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Background: While representing a significant improvement, the introduction of next-generation sequencing in genetic diagnosis also prompted new challenges. Despite widely recognized consensus guidelines for the interpretation of sequence variants, many variants remain unclassified or are discordantly interpreted. In heritable thoracic aortic aneurysms with dissection (HTAAD), most cases are caused by a heterozygous, private missense mutation, possibly contributing to the relatively common reports of variants with uncertain significance in this group. Segregation analysis necessitates advanced likelihood-based methods typically inaccessible to non-experts and is hampered by reduced penetrance, possible phenocopies, and non-availability of DNA from deceased relatives., Methods: In this report, challenges in variant interpretation and the use of segregation analyses were illustrated in two families with a suspected HTAAD disorder. The R package segregatr, a novel implementation of full-likelihood Bayes factor (FLB), was performed to explore the cosegregation of the variants in these families., Conclusion: Using the R package segregatr, cosegregation in the reported families concluded with strong and supporting evidence for pathogenicity. Surveillance of families in a multidisciplinary team enabling systematic phenotype description for standardized segregation analysis with a robust calculation method may be imperative for reliable variant interpretation in HTAAD., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: In approximately 20% of patients with thoracic aortic aneurysms or dissections a heritable thoracic aortic disease (HTAD) is suspected. Several monogenic connective tissue diseases imply high risk of aortic disease, including both non-syndromic and syndromic forms. There are some studies assessing inflammation and extracellular matrix remodeling in patients with non-hereditary aortic disease, but such studies in patients with hereditary diseases are scarce., Aims: To quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls., Methods: Patients with Loeys-Dietz syndrome (LDS, n = 12), Marfan syndrome (MFS, n = 11), and familial thoracic aortic aneurysm 6 (FTAA6, n = 9), i.e., actin alpha 2 (ACTA2) pathogenic variants, were recruited. Exome or genome sequencing was performed for genetic diagnosis. Several markers of inflammation and ECM remodeling were measured in plasma by enzyme immunoassays. Flow cytometry of T-cell subpopulations was performed on a subgroup of patients. For comparison, blood samples were drawn from 14 healthy controls., Results: (i) All groups of HTAD patients had increased levels matrix metalloproteinase-9 (MMP-9) as compared with healthy controls, also in adjusted analyses, reflecting altered ECM remodeling. (ii) LDS patients had increased levels of pentraxin 3 (PTX3), reflecting systemic inflammation. (iii) LDS patients have increased levels of soluble CD25, a marker of T-cell activation., Conclusion: Our data suggest that upregulated MMP-9, a matrix degrading enzyme, is a common feature of several subgroups of HTAD. In addition, LDS patients have increased levels of PTX3 reflecting systemic and in particular vascular inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Seim, Holt, Ratajska, Michelsen, Ringseth, Halvorsen, Skjelland, Kvitting, Lundblad, Krohg-Sørensen, Osnes, Aukrust, Paus and Ueland.)

