IL-1ß Inhibition Partially Negates the Beneficial Effects of Diet-Induced Atherosclerosis Regression in Mice.

BACKGROUND: Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. METHODS: Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1ß or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis. RESULTS: Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1ß antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1ß antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap. CONCLUSIONS: Taken together, IL-1ß appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.

Sustained Focal Vascular Inflammation Accelerates Atherosclerosis in Remote Arteries.

OBJECTIVE: Evidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown. Approach and Results: We used a novel ApoE-/- knockout mouse model of sustained arterial inflammation, initiated by mechanical injury in the abdominal aorta. Using serial in vivo molecular MRI and ex vivo histology and flow cytometry, we demonstrate that focal arterial inflammation triggered by aortic injury, accelerates atherosclerosis in the remote brachiocephalic artery. The brachiocephalic artery atheroma had distinct histological features including increased plaque size, plaque permeability, necrotic core to collagen ratio, infiltration of more inflammatory monocyte subsets, and reduced collagen content. We also found that arterial inflammation following focal vascular injury evoked a prolonged systemic inflammatory response manifested as a persistent increase in serum IL-6 (interleukin 6). Finally, we demonstrate that 2 therapeutic interventions-pravastatin and minocycline-had distinct anti-inflammatory effects at the plaque and systemic level. CONCLUSIONS: We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.

Fibronectin Containing Extra Domain A Induces Plaque Destabilization in the Innominate Artery of Aged Apolipoprotein E-Deficient Mice.

OBJECTIVE: Fibronectin containing extra domain A (Fn-EDA) is an endogenous ligand of TLR4 (toll-like receptor 4) and is abundant in the extracellular matrix of advanced atherosclerotic lesions in human and mice. Irrespective of sex, deletion of Fn-EDA reduces early atherosclerosis in apolipoprotein E-deficient (Apoe-/-) mice. However, the contribution of Fn-EDA in advanced atherosclerosis remains poorly characterized. We determined the contribution of Fn-EDA in advanced atherosclerotic lesions of aged (1-year-old) Apoe-/- mice. APPROACH AND RESULTS: Plaque composition was determined in the innominate artery, a plaque instability site that is known to mimic several histological features of vulnerable human plaques. Female Apoe-/-, Fn-EDA-/-Apoe-/-, TLR4-/-Apoe-/-, and Fn-EDA-/-TLR4-/-Apoe-/- mice were fed a high-fat Western diet for 44 weeks. Fn-EDA-/-Apoe-/- mice exhibited reduced plaque size characterized by smaller necrotic cores, thick fibrous caps containing abundant vascular smooth muscle cells and collagen, reduced CD68/MMP9 (matrix metalloproteinase 9)-positive content, less accumulation of MMP-cleaved extracellular matrix aggrecan, and decreased vascular smooth muscle cell and macrophage apoptosis (P<0.05 versus Apoe-/- mice). Together these findings suggest that Fn-EDA induces plaque destabilization. Deletion of TLR4 reduced histological features of plaque instability in Apoe-/- mice but did not further reduce features of plaque destabilization in Fn-EDA-/-Apoe-/- mice, suggesting that TLR4 may contribute to Fn-EDA-induced plaque destabilization. Fn-EDA potentiated TLR4-dependent MMP9 expression in bone marrow-derived macrophages, suggesting that macrophage TLR4 may contribute to Fn-EDA-mediated plaque instability. CONCLUSIONS: Fn-EDA induces histological features of plaque instability in established lesions of aged Apoe-/- mice. The abundance of Fn-EDA in advanced atherosclerotic lesions may increase the risk of plaque destabilization.

Balloon-like Mobile Plaque in the Innominate Artery: Ultrasonographic and Pathological Perspectives of Repetitive Embolism.

