Can Internal Carotid Arteries Be Used for Noninvasive Quantification of Brain PET Studies?

Because of the limited axial field of view of conventional PET scanners, the internal carotid arteries are commonly used to obtain an image-derived input function (IDIF) in quantitative brain PET. However, time-activity curves extracted from the internal carotids are prone to partial-volume effects due to the limited PET resolution. This study aimed to assess the use of the internal carotids for quantifying brain glucose metabolism before and after partial-volume correction. Methods: Dynamic [18F]FDG images were acquired on a 106-cm-long PET scanner, and quantification was performed with a 2-tissue-compartment model and Patlak analysis using an IDIF extracted from the internal carotids. An IDIF extracted from the ascending aorta was used as ground truth. Results: The internal carotid IDIF underestimated the area under the curve by 37% compared with the ascending aorta IDIF, leading to Ki values approximately 17% higher. After partial-volume correction, the mean relative Ki differences calculated with the ascending aorta and internal carotid IDIFs dropped to 7.5% and 0.05%, when using a 2-tissue-compartment model and Patlak analysis, respectively. However, microparameters (K 1, k 2, k 3) derived from the corrected internal carotid curve differed significantly from those obtained using the ascending aorta. Conclusion: These results suggest that partial-volume-corrected internal carotids may be used to estimate Ki but not kinetic microparameters. Further validation in a larger patient cohort with more variable kinetics is needed for more definitive conclusions.

Plasticity of the bony carotid canal and its clinical use for assessing negative remodeling of the internal carotid artery.

BACKGROUND AND OBJECTIVE: It has long been believed that the bony carotid canal has no plasticity and that a small canal represents a hypoplastic internal carotid artery. We aimed to show whether the carotid canal can narrow according to morphological changes in the internal carotid artery. MATERIALS AND METHODS: The carotid canal diameter was longitudinally measured in seven individuals who underwent carotid artery ligation. As moyamoya disease is known to be associated with negative remodeling of the internal carotid artery, the carotid canal diameter was measured in 106 patients with moyamoya disease, and an association with the outer diameter of the internal carotid artery or a correlation with the disease stage was investigated. The carotid canal was measured by computed tomography (106 patients), and the outer diameter of the artery was measured by high-resolution magnetic resonance imaging (63 patients). The carotid canal area was calculated by the product of the maximum axial diameter and its perpendicular diameter. RESULTS: All seven patients who underwent carotid artery ligation showed narrowing of the carotid canal, and the carotid canal area decreased by 12.2%-28.9% during a mean follow-up period of 4.2 years. In patients with moyamoya disease, the carotid canal area showed a linear correlation with the outer area of the internal carotid artery (r = 0.657, p < 0.001), and a negative correlation with the disease stage (ρ = -0.283, p < 0.001). CONCLUSION: The bony carotid canal has plasticity, and its area reflects the outer area of the internal carotid artery, therefore, it can be used to assess the remodeling of the carotid artery. A narrow carotid canal may not necessarily indicate hypoplastic internal carotid artery.

Crossed Cerebellar Diaschisis Indicates Hemodynamic Compromise in Ischemic Stroke Patients.

Crossed cerebellar diaschisis (CCD) in internal carotid artery (ICA) stroke refers to attenuated blood flow and energy metabolism in the contralateral cerebellar hemisphere. CCD is associated with an interruption of cerebro-cerebellar tracts, but the precise mechanism is unknown. We hypothesized that in patients with ICA occlusions, CCD might indicate severe hemodynamic impairment in addition to tissue damage. Duplex sonography and clinical data from stroke patients with unilateral ICAO who underwent blood oxygen-level-dependent MRI cerebrovascular reserve (BOLD-CVR) assessment were analysed. The presence of CCD (either CCD+ or CCD-) was inferred from BOLD-CVR. We considered regions with negative BOLD-CVR signal as areas suffering from hemodynamic steal. Twenty-five patients were included (11 CCD+ and 14 CCD-). Stroke deficits on admission and at 3 months were more severe in the CCD+ group. While infarct volumes were similar, CCD+ patients had markedly larger BOLD steal volumes than CCD- patients (median [IQR] 122.2 [111] vs. 11.6 [50.6] ml; p < 0.001). Furthermore, duplex revealed higher peak-systolic flow velocities in the intracranial collateral pathways. Strikingly, posterior cerebral artery (PCA)-P2 velocities strongly correlated with the National Institute of Health Stroke Scale on admission and BOLD-CVR steal volume. In patients with strokes due to ICAO, the presence of CCD indicated hemodynamic impairment with larger BOLD-defined steal volume and higher flow in the ACA/PCA collateral system. Our data support the concept of a vascular component of CCD as an indicator of hemodynamic failure in patients with ICAO.

