Angiotensin-converting enzyme gene insertion/deletion polymorphism and carotid artery wall thickness in patients with peripheral arterial occlusive disease.

BACKGROUND: It has been suggested that the deletion polymorphism of the angiotensin converting enzyme (ACE) gene is linked to a high risk of cardiovascular disease. The relationship between the insertion/deletion (I/D) polymorphism of the ACE gene and the carotid intima-media thickness in patients with peripheral arterial occlusive disease is unknown. We tested the hypothesis that the early progression of atherosclerosis in the extracranial carotid arteries in patients with peripheral arterial disease is associated with a genetic predisposition. METHODS: This prospective trial included 98 patients who only had manifestations of arteriosclerotic disease in peripheral arterial vascular regions of the lower extremities (stable stage II PAOD). Maximal common carotid intima-media thickness (mIMT) was measured using high resolution B-mode ultrasonography. Determinations of ACE gene polymorphism were made using a polymerase chain reaction technique. Multivariate regression analysis was performed to assess the influence of ACE genotypes, ACE activity and vascular risk factors on intima-media thickness. RESULTS: There was no significant association between intima-media thickness and ACE gene polymorphism. History of symptomatic peripheral arterial disease without local or systemic progression exists in subjects with the II-genotype significantly longer than in subjects with the DD genotype (p=0.01). With the presence of an II-genotype, there was also a tendency towards a thinner intima-media thickness. We found significant correlations between intima-media thickness and age (p<0.0001), fasting serum insulin (p=0.001), and lipoprotein (a) (p=0.008). CONCLUSIONS: In the present study involving patients with stage II peripheral arterial occlusive disease, ACE gene polymorphism could not be identified as a determining marker for the development of intima-media thickening in the common carotid artery. However, it can be assumed that there is a reduced risk for the systemic progression of atherosclerosis in patients with the II genotype.     

Common Carotid Intima-media Thickness in Peripheral Arterial Disease

The common carotid intima-media thickness (IMT) is regarded as a reliable predictor of cardiovascular morbidity. Patients with peripheral arterial disease (PAD) have an increased risk of cardiovascular morbidity and mortality, and PAD is associated with increases in IMT. The aim of this study was to establish whether IMT would be a suitable parameter for predicting cardiovascular risk in individual patients with PAD and the factors involved in determining IMT in these patients. This prospective study included 314 subjects: 112 patients with isolated PAD, 85 patients with PAD and additional coronary and/or cerebrovascular atherosclerosis, and 117 subjects without atherosclerotic disease. Maximum IMT (mIMT) was measured using high-resolution B-mode ultrasonography. Patients with isolated PAD were examined for influencing factors on mIMT. The mIMT in patients with isolated PAD (1.01±0.2 mm) was not significantly different from that of patients with PAD and additional systemic atherosclerosis (1.01±0.17 mm). Controls showed a significantly lower mIMT (0.71±0.15 mm). In multivariate stepwise regression analysis, the chief influencing factors on mIMT in patients with isolated PAD included age as well as fasting insulin and plasminogen activator inhibitor-1 (PAI-1). We found significant correlations between mIMT and the presence of microalbuminuria in nondiabetics with PAD. The highly increased mIMT values of patients with isolated PAD reflect the elevated cardiovascular risk which is already present in the early clinical stages of PAD. The links between fasting insulin, PAI-1, microalbuminuria, and older age with mIMT in isolated PAD are at the same time important predictors of the development of systemic atherosclerosis in PAD.     

„Korallenriffatherosklerose“

Hemodynamically relevant stenoses of the thoracic and suprarenal aorta in atherosclerotic patients are extremely rare. This entity is different from in-flammatory aortic arch lesions or from infrarenal atherosclerotic stenoses. In a 55-year-old woman suf-fering from hypertension and bilateral arterial occlusive disease, multiple calcified subtotal stenoses of the aorta are diagnosed, suggesting “coral reef atherosclerosis”. Based on this example, the thoracoabdominal bypass in a retropancreatic position is compared to a retroperitoneal thoracoabdominal transaortic endarterectomy.     

Metabolomics reveals the depletion of intracellular metabolites in HepG2 cells after treatment with gold nanoparticles

Studies on the safety of gold nanoparticles (GNPs) are plentiful due to their successful application in drug delivery and treatment of diseases in trials. Cytotoxicity caused by GNPs has been studied on the physiological and biochemical level; yet, the effect of GNPs (particularly gold nano-spheres) on the metabolome of living organisms remains understudied. In this investigation, metabolomics was used to comprehensively study the metabolic alterations in HepG2 cells caused by GNPs; and to investigate the role of representative GNP coatings. GNPs were synthesized, coated and characterized before use on HepG2 cell cultures. Cells were treated for 3?h with citrate-, poly-(sodiumsterene sulfunate)-, and poly-vinylpyrrolidone (PVP)-capped GNPs, respectively. The internalization of the different GNPs and their effect on mitochondrial respiration and the metabolome were studied. Results indicated that the PVP-capped GNPs internalized more and also caused a more observable effect on the metabolome. Conversely, it was the citrate- and poly-(sodiumsterene sulfunate) coated particles that influenced ATP production in addition to the metabolomic changes. A holistic depletion of intracellular metabolites was observed regardless of GNP coating, which hints to the binding of certain metabolites to the particles.     