Mobile plaque in the innominate artery is extremely rare and difficult to diagnose, especially in its acute stage. Its diagnosis is often delayed in many cases, resulting in delayed treatment and poor prognosis. Herein, we report the case of a 69-year-old patient with multiple cerebral infarction only in the right internal carotid artery and vertebrobasilar territories. No embolic sources were found until arterial ultrasonography detected a large balloon-like mobile plaque in the IA. Mobile plaque consisted of high-and low-echoic components and showed balloon-like plaque. Despite sufficient antiplatelet therapy, recurrence of cerebral embolism could not be prevented. IA replacement was eventually performed by cardiac surgeons. Pathological examinations showed that organized mobile plaque could have existed previously and acute thrombi, generated after the atheromatous plaque rupture caused by the mechanical burden of organized mobile plaque, could expand along with the organized mobile plaque and caused balloon-like plaque and related with repeated embolism. The IA should be explored immediately in cases of repetitive right-sided cerebral embolisms to prevent further recurrence.

Complete filter-based cerebral embolic protection with transcatheter aortic valve replacement.

OBJECTIVES: To evaluate the value of left vertebral artery filter protection in addition to the current filter-based embolic protection technology to achieve complete cerebral protection during TAVR. BACKGROUND: The occurrence of cerebrovascular events after transcatheter aortic valve replacement (TAVR) has fueled concern for its potential application in younger patients with longer life expectancy. Transcatheter cerebral embolic protection (TCEP) devices may limit periprocedural cerebrovascular events by preventing macro and micro-embolization to the brain. Conventional filter-based TCEP devices cover three extracranial contributories to the brain, yet leave the left vertebral artery unprotected. METHODS: Patients underwent TAVR with complete TCEP. A dual-filter system was deployed in the brachiocephalic trunk and left common carotid artery with an additional single filter in the left vertebral artery. After TAVR all filters were retrieved and sent for histopathological evaluation by an experienced pathologist. RESULTS: Eleven patients received a dual-filter system and nine of them received an additional left vertebral filter. In the remaining two patients, the left vertebral filter could not be deployed. No periprocedural strokes occurred. We found debris in all filters, consisting of thrombus, tissue derived debris, and foreign body material. The left vertebral filter contained debris in an equal amount of patients as the Sentinel filters. The size of the captured particles was similar between all filters. CONCLUSIONS: The left vertebral artery is an important entry route for embolic material to the brain during TAVR. Selective filter protection of the left vertebral artery revealed embolic debris in all patients. The clinical value of complete filter-based TCEP during TAVR warrants further research.

[Ultrasonographic control of cerebral blood flow in patients with stenosis of brachiocephalic arteries before and after carotid endarterectomy]. / Ul'trazvukovoi kontrol' mozgovogo krovotoka u bol'nykh so stenozom brakhiotsefal'nykh arterii do i posle karotidnoi éndarteréktomii.

The authors studied the parameters of arterial and venous blood flow in patients presenting with haemodynamically significant atherosclerosis of the carotid arteries before and after carotid endarterectomy, as well as while carrying out functional tests. Comparing the indices of arterial blood flow in the Study Group consisting of 52 patients and the Control Group comprising 15 apparently healthy volunteers at rest prior to the operation revealed statistically significant differences of volumetric parameters of blood flow in the internal carotid artery. The obtained results showed that the breath-holding test was accompanied and followed by increased velocity of blood flow in the middle cerebral artery (MCA) on the side contralateral to stenosis, with the reactivity index (RI) amounting to 0.98±0.20, which statistically significantly differed from the RI in the Control Group patients (1.28±0.13). The forced respiration test demonstrated a decrease in the volumetric indices of blood flow in the MCA on the side of stenosis, as well as an increase of the maximum end-diastolic velocity of blood flow on the side contralateral to stenosis. The test with sublingual administration of nitroglycerin appeared to result in reduced blood flow in the MCA. The supratrochlear test demonstrated decreased velocity of blood flow in the supratrochlear artery. Studying the venous link of cerebral vessels after the operation showed that statistically significant differences were revealed only on the side contralateral to stenosis as compared with the values prior to revascularization. An increase of blood flow in the internal jugular veins after the operation on the side contralateral to the operation was apparently suggestive of an adequate distribution of blood flow through the main vessels of the brain.

[Endovascular interventions for stenoses and occlusions of the brachiocephalic trunk]. / Éndovaskuliarnye vmeshatel'stva pri stenozakh i okkliuziiakh brakhiotsefal'nogo stvola.

