Fibrotic Plaque Research Articles

Temporal changes in MMP mRNA expression in the lens epithelium during anterior subcapsular cataract formation

Transforming growth factor beta (TGFβ) has been known to play a role in anterior subcapsular cataract (ASC) formation and posterior capsule opacification (PCO), both of which are fibrotic pathologies of the lens. Several models have been utilized to study ASC formation, including the TGFβ1 transgenic mouse model and the ex-vivo rat lens model. A distinct characteristic of ASC development within these models includes the formation of isolated fibrotic plaques or opacities which form beneath the lens capsule. A hallmark feature of ASC formation is the epithelial to mesenchymal transition (EMT) of lens epithelial cells (LECs) into myofibroblasts. Recently, the matrix metalloproteinases (MMPs) have been implicated in the formation of these cataracts through their involvement in EMT. In the present study, we sought to further investigate the role of MMPs in subcapsular cataract formation in a time course manner, through the examination of gene expression and morphological changes which occur during this process. RT-QPCR and immunohistochemical analysis was carried out on lenses treated with TGFβ for a period of 2, 4 and 6 days. Laser capture microdissection (LCM) was utilized to specifically isolate cells within the plaque region and cells from the adjacent epithelium in lenses treated for a 6 day period. Multilayering of LECs was observed as early as day 2, which preceded the presence of alpha smooth muscle actin (α-SMA) immunoreactivity that was evident following 4 days of treatment with TGFβ. A slight reduction in E-cadherin mRNA was detected at day 2, although this was not significant until the day 4 time point. Importantly, our results also indicate an early induction of MMP-9 mRNA following 2 days of TGFβ treatment, whereas MMP-2 was found to be upregulated at the later 4 day time point. Further experiments using FHL 124 cells show an induction in MMP-2 protein levels following treatment with recombinant MMP-9. Together these findings suggest an upstream role for MMP-9 in ASC formation.

TGFβ promotes Wnt expression during cataract development

TGFβ induces lens epithelial cells to undergo epithelial mesenchymal transition (EMT) and many changes with characteristics of fibrosis including posterior capsular opacification (PCO). Consequently much effort is directed at trying to block the damaging effects of TGFβ in the lens. To do this effectively it is important to know the key signaling pathways regulated by TGFβ that lead to EMT and PCO. Given that Wnt signaling is involved in TGFβ-induced EMT in other systems, this study set out to determine if Wnt signaling has a role in regulating this process in the lens. Using RT-PCR, in situ hybridization and immunolocalization this study clearly shows that Wnts 5a, 5b, 7b, 8a, 8b and their Frizzled receptors are upregulated in association with TGFβ-induced EMT and cataract development. Both rat in vitro and mouse in vivo cataract models show similar profiles for the Wnt and Frizzled mRNAs and proteins that were assessed. Currently it is not clear if the canonical β-catenin/TCF signaling pathway, or a non-canonical pathway, is activated in this context. Overall, the results from the current study indicate that Wnt signaling is involved in TGFβ-induced EMT and development of fibrotic plaques in the lens.

