Vessel Wall Lesions Research Articles

Accidents vasculaires des transports, le train aussi

The risk of thromboembolic events related to travel is not exclusively due to air travel. We report the case of a patient who presented pulmonary embolism after prolonged train travel. An 82 Year-old patient had a significant past history of ischemic heart disease. He traveled by train, in a sitting position, for around 12 hours from Barcelona (Spain) to Paris (France). Approximately 24 hours after the journey, he presented pain in the right leg and dyspnea, which increased during the following 48 hours. Ultrasonographic cardiac examination revealed pulmonary arterial hypertension (54mm Hg), acute right ventricular failure and showed a thrombus located in the pulmonary artery, confirming the diagnosis of pulmonary embolism. Ultrasonography diagnosed deep venous thrombosis of the right leg. Treatment with heparin and oral anticoagulant was initiated. Evolution was favorable and the patient was discharged home 14 days later. No further medical event occurred during the Year that followed. The mechanisms that precede the development of a venous thrombosis are not specific to the method of transport. Blood vessel wall lesions, venous stasis and blood clotting component abnormalities, principle elements in the development of thrombosis according to Virchow's triad, are enhanced by prolonged sitting position, during travel, whether in planes or not. The role of other risk factors, personal or depending on the condition of travel, remains unknown. Simple prophylactic measures should be widely proposed during long travel, whatever the mode of transport. The development of a venous thrombosis, enhanced by prolonged sitting position, can occur whatever the form of travel. Prophylactic measures should be widely prescribed for prolonged travel, taking in consideration personal thromboembolic risk factors and circumstances of travel.

Angioscopy and ischemic heart disease.

Angioscopy allows direct visualization of the coronary artery lumen and provides detailed information regarding the surface characteristics of the vessel wall and specific lesions causing acute coronary syndromes. Disruption of a plaque, ulceration, tears, fissures, lipid-rich or fibrous lesions, and luminal or mural thrombus can be readily detected in vivo. Characterization of culprit lesions in various coronary syndromes reveals the different mechanisms of ischemia. The predominant lesion in acute myocardial infarction is an ulcerated, yellow plaque with thrombus. In unstable angina, different substrates can be seen, from the lipid-rich lesion with thrombus to the fibrous smooth plaque, reflecting a varied physiopathology. Because of its ability to detect superficial lipid pools, angioscopy may be valuable for the detection of vulnerable plaques.

Patterns of oxidized epitopes, but not NF-κB expression, change during atherogenesis in WHHL rabbits

Oxidative modification of lipoproteins plays an important role in atherogenesis. We investigated a variety of different oxidatively modified epitopes (malondialdehyde (MDA)-2, hydroxynonenal (HNE)-7, peroxynitrite, hypochlorite, EO-6) in parallel and compared normal vessel wall, early and advanced atherosclerotic lesions in WHHL rabbits. Early atherosclerotic lesions showed abundant intracellular staining in macrophages for all ox-epitopes, apo B and apo E; advanced lesions showed a more prominent peri- and extracellular staining for ox-epitopes, which tended to colocalize more with apo B than apo E. Hypochlorite-modified epitopes showed intense staining in all types of lesions, followed by MDA-2. Early and advanced atherosclerotic lesions differed significantly in that early stages revealed abundant cellular positivity for EO-6 and weak staining for HNE-7 modified proteins whereas the opposite was observed in advanced lesions. Nuclear factor-κB (NF-κB) was nearly exclusively detected in macrophages with no difference between early and advanced lesions. We conclude that hypochlorite-modified epitopes are abundantly present at all stages of atherogenesis. EO-6 might be a marker for early, HNE-7 a marker for advanced lesions. Colocalization of ox-epitopes with apolipoproteins further supports that oxidation of lipoproteins is one of the key mechanisms in atherogenesis. Chronic stable expression and activation of NF-κB could be a useful target for therapeutic interventions.

