venous angioplasty and stent placement, using postthrombotic and healthy biomechanical properties from an ovine venous stenosis and thrombosis model. Finite element analysis demonstrated more pronounced inflow channel narrowing in the postthrombotic vein compared with the healthy control vein during angioplasty and stent placement (relative inflow diameter reduction of 42% versus 13%, P < .0001). Computational fluid dynamics modeling showed increased relative areas of low wall shear rate in the postthrombotic vein compared with the normal vein (0.46 vs 0.24 for shear rate < 50 s-1; 0.13 vs 0.07 for shear rate < 15 s-1; P < .05), with flow stagnation and recirculation. Since inflow narrowing and low wall shear rate are associated with in-stent restenosis and reintervention, these computational results based on experimentally obtained biomechanical values highlight the significance of postthrombotic venous properties in optimizing venous intervention outcomes.

Embolic Characteristics of Imipenem-Cilastatin Particles in Vitro and in Vivo: Implications for Transarterial Embolization in Joint Arthropathies.

PURPOSE: To elucidate in vitro and in vivo characteristics and embolic properties of imipenem-cilastatin (IPM-CS) compared with hydrogel microspheres. MATERIALS AND METHODS: Particle size distribution was microscopically evaluated with 3 samples of 50 mg IPM-CS suspensions in each of 6 conditions by a mixture of contrast volume: 500 or 1000 µL and vortex mixing time: 5, 10, or 30 s. Time-dependent changes up to 3 h post-mixing were also evaluated. Fifteen male Sprague-Dawley rats (460.2 ± 5.0 g) underwent unilateral renal artery embolization using IPM-CS (n = 11) or hydrogel microspheres (n = 4). Follow-up angiography 48 h after embolization and histological evaluation, including acute tubular necrosis (ATN) and inflammation, were scored using a 5-point scale (from 0 = normal to 4 = severe). RESULTS: Over 91% of IPM-CS particles were <40 µm under all in vitro conditions. With the increased contrast volume, the average particle size also increased (mean ± standard deviation: 11.6 ± 13.9 vs 16.7 ± 18.2 µm for 500 and 1000 µL iodinated contrast, P < .001); however, the impact of the mixing/elapsed time were limited. At 48 h after embolization, all cases in the IPM-CS groups (11/11) showed major to complete recanalization versus no recanalization with hydrogel microspheres (0/4) (P < .001). The following are the median ATN and inflammation grades in the cortex (ventral/dorsal) and medulla (ventral/dorsal) in both groups: IPM-CS, ATN in cortex (2/4) and medulla (1/1), inflammation in cortex (0/0) and medulla (0/0); hydrogel microspheres, ATN in cortex (4/4) and medulla (3/2), inflammation in cortex (1/1) and medulla (1/1). CONCLUSIONS: IPM-CS suspension generated particles that were predominantly smaller than 40 µm and with unique short-term embolic effects, leaving predominantly peripheral ischemic changes.

Transtail Artery Access in Rats: A New Technique for Repeatable Selective Angiography.

Transtail artery approach successfully enables selective arterial catheterization and angiography in the rat. This technique is effective and repeatable. In addition to its utility in imaging, it may also have a wide range of applications in transcatheter therapy and experimental cerebral stroke models.

Transjugular Intrahepatic Portosystemic Shunt Creation Using a Radiofrequency Wire: Acute Feasibility Study in Swine.

The feasibility of a radiofrequency (RF) wire to replace the needle trocar for the creation of a transjugular intrahepatic portosystemic shunt (TIPS) was assessed in 3 swine by using fluoroscopy and intravascular ultrasonography (IVUS). RF wire passes were successful from hepatic to portal vein and from inferior vena cava to portal vein. Technical success was achieved using both IVUS guidance and carbon dioxide portography. The wire tracked a straight course under RF energy application without subjective deflection and, when centrally advanced, served as the working wire for completing the TIPS in 2 attempts with stent graft deployment. No procedural adverse events from the use of RF wire were observed.

Venous Biomechanics of Angioplasty and Stent Placement: Implications of the Poisson Effect.