Leishmania (Leishmania) amazonenisInfection, Suriname

To the Editor: A 17-year-old man was seen at the Dermatology Service in Paramaribo (Suriname) with a skin condition that he had had since he was 5 years of age. The condition consisted of multiple cutaneous ulcerations, nodules, and fibrotic plaques disseminated on his face, limbs, and trunk, and subcutaneous nodules on lymph-draining tracts on his hands, arms, and legs (Appendix Figure, panel A). He had lived his entire life in an inland village, located at Brokopondo Lake (central-eastern Suriname); he had never traveled outside the country. The diagnosis of cutaneous leishmaniasis (CL, a parasitic disease caused by the protozoa Leishmania) was presumed. The patient received pentamidine therapy in 1997, 1998, and 2005, but without sustained clinical effect. Rapid screening tests for HIV were negative (Determine [Abbott Laboratories, Tokyo, Japan] and Unigold [Trinity Biotech, Co. Wicklow, Ireland]). In 2006, the diagnosis of CL was confirmed with histopathology, culture, and PCR. The parasite was identified by a PCR restriction fragment length polymorphism method on the small subunit–internal transcribed spacer genes (1) and by multilocus enzyme electrophoresis at the National Reference Center of Leishmania (Montpellier, France). After promising results were obtained with miltefosine in a patient with anergic diffuse cutaneous leishmaniasis (ADCL) in Venezuela (2), the patient received 150 mg/day oral miltefosine (Impavido, Zentaris, Germany) for 98 days and the lesional parasite load was quantified with quantitative nucleic acid sequence-based amplification (3). Skin biopsy specimens were collected from 1 target lesion before treatment; during treatment at day 14, day 28, day 42 (all in duplicate); and at day 70 (single biopsy). The strain causing infection (MHOM/SR/2006/SP100) was identified as Leishmania (Leishmania) amazonensis, and the enzymatic profile was equal to L. (L.) amazonensis zymodeme MON-41. Histopathology showed large macrophages containing abundant Leishmania amastigotes and few lymphocytes and plasma cells without granuloma formation. A considerable clinical improvement was observed during the first 2 months of therapy. The lesions slowly decreased in size and duration. At day 70, all ulcerative lesions were re-epithelialized, without signs of infiltration or lymphangitis (Appendix Figure, panel B). At start of treatment, parasite counts of 360,000 and 310,000 parasites per biopsy were detected; these counts decreased to 0 parasites/biopsy at day 70. Histopathologic studies at day 70 showed no Leishmania bodies, a dense lymphocytic and plasma cellular infiltrate, and fibrosis. Apart from mild elevation of creatine and urea during treatment, no subjective or adverse side effects were reported. L. (L.) amazonensis causes CL and 2 very serious manifestations of CL, disseminated cutaneous leishmaniasis (DCL) and ADCL (4). Both forms are histopathologically characterized by heavily parasitized macrophages and an absence of cell-mediated immune responses in therapy-naive patients (4). ADCL is resistant to any form of therapy, and cell-mediated immune responses never seem to occur. In contrast, the cell-mediated immune response in DCL can eventually arise upon therapy response, even in patients with previous therapy failures (4). The therapy response in DCL patients is histopathologically characterized by the appearance of a lymphocytic and plasma cellular infiltrate. The diagnosis of DCL is plausible in our patient based on the histopathologic findings before, during, and after therapy; the clinical picture (erythematous infiltrated plaques, lymphadenitis, and lymphangitis), and the favorable therapy response. He was last seen 7 months after end of therapy, at which time new lesions had not developed. In general, L. (L.) amazonensis infection is rare in humans (5). In French Guiana, bordering the eastern side of Suriname, few patients (≈1.9%) are reported to be infected with this species (5). However, the sandfly vector of L. (L.) amazonensis, Lutzomyia flaviscutellata, was detected earlier in Suriname (6), which may indicate transmission of L. (L.) amazonensis infection to humans by means of the bite of this sandfly in Suriname. Our patient had no history of transfusion or intravenous drug use. Many gold diggers from the northern part of Brazil work and travel in Suriname and are familiar with CL. In the Brazilian State Para, a region bordering Suriname in the South, the infection rate with L. (L.) amazonensis is high (34.8%) (7). It is thus conceivable that infected gold diggers from that area have introduced L. (L.) amazonensis into Suriname. Our patient used to live in a village where many Brazilian gold diggers worked around the time that his skin lesions developed. Migration of laborers is associated with an increased risk for CL infection (8). The zymodeme MON-41 is widespread in Central America and the northern part of South America, and has been reported in Venezuela, Brazil, Panama, French Guiana, and Colombia (F. Pratlong and J.P. Dedet, Montpellier International Cryobank of Leishmania, pers. comm., 2007). Therefore, speculations on the exact origin of the infection need to be made cautiously.

