Treatment of branch retinal vein occlusion induced macular edema with bevacizumab

Branch retinal vein occlusion is a frequent cause of visual loss with currently insufficient treatment options. We evaluate the effect of Bevacizumab (Avastin) treatment in patients with macular edema induced by branch retinal vein occlusion.

Simultaneous, bilateral anterior ischemic optic neuropathy (AION) in polycythemia vera: a case report

BACKGROUND: Polycythemia vera (PV) is a hemopoetic disorder. Apparently, although thrombosis accounts for the majority of morbidity, AION has not been associated with PV so far. PATIENT AND FINDINGS: A 63 y-old woman with PV was hospitalized because of acute liver failure. She also experienced bilateral painless loss of vision. Bilateral, pale optic disc swelling with flame-like hemorrhages, more pronounced in the right eye, constricted visual fields, and relative afferent papillary defect (RAPD) on the right side were present. Computer tomography scan revealed no signs of intraorbital pathology, elevated intracranial pressure or hemorrhages. CLINICAL COURSE: We interpreted the findings as AION associated with the hyperviscosity syndrome. Liver transplantation had to be carried out in the next days. Three weeks later, vision improved slightly, but RAPD persisted, and disc pallor developed in both eyes. The patient died two months later. DISCUSSION: Central retinal artery and vein occlusions have been described as complications of Essential thrombocythemia, but not of PV. We observed a rare case of bilateral neuropathy suggestive of AION. This condition has so far not been associated with PV.

Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies

BACKGROUND/AIMS: The integrin alphavbeta6 promotes proliferation of specialized epithelia and acts as a receptor for the activation of latent TGFbeta1. We studied alphavbeta6 expression in experimental and human liver fibrosis and the potential of its pharmacological inhibition for treatment of hepatic fibrosis. METHODS: alphavbeta6 expression was studied by quantitative PCR and immunohistochemistry in rats with cirrhosis due to bile duct ligation (BDL), administration of thioacetamide (TAA), in Mdr2(Abcb4)(-/-) mice with spontaneous biliary fibrosis, and in livers of patients with chronic hepatitis C (n=79) and end-stage liver disease due to various etiologies (n=18). The effect of a selective alphavbeta6 inhibitor was evaluated in Mdr2(Abcb4)(-/-) mice with ongoing fibrogenesis. RESULTS: Integrin beta6 mRNA increased with fibrosis stage in hepatitis C and was upregulated between 25- and 100-fold in TAA- and BDL-induced cirrhosis, in Mdr2(Abcb4)(-/-) mice and in human end-stage liver disease. alphavbeta6 protein was absent in normal livers and expressed de novo on (activated) bile duct epithelia and transitional hepatocytes. A single dose of the alphavbeta6 inhibitor injected into Mdr2(Abcb4)(-/-) mice significantly induced profibrolytic matrix metalloproteinases (MMP)-8 and -9 after 3 h, with a corresponding increase in extracellular matrix-degrading activities. In parallel profibrogenic transcripts (procollagen alpha1(I), TGFbeta2, and MMP-2) showed a trend of downregulation. CONCLUSIONS: (1) Integrin alphavbeta6 is induced de novo in rodent and human liver fibrosis, where it is expressed on activated bile duct epithelia and (transitional) hepatocytes during fibrosis progression. (2) In vivo a single dose of a small molecule alphavbeta6 inhibitor induced antifibrogenic and profibrolytic genes and activities, suggesting alphavbeta6 is a unique target for treatment of liver fibrosis.