The study was undertaken to evaluate the efficacy and safety of endovascular interventions in the treatment of stenoses and occlusions of the brachiocephalic trunk (BCT). Described in the article are the results of retrospectively analysing the efficacy of endovascular interventions performed in a total of forty-five patients presenting with lesions of the BCT. Depending on the type of the BCT lesion, the patients were divided into 2 groups: Group One consisted of 28 patients diagnosed with stenoses of the BCT and Group Two included 17 patients found to have occlusions of the BCT. The outcomes of the interventions were assessed with due regard for the findings obtained by angiography, ultrasonographic duplex scanning of the brachiocephalic vessels, as well as by the examination of the patient's neurological status. The remote results were evaluated at follow-up terms ranging from 6 months to 4 years. No ischaemic strokes, myocardial infarctions, nor lethal outcomes were observed during 30 days after the intervention. In the early postoperative period, there occurred 1 (3.6%) case of transitory ischaemic attack in Group One, with also 1 (5.9%) case thereof encountered in Group Two. Within the time frame of the follow-up period (48 months), recurrent occlusion of the stented segment of the BCT was registered in 2 (7.1%) patients from Group One and in 1 (5.8%) patient from Group Two (p=0.87). The primary patency rate at 4 years in Group One and Group Two patients amounted to 86.8 and 88.3%, respectively (p=0.84). A conclusion thus drawn was as follows: endovascular intervention for stenoses and occlusions of the BCT is an effective and safe method of preventing acute cerebral circulation impairments in the vertebrobasilar basin.

[Dynamics of asymptomatic atherosclerosis of carotid arteries depending on the achieved level of cholesterol in moderate-risk patients]. / Dinamika bessimptomnogo ateroskleroza sonnykh arterii v zavisimosti ot dostignutogo urovnia kholesterina u patsientov s umerennym riskom.

The study was aimed at assessing the dynamics of asymptomatic atherosclerosis of carotid arteries (CA) depending upon the achieved level of low-density lipoprotein cholesterol (LDLC) in patients with moderate total risk by the SCORE scale. We followed up a total of eighty-two 40-to-65-year-old patients with the LDLC level above 2.6 mmol/l, being at moderate total risk by the SCORE scale and having symptom-free atherosclerosis of the extracranial portion of brachiocephalic arteries (up to 50% narrowing of their lumen) as diagnosed by duplex scanning. The patients were randomly divided into two groups. Group One patients (n=41) received therapy with atorvastatin in order to achieve the LDLC level less than 1.8 mmol/l. Group Two patients (n=41) were treated in order to achieve the LDLC level below 2.6 mmol/l. At 12 months of follow up we compared the dynamics of carotid atherosclerosis (change in the number, total height, structure, echogenicity, as well as the state of the surface of atherosclerotic plaques, alteration of the thickness of the CA intima-media complex). Group Two patients were found to have an increase in the number and average sum of the heights of atherosclerotic plaques. An increase of the maximum thickness of the intima-media complex of the wall of the right and left CA was more pronounced as compared with that in Group One patients. Aggressive hypolipidemic therapy aimed at achieving the LDLC level below 1.8 mmol/l turned out to be more effective in slowing down the progression of asymptomatic carotid atherosclerosis in patients with moderate cardiovascular risk than therapy targeted at achieving the LDLC level below 2.6 mmol/l.

[Staged treatment of a multilevel lesion of brachiocephalic arteries in combination with coronary and valvular pathology of the heart]. / Étapnoe lechenie mnogourovnevogo porazheniia brakhiotsefal'nykh arterii v sochetanii s koronarnoi i klapannoi patologiei serdtsa.

Prevention of neurological complications in cardiosurgical and reconstructive vascular surgery is one of the priority tasks of preserving ability to work and decreasing invalidization of patients in the postoperative period. Presented in the article is a clinical case report regarding multiple-stage treatment of a female patient with a combined aortic defect, coronary pathology, and a multilevel bilateral lesion of the brachiocephalic arteries. The first stage consisted in performing a hybrid operation, i. e., carotid endarterectomy from the right internal carotid artery and stenting of the ostium of the right common carotid artery (CCA). The second stage involved balloon angioplasty with stenting of the left CCA, and the third stage was prosthetic repair of the aortic valve by a mechanical prosthesis with simultaneous coronary artery bypass grafting. The woman was discharged in a satisfactory condition. Described in details is the technique of performing the hybrid vascular operation, followed by substantiating the stagewise nature of surgical interventions. The policy chosen demonstrates effective and safe correction of haemodynamically significant tandem stenoses of brachiocephalic arteries, without neurological complications during treatment of patients with cardiological pathology.

