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.

Inversão total do fluxo em artéria carótida interna direita em paciente com estenose grave do tronco braquiocefálico / Total reversal of internal carotid blood flow in a patient with severe stenosis of the brachiocephalic trunk

RESUMO As estenoses graves e oclusões do tronco braquiocefálico (artéria inominada) são raras, e apresentam uma grande variedade de manifestações clínicas, com alterações relacionadas a isquemia cerebral hemisférica, vertebrobasilar e de membro superior direito. A causa mais comum é a aterosclerose. A ultrassonografia vascular com Doppler pode revelar inversão de fluxo na artéria vertebral direita, hipofluxo na subclávia, e vários tipos de alterações no fluxo da carótida direita, incluindo hipofluxo, inversão parcial do fluxo durante o ciclo cardíaco, e até mesmo inversão completa do fluxo na carótida interna, achado este bastante raro. Os autores descrevem o caso de paciente do sexo feminino, tabagista, com estenose grave do tronco braquiocefálico e crises de lipotimia. Além do roubo de artéria subclávia e do fluxo parcialmente invertido na carótida comum direita, a paciente apresentava exuberante fluxo invertido na carótida interna durante todo o ciclo cardíaco, achado este não encontrado na literatura em tamanha magnitude.

ABSTRACT Occlusions and severe stenoses of the innominate artery (brachiocephalic trunk) are rare and present with a wide variety of clinical manifestations, with hemispheric, vertebrobasilar and right upper limb ischemic symptoms. The most common cause is atherosclerosis. Duplex scanning may show right vertebral artery flow reversal, diminished subclavian flow, and several patterns of right carotid flow disturbance, including slow flow, partial flow reversal during the cardiac cycle and even complete reversal of flow in the internal carotid artery, which is a very uncommon finding. Herein, the authors describe the case of a female patient who was a heavy smoker, had severe stenosis of the brachiocephalic trunk, and had episodes of collapse. Besides the subclavian steal and partial flow reversal in the common carotid artery, duplex scanning also showed high-velocity reversed flow in the internal carotid artery during the entire cardiac cycle, a finding that is not reported in the literature at this magnitude.

Relaciones anatómicas en el síndrome de compresión traqueal por la arteria innominada: estudio de casos y controles retrospectivo / Anatomical relations in innominate artery compression syndrome: retrospective case-control study

Objetivo. Analizar las distintas relaciones anatómicas entre el tronco braquiocefálico (TB), la tráquea, la columna vertebral y el esternón en pacientes diagnosticados de síndrome de compresión de la arteria innominada (SCAI) y compararlas con las de los pacientes controles. Material y métodos. Estudio retrospectivo de casos y controles de los pacientes diagnosticados de SCAI en nuestro centro, a los que se realizó una tomografía computarizada con contraste (TC) y/o resonancia magnética (RM). Se compararon con pacientes controles, elegidos entre enfermos sin malformación cardiaca ni masa torácica deformante, y a los que se les había realizado una TC vascular torácico por distintos problemas respiratorios no obstructivos. Por cada caso, se seleccionaron tres controles, agrupándolos por grupos de edades. Se estableció p<0,05 como valor de significancia estadística. Resultados. Se incluyeron 9 casos (7 niños y 2 niñas) y 27 controles (20 niños y 7 niñas). Se estudió en cortes transversales de la TC la posición horaria del nacimiento del TB respecto a la tráquea, resultando en los casos una posición mediana correspondiente a las 01:30 (00:30- 03:00) y en los controles a las 01:30 (00:30-02:30), sin hallarse diferencias significativas (p= 0,72). Se midió el ratio entre el diámetro anteroposterior/diámetro transverso de la tráquea, este fue de 0,44 (0,184-0,6) en los casos y 0,885 (0,64-1,16) en los controles (p=0,00001). El ratio de la distancia esternón-tráquea/esternón-columna fue 0,685 (0,6-0,76) en los casos y 0,67 (0,49-0,79) en los controles (p=0,75). El ángulo de la cifosis torácica fue 29º (9-34) en los casos y 24º (4-33) en los controles (p=0,45). Conclusiones. No observamos la existencia de diferencias en el nacimiento del TB en pacientes con SCAI respecto a la población general. El TB nace en todos los niños en el lado izquierdo del cuerpo, poniendo en duda que el SCAI sea debido a un nacimiento más izquierdo del TB

