-
[show abstract]
[hide abstract]
ABSTRACT: Metalloproteases with a disintegrin domain (ADAM) has already been implicated in various cellular processes such as cytokine and growth factor shedding, proliferation, migration, and degradation of extracellular matrix. Their role in the development and progression of atherosclerosis in carotid lesions is however unknown. The aim of the study was to analyze expression of proteolytic ADAMs (8, 9, 10, 12, 15, 17) and their inhibitors TIMP-1, -3 in patients with high-graded carotid artery stenosis. Atherosclerotic plaques were obtained from 44 patients undergoing carotid endarterectomy (CEA) and analyzed by histochemistry, immunohistochemistry, and SYBR green-based real-time PCR. All ADAMs analyzed in our study were expressed in early as well as in advanced atherosclerotic carotid lesions. The highest expression within the plaque was observed for ADAM15 followed by ADAM8. Furthermore, a significant increase was observed in the expression of ADAM10 and ADAM12 in unstable plaques compared to unstable lesions (p = 0.05 and p = 0.036, respectively). In contrast, expression of TIMP-1 was significantly reduced in the same lesions (p = 0.020). Macrophages and smooth muscle cells showed the highest staining intensity and were positive for all ADAMs and TIMPs tested, with the exception of ADAM9. Endothelial cells at the lumen side were positive for ADAM 15 and TIMP-1, neovessels were positive also for ADAM12. In conclusion, the ADAM family of proteases seems to play an important role in the maintenance of proper vessel physiology and some ADAMs such as ADAM10 and ADAM12 might also contribute to the progression of atherosclerosis.
Scandinavian journal of clinical and laboratory investigation 10/2012; · 1.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: An important feature of abdominal aortic aneurysm (AAA) is the destruction of vessel wall, especially elastin and collagen. Besides matrix metalloproteinases, cathepsins are the most potent elastolytic enzymes. The expression of cathepsins with known elastolytic and collagenolytic activities in the individual cells within AAA has not yet been determined. The vessel wall of 32 AAA patients and 10 organ donors was analysed by immunohistochemistry for expression of cathepsins B, D, K, L and S, and cystatin C in all cells localized within AAA. Luminal endothelial cells (ECs) of AAA were positive for cathepsin D and partially for cathepsins B, K and S. Endothelial cells of the neovessels and smooth muscle cells in the media were positive for all cathepsins tested, especially for cathepsin B. In the inflammatory infiltrate all cathepsins were expressed in the following pattern: B > D = S > K = L. Macrophages showed the highest staining intensity for all cathepsins. Furthermore, weak overall expression of cystatin C was observed in all the cells localized in the AAA with the exception of the ECs. There is markedly increased expression of the various cathepsins within the AAA wall compared to healthy aorta. Our data are broadly consistent with a role for cathepsins in AAA; and demonstrate expression of cathepsins D, B and S in phagocytic cells in the inflammatory infiltrate; and also may reveal a role for cathepsin B in lymphocytes.
International Journal of Experimental Pathology 08/2012; 93(4):252-8. · 2.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Inflammatory-proteolytic processes in the vessel wall are essential in the pathophysiology of abdominal aortic aneurysm (AAA). It has been demonstrated that, (18)F-FDG-PET/CT may be useful for detection of pathological wall metabolism and therefore risk stratification. Quantification of the FDG-uptake in AAA wall is hampered by partial-volume (PV)-effects. For correction and accurate quantitative (18)F-FDG-uptake analysis we designed and validated a novel IDL-based software in correlation to phantom studies, histopathology and clinical presentation of AAA patients. For in vivo studies 23 patients with symptomatic and asymptomatic AAA underwent (18)F-FDG-PET/CT before surgery. In areas with (18)F-FDG-uptake the maximum and mean standardized uptake values in the vessel wall with (PVC-SUV(max), PVC-SUV(mean)) and without (SUV(max), SUV(mean)) PV-correction were determined. Results were correlated with clinical presentation, corresponding macrophage-infiltration and MMP-2- and -9-expression in surgical specimens. In patients, SUV(max), SUV(mean) as well as PVC-SUV(max) or PVC-SUV(mean) enabled a highly significant (p < 0.005) discrimination of symptomatic and asymptomatic AAA. Uncorrected and corrected SUVs showed comparable correlations with macrophage-infiltration and MMP-9 expression. No correlation of (18)F-FDG-uptake and MMP-2 was found. In vivo correlations of detected FDG-uptake with clinical and histological results showed comparable results for corrected and uncorrected SUVs. PV-correction is not mandatory for qualitative clinical assessment of glucose metabolism in the vessel wall of AAA-patients but may be necessary to establish quantitative cut off values to stratify patients for aneurysm repair.