Endomyocardial fibrosis: pathological findings in surgical specimens and clinicopathological correlation

BACKGROUND: Endomyocardial fibrosis (EMF) is a restrictive cardiomyopathy of unknown etiology prevalent in tropical regions. The disease involves the inflow tract and apex of either one or both ventricles and is characterized by a fibrous thickening of the endocardium and the underlying myocardium. Although its etiology remains unknown, most authors believe it could be related to systemic or heart infection/parasitism, previous blood eosinophilia or malnutrition. Surgical resection of the thickened endocardium is recommended to patients with advanced heart failure of functional class III or IV, New York Heart Association (NYHA). The gross and histological features of the heart have been comprehensively studied in autopsies and endomyocardial biopsies. Studies in surgical samples, however, are still lacking. AIMS: This study was conducted to evaluate: (1) the histomorphological changes of EMF as seen in surgical specimens by means of routine histological and immunohistochemical methods in an attempt to correlate them with clinical symptoms and coronary angiographic features; (2) to compare histological data between surgical and autopsy samples, and (3) to discuss probable pathogenetic mechanisms of the disease, as well as to investigate cardiotropic infective agents by means of molecular analysis of endomyocardial surgical samples. METHODS: We collected all available clinical records and endomyocardial surgical samples from 31 patients with EMF who had been submitted to surgery between 1991 and 2005 at InCor. The diagnosis was based on clinical, hemodynamic and angiocardiographic findings. The surgical samples were fixed in 10% formalin, submitted to standard processing, and stained with HE two of them were positive for cytomegalovirus (CMV), two for enterovirus (EV), one for both (CMV and EV) and one for T. gondii. No histopathological differences between surgical samples and autopsy fragments were observed. Vascular blush or neovascularity was detected in nine of the 16 coronary cineangiocardiographies reviewed. Clinicopathologic characteristics are associated neither with infective genomes in the endocardium nor with vascular blush. CONCLUSIONS: Results indicate that there is a non specific chronic inflammatory process maintained by an anomalous vascular net rich in lymphatics situated deep within the endocardium. This angiolymphatic web probably contributes to the maintenance of the fibrotic plaque and might be considered an important pathological finding concerning in the pathogenesis of EMF. Histopathological changes as seen in surgical material are diagnostic of EMF. Molecular analysis of the endomyocardium revealed high incidence of cardiotropic infective agents, but their role in the pathogenesis of the disease is still controversial.

Assessment and Characterization of Time-related Differences in Plaque Composition by Intravascular Ultrasound–derived Radiofrequency Analysis in Heart Transplant Recipients

The survival of heart transplant patients is limited by cardiac allograft vasculopathy (CAV). Intravascular ultrasound (IVUS) and IVUS-derived radiofrequency plaque composition analysis (IVUS-RF) provide further information about the process of coronary atherosclerosis. In this study we aimed to assess the time-dependent differences in disease progression in patients with CAV. Fifty-six patients were divided into three groups according to time interval after transplantation (Group I: 1 to 3 months, 18 patients; Group II, 1 to 5 years, 20 patients; Group III: 5 to 15 years, 18 patients). IVUS-RF revealed time-dependent increases in all plaque components. The largest increase was shown for fibrotic, fibrofatty and necrotic tissue between Groups I and II. Dense calcium area increased uniformly in all groups. IVUS-RF-derived plaque type analysis revealed predominantly fibrotic plaques in all groups with a decrease of frequency over time. Fibrolipidic and fibrotic-calcific plaques increased uniformly. High-risk lesions, such as thick-cap fibroatheromas (FAs), increased in Groups I and II and decreased in Group III. Thin-cap FAs were detected only in Group III. IVUS-RF, as compared with gray-scale IVUS, provides better detailed information about the development of CAV by plaque morphology and composition analysis in different stages after heart transplantation. Serial IVUS-RF analysis in these patients may improve the stratification of heart transplant recipients.

Atherosclerosis—Underlying inflammatory mechanisms and clinical implications

Inflammation plays an important role in the initiation and progression of atherosclerosis but many of its underlying mechanisms remain to be explored. Atherosclerotic plaques which are more prone to destabilisation and rupture, leading to clinical events, are characterised by increased infiltration of leukocytes and other inflammatory mediators, compared with stable fibrotic plaques. T cell mediated responses, through expression of cytokines and chemokines, play an important role in the inflammatory process; and more recently potentially anti-inflammatory markers have also been identified. Current management involves both mechanical restoration of blood flow and pharmacotherapy aimed in part at suppressing the underlying inflammatory mechanisms. The aims of this review are to outline the pro- and anti-inflammatory processes in atherosclerosis, as well as their clinical implications.