Role of Magnetic Resonance Spectroscopy in Evaluation of Cerebral Metabolic Status Before and After Carotid Endarterectomy/Thromboendarterectomy and Carotid Artery Stenting in Patients with Asymptomatic Critical Internal Carotid Artery Stenosis.

BACKGROUND The relative efficacy of carotid endarterectomy (CEA)/thromboendarterectomy (TEA) and carotid artery stenting (CAS) already has been compared in randomized controlled trials and a meta-analysis, but only limited data exist describing the status of cerebral metabolism before and after these interventions. The aim of the present study was to compare metabolic changes before and after treatment of carotid stenosis and assess their potential clinical implications.   MATERIAL AND METHODS Patients with asymptomatic unilateral critical internal CAS were imaged with proton 3T magnetic resonance spectroscopy (H-MRS) because the technique is more sensitive than regular magnetic resonance imaging for detection of the early signs of ischemic events. Abnormal metabolite ratios detected with H-MRS may precede actual morphological changes associated with hypoperfusion as well as reperfusion changes. Ipsilateral and contralateral middle cerebral artery vascular territories were both evaluated before and after vascular intervention. H-MRS was performed within 24 h before and after surgery. Correlations in the metabolic data from H-MRS for N-acetylaspartic acid (NAA)+N-acetylaspartylglutamate, creatinine (Cr)+phosphocreatinine, and phosphocholine+glycerophosphocholine (Cho) were sought. RESULTS H-MRS voxels from 11 subjects were analyzed. Values for dCho/CrI, dCho/CrC and Cho/Naal (P<0.001) were significantly higher ipsilaterally than contralaterally. Ratios for dNaa/ChoC and Cho/NaaC were significantly higher on the non-operated side (P<0.001). CONCLUSIONS H-MRS may be helpful for assessment of patients with CAS, particularly because unlike other modalities, it reveals postoperative changes in metabolic brain status. Initial results indicate the important role of perioperative neuroprotective treatment.

[Surgical treatment of internal carotid artery kinking following fibromuscular dysplasia]. / Rezul'taty khirurgicheskogo lecheniya patologicheskoi izvitosti vnutrennei sonnoi arterii na fone fibrozno-myshechnoi displazii.

OBJECTIVE: To evaluate the results of surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. MATERIAL AND METHODS: There were 32 patients who underwent surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. Structural changes of carotid artery wall were analyzed using immunohistochemical survey. Considering destructive changes revealed, we divided all patients into 2 groups in order to assess long-term postoperative outcomes: 1 - ICA resection followed by anastomosis in end-to-end fashion; 2 - ICA replacement. Postoperative analysis included incidence of stroke, thrombosis and deformities of anastomosis zone, regression of cerebrovascular insufficiency. RESULTS: The main «phenotype¼ of arterial wall in patients with ICA kinking following fibromuscular dysplasia is a large number of smooth muscle cells releasing matrix matelloproteinases-2 and -9 and low level of their tissue inhibitor type 1. Postoperative deformities are more common within a year after surgery. Maximum incidence is observed after 12 months. Both ICA resection and replacement are followed by similar incidence of deformity later. No severe deformities were diagnosed. Resection of ICA kinking on the background of fibromuscular dysplasia is followed by comparable results with ICA replacement regarding the incidence stroke, thrombosis and regression of cerebrovascular insufficiency. CONCLUSION: Despite degradation of extracellular matrix, destruction of elastic fibers and their fragmentation, no significant deformities are observed in long-term postoperative period in patients with ICA kinking and fibromuscular dysplasia.