The international journal of cardiovascular imaging 07/2012; · 2.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The a disintegrin and metalloprotease (ADAM) family of metalloproteases possesses a proteolytic function and activates various inflammatory factors. Their expression pattern in an abdominal aortic aneurysm (AAA) is as yet unknown. The aim of this study was to make a detailed analysis of the expression of ADAMs 8, 9, 10, 12, 15 and 17, and their tissue inhibitors of metalloprotease (TIMP)-1 and TIMP-3 in patients with AAA.
The aortic vessel walls of AAA patients (n=20) and non-aneurysmal aortic specimens (n=10) were obtained by conventional surgical repair and autopsy. SYBR green-based real-time PCR, histology and immunohistochemistry were performed on all samples.
Quantitative expression analysis and the localisation of various ADAMs in AAA.
ADAMs tested in our study were expressed in both AAA and control aorta without any significant differences between the groups. In contrast, expression of TIMP-1 was significantly reduced in AAA compared to control vessels. Smooth muscle cells (SMCs), neovessels and macrophages were positive for all ADAMs and TIMPs tested. Infiltrates were negative for TIMP-3, and luminal endothelial cells were positive for ADAMs 15 and 17. A significant positive correlation was observed between ADAMs 10, 12, 15, 17, TIMP-3 and SMCs.
ADAMs are constitutively expressed in normal aortic vessel walls and AAA, particularly in SMCs.
Journal of Vascular Research 03/2012; 49(3):198-206. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Most atherosclerotic lesions are vascularized, so neovessels may also contribute to plaque progression and vulnerability, but their precise role of neovessels in atherosclerosis is still unknown. The aim of this study was to analyze the possible relationships among neovascularization, relevant angiogenic factors, and plaque vulnerability in patients with advanced carotid artery stenosis.
The study group comprised 56 patients (stable: n=28, unstable: n=28) with advanced carotid artery stenosis (>70%). Immunohistochemistry was performed for smooth muscle, endothelial, and inflammatory cells, macrophages, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), platelet-derived growth factor (PDGF), and angiopoietin-1,-2 (Ang-1,-2). Furthermore, the concentrations of angiogenic factors were measured in serum. Quantitative expression analysis was performed by SYBR-Green-based real-time polymerase chain reaction. Compared with stable carotid lesions, unstable carotid lesions showed 1.8-fold increase in neovascularization (P=0.013), which significantly correlated with accumulation of inflammatory cells (factor 1.9, P<0.001). In unstable lesions, compared with stable lesions, VEGF was 1.7-fold increased (P=0.032) and Ang-1 was 1.9-fold reduced (P=0.029). Furthermore, VEGF was higher in the blood of patients with unstable plaques than in stable plaques (0.32 ± 0.22 vs. 0.22 ± 0.16 ng/ml; P=0.002). Significant correlations were observed between plaque vulnerability, VEGF, neovascularization and inflammatory cells.
Our results show a close association between neovascularization, expression of angiogenic factors, inflammation, and plaque vulnerability in patients with advanced carotid stenosis.
Circulation Journal 03/2012; 76(5):1274-82. · 3.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Indocyanine green (ICG) fluorescence angiography is used to evaluate tissue perfusion in many different medical fields. This study aims to evaluate the value of ICG angiography in the determination of tissue perfusion in the PAD lower extremities.
In a prospective clinical study, ICG angiography was used to evaluate tissue perfusion and collateralization in 30 PAD patients. The perfusion index and maximum fluorescence intensity (MPI) were calculated as arterial perfusion parameters.
Significant differences in the perfusion index were found for the different PAD stages (p < 0.001). Poor collateralization was associated with a significantly lower perfusion index than good collateralization (p = 0.003). A ROC analysis for the perfusion index showed a positive likelihood ratio of 6.00 and a negative likelihood ratio of 0.00 with an area under the curve of 0.949 to discriminate critical and non-critical PAD.