Objective. To compare the anatomical relations between brachioce-phalic trunk (BT), trachea, spine and sternum in patients with Innominate Artery Compressing Syndrome (IACS) and control patients. Methods. Retrospective case-control study of patients diagnosed with IACS in our center, in whom vascular computerized tomography (CT) was performed. The CT were compared with those of control patients free of obstructive respiratory pathology, without congenital heart disease and free of deforming thoracic mass, in whom CT was performed due to other reason. Each case was paired with three controls per case, in similar age groups. The significance value was set as p<0,05.Results. Nine cases were included (7 boys and 2 girls) with their 27 respective controls (20 boys and 7 girls). The BT origin position with respect to the trachea, thought as a clock face, was 01:30 (00:30- 03:00) in cases and 01:30 (00:30-02:30) in controls. No differences were observed (p=0.72). The relation between anteroposterior/transversal tracheal diameters was 0.44 (0.184-0.6) in cases, 0.885 (0.64-1.16) in controls. The sternum-trachea/sternum-vertebra relation was 0.685 (0.6-0.76) in cases, 0.67 (0.49-0.79) in controls. No differences were observed (p=0.75). The angle of thoracic kyphosis was 29º (9º-34º) in cases, 24º (4º-33º) in controls. There were no statistically significant differences (p=0.45). Conclusions. We found no differences between the two groups in the BT origin in relation to the trachea. In all cases, the origin was on the left side of the body. Therefore, we question the premise that IACS is due to a more left origin of BT

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.

Innominate artery pathology in the setting of aortic arch surgery: incidences, surgical considerations and operative outcomes.

OBJECTIVES: The aim of the study was to evaluate the incidences of innominate artery (IA) involvement in aortic arch pathology necessitating surgery, the surgical strategies and the operative results. METHODS: Among the 366 patients who underwent total/subtotal arch replacement because of non-acutely dissected aortic pathology between 2004 and June 2017, there were 46 (12.6%) patients (29 males; mean age 69 ± 10, range 35-84 years) with IA involvement. Pathologies necessitating replacement of the IA were chronic aneurysm including progression of chronic dissection, severe atherosclerosis with or without an aneurysmatic dilatation, and inflammatory vasculitis in 34, 11 and 1 patient, respectively. All data were collected prospectively, and intention-to-treat analysis was performed. RESULTS: All patients underwent total/subtotal aortic arch replacement using unilateral cerebral perfusion (mean duration 44.6 ± 15.7 min) under mild hypothermia (30.6 ± .4°C). In addition to arch and IA replacement, repair of one or two further supra-aortic arteries was performed in 20 and 23 patients, respectively. One patient underwent complete thoracic aorta replacement via clamshell thoracotomy. The aortic valve, which was the most frequent object of concomitant surgery, was replaced in 18 (including 3 valve composite-grafts) and repaired in 20 (18 valve-sparing root repairs) patients. Early (30-day and/or in-hospital) mortality was 0. The rate of permanent neurological deficit was 2.2% (1 patient with a huge, partially thrombosed arch and innominate aneurysm). Transient neurological dysfunctions such as agitation were observed in 6 patients. CONCLUSIONS: Involvement of the IA in aortic arch surgery is not infrequent, and its concomitant replacement using well-considered cannulation, perfusion and surgical strategy offers excellent operative outcomes.

