Fragmentation Of Internal Elastic Lamina Research Articles

Morphologic vascular anomalies detected during migraine surgery.

Although there is increasing evidence of migraine headaches having extracranial origins, the exact mechanisms underlying the pathogenesis of surgically treated migraines continue to be poorly investigated and described. We studied the microscopic and ultrastructural characteristics of superficial temporal artery (STA) and occipital (OA) artery in the auriculotemporal and great occipital trigger points of migraine patients to determine their possible role in migraine etiopathogenesis. Fifteen biopsies, 10 of STA and 5 from OAs, were collected intraoperatively during migraine surgery and immediately processed for optical and ultramicroscopic analysis. We detected the following anomalies in all the specimens: (a) endothelial damage with internal elastic lamina fragmentation and intimal thickening; (b) marked irregularity in the shape and metachromasia of the vascular smooth muscle cells (VSMCs), separation of cells by abundant extracellular matrix and vacuoles. The electron microscopy analysis confirmed that presumed VSMCs infiltrated the intima layer revealing a consistent shift of VSMCs from contractile to synthetically active phenotypes, endosome-like organelles, multilamellar structures, abundant extracellular vacuoles filled with fine granular material and membranes, and extracellular vesicles in the matrix space surrounding synthetically active cells. Our study revealed specific alterations in the vasculature at the neurovascular bundles of the temporal and occipital trigger sites. These findings are indicative of an active involvement of the arteries in the auriculotemporal and great occipital trigger sites in evoking migraine.

Ultrastructural imaging reveals vascular remodeling in migraine patients.

Migraine is a neurological disorder and one of the most common pain conditions worldwide. Despite its prevalence, the basic biology and underlying mechanisms contributing to the development of migraine are still poorly understood. It is still unclear, for instance, whether the vasculature, both extra and intracranial, plays a significant role in the generation of migraine pain. Neuroimaging data, indeed, have reported conflicting results on blood vessels abnormalities like vasodilation, while functional studies suggest that vessels dysfunction may extend beyond vasodilation. Here we combined light and electron microscopy imaging to investigate the fine structure of superficial temporal (STA) and occipital arteries (OA) from patients that underwent minimally invasive surgery for migraine. Using optical microscopy, we observed that both STA and OA vessels showed marked endothelial thickening and internal elastic lamina fragmentation. In the muscular layer, we found profound shape changes of vascular smooth muscle cells (VSMCs), abundant extracellular matrix, and the presence of clear extracellular vacuoles. The electron microscopy analysis confirmed putative VSMCs infiltrated within the intima layer and revealed a consistent shifting of VSMCs from contractile to a synthetically active phenotype. We also report the presence of (i) abundant extracellular vacuoles filled with fine granular material and membranes, (ii) multilamellar structures, (iii) endosome-like organelles, and (iv) bona fide extracellular vesicles in the matrix space surrounding synthetically active cells. As both the endothelial layer and VSMCs coordinate a variety of vascular functions, these results suggest that a significant vascular remodeling is occurring in STA and OA of migraine patients. Thus, this phenomenon may represent an important target for future investigation designed toward the development of new therapeutic approaches.

Histological Analysis of a Long Term Patent Subintimal Canal in the Superficial Femoral Artery

IntroductionSubintimal angioplasty (SIA) was introduced in the late 1980s and is a supplement to bypass surgery. Adaptation of the technique has been hampered by high rates of early intervention to maintain patency, but the long term assisted patency is good.ReportThe superficial femoral and popliteal artery containing a patent subintimal canal were explanted from a patient who died in the authors' ward. Histological analysis indicated that the lumen was created in the medial layer of the vessel wall. A collagen rich neointima and fragmented internal elastic lamina were observed, presumably as a result of activated smooth muscle cells. The luminal surface was partly covered by a single layer of CD31, von Willebrand factor, and partly CD144 positive cells. An early atherosclerotic lesion was observed distally in the subintimal canal.DiscussionRemodelling and neo-cellularisation of the vascular wall after SIA are described. Notably, hallmarks of early and late stage atherosclerotic disease were evident throughout the subintimal canal. These observations require confirmation in a larger number of specimens but underscore the need for surveillance after SIA.

