Common Carotid Artery Stenosis Research Articles

Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia.

Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBα-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0350-3) contains supplementary material, which is available to authorized users.

Substantial Reduction of Parenchymal Cerebral Blood Flow in Mice with Bilateral Common Carotid Artery Stenosis.

The bilateral common carotid artery stenosis (BCAS) mouse model, which replicates chronic cerebral hypoperfusion and white matter ischemic lesions, is considered to model some aspects of vascular cognitive impairment. Cerebral blood flow (CBF) changes in the brain surface post-BCAS have been demonstrated by laser speckle flowmetry, but CBF levels in the brain parenchyma remain unknown. Adult C57BL/6J male mice were subjected to BCAS using external microcoils. Brain magnetic resonance angiography (MRA) was conducted to visualize the intracranial main arteries while arterial spin labeling (ASL) was used to measure cortical and subcortical parenchymal CBF levels before and after BCAS. Brain MRA showed anterior circulation flow was substantially decreased until 14 days post-BCAS, which gradually but incompletely recovered over the following 14 days, with probable growth of collaterals from the posterior cerebral artery. ASL showed that cortical and subcortical parenchymal CBF remained decreased at approximately 50% of the baseline level during 1 and 14 days post-BCAS, recovering to approximately 70% at day 28. CBF levels in the parenchyma were lower than the cortical superficial region in the BCAS model and remained decreased without recovery during the first 2 weeks post-BCAS. These results suggest that the BCAS model reliably replicates chronic cerebral hypoperfusion.

Necrostatin-1 Attenuates Inflammatory Response and Improves Cognitive Function in Chronic Ischemic Stroke Mice.

Multiple cell death is involved in ischemic brain injury. Necroptosis, a recently reported cell death, may be the most suitable cell death mechanism in a subpopulation of neurons under ischemic injury. It reported that a small molecule, necrostatin-1 (Nec-1), has a potent inhibitory effect on necroptotic cell death in vivo and in vitro. The aim of the current study was to investigate the role of Nec-1 on cognitive function in chronic ischemic stroke mice induced by bilateral common carotid artery stenosis (BCAS). Here, 12-week-old C57BL/6 mice received intragastric administration with Nec-1 or vehicle for two weeks after stroke, and then, the effect and possible mechanism were determined. We demonstrated that inhibition of necroptosis prevented cognitive impairment and reduced inflammatory response in the ischemic brain injury mouse model. These data suggested that inhibition of necroptosis provided a potential therapeutic option for cognitive rehabilitation in chronic ischemic stroke.

Electroacupuncture ameliorates memory impairments by enhancing oligodendrocyte regeneration in a mouse model of prolonged cerebral hypoperfusion

We modeled prolonged cerebral hypoperfusion in mice using bilateral common carotid artery stenosis (BCAS) and electroacupuncture (EA) stimulation was applied at two acupoints, Baihui (GV20) and Dazhui (GV14). In behavioral tests of memory, BCAS produced impairments in spatial and short-term memory in mice that were attenuated by therapeutic EA stimulation. Therapeutic use of EA in BCAS also enhanced oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs), in association with white matter improvements in the corpus callosum (CC). In PCR analyses of growth factor gene expression, significant positive changes in 3 genes were observed following EA stimulation in BCAS, and here we highlight alterations in neurotrophin-4/5 (NT4/5). We confirmed EA-mediated positive changes in the expression of NT4/5 and its receptor, tyrosine receptor kinase B (TrkB). Treatment of naïve and BCAS + EA animals with a selective TrkB antagonist, ANA-12, produced losses of myelin and cognitive function that were ameliorated by EA therapy. Moreover, following BCAS we observed an EA-dependent increase in phospho-activated CREB (a downstream mediator of NT4/5-TrkB signaling) in OPCs and OLs of the CC. Our results suggest that EA stimulation promotes the recovery of memory function following white matter injury via a mechanism that promotes oligodendrocyte regeneration and involves NT4/5-TrkB signaling.

Combined Carotid Endarterectomy and Retrograde Stenting of the Supra-Aortic Trunk: Does Cervical Block Offer Advantages?

