Gene deletion of dopamine beta-hydroxylase and alpha1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling.

In vitro studies have shown that stimulation of alpha1-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine beta-hydroxylase (DBH-/-)] or deficient in alpha1-AR subtypes expressed in murine carotid (alpha1B-AR-/- and alpha1D-AR-/-) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DBH-/- and alpha1B-AR-/- mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50-91%, resulting in restoration of wall tension to nearly normal (DBH-/-) or normal (alpha1B-AR-/-). In contrast, in alpha1D-AR-/- mice, increases in lumen area, circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DBH-/- mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by alpha1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury.

Ultrasound assessment of ocular vascular effects of repeated intravitreal injections of ranibizumab for wet age-related macular degeneration.

PURPOSE: Determine the effect of repeated intravitreal injections of ranibizumab (0.5 mg; 0.05 ml) on retrobulbar blood flow velocities (BFVs) using ultrasound imaging quantification in twenty patients with exudative age-related macular degeneration treated for 6 months. METHODS: Visual acuity (ETDRS), central macular thickness (OCT), peak-systolic, end-diastolic and mean-BFVs in central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries were measured before, 2 days, 3 weeks and 6 months after the first injection. Patients were examined monthly and received 1-5 additional injections depending on ophthalmologic examination results. RESULTS: Six months after the first injection, a significant increase in visual acuity 50.9 ± 25.9 versus 44.4 ± 21.7 (p < 0.01) and decrease in mean central macular thickness 267 ± 74 versus 377 ± 115 μm (p < 0.001) were observed compared to baseline. Although mean-BFVs decreased by 16%±3% in CRA and 20%±5% in TPCA (p < 0.001) 2 days after the first injection, no significant change was seen thereafter. Mean-BFVs in OA decreased by 19%±5% at week 3 (p < 0.001). However, the smallest number of injections (two injections) was associated with the longest time interval between the last injection and month 6 (20 weeks) and with the best return to baseline levels for mean-BFVs in CRA, suggesting that ranibizumab had reversible effects on native retinal vascular supply after its discontinuation. Moreover, a significant correlation between the number of injections and percentage of changes in mean-BFVs in CRA was observed at month 6 (R = 0.74, p < 0.001) unlike TPCA or OA. CONCLUSION: Ranibizumab could impair the native choroidal and retinal vascular networks, but its effect seems reversible after its discontinuation.

Influence of arterial occlusion on outcome after intravenous thrombolysis for acute ischemic stroke

BACKGROUND AND PURPOSE: We aimed to assess the interaction between intravenous thrombolysis (IVT) and arterial occlusion on acute cervicocerebral computed tomographic angiography on the outcome of patients with acute ischemic stroke. METHODS: Patients from the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) registry with onset-to-door-time ≤4 hours, acute cervicocerebral computed tomographic angiography, a premorbid modified Rankin Scale ≤2, and a National Institute of Health Stroke Scale (NIHSS) >4 were selected. Patients with significant intracranial arterial obstruction (≥50%-99%) and undergoing acute endovascular treatment were excluded. An interaction analysis of IVT and initial arterial occlusion for favorable 3 months outcome (modified Rankin Scale <3) were performed with adjustment for potential confounders. RESULTS: Among 654 included patients, 382 (58%) showed arterial occlusion, of whom 263 (69%) received IVT. Two hundred seventy-two showed no/minimal obstruction of whom 139 (51%) received IVT. In the adjusted interaction analysis, there was a trend in favor of the arterial occlusion group (odds ratio [OR]=3.97; 95% confidence interval [CI], 0.83-18.97; P=0.08). IVT (versus no IVT) was associated with better outcome in patients with occlusion (adjusted OR for favorable outcome, 3.01; 95% CI, 1.10-8.28) but not in patients with no/minimal obstruction (OR, 0.76; 95% CI, 0.21-2.74). Conversely, patients with occlusion had a similar rate of favorable outcome as no/minimal obstruction when thrombolysed (OR, 0.5; 95% CI, 0.17-1.47) but had a less favorable outcome without thrombolysis (OR, 0.13; 95% CI, 0.04-0.44). CONCLUSIONS: In this retrospective analysis of consecutive patients with acute ischemic stroke, there was a trend for more favorable outcomes with IVT in the setting of initial arterial occlusion than in the setting of no/minimal obstruction. Before confirmation in randomized controlled studies, this information should not influence thrombolysis decisions, however.