Central Retinal Artery Occlusion as the Initial Manifestation of Occult Giant Cell Arteritis - A Diagnostic Enigma

Giant cell arteritis (GCA) is a systemic vasculitis with a myriad of ocular manifestations such as Anterior Ischaemic Optic Neuropathy (AION), Central Retinal Artery Occlusion (CRAO), choroidal infarction, occipital lobe infarction and ocular motor nerve palsies. The predominant systemic features include fever, polymyalgia rheumatica, jaw claudication, weight loss and fatigue. Occult GCA accounts for a minority of cases presenting without systemic symptoms. It is a potential cause of bilateral blindness unless a high index of suspicion is contemplated. A 60 year old female presented with CRAO with no systemic symptoms of GCA. Cardiovascular examination, electrocardiography, echocardiography and carotid doppler were unremarkable. Erythrocyte Sedimentation Rate (ESR), C Reactive Protein (CRP) and platelets were normal. Bilateral prominent temporal arteries were noted but were non tender with subtle pulsations, leading to a suspicion of GCA. Temporal artery biopsy disclosed transmural granulomatous inflammation and fragmentation of internal elastic lamina, ascertaining the diagnosis. Systemic steroids were administered promptly. Although an unusual etiology of CRAO, GCA must be ruled out with utmost priority in patients older than 50 years. The diagnosis can be elusive in occult GCA and CRAO may be the inceptive manifestation, further compounding the diagnostic enigma. Urgent temporal artery biopsy is warranted in occult cases of GCA and substantiates the diagnosis in dubious cases. Occult GCA constitutes an ophthalmic emergency and the imperativeness of urgent systemic steroid therapy to prevent visual loss in the other eye cannot be overemphasized.

A refined experimental model of fusiform aneurysms in a rabbit carotid artery.

Reliable animal models are an important aspect of translational research, especially for relatively uncommon clinical entities such as fusiform aneurysms. While several animal models exist, very few are tailored to cerebral fusiform aneurysms, which have unique attributes compared to abdominal fusiform aneurysms. The authors aimed to build from previous models to create a cerebral fusiform aneurysm model that is simple to use and reliable. Twelve female New Zealand White rabbits were assigned to 3 groups: group E, elastase only; group C, CaCl2 only; group EC, elastase + CaCl2. All rabbits underwent surgical exposure of the right common carotid artery (CCA) and 20 minutes of peri-carotid incubation with their respective chemicals. Angiography was performed 6 weeks later for arterial dilation measurements, with 50% increase in diameter being defined as fusiform aneurysm formation. The arterial segments, along with the contralateral CCAs, were harvested and assessed histologically for wall component measurements and elastin semiquantification. A separate rabbit underwent aneurysm creation per the group EC protocol and was treated with an endovascular flow-diversion device. All of the group EC rabbits developed fusiform aneurysms (mean dilation of 88%), while none of the group E or group C rabbits developed aneurysms (p = 0.001). Histological analysis revealed increased internal elastic lamina fragmentation in the group EC aneurysms, which also had less tunica intima hyperplasia. All aneurysms exhibited thinning of the tunica media and reduction in elastin content. The use of an endovascular flow-diverting stent was successful, with complete parent vessel remodeling, as expected, 4 weeks after deployment. The peri-arterial application of combined elastase and CaCl2 to the CCA appears sufficient to reliably produce fusiform aneurysms after 6 weeks. Exposure to elastase or CaCl2 individually appears insufficient, despite the observed histological changes to the arterial wall. The proposed fusiform aneurysm model is able to accommodate endovascular devices, simulating the tortuous pathway experienced in using such devices in human cerebral aneurysms and thus is a satisfactory model to use in translational research.