Premature Collagen Fibril Formation,Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

Keloids are benign hyper-proliferative growths of fibrous tissue where increased fibroblast activity results in abnormal collagen deposition. Excessive inflammation is a characteristic feature of keloids, but little is known about the underlying ultrastructural features of keloids related to collagen processing, fibril and fiber formation, the interaction between fibroblasts and associated collagen fibers and mast cells. In this study, the ultrastructure of the dermis of keloid patients was evaluated using light and transmission electron microscopy techniques. Abnormal intracellular premature collagen fibril formation was observed. Phagocytosis of collagen fibrils by mast cells was a common ultrastructural feature of keloid tissue as was a close or direct association between fibroblasts and mast cells. Based on these findings and recent advances in knowledge related to collagen synthesis, fibril formation and processing, we hypothesize that keloid formation is primarily due to abnormal collagen synthesis where the consequent accumulation of collagen fibers causes increased mast cell recruitment and collagen phagocytosis. Subsequent release of mast cell-derived mediators then promotes further collagen synthesis. The observation of early formation in keloid tissue of premature insoluble collagen fibrils supports previous studies that enzymes such as procollagen C-proteinase are important early therapeutic targets.     

Hyperhomocysteinemia: marker of systemic atherosclerosis in peripheral arterial disease.

AIM: Patients suffering from peripheral arterial disease (PAD) are increasingly described as having hyperhomocysteinemia more than in patients with coronary artery or cerebrovascular disease. Cases of symptomatic PAD usually present with associated coronary artery or cerebrovascular disease and renal artery disease. It can thus be postulated that multilocular atherosclerosis is linked to hyperhomocysteinemia and that the extent of atherosclerosis has a possible correlation with homocysteine concentrations. The aim of this study was to ascertain whether fasting total homocysteine concentrations in patients with PAD are associated with the extent and the localization of systemic atherosclerosis in cerebrovascular, coronary and/or renal vascular zones. METHODS: A total of 183 patients with PAD, Fontaine stages II-IV, were divided into 2 groups: Group A contained patients with isolated PAD (n=98) and Group B patients with systemic atherosclerosis in PAD (n=85). Characterization of vascular disease in various vascular zones was indication-adapted using non-invasive and/or invasive METHODS: Patients with renal insufficiency were excluded from the study. RESULTS: Homocysteine concentrations were significantly lower in patients with isolated PAD than in patients with additional systemic atherosclerosis (10.1+/-4.4 vs 16.7+/-7.04 micromol/l, p<0.0001). There were no differences in localization or extent of concomitant systemic atherosclerosis. Logistic regression analysis indicated that elevated plasma homocysteine and decreasing ABPI served independently as significant risk indicators for systemic atherosclerosis in patients with PAD (p<0.0001). CONCLUSION: Hyperhomocysteinemia is a precursoral marker of systemic atherosclerosis and thus a prognostic indicator of cardiovascular morbidity and mortality in PAD.     

Progression of atherosclerosis in patients with peripheral arterial disease as a function of angiotensin-converting enzyme gene insertion/deletion polymorphism

Angiotensin-converting enzyme insertion/deletion (I/D) gene polymorphism plays a role in determining the inter-individual variability of circulating angiotensin-converting enzyme activity and intracellular angiotensin-converting enzyme levels. Angiotensin-converting enzyme, as a key enzyme in the renin-angiotensin system, catalyzes the activation of the vasoconstricting and proliferation-stimulating angiotensin II and breaks down the vasodilatory peptide bradykinin. It is assumed that the excess supply of angiotensin II (due to the deletion polymorphism of the angiotensin-converting enzyme gene) contributes to endothelial dysfunction and in this way promotes the onset and progression of atherosclerosis. The aim of this study was to test whether the presence of the deletion allele of the angiotensin-converting enzyme gene predisposes a more rapid systemic progression of a preexisting peripheral arterial disease. To this end, the course of disease was surveyed for an average of 5 years in 97 patients who were angiotensin-converting enzyme gene-typed and suffered from a stable stage II peripheral arterial disease according to Fontaine. These patients did not suffer from an additional coronary artery disease, a cerebrovascular disease, or other serious illness. A local progression in the periphery or a systemic progression in the coronary or cerebrovascular areas was regarded as study endpoints. Of the patients, 49.5% showed an atherosclerosis progression during the surveillance period. With II-carriers, a progression was registered in 42.1% and with DD carriers, progression was seen in 59.4%. D/I allele frequencies were seen in patients with progression at a level of 0.60/0.40 vs 0.55/0.45 for patients without progression. The average duration of disease in stable stage II (before progression appeared) amounted to 108 +/- 14 months for II carriers, 88 +/- 8 months for ID carriers, and 92 +/- 11 months for DD carriers (p = 0.21). Based on these findings, the deletion polymorphism of the angiotensin-converting enzyme gene is not an independent risk factor for progression of atherosclerosis in patients with peripheral arterial disease.