Endovascular abdominal aneurysm repair and impact of systematic preoperative embolization of collateral arteries: endoleak analysis and long-term follow-up.

PURPOSE: To report our results of endovascular aneurysm repair (EVAR) over a 10-year period using systematic preoperative collateral artery embolization. METHODS: From 1999 until 2009, 124 patients (117 men; mean age 70.8 years) with abdominal aortic aneurysm (AAA) underwent embolization of patent lumbar and/or inferior mesenteric arteries prior to elective EVAR procedures. Embolization was systematically attempted and, whenever possible, performed using microcoils and a coaxial technique. Follow-up included computed tomography and/or magnetic resonance imaging and abdominal radiography. RESULTS: The technical success for EVAR was 96% (119/124), with 4 patients dying within 30 days (3.2% perioperative mortality) and 1 type III endoleak accounting for the failures. Collateral arteries were occluded spontaneously or by embolization in 60 (48%) of 124 patients. The endoleak rate was 50.9% (74 in 61 patients), most of which were type II (19%). Over a mean clinical follow-up of 60.5±34.1 months (range 1-144), aneurysm sac dimensions decreased in 66 patients, increased in 19 patients, and were stable in 35. The endoleak rate was significantly higher in the patients with increasing sac diameter (p<0.001). Among the patients with patent collateral arteries, 38/64 (59.3%) developed 46 leaks, while 28 leaks appeared in 23 (41%) of 56 patients with collateral artery occlusion (p=0.069). The type II endoleak rate significantly differed between these two groups (47.8% vs. 3.6%, p<0.001). CONCLUSION: Preoperative collateral embolization seems to be a valid method of reducing the incidence of type II endoleak, improving the long-term outcome.

Incidence of stent thrombosis and adverse cardiac events 5 years after sirolimus stent implantation in clinical practice.

BACKGROUND: The long-term incidence of stent thrombosis (ST) and complications after sirolimus-eluting stents (SES) implantation is still a matter of debate. METHOD: We conducted a systematic follow-up on the day of their 5-year SES implantation anniversary, in a series of consecutive real-world patients treated with a SES. The use of SES implantation was not restricted to "on-label" indications, and target lesions included in-stent restenosis, vein graft, left main stem locations, bifurcations, and long lesions. The Academic Research Consortium criteria were used for ST classification. RESULTS: Three hundred fifty consecutive patients were treated with SES between April and December 2002 in 3 Swiss hospitals. Mean age was 63 +/- 6 years, 78% were men, 20% presented with acute coronary syndrome, and 19% were patients with diabetes. Five-year follow-up was obtained in 98% of eligible patients. Stent thrombosis had occurred in 12 patients (3.6%) [definite 6 (1.8%), probable 1 (0.3%) and possible 5 (1.5%)]. Eighty-one percent of the population was free of complications. Major adverse cardiac events occurred in 74 (21%) patients and were as follows: cardiac death 3%, noncardiac death 4%, myocardial infarction 2%, target lesion revascularization 8%, non-target lesion revascularization target vessel revascularization 3%, coronary artery bypass graft 2%. Non-TVR was performed in 8%. CONCLUSION: Our data confirm the good long-term outcome of patients treated with SES. The incidence of complications and sub acute thrombosis at 5 years in routine clinical practice reproduces the results of prospective randomized trials.

Prevalence of vascular disease in systemic lupus erythematosus compared with type-1 diabetes mellitus: A cross-sectional study of two cohorts.

OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with considerable cardiovascular morbidity that has not yet been directly compared with other diseases with known cardiovascular risk. METHODS: Two hundred and forty-one patients of the multicentre Swiss SLE cohort study (SSCS) were cross-sectionally assessed for coronary heart disease (CHD), cerebrovascular disease (CVD) and peripheral artery disease (PAD). SLE patients were compared with a cohort of 193 patients with type-1 diabetes mellitus being followed at the University Hospital Basel. A subgroup analysis of 50 age- and sex-matched patients from the University Hospital Basel was performed. RESULTS: Of patients within the SSCS 13.3% had one or more vascular events: 8.3% CHD, 5% CVD and 1.2% PAD. In type-1 diabetes mellitus patients, 15% had vascular events: 9.3% CHD, 3.1% CVD and 5.6% PAD. In the matched subgroup, 26% of SLE patients had vascular events (14% CHD) compared with 12% in type-1 DM patients (2% CHD). Cardiovascular risk factors were similar in both groups. Vascular events in SLE patients were associated with age, longer disease duration, dyslipidaemia, and hypertension. CONCLUSION: Cardiovascular morbidity in SLE is at least as frequent as in age- and sex-matched type-1 diabetes mellitus patients. Therefore, aggressive screening and management of cardiovascular risk factors should be performed.

Asymptomatic high flow subclavian steal in a patient with hemodialysis access.

Subclavian steal phenomenon due to proximal subclavian artery stenosis or occlusion is not un-common but often remains asymptomatic. We describe the case of a 66-year-old man with end-stage renal disease hemodialysed through a brachio-brachial loop graft of the left forearm. Echo-Doppler precerebral examination showed a high reversed flow of 570 ml/min in the ipsilateral vertebral artery. After successful endovascular recanalization of the subclavian artery, access blood flow increased and vertebral flow decreased to 30 ml/min. Complete neurological examination was normal both before and after endovascular treatment. This case demonstrates how high a subclavian steal can be without causing symptoms and how well precerbral and cerebral circulation can adapt to hemodynamic changes.

Expression of E-Selectin and Vascular Cell Adhesion Molecule-1 in So-Called 'Negative' Appendices: First Results to Support the Pathological Diagnosis in Borderline Cases.

Background: Since the rate of histologically 'negative' appendices still ranges between 15 and 20%, appendicitis in 'borderline' cases remains a challenging disease. As previously described, cell adhesion molecule expression correlates with different stages of appendicitis. Therefore, it was of interest to determine whether the 'negative' appendix correlated with the absence of E-selectin or vascular cell adhesion molecule-1 (VCAM-1). Methods: Nineteen grossly normal appendices from a series of 120 appendectomy specimens from patients with suspected appendicitis were analysed in frozen sections for the expression of E-selectin and VCAM-1. As control, 5 normal appendices were stained. Results: This study showed a coexpression of E-selectin and VCAM-1 in endothelial cells in early and recurrent appendicitis. In patients with symptoms for less than 6 h, only E-selectin was detected. Cases with fibrosis and luminal obliteration were only positive for VCAM-1. In cases of early appendicitis with symptoms of less than 6 h duration, a discordance between histological and immunohistochemical results was found. Conclusions: This report indicates that E-selectin and VCAM-1 expression could be useful parameters in the diagnosis of appendicitis in borderline cases.

Transapical aortic valve replacement in extreme-risk patients: outcome, risk factors and mid-term results.