Abstract WP346: A Cost-effective and Reproducible Mouse Model of Intracranial Aneurysm: Renal Hypertension and Local Hemodynamic Change Combined With Elastase Infusion

Introduction: The study of animal models of intracranial aneurysms (IA) can improve our understanding of the IA pathogenesis and identify the potential pharmaceutical targets. Although a variety of mouse models of IA have been described, all the models have their limitations. We here modified the current models and established a cost-effective and reproducible mouse model that recapitulates the key features of human IA. Methods: In adult C57black/6 male mice, the left common carotid arteries and the left renal arteries were ligated with high salt diet. One week later, 35 mU elastase was stereotactically injected into the right basal cistern. The animals were closely monitored each day for any neurological symptoms until the end of the study. All asymptomatic mice were euthanized 4 weeks after stereotactic injection and the circle of Willis (COW) was inspected under microscope for the presence of aneurysm and/or signs of rupture. Histological analyses were then performed to evaluate the pathological features of IA. Quantitative real-time PCR was employed on COW tissue to compare the expression of IA-pathogenesis associated genes between IA-inducing group and sham operative controls group. Results: All of the mice in the IA-inducing group were developed various aneurysmal changes within COW (n=40). A total of 67.5% (27/40) of the mice were successfully induced saccular IA (sIA) and 11% (3/27) had ruptured aneurysms. The average sIA number for each mouse is 1.4 (38/27). Histologically, aneurysms observed in this model closely resembled human IA including fragmentation of internal elastic lamina, thinning or discontinuities of the smooth muscle cell layer, and F4/80 positive macrophage infiltration within the aneurysm wall. Gene expression assay revealed that IA induction significantly increased expression of inflammation ( NF-κBp65, TNF-α, IL-1β, IL-8 ), matrix remodeling ( MMP-2, TIMP-3 ), EC marker ( Vinculin ) and VSMC marker ( KIF5 ) genes. Conclusion: This model can serve as a useful tool for future studies that utilize various inhibitors, knockout mice, or transgenic mice to test how specific molecules and pathways influence IA development.

Comparative Ultrastructural and Stereological Analyses of Unruptured and Ruptured Saccular Intracranial Aneurysms.

Insight into processes leading to rupture of intracranial aneurysms (IAs) may identify biomarkers for rupture or lead to management strategies reducing the risk of rupture. We characterized and quantified (ultra)structural differences between unruptured and ruptured aneurysmal walls. Six unruptured and 6 ruptured IA fundi were resected after microsurgical clipping and analyzed by correlative light microscopy for quantitative analysis (proportion of the vessel wall area) and transmission electron microscopy for qualitative ultrastructural analysis. Quantitative analysis revealed extensive internal elastic lamina (IEL) thickening in ruptured IA (36.3% ± 15%), while thin and fragmented IEL were common in unruptured IA (5.6% ± 7.1%). Macrophages were increased in ruptured IA (28.3 ± 24%) versus unruptured IA (2.7% ± 5.5%), as were leukocytes (12.85% ± 10% vs 0%). Vasa vasorum in ruptured but not in unruptured IA contained vast numbers of inflammatory cells and extravasation of these cells into the vessel wall. In conclusion, detection of thickened IEL, leaky vasa vasorum, and heavy inflammation as seen in ruptured IA in comparison to unruptured IA may identify aneurysms at risk of rupture, and management strategies preventing development of vasa vasorum or inflammation may reduce the risk of aneurysmal rupture.

The effect of clinical features and glucocorticoids on biopsy findings in giant cell arteritis.