ICG angiography is a promising diagnostic tool to quantify tissue perfusion and demonstrate critical limb ischemia and collateralization in lower extremities affected by PAD.
Clinical hemorheology and microcirculation 01/2012; 50(3):157-66. · 3.40 Impact Factor
-
International Journal for Numerical Methods in Biomedical Engineering. 09/2011; 28(1):87 - 99.
-
[show abstract]
[hide abstract]
ABSTRACT: Little is known about the effect of chronic kidney disease (CKD) on plaque morphology in cerebral vessels. We therefore analyzed plaque composition and metabolic and chemical parameters with regard to clinical outcome in patients with advanced carotid artery stenosis (>70%) and normal or impaired renal function.
Carotid endarterectomy plaques were collected from 114 patients, 51 with CKD and 63 without CKD (mean estimated glomerular filtration rate, 49 ± 9 vs 88 ± 14 mL/min), and analyzed by histology and immunohistochemistry. Serum levels of matrix metalloproteinases (MMP-1, -2, -3, -7, -8, and -9), calcium, phosphate, parathyroid hormone, fetuin-A, osteoprotegerin, and inflammatory factors, including fibrinogen, and high-sensitive C-reactive protein (hsCRP) were measured by appropriate enzyme-linked immunosorbent assay.
Compared with patients without CKD, patients with CKD had significantly more early-stage (11.2% vs 2.8%, P = .002) and end-stage (7.4% vs 0.2%, P = .036) calcification, unstable (50.8% vs 20.4%, P = .001) and ruptured (53.1% vs 32.8%, P = .035) lesions, and a significantly lower amount of collagenous fibers (39.2% vs 54.6%, P = .001). Serum samples of CKD patients had significantly enhanced levels of fibrinogen (393 ± 88 vs 331 ± 60 mg/dL, P = .018), hsCRP (1.7 ± 2.9 vs 0.8 ± 0.9 mg/dL; P = .042), parathyroid hormone (47.3 ± 24.1 vs 32.8 ± 12.2 ng/L, P = .010), fetuin-A (0.21 ± 0.05 vs 0.18 ± 0.04 mg/mL, P = .039), and MMP-7 (13.0 ± 5.3 vs 8.3 ± 3.0 ng/mL; P < 0.001). The incidence of cerebrovascular events >6 months before carotid surgery was significantly increased in CKD patients (84.0% vs 26.2% P < .001).
In patients with CKD and advanced carotid artery stenosis, morphologic changes in plaque composition may contribute to plaque vulnerability and consequently to the risk of cerebrovascular events. Furthermore, relevant serum markers of inflammation, vascular calcification, and vessel wall degradation might be an indication of stroke risk in CKD patients.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 07/2011; 54(6):1643-9. · 3.52 Impact Factor
-
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 10/2010; 52(4):1124-5. · 3.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: By conventional imaging modalities, the discrimination between acute and chronic aortic dissection (AD) for surgical risk evaluation is not possible. However, acute and chronic stable AD potentially may be distinguished by detection of reparatory hypermetabolism in the lacerated aortic wall of acute AD using (18)F-FDG PET/CT. In this study, we analyzed the (18)F-FDG uptake in the aortic wall of acute and chronic stable AD.
Eighteen patients with acute (n = 9), symptomatic progressive (n = 2), or known chronic stable (n = 7) type B AD underwent (18)F-FDG PET/CT. Images were analyzed qualitatively and quantitatively considering (18)F-FDG uptake patterns and the standardized uptake values (SUVs) of the aortic wall, dissection membrane, and luminal (18)F-FDG activity. The SUV ratio (maximum SUV in the aorta divided by mean SUV in the blood pool) was calculated to relativize individual luminal (18)F-FDG spillover effects.
In contrast to chronic stable AD, all acute or acute progressive AD showed accentuated (18)F-FDG uptake at the injured aortic wall or dissection membrane. The maximum SUV of the dissection membrane or aortic wall was significantly higher (P = 0.02) in acute AD than in chronic stable AD. Thereby, SUV varied from 3.03 to 4.64 (average maximum SUV, 3.84 +/- 0.51) for the dissection membrane and from 2.22 to 4.60 (average maximum SUV, 2.94 +/- 0.81) for the aortic wall, with false-negative and false-positive outliers. The discrimination between acute and stable AD was improved significantly (P < 0.001), and false-positive or -negative outliers were eliminated, using the SUV ratio method.