Aims: We aimed to assess the prevalence of mitral annulus disjunction (MAD) and to explore the association with aortic disease and mitral valve surgery in patients with Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS)., Methods and Results: We included consecutive MFS patients fulfilling Revised Ghent Criteria and LDS patients fulfilling Loeys-Dietz Revised Nosology. MAD was identified by echocardiography and was quantified as the longitudinal distance from the ventricular myocardium to the hinge point of the posterior mitral leaflet. Aortic events were defined as aortic dissection or prophylactic aortic surgery. We recorded the need of mitral valve surgery including mitral valve repair or replacement. We included 168 patients (103 with MFS and 65 with LDS). The prevalence of MAD was 41%. MAD was present in all age groups. Aortic events occurred in 112 (67%) patients (27 with dissections and 85 with prophylactic surgical interventions). Patients with MAD were younger at aortic event than those without MAD (log rank = 0.02) Patients with aortic events had greater MAD distance in posterolateral wall [8 (7-10) mm vs. 7 (6-8) mm, P = 0.04]. Mitral events occurred more frequently in patients with MAD (P < 0.001)., Conclusion: MAD was highly prevalent in patients with MFS and LDS. MAD was a marker of severe disease including aortic events at younger age and need of mitral valve surgery. Screening patients with MFS an LDS for MAD may provide prognostic information and may be relevant in planning surgical intervention. Detection of MAD in patients with MFS and LDS may infer closer clinical follow-up from younger age., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: To explore survival, causes of death, and the prevalence of cardiovascular events in a Norwegian Marfan syndrome (MFS) cohort. MFS is a heritable connective tissue disorder associated with reduced life expectancy-primarily due to aortic pathology., Methods: A follow-up study of 84 MFS adults, initially investigated in 2003-2004. In 2014-2015, 16 were deceased, 47 of 68 survivors consented to new clinical investigations. Analyses of events were performed for 47 survivors and 16 deceased at follow-up. Standardized mortality ratios (SMR), using the mortality rate of the Norwegian population as reference, were calculated for all 84 and calculated for men and women separately. Causes of death and information on cardiovascular events were retrieved from death certificates and medical records., Results: Standardized mortality ratios (95% confidence interval): for the whole cohort: 5.24 (3.00-8.51); for men: 8.20 (3.54-16.16); for women: 3.85 (1.66-7.58). Cardiovascular causes were found in 11 of 16 deceased, eight of these related to aortic pathology. Cancer was the cause of death in three patients. At follow-up, 51% had new cardiovascular events; 59% had undergone aortic surgery. Men experienced aortic events at younger age than women. 32% of the survivors were not followed-up as recommended., Conclusion: Life expectancy is reduced in this MFS cohort compared to the Norwegian population. Cardiovascular complications develop throughout life, particularly aortic pathology, the major cause of death in MFS. Death and aortic pathology seem to occur earlier in men. There is a need to improve follow-up according to guidelines., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been shown to be increased in patients with acute ischemic stroke. Here, we evaluated plasma sLOX-1 levels and vascular carotid plaque LOX-1 (ie, OLR1 ) gene expression in patients with ischemic stroke and transient ischemic attack (TIA) with particular focus on their relation to time since symptom onset., Methods and Results: Plasma sLOX-1 (n=232) and carotid plaque OLR1 gene expression (n=146) were evaluated in patients who were referred to evaluation for carotid endarterectomy, as well as in healthy control plasma (n=81). Patients were categorized according to presence of acute ischemic stroke or transient ischemic attack (n=35) ≤7 days, >7 days ≤3 months (n=90), >3 months (n=40), or no reported symptoms before study inclusion (n=67). Our major findings were the following: (1) Patients with carotid atherosclerosis had increased plasma sLOX-1 levels as compared with controls. (2) Plaque OLR1 mRNA levels were increased in carotid plaques (n=146) compared with nonatherosclerotic vessels (ie, common iliac arteries of organ donors, n=10). (3) There were no differences in sLOX plasma levels or OLR1 gene expression when analyzed according to the time since relevant cerebral ischemic symptoms. (4) Also patients with severe carotid atherosclerosis without any previous ischemic events had raised sLOX-1 levels. (5) Immunostaining showed colocalization between LOX-1 and macrophages within the carotid plaques. (6) Also patients with acute stroke (within 7 days) caused by atrial fibrillation (n=22) had comparable raised sLOX-1 levels., Conclusions: sLOX-1 levels are elevated in patients with ischemic stroke and transient ischemic attack independent of cause and time since the ischemic event., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objectives: The first publication of Loeys-Dietz syndrome (LDS) described aortic rupture at young ages. Experience with new LDS types showed that the clinical course varies, and thresholds for prophylactic surgery are discussed. As this is an uncommon disease, experience needs to be shared., Methods: Retrospective review of patients with LDS types 1-4 undergoing cardiovascular surgery during the years 1991-2016., Results: Thirty-five patients (including 6 children with LDS2) underwent 57 operations. LDS 1, 2, 3 and 4 included 4, 17, 11 and 3 patients, respectively. Mean age at first surgery was 36 years, with a non-significant trend that LDS2 patients were younger. Of the 9 emergency surgeries, 7 were type A dissections, with 1 postoperative death. Twenty-two patients had prophylactic aortic root surgery (17 valve-sparing root replacements), with 1 postoperative death, 1 reoperation with valve replacement and 1 late death. Freedom from root reintervention and death was 92% at 13 years. Of the 11 patients with LDS3, 5 needed mitral valve surgery. Mitral valve disease was not found in the other LDS types. Ten patients needed >1 operation. Of the 57 operations, 33 were in the ascending aorta, 20 in the aorta distal to the arch including branches and 4 were isolated heart surgeries. Of the 20 vascular operations, 16 were in LDS2. Cumulative survival 20 years after first surgery (all patients) was 94.3%., Conclusions: Clinical course seems to be more aggressive in LDS2, with index operation at a younger age, and higher risk of needing several operations. Vascular disease distal to the arch is not uncommon. LDS3 seems to be associated with mitral valve disease. Prophylactic aortic root surgery is safe and durable., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aim: Interleukin-27 (IL-27) is involved in different inflammatory diseases; however, its role in atherosclerosis is unclear. In this study we investigated the expression of IL-27 and its receptor in patients with carotid atherosclerosis and if IL-27 could modulate the inflammatory effects of the NLRP3 inflammasome in vitro., Methods: Plasma IL-27 was measured by enzyme immunoassay in patients with carotid stenosis (n = 140) and in healthy controls (n = 19). Expression of IL-27 and IL-27R was analyzed by quantitative PCR and immunohistochemistry in plaques from patients and in non-atherosclerotic vessels. THP-1 monocytes, primary monocytes and peripheral blood mononuclear cells (PBMCs) were used to study effects of IL-27 in vitro., Results: Our main findings were: (i) Plasma levels of IL-27 were significantly elevated in patients with carotid atherosclerotic disease compared to healthy controls. (ii) Gene expression of IL-27 and IL-27R was significantly elevated in plaques compared to control vessels, and co-localized to macrophages. (iii) In vitro, IL-27 increased NLRP3 inflammasome activation in monocytes with enhanced release of IL-1 β., Conclusions: We demonstrate increased levels of IL-27 and IL-27R in patients with carotid atherosclerosis. Our in vitro findings suggest an inflammatory role for IL-27, which can possibly be linked to atherosclerotic disease development.