BackgroundTo investigate the effect of baseline clinical characteristics and glucocorticoid treatment on temporal artery biopsy (TAB) findings in patients with giant cell arteritis (GCA).MethodsIndividuals who developed GCA after inclusion in two population-based health surveys were identified through linkage to the local and the national patient registers. In addition, other patients diagnosed with GCA at the Departments of Internal Medicine and Rheumatology at an area hospital were included. A structured review of medical records and TAB pathology reports was performed. The presence or absence of giant cells, granuloma, fragmented internal elastic lamina, fibrosis and grade of inflammatory infiltrates were recorded.ResultsIn 183 cases with a confirmed clinical diagnosis of GCA, 139 were biopsied after start of glucocorticoids (median treatment duration 3 days; interquartile range 2–5). Patients with a positive TAB (77 %) had significantly higher C-reactive protein (CRP; p = 0.007) and erythrocyte sedimentation rate (ESR; p = 0.03) at the time of clinical diagnosis. A positive TAB tended to more common in women, but there was no difference in the proportion of patients with polymyalgia rheumatica or visual symptoms.Patients biopsied before or on the same day as initial treatment where more likely than those biopsied 1–3 days after treatment start to have positive biopsy [odds ratio (OR) 2.86; 95 % CI 1.06–7.70] as well as inflammatory infiltrates (OR 3.30; 95 % CI 1.15–9.49).There was no significant difference in the proportions of a fragmented internal lamina (p = 0.86), giant cells (p = 0.10), granuloma (p = 0.19), minor inflammatory infiltrates (p = 0.47), major inflammatory infiltrates (p = 0.09), or overall positive biopsy (p = 0.17) report by treatment duration comparing: ≤ 0 days, 1–3 days, 4–6 days, 7–28 days. Among those biopsied 7–28 days after start of treatment, 80 % of TABs were positive, and histopathology features were not substantially different from those biopsied after shorter glucocorticoid treatment.ConclusionBiopsies were more likely to be positive and have characteristic histopathologic features in patients with high CRP and ESR, and prior to start of corticosteroid treatment TABs taken 1–4 weeks after initiation of glucocorticoid treatment reveal changes consistent with GCA and therefore still yields clinically useful information for the diagnosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-016-1225-2) contains supplementary material, which is available to authorized users.

Abstract 9601: Early Coronary Atherosclerotic Morphology in Pseudoxanthoma Elasticum: Images From Intravascular Ultrasound and Optical Coherence Tomography

Background: Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterized pathologically by fragmentation and calcification of elastic fiber. However, few data exist regarding the pathogenesis of the coronary atherosclerosis due to the rarity of this disease. The aim of the present study was to assess the early atherosclerotic morphology in PXE using intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Methods: We assessed detailed morphological changes of the coronary arterial wall by IVUS and OCT of the two PXE cases (73 yr male and 69 yr female), both of whom were without any evidence of coronary risk factor. Distal portion of the left anterior descending artery, that was not evident of plaques by angiography, was evaluated using commercially available IVUS system and OCT system. Results: Using IVUS modality, an additional high-gain layer without acoustic shadow, which was located in the intima-media complex, was detected. This additional layer represented several tissue characteristics including fibrosis, dense fibrosis, and calcification using integrated backscatter-IVUS. The OCT image revealed this abnormal layer as heterogeneous shaggy intima without thickness, suggesting the presence of calcified fragmented internal elastic lamina. Conclusions: We report the first IVUS and OCT findings in the coronary artery in patients with PXE. These images suggest that the unique morphology found in those subjects represent a preclinical, early stage of coronary atherosclerosis in PXE.

SAT0271 The Impact of Clinical Features and Corticosteroids on Biopsy Findings in GIANT Cell Arteritis

BackgroundTemporal artery biopsy (TAB) is often used to confirm or reject the diagnosis both in uncertain cases and when the clinical picture indicates giant cell arteritis (GCA). There are conflicting...

Pathogénie de l’artérite à cellules géantes

Giant-cell arteritis (GCA) involves larges arteries, especially aorta and extra-cranial branches of external carotid. Histo-pathological lesions affect all the layers of the artery leading to a segmental and focal panarteritis with a polymorphic cell infiltrate including T cells, macrophages and multinucleated giant cells, a fragmented internal elastic lamina and an intimal hyperplasia. The pathophysiology of GCA is not fully understood. After dendritic cell activation in the adventitia, CD4T cells are recruited in the arterial wall and polarized into Th1 and Th17 cells that produce IFN-γ and IL-17. These cytokines activate macrophages, giant cells and smooth muscle cells inducing vascular remodeling leading to ischemic manifestations of GCA. Macrophages infiltrating the adventitia produce IL-1β and IL-6 that are responsible for general symptoms encountered in GCA. In this review, we discuss GCA pathogenesis, with emphasis on the role of IL-6 as a promising therapeutic target.