Antiaggregatory and proangiogenic effects of a novel recombinant human dual specificity anti-integrin antibody

BACKGROUND: beta(3)-Integrins are involved in platelet aggregation via alpha(IIb)beta(3) [glycoprotein (GP)IIb-GPIIIa], and in angiogenesis via endothelial alpha(V)beta(3). Cross-reactive ligands with antiaggregatory and proangiogenic effects, both desirable in peripheral vasculopathies, have not yet been described. OBJECTIVES: In vitro and in vivo characterization of antiaggregatory and proangiogenic effects of two recombinant human Fab fragments, with emphasis on beta(3)-integrins. METHODS: Recombinant Fab fragments were obtained by phage display technology. Specificity, affinity and IC(50) were determined by immunodot assays, enzyme-linked immunosorbent assay (ELISA), and Scatchard plot analysis, and by means of human umbilical vein endothelial cells (HUVECs). Functional analyses included ELISA for interaction with fibrinogen binding to GPIIb-GPIIIa, flow cytometry for measurement of activation parameters and competitive inhibition experiments, human platelet aggregometry, and proliferation, tube formation and the chorioallantoic membrane (CAM) assay for measurement of angiogenic effects. RESULTS: We observed specific and high-affinity binding to an intact GPIIb-GPIIIa receptor complex of two human Fab autoantibody fragments, with no platelet activation. Dose-dependent fibrinogen binding to GPIIb-GPIIIa and platelet aggregation were completely inhibited. One Fab fragment was competitively inhibited by abciximab and its murine analog monoclonal antibody (mAb) 7E3, whereas the other Fab fragment bound to cultured HUVECs, suggesting cross-reactivity with alpha(V)beta(3), and also demonstrated proangiogenic effects in tube formation and CAM assays. CONCLUSIONS: These Fab fragments are the first entirely human anti-GPIIb-GPIIIa Fab fragments with full antiaggregatory properties; furthermore, they do not activate platelets. The unique dual-specificity anti-beta(3)-integrin Fab fragment may represent a new tool for the study and management of peripheral arterial vasculopathies.

Correlation of intravascular ultrasound findings with histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis

BACKGROUND: Intravascular ultrasound of drug-eluting stent (DES) thrombosis (ST) reveals a high incidence of incomplete stent apposition (ISA) and vessel remodeling. Autopsy specimens of DES ST show delayed healing and hypersensitivity reactions. The present study sought to correlate histopathology of thrombus aspirates with intravascular ultrasound findings in patients with very late DES ST. METHODS AND RESULTS: The study population consisted of 54 patients (28 patients with very late DES ST and 26 controls). Of 28 patients with very late DES ST, 10 patients (1020+/-283 days after implantation) with 11 ST segments (5 sirolimus-eluting stents, 5 paclitaxel-eluting stents, 1 zotarolimus-eluting stent) underwent both thrombus aspiration and intravascular ultrasound investigation. ISA was present in 73% of cases with an ISA cross-sectional area of 6.2+/-2.4 mm(2) and evidence of vessel remodeling (index, 1.6+/-0.3). Histopathological analysis showed pieces of fresh thrombus with inflammatory cell infiltrates (DES, 263+/-149 white blood cells per high-power field) and eosinophils (DES, 20+/-24 eosinophils per high-power field; sirolimus-eluting stents, 34+/-28; paclitaxel-eluting stents, 6+/-6; P for sirolimus-eluting stents versus paclitaxel-eluting stents=0.09). The mean number of eosinophils per high-power field was higher in specimens from very late DES ST (20+/-24) than in those from spontaneous acute myocardial infarction (7+/-10), early bare-metal stent ST (1+/-1), early DES ST (1+/-2), and late bare-metal stent ST (2+/-3; P from ANOVA=0.038). Eosinophil count correlated with ISA cross-sectional area, with an average increase of 5.4 eosinophils per high-power field per 1-mm(2) increase in ISA cross-sectional area. CONCLUSIONS: Very late DES thrombosis is associated with histopathological signs of inflammation and intravascular ultrasound evidence of vessel remodeling. Compared with other causes of myocardial infarction, eosinophilic infiltrates are more common in thrombi harvested from very late DES thrombosis, particularly in sirolimus-eluting stents, and correlate with the extent of stent malapposition.