Objective: The numbers of lower extremity revascularisations and amputations are insufficiently reported in Norway. To support future policy decisions regarding the provision of vascular treatment, knowledge of such trends is important., Methods: This retrospective cross-sectional study from 2001 to 2014 used data from the Norwegian Patient Registry. The revascularisation treatments were categorised in multilevel, aortoiliac, femoral to popliteal and popliteal to foot levels and sorted as open, endovascular and hybrid. The sessions in amputations were divided in major (thigh and below knee) and minor (ankle, foot or digit). Incidence rates were assessed per 100 000 for patients in the age group > 60 years. The diabetic prevalence was calculated and the endovascular numbers at the South-Eastern, Western, Central and Northern Norway Regional Health Authority were compared., Results: The overall revascularisation rates increased from 308.7 to 366.8 (p=0.02). Open revascularisations decreased from 158.9 to 98.7 (p<0.01) while endovascular revascularisations increased from 142.2 to 243.4 (p<0.01). Hybrid revascularisations increased from 7.4 to 24.8 (p<0.01). Major amputation rates decreased from 87.8 to 48.7 (p<0.01) while minor amputations increased from 12.3 to 19.6 (p=0.01). The diabetic percentages increased from 12.2 to 22.3 (p<0.01) in revascularisations, from 26.5 to 30.8 (p=0.02) in major amputations and from 43.0 to 49.3 (p=0.13) in minor. (p values refer to average annual changes.) The regional trends in endovascular treatments varied within and between the vascular groups., Conclusion: From 2001 to 2014, the revascularisation rates increased due to the rise in endovascular procedures. Open revascularisations and major amputation rates decreased, minor increased. The regional variances in endovascular treatments indicate that the availability of this technology differed between the health regions of Norway. The increase in patients with diabetes requires continued awareness of diabetes and its complications., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe(-/-)Neil3(-/-) mice on high-fat diet showed accelerated plaque formation as compared to Apoe(-/-) mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe(-/-)Neil3(-/-) mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage.

Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1β and IL-18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood., Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for IL-1β release. The Swedish First-ever myocardial Infarction study in Ac-county (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68-positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL-1β release from lipopolysaccharide-primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction., Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background and Purpose: Interleukin (IL)-23 is a cytokine in the IL-12 family, mainly produced by antigen-presenting cells with a central role in inflammation. We hypothesize that IL-23 is also important in atherogenesis and investigate this in a population with carotid atherosclerosis., Methods: Plasma levels of IL-23 were measured in patients with carotid artery stenosis and in healthy controls. The mRNA levels of IL-23 and its receptor, IL-23R, were measured in atherosclerotic plaques, nonatherosclerotic vessels, peripheral blood mononuclear cells, and plasmacytoid dendritic cells., Results: Our findings were as follows: (1) patients with carotid atherosclerosis (n=177) had significantly raised plasma levels of IL-23 when compared with healthy controls (n=24) with particularly high levels in those with the most recent symptoms. (2) mRNA levels of IL-23 and IL-23R were markedly increased in carotid plaques (n=68) when compared with nonatherosclerotic vessels (n=8-10). Immunostaining showed colocalization to plaque macrophages. (3) Patients with carotid atherosclerosis had increased mRNA levels of both IL-23 and IL-23R in plasmacytoid dendritic cells, but not in peripheral blood mononuclear cells. (4) IL-23 increased IL-17 release in monocytes and particularly in peripheral blood mononuclear cells from patients with carotid atherosclerosis, but not in cells from healthy controls. (5) IL-23 gave a prominent tumor necrosis factor release in monocytes from patients with carotid atherosclerosis but not in cells from healthy controls. (6) High plasma levels of IL-23 were associated with increased mortality during follow-up., Conclusions: We have shown an association between IL-23 and disease progression in patients with carotid atherosclerosis, potentially involving IL-17-related mechanisms., (© 2015 American Heart Association, Inc.)

Aims: The homeostatic chemokines, CCL19 and CCL21 and their receptor CCR7, have recently been linked to atherogenesis. We investigated the expression of CCL19/CCL21/CCR7 in carotid atherosclerosis as well as the ability of these chemokines to modulate lipid accumulation in macrophages and vascular smooth muscle cell (SMC) phenotype., Methods and Results: Our major findings were: (i) patients with carotid atherosclerosis (n = 158) had increased plasma levels of CCL21, but not of CCL19, compared with controls (n = 20), with particularly high levels in symptomatic (n = 99) when compared with asymptomatic (n = 59) disease. (ii) Carotid plaques showed markedly increased mRNA levels of CCL21 and CCL19 in symptomatic (n = 14) when compared with asymptomatic (n = 7) patients, with CCR7 localized to macrophages and vascular SMC (immunohistochemistry). (iii) In vitro, CCL21, but not CCL19, increased the binding of modified LDL and promoted lipid accumulation in THP-1 macrophages. (iv) CCL19, but not CCL21, increased proliferation and release and activity of matrix metalloproteinase (MMP) 1 in vascular SMC. (v) The differential effects of CCL19 and CCL21 in macrophages and SMC seem to be attributable to divergent signalling pathways, with CCL19-mediated activation of AKT in SMC- and CCL21-mediated activation of extracellular signal-regulated kinase 1/2 in macrophages., Conclusion: CCL19 and CCL21 are up-regulated in carotid atherosclerosis. The ability of CCL21 to promote lipid accumulation in macrophages and of CCL19 to induce proliferation and MMP-1 expression in vascular SMC could contribute to their pro-atherogenic potential.

Background: Atherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process., Methods: Plasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50-69%) or severe (≥70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined., Results: Our major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-α in combination with hypoxia and oxidized LDL markedly increased MMP-7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality., Conclusion: Our findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms.

Background and Purpose: Atherosclerosis is a progressive chronic disease, in which inflammation plays a key role. The calcium-binding proteins calgranulins including S100A8, S100A9, and S100A12 are involved in many cellular activities and pathological processes including inflammation. We therefore hypothesized that calgranulins may be markers of plaque instability in patients with carotid atherosclerosis., Methods: Plasma levels of S100A8/A9 and S100A10 were measured in 159 consecutive patients with high-grade carotid stenosis and in 22 healthy control subjects. The mRNA levels of calgranulins were also measured within the atherosclerotic carotid plaques, and their regulation was analyzed in vitro in monocytes., Results: Our main findings were: (1) plasma levels of S100A12 were significantly higher in patients with carotid atherosclerosis compared with healthy control subjects with the highest levels in patients with the most recent symptoms (ie, within 2 months); (2) plasma levels of S100A8/S100A9 showed a modest increase in patients with symptoms in the previous 2 to 6 months but not in the other patients; (3) mRNA levels of S100A8, S100A9, and S100A12 showed increased expression in atherosclerotic carotid plaques from patients with the most recent symptoms compared with the remaining patients; (4) in THP-1 monocytes, activation of Toll-like receptors 2 and 4 increased mRNA levels of S100A8, S100A9, and S10012 and interleukin-1β, interferon γ, and releasate from thrombin-activated platelets significantly enhanced the expression of S100A12., Conclusions: Our findings support a link between calgranulins and atherogenesis and suggest that these mediators, and in particular S100A12, may be related to plaque instability.