Abstract 515: Increased Adventitial Inflammation Occurs in Regions of Low Endothelial Shear Stress in a Swine Model of Coronary Atherosclerosis

Introduction: Plaque inflammation is a critical step in the initiation and progression of atherosclerosis. Such inflammation is thought to originate from the luminal surface of plaque and infiltrate the intima-media in advanced lesions. Low endothelial shear stress (ESS) is known to induce intima-media inflammation and plaque growth. In this study we investigated in-vivo the hypothesis that low ESS induces also adventitial inflammation. Methods: We studied 11 swine at 23 (baseline) and 30 (followup) weeks after the induction of diabetes and hyperlipidemia. Using angiography and intravascular ultrasound data, we performed 3D coronary reconstruction of coronary arteries and calculated the ESS with computational fluid dynamics. In 56 segments, we assessed the adventitial inflammatory (CD45) and antigen-presenting (MHC-II) cell content at followup with immunohistochemistry. Segments were classified as low (≤ 1 Pa) or higher (>1 Pa) ESS. Results: MHC-II content in the adventitia (1.3±0.3%) was higher than in the media (0.3±0.1%, p<0.001) but lower than in the intima (9.3±2.3%, p<0.001). Low-ESS regions had increased adventitial MHC-II content compared to high-ESS regions (1.6±0.4 vs. 0.9±0.3%, p<0.05). Adventitial MHC-II content was not influenced by plaque size (large plaques 1.7±0.5 vs. intermediate plaques 0.8±0.3%, p=0.24), internal elastic lamina fragmentation (IEL) grade (minimal/absent 0.6±0.3 vs. moderate/large 1.4±0.3, p=0.9), or remodeling pattern (inadequate 1.7±0.6 vs. compensatory 1.2±0.4 vs. expansive 0.6±0.2%, p=0.6). Adventitial CD45 content was not significantly different between low- and high-ESS segments, and also not different in large vs. intermediate plaques, in segments with various IEL fragmentation grades or remodeling patterns. Conclusion: Although total inflammation is not dependent on ESS, low ESS induces higher adventitial activated inflammatory cell content, as assessed by MHC-II immunostaining. This, in conjunction with the higher MHC-II content in the adventitia than in the media and the presence of an intact IEL suggests an additional source of inflammation in low-ESS plaque regions, originating from the vessel outer wall. The induction of neovascularization possibly accounts for this phenomenon.

Diagnosis and management of fibromuscular dysplasia: an expert consensus

Diagnosis and management of fibromuscular dysplasia: an expert consensus

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Augmented Expression and Activity of Extracellular Matrix-Degrading Enzymes in Regions of Low Endothelial Shear Stress Colocalize With Coronary Atheromata With Thin Fibrous Caps in Pigs

Background- The molecular mechanisms that determine the localized formation of thin-capped atheromata in the coronary arteries remain unknown. This study tested the hypothesis that low endothelial shear stress augments the expression of matrix-degrading proteases and thereby promotes the formation of thin-capped atheromata. Methods and Results- Intravascular ultrasound-based, geometrically correct 3-dimensional reconstruction of the coronary arteries of 12 swine was performed in vivo 23 weeks after initiation of diabetes mellitus and a hyperlipidemic diet. Local endothelial shear stress was calculated in plaque-free subsegments of interest (n=142) with computational fluid dynamics. At week 30, the coronary arteries (n=31) were harvested and the same subsegments were identified. The messenger RNA and protein expression and elastolytic activity of selected elastases and their endogenous inhibitors were assessed. Subsegments with low preceding endothelial shear stress at week 23 showed reduced endothelial coverage, enhanced lipid accumulation, and intense infiltration of activated inflammatory cells at week 30. These lesions showed increased expression of messenger RNAs encoding matrix metalloproteinase-2, -9, and -12, and cathepsins K and S relative to their endogenous inhibitors and increased elastolytic activity. Expression of these enzymes correlated positively with the severity of internal elastic lamina fragmentation. Thin-capped atheromata developed in regions with lower preceding endothelial shear stress and had reduced endothelial coverage, intense lipid and inflammatory cell accumulation, enhanced messenger RNA expression and elastolytic activity of MMPs and cathepsins, and severe internal elastic lamina fragmentation. Conclusions- Low endothelial shear stress induces endothelial discontinuity and accumulation of activated inflammatory cells, thereby augmenting the expression and activity of elastases in the intima and shifting the balance with their inhibitors toward matrix breakdown. Our results provide new insight into the mechanisms of regional formation of plaques with thin fibrous caps.