OBJECTIVES: Transcatheter aortic valve replacement (TAVR) provides good results in selected high-risk patients. However, it is unclear whether this procedure carries advantages in extreme-risk profile patients with logistic EuroSCORE above 35%. METHODS: From January 2009 to July 2011, of a total number of 92 transcatheter aortic valve procedures performed, 40 'extreme-risk' patients underwent transapical TAVR (TA-TAVR) (EuroSCORE above 35%). Variables were analysed as risk factors for hospital and mid-term mortality, and a 2-year follow-up (FU) was obtained. RESULTS: The mean age was: 81 ± 10 years. Twelve patients (30%) had chronic pulmonary disease, 32 (80%) severe peripheral vascular disease, 14 (35%) previous cardiac surgery, 19 (48%) chronic renal failure (2 in dialysis), 7 (17%) previous stroke (1 with disabilities), 3 (7%) a porcelain aorta and 12 (30%) were urgent cases. Mean left ventricle ejection fraction (LVEF) was 49 ± 13%, and mean logistic EuroSCORE was 48 ± 11%. Forty stent-valves were successfully implanted with six Grade-1 and one Grade-2 paravalvular leakages (success rate: 100%). Hospital mortality was 20% (8 patients). Causes of death following the valve academic research consortium (VARC) definitions were: life-threatening haemorrhage (1), myocardial infarction (1), sudden death (1), multiorgan failure (2), stroke (1) and severe respiratory dysfunction (2). Major complications (VARC definitions) were: myocardial infarction for left coronary ostium occlusion (1), life-threatening bleeding (2), stroke (2) and acute kidney injury with dialysis (2). Predictors for hospital mortality were: conversion to sternotomy, life-threatening haemorrhage, postoperative dialysis and long intensive care unit (ICU) stay. Variables associated with hospital mortality were: conversion to sternotomy (P = 0.03), life-threatening bleeding (P = 0.02), acute kidney injury with dialysis (P = 0.03) and prolonged ICU stay (P = 0.02). Mean FU time was 24 months: actuarial survival estimates for all-cause mortality at 6 months, 1 year, 18 months and 2 years were 68, 57, 54 and 54%, respectively. Patients still alive at FU were in good clinical condition, New York Heart Association (NYHA) class 1-2 and were never rehospitalized for cardiac decompensation. CONCLUSIONS: TA-TAVR in extreme-risk patients carries a moderate risk of hospital mortality. Severe comorbidities and presence of residual paravalvular leakages affect the mid-term survival, whereas surviving patients have an acceptable quality of life without rehospitalizations for cardiac decompensation.

Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis.

BACKGROUND: The excess in cardiovascular risk in patients with rheumatoid arthritis provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and rheumatoid arthritis and the proven benefit of angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease, it was the aim of the present study to delineate the impact of ramipril on endothelial function as well as on markers of inflammation and oxidative stress in patients with rheumatoid arthritis. METHODS AND RESULTS: Eleven patients with rheumatoid arthritis were included in this randomized, double-blind, crossover study to receive ramipril in an uptitration design (2.5 to 10 mg) for 8 weeks followed by placebo, or vice versa, on top of standard antiinflammatory therapy. Endothelial function assessed by flow-mediated dilation of the brachial artery, markers of inflammation and oxidative stress, and disease activity were investigated at baseline and after each treatment period. Endothelial function assessed by flow-mediated dilation increased from 2.85+/-1.49% to 4.00+/-1.81% (P=0.017) after 8 weeks of therapy with ramipril but did not change with placebo (from 2.85+/-1.49% to 2.84+/-2.47%; P=0.88). Although systolic blood pressure and heart rate remained unaltered, diastolic blood pressure decreased slightly from 78+/-7 to 74+/-6 mm Hg (P=0.03). Tumor necrosis factor-alpha showed a significant inverse correlation with flow-mediated dilation (r=-0.408, P=0.02), and CD40 significantly decreased after ramipril therapy (P=0.049). CONCLUSIONS: Angiotensin-converting enzyme inhibition with 10 mg/d ramipril for 8 weeks on top of current antiinflammatory treatment markedly improved endothelial function in patients with rheumatoid arthritis. This finding suggests that angiotensin-converting enzyme inhibition may provide a novel strategy to prevent cardiovascular events in these patients.

Fonction ventriculaire gauche après revascularisation pour occlusion d'une coronaire d'une durée de 1-2 heures [Left ventricular function following revascularization for occlusion of a coronary artery lasting 1 to 2 hours].

The time-lag between coronary occlusion and irreversible damage to the myocardium is ill-defined in man. In 10 patients the changes in left ventricular function have been studied after coronary occlusion during diagnostic or therapeutic cardiac catheterization of 1-2 hours' duration. Revascularization was achieved either surgically or through intracoronary streptokinase infusion. The interval between occlusion and onset of extracorporal circulation or reopening was 61 to 119 minutes. Despite enzyme elevation (CPK, CK-MB, SGOT) and appearance of Q-waves in 5 patients, no significant alteration of left ventricular function was noted on repeat cardiac catheterization 10 to 230 days after the accident. These observations, suggest that coronary occlusion of 1-2 hours' duration fails to produce significant irreversible damage to the myocardium despite electrocardiographic and enzymatic signs of myocardial infarction.