Atherosclerosis of the carotid artery is a major source of stroke. In some cases, atherosclerosis occurs at several positions within the carotid artery. Carotid endarterectomy (CEA) in combination with retrograde balloon angioplasty and stenting of a brachiocephalic or common carotid artery stenosis has been described as efficacious and safe procedure to prevent stroke in these cases. The aim of this study was to analyze the impact of anesthetic techniques on hemodynamic factors, operation time, duration of clamping, and postoperative pain. A retrospective analysis of patients undergoing CEA in combination with retrograde stenting under either general anesthesia (GA) or cervical block (CB) was carried out. Preoperative risk factors were analyzed as well as operating and cross-clamping time, hemodynamic factors, perioperative complications, postoperative pain, application of pain killers, and duration of intensive care unit (ICU) and hospital stay. Operating (GA: 193±91min vs. CB: 125±52min, P=0.029) and cross-clamping time (GA: 34±12min vs. CB: 26±9min, P<0.001) were shorter under CB. Patients under CB were hemodynamically more stable and required less norepinephrine (GA: 1.1±0.6mg vs. CB: 0.1±0.1mg, P<0.001) and crystalloids (GA: 2,813±1,173mL vs. CB: 1,088±472mL, P<0.001). Postoperative pain levels (GA: numeric rating scale 4.3/10 vs. 2.0/10; P=0.004) and requirement of pain killers were also lower within the CB group. Synchronous CEA and retrograde balloon angioplasty and stenting of a brachiocephalic or common carotid artery stenosis under CB is associated with reduction of operating and cross-clamping time, improved hemodynamical stability, lower postoperative pain, shorter ICU and hospital stay, and it offers the advantage of a continuous neurological monitoring.

Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles.

Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.

Animal Models of Vascular Cognitive Impairment and Dementia (VCID).

Vascular cognitive impairment and dementia (VCID) is the most common etiology of dementia in the elderly. Both, vascular and Alzheimer's disease, pathologies work synergistically to create neurodegeneration and cognitive impairments. The main causes of VCID include hemorrhage/microbleed (i.e., hyperhomocysteinemia), cerebral small vessel disease, multi-infarct dementia, severe hypoperfusion (i.e., bilateral common carotid artery stenosis), strategic infarct, angiopathy (i.e., cerebral angiopathy), and hereditary vasculopathy (i.e., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). In this review, we will discuss the experimental animal models that have been developed to study these pathologies. We will discuss the limitations and strengths of these models and the important research findings that have advanced the field through the use of the models.

Abstract WP264: Possible Epigenetic Modulation of Cerebral Angiotensin Type 2 Receptor in the Cognitive Function in Vascular Dementia

Introduction: It is well known that activation of angiotensin type 1 (AT1) receptor results in cognitive impairment. In contrast, accumulating evidences suggest that angiotensin II type 2 (AT2) receptor stimulation might prevent cognitive impairment in mice. We recently reported that administration of compound 21, newly developed direct AT2 receptor agonist, improved cognitive decline in the mouse model of vascular dementia induced by bilateral common carotid artery stenosis (BCAS). Cerebral histone deacetylase (HDAC) 2 has been highlighted in terms of epigenetic modulation of cognitive function. These results led us to examine the effects of HDAC on AT2 receptor-mediated improvement of cognitive decline. Methods: Ten-week-old male wild type (WT) (C57BL/6) or AT2 receptor knockout (AT2KO) mice were subjected to BCAS. HDAC inhibitor (SAHA; 25 mg/kg/day) was administrated from 4 weeks after BCAS operation. The Morris water maze task was performed 6 weeks after BCAS operation. HDAC2 and inflammatory cytokine levels in the hippocampus were determined. Cerebral blood flow (CBF) were assessed by laser speckle flowmetry. Results: HDAC2 protein level in the hippocampus did not differ between WT and AT2KO mice at 10 weeks of age, whereas HDAC2 of AT2KO mice at 20 weeks of age was higher compared with that of WT mice. Cognitive impairment after BCAS was more marked in AT2KO mice. Treatment with SAHA attenuated BCAS-induced prolongation of escape latency in the Morris water maze test both in WT and AT2KO mice; however this effect of SAHA was more marked in AT2KO mice. Decrease in CBF after BCAS was not affected by SAHA treatment. Expression of inflammatory cytokine mRNA was increased by BCAS and this increase was attenuated by SAHA treatment. Conclusions: We speculate that modulation of cerebral AT2 receptor could be new therapeutic tool to prevent cognitive impairment via epigenetic abnormalities.