Multifocal arterial wall contrast - enhancement in ischemic stroke: A mirror of systemic inflammatory response in acute stroke.

PURPOSE: Intracranial plaque gadolinium enhancement revealed by high-resolution MRI imaging (HR MRI) is considered as a marker of plaque inflammation, a contributing factor of plaque unstability. The aim of the present study was to assess the distribution of gadolinium enhancement in intracranial atherosclerosis. METHODS: Single center analysis of ischemic stroke patients with intracranial atherosclerotic stenosis of M1 or M2 segments of middle cerebral artery, or terminal internal carotid artery (ICA) based on CT-angio or MR-angio. High-resolution MRI imaging (HRMRI) was performed within 6 first weeks following the index event, with 3DT2 BB (black-blood) and 3D T1 BB MR sequences pre and post-contrast administration. RESULTS: We identified 8 patients with 14 plaques, 4 were deemed non-culprit and 10 culprit. All culprit plaques (10/10 plaques) and 3 out of 4 non-culprit plaques showed a gadolinium enhancement. CONCLUSION: At the acute/subacute stage of stroke, a gadolinium enhancement may affect multiple asymptomatic intracranial plaques and may reflect a global inflammatory state.

Steady-state cerebral blood flow regulation at altitude: interaction between oxygen and carbon dioxide.

High-altitude ascent imposes a unique cerebrovascular challenge due to two opposing blood gas chemostimuli. Specifically, hypoxia causes cerebral vasodilation, whereas respiratory-induced hypocapnia causes vasoconstriction. The conflicting nature of these two superimposed chemostimuli presents a challenge in quantifying cerebrovascular reactivity (CVR) in chronic hypoxia. During incremental ascent to 4240 m over 7 days in the Nepal Himalaya, we aimed to (a) characterize the relationship between arterial blood gas stimuli and anterior, posterior and global (g)CBF, (b) develop a novel index to quantify cerebral blood flow (CBF) in relation to conflicting steady-state chemostimuli, and (c) assess these relationships with cerebral oxygenation (rSO2). On rest days during ascent, participants underwent supine resting measures at 1045 m (baseline), 3440 m (day 3) and 4240 m (day 7). These measures included pressure of arterial (Pa)CO2, PaO2, arterial O2 saturation (SaO2; arterial blood draws), unilateral anterior, posterior and gCBF (duplex ultrasound; internal carotid artery [ICA] and vertebral artery [VA], gCBF [{ICA + VA} × 2], respectively) and rSO2 (near-infrared spectroscopy). We developed a novel stimulus index (SI), taking into account both chemostimuli (PaCO2/SaO2). Subsequently, CBF was indexed against the SI to assess steady-state cerebrovascular responsiveness (SS-CVR). When both competing chemostimuli are taken into account, (a) SS-CVR was significantly higher in ICA, VA and gCBF at 4240 m compared to lower altitudes, (b) delta SS-CVR with ascent (1045 m vs. 4240 m) was higher in ICA vs. VA, suggesting regional differences in CBF regulation, and (c) ICA SS-CVR was strongly and positively correlated (r = 0.79) with rSO2 at 4240 m.

Vagal baro- and chemoreceptors in middle internal carotid artery and carotid body in rat.

