The role of oxygen transport in atherosclerosis and vascular disease.

Atherosclerosis and vascular disease of larger arteries are often associated with hypoxia within the layers of the vascular wall. In this review, we begin with a brief overview of the molecular changes in vascular cells associated with hypoxia and then emphasize the transport mechanisms that bring oxygen to cells within the vascular wall. We focus on fluid mechanical factors that control oxygen transport from lumenal blood flow to the intima and inner media layers of the artery, and solid mechanical factors that influence oxygen transport to the adventitia and outer media via the wall's microvascular system-the vasa vasorum (VV). Many cardiovascular risk factors are associated with VV compression that reduces VV perfusion and oxygenation. Dysfunctional VV neovascularization in response to hypoxia contributes to plaque inflammation and growth. Disturbed blood flow in vascular bifurcations and curvatures leads to reduced oxygen transport from blood to the inner layers of the wall and contributes to the development of atherosclerotic plaques in these regions. Recent studies have shown that hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor associated with hypoxia, is also activated in disturbed flow by a mechanism that is independent of hypoxia. A final section of the review emphasizes hypoxia in vascular stenting that is used to enlarge vessels occluded by plaques. Stenting can compress the VV leading to hypoxia and associated intimal hyperplasia. To enhance oxygen transport during stenting, new stent designs with helical centrelines have been developed to increase blood phase oxygen transport rates and reduce intimal hyperplasia. Further study of the mechanisms controlling hypoxia in the artery wall may contribute to the development of therapeutic strategies for vascular diseases.

Heterogeneity in the nonplanarity and arterial curvature of arteriovenous fistulas in vivo.

OBJECTIVE: Native arteriovenous fistulas (AVFs) for hemodialysis are susceptible to nonmaturation. Adverse features of local blood flow have been implicated in the formation of perianastomotic neointimal hyperplasia that may underpin nonmaturation. Whereas computational fluid dynamic simulations of idealized models highlight the importance of geometry on fluid and vessel wall interactions, little is known in vivo about AVF geometry and its role in adverse clinical outcomes. This study set out to examine the three-dimensional geometry of native AVFs and the geometric correlates of AVF failure. METHODS: As part of an observational study between 2013 and 2016, patients underwent creation of an upper limb AVF according to current surgical best practice. Phase-contrast magnetic resonance imaging was performed on the day of surgery to obtain luminal geometry along with ultrasound measurements of flow. Magnetic resonance imaging data sets were segmented and reconstructed for quantitative and qualitative analysis of local geometry. Clinical maturation was evaluated at 6 weeks. RESULTS: There were 60 patients who were successfully imaged on the day of surgery. Radiocephalic (n = 17), brachiocephalic (n = 40), and brachiobasilic (n = 3) fistulas were included in the study. Centerlines extracted from segmented vessel lumen exhibited significant heterogeneity in arterial nonplanarity and curvature. Furthermore, these features are more marked in brachiocephalic than in radiocephalic fistulas. Across the cohort, the projected bifurcation angle was 73 ± 16 degrees (mean ± standard deviation). Geometry was preserved at 2 weeks in 20 patients who underwent repeated imaging. A greater degree of arterial nonplanarity (log odds ratio [logOR], 0.95 per 0.1/vessel diameter; 95% confidence interval [CI], 0.22-1.90; P = .03) and a larger bifurcation angle (logOR, 0.05 per degree; 95% CI, 0.01-0.09; P = .02) are associated with a greater rate of maturation, as is fistula location (upper vs lower arm; logOR, -1.9; 95% CI, -3.2 to 0.7; P = .002). CONCLUSIONS: There is significant heterogeneity in the three-dimensional geometry of AVFs, in particular, arterial nonplanarity and curvature. In this largest cohort of AVF geometry to date, the effect of individual geometric correlates on maturation is uncertain but supports the premise that future modeling studies will need to acknowledge the complex geometry of AVFs.

Swirling Flow and Wall Shear: Evaluating the BioMimics 3D Helical Centerline Stent for the Femoropopliteal Segment.

The BioMimics 3D self-expanding nitinol stent represents a strategy for femoropopliteal intervention that is alternative or complementary to deployment of drug-coated stents or balloons. Whereas conventional straight stents reduce arterial curvature and disturb blood flow, creating areas of low wall shear, where neointimal hyperplasia predominantly develops, the helical centerline geometry of the BioMimics 3D maintains or imparts arterial curvature, promotes laminar swirling blood flow, and elevates wall shear to protect against atherosclerosis and restenosis. In the multicenter randomized MIMICS trial, treatment of femoropopliteal disease with the BioMimics 3D (n = 50) significantly improved 2-year primary patency (log-rank test p = 0.05) versus a control straight stent (n = 26), with no cases of clinically driven target lesion revascularization between 12 and 24 months (log-rank test p = 0.03 versus controls). In geometric X-ray analysis, the BioMimics stent was significantly more effective in imparting a helical shape even when the arterial segment was moderately to severely calcified. Computational fluid dynamics analysis showed that average wall shear was significantly higher with the helical centerline stent (1.13 ± 0.13 Pa versus 1.06 ± 0.12 Pa, p = 0.05). A 271-patient multicenter international MIMICS-2 trial and a 500-patient real-world MIMICS-3D registry are underway.