PURPOSE: To characterize the Poisson effect in response to angioplasty and stent placement in veins and identify potential implications for guiding future venous-specific device design. MATERIALS AND METHODS: In vivo angioplasty and stent placement were performed in 3 adult swine by using an established venous stenosis model. Iron particle endothelium labeling was performed for real-time fluoroscopic tracking of the vessel wall during intervention. A finite-element computational model of a vessel was created with ADINA software (version 9.5) with arterial and venous biomechanical properties obtained from the literature to compare the response to radial expansion. RESULTS: In vivo angioplasty and stent placement in a venous stenosis animal model with iron particle endothelium labeling demonstrated longitudinal foreshortening that correlated with distance from the center of the balloon (R2 = 0.87) as well as adjacent segment narrowing that correlated with the increase in diameter of the treated stenotic segment (R2 = 0.89). Finite-element computational analysis demonstrated increased Poisson effect in veins relative to arteries (linear regression coefficient slope comparison, arterial slope 0.033, R2 = 0.9789; venous slope 0.204, R2 = 0.9975; P < .0001) as a result of greater longitudinal Young modulus in veins compared with arteries. CONCLUSIONS: Clinically observed adjacent segment narrowing during venous angioplasty and stent placement is a result of the Poisson effect, with redistribution of radially applied force to the longitudinal direction. The Poisson effect is increased in veins relative to arteries as a result of unique venous biomechanical properties, which may be relevant to consider in the design of future venous interventional devices.

Transarterial Delivery of a Biodegradable Single-Agent Theranostic Nanoprobe for Liver Tumor Imaging and Combinatorial Phototherapy.

PURPOSE: To assess selective accumulation of biodegradable nanoparticles within hepatic tumors after transarterial delivery for in vivo localization and combinatorial phototherapy. MATERIALS AND METHODS: A VX2 hepatic tumor model was used in New Zealand white rabbits. Transarterial delivery of silicon naphthalocyanine biodegradable nanoparticles was performed using a microcatheter via the proper hepatic artery. Tumors were exposed via laparotomy, and nanoparticles were observed by near-infrared (NIR) fluorescence imaging. For phototherapy, a handheld NIR laser (785 nm) at 0.6 W/cm2 was used to expose tumor or background liver, and tissue temperatures were assessed with a fiberoptic temperature probe. Intratumoral reactive oxygen species formation was assessed using a fluorophore (2',7'-dichlorodihydrofluorescein diacetate). RESULTS: Nanoparticles selectively accumulated within viable tumor by NIR fluorescence. Necrotic portions of tumor did not accumulate nanoparticles, consistent with a vascular distribution. NIR-dependent heat generation was observed with nanoparticle-containing tumors, but not in background liver. No heat was generated in the absence of NIR laser light. Reactive oxygen species were formed in nanoparticle-containing tumors exposed to NIR laser light, but not in background liver treated with NIR laser or in tumors in the absence of NIR light. CONCLUSIONS: Biodegradable nanoparticle delivery to liver tumors from a transarterial approach enabled selective in vivo tumor imaging and combinatorial phototherapy.

VIDEO: Technique to Restrict the Gore Viatorr Stent-Graft for TIPS Reduction.

OBJECTIVE: The Viatorr stent-graft (W. L. Gore and Associates), specifically made for transjugular intrahepatic portosystemic shunt (TIPS) creation, has significantly improved TIPS patency compared with bare metal stents. Post-TIPS hepatic encephalopathy (HE), however, remains relatively common after TIPS creation. We describe a technique to secondarily restrict a Viatorr stent-graft to treat post-TIPS refractory HE and maintain use of the Viatorr device. CONCLUSION: We show a simple technique to modify the Viatorr stent-graft for TIPS reduction.

Embolization of Arteriovenous Malformations: Effect of Flow Control and Composition of n-Butyl-2 Cyanoacrylate and Iodized Oil Mixtures with and without Ethanol in an in Vitro Model.

Purpose To elucidate the effect of flow control (ie, balloon occlusion) and the composition of various mixtures of n-butyl-2 cyanoacrylate (NBCA) and iodized oil, with and without the addition of ethanol, for the treatment of arteriovenous malformations in an in vitro model. Materials and Methods A simulation circuit device that featured an artificial nidus was filled with heparinized swine blood obtained during exsanguination from another Institutional Animal Care and Use Committee-approved protocol and was constructed to generate pulsatile flow. Mixtures of NBCA and iodized oil (NL) at a 1:1 ratio (NL 1:1); NL and ethanol (NLE) at a 1:1:3 ratio (NLE 1:1:3) with or without flow control; and NL at 1:3, 1:5, and 1:10 ratios without flow control were injected six times each for a total of 42 trials. Embolization was classified as complete filling, proximal occlusion, pass through, or distal overpenetration after occlusion balloon deflation, and the trial results were compared. The results of the embolization test were evaluated by using the Fisher exact probability test to compare optimal and suboptimal embolization groups. Results NLE 1:1:3 with flow control completely filled the nidus in all six trials. NL 1:1 delivered with flow control achieved complete nidus filling in three of six injections, as did the NL 1:5 ratio trial without flow control. Complete embolization with NLE 1:1:3 with flow control was more feasible to achieve complete nidus filling than was NL 1:1 with flow control or NL 1:5 without flow control, although there was no statically significant difference (all, P = .09). None of the other mixtures produced complete embolization. Conclusion NLE 1:1:3 showed consistent and reproducible complete embolization with flow control and was stable after balloon deflation, making it an acceptable material for embolization in an in vitro arteriovenous malformation model. Further study should be performed before the NLE 1:1:3 mixture is used in routine clinical practice. (©) RSNA, 2015.