Abstract 1984: Histopathologic Validation of Virtual Histology Intravascular Ultrasound Analysis of Peri-calcific Necrotic Core Area

The effect of calcium-associated acoustic shadowing on Virtual Histology intravascular ultrasound (VH-IVUS) plaque component analysis is unknown. Methods. We harvested 87 coronary arteries from 30 autopsied specimens. IVUS imaging was performed 50mm from the LMCA ostium. We then selected 10 calcified segments for comparative VH-IVUS vs pathologic comparisons. Results. Pt age was 46±8.9yrs and 90% were males. VH-IVUS analysis of the calcified plaque showed 11±3.8% necrotic core, 8±1.9% fibrofatty plaque, 69±9.9% fibrotic plaque, and 10±6.6% dense calcium. Dense calcium was correlated with the size of the necrotic core (r=0.774, p=0.009). Three coronary arteries with moderate to severe calcium were examined histopathologically. VH-IVUS analysis showed fibrotic tissue behind the calcium, but histopathology showed an acellular sclerotic area (dense collagenous tissue) just beneath the calcium with a relatively well-preserved vascular smooth muscle layer. Within the necrotic core, VH-IVUS showed prominent red necrotic core area combined with calcium; however, histopathology showed empty space of decalcification surrounded by just collagenous tissue with outer smooth muscle actin positive cell layer. More importantly, no active inflammation was present around calcium. Conclusion. VH-IVUS necrotic core surrounding areas of dense calcium correlated with dense collagenous tissue histopathologically. It is important not to overinterpret VH IVUS studies of dense calcium with prominent necrotic core. More precise classification/validation for necrotic core is necessary.

Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome

Acute coronary syndrome (ACS) represents a series of indications of sudden cardiac ischemia that involve a variety of causes, including acute myocardial infarction and unstable angina.1 ACS usually is associated with thrombus formation in the coronary artery or coronary artery vasospasm, resulting in myocardial ischemia. 2 Thrombus formation may involve platelet adhesion and degranulation on damaged or dysfunctional endothelium overlying the intact or ruptured atherosclerotic plaque, as well as microthrombi.3 Atherosclerotic plaque rupture represents a series of deleterious events linked to the breakdown of the fibrous cap. This process may occur as a result of the increased secretion of matrix metalloproteinases by lesion resident macrophages or enhanced apoptotic cell death within the fibrous cap. However, viable smooth muscle cells (SMCs) within the fibrous cap synthesize interstitial collagen fibers that enhance the structural integrity of the plaque and prevent its rupture.4

Repeated intratunical injection of adenovirus expressing transforming growth factor‐β1 in a rat induces penile curvature with tunical fibrotic plaque: a useful model for the study of Peyronie’s disease

This study was undertaken to establish a Peyronie's disease model with penile curvature by using recombinant transforming growth factor-beta1 (TGF-beta1) protein or adenovirus (ad-TGF-beta1). Four-month-old male Sprague-Dawley rats were divided into seven groups (n = 18 per group): G1 received a single injection of saline into the tunica albuginea (0.1 mL); G2, repeated injections of ad-LacZ (days 0, 3, and 6; 1 x 10(10) particles/0.1 mL respectively); G3, a single injection of recombinant TGF-beta1 protein (700 ng/0.1 mL); G4, repeated injections of recombinant TGF-beta1 protein (days 0, 3 and 6; 700 ng/0.1 mL respectively); G5, a single injection of low-dose ad-TGF-beta1 (1 x 10(10) particles/0.1 mL); G 6, a single injection of high-dose ad-TGF-beta1 (3 x 10(10) particles/0.1 mL); and G7, repeated injections of low-dose ad-TGF-beta1 (days 0, 3, and 6; 1 x 10(10) particles/0.1 mL respectively). Penile curvature was evaluated 30, 45 and 60 days after treatment, and the penis was then harvested for histological examination. Repeated injection of low-dose ad-TGF-beta1 not only induced fibrous scar in the tunica, which lasted up to 60 days after injection, but also resulted in significant penile curvature by artificial erection test 45 days after treatment. A peculiar histological finding in this group was trapping of inflammatory cells in the tunica, subsequent fibrosis, and formation of cartilage and calcification as well as loss of elastin fibres. This model involving repeated injection of ad-TGF-beta1 may contribute to further investigation of the pathogenesis of Peyronie's disease and the development of new therapeutics targeting this pathway.

