Berberine inhibited carotid atherosclerosis through PI3K/AKTmTOR signaling pathway.

Atherosclerosis, a multifactorial vascular disease resulting from lipid metabolism disorders, features chronic inflammatory damage resulting from endothelial dysfunction, which usually affects multiple arteries. The carotid artery is a common site for clinical atherosclerosis evaluation. The aortic root is the standard site for quantifying atherosclerosis in mice. Due to the adverse reactions of first-line drugs, it is necessary to discover new drugs to prevent and treat atherosclerosis. Berberine (BBR) is one of the most promising natural products derived from herbal medicine Coptidis Rhizoma (Huanglian) that features significant anti-atherosclerosis properties. However, overall BBR mechanism against carotid atherosclerosis has not been clearly discovered. Our work aimed to investigate potential BBR mechanism in improving carotid atherosclerosis in ApoE knockout mice. Here, we proved that in ApoE -/- mice receiving high-fat diet for 12 weeks, BBR can reduce serum lipid levels, improve intimal hyperplasia, and antagonize carotid lipid accumulation, which may be achieved through regulating the PI3K/AKT/mTOR signaling pathway, regulating autophagy, promoting cell proliferation and inhibiting cell apoptosis. In summary, these data indicate that BBR can ameliorate carotid atherosclerosis. Therefore, it could be a promisingly therapeutic alternative for atherosclerosis.

Anti-inflammatory efficacy of Berberine Nanomicelle for improvement of cerebral ischemia: formulation, characterization and evaluation in bilateral common carotid artery occlusion rat model.

BACKGROUND: Berberine (BBR) is a plant alkaloid that possesses anti-inflammatory and anti-oxidant effects with low oral bioavailability. In this study, micelle formulation of BBR was investigated to improve therapeutic efficacy and examined its effect on the secretion of inflammatory cytokines in cerebral ischemia in the animal model. MATERIAL AND METHODS: Nano formulation was prepared by thin-film hydration method, and characterized by particle size, zeta potential, morphology, encapsulation efficacy, and drug release in Simulated Gastric Fluid (SGF) and Simulated Intestine Fluid (SIF). Then, Wistar rats were pretreated with the drug (100 mg/kg) and nano-drug (25, 50, 75, 100 mg/kg) for 14 days. Then, on the fourteenth day, stroke induction was accomplished by Bilateral Common Carotid Artery Occlusion (BCCAO); after that, Tumor Necrosis Factor - Alpha (TNF-α), Interleukin - 1 Beta (IL-1ß), and Malondialdehyde (MDA) levels were measured in the supernatant of the whole brain, then the anti-inflammatory effect of BBR formulations was examined. RESULT AND DISCUSSION: Micelles were successfully formed with appropriate characteristics and smaller sizes than 20 nm. The Poly Dispersity Index (PDI), zeta potential, encapsulation efficacy of micelles was 0.227, - 22 mV, 81%, respectively. Also, the stability of nano micelles was higher in SGF as compared to SIF. Our outcomes of TNF-a, IL-1B, and MDA evaluation show a significant ameliorating effect of the Berberine (BBR) and BBR-loaded micelles in pretreated groups. CONCLUSION: Our experimental data show that pretreated groups in different doses (nano BBR 100, 75, 50 mg/kg, and BBR 100 mg/kg) successfully showed decreased levels of the inflammatory factors in cerebral ischemia compared with the stroke group and pretreated group with nano BBR in the dose of 25 mg/kg. Nano BBR formulation with a lower dose can be a better candidate than conventional BBR formulation to reduce oxidative and inflammatory factors in cerebral ischemia. Therefore, BBR-loaded micelle formulation could be a promising protective agent on cerebral ischemia.

Reduction of TMAO level enhances the stability of carotid atherosclerotic plaque through promoting macrophage M2 polarization and efferocytosis.