Abstract TMP111: Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans

Rationale: Existing rodent models of vascular cognitive impairment (VCI) show abrupt change in cerebral blood flow (CBF) and do not completely mirror clinical pathogenesis of VCI. Objective: To establish a mouse model of VCI where CBF gradually decreases with subsequent motor and cognitive impairment. Methods and Results: Adult C57BL/6J male mice were subjected to gradual common carotid artery stenosis (GCAS) surgery using an ameroid constrictor (AC) vessel-constricting device with inner diameter of 0.75 mm. The common carotid arteries narrowed gradually after gradual constriction of ACs over 28 days after GCAS, with subsequent 79.3% area stenosis due to smooth muscle cell proliferation and macrophage infiltration in the tunica intima. The 28-day survival rate was 100%. Arterial spin labeling demonstrated gradual and continuous reduction of cortical and subcortical CBF (ratio to the preoperative value) to 54.6% and 51.5%, respectively, over 28 days. However, magnetic resonance angiography showed increment of collateral flow signals in the leptomeningeal artery. Rarefaction and proliferation of astrocytes and microglia with loss of oligodendrocytes was found in the white matter at 32 days. Hippocampal neuronal loss was observed in only 25% of GCAS mice, consistent with lack of abnormalities in the Morris water maze test. The rotarod test showed motor impairment whereas the Y-maze test showed that working memory was impaired. Conclusions: The GCAS model successfully generated gradual and continuous CBF reduction over 28 days, with replication of key histological, radiological, and behavioral features associated with cerebral hypoperfusion leading to VCI.

Abstract WP266: Deficiency of Angiotensin Converting Enzyme 2 Causes Deterioration of Cognitive Function

Introduction: The classical renin-angiotensin system (RAS), known as the angiotensin (Ang) converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, induces various organ damage including cognitive decline. On the other hand, the ACE2/Ang-(1-7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the classical RAS axis in the cardiovascular system. However, the roles of the ACE2/Ang-(1-7)/Mas axis in cognitive function largely remain to be elucidated, and we therefore examined possible roles of ACE2 in cognitive function. Methods: Male 10-week-old C57BL6 (wild-type: WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task to evaluate spatial cognitive function. Vascular dementia model were induced by bilateral common carotid artery stenosis (BCAS). The Morris water maze task was performed 6 weeks after BCAS operation. Results: ACE2KO mice exhibited significant impairment of spatial cognitive function, compared with that in WT mice, without significant difference in cerebral blood flow determined by laser speckle flowmetry and morphological changes in the hippocampus between both strains. Superoxide anion production in the hippocampus tended to be increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit in the hippocampus of ACE2KO compared with WT mice. Protein level of superoxide dismutase (SOD) 3 tended to be decreased in ACE2KO mice compared with WT mice. AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, AT2 receptor mRNA level in the hippocampus did not differ between the two strains. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex, with no significant difference between ACE2KO and WT mice. Brain-derived neurotrophic factor (BDNF) mRNA was lower in the hippocampus in ACE2KO mice compared with WT mice. Escape latency after BCAS was prolonged in WT mice compared with sham operated mice, whereas impaired cognitive function in ACE2 KO mice was not further exaggerated after BCAS. Conclusion: Taken together ACE2 deficiency resulted in impaired cognitive function probably due to enhanced oxidative stress and a decrease in BDNF.

Efficacy of early carotid endarterectomy for vulnerable plaque in the common carotid artery