Combined orcein and martius scarlet blue (OMSB) staining for qualitative and quantitative analyses of atherosclerotic plaques in brachiocephalic arteries in apoE/LDLR-/- mice.

Numerous cellular and extracellular components should be analyzed in sections of atherosclerotic plaques to assess atherosclerosis progression and vulnerability. Here, we combined orcein (O) staining for elastic fibers and martius scarlet blue (MSB) polychrome to visualize various morphological contents of plaque in brachiocephalic arteries (BCA) of apoE/LDLR-/- mice. Elastic fibers (including broken elastic laminae and 'buried' fibrous caps) were stained purple and they could be easily distinguished from collagen fibers (blue). Orcein allowed clear identification of even the finest elastic fibers. Erythrocytes were stained yellow and they could easily be discerned from mature fibrin (red). Old fibrin tends to acquire blue color. The method of OMSB staining is simple, takes less than 1 h to perform and can be adapted to automatic stainers. Most importantly, the color separation is good enough to allow digital automatic segmentation of specific components in tissue section and quantitative analysis of the plaque constituents. OMSB was used to compare atherosclerotic plaques in proximal and distal regions of BCA in apoE/LDLR-/- mice. In conclusion, OMSB staining represents a novel staining that could be routinely used for qualitative and quantitative microscopic assessments of formaldehyde-fixed and paraffin-embedded sections of arteries with atherosclerotic lesions.

Enlargement of aortic arch vessels after surgical repair of type A aortic dissection.

BACKGROUND: Information on the growth rate of the diameter of the residual dissected supra-aortic trunk after surgical repair of type A aortic dissection is limited. METHODS: We retrospectively reviewed 95 consecutive postsurgical patients with type A aortic dissection (acute, 91; chronic, 4) between 2005 and 2016 who were followed up with computed tomography. The diameter of the residual dissected supra-aortic trunk was measured by axial images and multiplanar reformatting, and the growth rate was calculated. RESULTS: The mean age was 67.2 ± 12.8 years (range, 34-89 years). Forty-one brachiocephalic arteries (43%), 14 left common carotid arteries (15%), and 7 left subclavian arteries (10%) exhibited residual dissection. The diameter of the residual dissected branch with a patent false lumen (FL) gradually increased over time, whereas that with a thrombosed FL decreased and reached a plateau. The growth rate of brachiocephalic, left common carotid, and left subclavian arteries with a patent FL was 1.3 ± 1.2, 0.8 ± 0.3, and 0.6 ± 0.4 mm/y, respectively. One patient required surgical intervention for dilation of the brachiocephalic artery 8 years postoperatively. Multivariate analysis showed that male sex was an independent risk factor for a patent FL in the brachiocephalic artery (P = .0431; odds ratio, 2.04). CONCLUSIONS: A residual dissected supra-aortic trunk with a thrombosed FL seems to be a benign condition. However, long-term follow-up is necessary for patients with a patent FL of residual dissected supra-aortic trunk, which might occasionally require surgical intervention.

Effects of DNA damage in smooth muscle cells in atherosclerosis.