Practical Tantalum Coating of Microspheres for Experimental Visualization under Fluoroscopy and CT.

The present report describes a simple technique for tantalum coating of microspheres for visualization by fluoroscopy and computed tomography (CT). Spherical microspheres were soaked with Ta powder under different conditions and microscopically evaluated for Ta-coating quality by assessing bound and unbound Ta. For 100-300-µm Embosphere particles, soaking with 0.05 mL Ta powder for 30 minutes and centrifugation at 500 rpm produced optimal coating. Optimized microspheres were injected in swine renal arteries and assessed by fluoroscopy and micro-CT for the opacification of segmental, arcuate, and interlobular arteries. This practical method can be used for experimental studies with commonly available microspheres.

Iodine based radiopacity of experimental blood clots for testing of mechanical thrombectomy devices.

BACKGROUND: Barium sulfate powder used for radiopacity of experimental blood clots (EBCs) for testing mechanical thrombectomy devices (MTD) has negative effects on EBCs mechanical properties. In vitro and in vivo exploration was performed to determine if the iodine based contrast medium will have less negative effects on the EBCs than barium. MATERIALS AND METHODS: Fresh blood from 2 swine was used to create fibrinogen enhanced and thrombin initiated EBC in tubes. Iodine radiopacity was achieved by mixing the blood with 65% Iohexol or by soaking the EBCs for 2 or 24 hours in Iohexol. The EBCs opacified with barium served as controls. In vitro study: The EBCs were subjected to four tests, manual elongation, catheter injection, radiopacity and contrast wash out tests. In vivo study: The common carotid arteries of 2 swine were embolized by either barium EBC or EBC soaked for 24 hours in Iohexol. The duration of radiopacity of the different EBCs was compared. RESULTS: The EBCs opacified with Iohexol initially had higher radiopacity than the barium opacified EBCs. However, their opacity rapidly decreased with saline soaking and, particularly, after they were embolized in live animals. The mechanical properties of Iohexol opacified EBCs were inferior to barium opacified EBCs. The Iohexol mixed EBCs were less firm and elastic and half of them fragmented during catheter injection. The Iohexol soaked EBCs exhibited decreased tensile strength and elasticity compared to the barium EBCs. CONCLUSIONS: Compared to barium, iodine based contrast medium does not offer any advantage for opacifying EBCs.

Creation of fibrinogen-enhanced experimental blood clots to evaluate mechanical thrombectomy devices for treatment of acute stroke: an in vitro study.

PURPOSE: To explore if addition of fibrinogen to the most commonly used experimental blood clot (EBC) model would improve its mechanical properties and histologic structure. MATERIALS AND METHODS: Fresh blood from three swine was used to create four EBC types. The Gralla model of thrombin-induced barium-opaque EBC served as the control. In three other EBC types, 50 mg, 100 mg, and 200 mg of bovine fibrinogen were added. Evaluation of EBCs was done with three tests: manual elongation, injection through an 8-F catheter, and an opacity test. Thirty EBCs of each type were evaluated with each test. Histologic evaluation followed. RESULTS: The control EBCs had low tensile strength and broke at 165% elongation. However, they were elastic and returned to their original length after catheter injection. The EBCs with fibrinogen exhibited increased tensile strength with increasing fibrinogen doses and withstood elongation to 213% (P < .01). Their elasticity decreased with increased tensile strength, and they remained elongated after catheter injection (P < .01 for EBC with 100 mg and 200 mg fibrinogen). Histologic examination showed more thorough mixing of blood with barium and a significantly increased amount of fibrin after addition of fibrinogen. CONCLUSIONS: Addition of fibrinogen to a Gralla EBC model changes its mechanical properties proportionately to the fibrinogen dose. Fibrinogen increases EBC tensile strength but decreases its elasticity. Fibrinogen also significantly increases the binding of blood cells with fibrin on histologic slides.

