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1.  Ischemic Brain Lesions After Carotid Artery Stenting Increase Future Cerebrovascular Risk 
Brain lesions on diffusion-weighted imaging (DWI) are frequently found after carotid artery stenting (CAS), but their clinical relevance remains unclear.
This study sought to investigate whether periprocedural ischemic DWI lesions after CAS or carotid endarterectomy (CEA) are associated with an increased risk of recurrent cerebrovascular events.
In the magnetic resonance imaging (MRI) substudy of ICSS (International Carotid Stenting Study), 231 patients with symptomatic carotid stenosis were randomized to undergo CAS (n = 124) or CEA (n = 107). MRIs were performed 1 to 7 days before and 1 to 3 days after treatment. The primary outcome event was stroke or transient ischemic attack in any territory occurring between the post-treatment MRI and the end of follow-up. Time to occurrence of the primary outcome event was compared between patients with (DWI+) and without (DWI–) new DWI lesions on the post-treatment scan in the CAS and CEA groups separately.
Median time of follow-up was 4.1 years (interquartile range: 3.0 to 5.2). In the CAS group, recurrent stroke or transient ischemic attack occurred more often among DWI+ patients (12 of 62) than among DWI– patients (6 of 62), with a cumulative 5-year incidence of 22.8% (standard error [SE]: 7.1%) and 8.8% (SE: 3.8%), respectively (unadjusted hazard ratio: 2.85; 95% confidence interval: 1.05 to 7.72; p = 0.04). In DWI+ and DWI– patients, 8 and 2 events, respectively, occurred within 6 months after treatment. In the CEA group, there was no difference in recurrent cerebrovascular events between DWI+ and DWI– patients.
Ischemic brain lesions discovered on DWI after CAS seem to be a marker of increased risk for recurrent cerebrovascular events. Patients with periprocedural DWI lesions might benefit from more aggressive and prolonged antiplatelet therapy after CAS. (A Randomised Comparison of the Risks, Benefits and Cost Effectiveness of Primary Carotid Stenting With Carotid Endarterectomy: International Carotid Stenting Study; ISRCTN25337470)
PMCID: PMC4323145  PMID: 25677309
carotid stenosis; DWI lesions; endarterectomy; long-term outcome; stenting; ARWMC, age-related white matter changes; CAS, carotid artery stenting; CEA, carotid endarterectomy; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; TIA, transient ischemic attack
2.  Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial 
Lancet  2015;385(9967):529-538.
Stenting is an alternative to endarterectomy for treatment of carotid artery stenosis, but long-term efficacy is uncertain. We report long-term data from the randomised International Carotid Stenting Study comparison of these treatments.
Patients with symptomatic carotid stenosis were randomly assigned 1:1 to open treatment with stenting or endarterectomy at 50 centres worldwide. Randomisation was computer generated centrally and allocated by telephone call or fax. Major outcomes were assessed by an independent endpoint committee unaware of treatment assignment. The primary endpoint was fatal or disabling stroke in any territory after randomisation to the end of follow-up. Analysis was by intention to treat ([ITT] all patients) and per protocol from 31 days after treatment (all patients in whom assigned treatment was completed). Functional ability was rated with the modified Rankin scale. This study is registered, number ISRCTN25337470.
1713 patients were assigned to stenting (n=855) or endarterectomy (n=858) and followed up for a median of 4·2 years (IQR 3·0–5·2, maximum 10·0). Three patients withdrew immediately and, therefore, the ITT population comprised 1710 patients. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the stenting and endarterectomy groups (6·4% vs 6·5%; hazard ratio [HR] 1·06, 95% CI 0·72–1·57, p=0·77). Any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs 72 events; ITT population, 5-year cumulative risk 15·2% vs 9·4%, HR 1·71, 95% CI 1·28–2·30, p<0·001; per-protocol population, 5-year cumulative risk 8·9% vs 5·8%, 1·53, 1·02–2·31, p=0·04), but were mainly non-disabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups.
Long-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis.
Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union.
PMCID: PMC4322188  PMID: 25453443
3.  Leukotriene B4 Levels in Human Atherosclerotic Plaques and Abdominal Aortic Aneurysms 
PLoS ONE  2014;9(1):e86522.
Leukotriene B4 (LTB4) has been associated with the initiation and progression of atherosclerosis and abdominal aortic aneurysm (AAA) formation. However, associations of LTB4 levels with tissue characteristics and adverse clinical outcome of advanced atherosclerosis and AAA are scarcely studied. We hypothesized that LTB4 levels are associated with a vulnerable plaque phenotype and adverse clinical outcome. Furthermore, that LTB4 levels are associated with inflammatory AAA and adverse clinical outcome.