Glucose and Insulin Modulate the Capacity of Endothelial Cells (HUVEC) to Express P-selectin and Bind a Monocytic Cell Line (U937)

Diabetes mellitus is associated with increased prevalence of endothelial cell dysfunction and vascular diseases. Mechanisms leading to alterations in endothelial cell function are poorly understood. We report here that hyperglycaemia results in the expression of endothelial adhesion molecules involved in leukocyte adhesion and extravasation. Incubation of human umbilical cord endothelial cells (HUVEC) with 25 mM glucose induced the expression of P-selectin. This effect was reversed by the addition of 1 nM insulin. Moreover, increased ICAM-1 expression was observed upon HUVEC incubation with 25 mM glucose. Increased adhesion of U937 cells (a monocytic cell line) to endothelial cells cultured with 25 mM glucose was observed. High glucose-induced monocytes cell adhesion was inhibited by an anti-P-selectin monoclonal antibody (LYP20). These results show that high glucose concentration activates endothelial cells leading to monocytes adhesion providing further evidence that hyperglycaemia might be implicated in vessel wall lesions contributing to diabetic vascular disease.

Large Scale Gene Expression Analysis of Cholesterol-loaded Macrophages

We conducted large scale gene expression analysis of the response of macrophages to exposure to oxidized low density lipoprotein (Ox-LDL). Much of the vessel wall lesion of atherosclerosis is composed of macrophages that have become engorged with cholesterol. These resulting "foam cells" contribute to the progression of vascular disease through several pathways. As a potential model of foam cell formation, we treated THP-1 cells with 12-O-tetradecanoylphorbol 13-acetate to differentiate them into a macrophage-like phenotype and subsequently treated them with oxidized low density lipoprotein for various time periods. RNA from Ox-LDL treated and time-matched control untreated cells was hybridized to microarrays containing 9808 human genes. 268 genes were found to be at least 2-fold regulated at one or more time points. These regulation patterns were classified into seven clusters of expression profiles. The data is discussed in terms of the overall pattern of gene expression, the thematic classification of the responding genes, and the clustering of functional groups in distinct expression patterns. The magnitude and the temporal patterns of gene expression identified known and novel molecular components of the cellular response that are implicated in the growth, survival, migratory, inflammatory, and matrix remodeling activity of vessel wall macrophages. In particular, the role of nuclear receptors in mediating the gene expression modulation by Ox-LDL is highlighted.

Plasma endothelin-1 levels and circulating endothelial cells in patients with aortoarteritis.

To investigate the correlation between plasma endothelin-1 (ET-1), circulating endothelial cells (CECs), and the disease activity in patients with aortoarteritis. In this study, radioimmunoassay was used to measure plasma levels of ET-1 in 56 patients with aortoarteritis. Circulating endothelial cell counts were also carried out as an indicator of vessel wall lesions. The plasma levels of ET-1 and CECs in the active disease patient group were significantly higher than those in inactive patient group (p<0.001). A significant positive correlation was found between plasma ET-1 levels and erythrocyte sedimentation rates (ESRs) in patients with aortoarteritis (r=0.645, p<0.001), as well as CECs (r=0.876, p<0.001). These results suggested that the ET-1 secreted during the active stages of aortoarteritis may cause constriction and proliferation of vascular smooth muscle cells, thus contributing to the pathogenesis of luminal narrowing. The increased CECs might serve as a marker of disease activity.

Fibrinolysis and thrombosis

The fibrinolytic system generates plasmin, which dissolves fibrin in haemostatic plugs and in thrombi. It is often regarded simply as a secondary phenomenon responsive to the generation of thrombi but it is, rather, in dynamic balance with fibrin formation, such that abnormalities in either can lead to thrombosis. This chapter summarizes the fibrinolytic system and its regulation. It considers the components of the system in blood, both in plasma and in circulating cells, with emphasis on protease–inhibitor balance. It goes on to discuss local fibrinolytic potential in thrombi, both venous and arterial, and in the diseased vessel wall, presenting evidence that increased local inhibition of fibrinolysis by PAI-1, PAI-2 and α2-antiplasmin is intimately involved in thrombus stability and in the generation of fibrin-rich vessel wall lesions. Finally, it reviews the evidence that defective plasma fibrinolysis has a causal role in venous and arterial thrombosis.