Biodisk: a new device for closure of patent foramen ovale: a feasibility study in swine.

PURPOSE: To evaluate the feasibility, effectiveness, and safety of a porcine small intestinal submucosa (SIS)-covered Biodisk (BD) for the closure of patent foramen ovale (PFO) in swine. METHODS: Twelve piglets (9-30 kg) with PFO ranging in size from 6 to 12 mm were used for the in vivo testing. The BD device consisted of two basic nitinol wire components covered with platinum coil, a flexible SIS-covered ring, and an anchor. The BD was advanced through an 8-Fr sheath from the femoral vein. Nine acute animals were used to test the BD for deployment, stability, immediate shunt closure, and device repositioning before or after its detachment. To assess retrievability, four devices were deployed and intentionally embolized into the RA (n = 2) and LA (n = 2). The effectiveness of the device was evaluated by angiocardiography. EKG was recorded before and after PFO closure for 3 hr. From the 12 animals, nine were acute and three were followed; one for 6 weeks, one for 12 weeks, and one for 16 weeks. RESULTS: Successful device implantation was achieved in all animals with no shunting of contrast media observed during follow-up in. One animal needed to have device repositioned for complete PFO occlusion because of suboptimal placement at the first attempt. The device was easily placed and retrieved before detachment in all nine animals in the acute study. None of the BDs spontaneously embolized during release or on follow-up. EKG did not demonstrate arrhythmias during or after treatment. Four intentionally embolized BDs were easily retrieved with an Amplatz goose neck snare. Macroscopic and histologic evaluation of the three long-term animals showed that devices were well incorporated in the atrial septum with complete shunt closure. The SIS showed progressive remodeling with the host cells. There was also progressive endothelization of the BD device. CONCLUSION: The BD device deployment is feasible, safe, and effective. Long-term studies are needed to evaluate its long-term effectiveness.

Hemostatic efficacy of chitosan-based bandage for closure of percutaneous arterial access sites: An experimental study in heparinized sheep model.

BACKGROUND: Most of the presently used percutaneous arterial closure devices (PACD) for hemostasis after interventional vascular procedures are effective, but carry risk of complications by deposition of a foreign body. A new promising externally applied PACD - chitosan-based HemCon Bandage (HCB) was explored in sheep. The HCB hemostatic efficacy and complications occurring with its use were compared to those with the standard manual compression (SMC). MATERIAL AND METHODS: Both superficial femoral arteries (SFA) of 9 heparinized sheep were catheterized with an 8F sheath for 5 minutes. After the sheath withdrawal, hemostasis with the HCB was compared with hemostasis achieved with SMC in the contralateral SFA. Iliac angiograms performed by carotid artery approach determined the hemostasis time. RESULTS: The HCB use shortened time to hemostasis with a mean time of 6.9 ± 3.9 minutes versus 10.8 ± 2.8 minutes for the SMC (P-value 0.019). Seven SFAs in the HCB group and only 1 SFA in the SMC group exhibited hemostasis in 5 minutes. All nine SFAs using the HCB showed femoral artery patency and demonstrated less hematoma (2/9) than in the SMC group (8/9). No complications developed in the HCB group, one SFA occlusion was seen in the SMC group. CONCLUSIONS: The externally applied HCB in heparinized sheep was safe and effective. It significantly shortened time to hemostasis at the SFA access sites following 8F sheath removal. Proper application of the HCB was necessary to shorten hemostasis and prevent hematoma formation. The HCB should be tested in a clinically controlled study to evaluate its efficacy in humans.

Optional vena cava filter with disengaging centering struts: retrieval in an animal model.

An optional inferior vena cava (IVC) filter prototype was evaluated for safety and long-term retrievability as an initial feasibility study in an animal model. This filter has four centering struts that have the ability to disengage from the filtering cone portion, allowing the legs to slide out of endothelial growth. Retrieval of six filters in three animals was successful up to 27 weeks. There was no substantial filter tilt, migration, or IVC damage. In conclusion, this filter design may help overcome some of the shortcomings in currently approved optional IVC filters, including long-term retrieval difficulties, tilting, or migration.

Effects of Different Mixing Agents on the Stability of Sodium Tetradecyl Sulfate (STS) Foam: An Experimental Study.