It has been demonstrated that trimethylamine N-oxide (TMAO) serves as a driver of atherosclerosis, suggesting that reduction of TMAO level might be a potent method to prevent the progression of atherosclerosis. Herein, we explored the role of TMAO in the stability of carotid atherosclerotic plaques and disclosed the underlying mechanisms. The unstable carotid artery plaque models were established in C57/BL6 mice. L-carnitine (LCA) and methimazole (MMI) administration were applied to increase and reduce TMAO levels. Hematoxylin and eosin (H&E) staining, Sirius red, Perl's staining, Masson trichrome staining and immunohistochemical staining with CD68 staining were used for histopathology analysis of the carotid artery plaque. M1 and M2 macrophagocyte markers were assessed by RT-PCR to determine the polarization of RAW264.7 cells. MMI administration for 2 weeks significantly decreased the plaque area, increased the thickness of the fibrous cap and reduced the size of the necrotic lipid cores, whereas 5-week of administration of MMI induced intraplate hemorrhage. LCA treatment further deteriorated the carotid atherosclerotic plaque but with no significant difference. In mechanism, we found that TMAO treatment impaired the M2 polarization and efferocytosis of RAW264.7 cells with no obvious effect on the M1 polarization. In conclusion, the present study demonstrated that TMAO reduction enhanced the stability of carotid atherosclerotic plaque through promoting macrophage M2 polarization and efferocytosis.

Ipsilateral Nonstenotic Carotid Disease in Minor Ischemic Stroke: an Exploratory Analysis of The POINT Randomized Clinical Trial.

BACKGROUND AND AIM: Ipsilateral nonstenotic carotid disease is increasingly recognized as an etiology of ischemic stroke, however tailored treatment strategies are lacking. We aimed to examine clinical characteristics and treatment effects in patients with minor ischemic stroke associated with ipsilateral nonstenotic carotid disease in the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial. METHODS: We performed an exploratory analysis of the interaction of the treatment effects of aspirin plus clopidogrel versus aspirin monotherapy, stratified by presence of ipsilateral nonstenotic carotid disease in patients with minor ischemic stroke in the POINT trial. RESULTS: For this exploratory analysis, 167 patients presenting with ischemic stroke and ipsilateral nonstenotic carotid disease, defined as 1%-49% carotid stenosis ipsilateral to the corresponding territory of ischemic stroke, and 833 patients no carotid disease were included. Compared to patients with no carotid disease, patients with ipsilateral nonstenotic carotid disease were older (68.5 ± 11.3 years versus 61.3 ± 12.8 years; P < 0.001), and had a higher prevalence of hypertension (76.6% versus 59.2%, P < 0.001), ischemic heart disease (13.8% versus 5.4%, P < 0.001), and tobacco use (past: 34.1% versus 25.2%, P = 0.005; present: 27.5% versus 22.8%, P = 0.005). 5.4% of patients with ipsilateral nonstenotic carotid disease had recurrent ischemic stroke within 14 days. Patients receiving dual antiplatelet therapy had a numerical reduction in recurrent ischemic stroke compared to patients receiving aspirin monotherapy, however the exploratory analysis was underpowered to detect a statistically significant difference in treatment effect (HR 0.50, 95% CI 0.18-1.40, P = 0.19). CONCLUSION: Patients with minor ischemic stroke and ipsilateral nonstenotic carotid disease had a high risk of early stroke recurrence in the POINT trial. Dual antiplatelet therapy provided a non-statistically significant reduction in recurrent ischemic stroke with no difference in safety outcomes compared to aspirin monotherapy. Further study is needed to determine if early and short duration dual antiplatelet therapy is beneficial for all patients with ipsilateral nonstenotic carotid disease.

Resistance to Antiplatelet Therapy Is Associated With Symptoms of Cerebral Ischemia in Carotid Artery Disease.

