S100A9-RAGE Axis Accelerates Formation of Macrophage-Mediated Extracellular Vesicle Microcalcification in Diabetes Mellitus.

OBJECTIVE: Vascular calcification is a cardiovascular risk factor and accelerated in diabetes mellitus. Previous work has established a role for calcification-prone extracellular vesicles in promoting vascular calcification. However, the mechanisms by which diabetes mellitus provokes cardiovascular events remain incompletely understood. Our goal was to identify that increased S100A9 promotes the release of calcification-prone extracellular vesicles from human macrophages in diabetes mellitus. Approach and Results: Human primary macrophages exposed to high glucose (25 mmol/L) increased S100A9 secretion and the expression of receptor for advanced glycation end products (RAGE) protein. Recombinant S100A9 induced the expression of proinflammatory and osteogenic factors, as well as the number of extracellular vesicles with high calcific potential (alkaline phosphatase activity, P<0.001) in macrophages. Treatment with a RAGE antagonist or silencing with S100A9 siRNA in macrophages abolished these responses, suggesting that stimulation of the S100A9-RAGE axis by hyperglycemia favors a procalcific environment. We further showed that an imbalance between Nrf-2 (nuclear factor 2 erythroid related factor 2) and NF-κB (nuclear factor-κB) pathways contributes to macrophage activation and promotes a procalcific environment. In addition, streptozotocin-induced diabetic Apoe-/-S100a9-/- mice and mice treated with S100a9 siRNA encapsulated in macrophage-targeted lipid nanoparticles showed decreased inflammation and microcalcification in atherosclerotic plaques, as gauged by molecular imaging and comprehensive histological analysis. In human carotid plaques, comparative proteomics in patients with diabetes mellitus and histological analysis showed that the S100A9-RAGE axis associates with osteogenic activity and the formation of microcalcification. CONCLUSIONS: Under hyperglycemic conditions, macrophages release calcific extracellular vesicles through mechanisms involving the S100A9-RAGE axis, thus contributing to the formation of microcalcification within atherosclerotic plaques.

Economic implications of endovenous great saphenous ablation in a public health care system.

BACKGROUND: In mid-2007, endovenous ablation (EVA) of the great saphenous vein was introduced into the publicly funded health care system in Saskatchewan, Canada. We hypothesize that the introduction of EVA resulted in a decrease in use of high ligation and stripping (HL/S), decreased costs to the health care system, and increased demand of patients for great saphenous vein ablative procedures. METHODS: We retrospectively reviewed administrative data to capture cases of HL/S between 2003 and 2014 and cases of EVA of the great saphenous vein (endovenous laser treatment and radiofrequency ablation) between 2007 and 2014. Accounting for the change in practice pattern that occurred slowly between 2007 and 2009, we divided our patients into the pre-EVA era (2003-2006) and the post-EVA era (2010-2014). Procedure costs were determined with models used by our health region for this purpose. RESULTS: Utilization rates for great saphenous vein intervention remained similar in the pre-EVA (90 procedures per year) and post-EVA (92 procedures per year; P = .83) eras. Case costs of HL/S ($1965.12/case) were higher than those of EVA (endovenous laser treatment, $1295.08/case; radiofrequency ablation, $1410.54/case). The total annual costs of great saphenous vein intervention decreased from $176,861 in the pre-EVA era to $134,525 (P = .02). CONCLUSIONS: Introduction of publicly funded EVA has reduced rates of HL/S and reduced costs to our health system by approximately $42,000 per year, without increasing great saphenous vein intervention rates.

The Nature of Iron Deposits Differs between Symptomatic and Asymptomatic Carotid Atherosclerotic Plaques.

Iron within atherosclerotic plaque has been implicated as a catalyst of oxidative stress that causes progression of plaque, and plaque rupture. Iron is believed to accumulate within plaque by incorporation of erythrocytes following plaque rupture and hemorrhage. There is only indirect evidence to support this hypothesis. Plaque specimens were obtained from ten symptomatic and fifteen asymptomatic patients undergoing carotid endarterectomy at a single institution. Plaques were sectioned for study using synchrotron radiation induced X-ray fluorescence the study the distribution of zinc, calcium and iron. Histologic staining was carried out with Prussian Blue, and immunohistochemical staining was done to localize macrophages with CD68. Data were compared against patient clinical variables. Ten symptomatic (15 ± 10 days between index symptoms and surgery) and fifteen asymptomatic carotid plaques were studied. Zinc and calcium co-localized in mineralized areas of symptomatic and asymptomatic plaque. Iron was identified away from zinc and calcium in both symptomatic and asymptomatic plaques. Within the symptomatic plaques, iron was found within the thrombus associated with plaque rupture and hemorrhage. It did not stain with Prussian Blue, but was found in association with CD68 positive macrophages. In symptomatic plaques, the abundance of iron showed an association with the source patient's LDL cholesterol (R2 = 0.39, Significance F = 0.05). Iron in asymptomatic plaque was present as hemosiderin/ferritin that stained positive with Prussian Blue, and was observed in association with CD68 positive macrophages. Iron in acutely symptomatic plaques is found within thrombus, in the presence of macrophages. The abundance of iron in symptomatic plaques is associated with the source patient's LDL cholesterol. Within asymptomatic plaques, iron is found in association with macrophages, as hemosiderin/ferritin.