Drug-eluting stent thrombosis

Drug-eluting stents (DES) have reduced the risk of repeat revascularization procedures by 50-70% compared with bare metal stents across a wide range of lesion and patients subsets. Stent thrombosis is a rare but devastating adverse event, which results in abrupt closure of the treated artery with the incumbent risk of sudden death or myocardial infarction. Although stent thrombosis has been recognized as a shortcoming of coronary artery stents since there inception, very late stent thrombosis occurring more than one year after stent implantation emerged as a new entity complicating the use of DES. The mechanisms leading to very late ST are complex and only incompletely understood. Delayed healing and incomplete re-endothelialization emerged as prevailing mechanism of thrombosis in autopsy studies. Various components of DES may give rise to very late stent thrombosis, notably the polymers used for controlled drug-release. Newer generation DES attempt to address these concerns by aiming at improved vascular healing while maintaining potent neointimal suppression.

Stent thrombosis is associated with an impaired response to antiplatelet therapy

OBJECTIVES: We sought to evaluate the response to antiplatelet therapy in patients with stent thrombosis (ST). BACKGROUND: Stent thrombosis is associated with considerable morbidity and mortality. An impaired response to antiplatelet therapy might be related to an increased risk for ST. METHODS: Eighty-two patients were included in the present study: 23 patients with previous ST, 50 matched controls (coronary stenting without ST), and 9 healthy volunteers. Platelet aggregation (PA) was studied (optical aggregometry) under monotherapy with acetylsalicylic acid (ASA) 100 mg daily for one month, followed by dual therapy with ASA 100 mg and clopidogrel 75 mg daily (loading dose 300 mg) for another month. RESULTS: Maximal (5 and 20 micromol) adenosine diphosphate-induced PA was significantly higher in patients with ST compared with controls (5 micromol, p < 0.005; 20 micromol, p < 0.05) and volunteers (5 micromol, p < 0.005; 20 micromol, p < 0.05). Resistance to ASA (>20% aggregation with 0.5 mg/ml arachidonic acid) was more prevalent in patients with ST (48%) compared with control patients (32%, p = ns) and volunteers (0%, p = 0.01). Clopidogrel significantly reduced PA in all three groups, but intergroup differences persisted. Clopidogrel resistance (<10% relative change) was similar in patients with ST, control patients, and volunteers (4%, 6%, and 11%, respectively, all p = NS). However, combined ASA and clopidogrel resistance was more prevalent in patients with ST (52%) compared with controls (38%, p = NS) and volunteers (11%, p < 0.05). CONCLUSIONS: Patients with previous ST show an impaired response to antiplatelet therapy with ASA compared with controls and volunteers. Additional treatment with clopidogrel is not able to overcome these differences in PA. Acetylsalicylic acid but not clopidogrel resistance appears to be associated with ST.

Depiction of small veins draining into the vein of galen using preoperative 3-dimensional navigation in living patients

OBJECTIVE: The purpose of this study was to delineate the anatomy of the precentral cerebellar vein, superior vermian vein, and internal occipital vein using reconstructions of computed tomographic and magnetic resonance imaging scans with navigation software. These data were compared with previous anatomic and angiographic findings to show the resolution and accuracy of the system. METHODS: We retrospectively reviewed 100 patients with intracranial pathologies (50 computed tomographic scans with contrast and 50 magnetic resonance imaging scans with gadolinium) using a neuronavigation workstation for 3-dimensional reconstruction. Particular attention was paid to depiction of the precentral cerebellar vein, superior vermian vein, and internal occipital vein. The data were reviewed and analyzed. RESULTS: The precentral cerebellar vein, superior vermian vein, and its tributary, the supraculminate vein, were depicted in 52 (52%) patients. The internal occipital vein was delineated on 99 (49.5%) sides and joined the basal vein and vein of Galen in 39 (39.4%) and 60 (60.6%) hemispheres, respectively. Comparing these results with previous angiographic studies, the ability of the neuronavigation system for depicting these vessels is similar to that of digital subtraction angiography. CONCLUSION: This study illustrates the possibility of depicting the small vessels draining into the pineal region venous complex using 3-dimensional neuronavigation with an accuracy comparable to that of digital subtraction angiography. This tool provides important information for both surgical planning and intraoperative orientation.