Comparison of Virtual Histology to Intravascular Ultrasound of Culprit Coronary Lesions in Acute Coronary Syndrome and Target Coronary Lesions in Stable Angina Pectoris

Coronary plaque composition cannot be assessed accurately using gray-scale intravascular ultrasound (IVUS). Using virtual histology IVUS (VH-IVUS), a comparison of coronary plaque composition between acute coronary syndromes (ACS) and stable angina pectoris (SAP) was performed. Preintervention IVUS of de novo culprit and target lesions was performed in 318 patients (123 with ACS and 195 with SAP). Using VH-IVUS, plaque was characterized as fibrotic, fibrofatty, dense calcium, and necrotic core. VH-IVUS-derived thin-cap fibroatheroma (VH-TCFA) was defined as necrotic core>or=10% of plaque area without overlying fibrous tissue in a plaque burden>or=40%. Lesions were classified into 3 groups: ruptured, VH-TCFA, and non-VH-TCFA plaque. Unstable lesions were defined as either VH-TCFA or ruptured plaque. Compared with patients with SAP, those with ACS had significantly more unstable lesions (89% vs 62%, p<0.001). Planar VH-IVUS analysis at the minimum luminal site and at the largest necrotic core site and volumetric analysis over a 10-mm-long segment centered at the minimum luminal site showed that the percentage of necrotic core was significantly greater and that the percentage of fibrofatty plaque was significantly smaller in patients with ACS. The percentages of fibrotic and fibrofatty plaque areas and volumes were smaller, and the percentages of necrotic core areas and volumes were larger in VH-TCFAs compared with non-TCFAs. Ruptured plaques in VH-IVUS analyses showed intermediate findings between VH-TCFAs and non-VH-TCFAs. In conclusion, culprit lesions in patients with ACS were more unstable and had greater amounts of necrotic core and smaller amounts of fibrofatty plaque compared with target lesions in patients with SAP.

Investigation of the Antifibrotic Effect of IFN-γ on Fibroblasts in a Cell Culture Model of Peyronie's Disease

ObjectiveA broad spectrum of options is available for treatment of Peyronie's disease; however, the effects of minimally invasive therapy are generally inadequate. Although useful, oral drugs must be administered at onset of the disease. Only a few patients request penile surgery. Therefore, new medical treatments for Peyronie's disease are needed. A better understanding of the pathogenesis of Peyronie's disease is required to facilitate development of these new medical treatments. Several studies have described an increased level of TGF-β in the fibrotic plaques of patients with Peyronie's disease, underscoring this important signalling pathway in the onset and/or development of Peyronie's disease. MethodsPlaque biopsies were taken from 16 patients with Peyronie's disease. Furthermore, 7 patients without Peyronie's disease were biopsied to provide control material. Fibroblasts were cultured from biopsy tissue, and cultured fibroblasts were stimulated with TGF-β1, BMP-2, IFN-γ, and IFN-γ combined with one of the other stimuli. Protein was extracted from treated fibroblasts and prepared for immunoblots. The membranes were probed for phosphorylated Smad and total Smad to indicate activation of TGF-β signalling. ResultsAn agonistic effect of IFN-γ on TGF-β signalling was observed. Stimulation with TGF-β1 increased levels of phospho-Smad2 and phospho-Smad3. After stimulation with TGF-β1 and IFN-γ combined, the levels of phospho-Smads were higher than those observed with stimulation withTGF-β1 alone. ConclusionsThe profibrotic effect of TGF-β1 is enhanced by IFN-γ in fibroblasts from patients with Peyronie's disease. The inhibitory effects of IFN-γ on the TGF-β pathway do not appear in Peyronie's disease. Therefore, IFN-γ cannot be taken as a useful tool in the therapy of Peyronie's disease.