BACKGROUND: Platelet inhibitory therapy is prescribed to prevent arterial thromboembolism in patients with atherosclerotic disease. Although taken by millions of people, around 30% are resistant to the treatment they are being prescribed. AIMS: To determine whether symptoms of cerebral ischemia, or pre-operative cerebral emboli, in patients admitted for a carotid endarterectomy were associated with resistance to aspirin or clopidogrel. METHODS: Venous blood from 133 patients immediately before carotid endarterectomy (CEA) was analyzed for resistance to aspirin and clopidogrel by multiplate impedance aggregometry. The number of emboli/hour entering the ipsilateral middle cerebral artery was counted by transcranial Doppler (TCD) on the day before surgery in 33 of these patients. RESULTS: Resistance was found in 21 (26.3%) of 100 patients taking aspirin and 14 (42%) of 33 taking clopidogrel. Mean (sd) residual platelet aggregation was significantly higher at 41.9(32) Au in patients who had suffered recent symptoms of cerebral ischemia compared with 30.8(16) Au in asymptomatic patients (p = 0.012). Residual platelet aggregation also correlated significantly with the number of emboli/hour counted by TCD in the ipsilateral middle cerebral artery (r = 0.45, p = 0.009). CONCLUSION: Antiplatelet resistance was associated with the frequency of cerebral emboli and recent symptoms of cerebral ischemia in patients with carotid disease. Definitive clinical studies are needed to explore whether testing for antiplatelet resistance should be undertaken routinely in patients starting platelet inhibitory therapy for cardiovascular disease.

Changes in carotid stiffness in patients with familial hypercholesterolemia treated with Evolocumab®: A prospective cohort study.

BACKGROUND AND AIM: Protein convertase subtilisin kexin type 9 (PCSK-9) inhibitors demonstrated efficacy in cholesterol reduction and in the prevention of cardiovascular events. We evaluated changes in lipid profile and carotid stiffness in patients with familial hypercholesterolemia during 12 weeks of treatment with a PCSK-9 inhibitor, Evolocumab®. METHODS AND RESULTS: Patients with familial hypercholesterolemia starting a treatment with Evolocumab® were included. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), small dense LDL (assessed by LDL score) and carotid stiffness were evaluated before starting treatment with Evolocumab® and during 12 weeks of treatment. Twenty-five subjects were enrolled (52% males, mean age 51.5 years). TC and LDL-C were reduced of 38% and 52%, respectively during treatment, with LDL score reduced of 46.1%. In parallel, carotid stiffness changed from 8.8 (IQR: 7.0-10.4) m/sec to 6.6 (IQR: 5.4-7.5) m/sec, corresponding to a median change of 21.4% (p < 0.001), with a significant increase in carotid distensibility (from 12.1, IQR: 8.73-19.3 kPA-1 × 10-3 at T0 to 21.8, IQR: 16.6-31.8 kPA-1 × 10-3 at T12w) corresponding to a median change of 62.8% (p < 0.001). A multivariate analysis showed that changes in LDL score were independently associated with changes in carotid stiffness (ß = 0.429, p = 0.041). CONCLUSION: Small dense LDL reduction, as assessed by LDL score, is associated with changes in carotid stiffness in patients with familial hypercholesterolemia treated with Evolocumab®.

Intensive Statin Therapy Compromises the Adiponectin-AdipoR Pathway in the Human Monocyte-Macrophage Lineage.