The glossopharyngeal nerve, via the carotid sinus nerve (CSN), presents baroreceptors from the internal carotid artery (ICA) and chemoreceptors from the carotid body. Although neurons in the nodose ganglion were labelled after injecting tracer into the carotid body, the vagal pathway to these baro- and chemoreceptors has not been identified. Neither has the glossopharyngeal intracranial afferent/sensory pathway that connects to the brainstem been defined. We investigated both of these issues in male Sprague-Dawley rats (n = 40) by injecting neural tracer wheat germ agglutinin-horseradish peroxidase into: (i) the peripheral glossopharyngeal or vagal nerve trunk with or without the intracranial glossopharyngeal rootlet being rhizotomized; or (ii) the nucleus of the solitary tract right after dorsal and ventral intracranial glossopharyngeal rootlets were dissected. By examining whole-mount tissues and brainstem sections, we verified that only the most rostral rootlet connects to the glossopharyngeal nerve and usually four caudal rootlets connect to the vagus nerve. Furthermore, vagal branches may: (i) join the CSN originating from the pharyngeal nerve base, caudal nodose ganglion, and rostral or caudal superior laryngeal nerve; or (ii) connect directly to nerve endings in the middle segment of the ICA or to chemoreceptors in the carotid body. The aortic depressor nerve always presents and bifurcates from either the rostral or the caudal part of the superior laryngeal nerve. The vagus nerve seemingly provides redundant carotid baro- and chemoreceptors to work with the glossopharyngeal nerve. These innervations confer more extensive roles on the vagus nerve in regulating body energy that is supplied by the cardiovascular, pulmonary and digestive systems.

Metabolic profiling of intra- and extracranial carotid artery atherosclerosis.

BACKGROUND AND AIMS: Increasing evidence shows that intracranial carotid artery atherosclerosis may develop under the influence of a differential metabolic risk factor profile than atherosclerosis in the extracranial part of the carotid artery. To further elucidate these differences, we investigated associations of a wide range of circulating metabolites with intracranial and extracranial carotid artery atherosclerosis. METHODS: From the population-based Rotterdam Study, blood samples from 1111 participants were used to determine a wide range of metabolites by proton nuclear magnetic resonance (NMR). Moreover, these participants underwent non-contrast computed tomography of the neck and head to quantify the amount of extra- and intracranial carotid artery calcification (ECAC and ICAC), as a proxy of atherosclerosis. We assessed associations of the metabolites with ICAC and ECAC and compared the metabolic association patterns of the two. RESULTS: We found that one standard deviation (SD) increase in concentration of 3-hydroxybutyrate, a ketone body, was significantly associated with a 0.11 SD increase in ICAC volume (p = 1.8 × 10-4). When we compared the metabolic association pattern of ICAC with that of ECAC, we observed differences in glycolysis-related metabolite measures, lipoprotein subfractions, and amino acids. Interestingly, glycoprotein acetyls were associated with calcification in both studied vessel beds. These associations were most prominent in men. CONCLUSIONS: We found that a higher circulating level of 3-hydroxybutyrate was associated with an increase in ICAC. Furthermore, we found differences in metabolic association patterns of ICAC and ECAC, providing further evidence for location-specific differences in the etiology of atherosclerosis.

Blunted shear-mediated dilation of the internal but not common carotid artery in response to lower body negative pressure.

Shear-mediated dilation in peripheral conduit arteries is blunted with sympathetic nervous system (SNS) activation; however, the effect of SNS activation on shear-mediated dilation in carotid arteries is unknown. We hypothesized that SNS activation reduces shear-mediated dilation in common and internal carotid arteries (CCA and ICA, respectively), and this attenuation is greater in the ICA compared with the CCA. Shear-mediated dilation in the CCA and ICA were measured in nine healthy men (24 ± 1 yr) with and without SNS activation. Shear-mediated dilation was induced by 3 min of hypercapnia (end-tidal partial pressure of carbon dioxide +10 mmHg from individual baseline); SNS activity was increased with lower body negative pressure (LBNP; -20 mmHg). CCA and ICA measurements were made using Doppler ultrasound during hypercapnia with (LBNP) or without (Control) SNS activation. LBNP trials began with 5 min of LBNP with subjects breathing hypercapnic gas during the final 3 min. Shear-mediated dilation was calculated as the percent rise in peak diameter from baseline diameter. Sympathetic activation attenuated shear-mediated dilation in the ICA (Control vs. LBNP, 5.5 ± 0.7 vs. 1.8 ± 0.4%, P < 0.01), but not in the CCA (5.1 ± 1.2 vs. 4.2 ± 1.0%, P = 0.31). Moreover, absolute reduction in shear-mediated dilation via SNS activation was greater in the ICA than the CCA (-3.6 ± 0.7 vs. -0.9 ± 0.8%, P = 0.02). Our data indicate that shear-mediated dilation is attenuated during LBNP to a greater extent in the ICA compared with the CCA. These results potentially provide insight into the role of SNS activation on cerebral perfusion, as the ICA is a key supplier of blood to the brain. NEW & NOTEWORTHY We explored the effect of acute sympathetic nervous system (SNS) activation on shear-mediated dilation in the common and internal carotid arteries (CCA and ICA, respectively) in young healthy men. Our data demonstrate that hypercapnia-induced vasodilation of the ICA is attenuated during lower body negative pressure to a greater extent than the CCA. These data may provide novel information related to the role of SNS activation on cerebral perfusion in humans.