RATIONALE: DNA damage and the DNA damage response have been identified in human atherosclerosis, including in vascular smooth muscle cells (VSMCs). However, although double-stranded breaks (DSBs) are hypothesized to promote plaque progression and instability, in part, by promoting cell senescence, apoptosis, and inflammation, the direct effects of DSBs in VSMCs seen in atherogenesis are unknown. OBJECTIVE: To determine the presence and effect of endogenous levels of DSBs in VSMCs on atherosclerosis. METHODS AND RESULTS: Human atherosclerotic plaque VSMCs showed increased expression of multiple DNA damage response proteins in vitro and in vivo, particularly the MRE11/RAD50/NBS1 complex that senses DSB repair. Oxidative stress-induced DSBs were increased in plaque VSMCs, but DSB repair was maintained. To determine the effect of DSBs on atherosclerosis, we generated 2 novel transgenic mice lines expressing NBS1 or C-terminal deleted NBS1 only in VSMCs, and crossed them with apolipoprotein E(-/-) mice. SM22α-NBS1/apolipoprotein E(-/-) VSMCs showed enhanced DSB repair and decreased growth arrest and apoptosis, whereas SM22α-(ΔC)NBS1/apolipoprotein E(-/-) VSMCs showed reduced DSB repair and increased growth arrest and apoptosis. Accelerating or retarding DSB repair did not affect atherosclerosis extent or composition. However, VSMC DNA damage reduced relative fibrous cap areas, whereas accelerating DSB repair increased cap area and VSMC content. CONCLUSIONS: Human atherosclerotic plaque VSMCs show increased DNA damage, including DSBs and DNA damage response activation. VSMC DNA damage has minimal effects on atherogenesis, but alters plaque phenotype inhibiting fibrous cap areas in advanced lesions. Inhibiting DNA damage in atherosclerosis may be a novel target to promote plaque stability.

Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE-/- Mice.

OBJECTIVE: Inflammatory monocytes/macrophages produce various proteinases, including matrix metalloproteinases, and degradation of the extracellular matrix by these activated proteinases weakens the mechanical strength of atherosclerotic plaques, which results in a rupture of the plaque. Peroxisome proliferator-activated receptor-γ induces a polarity shift of monocytes/macrophages toward less inflammatory phenotypes and has the potential to prevent atherosclerotic plaque ruptures. Therefore, we hypothesized that nanoparticle-mediated targeted delivery of the peroxisome proliferator-activated receptor-γ agonist pioglitazone into circulating monocytes could effectively inhibit plaque ruptures in a mouse model. APPROACH AND RESULTS: We prepared bioabsorbable poly(lactic-co-glycolic-acid) nanoparticles containing pioglitazone (pioglitazone-NPs). Intravenously administered poly(lactic-co-glycolic-acid) nanoparticles incorporated with fluorescein isothiocyanate were found in circulating monocytes and aortic macrophages by flow cytometric analysis. Weekly intravenous administration of pioglitazone-NPs (7 mg/kg per week) for 4 weeks decreased buried fibrous caps, a surrogate marker of plaque rupture, in the brachiocephalic arteries of ApoE(-/-) mice fed a high-fat diet and infused with angiotensin II. In contrast, administration of control-NPs or an equivalent dose of oral pioglitazone treatment produced no effects. Pioglitazone-NPs inhibited the activity of matrix metalloproteinases and cathepsins in the brachiocephalic arteries. Pioglitazone-NPs regulated inflammatory cytokine expression and also suppressed the expression of extracellular matrix metalloproteinase inducer in bone marrow-derived macrophages. CONCLUSIONS: Nanoparticle-mediated delivery of pioglitazone inhibited macrophage activation and atherosclerotic plaque ruptures in hyperlipidemic ApoE(-/-) mice. These results demonstrate a promising strategy with a favorable safety profile to prevent atherosclerotic plaque ruptures.

[Asymptomatic atherosclerosis of the brachiocephalic arteries: Current approaches to diagnosis and treatment]. / Bessimptomnyi ateroskleroz brakhiotsefal'nykh arterii - sovremennye podkhody k diagnostike i lecheniiu.

Acute cerebrovascular accident (ACVA) and transient ischemic attack are among the leading causes of morbidity, disability, and mortality in the Russian Federation and the world. Ischemic strokes account for 70-80% of all ACVAs, with 20-30% of them being associated with stenotic atherosclerosis of the brachiocephalic arteries (BCA). The paper describes modern views on the problem of asymptomatic BCA atherosclerosis and considers the possibilities of identifying risk groups among the patients with asymptomatic atherosclerosis of the BCA.

[The use of high-flow extracranial-intracranial artery bypass in pathology of the cerebral and brachiocephalic arteries: technical features and surgical outcomes]. / Ispol'zovanie metoda obkhodnogo vysokopotochnogo ékstra-intrakranial'nogo arterial'nogo shuntirovaniia pri patologii tserebral'nykh i brakhiotsefal'nykh arteriĭ: tekhnicheskie osobennosti i rezul'taty operatsiĭ.