The role of low endothelial shear stress in the conversion of atherosclerotic lesions from stable to unstable plaque.

Local hemodynamic factors are major determinants of the natural history of individual atherosclerotic plaque progression in coronary arteries. The purpose of this review is to summarize the role of low endothelial shear stress (ESS) in the transition of early, stable plaques to high-risk atherosclerotic lesions. Low ESS regulates multiple pathways within the atherosclerotic lesion, resulting in intense vascular inflammation, progressive lipid accumulation, and formation and expansion of a necrotic core. Upregulation of matrix-degrading proteases promotes thinning of the fibrous cap, severe internal elastic lamina fragmentation, and extracellular matrix remodeling. In the setting of plaque-induced changes of the local ESS, coronary regions persistently exposed to very low ESS develop excessive expansive remodeling, which further exacerbates the proinflammatory low ESS stimulus. Recent studies suggest that the effect of recognized cardioprotective medications may be mediated by attenuation of the proinflammatory effect of the low ESS environment in which a plaque develops. Low ESS determines the severity of vascular inflammation, the status of the extracellular matrix, and the nature of wall remodeling, all of which synergistically promote the transition of stable lesions to thin cap fibroatheromata that may rupture with subsequent formation of an occlusive thrombus and result in an acute coronary syndrome.

In vivo assessment of rapid cerebrovascular morphological adaptation following acute blood flow increase

Pathological extremes in cerebrovascular remodeling may contribute to basilar artery (BA) dolichoectasia and fusiform aneurysm development. Factors regulating cerebrovascular remodeling are poorly understood. To better understand hemodynamic influences on cerebrovascular remodeling, we examined BA remodeling following common carotid artery (CCA) ligation in an animal model. Rabbits were subjected to sham surgery (3 animals), unilateral CCA ligation (3 animals), or bilateral CCA ligation (5 animals). Transcranial Doppler ultrasonography and rotational angiography were used to compute BA flow, diameter, wall shear stress (WSS), and a tortuosity index on Days 0, 1, 4, 7, 14, 28, 56, and 84. Basilar artery tissues were stained and analyzed at Day 84. Statistical analysis was performed using orthogonal contrast analysis, repeated measures analysis of variance, or mixed regression analysis of repeated measures. Statistical significance was defined as a probability value < 0.05. Basilar artery flow and diameter increased significantly after the procedure in both ligation groups, but only the bilateral CCA ligation group demonstrated significant differences between groups. Wall shear stress significantly increased only in animals in the bilateral CCA ligation group and returned to baseline by Day 28, with 52% of WSS correction occurring by Day 7. Only the bilateral CCA ligation group developed significant BA tortuosity, occurring within 7 days postligation. Unlike the animals in the sham and unilateral CCA ligation groups, the animals in the bilateral CCA ligation group had histological staining results showing a substantial internal elastic lamina fragmentation. Increased BA flow results in adaptive BA remodeling until WSS returns to physiological baseline levels. Morphological changes occur rapidly following flow alteration and do not require chronic insult to affect substantial and significant structural transformation. Additionally, it appears that there exists a flow-increase threshold that, when surpassed, results in significant tortuosity.