PACAP deficiency aggravates atherosclerosis in ApoE deficient mice.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) plays an important role in cytoprotection, inflammation and cardiovascular regulation. Thus, we studied the involvement of PACAP in atherogenesis. Differentiated human THP-1 macrophages (MΦ) were stimulated with oxidized low-density lipoproteins (oxLDL) and the influence of PACAP38 treatment on lipid content and TNF release was determined. To test the effect of PACAP deficiency (PACAP-/-) on the development of atherosclerosis under standard chow (SC) or cholesterol-enriched diet (CED) in vivo, PACAP-/- mice were crossbred with ApoE-/- to generate PACAP-/-/ApoE-/- mice. Blood cholesterol and triglyceride levels were quantified. Lumen stenosis in the brachiocephalic trunk, cellularity and amounts of pro-inflammatory as well as autophagy-, apoptosis- and necroptosis-relevant proteins were analysed in atherosclerotic plaques by quantitative immunohistochemistry. In vitro, PACAP38 inhibited oxLDL-induced intracellular lipid storage as well as TNF release in MФ. In vivo, after SC, but not under CED, PACAP-/-/ApoE-/- mice showed an increased lumen stenosis compared to ApoE-/- mice. In atherosclerotic plaques of PACAP-/-/ApoE-/- mice, the immunoreactive areas of TNF+, IL-1ß+, autophagic, apoptotic and necroptotic cells were increased. In contrast, the overall cell density was decreased compared to ApoE-/- under SC, while no differences were seen under CED. Similar plasma cholesterol levels were observed in PACAP-/-/ApoE-/- and ApoE-/- mice under the respective feeding regime. Thus, PACAP-/-/ApoE-/- mice represent a novel mouse model of accelerated atherosclerosis where CED is not required. Our data indicate that PACAP acts as an endogenous atheroprotective neuropeptide. Thus, stable PACAP agonists may have potential as anti-atherosclerotic therapeutics. The specific PACAP receptor(s) mediating atheroprotection remain(s) to be identified.

[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.

A diet enriched with tree nuts reduces severity of atherosclerosis but not abdominal aneurysm in angiotensin II-infused apolipoprotein E deficient mice.

BACKGROUND AND AIMS: Diets enriched with tree nuts have been demonstrated to reduce the risk of atherosclerosis-related cardiovascular events. Abdominal aortic aneurysm (AAA) shares common risk factors with atherosclerosis and AAA patients commonly have atherosclerosis related cardiovascular events. AAA has some distinct pathological and clinical characteristics to those of atherosclerosis. No previous study has examined the effect of a diet enriched with tree nuts on experimental or clinical AAA. This study investigated the effect of a diet enriched with tree nuts on the development and severity of AAA within an experimental rodent model. METHODS: Male apolipoprotein E deficient mice were allocated to a diet enriched with tree nuts or control diet for 56 days (n = 17 per group). After 28 days, all mice were infused with angiotensin II whilst being maintained on their respective diets. The primary outcome was AAA severity assessed by the supra-renal aortic diameter, measured by ultrasound and ex vivo morphometric analysis. The severity of atherosclerosis was assessed by computer-aided analysis of Sudan IV stained aortic arches and sections of brachiocephalic arteries prepared with Van Gieson's stain. RESULTS: The diet enriched with tree nuts did not influence aortic diameter or aortic rupture incidence. Mice receiving the diet enriched with tree nuts had significantly less atherosclerosis within the brachiocephalic artery (p = 0.033) but not in the aortic arch. CONCLUSIONS: This experimental study suggests that a diet enriched with tree nuts does not reduce the severity of AAA, but does reduce the severity of atherosclerosis within the brachiocephalic artery. The study was not powered to identify a moderate effect of the diet on the primary outcome and therefore this cannot be excluded.

Irradiation abolishes smooth muscle investment into vascular lesions in specific vascular beds.