BACKGROUND: Poor outcomes of surgical treatment for complex cerebral aneurysms due to the development of cerebral ischemia were the cause to use cerebral revascularization surgery for this pathology. OBJECTIVE: the study objective was to master a high-flow extracranial-intracranial (EC-IC) artery bypass technique and evaluate its application in surgical treatment of complex and giant cerebral aneurysms as well as complex lesions of the brachiocephalic arteries. MATERIAL AND METHODS: Fifty two patients underwent high-flow IC-EC bypass surgery; of these, 34 patients had complex cerebral aneurysms, and 18 patients had complex stenotic occlusive lesions of the brachiocephalic arteries. After bypass placement, the patients with aneurysms underwent different variants of aneurysm exclusion (trapping or proximal clipping/ligation of the parent artery). All patients underwent follow-up studies of the bypass function and clinical condition in the early postoperative period and 6 and 12 months after surgery. RESULTS: High-flow IC-EC bypass surgery is routinely used in clinical practice of the Novosibirsk Federal Center of Neurosurgery. Fifty one out of the 52 patients were followed-up in a range of 4 to 56 months. According to the direct or CT angiography data, bypasses functioned in 51 (98.1%) patients in the early and long-term postoperative periods. The clinical efficacy (no ischemic changes and improved cerebral perfusion) of high-flow IC-EC bypasses was demonstrated in 31 (91.2%) of 34 patients with aneurysms and in 17 (94.4%) of 18 patients with complex lesions of the brachiocephalic arteries. The total number of surgical complications was 8 (15.4%) cases: 7 complications occurred in patients with aneurysms, and 1 complication developed in a patient with bilateral ICA occlusion. Of these, ischemic complications developed in 4 (7.7%) cases, hemorrhagic complications occurred in 2 (3.8%) cases, and cranial nerve complications were found in 2 (3.8%) cases. One (1.9%) female patient with a giant aneurysm died from hemispheric stroke due to insufficient blood flow through the bypass. CONCLUSION: Implementation of a large number of surgeries enabled improvement of the technique and clarification of the prerequisites for preoperative examination, intraoperative control, and postoperative management of patients. A low mortalits rate suggests this technique for use in clinical practice. The surgery is indicated for the treatment of giant aneurysms of the petrous, cavernous, and clinoid segments of the ICA. In the case of giant supraclinoid aneurysms, the surgery may be combined with removal of thrombotic masses from the aneurysm sac for rapid decompression of the cranial nerves. Application of this surgery for treatment of giant aneurysms of the trunk and bifurcation of the basilar artery is promising but requires further investigation. The surgery is also recommended for improving cerebral perfusion in the setting of complex stenotic occlusive lesions of the BCA: prolonged BCA stenoses, tandem ICA stenoses located in both the extracranial and intracranial segments, nonspecific vasculitis and arteriitis, subcranial aneurysms, kinking etc.

[Use of a filtering protective device during angioplasty and stenting of the brachiocephalic trunk]. / Primenenie fil'truiushchego zashchitnogo ustroistva pri angioplastike i stentirovanii brakhiotsefal'nogo stvola.

The authors carried out a pilot study aimed at assessing the possibility and efficacy of using filtering systems for protection of cerebral arteries from distal embolism during angioplasty and stenting of the brachiocephalic trunk. A total of five patients presenting with lesions of the brachiocephalic trunk underwent 5 roentgenoendovascular interventions with the use of the filtering protective device Spider FX. Angiographic and clinical success was achieved in 100% of cases. Particles of debris were obtained from the protective device in all cases. All the five patients were found to have symptoms of vertebrobasilar insufficiency. During follow-up in the medium-term period at check examinations the implanted stents were patent, with neither major nor minor neurological complications observed. The patients turned out to be free from cerebrovascular insufficiency relapses. Presented herein are clinical case reports describing technical peculiarities of using the protective device in different variants of the anatomy and vascular lesion.

[Early reconstruction of brachiocephalic arteries as a prevention of recurrent ischemic stroke]. / Ranniaia rekonstruktsiia brakhitsefal'nykh arterii kak profilaktika povtornogo ishemicheskogo insul'ta.