Background and Purpose- Statins are widely used for cardiovascular disease prevention through cholesterol-lowering and anti-inflammatory effects. Adiponectin, an anti-inflammatory adipokine, acts via two receptors, AdipoR1 and AdipoR2, to exert atheroprotective effects on the vasculature. We investigated whether statins can modulate the adiponectin-AdipoR pathway in the human monocyte-macrophage lineage. Methods- Monocytes were isolated from the whole blood of patients with severe carotid atherosclerosis (cross-sectional study) or from patients with cardiovascular risk factors (longitudinal study) and assessed for AdipoR1 and AdipoR2 gene expression using quantitative real-time polymerase chain reaction. In vitro, THP-1 (Tamm-Horsfall protein 1) macrophages were treated with increasing atorvastatin or rosuvastatin doses for 24- or 72-hours to determine the effect of statins on AdipoR expression and activity. Macrophage cytokine secretion (IL [interleukin]-1ß, IL-10, IL-6, and TNF [tumor necrosis factor]-α) was assessed by electrochemiluminescence. Results- AdipoR1 and AdipoR2 mRNA expression on circulating monocytes from patients with carotid atherosclerosis, was significantly lower by 1.36- and 1.17-fold, respectively, in statin users versus statin-naïve patients. Specifically, patients on high doses of atorvastatin (40-80 mg) or rosuvastatin (20-40 mg) had significantly lower AdipoR gene expression versus statin-naïve patients. Similarly, in the longitudinal in vivo study, longer atorvastatin/rosuvastatin treatment (≥5 months) in patients with cardiovascular risk factors resulted in lower AdipoR gene expression on circulating monocytes versus prestatin levels. In vitro, higher statin doses and longer exposure resulted in a greater decrease in AdipoR mRNA expression and greater macrophage secretion of pro-inflammatory cytokines, IL-1ß, IL-6, and TNF-α. High statin doses also reduced adiponectin's capacity to suppress intracellular cholesteryl ester levels in oxLDL (oxidized LDL)-loaded macrophages, with rosuvastatin exhibiting higher potency than atorvastatin. Conclusions- Our in vivo and in vitro studies identified a novel pleiotropic property of statins in modulating the adiponectin-AdipoR pathway in the human monocyte-macrophage lineage, where intensive statin therapy compromised the expression and function of adiponectin and its receptors.

Cervical arterial dissection: clinical characteristics in a neurology service in São Paulo, Brazil.

Cervical arterial dissection accounts for only a small proportion of ischemic stroke but arouses scientific interest due to its wide clinical variability. OBJECTIVE This study aimed to evaluate its risk factors, outline its clinical characteristics, compare treatment with antiaggregation or anticoagulation, and explore the prognosis of patients with cervical arterial dissection. METHODS An observational, retrospective study using data from medical records on patients with cervical arterial dissection between January 2010 and August 2015. RESULTS The total number of patients was 41. The patients' ages ranged from 19 to 75 years, with an average of 44.5 years. The most common risk factor was smoking. Antiaggregation was used in the majority of patients (65.5%); 43% of all patients recanalized in six months, more frequently in patients who had received anticoagulation (p = 0.04). CONCLUSION The presence of atherosclerotic disease is considered rare in patients with cervical arterial dissection; however, our study found a high frequency of hypertension, smoking and dyslipidemia. The choice of antithrombotic remains controversial and will depend on the judgment of the medical professional; the clinical results with anticoagulation or antiaggregation were similar but there was more recanalization in the group treated with anticoagulation; its course was favorable in both situations. The recurrence of cervical arterial dissection and stroke is considered a rare event and its course is favorable.

Cervical arterial dissection: clinical characteristics in a neurology service in São Paulo, Brazil / Dissecção arterial cervical: características clínicas em um serviço de neurologia de São Paulo, Brasil

ABSTRACT Cervical arterial dissection accounts for only a small proportion of ischemic stroke but arouses scientific interest due to its wide clinical variability. Objective: This study aimed to evaluate its risk factors, outline its clinical characteristics, compare treatment with antiaggregation or anticoagulation, and explore the prognosis of patients with cervical arterial dissection. Methods: An observational, retrospective study using data from medical records on patients with cervical arterial dissection between January 2010 and August 2015. Results: The total number of patients was 41. The patients' ages ranged from 19 to 75 years, with an average of 44.5 years. The most common risk factor was smoking. Antiaggregation was used in the majority of patients (65.5%); 43% of all patients recanalized in six months, more frequently in patients who had received anticoagulation (p = 0.04). Conclusion: The presence of atherosclerotic disease is considered rare in patients with cervical arterial dissection; however, our study found a high frequency of hypertension, smoking and dyslipidemia. The choice of antithrombotic remains controversial and will depend on the judgment of the medical professional; the clinical results with anticoagulation or antiaggregation were similar but there was more recanalization in the group treated with anticoagulation; its course was favorable in both situations. The recurrence of cervical arterial dissection and stroke is considered a rare event and its course is favorable.