Dear Editor Steno-occlusive disease in the common carotid artery (CCA) is relatively rare. Clinical and plaque features of CCA stenosis have thus seldom been investigated [6, 7]. We report here a case of refractory ischemia due to mild common carotid artery stenosis treated with carotid endarterectomy (CEA). A 59-year-old Japanese male developed mild right hemiparesis. Ischemic lesions in the left hemisphere due to mild left distal CCA stenosis with vulnerable plaque were revealed on diffusion-weighted imaging (DWI), time-of-flight imaging (TOF), and three-dimensional computed tomography angiography (3DCTA). Oral clopidgrel and rosuvastatin were initiated. Ten months later, symptoms recurred, and DWI revealed new ischemic lesions (Fig. 1a). Oral aspirin was added. TOF showed an increased plaque volume with retention of the lumen (Fig. 1b, c), indicating expansive remodeling. A fibrous cap (Fig. 1b) was disrupted, and the plaque was directly exposed to the lumen (Fig. 1c). The stenosis remained mild on 3DCTA (Fig. 1d, e upper). However, an intraluminal filling defect implied a mobile plaque (Fig. 1e lower). T1-weighted black-blood imaging showed protrusion of a high-intensity plaque into the lumen (Fig. 1f). Intravenous heparin was therefore started. Nevertheless, the third ischemic event occurred 4 days after the second onset. Six days after the third event, CEAwas performed without major perioperative complications. A large amount of fragile plaque with inner fibrous tissues was resected. A portion of the plaque was exposed directly to the lumen (Fig. 1g). No intraluminal thrombus was identified. Histopathological study showed fragile atheroma containing intraplaque hemorrhage. A portion of the inner fibrous tissues was disrupted (Fig. 1h). The patient has not developed further events after 12months of follow-up. Recently, plaque characteristics have been accurately evaluated using MRI [8, 10]. Intraplaque hemorrhage [1, 9], fibrous cap rupture [5, 9], expansive arterial remodeling [4], and a mobile plaque [2, 3] indicate plaque fragility and a higher risk of ischemic events. Steno-occlusive disease of the CCA is rare (1 %–5 % of stroke patients) because extracranial carotid atherosclerotic disease usually arises from the ICA [6, 7]. CCA lesions are supposed to frequently cause amaurosis fugax due to hemodynamic insufficiency [6]. In this case, the patient suffered repeated cerebral embolisms from mild CCA stenosis. A previous study reported that all CCA lesions showed less than 75 % stenosis [7]. However, from this case, we learned a lesson that an extent of stenosis in the CCA is not necessarily correlated with a risk of stroke as seen in the ICA. Although the vessel retains its lumen, the outer circumference might be increasing, which implies increasing plaque volume and vulnerability [4]. In this case, plaque imaging studies suggested plaque fragility and a higher * Yoshio Araki y.araki@med.nagoya-u.ac.jp

Association between Carotid Artery Stenosis and Cognitive Impairment in Stroke Patients: A Cross-Sectional Study.

To investigate potential associations between carotid artery stenosis and cognitive impairment among patients with acute ischemic stroke and to provide important clinical implications. We measured the degree of carotid artery stenosis and recorded the Mini-Mental State Examination score (MMSE) at admission in 3116 acute ischemic stroke patients. The association between carotid stenosis and cognitive impairment assessed by MMSE was tested using multivariate regression analysis. Other clinical variables of interest were also studied. After adjusting for age, gender, education level, marriage, alcohol use, tobacco use, physical activity, hypertension, diabetes, hypercholesterolemia, atrial fibrillation, myocardial infarction and NIHSS (National Institutes of Health Stroke Scale) score, we found that participants with high-grade stenosis of the carotid artery had a higher likelihood of cognitive impairment compared to those without carotid artery stenosis (OR = 1.49, 95%CI: 1.05–2.11, p<0.001). Left common carotid artery stenosis was associated with cognitive impairment in the univariate analysis, although this effect did not persist after adjustment for the NIHSS score. Cognitive impairment was associated with high-grade stenosis of the right carotid artery.

Validity of a Newly Developed Noninvasive Method for Estimating Cerebral Blood Flow Using 123I-IMP Acquisition Data from the Lungs and Brain