AIM: To assess an efficacy and safety of brachiocephalic arteries reconstruction at the acute stage of stroke. MATERIAL AND METHODS: Early reconstruction of brachiocephalic arteries was made in 7 patients (mean age 67±9 years). Mean terms of brachiocephalic arteries reconstruction after stroke were 4.6 days (range 2-7 days). Pre- and postoperative neurological state was assessed by NIHSS score (mean preoperative score was 3.9±2.7 in these 7 patients, range 0-7). All patients had ipsilateral cerebral ischemic lesions with stenosis/occlusion of brachiocephalic artery. Their mean dimension was 10 mm (range 4-32 mm). Internal carotid artery stenting was made in 2 patients, carotid endarterectomy - in 4 patients, stenting of the 1st segment of left subclavian artery - in 1 patient. RESULTS: There were no deaths and recurrent postoperative ischemic strokes. Complications developed in 2 patients: postoperative hematoma and intraoperative transient ischemic attack during ICA stenting in 5 days after stroke. There was a positive course of neurological state after brachiocephalic arteries reconstruction: mean score of neurological deficit decreased by almost 2 times (from 3.9±2.7 to 2±1.7). CONCLUSION: Early surgical prevention (within 7 days after stroke) may be effective and safe in certain patients with ischemic stroke (neurological deficit by Rankin score ≤3 and NIHSS ≤7, ischemic focus dimension less than 4 cm). Brachiocephalic arteries reconstruction early after stroke improves neurological state postoperatively by reducing motor and sensitive disorders. However, at present time there are no clear indications for early revascularization depending on either neurological deficit severity and ischemic focus dimension. So, our data should be confirmed by large trials.

Endothelial glucocorticoid receptor suppresses atherogenesis--brief report.

OBJECTIVE: The purpose of this study was to determine the role of the endothelial glucocorticoid receptor in the pathogenesis of atherosclerosis. APPROACH AND RESULTS: Control mice and mice lacking the endothelial glucocorticoid receptor were bred onto an Apoe knockout background and subjected to high-fat diet feeding for 12 weeks. Assessment of body weight and total cholesterol and triglycerides before and after the diet revealed no differences between the 2 groups of mice. However, mice lacking the endothelial glucocorticoid receptor developed more severe atherosclerotic lesions in the aorta, brachiocephalic artery, and aortic sinus, as well as a heightened inflammatory milieu as evidenced by increased macrophage recruitment in the lesions. CONCLUSIONS: These data suggest that the endothelial glucocorticoid receptor is important for tonic inhibition of inflammation and limitation of atherosclerosis progression in this model.

[Outcomes of surgical management of patients with nonspecific aortoarteritis with isolated lesion of brachiocephalic arteries]. / Rezul'taty khirurgicheskogo lecheniya bol'nykh nespetsificheskim aortoarteriitom s izolirovannym porazheniem brakhiotsefal'nykh arterii.

The authors analysed herein the results of examination and surgical treatment of patients presenting with Takayasu aortoarteritis with an isolated lesion of the aortic arch branches. Discrepancy between the degree of ischaemia, dissemination, and localization of lesions, as well as ambiguity of neurological manifestations suggests large compensatory possibilities of the cerebral circulation in this disease. The revealed peculiarities of lesions of the brachiocephalic arteries characteristic the pathology concerned were as follows: high incidence of lesions of subclavian arteries (mainly in the second and third segments), utterly rare involvement of the brachiocephalic trunk, a stenosisng pattern of lesion of carotid arteries with predominant localization in the common carotid artery, not involving it into the process of bifurcation. The outcomes of surgical treatment of patients suggest high efficacy of reconstructive operations in the overwhelming majority of the operated patients, also demonstrating considerable advantage of extrathoracic operations as compared with transthoracic ones.

Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes.

BACKGROUND: Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture. METHODS AND RESULTS: We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2(+/+)Ly-6C(high) inflammatory macrophages, but not CCR2(-/-) leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-1), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G(-)CD11b(+) monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated anti-MCP-1 gene therapy reduced the incidence of plaque destabilization and rupture. CONCLUSIONS: The recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture, and nanoparticle-mediated pitavastatin delivery is a promising therapeutic strategy to inhibit plaque destabilization and rupture by regulating MCP-1/CCR2-dependent monocyte recruitment in this model.