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Objective: Atherosclerosis is accumulation of lipids and extracellular matrix in the arterial wall. TIMPs (tissue inhibitor of metalloproteinases) can impact plaque deposition by regulating ECM (extracellular matrix) turnover. TIMP4 also influences lipid metabolism and smooth muscle cell (SMC) proliferation. We investigated the role of TIMP4 in atherosclerosis. Approach and Results: Mice lacking low-density lipoprotein receptor ( Ldlr −/− ) and Timp4 ( Timp4 −/− / Ldlr −/− ) were fed high-fat diet (HFD) or regular laboratory diet. After 3 or 6 months, HFD-fed male and female Timp4 −/− / Ldlr −/− mice exhibited higher plaque density in the abdominal aorta (but not in aortic valves, arch, thoracic aorta) compared with Ldlr −/− mice. Although plasma lipid and cholesterol levels were lower in Timp4 −/− / Ldlr −/− -HFD, cholesterol content in the abdominal aorta was higher along with elevated inflammatory cytokines, MMP (matrix metalloproteinase) activities, CD68 + /calponin + macrophage-like SMCs in Timp4 −/− / Ldlr −/− -HFD compared with Ldlr −/− -HFD mice. In vitro, oxidized LDL (low-density lipoprotein) markedly increased CD68 expression, reduced SMC markers, increased lipid uptake, and reduced cholesterol efflux protein ABCA1 (ATP-binding cassette transporter A1) in Timp4 −/− / Ldlr −/− compared with Ldlr −/− primary SMCs from abdominal, but not thoracic aorta. TIMP4 expression in the abdominal aorta (in vivo) and its corresponding SMCs (in vitro) was ≈2-fold higher than in the thoracic aorta and SMCs; TIMP4 levels decreased following HFD. Timp4 -deficiency in bone marrow–derived macrophages did not alter their foam cell formation capacity. Conclusions: TIMP4 protects against plaque deposition in the abdominal aorta independent of plasma cholesterol levels. TIMP4 prevents proteolytic degradation of ABCA1 in SMCs, hindering cholesterol accumulation and transdifferentiation to macrophage-like foam cells, representing a novel negative regulator of atherosclerosis.

Supplemental Digital Content is available in the text., Objective: ADAM (a disintegrin and metalloproteinase) 15—a membrane-bound metalloprotease from the ADAM (disintegrin and metalloproteinase) family—has been linked to endothelial permeability, inflammation, and metastasis. However, its function in aortic aneurysm has not been explored. We aimed to determine the function of ADAM15 in the pathogenesis of aortic remodeling and aneurysm formation. Approach and Results: Male Adam15-deficient and WT (wild type) mice (10 weeks old), on standard laboratory diet, received Ang II (angiotensin II; 1.5 mg/kg per day) or saline (Alzet pump) for 2 or 4 weeks. Ang II increased ADAM15 in WT aorta, while Adam15-deficiency resulted in abdominal aortic aneurysm characterized by loss of medial smooth muscle cells (SMCs), elastin fragmentation, inflammation, but unaltered Ang II–mediated hypertension. In the abdominal aortic tissue and primary aortic SMCs culture, Adam15 deficiency decreased SMC proliferation, increased apoptosis, and reduced contractile properties along with F-actin depolymerization to G-actin. Ang II triggered a markedly greater increase in THBS (thrombospondin) 1 in Adam15-deficient aorta, primarily the medial layer in vivo, and in aortic SMC in vitro; increased SSH1 (slingshot homolog 1) phosphatase activity and cofilin dephosphorylation that promoted F-actin depolymerization and G-actin accumulation. rhTHBS1 (recombinant THBS1) alone was sufficient to activate the cofilin pathway, increase G-actin, and induce apoptosis of aortic SMCs, confirming the key role of THBS1 in this process. Further, in human abdominal aortic aneurysm specimens, decreased ADAM15 was associated with increased THBS1 levels and loss of medial SMCs. Conclusions: This study is the first to demonstrate a key role for ADAM15 in abdominal aortic aneurysm through regulating the SMC function, thereby placing ADAM15 in a critical position as a potential therapeutic target for abdominal aortic aneurysm.