Objective: Previously we devised a method for estimating 123I-IMP activity at 10 min after intravenous injection of 123I-IMP (Ca10) without any blood sampling using 123I-IMP autoradiography (ARG) acquisition data, and verified its usefulness for quantification of the regional cerebral blood flow (rCBF). In this study, we attempted to develop a more simplified method for estimation of Ca10 and to validate its usefulness for quantification of rCBF in a number of patients with different cerebrovascular diseases.Methods: Consecutive 134 patients were examined for 123I-IMP ARG study. Dynamic images of the lungs for 5 min and brain SPECT images for 30 min (6×5 min) and Ca 10 values were acquired from the first 35 patients. Using the data of the 35 patients, the regression equation for estimating Ca10 was calculated by the multiple regression analysis. The regression equation was applied to the other 99 patients who comprised 29 patients with Parkinson’s disease, 32 with common or internal carotid artery occlusion or stenosis, 14 with moyamoya disease, 12 with cerebral infarction, and 12 with other diseases. The mean of rCBFs in various regions of the brain (mCBF) calculated using the estimated Ca10 was compared with that calculated using directly measured Ca10 in the 99 patients. Results: The regression equation obtained was as follows: Estimated Ca10 =1070.1 +2.17 ×10-3a-8.08 ∙ b - 2.23 ×c +2.47 ×10-3d, where a: the area under the time-activity curve of the lungs (UCL), b: body weight, c: sum of UCL and the counts of brain projection data from 10 to 15 min after injection (CB1), d: those from 35 to 45 min (CB6), respectively. The estimated Ca10 closely correlated with the directly measured Ca10 (r=077). The mCBF values calculated using the estimated Ca10 closely correlated with those calculated using the directly measured Ca10 in all the patient groups (r=0.80, 0.78, 0.62, 0.77, 0.85 and 0.79 in patients with Parkinson’s disease, common or internal carotid artery occlusion or stenosis, moyamoya disease, cerebral infarction, and the other diseases, and total 99 patients, respectively). Conclusion: This study verified that the newly developed noninvasive method, which is more simplified than the previous method, can estimate reliably the Ca10 values which are available for quantification of rCBF in different patient groups.

The waveform index of the ophthalmic artery predicts impaired coronary flow reserve

BackgroundCoronary flow reserve (CFR) can decrease with impairment in coronary microcirculation, even in the absence of epicardial conduit obstruction. Recently, the ophthalmic artery (OA), which is the first major branch of the internal carotid artery and is representative of microarterioles, has been identified using color Doppler sonography. However, the features of ultrasound waveform indices suggestive of impaired OA microcirculation and the relationships between these indices and CFR have not been elucidated. The present study aimed to assess the features of ultrasound waveform indices suggestive of impaired OA microcirculation and the relationships between these indices and CFR. Methods and resultsA total of 30 consecutive patients with a normal coronary angiogram and normal left ventricular function were studied. Patients with ≥25% stenosis of the right common or internal carotid artery were excluded. The CFR was defined as the ratio of adenosine-induced hyperemic to baseline blood flow velocity with an intracoronary Doppler guidewire. Color Doppler imaging was used to determine the blood flow velocity of the right OA, and the indices of peripheral resistance (resistance index [RI], pulsatility index [PI], and systolic mean velocity to diastolic mean velocity [Sm/Dm] ratio) were calculated. The ultrasound form showed a distinctive biphasic wave during systole followed by a monophasic wave during diastole. The velocity component in the early-systolic wave was higher than that in the mid-systolic wave or the diastolic wave (31.4±5.1 vs. 26.1±5.4 vs. 15.9±4.0cm/s, P<0.0001). The RI and PI were not related to the CFR, and the Sm/Dm ratio was negatively correlated with the CFR (β=−0.415, P=0.022). However, the relationship was attenuated by clinical variables closely associated with the Sm/Dm ratio or CFR, and hemoglobin A1c was a common mediator. The best Sm/Dm ratio cutoff for predicting an impaired CFR was 2.5 based on a receiver operating characteristic curve analysis. ConclusionsAn increase in the Sm/Dm ratio, which reflects a characteristic waveform, indicates impaired OA microcirculation. The ratio is negatively correlated with CFR, and therefore, it may be applied for the noninvasive evaluation of coronary physiology. Furthermore, hemoglobin A1c may be a common mediator for the OA and coronary microcirculation.

Endovascular treatment of carotid artery stenosis: evidences from randomized controlled trials and actual indications

Atherosclerotic stenosis of common and internal carotid arteries is a well-recognized risk factor for ischemic stroke, and revascularization has been proven to be the main tool of prevention, particularly for patients with stenosis-related symptoms. While for many years surgical carotid endarterectomy (CEA) has been considered the gold-standard strategy to restore vascular patency, recently the endovascular treatment through percutaneous angioplasty and stent implantation (CAS) has become a valid alternative. In the last years, interesting data about the comparison of these strategies have emerged. CAS seems to cause more peri-procedural strokes, but may also avoid many adverse events related to surgery and general anaesthesia, including peri-procedural myocardial infarction. For these reasons, it was initially considered a second-choice strategy to be adopted in patients for whom surgery was contraindicated. However, more recent trials have shown that CAS might be considered an effective alternative to CEA. Moreover, the rapid evolution of CAS technique and materials suggests its potential to improve outcome and possible superiority compared to CEA in the next future. Purpose of this review is to discuss the most recent clinical evidences concerning the treatment of carotid artery stenosis, with a special focus on the endovascular treatment.