In Vivo Magnetic Resonance Imaging of Post Angioplasty Coronary Vessel Wall Lesions in Pigs

In Vivo Magnetic Resonance Imaging of Post Angioplasty Coronary Vessel Wall Lesions in Pigs

Lipoprotein Lipase Reduces Secretion of Apolipoprotein E from Macrophages

Macrophages are a significant source of lipoprotein lipase (LPL) and apolipoprotein E (apo E) in the developing arterial wall lesion, and each of these proteins can importantly modulate lipid and lipoprotein metabolism by arterial wall cells. LPL and apo E share a number of cell surface binding sites, including proteoglycans, and we have previously shown that proteoglycans are important for modulating net secretion of apoprotein E from macrophages. We therefore evaluated a potential role for LPL in modulating net secretion of macrophage-derived apo E. In pulse-chase experiments, addition of LPL during the chase period produced a decrease in secretion of apoprotein E from human monocyte-derived macrophages, from the human monocytic THP1 cell line, and from J774 cells transfected to constitutively express a human apo E cDNA. LPL similarly reduced apo E secretion when it was prebound to the macrophage cell surface at 4 degrees C. A native LPL particle was required to modulate apo E secretion; addition of monomers and aggregates did not produce the same effect. Depletion of cell surface proteoglycans by a 72-h incubation in 4-methylumbelliferyl-beta-D-xyloside did not attenuate the ability of LPL to reduce apo E secretion. However, addition of receptor-associated protein attenuated the effect of LPL on apo E secretion. Although LPL could mediate removal of exogenously added apo E from the culture medium, detailed pulse-chase analysis suggested that it primarily prevented release of newly synthesized apo E from the cell layer. Cholesterol loading of cells or antibodies to the low density lipoprotein receptor attenuated LPL effects on apo E secretion. We postulate that LPL sequesters endogenously synthesized apo E at the cell surface by a low density lipoprotein receptor-dependent mechanism. Such post-translational regulation of macrophage apo E secretion by LPL could significantly influence apo E accumulation in arterial vessel wall lesions.

Tumor necrosis factor-alpha modulates monocyte/macrophage apoprotein E gene expression.

apo E has been shown to modulate cholesterol balance in arterial wall cells. Production of apo E by macrophages in atherosclerotic plaques could thereby influence the development of the plaque lesion. Cytokines, including TNF alpha, have been identified in human lesions, therefore, we undertook a series of studies to evaluate the effect of TNF alpha on monocyte/macrophage apo E production. The addition of TNF alpha to freshly isolated human monocytes led to a four- to fivefold increase of apo E mRNA abundance. The addition of TNF alpha to fully differentiated macrophages either had no effect or modestly inhibited apo E mRNA expression. THP1 human monocytic cells also responded to TNF alpha in a phenotype-specific manner. Treatment of these cells with TNF alpha produced a dose- and time-dependent increase in apo E mRNA. This increase was reflected in apo E synthesis and was associated with inhibition of DNA synthesis, and with induction of c-fos and ICAM-1 gene expression. Cell-permanent analogues of ceramide did not reproduce TNF alpha effect on apo E, but antagonists of protein kinase C did inhibit its effect. TNF alpha induction of apo E mRNA abundance was associated with stimulation of apo E promoter-dependent gene transcription. In summary, TNF alpha stimulates apo E gene transcription, mRNA abundance, and protein synthesis in the monocyte/macrophage in a phenotype-specific manner. Such regulation could significantly modify the amount of apo E present in vessel wall lesions.

Prevention of laser arterial thrombus formation with unfractionated heparin.

A method to induce microthrombi in small mesenteric arteries (30-40 microns) has been developed to study platelet reactions and to investigate antithrombotic drugs. This model was used to evaluate the effect of Ca-heparin. Mesenteric lesions are induced in the vascular system of Wistar rats with an argon laser. The laser induced the formation of vessel wall lesion with damage of endothelial cells. Thrombi formed within seconds after the laser lesion and grew rapidly. Embolization began within a minute following the laser flash. Thrombus formation and embolization were repetitive phenomena. The administration of Ca-heparin at different dosages (0.5, 1.0 and 2.0 mg/kg) increases the number of laser injuries required to induce thrombus formation, and dose-dependently decreases the number of emboli and the duration of embolization. The highest dose injected (2.0 mg/kg) induced the strongest reduction in the number of emboli and duration of embolization.

