Natriuretic peptide receptor-C is up-regulated in the intima of advanced carotid artery atherosclerosis

OBJECTIVE: Natriuretic peptide receptor-C (NPR-C/NPR-3) is a cell surface protein involved in vascular remodelling that is up-regulated in atherosclerosis. NPR-C expression has not been well characterized in human carotid artery occlusive lesions. We hypothesized that NPR-C expression correlates with intimal features of vulnerable atherosclerotic carotid artery plaque. METHODS: To test this hypothesis, we evaluated NPR-C expression by immunohistochemistry (IHC) in carotid endarterectomy (CEA) specimens isolated from 18 patients. The grade, location, and co-localization of NPR-C in CEA specimens were evaluated using two tissue analysis techniques. RESULTS: Relative to minimally diseased CEA specimens, we observed avid NPR-C tissue staining in the intima of maximally diseased CEA specimens (65%; p=0.06). Specifically, maximally diseased CEA specimens demonstrated increased NPR-C expression in the superficial intima (61%, p=0.17), and deep intima (138% increase; p=0.05). In the superficial intima, NPR-C expression significantly co-localized with vascular smooth muscle cells (VSMCs) and macrophages. The intensity of NPR-C expression was also higher in the superficial intima plaque shoulder and cap regions, and significantly correlated with atheroma and fibroatheroma vulnerable plaque regions (β=1.04, 95% CI=0.46, 1.64). CONCLUSION: These findings demonstrate significant NPR-C expression in the intima of advanced carotid artery plaques. Furthermore, NPR-C expression was higher in vulnerable carotid plaque intimal regions, and correlate with features of advanced disease. Our findings suggest that NPR-C may serve as a potential biomarker for carotid plaque vulnerability and progression, in patients with advanced carotid artery occlusive disease

Patient characteristics can influence the incidence of perioperative microemboli during carotid artery interventions

Purpose. Perioperative cerebral microembolization demonstrated on diffusion-weighted MRI (DWI) can occur following carotid endarterectomy (CEA) and carotid artery stenting (CAS). We sought to explore potential risk factors for this in the large patient cohort. Methods. We reviewed a 6-year consecutive patient cohort that received either CEA or CAS, and perioperative DWI evaluations. Results. 303 patients were reviewed, and 56 (19.4%) patients were found to have perioperative microemboli. The incidence was higher among patients who received CAS (P &lt; 0.001). Hypertension (P = 0.03), smoking (P = 0.001), and a history of transient ischemic attacks (P = 0.04) were risk factors for microembolization. The risk was higher among CEA patients with obesity (P = 0.05), and among CAS patients with coronary artery disease (P = 0.03). Conclusion. Specific patient populations are likely more prone to develop perioperative cerebral microemboli following carotid intervention. Continued risk stratification may help decrease future perioperative cerebral microembolization rates.</jats:p

Venous microtrauma associated with pharmacomechanical catheter-directed thrombolysis in a large animal acute deep venous thrombosis model

BackgroundPharmacomechanical catheter-directed thrombolysis (PCDT) is commonly used to treat acute deep venous thrombosis (DVT). The AngioJet Rheolytic Thrombectomy (ART) device is a widely used option. However, previous serious adverse events led to an FDA black-box warning. Limited large animal studies have assessed ART's efficacy and safety. We investigated the periprocedural outcomes and venous histomorphic impact of ART in a novel large animal acute DVT model.MethodsSix adult male Yorkshire pigs (96–113 kilograms) underwent general anesthesia and continuous hemodynamic monitoring. Acute DVT was induced in the infrarenal IVC using occlusive balloons. Three pigs were treated with ART's thrombectomy mode (MT) for 10 min. Another three pigs underwent PCDT with 250 ml saline and 50,000 IU Streptokinase over 10 min. Serial venograms assessed thrombus formation and post-treatment results, and then iliocaval venous segments were resected for histomorphic analysis.ResultsART significantly reduced thrombus in all pigs without complications (64.7% ± 9.7% vs. 16.1% ± 10.5%; P = 0.02). Retroperitoneal staining was observed around treated venous segments in all pigs, with a higher mean staining score in the PCDT group compared to the MT group (2 ± 0 vs. 1.3 ± 0.57; P = 0.11). Histopathology revealed more venous wall intimal tears in ART-treated segments compared to untreated segments (18 ± 5.79 vs. 6.3 ± 2.51, P = 0.01).ConclusionsART effectively removes acute thrombus in a large animal DVT model without periprocedural complications. The observed retroperitoneal staining following PCDT raises some concerns regarding venous wall integrity following ART, for which the long-term consequences are unknown

Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis

Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy-lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy-lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease

CIB1 Mediated Regulation of Endothelial Cells and Pathological Angiogenesis

Calcium and integrin binding protein 1 (CIB1), a 22kDa EF-hand containing protein, that was originally identified to bind the platelet integrin [alpha]IIb, can also bind and regulate various other proteins. Among the newly identified CIB1-binding partners is the p21-activated kinase 1 (PAK1), which is known to regulate ECs and contribute to angiogenesis in vivo. Since CIB1 is present in highly vascularized tissue and is expressed in various types of ECs, we hypothesized that it may also have an important role in vascular tissue. The work described herein is a collection of studies that for the first time investigates the role of CIB1 in EC signaling, function, and angiogenesis. Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. We demonstrate here that CIB1 is necessary for various EC functions such as migration, proliferation, tubule formation, and monolayer permeability. CIB1 also regulates PAK1 activation, as well as downstream ERK1/2 phosphorylation and MMP-2 expression. Depletion of CIB1 in ECs attenuates their response to angiogenic growth factors such as VEGF and bFGF. In ex vivo and in vivo assays, CIB1-KO tissue also has an attenuated response to growth factors, demonstrating that CIB1 is necessary for a robust angiogenic response. Moreover, although we confirm that CIB1-KO mice have no defects in developmental vasculogenesis and angiogenesis, we demonstrate that CIB1 is essential for ischemia-induced and tumor-induced pathological angiogenesis. These findings are important since they differentiate between physiological and pathological forms of angiogenesis and identify CIB1 as novel target for pro- and anti-angiogenic therapy

Modified bare-back micro-retrograde tibial arterial access to facilitate peripheral endovascular therapy

Patients with critical limb threatening ischemia often present with complex segmental peripheral arterial chronic total occlusions, which might not be amenable to traditional antegrade revascularization techniques. For these patients, alternative retrograde revascularization techniques could be necessary. In the present report, we describe a novel modified retrograde cannulation technique using a bare back technique that eliminates the need for conventional tibial access sheath placement and, instead, facilitates distal arterial blood sampling, blood pressure monitoring, retrograde administration of contrast agents and vasoactive substances, and a rapid-exchange strategy. This cannulation strategy can serve as part of the armamentarium in the treatment of patients with complex peripheral arterial occlusions

Examining the Influential Factors on Urban Growth and Population Attraction: A Case Study of Almere, Netherlands

This paper explores the intricate nature of population attraction and urban growth, which are influenced by a wide range of social, economic, and environmental factors. Through a case study of Almere, Netherlands, this study investigates the connection between population attraction, urban quality of life, livability, and sustainability. To assess the impact of these factors on urban growth, the study developed a measurable indicator matrix based on a theoretical framework. The study’s results demonstrate that social life, urban economy, population standards, ease of access to services, transportation, and the quality of the built environment are significant factors in population attraction and urban growth. Additionally, the study revealed some previously unconsidered factors that play a crucial role in sustaining population attraction and urban growth. The study’s findings offer insights for urban planners and policymakers to design effective strategies that promote population attraction and foster sustainable urban growth