Background and Purpose: Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke., Methods: We examined plasma FABP4 levels in asymptomatic (n = 28) and symptomatic (n = 31) patients with carotid atherosclerosis, as well as in 202 subjects with acute ischemic stroke. In a subgroup of patients we also analysed the expression of FABP4 within the atherosclerotic lesion. In addition, we investigated the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in monocytes/macrophages., Results: FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms. Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in monocytes/macrophages in vitro. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with total and cardiovascular mortality during follow-up, although we did not find that addition of FABP4 to the fully adjusted multivariate model had an effect on the prognostic discrimination for all-cause mortality as assessed by c-statistics., Conclusions: FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke.

Aims: Several studies suggest a pro-atherogenic role for the CC chemokine receptor 2 (CCR2), thought to reflect interaction with monocyte chemoattractant protein (MCP)-1. Based on its ability to attract leucocytes into inflamed tissue, we hypothesized a pro-atherogenic role for MCP-4, another CCR2 ligand., Methods and Results: Our main findings were: (i) patients with symptomatic carotid stenosis (n = 29), but not those with asymptomatic plaques (n = 31), had significantly raised plasma levels of MCP-4 compared with healthy controls (n = 20); (ii) in vitro, releasate from activated platelets markedly increased the expression of MCP-4 and CCR2 in THP-1 monocytes, and enhanced the MCP-4-mediated effect on interleukin-8 secretion in these cells, involving the platelet-derived chemokine RANTES; (iii) while MCP-1 had no effect on the release of RANTES and interferon-inducible protein of 10 kDa in tumour necrosis factor alpha-pre-activated THP-1 monocytes, MCP-4 profoundly enhanced the release of these pro-atherogenic chemokines; and (iv) the data indicate an inflammatory interaction between RANTES and MCP-4, involving CCR2, and mRNA levels of these mediators were markedly up-regulated within symptomatic atherosclerotic carotid plaque (n = 81)., Conclusion: Our findings suggest that the pro-atherogenic effects of CCR2 may not be restricted to interaction with MCP-1, but could also involve activation by MCP-4, being an inflammatory link between platelet and monocyte activation.

Background: Patients who have a carotid stenosis and suffer a TIA have a high risk of stroke shortly afterwards, and should be offered prophylactic surgery within 2 weeks. We present the results for treatment of carotid stenosis from Oslo University Hospital, Rikshospitalet in the period 2001-2008., Material and Methods: The material comprises all patients treated for carotid stenosis, with either carotid thrombendarterectomy (CEA) or endovascular stenting, in the period 2001-2008. All procedures were prospectively recorded in a database. A neurologist examines the patients before, and 1 and 12 months after treatment., Results: 408 carotid stenoses were treated in the observation period. Median age (range) was 68 years (21-85), and 125 (31 %) patients were women. 206 (64.2 %) of the 321 stenoses treated with CEA were symptomatic as were 53 (61 %) of the 87 who underwent endovascular treatment (87). The rate of serious stroke and/or death within 30 days after CEA was 1.9 % for symptomatic stenoses and 1.1 % for asymptomatic stenoses; after endovascular treatment the corresponding numbers were 1.9 % and 3.8 %., Interpretation: We have offered endovascular treatment to patients in whom surgery would be complicated (restenosis, radiation-induced stenosis etc). Results could therefore not be compared within our material. CEA prevents stroke, and it has been shown that the risk of complications is higher with stenting. Evaluation and treatment of patients with carotid stenosis should be included in the planned National guidelines for stroke treatment.

Background: Stroke is the most common cause of disability in Norway. Most strokes are ischemic, and 25-30% are caused by emboli from atherosclerotic plaques in pre-cerebral arteries. The aim of this study was to review the literature on effectiveness of stroke prevention by surgical and endovascular treatment of carotid bifurcation stenoses., Material and Methods: Search of the PubMed and Cochrane Library. Relevant textbook chapters and personal experience have also supported the evaluation., Results and Interpretation: Prevention of stroke by carotid endarterectomy is documented in several large randomised controlled trials. For carotid stenoses with reduced diameters of more than 50%, a significant reduction of 5-year stroke risk is achieved with surgery and best medical treatment, compared to best medical treatment alone. The benefit is greatest with symptomatic stenoses, especially if surgery is performed shortly after onset of symptoms. Patients with transient ischemic attack (TIA), minor stroke or amaurosis fugax should without delay be referred to an ultrasound examination of the carotid. Surgery as soon as possible is indicated if > 70% stenosis is found, and for men also with moderate stenoses (50-69%). The benefit is less pronounced for women with moderate stenosis and they should be considered individually. In asymptomatic patients, surgery reduces the 5-year stroke risk from 11.8 to 6.4%. The indication for surgery in asymptomatic patients must be balanced against age, co-morbidity, and the quality of surgery at each centre. A low operative morbidity is a prerequisite. No comparable evidence exists for endovascular treatment, and it is recommended that patients eligible for stent treatment are included in ongoing randomised trials comparing stent treatment and endarterectomy.