Atherosclerotic plaques and AAA specimens were selected from two independent databases for LTB4 measurements. Plaques were isolated during carotid endarterectomy from asymptomatic (n = 58) or symptomatic (n = 317) patients, classified prior to surgery. LTB4 levels were measured without prior lipid extraction and levels were corrected for protein content. LTB4 levels were related to plaque phenotype, baseline patient characteristics and clinical outcome within three years following surgery. Seven non-diseased mammary artery specimens served as controls. AAA specimens were isolated during open repair, classified as elective (n = 189), symptomatic (n = 29) or ruptured (n = 23). LTB4 levels were measured similar to the plaque measurements and were related to tissue characteristics, baseline patient characteristics and clinical outcome. Twenty-six non-diseased aortic specimens served as controls.
LTB4 levels corrected for protein content were not significantly associated with histological characteristics specific for vulnerable plaques or inflammatory AAA as well as clinical presentation. Moreover, it could not predict secondary manifestations independently investigated in both databases. However, LTB4 levels were significantly lower in controls compared to plaque (p = 0.025) or AAA (p = 0.017).
LTB4 levels were not associated with a vulnerable plaque phenotype or inflammatory AAA or clinical presentation. This study does not provide supportive evidence for a role of LTB4 in atherosclerotic plaque destabilization or AAA expansion. However, these data should be interpreted with care, since LTB4 measurements were performed without prior lipid extractions.
PMCID: PMC3903534  PMID: 24475136
4.  A gene-centric study of common carotid artery remodelling 
Atherosclerosis  2013;226(2):440-446.
Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized.
Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA).
rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling.
Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
► In the IMPROVE study (n > 3000) variants at 1q24.3 were strongly associated with larger carotid diameters. ► The lead variant was associated with Abdominal Aortic Aneurysm (AAA) in meta-analysis of 5 studies (n > 50,000). ► Variants at 1q24.3 appear to be associated with vascular remodelling and risk of AAA.
PMCID: PMC3573227  PMID: 23246012
Abdominal aortic aneurysm; Genome-wide association studies; Vascular remodelling; Carotid artery
5.  Is Age of 80 Years a Threshold for Carotid Revascularization? 
Current Cardiology Reviews  2011;7(1):15-21.
Background and purpose:
Carotid Angioplasty and Stenting (CAS) has emerged as an alternative to Carotid Endarterectomy (CEA) in treatment of carotid stenotic disease. With increasing life expectancy clinicians are more often confronted with patients of higher age. Octogenarians were often excluded from randomized trials comparing CAS to CEA because they were considered high-risk for revascularization. Conflicting results on the peri-procedural outcome of carotid revascularization in these patients have been reported. In order to objectively evaluate whether age above 80 years should be an upper limit for indicating carotid revascularization we systematically reviewed the currently available literature.
Literature was systematically reviewed between January 2000 and June 2010 using Pubmed and Embase, to identify all relevant studies concerning CAS and CEA in octogenarians. Inclusion criteria were 1) reporting outcome on either CEA or CAS; and 2) data subanalysis on treatment outcome by age. The 30-day Major Adverse Event (MAE) rate (disabling stroke, myocardial infarction or death) was extracted as well as demographic features of included patients.
After exclusion of 23 articles, 46 studies were included in this review, 18 involving CAS and 28 involving CEA. A total of 2.963 CAS patients and 14.365 CEA patients with an age >80 years were reviewed. The MAE rate was 6.9% (range 1.6 - 24.0%) following CAS and 4.2% (range 0 – 8.8%) following CEA.
A separate analysis in this review included the results of one major registry 140.376 patients) analyzing CEA in octogenarians only reporting on 30-day mortality and not on neurological or cardiac adverse events. When these data were included the MAE following CEA is 2.4% (range 0 – 8.8%)
MAE rates after CEA in octogenarians are comparable with the results of large randomized trials in younger patients. Higher complication rates are described for CAS in octogenarians. In general, age > 80 years is not an absolute cut off point to exclude patients from carotid surgery. In our opinion, CEA should remain the golden standard in the treatment of significant carotid artery stenoses, even in the very elderly.
PMCID: PMC3131710  PMID: 22294970
Carotid revascularization; angioplasty; stenting; octogenarians; demographic features; revascularization.
6.  An animal paired crossover ePTFE arteriovenous graft model 
Previously, we developed a porcine model for Arterio Venous Graft (AVG) failure to allow assessment of new access strategies. This model was limited concerning graft length. In the present technical report, we describe a modification of our model allowing the assessment of long AVGs.
In 4 pigs, AVGs of 15 cm length were created bilaterally in a cross-over fashion between the carotid artery and the contralateral jugular vein. Two days (2 pigs) and two weeks (2 pigs) after AV shunting, graft patency was evaluated by angiography, showing all four grafts to be patent, with no sign of angiographic or macroscopic narrowing at the anastomoses sites.
In this modified pig AVG failure model, implantation of a bilateral cross-over long AVG is a feasible approach. The present model offers a suitable tool to study local interventions or compare various long graft designs aimed at improvement of AVG patency.
PMCID: PMC3006397  PMID: 21110903

Results 1-6 (6)