Retroperitoneale Fibrose

Retroperitoneal fibrosis (RPF) is characterised by inflammatory fibrotic processes affecting the retroperitoneal structures. Its prevalence of 1 - 2/200,000 makes it a rare disease. To date, there are no guidelines for the diagnosis of or therapy for the disease. If untreated, the disease may be fatal. In 2006, the Department of Urology of the HELIOS Klinikum Wuppertal undertook to establish a nationwide patient registry, which would facilitate prospective therapy trials and the drafting of recommendations for diagnostic procedures. The pathogenesis of the disease is still unclear. Since some RPF-patients present with associated autoimmune diseases, autoimmune processes are suspected to play a role in causing the disease. The presence of autoantibodies and histological similarities with vasculitis support this hypothesis. Following initial general symptoms, patients display localised symptoms (flank pain, leg oedema, abdominal discomfort), caused by the displacing effect of the fibrotic plaques. Laboratory tests show elevated ESR and C-reactive protein and in some cases a moderate anaemia. Histological examinations should be undertaken to rule out the presence of malignant tumours. Radiological diagnostics (excretory urography, CT, MRI) show a retroperitoneal mass which blocks, compresses and displaces, completely or in part, the large vessels and the ureter. Initial therapy aims at restoring the function of the affected hollow organs through the application of (ureteric) stents, followed by immunosuppressive therapy. If drug therapy is unsuccessful, surgical procedures will follow to protect the ureter from compression. In some cases, ureteral replacement or an autotransplant of the kidney may be necessary. Life-long observation of the patients is necessary, as the disease may be chronic and relapsing. Interdisciplinary and nationwide cooperation is of crucial importance to further investigate this disease.

Histological composition and progression of carotid plaque

BackgroundTo analyse histological composition and progression of carotid plaque.MethodsThirty-one patients (22 males, mean age 68.03 ± 7.3 years) admitted for carotid endarterectomy for extracranial high-grade internal carotid artery stenosis (≥ 70% luminal narrowing) were enrolled. The patients were divided into 2 groups according to symptomatology (group I, 17 symptomatic patients; and group II, 14 asymptomatic patients). A histological analysis and inflammatory cell quantification of each excised carotid plaque was made. Nine carotid arteries were removed from human cadavers that were not preselected for carotid artery disease. These specimens were used as a control tissue without any macroscopic signs of atherosclerotic plaques.ResultsFifty eight percent of all carotid plaques were classified as complex plaque with possible surface defect, hemorrhage or thrombus. The inflammatory cells concentration did not differ between the two groups. All specimens from human cadavers were classified as preatheroma with extracellular lipid pools.ConclusionAsymptomatic and symptomatic patients could have the same histological components on their carotid plaques. Fibrotic and calcific plaques could become vulnerable as complex plaques with surface defect, hemorrhage and thrombus could remain silent. Asymptomatic carotid stenosis should be followed close with no invasive diagnostic methods and clinical evaluation.

Histological examination of primary posterior capsule plaques

To understand the source and evolution of the cellular elements of posterior capsule plaques. Department of Ophthalmology, University of Sciences, Faculty of Medicine, Pécs, Hungary. In 24 eyes of 24 patients, the primary fibrotic plaques were carefully peeled off the posterior capsule with forceps and sent for histological examination. The samples were stained with hematoxylin-eosin and with picrosirius to demonstrate collagen content. Most plaques were found in elderly patients with mature cataracts. However, one was found in a patient with congenital cataract. The histological examination revealed different stages of plaques, permitting discrimination of early (cellular), transitional, and late (fibrotic) stages. The plaques in the early stage contained cuboidal cells with nuclei; collagen deposition led to the development of the transitional stage; and further collagen deposition led to the fibrotic stage. There was no significant correlation between the maturity of the cataract and the plaque stage, but other factors such as previous eye surgery (vitrectomy, glaucoma surgery), long-standing diabetes mellitus (DM), and a high degree of myopia appeared to contribute to the development of plaques. Primary posterior capsule plaques were found primarily in elderly patients with mature cataracts but were also present post vitrectomy in those who had DM from a young age and had early stages of cataract. In the early plaque stage, cells with nuclei were found. It follows that plaques are capable of proliferation at this stage, aggravating visual disturbance. Therefore, removing the plaques by peeling from the posterior capsule or by posterior capsulorhexis during surgery is suggested.