Our results indicate that (18)F-FDG PET/CT might be useful in differentiation of acute from chronic AD in clinically unclear cases. However, larger studies are needed to confirm our preliminary results.
Journal of Nuclear Medicine 05/2010; 51(5):686-91. · 6.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In principle, superiority of computational wall stress analyses compared with the maximum diameter criterion for rupture risk evaluation of abdominal aortic aneurysm (AAA) has been demonstrated. The results of finite element analyses should be evaluated carefully, however, because computational strains and stresses are highly dependent on the quality and complexity of each step of AAA simulation. Most clinically active vascular specialists are not familiar with the processes of computational mechanics to evaluate the quality of AAA simulations. For better understanding and to provide insights in computational biomechanics of AAA, the effect of different computational model assumptions on the results of simulation are explained and demonstrated.
Four patients with asymptomatic (n = 3) and symptomatic (n = 1) infrarenal AAAs with distinctly different aneurysm morphologies were exemplarily studied. For segmentation and 3-dimensional (3D) reconstruction of AAA and thrombus, 3-mm computed tomography (CT) slices were used, and a high-density hexahedral element-dominated finite element mesh was generated. Subsequent AAAs were simulated on seven different levels, culminating in the most realistic ortho-pressure-finite element analyses simulations, including thrombus, wall calcifications, and prestress state of AAA geometry with nonlinear hyperelastic material and geometric model assumptions.
Alterations in displacements due to model assumptions are up to 740% for a specific aneurysm. The average maximum discrepancy among the four morphologies between simple and advanced models is 607%. Differences in peak wall stress between simple and realistic models are up to 210% individually and 170% on average.
Differences of model assumptions are more important for simulation results than differences between patient-specific morphologies. Because the biomechanical behavior of AAA is nonlinear in many senses, comparisons between individual morphologies and statistics are only valid when detailed information about preconditions and model assumptions is provided.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 03/2010; 51(3):679-88. · 3.52 Impact Factor
-
Circulation Cardiovascular Imaging 11/2009; 2(6):507-9. · 5.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In this study a multiscore analysis of various biomarkers including matrix metalloproteinases (MMPs), inflammatory factors and other clinical parameters was performed to establish a set of reliable biomarkers for improved detection of plaque instability in patients with advanced carotid stenosis.
Study patients (n = 101) were classified as histologically stable (n = 37) or unstable (n = 64). Serum levels of MMP-1, -2, -3, -7, -8, -9, MMP inhibitors TIMP-1, -2, and inflammatory factors such as tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta, -6, -8, -10, and -12 were measured by ELISA assays. Multiscore analysis was performed using multiple receiver operating characteristics analysis and determination of appropriate cutoff values.
Circulating levels of MMP-1, -7, TIMP-1, TNF-alpha, and IL-8 were significantly enhanced in patients with unstable plaques compared to individuals with stable lesions, mean differences being 1.2 (p = 0.032), 2.5 (p = 0.004), 30.0 (p = 0.014), 1.3 (p = 0.047), and 2.2 (p = 0.033), respectively. The combination of MMP-1, -7, TIMP-1 and IL-8 demonstrated the highest positive predictive value of 89.4% and negative predictive value of 60.1% for patients correctly classified as individuals with unstable and stable carotid lesions by means of blood sample analysis.
Multiple relevant biomarkers that play a decisive role in plaque instability can improve the correct determination of vulnerable carotid plaques in patients with advanced carotid artery stenosis.
Cerebrovascular Diseases 10/2009; 28(6):601-10. · 2.72 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Abdominal aortic aneurysm (AAA) wall is characterized by degradation of extracellular matrix through matrix metalloproteinases (MMPs), chronic inflammatory cell infiltration and extensive neovascularization. So far, MMP expression within AAA wall in association with infiltrates and neovascularization has not yet been studied.
Vessel walls of 15 AAA patients and 8 organ donors were analyzed by immunohistochemistry for expression of various MMPs (MMP-1, -2, -3, -7, -8, -9, -12 and -13) in all cells located within the AAAs and correlated with infiltrates and neovascularization.