Molecular mechanisms of the vascular responses to haemodynamic forces

Blood vessels are permanently subjected to mechanical forces in the form of stretch, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow and shear stress. Significant variations in mechanical forces, of physiological or physiopathological nature, occur in vivo. These are accompanied by phenotypical modulation of smooth muscle cells and endothelial cells, producing structural modifications of the arterial wall. In all the cases, vascular remodelling can be allotted to a modification of the tensional strain or shear, and underlie a trend to reestablish baseline mechanical conditions. Vascular cells are equipped with numerous receptors that allow them to detect and respond to the mechanical forces generated by pressure and shear stress. The cytoskeleton and other structural components have an established role in mechanotransduction, being able to transmit and modulate tension within the cell via focal adhesion sites, integrins, cellular junctions and the extracellular matrix. Mechanical forces also initiate complex signal transduction cascades, including nuclear factor-kappaB and mitogen-activated protein kinase pathways, leading to functional changes within the cell.

Surrogate markers for cardiovascular disease: structural markers.

Pignoli et al1 validated the concept that intima-media thickness (IMT), as measured by B-mode ultrasound and applied either in vitro or in situ at the time of autopsy, reflected direct measurements of aortic and/or carotid specimens. Values obtained by ultrasound at autopsy and by direct measurement were similar to those obtained from living subjects. The characteristic double-line pattern was most consistently found in the far wall of postmortem specimens judged to be relatively normal or affected only by fatty streaks. Histologically, these segments showed homogeneous intima with varying amounts of intimal thickening, intimal fibrosis, internal elastic lamina fragmentation, and duplication. In specimens with more advanced atherosclerosis, the double-line pattern was sometimes perturbed and more complex; these samples showed evidence of a fibrous/muscular cap with a lipid and/or necrotic core and, histologically, the intima showed focal areas of fibrotic smooth muscle cell proliferation, microcalcification, and necrosis. Based on this important article, it is clear that carotid IMT is a direct measure of the status of the vascular wall, and abnormalities are not a surrogate but a direct measure of atherosclerotic and arteriosclerotic processes. The issue of surrogacy pertains to whether a measurement in the carotid bed is associated with atherosclerosis in other beds, particularly the coronary bed and, even more important, whether this measurement is predictive of vascular events that result from atherothrombotic disease. ### Methodology Carotid ultrasound is routinely applied for evaluation of ischemic cerebrovascular signs (eg, bruits) and symptoms. In the context of risk stratification, however, the goal is to identify preclinical disease. The degree of carotid disease that appears to be of prognostic value is much subtler, requiring meticulous and detailed measurements of IMT through B-mode ultrasound. These measurements can be made in a reproducible and reliable fashion if sonographers and those making the measurements are trained comprehensively and …

Role of elastolytic cathepsins in vascular remodeling

Background: We now appreciate that the pathogenesis of atherosclerosis and abdominal aortic aneurysms (AAA) involves breakdown of extracellular matrix (ECM). We recently implicated certain elastolytic cysteine-dependent cathepsins in these pathological processes. Results: We demonstrated over-expression of cathepsins S and K in human atheroma and AAA, and colocalized cathepsin S-positive medial smooth muscle cells (SMC) with sites of internal elastic lamina fragmentation. Moreover, depletion of cystatin C, the most abundant endogenous cysteine protease inhibitor, characterizes both atherosclerotic and aneurysmal lesions. To test directly the role of cathepsin S in atherogenesis, we studied targeted disruption of the cathepsin S gene in atherosclerosis-prone LDLr −/− mice consuming a western diet. Cathepsin S deficiency significantly decreased atherosclerosis. Better-preserved elastin in the tunica media of cathepsin S-deficient mice likely reflected the diminished elastolytic activity in cathepsin S −/− SMC ( p<0.0001) compared with wild-type SMC. These mice had fewer SMC and less collagen in their intimal lesions, probably because SMC migration requires degradation of elastin. Conclusions: Our findings in situ, in vitro and in vivo establish an important role for cathepsins in vascular remodeling.