Subalpine-nival gradient of species richness for vascular plants, lichens and bryophytes in the Swiss Inner Alps

In the European GLORIA project, 12 summits (treeline to nival belt) were inventoried in three regions of Switzerland: two in the Swiss National Park Graubünden and one in Valais. Vascular plants were recorded in all three regions and bryophytes and lichens were recorded only in Valais. On each summit, vegetation and temperature data were sampled using sampling protocols for the GLORIA project (Global Observation Research Initiative in Alpine environment) on large summit sections and in clusters of four 1x1-m quadrats. We observed a general decrease of species richness for all three systematic groups with increasing elevation in the summit sections, but only for vascular plants in the quadrats. In Valais, there was higher species richness for vascular plants than for bryophytes and lichens on the lower summits, but as the decrease in species richness was less pronounced for cryptogams, the latter were more numerous than vascular plants on the highest summit. Vascular species showed a clear shift of the dominant life form with elevation, with chamaephytes replacing hemicryptophytes. Bryophytes and lichens showed a weak trend among the life forms at the summit section scale, but a stronger shift of the dominant forms was seen in the quadrats, with cushion replacing turf bryophytes and crustaceous replacing fruticose lichens. Altogether, these results sustain the temperature-physiographic hypothesis to explain the species richness decrease along the altitudinal gradient: the harsh climatic conditions of the alpine-nival belts act as a filter for species, but the diminishing diversity of microhabitats is also an important factor. Because cryptogams depend more on humidity than temperature and more on smaller microhabitats than vascular plants, the decrease of species richness is more gradual with elevation for bryophytes and lichens.

Gene expression profiles in rat mesenteric lymph nodes upon supplementation with Conjugated Linoleic Acid during gestation and suckling

Background Diet plays a role on the development of the immune system, and polyunsaturated fatty acids can modulate the expression of a variety of genes. Human milk contains conjugated linoleic acid (CLA), a fatty acid that seems to contribute to immune development. Indeed, recent studies carried out in our group in suckling animals have shown that the immune function is enhanced after feeding them with an 80:20 isomer mix composed of c9,t11 and t10,c12 CLA. However, little work has been done on the effects of CLA on gene expression, and even less regarding immune system development in early life. Results The expression profile of mesenteric lymph nodes from animals supplemented with CLA during gestation and suckling through dam's milk (Group A) or by oral gavage (Group B), supplemented just during suckling (Group C) and control animals (Group D) was determined with the aid of the specific GeneChip® Rat Genome 230 2.0 (Affymettrix). Bioinformatics analyses were performed using the GeneSpring GX software package v10.0.2 and lead to the identification of 89 genes differentially expressed in all three dietary approaches. Generation of a biological association network evidenced several genes, such as connective tissue growth factor (Ctgf), tissue inhibitor of metalloproteinase 1 (Timp1), galanin (Gal), synaptotagmin 1 (Syt1), growth factor receptor bound protein 2 (Grb2), actin gamma 2 (Actg2) and smooth muscle alpha actin (Acta2), as highly interconnected nodes of the resulting network. Gene underexpression was confirmed by Real-Time RT-PCR. Conclusions Ctgf, Timp1, Gal and Syt1, among others, are genes modulated by CLA supplementation that may have a role on mucosal immune responses in early life.

Vascular continuity, cell axialization and auxin.

Phytohormones have been implicated in vascular development in various ways, but their precise function and the extent of their influence is still controversial. Recent results from experimental manipulation of developing organs and Arabidopsis developmental genetics support a role for polar auxin flow in cell axis formation within the vascular system and, interestingly, also in the embryonic establishment of the plant body axis. Vascular responses to auxin transport inhibition indicate patterns of auxin distribution during leaf development and new technologies may enable these predictions to be tested within the near future. Moreover, recently discovered Arabidopsis axialisation mutants seem to identify essential genes that relay auxin signals in vascular development. A first gene in this class, MONOPTEROS (MP) has been cloned and encodes a transcription factor capable of binding to auxin response elements in the control regions of auxin regulated genes. Molecular identification of further axialisation genes may provide access to a mechanistic understanding of plant cell axis formation.