Luminal endothelial cells (ECs) were positive for MMP-1, -3 and -9, ECs of mature neovessels were furthermore positive for MMP-2. Immature neovessels expressed all MMPs tested except for MMP-13. Aortic medial smooth muscle cells (SMCs) expressed MMP-1, -2, -3 and -9, SMCs of mature neovessels, only MMP-1, -3 and -9. Inflammatory infiltrates expressed all MMPs tested except for MMP-2, macrophages expressed all MMPs. Infiltrates were composed mainly of B cells (58.5 +/- 10.9%) and T lymphocytes (26.3 +/- 9.5%). Furthermore, significant inverse correlations were found between the amounts of inflammatory cells, neovessels and collagen/elastin content of the aortic vessel wall (r = +0.806/p < 0.001, r = -0.650/p = 0.012, r = -0.63/p < 0.015; respectively).
Inflammatory infiltrates and invading neovessels are relevant sources of MMPs in the AAA wall and may substantially contribute to aneurysm wall instability.
Pathobiology 01/2009; 76(5):243-52. · 1.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: With the established computed tomographic (CT)- morphologic parameters, only the relative, but not the individual rupture risk of abdominal aortic aneurysm (AAA), can be determined. So far, increased aortic 18F-fluorodeoxyglucose (FDG) metabolism measured by positron emission tomography (PET) has been reported in AAA with increased rupture risk. The aim of the study was to analyze the histopathologic changes in AAA wall correlated with increased FDG uptake for further implications on aortic wall stability and AAA rupture risk.
Fifteen patients with asymptomatic (n = 12) and symptomatic (n = 3) AAA underwent FDG-PET/CT, followed by open AAA repair. FDG-PET/CT was used for precise localization of maximum FDG uptake, and the maximum standard uptake values (SUV(max)) were calculated. Biopsies of the AAA wall were operatively collected from areas with maximum FDG uptake, immunohistologically stained, and semiquantitatively analyzed for inflammatory infiltrates, vascular smooth muscle cells (VSMC), matrix metalloproteinase (MMP)-2 and -9 expression, as well as for elastin and collagenous fibers.
Symptomatic AAA showed significantly increased FDG uptake compared with asymptomatic AAA (SUV(max), 3.5 +/- 0.6 vs 7.5 +/- 3; P < .001). Thus, increased FDG uptake was correlated with higher densities of inflammatory infiltrates (r = +0.87, P < .01) and macrophage and T-cell infiltrations (r = +0.95, P < .01 and r = +0.66, P < .05), with higher MMP-9 expressions (r = +0.86; P < .01), and with reduction of collagen fiber (r = -0.76; P < .01) and VSMCs (r = -0.71; P < .01). Consecutive correlations were found for total inflammatory infiltrates, T lymphocytes, and macrophages with MMP-9 expression (r = +0.79, +0.79 and +0.74; P < .01). Moreover, MMP-9 expression was correlated with decreasing collagen fiber content (r = -0.53, P < .05) and VSMC density (r = -0.57, P < .05).
Maximum aortic FDG uptake correlated significantly with inflammation, followed by increased MMP expression and histopathologic characteristics of aneurysm wall instability and clinical symptoms. Therefore, FDG-PET/CT might be a new diagnostic technique to study AAA disease in vivo and may contribute to improve prediction of individual AAA rupture risk.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 07/2008; 48(2):417-23; discussion 424. · 3.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We describe the case of a 37-year-old pregnant woman, who was admitted to hospital for suspicion of chorioamnionitis. An emergency C-section was performed. Four days later, the patient suffered from abdominal pain and fever. Computed tomographic scanning demonstrated only a thrombosis of the right ovarian vein. Anticoagulation and antibiotic therapy was started immediately. Color duplex imaging performed 3 days later revealed a free-floating caval thrombus reaching the confluence of hepatic veins while the patient was fully anticoagulated. Emergency thrombectomy was performed by laparotomy, and the thrombus was removed by caval incision during suprahepatic clamping of the inferior vena cava. The patient recovered rapidly from surgery and was discharged on the tenth postoperative day.
Annals of Vascular Surgery 23(5):688.e7-9. · 1.03 Impact Factor