Low WSS Induces Intimal Thickening, while Large WSS Variation and Inflammation Induce Medial Thinning, in an Animal Model of Atherosclerosis

ObjectiveAtherosclerotic plaque development in the arterial wall is the result of complex interaction between the wall’s endothelial layer and blood hemodynamics. However, the interaction between hemodynamic parameters and inflammation in plaque evolution is not yet fully understood. The aim of the present study was to investigate the relation between wall shear stress (WSS) and vessel wall inflammation during atherosclerotic plaque development in a minipig model of carotid stenosis.MethodsA surgical procedure was performed to create left common carotid artery stenosis by placement of a perivascular cuff in minipigs under atherogenic diet. Animals were followed up on 3T MRI, 1 week after surgery and 3, 6, and 8 months after initiation of the diet. Computational fluid dynamics simulation estimated WSS distribution for the first imaging point. Vascular geometries were co-registered for direct comparison of plaque development and features (Gadolinium- and USPIO-Contrast Enhanced MRI, for permeability and inflammation respectively) with the initial WSS. Histological analysis was performed and sections were matched to MR images, based on spatial landmarks.ResultsVessel wall thickening, permeability and inflammation were observed distally from the stenosis. They were eccentric and facing regions of normal wall thickness. Histological analysis confirmed eccentric plaque formation with lipid infiltration, intimal thickening and medial degradation. High phagocytic activity in the stenosis region was co-localized with high WSS, corresponding to intense medial degradation observed on histology samples.ConclusionLower WSS promotes atherosclerotic plaque development distal to an induced stenosis. Vascular and perivascular inflammation locations were predominant in the high WSS stenosis segment, where medial thinning was the major consequence.

Invited commentary

The authors have presented their results with a hybrid system to treat patients at “high” risk for carotid endarterectomy (CEA) with excellent results. However, comparable outcomes have been reported in similar high-risk patients undergoing CEA or redo CEA, suggesting nonsuperiority of one technique over the other. Among the symptomatic patients in this study, we do not know how many had experienced recent symptoms (≤7 to 14 days) of carotid artery stenting (CAS) as opposed to those with symptoms up to 6 months before CAS. Rantner et al1Rantner B. Goebel G. Bonati L.H. Ringlab P.A. Mas J.L. Fradrich G. The risk of carotid artery stenting compared with CEA is greatest in patients treated within 7 days of symptoms.J Vasc Surg. 2013; 57: 619-626Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar reported that the risk of CAS is greatest ≤7 days of a neurologic event. These patients would be expected to have a higher stroke rate than those with more remote symptoms. Advocates of the transcervical approach argue that avoiding catheter manipulation in the aortic arch is important in decreasing the risks of periprocedural strokes from macroemboli. Microembolic infarcts are seen after CAS with the transfemoral and transcervical approaches. Rapp et al2Rapp J.H. Wakil L. Sawhney R. Pan X.M. Yenari M.A. Glastonbury C. et al.Subclinical embolization after carotid artery stenting: new lesions on diffusion-weighted magnetic resonance imaging occur postprocedure.J Vasc Surg. 2007; 45: 867-874Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar demonstrated that most microembolic infarcts seen on magnetic resonance images (MRIs) are not seen on the initial post-CAS MRI but appear on the 48-hour MRI, suggesting that the microemboli arise from the stent itself. Unfortunately, the authors did not perform pre-CAS and post-CAS MRIs on their patients. Although most microemboli produce no symptoms, microembolic brain infarcts may have subsequent clinical significance. In a case-control study, Purandare et al3Purandare N. Burns A. Daily K.J. Hardicre J. Morrie J. MacFarlane G. et al.Cerebral emboli is a potential cause of Alzheimer's disease and vascular dementia: case-control study.BMJ. 2006; 332: 1119-1125Crossref PubMed Scopus (111) Google Scholar demonstrated a significantly higher incidence of cerebral emboli in patients with Alzheimer disease and vascular dementia compared with controls. Only long-term follow-up will tell us the possible significance of the microembolic brain infarcts frequently observed after CAS. Finally, there are the arterial complications associated with this device. There were eight carotid artery dissections. There was also one case of a severe common carotid artery stenosis caused by a pursestring suture. I suspect that on long-term follow-up, Duplex scans would demonstrate a significant number of common carotid artery stenoses at the site of the pursestring because the proximal common carotid artery is rarely a normal vessel. Only long-term follow-up and more experience will tell us if this device and technique is indeed a better “mousetrap.” I hope that the authors will provide such follow-up in subsequent reports. Results of the ROADSTER multicenter trial of transcarotid stenting with dynamic flow reversalJournal of Vascular SurgeryVol. 62Issue 5PreviewThis report presents the 30-day results of the Safety and Efficacy Study for Reverse Flow Used During Carotid Artery Stenting Procedure (ROADSTER) multicenter trial and evaluates the safety and efficacy of ENROUTE Transcarotid NPS (Silk Road Medical Inc, Sunnyvale, Calif), a novel transcarotid neuroprotection system that provides direct surgical common carotid access and cerebral embolic protection via high-rate flow reversal during carotid artery stenting (CAS). Full-Text PDF Open Archive