RESUMO As dissecções arterais cervicais correspondem somente a uma pequena proporção dos casos de acidente vascular cerebral (AVC) isquêmico, mas despertam interesse científico devido à sua alta variabilidade clínica. Objetivos: Este estudo destina-se a avaliar os fatores de risco, desfechos clínicos, comparar o tratamento com anticoagulação e antiagregação, e avaliar o prognóstico desses pacientes. Métodos: Estudo observacional, retrospectivo utilizando dados de prontuários de pacientes com dissecção arterial cervical entre os períodos de janeiro de 2010 e agosto de 2015. Resultados: O número de pacientes foi 41. A idade foi de 19 a 75 anos, com idade média de 44,5 anos. O fator de risco mais comum encontrado foi o tabagismo. Antiagregação foi utilizada na maioria dos pacientes (65,5%); 43% dos pacientes apresentaram recanalização em seis meses, sendo esta mais frequentemente observada nos pacientes que receberam anticoagulação (p = 0,04). Conclusão: A presença de doença aterosclerótica é considerada rara em pacientes com dissecção arterial cervical. Entretanto, nosso estudo encontrou alta frequência de hipertensão arterial, tabagismo e dislipidemia. A escolha pela terapia antitrombótica permanece controversa e dependerá do julgamento clínico do médico; os resultados clínicos com anticoagulação ou antiagregação foram similares, mas houve maior taxa de recanalização no grupo tratado com anticoagulação. A recorrência de dissecação arterial cervical e AVC foi considerada rara e o curso, favorável.

Resveratrol Regulates BDNF, trkB, PSA-NCAM, and Arc Expression in the Rat Cerebral Cortex after Bilateral Common Carotid Artery Occlusion and Reperfusion.

The polyphenol resveratrol (RVT) may drive protective mechanisms of cerebral homeostasis during the hypoperfusion/reperfusion triggered by the transient bilateral common carotid artery occlusion followed by reperfusion (BCCAO/R). This immunochemical study investigates if a single dose of RVT modulates the plasticity-related markers brain-derived neurotrophic factor (BDNF), the tyrosine kinase trkB receptor, Polysialylated-Neural Cell Adhesion Molecule (PSA-NCAM), and Activity-regulated cytoskeleton-associated (Arc) protein in the brain cortex after BCCAO/R. Frontal and temporal-occipital cortical regions were examined in male Wistar rats randomly subdivided in two groups, sham-operated and submitted to BCCAO/R. Six hours prior to surgery, half the rats were gavage fed a dose of RVT (180 mg·kg-1 in 300 µL of sunflower oil as the vehicle), while the second half was given the vehicle alone. In the frontal cortex of BCCAO/R vehicle-treated rats, BDNF and PSA-NCAM decreased, while trkB increased. RVT pre-treatment elicited an increment of all examined markers in both sham- and BCCAO/R rats. No variations occurred in the temporal-occipital cortex. The results highlight a role for RVT in modulating neuronal plasticity through the BDNF-trkB system and upregulation of PSA-NCAM and Arc, which may provide both trophic and structural local support in the dynamic changes occurring during the BCCAO/R, and further suggest that dietary supplements such as RVT are effective in preserving the tissue potential to engage plasticity-related events and control the functional response to the hypoperfusion/reperfusion challenge.

Development of a Two-Way Coupled Eulerian-Lagrangian Computational Magnetic Nanoparticle Targeting Model for Pulsatile Flow in a Patient-Specific Diseased Left Carotid Bifurcation Artery.