Effect of Platelet Encapsulated lloprost on Platelet Aggregation and Adhesion to Collagen and Injured Blood Vessels In Vitro

A novel approach to site-directed delivery of drugs in vivo using blood platelets as carrier vehicles is being investigated. In this context some initial studies are reported on the effect of platelet encapsulated anti-platelet drugs on platelet aggregation and adhesion to fibrillar collagen and injured arteries in vitro. The stable prostacyclin analogue Iloprost has been encapsulated within human and pig platelets by high voltage electroporation (Hughes and Crawford 1989 and 1990). After resealing the platelets, the packaged drug has a negligible effect upon platelet adhesion to a surface of fibrillar collagen or to damaged aorta (stripped to the tunica media to simulate deep injury). The rate of platelet recruitment to the collagen shows no dose dependency with respect to intracellular Iloprost concentrations. After high Iloprost loading, as few as 2% drug loaded platelets in a mixture with control (sham encapsulated) platelets, inhibit agonist-induced platelet aggregation > 50%. The prior deposition of a "lawn" of Iloprost-loaded platelets onto fibrillar collagen or damaged aorta has a substantial inhibitory effect (50-70%) upon the secondary recruitment of normal platelets compared with recruitment to a "lawn" of normal platelets. This inhibition of secondary recruitment occurs even in the presence of a platelet activator. If reduction of platelet recruitment to a vessel wall lesion results in a decrease in the local concentration of platelet granule-derived smooth muscle cell chemotactic and proliferative factors, this site-directed drug delivery may well have application for the prevention of restenosis following balloon angioplasty procedures.

Differential effects of thromboxane A2 synthase inhibition, singly or combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on occlusive thrombosis elicited by endothelial cell injury or by deep vascular damage in canine coronary arteries.

In open-chest dogs, cyclic flow reductions (CFRs, 5.1-6.6/hr in controls; n = 24) caused by platelet deposition/dislodgment at sites of endothelial cell injury in critically stenosed left anterior descending coronary arteries (59% flow reduction) were attenuated to the same extent either by single thromboxane A2 (TXA2) synthase inhibition (0.31 mg/kg i.v. ridogrel; CFR, 0.16 +/- 0.16/hr; n = 6; p less than 0.05) or by a comparatively modest degree of TXA2/prostaglandin endoperoxide receptor antagonism on top of TXA2 synthase inhibition (5 mg/kg i.v. ridogrel; CFR, 0.22 +/- 0.1/hr; n = 10; p less than 0.05). By contrast, occlusive thrombosis on deep vascular damage elicited by intraluminal stimulation (150-microA anodal constant current) in nonpreconstricted canine coronary arteries (time to occlusion, 237.1 +/- 13.9 minutes; n = 7; incidence of occlusion within 300 minutes, six of seven experiments) was not affected by platelet cyclooxygenase inhibition (5 mg/kg i.v. acetylsalicylic acid; n = 7), single TXA2 synthase inhibition (1.25 mg/kg i.v. ridogrel; n = 7), or single TXA2/prostaglandin endoperoxide receptor antagonism (10 mg/kg + 10 mg/kg/hr i.v. sulotroban for 300 minutes; n = 5). However, such an occlusive thrombus formation was significantly reduced by combined TXA2 synthase/prostaglandin endoperoxide receptor inhibition (5 mg/kg i.v. ridogrel; time to occlusion greater than 300 minutes, n = 7; incidence of occlusion within 300 minutes, one of seven experiments; p less than 0.05). This study reveals 1) a differential efficacy of TXA2 synthase inhibition, singly or combined with TXA2/prostaglandin endoperoxide receptor antagonism, depending on the extent of the vessel wall lesion triggering thrombosis and the size of the thrombus required to obstruct the vascular lumen and 2) a significant synergism in preventing occlusive thrombosis of extensively damaged coronary arteries between strong TXA2 synthase inhibition and comparatively modest TXA2/prostaglandin endoperoxide receptor antagonism with ridogrel.