Astrocytes Promote Oligodendrogenesis after White Matter Damage via Brain-Derived Neurotrophic Factor.

The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white matter. However, the underlying mechanisms are still mostly unknown. Here, we use a combination of cell biology and an animal model to report a new pathway in which astrocyte-derived BDNF supports oligodendrogenesis and regeneration after white matter damage. These findings provide new mechanistic insight into white matter physiology and pathophysiology, which would be broadly and clinically applicable to CNS disease.

Usefulness of a Transbrachial Guide Sheath Specifically Designed for Direct Common Carotid Artery Cannulation in Common Carotid Artery Stenting

The transfemoral approach is a common technique for carotid artery stenting(CAS)and involves the risk of distal embolism when a high-grade stenosis occurs at the common carotid artery(CCA). In this study, to minimize the risk of thromboembolic complications, we used a guide sheath that was specifically designed for direct cannulation to the CCA without the use of a guidewire or coaxial catheter. This study included 5 patients who underwent CAS of the CCA by using a guide sheath. Of these patients, 2 had right CCA stenosis and the other 3 had left CCA lesions. In all cases, direct cannulation to the target CCA by using the guide sheath was achieved, and CAS was performed safely. The median time from puncture to the end of the procedure was 61 min(interquartile range: 53-63). No periprocedural complications or cardiovascular events occurred within 30 days after CAS. CAS was safely and successfully performed for CCA stenosis by using the transbrachial guide sheath that was specifically designed for direct cannulation to the CCA.

Micro-heterogeneity of flow in a mouse model of chronic cerebral hypoperfusion revealed by longitudinal Doppler optical coherence tomography and angiography.

Although microvascular dysfunction accompanies cognitive decline in aging, vascular dementia, and Alzheimer's disease, tools to study microvasculature longitudinally in vivo are lacking. Here, we use Doppler optical coherence tomography (OCT) and angiography for noninvasive, longitudinal imaging of mice with chronic cerebral hypoperfusion for up to 1 month. In particular, we optimized the OCT angiography method to selectively image red blood cell (RBC)-perfused capillaries, leading to a novel way of assessing capillary supply heterogeneity in vivo. After bilateral common carotid artery stenosis (BCAS), cortical blood flow measured by Doppler OCT dropped to half of baseline throughout the imaged tissue acutely. Microscopic imaging of the capillary bed with OCT angiography further revealed local heterogeneities in cortical flow supply during hypoperfusion. The number of RBC-perfused capillaries decreased, leading to increased oxygen diffusion distances in the days immediately after BCAS. Linear regression showed that RBC-perfused capillary density declined by 0.3% for a drop in flow of 1 mL/100 g per minute, and decreases in RBC-perfused capillary density as high as 25% were observed. Taken together, these results demonstrate the existence of local supply heterogeneity at the capillary level even at nonischemic global flow levels, and demonstrate a novel imaging method to assess this heterogeneity.