Reproducibility of Carotid Atherosclerotic Lesion Type Characterization Using High Resolution Multicontrast Weighted Cardiovascular Magnetic Resonance

Cardiovascular magnetic resonance (CMR) can characterize carotid atherosclerosis. The purpose of this study is to evaluate reader agreement of carotid atherosclerotic lesion types by CMR. Carotid arteries of 34 patients (29 men, 5 women; mean age, 53 years) were imaged on a 1.5-T scanner. Images with 4 contrast weightings (T1, T2, proton density, and 3-dimensional time-of-flight) were acquired on each axial slice of the carotid arteries. Modified AHA criteria were used for lesion type assessment on the 4 selected axial slices (1 from the common carotid artery, 1 from the carotid bifurcation, and 2 from the internal carotid artery). The modified AHA criteria are as follows: type I-II, near-normal wall thickness without calcification; type III, diffuse wall thickening or small eccentric plaque without calcification; type IV-V, plaque with a lipid rich necrotic core surrounded by fibrous tissue with possible calcification; type VI, complex plaque with a possible surface defect, hemorrhage, or thrombus; type VII, calcified plaque; and type VIII, fibrotic plaque without a lipid core and with possible small calcifications. Of the 272 possible axial slices (34 patients x 2 arteries per patient x 4 slices per artery), 256 slices were available for lesion type assessment. The majority (94%) of the lesions were of type I-II and III. kappa was 0.80 and 0.60 for intra-reader and inter-reader agreement of lesion types, respectively. Inter-reader disagreement for type I-II and type III occurred in 82% of lesions. Weighted kappa was 0.92 and 0.83 for intra-reader and inter-reader agreement of lesion types, respectively. The difference between type I-II and III lesions lies in the definition of the vessel wall. The moderate inter-reader agreement suggests further efforts such as establishment of normal carotid artery wall thickness by a quantitative measure are needed for carotid atherosclerotic lesion characterization.

Quantitation and Localization of Matrix Metalloproteinases and Their Inhibitors in Human Carotid Endarterectomy Tissues

Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play a central role in arterial wall remodeling, affecting stability of fibrous caps covering atherosclerotic plaques. The objective of this study was to determine the spatial distribution of TIMP mass and MMP mass and activity of carotid endarterectomy (CEA) tissues and relate it to the distribution of atherosclerotic lesions. Fresh CEA tissues were imaged by multicontrast MRI to generate 3D reconstructions. Tissue segments were cut transversely from the common, bifurcation, internal, and external regions. Segments were subjected to total protein extractions and analyzed by ELISA for MMP-2 and -9 and TIMP-1 and -2 mass and by zymography for gelatinase activity. Segments at or near the bifurcation with highly calcified lesions contained higher MMP levels and activity than segments distant from the bifurcation; highly fibrotic or necrotic plaque contained lower MMP levels and activity and higher TIMP levels. Fatty streak, fibroatheroma with hemorrhage and calcification, and fully occluded lesions were enriched in MMP-2, MMP-9, and TIMP-1 and TIMP-2, respectively. The spatial distribution of MMPs and TIMPs in carotid atherosclerotic lesions is highly heterogeneous, reflecting lesion location, size, and composition. This study provides the first semi-quantitative maps of differential distribution of MMPs and TIMPs over atherosclerotic plaques.

Ultrasonic tissue characterization of vulnerable carotid plaque: correlation between videodensitometric method and histological examination

BackgroundTo establish the correlation between quantitative analysis based on B-mode ultrasound images of vulnerable carotid plaque and histological examination of the surgically removed plaque, on the basis of a videodensitometric digital texture characterization.MethodsTwenty-five patients (18 males, mean age 67 ± 6.9 years) admitted for carotid endarterectomy for extracranial high-grade internal carotid artery stenosis (≥ 70% luminal narrowing) underwent to quantitative ultrasonic tissue characterization of carotid plaque before surgery. A computer software (Carotid Plaque Analysis Software) was developed to perform the videodensitometric analysis. The patients were divided into 2 groups according to symptomatology (group I, 15 symptomatic patients; and group II, 10 patients asymptomatic). Tissue specimens were analysed for lipid, fibromuscular tissue and calcium.ResultsThe first order statistic parameter mean gray level was able to distinguish the groups I and II (p = 0.04). The second order parameter energy also was able to distinguish the groups (p = 0,02). A histological correlation showed a tendency of mean gray level to have progressively greater values from specimens with < 50% to >75% of fibrosis.ConclusionVideodensitometric computer analysis of scan images may be used to identify vulnerable and potentially unstable lipid-rich carotid plaques, which are less echogenic in density than stable or asymptomatic, more densely fibrotic plaques.