PURPOSE: The aim of the present work is to present the development of a computational two-way coupled (fluid and particle coupled) magnetic nanoparticle targeting model to investigate the efficacy of magnetic drug targeting (MDT) in a patient-specific diseased left carotid bifurcation artery. MDT of therapeutic agents using multifunctional carrier particles has the potential to provide effective treatment of both cancer and cardiovascular disease by enabling a variety of localized treatment and diagnostic modalities while minimizing side effects. METHODS: A computational model is developed to analyze pulsatile blood flow, particle motion, and particle capture efficiency in a diseased left carotid bifurcation artery using the magnetic properties of magnetite (Fe3O4) and equations describing the magnetic forces acting on particles produced by an external cylindrical electromagnetic coil. A Eulerian-Lagrangian technique is adopted to resolve the hemodynamic flow and the motion of particles under the influence of a magnetic field (Br= 2T). Particle diameter sizes of 20 nm-4 µm in diameter were considered. RESULTS: The computational simulations demonstrate that the greatest particle capture efficiency results for particle diameters within the micron range, specifically 4 µm in regions where flow separation and vortices are at a minimum. It was also determined that the capture efficiency of particles decreases substantially with particle diameter, especially in the superparamagnetic regime. Particles larger than 2 µm were targeted and captured at the desired location by the external magnetic field, and the largest capture efficiency observed was approximately 98%. CONCLUSION: The simulation results presented in the present work have shown to yield favorable capture efficiencies for micron range particles and a potential for enhancing capture efficiency of superparamagnetic particles in smaller arteries and/or using magnetized implants such as cardiovascular stents. The present work presents results for justifying further investigation of MDT as a treatment technique for cardiovascular disease.

Comparative effects of lipid lowering, hypoglycemic, antihypertensive and antiplatelet medications on carotid artery intima-media thickness progression: a network meta-analysis.

BACKGROUND: Carotid artery intima-media thickness (cIMT) progression is a surrogate marker of atherosclerosis with a high predictive value for future CVD risk. This study evaluates the comparative efficacies of lipid lowering, hypoglycemic, antihypertensive and antiplatelet medications on cIMT progression. METHODS: We conducted a network meta-analysis (NMA) to evaluate the relative efficacies of several drug classes in modifying cIMT progression. After a literature search in several electronic databases, studies were selected by following predetermined eligibility criteria. An inverse variance-heterogeneity model was used for NMA. Sensitivity analyses were performed to check the reliability of the overall NMA, and transitivity analyses were performed to examine the effects of modifiers on the NMA outcomes. RESULTS: Data were taken from 47 studies (15,721 patients; age: 60.2 years [95% confidence interval (CI) 58.8, 61.6]; BMI: 27.2 kg/m2 [95% CI 26.4, 28.0]; and gender: 58.3% males [95% CI 48.3, 68.3]). Treatment duration was 25.8 months [95% CI 22.9, 28.7]. Of the 13 drug classes in the network, treatment with phosphodiesterase III inhibitors was the most effective in retarding annual mean cIMT against network placebo (weighted mean difference (WMD) - 0.059 mm [95% CI - 0.099, - 0.020) followed by the calcium channel blockers (WMD - 0.055 mm [95% CI - 0.099, 0.001]) and platelet adenosine diphosphate inhibitors (WMD - 0.033 mm [95% CI - 0.058, 0.008]). These 3 drug classes also attained the same positions when the NMA was conducted by using first-year changes in mean cIMT. In transitivity analyses, longer treatment duration, higher body mass index (BMI), and a higher baseline cIMT were found to be independently associated with a lesser reduction in annual mean cIMT. However, in a multivariate analysis with these 3 modifiers, none of these factors was significantly associated with annual change in mean cIMT. In the placebo group, age was inversely associated with annual change in mean cIMT independently. CONCLUSION: Phosphodiesterase III inhibitors and calcium channel blockers are found more effective than other drug classes in retarding cIMT progression. Age, BMI, and baseline cIMT may have some impact on these outcomes.

Management of Patients with Asymptomatic and Symptomatic Carotid Artery Disease: Update on Anti-Thrombotic Therapy.

The most common causes of ischaemic stroke are represented by carotid artery atherosclerotic disease (CAAD) and atrial fibrillation. While oral anticoagulants substantially reduce the incidence of thromboembolic stroke (< 1%/year), the rate of ischaemic stroke and other cardiovascular disease events in patients with CAAD remains high, ranging from 8.4 to 18.1 events per 100 patient-years. Similar to any other atherosclerotic disease, anti-thrombotic therapies are proposed for CAAD to reduce stroke and other cardiovascular events. The 2017 European Society of Cardiology (ESC)/European Society for Vascular Surgery (ESVS) guidelines recommend for patients with asymptomatic CAAD ≥60% the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily at the exception of patient at very high bleeding risk. For patients with symptomatic CAAD ≥50%, the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily is recommended. New perspectives for anti-thrombotic therapy for the treatment of patients with CAAD come from the novel dual pathway strategy combining a low-dose anticoagulant (i.e. rivaroxaban) and aspirin that may help reduce long-term ischaemic complications in patients with CAAD. This review summarizes current evidence and recommendations for the anti-thrombotic management of patients with symptomatic or asymptomatic CAAD or those undergoing carotid revascularization.