Diameter of fluorescent microspheres determines their distribution throughout the cortical watershed area in mice.

A hemodynamic mechanism has long been assumed to play an important role in watershed infarction. In recent years, however, clinical evidence has indicated that an embolic mechanism is involved. The mechanism by which emboli are trapped preferentially in watershed areas remains unclear. In the present study, we developed a mouse embolus model using fluorescent microspheres with different diameters and evaluated the role of the microspheres' diameters in the generation of a watershed-patterned distribution. We injected fluorescent microspheres of four different diameters (i.e., 13, 24, 40, and 69 µm) into the internal carotid artery of C57BL/6 mice either (1) without ligation of the common carotid artery (normal perfusion pressure model: NPPM) or (2) with ligation of the common carotid artery (low perfusion pressure model: LPPM). Left common carotid artery ligation induced reductions in local cerebral blood flow in both the periphery and the core area of the left middle cerebral artery. A greater reduction in the border-zone area between the left anterior cerebral artery and the middle cerebral artery was also noted. After 24 h, the brains were removed and the distribution of the microspheres in the brain was evaluated using a fluorescence microscope. The 24-µm microspheres were distributed in the watershed area more frequently than the other microsphere sizes (P < .05, ANOVA followed by Tukey's test). Meanwhile, the distribution rates were similar between the NPPM and LPPM models for all microsphere sizes. This study suggested that the distribution pattern of the microspheres was only affected by the microspheres' diameters.

Repeated measurements of serum concentrations of TNF-alpha, interleukin-6 and interleukin-10 in the evaluation of internal carotid artery stenosis progression.

BACKGROUND AND AIMS: The inflammatory process (with TNFα, interleukin-6 and interleukin-10 involvement) plays a key role in the development, progression and destabilization of atherosclerotic plaques. The aim of this study was to assess the importance of double-checked measurements of TNFα, interleukin-6 (IL-6) and interleukin-10 (Il-10) serum levels in patients with internal carotid artery (ICA) stenosis to determine the dynamics of changes in the stenosis degree and in the ultrasound plaque morphology. METHODS: The study included 65 patients with ICA stenosis. Ultrasound of the carotid arteries was performed during qualification and every 3 months to identify any progression of stenosis degree and dynamics of changes in plaque morphology. Serum concentrations of TNF-alpha, IL-6 and IL-10 were measured during qualification and at month 6 of the study. Calculations considered cytokine concentrations and their indices determined as relative differences of cytokine levels assessed in the first and in second tests. RESULTS: Patients with increasing degree of ICA stenosis had higher indices of IL-6 and IL-10 than patients without any increase in the stenosis degree. In patients with unfavorable dynamics of changes in plaque morphology, significantly higher levels of interleukin-6 were found in the second test; these patients had higher indices of IL-6 and IL-10 than patients with favorable dynamics of atherosclerotic plaque morphology on ultrasound. CONCLUSIONS: Long-term trends in serum concentrations of IL-6 and IL-10 in patients with ICA stenosis allow to predict the progression of the degree of stenosis and the unfavorable change of atherosclerotic plaque morphology.

Agenesia de arteria carótida interna en paciente con hipopituitarismo congénito / Internal carotid artery agenesis in a patient with congenital hypopituitarism

No disponible

ß1-Blockade increases maximal apnea duration in elite breath-hold divers.