994: Reduction of the Fibrotic Plaque in a Rat Model of Peyronie's Disease by Long-Term PDE5 Inhibition

You have accessJournal of UrologyPodium, Monday, May 22, 2006, 3:30 - 5:30 pm1 Apr 2006994: Reduction of the Fibrotic Plaque in a Rat Model of Peyronie's Disease by Long-Term PDE5 Inhibition Monica G. Ferrini, Istvan Kovanecz, Gaby Nolazco, Dolores Vernet, Jacob Rajfer, and Nestor F. Gonzalez-Cadavid Monica G. FerriniMonica G. Ferrini More articles by this author , Istvan KovaneczIstvan Kovanecz More articles by this author , Gaby NolazcoGaby Nolazco More articles by this author , Dolores VernetDolores Vernet More articles by this author , Jacob RajferJacob Rajfer More articles by this author , and Nestor F. Gonzalez-CadavidNestor F. Gonzalez-Cadavid More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)33219-1AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "994: Reduction of the Fibrotic Plaque in a Rat Model of Peyronie's Disease by Long-Term PDE5 Inhibition." The Journal of Urology, 175(4S), pp. 320–321 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 175Issue 4SApril 2006Page: 320-321 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Monica G. Ferrini More articles by this author Istvan Kovanecz More articles by this author Gaby Nolazco More articles by this author Dolores Vernet More articles by this author Jacob Rajfer More articles by this author Nestor F. Gonzalez-Cadavid More articles by this author Expand All Advertisement PDF downloadLoading ...

998: Repetitive Intratunical Injection of Adenovirus Expressing Transforming Growth Factor-β1 in a Rat Induces Penile Curvature with Tunical Fibrotic Plaque: A Useful Model for the Study of Peyronie's Disease

998: Repetitive Intratunical Injection of Adenovirus Expressing Transforming Growth Factor-β1 in a Rat Induces Penile Curvature with Tunical Fibrotic Plaque: A Useful Model for the Study of Peyronie's Disease

Effects of long‐term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie's disease

To determine whether the phosphodiesterase-5 (PDE5) inhibitor, vardenafil, given orally and in different regimens, has a similar effect to that of the PDE5 inhibitor sildenafil, which prevented the development of a Peyronie's disease (PD)-like plaque formation induced by injecting transforming growth factor beta1 (TGF-beta1) into the tunica albuginea of the rat. Vardenafil was given to male rats (eight per group) either in the drinking water or as an oral instillation once daily, at approximately 1 and approximately 3 mg/kg/day for 45 days after one injection with TGF-beta1 into the tunica albuginea, as an 'early preventive' treatment for TGF-beta1-induced formation of a PD-like plaque. Other groups received the two doses of vardenafil only in the drinking water, starting with a well-formed plaque, for 42 days ('late, therapeutic' administration). Sections of penile tissue were stained histochemically or immunohistochemically, followed by quantitative image analysis for collagen/smooth muscle and collagen III/I ratios, myofibroblast content (alpha-smooth muscle actin), TGF-beta1 expression, and apoptotic index. Preventative treatment with vardenafil at the higher dose (both continuous and once-daily treatments) reduced the collagen/smooth muscle and collagen III/I ratios, and the numbers of myofibroblasts and TGF-beta1-positive cells, and selectively increased the apoptotic index in the PD-like plaque. The lower dose was less effective, When vardenafil was given continuously in the drinking water for 41 days after the PD-like plaque was formed, there was only a partial reduction of the plaque. Long-term oral treatment with vardenafil slows and reverses the early stages of an experimental PD-like plaque in the rat, and might ameliorate a more advanced plaque.