Atherosclerosis in the aorta of hypercholesterolemic rabbits and the influence of daltroban

These studies have examined aortic atherogenesis in cholesterol-fed rabbits and have correlated the effects of daltroban to the pathomechanism of the vessel wall lesions. After feeding a 0.5% cholesterol-enriched diet for 96 d atherosclerotic alterations were seen, which exhibited a proximo-distal pattern, to which the branching of the aorta contributed considerably. Depending on their localization and size a varying cellular constitution of the plaques was obvious. Large plaques, which were mainly seen in the aortic arch and the proximal descending thoracic aorta, consisted of numerous proliferating cells, masses of fibrillar ground substance, clusters of foam cells, and rarely contained cholesterol crystals and necroses. Emerging plaques mainly found in distal thoracic and abdominal aorta imposed as fatty streaks. Daltroban treatment, used in a clinically relevant doses of 10 mg/kg b. wt. per day, reduced extension and protrusional area of plaques to about 40%, which was evaluated using a newly developed computerized morphormetric method, in association with significant reductions in free cholesterol content within the aorta. The results suggest that daltroban inhibits the progression of atherosclerosis in cholesterol-fed rabbits. This effect may be related to its antagonistic interaction with the thromboxane A2 receptor and also to an inhibition of the cholesterol metabolism.

Leukocyte Stimulation of Intimal Lesion Formation Is Inhibited by Treatment with Diclofenac Sodium and Dexamethasone

This investigation tested the effect of anti-inflammatory agents acting at different levels of the arachidonic acid cascade on leukocyte migration into the vessel wall. An animal model of vasculitis was used in which leukocytes stimulate migration of smooth muscle cells from the media into the intima resulting in formation of intimal lesions. In this model, an endotoxin-soaked thread is implanted in the adventitia along the ventral side of the rat femoral artery. At 2 days, subendothelial and medial leukocyte accumulation occurs exclusively in the ventral half of the vessel. At 14 days, intimal lesions composed primarily of smooth muscle cells are localized to the ventral half of the vessel. Treatment with neither the lipoxygenase inhibitor L-651,392 nor the dual cyclooxygenase and lipoxygenase inhibitor BW755C affected leukocyte migration into the vessel wall or subsequent lesion formation. Treatment with the cyclooxygenase inhibitor diclofenac sodium greatly reduced both leukocyte accumulation and lesion formation, whereas leukocyte migration and lesion formation were nearly totally inhibited by treatment with dexamethasone. Thus, it has been demonstrated that although leukocyte accumulation in the vessel wall stimulates intimal lesion formation, pharmacologic inhibition of leukocyte accumulation prevents lesion formation.

Leukocyte Stimulation of Intimal Lesion Formation Is Inhibited by Treatment with Diclofenac Sodium and Dexamethasone

This investigation tested the effect of anti-inflammatory agents acting at different levels of the arachidonic acid cascade on leukocyte migration into the vessel wall. An animal model of vasculitis was used in which leukocytes stimulate migration of smooth muscle cells from the media into the intima resulting in formation of intimal lesions. In this model, an endotoxin-soaked thread is implanted in the adventitia along the ventral side of the rat femoral artery. At 2 days, subendothelial and medial leukocyte accumulation occurs exclusively in the ventral half of the vessel. At 14 days, intimal lesions composed primarily of smooth muscle cells are localized to the ventral half of the vessel. Treatment with neither the lipoxygenase inhibitor L-651,392 nor the dual cyclooxygenase and lipoxygenase inhibitor BW755C affected leukocyte migration into the vessel wall or subsequent lesion formation. Treatment with the cyclooxygenase inhibitor diclofenac sodium greatly reduced both leukocyte accumulation and lesion formation, whereas leukocyte migration and lesion formation were nearly totally inhibited by treatment with dexamethasone. Thus, it has been demonstrated that although leukocyte accumulation in the vessel wall stimulates intimal lesion formation, pharmacologic inhibition of leukocyte accumulation prevents lesion formation.

The beneficial influence of nifedipine on the regression of the cholesterol-induced atherosclerosis in rabbits.

