Stent thrombosis is a lethal complication of endovascular intervention. Concern has been raised about the inherent risk associated with specific stent designs and drug-eluting coatings, yet clinical ...and animal support is equivocal.
We examined whether drug-eluting coatings are inherently thrombogenic and if the response to these materials was determined to a greater degree by stent design and deployment with custom-built stents. Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P=0.011). Thick-strutted (162 μm) stents were 1.5-fold more thrombogenic than otherwise identical thin-strutted (81 μm) devices in ex vivo flow loops (P<0.001), commensurate with 1.6-fold greater thrombus coverage 3 days after implantation in porcine coronary arteries (P=0.004). When bare metal stents were deployed in malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P=0.001; and 2.32-fold, P<0.001). The thrombogenicity of polymer-coated stents with thin struts was lowest in all configurations and remained insensitive to incomplete deployment. Computational modeling-based predictions of stent-induced flow derangements correlated with spatial distribution of formed clots.
Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis. However, strut dimensions and positioning relative to the vessel wall are critical factors in modulating stent thrombogenicity. Optimal stent geometries and surfaces, as demonstrated with thin stent struts, help reduce the potential for thrombosis despite complex stent configurations and variability in deployment.
Stent thrombosis (ST), a postinterventional complication with a mortality rate of 50%, has an incidence that rises precipitously in patients at risk. Chronic renal failure and end-stage renal disease ...have emerged as particularly strong ST risk factors, yet the mechanism remains elusive. Tissue factor (TF) is a crucial mediator of injury-related thrombosis and has been implicated for ST. We posit that uremia modulates TF in the local vessel wall to induce postinterventional thrombosis in patients with end-stage renal disease.
As a model of the de-endothelialized, postinterventional state, we exposed primary human vascular smooth muscle cells (vSMCs) pretreated with uremic serum (obtained from ESRD patients on hemodialysis) to coronary-like blood flow. vSMC TF expression, activity, stability, and posttranslational modification were examined after vSMCs were treated with uremic serum or solutes. We found significantly greater clot formation after uremic serum exposure, which was substantially reduced with the prior treatment with anti-TF neutralizing antibody. Uremic sera induced 2- to 3-fold higher TF expression and activity in vSMCs independent of diabetes mellitus. Relevant concentrations of isolated uremic solutes such as indole-3-acetic acid (3.5 μg/mL), indoxyl sulfate (25 μg/mL), and uric acid (80 μg/mL) recapitulated these effects in cell culture and the flow loop model. We show further that TF undergoes ubiquitination at baseline and that uremic serum, indole-3-acetic acid, and indoxyl sulfate significantly prolong TF half-life by inhibiting its ubiquitination.
The uremic milieu is profoundly thrombogenic and upregulates vSMC TF levels by increasing TF stability and decreasing its ubiquitination. Together, these data demonstrate for the first time that the posttranslational regulation of TF in uremia may have a causative role in the increased ST risk observed in uremic patients. These data suggest that interventions that reduce vSMC TF may help to prevent ST and that uremic solutes should be considered as novel risk factors for ST in patients with chronic renal failure.
Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently ...demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.
Stent thrombosis is a major complication of coronary stent and scaffold intervention. While often unanticipated and lethal, its incidence is low making mechanistic examination difficult through ...clinical investigation alone. Thus, throughout the technological advancement of these devices, experimental models have been indispensable in furthering our understanding of device safety and efficacy. As we refine model systems to gain deeper insight into adverse events, it is equally important that we continue to refine our measurement methods. We used digital signal processing in an established flow loop model to investigate local flow effects due to geometric stent features and ultimately its relationship to thrombus formation. A new metric of clot distribution on each microCT slice termed normalized clot ratio was defined to quantify this distribution. Three under expanded coronary bare-metal stents were run in a flow loop model to induce clotting. Samples were then scanned in a MicroCT machine and digital signal processing methods applied to analyze geometric stent conformation and spatial clot formation. Results indicated that geometric stent features play a significant role in clotting patterns, specifically at a frequency of 0.6225 Hz corresponding to a geometric distance of 1.606 mm. The magnitude-squared coherence between geometric features and clot distribution was greater than 0.4 in all samples. In stents with poor wall apposition, ranging from 0.27 mm to 0.64 mm maximum malapposition (model of real-world heterogeneity), clots were found to have formed in between stent struts rather than directly adjacent to struts. This early work shows how the combination of tools in the areas of image processing and signal analysis can advance the resolution at which we are able to define thrombotic mechanisms in in vitro models, and ultimately, gain further insight into clinical performance.
While Epstein-Barr virus causes mostly asymptomatic infection, associated malignancies, and autoimmune and lymphoproliferative diseases occur. To dissect the evolution of humoral immune responses ...over the course of EBV infection and to gain a better understanding of the potential contribution of antibody (Ab) function to viral control, we comprehensively profiled Ab specificities and Fc-functionalities using systems serology and VirScan. Ab functions against latent (EBNA1), early (p47/54) and two late (gp350/220 and VCA-p18) EBV proteins were overall modest and/or short-lived, differing from humoral responses induced during acute infection by other viruses such as HIV. In the first year post infection, only p18 elicited robust IgM-driven complement deposition and IgG-driven neutrophil phagocytosis while responses against EBNA-1 were largely Fc-functionally silent and only matured during chronic infection to drive phagocytosis. In contrast, Abs against Influenza virus readily mediated broad Fc-activity in all participants. These data suggest that EBV evades the induction of robust Fc-functional Abs, potentially due to the virus’ life cycle, switching from lytic to latent stages during infection.
Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet ...therapies. Although the associations of indolic uremic solutes and vascular wall proteins such as tissue factor (TF) and aryl hydrocarbon receptor (AHR) are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute-specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box-containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute-AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.
Abstract Through decades of use and refinement, endovascular stents have become part and parcel of the management of obstructive atherosclerotic lesions. Upon stent placement, a variety of ...biophysical reactions ensue, governed not only by the mechanical and material properties of the device, but also the impact these properties have on the local vascular biology. Anatomic changes and vascular deformations give rise to solid mechanical and fluid forces that are the proximate, functional drivers of the induced reparative response. Powerful computational tools and advanced imaging techniques allow us to define these forces with high precision and increasingly, at a patient-specific level. We have also gained fundamental insights into how these forces influence subcellular and cellular processes, and, through application of a variety of model systems, how they subsequently drive an integrated tissue response. Clinical studies extend understanding to actual patients and pathophysiologic scenarios. These tools and insights take on added weight given the real risks that accompany the many substantial benefits of stenting. Complex lesions remain difficult to manage and continue to be associated with worse outcomes. While many patients respond well to treatment, others suffer treatment failures and recurrent events – sometimes catastrophic. Overcoming such variability requires that we move towards individualized treatment plans. Doing so necessitates that we develop not just a qualitative understanding of involved phenomena, but a quantitative ability to predict integrated outcomes. Given the multi-scale nature of the vascular response to stenting, it is critical that models, be they computational, bench-top, animal, or clinical, can be verified, validated, and made interrelated. This review provides an overview of the biophysics governing endovascular stenting, their integration in real-world endovascular settings, and how simulation and statistical approaches are helping to bridge the gap between qualitative model understanding and quantitative clinical prediction.
Stacking cross-sectional intravascular images permits three-dimensional rendering of endovascular implants, yet introduces between-frame uncertainties that limit characterization of device placement ...and the hemodynamic microenvironment. In a porcine coronary stent model, we demonstrate enhanced OCT reconstruction with preservation of between-frame features through fusion with angiography and a priori knowledge of stent design.
Strut positions were extracted from sequential OCT frames. Reconstruction with standard interpolation generated discontinuous stent structures. By computationally constraining interpolation to known stent skeletons fitted to 3D 'clouds' of OCT-Angio-derived struts, implant anatomy was resolved, accurately rendering features from implant diameter and curvature (n = 1 vessels, r2 = 0.91, 0.90, respectively) to individual strut-wall configurations (average displacement error ~15 μm). This framework facilitated hemodynamic simulation (n = 1 vessel), showing the critical importance of accurate anatomic rendering in characterizing both quantitative and basic qualitative flow patterns. Discontinuities with standard approaches systematically introduced noise and bias, poorly capturing regional flow effects. In contrast, the enhanced method preserved multi-scale (local strut to regional stent) flow interactions, demonstrating the impact of regional contexts in defining the hemodynamic consequence of local deployment errors.
Fusion of planar angiography and knowledge of device design permits enhanced OCT image analysis of in situ tissue-device interactions. Given emerging interests in simulation-derived hemodynamic assessment as surrogate measures of biological risk, such fused modalities offer a new window into patient-specific implant environments.
A wide range of interindividual variability in the measured and clinical effects of antiplatelet drugs exists. As patients with less platelet inhibition consistently have increased rates of adverse ...cardiovascular outcomes, a great deal of effort is being focused on understanding and treating this apparent 'resistance.' Pharmacogenomic and pharmacodynamic methods to better delineate responders from nonresponders are being developed, and innovative strategies and novel, potent drugs capable of overcoming nonresponsiveness are in active clinical trials. Less attention has been paid to the confounding role that patient nonadherence has on individual response to antiplatelet therapy, but accruing evidence indicates that nonadherence has a dominant impact in real-world, outpatient settings, as compared with true, biochemical antiplatelet nonresponsiveness. Understanding the mechanisms of nonadherence and rigorously testing methods to overcome it are urgently needed to avoid the potential harm in delivering increasingly intense and expensive therapies to those who may not need it, while at the same time offering a way to improve overall health-care efficiency.
Expanding the Roster Kleiman, Neal S., MD; Kolandaivelu, Kumaran, MD, PhD
Journal of the American College of Cardiology,
06/2015, Letnik:
65, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Among patients who were discharged alive after acute coronary syndromes (ACS) and enrolled in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), nearly 15% experienced ...MI, nearly 5% had strokes, and more than 15% had died by the end of 7 years despite aggressive lipid lowering (mean low-density lipoprotein cholesterol 53 mg/dl) (2). GPVI also shares some signaling pathways with GP Ib/IX/V. ...GPVI blockade should theoretically allow von Willebrand Factor-GP Ib/IX/V-mediated hemostasis to continue (12).
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