Summary Background Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. Methods In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Findings Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Interpretation Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Funding Boehringer Ingelheim and Canadian Institutes of Health Research.

Thoracic endovascular aortic repair (TEVAR) has emerged as an alternative to open surgical repair (OSR) of traumatic thoracic aortic injury (TTAI). Herein immediate and midterm outcomes of TEVAR are compared with those of OSR.Health records were used to identify patients with TTAI presenting between April 1995 and September 2006. Preoperative patient characteristics, intraoperative variables, procedural costs, and outcomes were recorded.A total of 103 patients were identified. Twenty-two died before treatment, 19 were treated conservatively, 36 received OSR, and 26 received TEVAR. In the OSR group, time from diagnosis to treatment was 8 hours, the 30-day mortality rate was 11.1%, and all deaths occurred intraoperatively. Thoracic nerve injury occurred in four patients (12.5%), pneumonia in 12 (37.5%), temporary renal failure in one (3%), paraparesis in three (9.4%), and paraplegia in five (15.6%). On follow-up (mean, 61 months), postthoracotomy pleural reaction was seen in three cases (9.4%). In the TEVAR group, time to treatment was 38 hours (P.01) and the 30-day mortality rate was 7.4% with no intraoperative deaths. Pneumonia was seen in two cases (8.3%) and left arm ischemia was seen in two of 17 patients in whom the left subclavian artery was covered. On midterm follow-up (mean, 17 months), there were no graft failures or repeat aortic interventions. Costs of each procedure were initially comparable, but follow-up expenses with TEVAR were $1,284 (Canadian) greater per year.TEVAR of TTAI is associated with lower perioperative mortality and morbidity rates than OSR, with no significant graft-related complications on midterm follow-up. The study data support the continued use of TEVAR in this context.

BACKGROUND Intestinal transplantation is now used for patients with severe malabsorption, however, little data exists quantifying the ability of the graft to absorb fat. This study tested the hypothesis that intestinal transplantation would not affect the lymphatic or venous uptake of fatty acids. METHODS A syngeneic rat model of intestinal transplantation (SIT) with caval drainage of the graft was used. Control animals underwent intestinal division and reanastomosis (n=15 in each group). The animals were followed for 6 weeks, and fat absorption in vivo was quantified. The animals were anesthetized, sampling catheters were placed in the jugular and superior mesenteric veins and in the mesenteric lymphatic duct, and a feeding tube was passed into the duodenum. Animals were allowed to recover, and a steady-state duodenal infusion of lauric (C12:0) and palmitic (C16:0) fatty acid emulsion was begun. A radiolabeled pulse of lauric (C12:0) and palmitic (C16:0) fatty acid was then given, and the subsequent appearance in the lymphatic and venous systems was quantified. RESULTS In vivo absorption of dietary fat was preserved, but after transplantation the mesenteric lymphatic flow and cumulative lymphatic appearance of both labels was significantly reduced (flow reduced from 4.8+/-1.1 in controls to 1.0+/-0.29 ml/hr in transplant animals, whereas lauric acid absorption was 33+/-11.4% in controls vs. 7.5+/-2.5% in transplant animals). There was a modest increase in the jugular venous appearance of the fatty acids (2.0+/-1.1% in transplant animals vs. 0.75+/-0.55% in controls for lauric acid; P

Objective The goals of our study were to retrospectively review our experience in using Tc-white blood cell (WBC) single-photon emission computed tomography/computed tomography (SPECT/CT) imaging in the evaluation of possible arterial graft infection and to attempt to establish objective criteria for assessment. Methods Eleven Tc-WBC SPECT/CT studies performed for the evaluation of clinically suspected arterial graft infection were retrospectively reviewed and compared with reference outcomes. In an attempt to define objective criteria for interpretation, comparison was also made with background liver and bone marrow activity. Results When compared with reference outcomes, the subjective scan interpretations showed 6 of 11 true positives (TP), 4 of 11 true negatives (TN), and 1 of 11 false positive (FP). Using the liver as a comparator resulted in 4 of 10 TP, 5 of 10 TN, and 1 of 10 FN. Using the bone marrow as a comparator resulted in 3 of 10 TP, 5 of 10 TN, and 2 of 10 FN. In one patient neither the liver nor the bone marrow was in the field of view. Conclusion These findings suggest a high accuracy for Tc-WBC SPECT/CT in assessing clinically suspected arterial graft infection. Furthermore, the liver may be the best objective comparator for standardized interpretation.