We hypothesized that the cardioselective ß1-adrenoreceptor antagonist esmolol would improve maximal apnea duration in elite breath-hold divers. In elite national-level divers (n = 9), maximal apneas were performed in a randomized and counterbalanced order while receiving either iv esmolol (150 µg·kg-1·min-1) or volume-matched saline (placebo). During apnea, heart rate (ECG), beat-by-beat blood pressure, stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were measured (finger photoplethysmography). Myocardial oxygen consumption (MV̇o2) was estimated from rate pressure product. Cerebral blood flow through the internal carotid (ICA) and vertebral arteries (VA) was assessed using Duplex ultrasound. Apnea duration improved in the esmolol trial when compared with placebo (356 ± 57 vs. 323 ± 61 s, P < 0.01) despite similar end-apnea peripheral oxyhemoglobin saturation (71.8 ± 10.3 vs. 74.9 ± 9.5%, P = 0.10). The HR response to apnea was reduced by esmolol at 10-30% of apnea duration, whereas MAP was unaffected. Esmolol reduced SV (main effect, P < 0.05) and CO (main effect; P < 0.05) and increased TPR (main effect, P < 0.05) throughout apnea. Esmolol also reduced MV̇o2 throughout apnea (main effect, P < 0.05). Cerebral blood flow through the ICA and VA was unchanged by esmolol at baseline and the last 30 s of apnea; however, global cerebral blood flow was reduced in the esmolol trial at end-apnea (P < 0.05). Our findings demonstrate that, in elite breath-hold divers, apnea breakpoint is improved by ß1-blockade, likely owing to an improved total body oxygen sparring through increased centralization of blood volume (↑TPR) and reduced MV̇o2NEW & NOTEWORTHY The governing bodies for international apnea competition, the Association Internationale pour le Développment de l'Apnée and La Confédération Mondaile des Activités Subaquatiques, have banned the use of ß-blockers based on anecdotal reports that they improve apnea duration. Using a randomized placebo-controlled trial, we are the first to empirically confirm that ß-blockade improves apnea duration. This improvement in apnea duration coincided with a reduced myocardial oxygen consumption.

A Novel Mutation in OTX2 Causes Combined Pituitary Hormone Deficiency, Bilateral Microphthalmia, and Agenesis of the Left Internal Carotid Artery.

BACKGROUND: Mutations in OTX2 cause hypopituitarism, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency (CPHD), which are commonly detected in association with severe eye abnormalities, including anophthalmia or microphthalmia. Pituitary phenotypes of OTX2 mutation carriers are highly variable; however, ACTH deficiency during the neonatal period is not common in previous reports. OBJECTIVE: We report a novel missense OTX2 (R89P) mutation in a CPHD patient with severe hypoglycemia in the neonatal period due to ACTH deficiency, bilateral microphthalmia, and agenesis of the left internal carotid artery (ICA). RESULTS: We identified a novel heterozygous mutation in OTX2 (c.266G>C, p.R89P). R89P OTX2 showed markedly reduced transcriptional activity of HESX1 and POU1F1 reporters compared with wild-type OTX2. A dominant negative effect was noted only in the transcription analysis with POU1F1 promoter. Electrophoretic mobility shift assay experiments showed that R89P OTX2 abrogated DNA-binding ability. CONCLUSION: OTX2 mutations can cause ACTH deficiency in the neonatal period. Our study also shows that OTX2 mutations are associated with agenesis of the ICA. To the best of our knowledge, this is the first report of a transcription factor gene mutation, which was identified due to agenesis of the ICA of a patient with CPHD. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in OTX2.

[Expression of matrix metalloproteinases and their inhibitors in the internal carotid artery wall in pathological tortuosity]. / Ekspressiya matriksnykh metalloproteinaz i ikh ingibitorov v stenke vnutrennei sonnoi arterii pri patologicheskoi izvitosti.