Helical Centerline Stent Improves Patency: Two-Year Results From the Randomized Mimics Trial.

BACKGROUND: Reintervention in the femoropopliteal artery is frequent and a major driver of cost-effectiveness. High wall shear generated by swirling blood flow is associated with reduced occurrence of atherosclerosis and restenosis. This trial investigated the clinical and hemodynamic outcomes of the BioMimics 3D self-expanding tubular nitinol stent with helical centerline geometry compared with a straight stent in the femoropopliteal artery. METHODS AND RESULTS: In a prospective, multicenter, randomized controlled trial, 76 patients with symptomatic peripheral arterial disease were randomized 2:1 to receive a helical or a straight stent. An independent core laboratory adjudicated angiographic and ultrasound parameters. The primary safety end point was freedom from a composite of all death, target limb amputation, and target lesion revascularization at 30 days. The primary effectiveness end point was freedom from clinically driven target lesion revascularization at 6 months. Patency was a secondary end point. Subjects were followed up for 2 years from intervention. The primary safety (1-sided P<0.01) and efficacy (1-sided P<0.001) end points for the helical stent were met. The proportion of patients treated with the helical stent who maintained patency at 12 and 24 months was 80% and 72%, respectively, compared with 71% and 55% for the control group. The difference was significant through 24 months (P=0.05). Freedom from clinically driven target lesion revascularization for the helical compared with straight stent was 91% versus 92% at 12 months and 91% versus 76% at 24 months. CONCLUSIONS: Both groups had similar safety outcomes and clinically driven target lesion revascularization to 2 years. However, after placement of a BioMimics 3D helical stent, there was improved patency to 2 years. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02163863.

Microbubble Void Imaging: A Non-invasive Technique for Flow Visualisation and Quantification of Mixing in Large Vessels Using Plane Wave Ultrasound and Controlled Microbubble Contrast Agent Destruction.

There is increasing recognition of the influence of the flow field on the physiology of blood vessels and their development of pathology. Preliminary work is reported on a novel non-invasive technique, microbubble void imaging, which is based on ultrasound and controlled destruction of microbubble contrast agents, permitting flow visualisation and quantification of flow-induced mixing in large vessels. The generation of microbubble voids can be controlled both spatially and temporally using ultrasound parameters within the safety limits. Three different model vessel geometries-straight, planar-curved and helical-with known effects on the flow field and mixing were chosen to evaluate the technique. A high-frame-rate ultrasound system with plane wave transmission was used to acquire the contrast-enhanced ultrasound images, and an entropy measure was calculated to quantify mixing. The experimental results were cross-compared between the different geometries and with computational fluid dynamics. The results indicated that the technique is able to quantify the degree of mixing within the different configurations, with a helical geometry generating the greatest mixing, and a straight geometry, the lowest. There is a high level of concordance between the computational fluid dynamics and experimental results. The technique could also serve as a flow visualisation tool.

Intimal hyperplasia following implantation of helical-centreline and straight-centreline stents in common carotid arteries in healthy pigs: influence of intraluminal flow.

Intimal hyperplasia (IH) is a leading cause of obstruction of vascular interventions, including arterial stents, bypass grafts and arteriovenous grafts and fistulae. Proposals to account for arterial stent-associated IH include wall damage, low wall shear stress (WSS), disturbed flow and, although not widely recognized, wall hypoxia. The common non-planarity of arterial geometry and flow, led us to develop a bare-metal, nitinol, self-expanding stent with three-dimensional helical-centreline geometry. This was deployed in one common carotid artery of healthy pigs, with a straight-centreline, but otherwise identical (conventional) stent deployed contralaterally. Both stent types deformed the arteries, but the helical-centreline device additionally deformed them helically and caused swirling of intraluminal flow. At sacrifice, one month post stent deployment, histology revealed significantly less IH in the helical-centreline than straight-centreline stented vessels. Medial cross-sectional area was not significantly different in helical-centreline than straight-centreline stented vessels. By contrast, luminal cross-sectional area was significantly larger in helical-centreline than straight-centreline stented vessels. Mechanisms considered to account for those results include enhanced intraluminal WSS and enhanced intraluminal blood-vessel wall mass transport, including of oxygen, in the helical-centreline stented vessels. Consistent with the latter proposal, adventitial microvessel density was lower in the helical-centreline stented than straight-centreline stented vessels.