PURPOSE: To evaluate the effect of air, CO2 and contrast medium-air on the dwell time (DT) stability of sodium tetradecyl sulfate (STS) foam. MATERIALS AND METHODS: Three types of foam sclerosants (air-foam, CO2-foam, contrast-air-foam) were injected eight times into an inclined straight plastic tube (internal diameters 4 mm and 10 mm) filled with a blood substitute. Injections were captured by CCD camera, and images were transferred for digital analysis and calculation of DT. RESULTS: Contrast-air-foam and air-foam in a 4-mm tube showed 5.6-/3.3-fold greater DT compared to CO2-foam, respectively (P = 0.001). Contrast-air-foam in a 10-mm tube showed 2.1-fold greater DT compared to CO2-foam (P = 0.0167). CONCLUSION: A mixture of air and iodinated contrast improves the stability of STS foam compared to mixtures using only air or CO2. Further, animal and clinical studies are needed to validate this in vitro result.

Medroxyprogesterone acetate and dihydrotestosterone induce coronary hyperreactivity in intact male rhesus monkeys.

Coronary hyperreactivity (CH), characterized by persistent severe vasoconstrictions in response to vasoconstrictor challenge, is oppositely influenced by progesterone (P) and medroxyprogesterone acetate (MPA) treatment in surgically menopausal primates. In this study we tested whether multiweek MPA or dihydrotestosterone (DHT) exposure induced CH in intact male rhesus monkeys. Coronary angiographic experiments with intracoronary serotonin and the thromboxane A(2) analog U46619 stimulated brief vasoconstriction (for 1-3 min) in large epicardial coronaries in untreated male monkeys. In contrast, MPA- and DHT-treated monkeys displayed long-duration constrictions (>5 min), with significantly greater reductions in the minimal diameters of epicardial coronaries. Immunocytochemistry demonstrated androgen receptors (AR) and P receptors in aorta and coronary arteries, and immunocytochemistry and Western blotting showed AR and P receptors in rhesus coronary vascular muscle cells. In vivo, MPA or DHT increased thromboxane prostanoid (TP) receptor expression in the aorta. In vitro, MPA or DHT increased, whereas P did not change, TP receptor expression in primary coronary vascular muscle cell. This MPA- or DHT-mediated increase in TP receptor expression was attenuated by the AR antagonist flutamide. MPA or DHT induction of CH in intact adult male primates, hypothesized to occur via androgenic up-regulation of vascular muscle TP receptor expression, could predispose to CH-mediated myocardial ischemia.

Prevention of coronary hyperreactivity in preatherogenic menopausal rhesus monkeys by transdermal progesterone.

OBJECTIVE: To test if transdermal progesterone (P) confers coronary vascular protection in surgically menopausal preatherosclerotic rhesus monkeys. METHODS AND RESULTS: Ovariectomized rhesus monkeys fed an atherogenic diet (AD) for 19 months were treated with an investigational transdermal P cream (n=7) or identical placebo cream (n=5) for 4 weeks. Aorta and carotids showed fatty streaks and Oil Red O staining demonstrated lipid deposition. Serum P levels in P-treated rhesus monkeys (0.6 ng/mL) were significantly greater than placebo (0.2 ng/mL). Significant elevation of cholesterol, LDL cholesterol, and HDL cholesterol, was noted in all animals. Lp(a) was significantly attenuated in the AD-fed P-treated monkeys. Coronary angiographic experiments stimulating vasoconstriction by intracoronary injections of serotonin plus U46619 showed exaggerated prolonged actions amplified by AD, but significant protection against severe prolonged vasoconstriction in P-treated monkeys. Immunocytochemistry confirmed co-expression of P and thromboxane prostanoid (TP) receptors in coronaries and aorta. Western blotting demonstrated TP receptor attenuation in vascular muscle after P treatment. CONCLUSIONS: Coronary hyperreactivity, a putative component of coronary artery disease mediated via increased vascular muscle thromboxane prostanoid receptors, can be prevented by subphysiological levels of P, not only in nonatherosclerotic (previously shown) but also in preatherosclerotic primates.

Percutaneous prosthetic venous valves: current state and possible applications.

The small-intestinal submucosa square-stent bicuspid venous valve has shown the most promising results of all of the artificial venous valves developed. In long-term experimental studies in sheep, 25 valves were placed into the jugular veins and 88% exhibited good function, whereas 12% had decreased function because of valve tilting. Only 4% had partial thrombosis in the tilted valve. Valves also were placed in 3 patients. The bicuspid venous valves remained patent without thrombosis or other complications. Proper sizing and proper placement of the valves was critical to their function. The valve construction needs to be improved to prevent occasional tilting during their deployment.