Alexander Zimmermann

Histopathological analysis of cellular localization of cathepsins in abdominal aortic aneurysm wall

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.

Histone acetylation and methylation significantly change with severity of atherosclerosis in human carotid plaques

BACKGROUND The aim of the study was to analyze histone acetylation, methylation, and the expression of their corresponding transferases in atherosclerotic plaques of patients with carotid artery stenosis. METHODS Atherosclerotic tissue from our biobank (n=80) was divided into various segments covering all plaque stages and classified according to the American Heart Association. The plaques were assigned to early (types I-III) or advanced (types V-VII) stage group of atherosclerosis. Ten healthy carotid arteries from transplant donors served as controls. The expression of histone acetyltransferases (GNAT group: GCN5L, P300/CBP group: P300, MYST group: MYST1 and MYST2) and histone methyltransferases (H3K4: MLL2/4, SET7/9, and hSET1A; H3K9: SUV39H1, SUV39H2, ESET/SETDB1, and EHMT1; H3K27: EZH2 and G9a) was analyzed by SYBR-green-based real-time polymerase chain reaction. Histone acetylation/methylation in the cells within atherosclerotic plaques was determined by immunohistochemistry. RESULTS Increased histone acetylation was observed on H3K9 and H3K27 in smooth muscle cells (SMCs) in advanced atherosclerotic lesions compared to healthy vessels (P=.002 and .034). H3K9 acetylation in SMCs and macrophages was associated with plaque severity of atherosclerosis (P=.048 and <.001). Expression of GCN5L and MYST1 also correlated with the severity of atherosclerosis (P<.001). Methylation of H3K9 and H3K27 was significantly reduced in atherosclerotic plaques in SMCs and inflammatory cells (P<.001 and .026). Methylation on H3K4 was significantly associated with the severity of atherosclerosis. Expression of methyltransferase MLL2/4 was increased in advanced stages of atherosclerosis (P<.001). CONCLUSIONS Histone acetylation and methylation seem to play a decisive role in atherosclerosis, showing significant differences between healthy vessels and vessels at different stages of atherosclerosis.

Eligibility for Endovascular Technique and Results of the Surgical Approach to Popliteal Artery Aneurysms at a Single Center

BACKGROUND Less than 0.1% of the population experiences a popliteal aneurysm (PA), and the consequences of not treating PA include a significant risk of embolization, thrombosis, and limb loss. Surgical treatment for this vascular disease has produced excellent clinical results, but there remain an increasing number of published reports that continue to question the efficacy of endovascular therapies. METHODS All consecutive patients operated on for PA at our hospital in the years 2000-2007 were reviewed retrospectively for clinicopathological data and applicability for endovascular treatment. RESULTS Forty-six patients were surgically treated for 56 PAs (42 vein, 11 alloplastic material, and one composite graft). Overall survival rates after 2 and 5 years were 77% and 54%, respectively. Reintervention-free survival rates at 2 and 5 years were 71% and 43%, respectively. Graft patency for veins was significantly higher, with a hazard ratio of 0.025 (95% confidence interval 0.002-0.304, p=0.004). Twenty-two of the 37 patients (59.5%) with a sufficient angiograph appeared to be eligible for endovascular treatment. CONCLUSION Despite the positive results of surgical repair shown in our study and in the existing literature, endovascular treatment has a high technical eligibility with good reported outcomes and represents an alternative for open surgery.

Histomorphological evaluation of atherosclerotic lesions in patients with peripheral artery occlusive disease

PURPOSE Peripheral arterial occlusive disease (PAOD) is mainly caused by atherosclerosis of the vessel wall. These pathological changes are classified into different stages and are well described for carotid and coronary vessels, but not for PAOD. The aim of our study was to analyze plaque morphology of femoral arteries in patients with intermittent claudication and critical limb ischemia. PATIENTS AND METHODS In this retrospective study 85 atherosclerotic plaques (common and superficial femoral artery) of 71 patients with a clinical symptomatic PAOD were analyzed, by histology (01/2009-07/2010). Atherosclerotic lesions were classified according to Stary (type I-VIII). For further characterization, plaques were evaluated for the presence of collagen, elastin, calcifications, smooth muscle cells, macrophages, leucocytes, and cellularity. RESULTS The majority (91%) of atherosclerotic lesions were of advanced types according to Stary (V-VII). Atherosclerotic lesion type VI was associated with significant higher amount of inflammatory cells in comparison to all other atherosclerotic plaque types (CD45: p<0.001; CD68: p=0.013). In addition, atherosclerotic plaques with a pronounced neovascularization contained a higher amount of CD45 (p=0.015; rho=0.273) and CD68 (p=0.016; rho=0.275) positive cells. CONCLUSION Atherosclerotic lesions of femoral arteries show similar morphological changes as coronary or carotid arteries. But inflammatory cells had a higher impact on plaque progression and destabilization than any other factor.

Early venous manifestation of Ehlers-Danlos syndrome Type IV through a novel mutation in COL3A1.

Ehlers-Danlos syndrome (EDS) leads to abnormalities in the synthesis of collagen and complications involving arterial vessels. We describe here a mutation in the intron 14 of the COL3A1 gene leading to EDS Type IV (EDS IV) associated with venous manifestations only. The patient, an 18-year-old male, suffered from truncal varicosity of the long saphenous vein on both sides. Conventional stripping surgery of the left saphenous vein revealed an extremely vulnerable ectatic superficial femoral vein. An inserted vein graft occluded, and venous thrombectomy was unsuccessful. A conservative anticoagulant and compression therapy finally succeeded. This is the first report describing EDS IV due to a mutation in intron 14 of the COL3A1 gene leading to venous manifestations without affecting arterial vessels at clinical presentation. Our findings imply that molecular genetic analysis should be considered in patients with unusual clinical presentation and that conservative therapy should be applied until a suspected clinical diagnosis has been secured.