The purpose of this study was to determine the efficacy of intraoperative intraarterial urokinase (UK) in patients who suffered an acute stroke immediately following carotid endarterectomy (CEA). From January 1995 to March 1998, 823 carotid endarterectomies were performed. The subsequent results showed that intraarterial UK in the setting of early post-CEA neurologic events appears to be safe and may be a useful adjunct to re-exploration in improving neurologic outcomes.

Medium-chain triglycerides are used for the treatment of malabsorptive states. We measured directly the absorption of medium- and long-chain fatty acids via the mesenteric lymphatics and portal vein in normal animals. These results may be useful in guiding therapy for short-bowel syndrome.Under anesthesia, male Lewis rats (n = 6) underwent placement of jugular and portal venous lines, mesenteric lymphatic duct cannula, and a duodenal tube. After recovery, a 0.3% lauric acid (C12:0) and 0.37% palmitic acid (C16:0) solution solublized with 3.25 mmol/L lecithin and 23.75 mmol/L taurocholic acid in phosphate-buffered saline was infused at a rate of 3 mL/h via the duodenal tube. After stabilization of lymphatic flow (6 hours), a pulse of radiolabeled lauric and palmitic acid was given via the duodenal tube; absorption was measured by collection of lymphatic fluid and sampling of the portal and jugular venous blood for 4 hours.The amount of acid recovered in the lymphatics was 51% +/- 6% (mean +/- SD) for lauric and 59% +/- 6% for palmitic. For both fatty acids,1% in total was recovered from the portal vein during the 4-hour postbolus period; thereafter, levels in the blood were constant and very low. At necropsy, the majority of the remaining label was found in the intestine.These results show no evidence for the preferential absorption of medium-chain fatty acids directly via the portal vein in this model. We suggest that further studies be done to measure directly portal vein absorption of the medium-chain fatty acids.

Purpose: The North American Symptomatic Carotid Endarterectomy Trial (NASCET) showed that selected patients benefited from surgery when their carotid artery was 50% or more stenosed. This study assessed the accuracy of color-flow duplex ultrasound scanning (DUS) parameters to detect 50% or greater carotid artery stenosis and to determine the situations in which carotid endarterectomy (CEA) without angiography could be justified. Methods: From March 1, 1995, to December 1, 1995, all patients considered for CEA were studied with DUS and carotid angiography. Results of the two tests were blindly compared. DUS measurements of internal carotid artery (ICA) peak systolic velocity (PSV), end diastolic velocity, and ratio of the ICA to common carotid artery PSV (ICA/CCA) were subjected to receiver operator characteristic curve analysis to determine the most accurate criterion predicting 50% or greater angiographic stenosis. The criterion for identifying patients for CEA without angiography was selected from criteria with a high positive predictive value (PPV) and sensitivity. Results: A total of 188 carotid bifurcations were available for comparison. A PSV (ICA/CCA) of 2 or higher was the most accurate criterion for detection of 50% or greater stenosis, with an accuracy rate of 93% (sensitivity, 96%; specificity, 89%; PPV, 92%). A PSV (ICA/CCA) of 3.6 or higher was the best criterion for identifying candidates for CEA who had not undergone earlier angiography, with PPV, sensitivity, specificity, and accuracy rates of 98%, 77%, 98%, and 86%, respectively. Conclusion: These redefined criteria detect the NASCET-defined threshold level of 50% or greater ICA stenosis, above which CEA results in stroke reduction. A management algorithm based on these criteria should help to minimize both angiography and unnecessary intervention. (J Vasc Surg 1999;29:986-94.)