Geographic disparities in the burden of ruptured and unruptured abdominal aortic aneurysms.

BACKGROUND: The province of Saskatchewan presents unique challenges for the care of ruptured abdominal aortic aneurysms (AAAs), including variable access to health care resources and long transportation distances to tertiary vascular care. This study assessed the rates of ruptured and total AAA to determine regional variations within Saskatchewan and ascertain whether there are areas of high AAA prevalence that would possibly benefit from the implementation of a targeted screening program. METHODS: All diagnoses of AAA from 2001 to 2012 in the province of Saskatchewan were reviewed, with patients grouped by health region of residence. Diagnoses of ruptured and unruptured AAAs were obtained from the Saskatchewan Discharge Abstracts Database, Medical Services Billings Claims data, and Vital Statistics data. RESULTS: During the study period, 6163 AAAs were diagnosed. The provincial age-adjusted rate of AAA was 53.0/100,000 person-years (95% confidence interval, 48.8-57.6). The highest age-adjusted rate of AAA was found in the Five Hills Health Region (FHHR), at 63.1/100,000 person-years (95% confidence interval, 57.6-69.0), which was significantly higher than the provincial average (P < .05). The rate of ruptured AAA in FHHR was nearly twofold higher than the provincial average (6.0 vs 2.9/100,000 person-years, respectively). CONCLUSIONS: There are significant geographic variations in the prevalence of AAA in the province of Saskatchewan, with the highest rate of AAA found in the FHHR.

Patient and observer scar assessment scores favour the late appearance of a transverse cervical incision over a vertical incision in patients undergoing carotid endarterectomy for stroke risk reduction.

BACKGROUND: Carotid endarterectomy (CEA) is a very common operation, but there is no agreement on the appropriate orientation of the surgical incision. METHODS: We retrospectively reviewed the charts of patients who had undergone CEA between Jul. 1, 2010, and Dec. 31, 2013. We contacted patients identified in the review to solicit participation in a clinical follow-up examination, during which the esthetic outcome of the scar was evaluated using the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: During the study period 237 CEAs were performed. Nine patients refused the use of their personal health information in this study. There were no significant differences in the neurologic outcomes of patients based on the incision orientation (perioperative stroke and death 1.4% with transverse incision v. 0% with a vertical incision, p = 0.44). Fifty-two patients presented for follow-up examination. Thirty-three had a transverse incision and 19 had a vertical incision. Results of the POSAS significantly favoured the transverse incision (p = 0.03). Vertical incisions were more often associated with persistent, mild marginal mandibular nerve dysfunction (p = 0.04). CONCLUSION: Carotid endarterectomy performed through a transverse skin incision compared with a vertically oriented skin incision is associated with improved esthetic outcome, as measured by the POSAS, without an observed statistically significant difference in the risk of perioperative stroke or death between the 2 techniques.

CONTEXTE: L'endartériectomie de la carotide est une intervention chirurgicale très courante. Toutefois, il n'existe aucun consensus sur l'orientation de l'incision. MÉTHODES: Nous avons analysé rétrospectivement les dossiers de patients ayant subi une endartériectomie de la carotide entre le 1er juillet 2010 et le 31 décembre 2013. Nous avions communiqué au préalable avec les patients concernés pour solliciter leur participation à un examen de suivi clinique au cours duquel le résultat esthétique de leur cicatrice serait évalué au moyen de l'échelle d'évaluation des cicatrices par les patients et les observateurs (POSAS). RÉSULTATS: Au cours de la période visée, 237 endartériectomies de la carotide ont été pratiquées. Neuf patients ont refusé qu'on utilise leurs renseignements médicaux personnels dans le cadre de l'étude. Aucune différence significative n'a été observée quant aux capacités neurologiques des patients selon l'orientation de leur incision chirurgicale (décès et accident vasculaire cérébral périopératoires : 1,4 % avec incision transversale contre 0 % avec incision verticale, p = 0,44). Au total, 52 patients se sont présentés pour un examen de suivi : 33 avaient eu une incision transversale et 19, une incision verticale. Les résultats à la POSAS étaient nettement meilleurs pour les incisions transversales (p = 0,03). Les incisions verticales étaient plus souvent associées à un dysfonctionnement léger, mais persistant de la branche marginale de la mandibule du nerf facial (p = 0,04). CONCLUSION: Notre étude indique que d'après la POSAS, l'endartériectomie de la carotide est associée à un meilleur résultat esthétique lorsqu'elle est pratiquée au moyen d'une incision cutanée transversale qu'au moyen d'une incision verticale. Par ailleurs, aucune différence statistiquement significative n'a été observée quant aux risques de décès et d'accident vasculaire cérébral périopératoires associés à l'une ou l'autre de ces 2 techniques.

Distal revascularization and interval ligation (DRIL) procedure requires a long bypass for optimal inflow.