Index proposal and basic estimator study for quantification of oscillation of the secondary flow pattern in tortuous vessels.

The development of atherosclerosis has been shown to correlate with regions of low wall shear stress and seemingly reduced mass transport. The local tortuosity of the arteries and local secondary flow oscillation also seem to be negatively correlated with the local occurrence of the disease. However there is currently no tool or physiological parameter that can be measured non-invasively to assess the local oscillation of the flow. Standard Colour Doppler imaging of secondary flow patterns during the blood pulse is studied and illustrated, and the local oscillation of the secondary flow pattern is proposed as an index, which could be an indicator of the likelihood of future disease development. Preliminary results are presented using a basic estimator developed for the proof of concept in the case of swirling flow, and based on colour-coded video signals collected in different configurations. In vitro results show that there is a correspondence between the Doppler patterns and the secondary flow patterns, the repeatability of the measures, and that the proposed index and its estimator reflect a joint influence of the local oscillation of the secondary flow pattern and of the flow rate. On another hand, while in vivo results still suffer from instabilities, noise and from scanners and processing limitations, they demonstrate that it is possible to use Colour Doppler imaging to image and characterize in vivo the secondary flow patterns and their oscillations non-invasively, and that it is possible for a trained clinician to perform manually such Doppler measurements for processing.

Preliminary comparative study of small amplitude helical and conventional ePTFE arteriovenous shunts in pigs.

Intimal hyperplasia (IH), which causes occlusion of arterial bypass grafts and arteriovenous (A-V) shunts, develops preferentially in low wall shear, or stagnation, regions. Arterial geometry is commonly three-dimensional, generating swirling flows, the characteristics of which include in-plane mixing and inhibition of stagnation. Clinical arterial bypass grafts are commonly two-dimensional, favouring extremes of wall shear. We have developed small amplitude helical technology (SwirlGraft) devices and shown them to generate physiological-type swirling flows. Expanded polytetrafluorethylene (ePTFE) grafts, although widely used as A-V shunts for renal dialysis access, are prone to thrombosis and IH. In a small preliminary study in pigs, we have implanted SwirlGraft ePTFE carotid artery-to-jugular vein shunts on one side and conventional ePTFE carotid artery-to-jugular vein shunts contralaterally. There was consistently less thrombosis and IH in the SwirlGraft than conventional shunts. At eight weeks (two animals), the differences were marked, with virtually no disease in the SwirlGraft devices and occlusion of the conventional grafts by thrombosis and IH. The study had limitations, but the lesser pathology in the SwirlGraft devices is likely to have resulted from their geometry and the associated swirling flow. The results could have implications for vascular biology and prolongation of the patency of arterial bypass grafts and A-V shunts.

Three-dimensional reconstruction of autologous vein bypass graft distal anastomoses imaged with magnetic resonance: clinical and research applications.

High-resolution magnetic resonance imaging was combined with computational modeling to create focused three-dimensional reconstructions of the distal anastomotic region of autologous vein peripheral bypass grafts in a preliminary series of patients. Readily viewed on a personal computer or printed as hard copies, a detailed appreciation of in vivo postoperative features of the anastomosis is possible. These reconstructions are suitable for analysis of geometric features, including vessel caliber, tortuosity, anastomotic angles, and planarity. Some potential clinical and research applications of this technique are discussed.

The geometry of unstented and stented pig common carotid artery bypass grafts.

The long-term success of arterial bypass grafting with autologous saphenous veins is limited by neointimal hyperplasia (NIH), which seemingly develops preferentially at sites where hydrodynamic wall shear is low. Placement of a loose-fitting, porous stent around end-to-end, or end-to-side, autologous saphenous vein grafts on the porcine common carotid artery has been found significantly to reduce NIH, but the mechanism is unclear. In a preliminary study, we implanted autologous saphenous vein grafts bilaterally on the common carotid arteries of pigs, placing a stent around one graft and leaving the contralateral graft unstented. At sacrifice 1 month post implantation, the grafts were pressure fixed in situ and resin casts were made. Unstented graft geometry was highly irregular, with non-uniform dilatation, substantial axial lengthening, curvature, kinking, and possible long-pitch helical distortion. In contrast, stented grafts showed no major dilatation, lengthening or curvature, but there was commonly fine corrugation, occasional slight kinking or narrowing of segments, and possible long-pitch helical distortion. Axial growth of grafts against effectively tethered anastomoses could account for these changes. CFD studies are planned, using 3D MR reconstructions, on the effects of graft geometry on the flow. Abnormality of the flow could favour the development of vascular pathology, including NIH.