The long-term adverse effects of radiotherapy on cardiovascular disease are well documented. However, the underlying mechanisms responsible for this increased risk are poorly understood. Previous studies using rigorous smooth muscle cell (SMC) lineage tracing have shown abundant SMC investment into atherosclerotic lesions, where SMCs contribute to the formation of a protective fibrous cap. Studies herein tested whether radiation impairs protective adaptive SMC responses during vascular disease. To do this, we exposed SMC lineage tracing (Myh11-ERT2Cre YFP+) mice to lethal radiation (1,200 cGy) followed by bone marrow transplantation prior to atherosclerosis development or vessel injury. Surprisingly, following irradiation, we observed a complete loss of SMC investment in 100% of brachiocephalic artery (BCA), carotid artery, and aortic arch lesions. Importantly, this was associated with a decrease in multiple indices of atherosclerotic lesion stability within the BCA. Interestingly, we observed anatomic heterogeneity, as SMCs accumulated normally into lesions of the aortic root and abdominal aorta, suggesting that SMC sensitivity to lethal irradiation occurs in blood vessels of neural crest origin. Taken together, these results reveal an undefined and unintended variable in previous studies using lethal irradiation and may help explain why patients exposed to radiation have increased risk for cardiovascular disease.

[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.

[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.

In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR-/-ApoB100/100 mice.

AIMS: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease. METHODS & RESULTS: IGF-II/LDLR-/-ApoB100/100 mice were generated by crossbreeding low-density lipoprotein receptor-deficient mice that synthesize only apolipoprotein B100 (LDLR-/-ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic ß cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment with the nuclear factor of activated T-cells blocker A-285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGF-II/LDLR-/-ApoB100/100 mice, as assessed non-invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of nuclear factor of activated T-cells was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells. CONCLUSION: Targeting the nuclear factor of activated T-cells signalling pathway may be an attractive approach for the treatment of diabetic macrovascular complications.

Fatal innominate artery hemorrhage in a patient with tetraplegia: Case report and literature review.

Context Hemorrhage is one of the potentially fatal complications of tracheostomy. A rare but lethal cause of tracheostomy related bleeding is hemorrhage from the innominate artery. This occurs following tracheo-innominate artery fistula (TIF) formation, which is associated with a mortality rate of more than 85%. Here, we report the case of an individual with tetraplegia and a tracheostomy who died as a result of innominate artery hemorrhage. This case highlights the possible causes and interventions associated with this complication, and provides insight into tracheostomy related bleeding in patients with spinal cord injury (SCI). Findings A 15-year-old boy with a diagnosis of incomplete SCI at the C5 level was admitted for rehabilitation 4 months after injury. He required a tracheostomy for ventilation, and underwent subglottic stenosis dilatation thrice. Multiple decannulation attempts were performed without success. He received intensive care on several occasions for respiratory failure. During the course of his rehabilitation, a minimal tracheostomy bleed was observed, which became profuse within a few hours and led to hypoxia with loss of consciousness. An urgent sternotomy identified bleeding from a TIF. He suffered severe brain damage following massive tracheal hemorrhage and died. Conclusion/clinical relevance Given the morbidity of TIF-related hemorrhage, it is important to increase awareness of this rare condition among health-care providers, especially those in non-acute settings. Patients with SCI and a tracheostomy pose unique challenges related to respiratory compromise, which may accentuate TIF formation.

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.

Bovine aortic arch: clinical significance and hemodynamic evaluation.

OBJECTIVE: The most common aortic arch branching variation described in literature is the common origin of the brachiocephalic trunk and left common carotid artery ("bovine arch" / type II aortic arch), with an incidence of 7.2-21.1%. The first aim of this study was to investigate the prevalence of bovine arch in the fetuses. The second aim was the hemodynamic evaluation of the epiaortic vessels. METHODS: In two years we examined 742 pregnant women and it was possible to obtain a good hemodynamic evaluation in 39 patients. Among the 39 fetuses, we found 6 with bovine arch. The blood flow of all epiaortic vessels and of MCA was evaluated. RESULTS: Among the 742 fetuses examined, the bovine aortic arch was identified in 45 patients (6.06%). The hemodynamic evaluation of the epiaortic vessels showed statistically significant differences between the bovine arch and normal aortic arch. CONCLUSION: The presence of bovine aortic arch in the fetus is characterized by some hemodynamical differences. They could have a possible relationship with the incidence of some pathologies in adult life. Prenatal knowledge of anatomic variants of the aortic arch can bring benefits to the individual's health for future possible cardiovascular investigations.

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.