Nifedipine has been implicated as an inhibitor of dietary induced atherosclerosis in rabbits. This study was designed to examine the effect of nifedipine on the regression of atherosclerotic lesions in this animal model. NZ-rabbits were fed a cholesterol-enriched diet (1.5%) for 4.8 months. A control group A was killed and the aorta removed for planimetry of the vessel wall lesions. The remaining animals were divided into two groups, group P receiving a placebo solution and group N a nifedipine solution (2 X 20 mg/day). They were maintained on a standard chow for a further 4.5 months. In the nifedipine-treated group N, sudanophilia of the aorta was reduced by more than 20% as compared to the cholesterol-fed control group A and was 50% lower than in the placebo-treated group. Total cholesterol of the aortic tissue was lowest in group N. No significant differences in plasma cholesterol, triglycerides or the platelet half-life time were observed between the placebo- and the nifedipine-treated group. These data indicate that nifedipine can stimulate regression of pre-existing atherosclerotic lesions in rabbits.

Influence of contralateral obstructions on Doppler-frequency spectral analysis of ipsilateral stenoses of the carotid arteries.

Contralateral obstructions have been suggested to be responsible for inaccuracy in Doppler sonographic diagnosis and estimation of severity of internal carotid artery stenoses. Therefore correlations of the systolic peak frequency of the internal carotid artery (Doppler-Frequency-Spectrum-Analysis) and severity of stenoses found by angiography have been compared in subgroups with (n = 36) and without (n = 48) additional contralateral obstructions. The linear regressions in both subgroups were found to be very similar (Y = 0.0098X - 12.4 and Y = 0.0099X - 14.0), the coefficients of correlation identical (r = 0.83). In 26 patients, the systolic peak frequency of the internal carotid artery did not demonstrate a significant change due to operation of the contralateral vascular lesion; thus indicating that contralateral obstructions do not influence CW-Doppler sonographic findings of an ipsilateral vessel wall lesion concerning diagnostic accuracy and non-invasive estimation of the severity of stenoses.

The cerebral angiogram in cases of stroke in youth (author's transl)

Sixty-seven patients (ages: 11-40 years) suffering from ischemic cerebral circulatory disturbances were investigated clinically and angiographically. In 34 cases, transient ischemic attacks or reversible ischemic neurological defects were diagnosed; 33 patients suffered from completed strokes. In most cases the completed stroke took place without previous transient ischemic attacks. A very good tendency toward recovery was observed in 60 of 67 cases. Stenoses or occlusions were found in only 21.5% of the clinically affected vessel regions. However, 50% of those patients, on whom panangiography was performed, were shown to have stenoses or occlusions. Stenotic vessel wall lesions are also obviously to be expected in clinically nonaffected vessel regions; consequently, in cases of cerebral circulatory disturbances, angiographic investigation of all craniocervical vessels is advisable.

Thrombotische Behandlung e iner experimentellen Koronarthrombose mit Streptokinase: Thrombolytic therapy of experimental coronary thrombosis with streptokinase

Question: The influence of streptokinase on coronary thrombosis produced by vessel wall lesions by means of direct current was studied in dogs. Material and methods: The experiments were performed on 23 dogs. Without opening the thorax coronary thrombosis was induced by a steel wire electrode inserted into the right coronary artery via the common carotid artery. One, 4 and 24 hours after thrombus induction a streptokinase dose was administered which caused a maximum fibrinolytic effect of the blood of the animals. The fibrinolytic effect was estimated by determination of the thrombin time fibrinogen content and platelet count as well as by thromboelastography. The influence of streptokinase was evaluated by angiography electrocardiography and pathologic-anatomical examination. Results: After streptokinase infusion for about 3 hrs the angiography revealed a recanalization of the common carotid artery in nearly 80 per cent of the animals. During streptokinase infusion regression of the electrocardiographic alterations was found in all animals. The angiographic findingswere verified in most cases by pathologic-anatomical examinations. In the animals treated with streptokinase subepicardial and intramyocardial haemorrhages and embolization of portions of theelectrically induced coronary thrombosis were found.