UNLABELLED: The principal morphological sign of fibromuscular dysplasia in pathological tortuosity (PT) of the internal carotid artery (ICA) is the fragmentation of elastic fibers that are degraded by matrix metalloproteinases 2 and 9 (MMP-2, MMP-9). Nevertheless, the role of MMPs and their inhibitors in the pathogenesis of ICA PT remains completely unexplored. AIM: to investigate the expression of elastin-degrading MMPs and their inhibitors in the wall of the ICA in PT by immunohistochemistry and confocal laser scanning microscopy. METHODS: Immunohistochemical examination was made using antibodies to MMP-2, MMP-9 and their tissue inhibitors TIMP-1 and TIMP-2. MMP-9 and TIMP-1 levels were determined by confocal laser scanning microscopy. RESULTS: Immunohistochemical examination revealed a statistically significant predominance of high concentrations of MMP-2 and MMP-9 and a low level of their inhibitor TIMP-1 in ICA PT, while simultaneous obvious accumulation of both markers was most often identified in the control group (p<0.05). Analysis of MMP-2/TIMP-2 and MMP-9/TIMP-2 ratios showed the prevalence of the simultaneously high expression of both proteins in ICA PT and in the control group too. The similar data were also obtained by confocal microscopy: the control group showed elevated MMP-9 and TIMP-1 expressions and the ICA PT control displayed a high proteinase and low inhibitor levels (p<0.05). CONCLUSION: Elastic fiber fragmentation in ICA PT is due to imbalance between MMPs and their inhibitors; namely, the prevalence of MMP-2 and MMP-9 over their inhibitor TIMP-1, which leads to the degradation of extracellular matrix components, primarily elastin.

15-oxo-ETE-induced internal carotid artery constriction in hypoxic rats is mediated by potassium channels.

Our own study as well as others have previously reported that hypoxia activates 15-lipoxygenase (15-LO) in the brain, causing a series of chain reactions, which exacerbates ischemic stroke. 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-oxo-eicosatetraenoic acid (15-oxo-ETE/15-KETE) are 15-LO-specific metabolites of arachidonic acid (AA). 15-HETE was found to be rapidly converted into 15-oxo-ETE by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in some circumstances. We have demonstrated that 15-HETE promotes cerebral vasoconstriction during hypoxia. However, the effect of 15-oxo-ETE upon the contraction of cerebral vasculature remains unclear. To investigate this effect and to clarify the underlying mechanism, we performed immunohistochemistry and Western blot to test the expression of 15-PGDH in rat cerebral tissue, examined internal carotid artery (ICA) tension in isolated rat ICA rings. Western blot and reverse transcription polymerase chain reaction (RT-PCR) were used to analyze the expression of voltage-gated potassium (Kv) channels (Kv2.1, Kv1.5, and Kv1.1) in cultured cerebral arterial smooth muscle cells (CASMCs). The results showed that the levels of 15-PGDH expression were drastically elevated in the cerebral of rats with hypoxia, and 15-oxo-ETE enhanced ICA contraction in a dose-dependent manner. This effect was more significant in the hypoxic rats than in the normoxic rats. We also found that 15-oxo-ETE significantly attenuated the expression of Kv2.1 and Kv1.5, but not Kv1.1. In conclusion, these results suggest that 15-oxo-ETE leads to the contraction of the ICA, especially under hypoxic conditions and that specific Kv channels may play an important role in 15-oxo-ETE-induced ICA constriction.

Investigating the Effect of a Single Infusion of Reconstituted High-Density Lipoprotein in Patients with Symptomatic Carotid Plaques.