Background: The proper management strategy for patients with combined carotid and cardiac disease remains unsettled. It is controversial whether the operations should be synchronous, staged or reversed staged, and most publications also lack conservatively treated control groups. The role of endovascular treatment in this situation has not been documented. We present our current treatment strategy and results., Material and Methods: During the period January 2001 to December 2003, 95 procedures for internal carotid artery stenosis were performed in 81 patients. Median age was 70 years, range 44-83; 24 were women. In 37 patients invasive treatment of carotid stenosis and cardiac disease was performed (group A). In another 23 patients the carotid stenoses were treated invasively, while the cardiac disease was treated conservatively (group B). No heart disease was diagnosed in 21 patients treated for carotid stenoses (group C). Postoperative stroke/death was registered after all interventions., Results: Stroke/death: Group A: one ipsilateral non-disabling stroke after carotid endarterectomy and one cardiac death after coronary artery bypass surgery (5.4%). Group B: one ipsilateral fatal cerebral haemorrhage and 1 contralateral ischaemic stroke (8.7%). Group C: none., Discussion: Meta-analyses have calculated the risk of stroke/death after treatment for combined carotid and cardiac disease to be 7-9%, independently of whether the procedures are performed synchronously, staged or reversed staged. Our results are comparable. The aim of treatment for carotid and cardiac disease is to prevent death, stroke and heart failure. The benefit from treatment thus depends on a low complication rate, but patients with combined disease have an increased risk of complications. Counseling of these patients should be based on a multidisciplinary approach, taking into account all possible treatment options including conservative, endovascular and surgical, with an aim to reducing total cardiovascular risk.

Background: Endovascular stent-graft repair of abdominal aortic aneurysms was introduced in 1991. Long-term results from randomised studies are still not available. Aneurysm ruptures after stent-graft repair have been reported, and there has been a considerable need for redo procedures., Material and Results: At Rikshospitalet in Oslo, Norway, 26 stent-graft implantations for abdominal aortic aneurysms were performed during the years 1996-2000, two of which were primary technical failures immediately converted to open repair. During follow-up, two patients have died from unrelated causes after six and 12 months. Eight patients were converted to open repair 8-50 months (median 31) after implantation. Indications for conversion were migration (n = 4), increasing aneurysm diameter (n = 3) and rupture (n = 1). Of the 14 patients still under observation, six have had one or more endovascular interventions (a total of 10) for failing graft., Interpretation: Continuous technology development has been used as an argument to postpone randomised studies, as improved results are expected with new generations of stent-grafts. There is a need for discussion of the strategy for the further use of endovascular repair of abdominal aortic aneurysm.

We present a case of abdominal aortic aneurysm treated with an endovascular bifurcated aortic graft in which a periprosthetic leak caused by a tear in the polyester prosthesis appeared between 9 and 12 months after surgery. The tear appeared adjacent to a suture breakage that caused separation of two struts of the nitinol wire framework in the body of the stent graft. The leak was sealed with insertion of a new endovascular tube graft into the body of the bifurcation. Eight months later, the patient had a nonfatal rupture of the abdominal aortic aneurysm because detachment of the second limb from the bifurcation caused a new major periprosthetic leak. According to the manufacturer of this device, suture breakage with separation of metal components is commonly seen, but perforation of the polyester prosthesis caused by movement of the metal stent against the fabric has not been reported. It is likely that this occurred in our patient. Detachment of the second limb from the bifurcated stent, causing a rupture, has been described before. Increasing angulation and tortuosity of the stent graft, as a result of either remodeling of the sac or elongation of the stent, and reduced compliance to angulation after the stent-in-stent procedure might have contributed to the detachment in this case.