BACKGROUND: Distal revascularization and interval ligation (DRIL) is commonly used to treat ischemic steal syndrome caused by arteriovenous hemodialysis access and has been associated with good outcomes. However, the literature lacks technical details of a successful intervention. We tested the hypothesis that a brachial-level arteriovenous fistula (AVF) generates a zone of low arterial blood pressure in the brachial artery near the AVF origin. METHODS: We identified patients with ischemic steal syndrome caused by an AVF originating from the brachial artery level who were eligible for the DRIL procedure. All patients were studied with invasive pressure monitoring in the brachial artery at the time of digital subtraction angiography. We measured systolic, diastolic and mean arterial blood pressure at 5 cm intervals from a point in the arterial circulation 5 cm distal to the origin of the AVF and continuing proximally into the subclavian artery. RESULTS: Our series involved 10 patients with a mean age of 66.5 (range 53-81) years. Four patients were women and 8 had diabetes. All patients had grade 3 ischemic steal syndrome with ischemic rest pain and/or ischemic tissue loss. Mean systolic, diastolic and arterial pressures increased from the level of the AVF until central pressures were reached. Systolic blood pressure was significantly lower than central blood pressure until a level 20-25 cm proximal to the AVF. CONCLUSION: The benefits of the DRIL procedure in alleviating ischemic steal syndrome associated with hemodialysis access are best achieved with a DRIL bypass for which inflow originates at least 20-25 cm proximal to the origin of the AVF.

CONTEXTE: On utilise souvent la revascularisation distale avec ligature intermédiaire (DRIL) pour traiter le syndrome d'hémodétournement ischémique causé par une fistule artérioveineuse pour hémodialyse et elle a été associée à de bons résultats. Or, la littérature donne peu de détails techniques sur les interventions réussies. Nous avons voulu tester l'hypothèse selon laquelle une fistule artérioveineuse (FAV) brachiale génère une zone de tension artérielle réduite dans l'artère brachiale près de la naissance de la FAV. MÉTHODES: Nous avons recensé des patients porteurs d'un syndrome de détournement ischémique causé par une FAV de l'artère brachiale qui étaient admissibles à l'intervention DRIL. Nous avons examiné les patients par monitorage endovasculaire de la pression de l'artère brachiale sous angiographie numérique avec soustraction. Nous avons mesuré les tensions artérielles systoliques, diastoliques et moyennes à des intervalles de 5 cm, à partir d'un point distal de la circulation artérielle éloigné de 5 cm de la naissance de la FAV, puis proximalement, jusqu'à la sous-clavière. RÉSULTATS: Notre série a regroupé 10 patients âgés en moyenne de 66,5 ans (de 53 à 81 ans). Quatre patients étaient des femmes et 8 souffraient de diabète. Tous les patients étaient porteurs d'un syndrome d'hémodétournement ischémique de grade 3 accompagné de douleur ischémique au repos et/ou d'ischémie tissulaire. Les tensions artérielles systoliques, diastoliques et moyennes allaient croissant à partir de la FAV, jusqu'à l'atteinte des tensions centrales. La tension systolique s'est révélée significativement plus faible que la tension centrale jusqu'à un point proximal situé à 20­25 cm de la FAV. CONCLUSION: Dans le traitement du syndrome d'hémodétournement ischémique associé à une fistule artérioveineuse pour hémodialyse, les avantages de l'intervention DRIL sont plus marqués avec un pontage dont l'influx tire son origine à au moins 20­25 cm de la naissance de la FAV.

Ruptured abdominal aortic aneurysms in southern Saskatchewan: a 10-year mortality review.

The Regina Qu'Appelle Health Region (RQHR) provides all tertiary vascular care for southern Saskatchewan and portions of southwestern Manitoba. The present study was undertaken to determine the regional mortality rates following rupture of an abdominal aortic aneurysm and to compare these rates with the published literature. A retrospective chart review was undertaken on all cases of ruptured abdominal aortic aneurysms (rAAA) presenting to the RQHR between March 1, 1996, and February 28, 2006. The demographic data and clinical outcomes were collected from hospital charts by a single reviewer. Over the 10-year study period, 101 cases of rAAA were presented to the RQHR. Patient demographics and comorbidities were comparable to other studies in the published literature. Thirty-seven percent of patients presented with systolic blood pressure below 90 mm Hg, and 7% had no recordable blood pressure. The overall mortality was 25%. Mortality risk was not statistically different between patients presenting within Regina (30%) and those referred from a distance of more than 35 km (21%, P = .353). Seven patients were treated palliatively, and 94 proceeded to open surgical repair. Within the group of patients undergoing surgery, there was a 19% mortality rate. The data show a low observed mortality rate for rAAA presenting to the RQHR. The favorable outcome of the patients is not associated with preselection bias of patients transported long distances to specialist vascular care.

Axillary artery to right atrium shunt for hemodialysis access in a patient with advanced central vein thrombosis: a case report.

Central venous thrombosis presents a challenge to the treatment of hemodialysis patients requiring vascular access. We present the case of a patient with renal failure and virulent thrombophilia causing severe central venous thrombosis. We discuss the use of a hemodialysis shunt from the right axillary artery to the right atrium and describe the technical details and the pitfalls encountered in our utilization of this technique.