BACKGROUND: Elevation of plasma high-density lipoprotein (HDL) cholesterol concentration reduces cardiovascular mortality and morbidity. HDLs have been shown to possess acute anti-inflammatory, antioxidant, and antithrombotic properties. We hypothesize that HDL therapy can acutely alter local and systemic manifestations of plaque instability. METHODS: Forty patients with early symptomatic carotid disease were randomized to either receive reconstituted HDL (rHDL) 40 mg/kg (n = 20) or placebo (n = 20). Carotid endarterectomies were performed 24 hr later. Plaques were obtained intraoperatively and used for measurement of thrombomodulatory genes expression. Plasma samples were collected before the infusion, 24 and 48 hr later to measure changes in systemic markers of plaque instability. RESULTS: No significant differences were noted in thrombomodulatory genes expression between the 2 groups. Systemic levels of tissue factor, matrix metalloproteinase 9 (MMP-9), and monocyte chemotactic factor-1 (MCP-1) were significantly reduced in the rHDL group. However, the effects on MMP-9 and MCP-1 were abolished in the immediate postoperative period. Although rHDL did not affect plasma interleukin-6 levels 24 hr following the infusion, it prevented the significant postoperative elevation seen in the placebo group. CONCLUSIONS: A single infusion of rHDL can acutely alter plasma biomarkers associated with plaque instability and cardiovascular morbidity.

Gene expression levels of elastin and fibulin-5 according to differences between carotid plaque regions.

AIM: The purpose of this study was to investigate the gene expression levels of elastin and fibulin-5 according to differences between carotid plaque regions and to correlate it with clinical features of plaque destabilization. MATERIALS AND METHODS: The study included 44 endarterectomy specimens available from operated symptomatic carotid artery stenoses. The specimens were separated according to anatomic location: internal carotid artery (ICA), external carotid artery (ECA) and common carotid artery (CCA), and then stored in liquid nitrogen. The amounts of cDNA for elastin and fibulin-5 were determined by Quantitative real-time PCR (Q-RT-PCR). Target gene copy numbers were normalized using hypoxanthine-guanine phosphoribosyltransferase (HPRT1) gene. The delta-delta CT method was applied for relative quantification. RESULTS: Q-RT-PCR data showed that relative fibulin-5 gene expression was increased in ICA plaque regions when compared to CCA regions but not reaching significance (p=0.061). At the same time, no differences were observed in elastin mRNA level between different anatomic plaque regions (p>0.05). Moreover, elastin and fibulin-5 mRNA expression and clinical parameters were compared in ICA plaques versus CCA and ECA regions, respectively. Up-regulation of elastin and fibulin-5 mRNA levels in ICA were strongly correlated with family history of cardiovascular disease when compared to CCA (p<0.05). Up-regulation of fibulin-5 in ICA was significantly associated with diabetes, and elevated triglycerides and very low density lipoprotein (VLDL) when compared to ECA (p<0.05). CONCLUSION: The clinical significance is the differences between the proximal and distal regions of the lesion, associated with the ICA, CCA and ECA respectively, with increased fibulin-5 in the ICA region.

A novel trigger for cholesterol-dependent smooth muscle contraction mediated by the sphingosylphosphorylcholine-Rho-kinase pathway in the rat basilar artery: a mechanistic role for lipid rafts.

Hyperlipidemia is a risk factor for abnormal cerebrovascular events. Rafts are cholesterol-enriched membrane microdomains that influence signal transduction. We previously showed that Rho-kinase-mediated Ca(2+) sensitization of vascular smooth muscle (VSM) induced by sphingosylphosphorylcholine (SPC) has a pivotal role in cerebral vasospasm. The goals of the study were to show SPC-Rho-kinase-mediated VSM contraction in vivo and to link this effect to cholesterol and rafts. The SPC-induced VSM contraction measured using a cranial window model was reversed by Y-27632, a Rho-kinase inhibitor, in rats fed a control diet. The extent of SPC-induced contraction correlated with serum total cholesterol. Total cholesterol levels in the internal carotid artery (ICA) were significantly higher in rats fed a cholesterol diet compared with a control diet or a ß-cyclodextrin diet, which depletes VSM cholesterol. Western blotting and real-time PCR revealed increases in flotillin-1, a raft marker, and flotillin-1 mRNA in the ICA in rats fed a cholesterol diet, but not in rats fed the ß-cyclodextrin diet. Depletion of cholesterol decreased rafts in VSM cells, and prevention of an increase in cholesterol by ß-cyclodextrin inhibited SPC-induced contraction in a cranial window model. These results indicate that cholesterol potentiates SPC-Rho-kinase-mediated contractions of importance in cerebral vasospasm and are compatible with a role for rafts in this process.