Retaining perivascular tissue of human saphenous vein grafts protects against surgical and distension-induced damage and preserves endothelial nitric oxide synthase and nitric oxide synthase activity

OBJECTIVE: Conventional harvesting of saphenous vein used for coronary artery bypass surgery induces a vasospasm that is overcome by high-pressure distension. Saphenous vein harvested with its cushion of perivascular tissue by a "no touch" technique does not undergo vasospasm and distension is not required, leading to an improved graft patency. The aim of this study is to investigate the effect of surgical damage and high-pressure distension on endothelial integrity and endothelial nitric oxide synthase expression and activity in saphenous vein harvested with and without perivascular tissue. METHODS: Saphenous veins from patients (n = 26) undergoing coronary artery bypass surgery were prepared with and without perivascular tissue. We analyzed the effect of 300 mm Hg distension on morphology and endothelial nitric oxide synthase/nitric oxide synthase activity using a combination of immunohistochemistry, Western blot analysis, reverse transcriptase polymerase chain reaction, and enzyme assay in distended (with and without perivascular tissue) compared with nondistended (with and without perivascular tissue) segments. RESULTS: Distension induced substantial damage to the luminal endothelium (assessed by CD31 staining) and vessel wall. Endothelial nitric oxide synthase expression and activity were significantly reduced by high-pressure distension and removal of, or damage to, perivascular tissue. The effect of distension was significantly less for those with perivascular tissue than for those without perivascular tissue in most cases. CONCLUSION: The success of the saphenous vein used as a bypass graft is affected by surgical trauma and distension. Veins removed with minimal damage exhibit increased patency rates. We show that retention of perivascular tissue on saphenous vein prepared for coronary artery bypass surgery by the "no touch" technique protects against distension-induced damage, preserves vessel morphology, and maintains endothelial nitric oxide synthase/nitric oxide synthase activity.

Improved safety and reduction in stent thrombosis associated with biodegradable polymer-based biolimus-eluting stents versus durable polymer-based sirolimus-eluting stents in patients with coronary artery disease: final 5-year report of the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) randomized, noninferiority trial

OBJECTIVES This study sought to report the final 5 years follow-up of the landmark LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial. BACKGROUND The LEADERS trial is the first randomized study to evaluate biodegradable polymer-based drug-eluting stents (DES) against durable polymer DES. METHODS The LEADERS trial was a 10-center, assessor-blind, noninferiority, "all-comers" trial (N = 1,707). All patients were centrally randomized to treatment with either biodegradable polymer biolimus-eluting stents (BES) (n = 857) or durable polymer sirolimus-eluting stents (SES) (n = 850). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization within 9 months. Secondary endpoints included extending the primary endpoint to 5 years and stent thrombosis (ST) (Academic Research Consortium definition). Analysis was by intention to treat. RESULTS At 5 years, the BES was noninferior to SES for the primary endpoint (186 [22.3%] vs. 216 [26.1%], rate ratio [RR]: 0.83 [95% confidence interval (CI): 0.68 to 1.02], p for noninferiority <0.0001, p for superiority = 0.069). The BES was associated with a significant reduction in the more comprehensive patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (297 [35.1%] vs. 339 [40.4%], RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority = 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (n = 5 [0.7%] vs. n = 19 [2.5%], RR: 0.26 [95% CI: 0.10 to 0.68], p = 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period (n = 3 of 749 vs. n = 14 of 738, RR: 0.20 [95% CI: 0.06 to 0.71], p = 0.005). CONCLUSIONS The safety benefit of the biodegradable polymer BES, compared with the durable polymer SES, was related to a significant reduction in very late ST (>1 year) and associated composite clinical outcomes. (Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS] trial; NCT00389220).