Delayed Pipeline Embolization of a Ruptured True Internal Carotid Artery Aneurysm Presenting with Epistaxis: Case Report and Review of the Literature.

BACKGROUND: Massive epistaxis from rupture of an intracavernous internal carotid artery aneurysm is a potentially fatal event. Although rare, this presentation is seen most often in patients after trauma or iatrogenic injury secondary to transsphenoidal surgery or radiation therapy. CASE DESCRIPTION: We present our unusual case of a patient with no significant risk factors who had recurrent epistaxis owing to a ruptured true cavernous internal carotid artery aneurysm. The patient was treated initially with coil embolization followed by placement of a Pipeline embolization device. The patient had complete resolution of her bleeding events. A follow-up arteriogram performed 14 months later confirmed aneurysm obliteration, with parent artery preservation and no evidence of in-stent stenosis. CONCLUSIONS: Our case highlights the importance of evaluating for intracranial pathological conditions in patients who present with refractory epistaxis. In selected patients, the use of flow-diversion technology as an adjunct or alternative to primary coil embolization for treatment should be considered.

Laboratory Monitoring of Platelet P2Y12 Receptor Inhibitors and Reversal of Antiplatelet Agents.

OBJECTIVES: To review the use of laboratory tests for antiplatelet agents to determine escalation of antiplatelet therapy and for emergent reversal of P2Y12 inhibitors. METHODS: A case scenario and review of cardiovascular and neurointerventional literature are described. RESULTS: In cardiovascular disease patients, large randomized trials failed to demonstrate superiority of tailored antiplatelet regimens using the VerifyNow P2Y12 assay, where earlier studies had shown promise. Platelet transfusions restored platelet function measured by vasodilator-stimulated phosphoprotein, light transmission aggregometry, or thromboelastography but not VerifyNow P2Y12, with the most restoration for clopidogrel and the least for ticagrelor. CONCLUSIONS: Current evidence does not support changing antiplatelet therapy based on the results of platelet function monitoring tests. For emergent reversal of P2Y12 inhibitors, test method can affect platelet dosing recommendations, as different methods may give different results.

Everolimus depletes plaque macrophages, abolishes intraplaque neovascularization and improves survival in mice with advanced atherosclerosis.

BACKGROUND AND AIMS: Inhibition of the mechanistic target of rapamycin (mTOR) is a promising approach to halt atherogenesis in different animal models. This study evaluated whether the mTOR inhibitor everolimus can stabilize pre-existing plaques, prevent cardiovascular complications and improve survival in a mouse model of advanced atherosclerosis. METHODS: ApoE-/-Fbn1C1039G+/- mice (n = 24) were fed a Western diet (WD) for 12 weeks. Subsequently, mice were treated with everolimus (1.5 mg/kg daily) or vehicle for another 12 weeks while the WD continued. RESULTS: Despite hypercholesterolemia, everolimus treatment was associated with a reduction in circulating Ly6Chigh monocytes (15 vs. 28% of total leukocytes, p = 0.046), a depletion of plaque macrophages (2.1 vs. 4.1%, p = 0.040) and an abolishment of intraplaque neovascularization, which are all indicative of a more stable plaque phenotype. Moreover, everolimus reduced hypoxic brain damage and improved cardiac function, which led to increased survival (100 vs. 67% of animals, p = 0.038). CONCLUSIONS: Everolimus enhances features of plaque stability and counters cardiovascular complications in ApoE-/-Fbn1C1039G+/- mice, even when administered at a later stage of the disease.