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OBJECT Patients presenting with large-territory ischemic strokes may develop intractable cerebral edema that puts them at risk of death unless intervention is performed. The purpose of this study was to identify predictors of outcome for decompressive hemicraniectomy (DH) in ischemic stroke. METHODS The authors conducted a retrospective electronic medical record review of 1624 patients from 2006 to 2014. Subjects were screened for DH secondary to ischemic stroke involving the middle cerebral artery, internal carotid artery, or both. Ninety-five individuals were identified. Univariate and multivariate analyses were performed for an array of clinical variables in relationship to functional outcome according to the modified Rankin Scale (mRS). Clinical outcome was assessed at 90 days and at the latest follow-up (mean duration 16.5 months). RESULTS The mean mRS score at 90 days and at the latest follow-up post-DH was 4. Good functional outcome was observed in 40% of patients at 90 days and in 48% of patient at the latest follow-up. The mortality rate at 90 days was 18% and at the last follow-up 20%. Univariate analysis identified a greater likelihood of poor functional outcome (mRS scores of 4–6) in patients with a history of stroke (OR 6.54 [95% CI1.39–30.66]; p = 0.017), peak midline shift (MLS) > 10 mm (OR 3.35 [95% CI 1.33–8.47]; p = 0.011), or a history of myocardial infarction (OR 8.95 [95% CI1.10–72.76]; p = 0.04). Multivariate analysis demonstrated elevated odds of poor functional outcome associated with a history of stroke (OR 9.14 [95% CI 1.78–47.05]; p = 0.008), MLS > 10 mm (OR 5.15 [95% CI 1.58–16.79; p = 0.007), a history of diabetes (OR 5.63 [95% CI 1.52–20.88]; p = 0.01), delayed time from onset of stroke to DH (OR 1.32 [95% CI 1.02–1.72]; p = 0.037), and evidence of pupillary dilation prior to DH (OR 4.19 [95% CI 1.06–16.51]; p = 0.04). Patients with infarction involving the dominant hemisphere had higher odds of unfavorable functional outcome at 90 days (OR 4.73 [95% CI 1.36–16.44]; p = 0.014), but at the latest follow-up, cerebral dominance was not significantly related to outcome (OR 1.63 [95% CI 0.61–4.34]; p = 0.328). CONCLUSIONS History of stroke, diabetes, myocardial infarction, peak MLS > 10 mm, increasing duration from onset of stroke to DH, and presence of pupillary dilation prior to intervention are associated with a worse functional outcome.

Deep-venous thrombosis (DVT) and pulmonary embolism (PE) are major causes of morbidity and mortality in patients with acute ischemic stroke. This study is the first to examine the risk of venous thromboembolism in patients with large hemispheric infarction undergoing decompressive hemicraniectomy. The study population included 95 consecutive patients with a large hemispheric infarction who underwent decompressive hemicraniectomy between 2006 and 2014 at our institution. All patients received prophylactic unfractionated heparin and intermittent compression devices (SCD). Patients were systematically screened for DVT at 5-day interval using Duplex ultrasound. PE was diagnosed on chest CT angiography. Mean age was 57 ± 12 years; mean BMI was 28.3 ± 7.4 kg/m2. 30.5 % of patients had infarction in the dominant hemisphere and 69.5 % in the non-dominant hemisphere. The mean NIHSS score was 16.0 ± 5 at admission. The mean length of stay was 22 ± 17 days. 35 % of patients developed a DVT including 27 % who developed above-knee DVT and required placement of an inferior vena cava filter. In multivariable analysis, predictors of DVT were an NIHSS ≥ 17 (p = 0.007), seizures (p = 0.003), hypertension (p = 0.03), and increasing length of stay (p = 0.01). The proportion of patients who developed PE was 13 %. In multivariate analysis, BMI ≥ 30 predicted PE (p = 0.05). The rate of DVT and PE is remarkably high in patients with large hemispheric infarction undergoing decompressive hemicraniectomy despite prophylactic measures. We recommend routine screening for DVT in this population. Interventions beyond the standard prophylactic measures may be necessary in this high-risk group.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used medications that can potentially increase the risk of bleeding and thrombosis.This study quantified the effect of NSAIDs in the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial.This was a post hoc analysis of NSAIDs in the RE-LY study, which compared dabigatran etexilate (DE) 150 and 110 mg twice daily (b.i.d.) with warfarin in patients with atrial fibrillation. Treatment-independent, multivariate-adjusted Cox regression analysis assessed clinical outcomes by comparing NSAID use with no NSAID use. Interaction analysis was obtained from treatment-dependent Cox regression modeling. Time-varying covariate analysis for NSAID use was applied to the Cox model.Among 18,113 patients in the RE-LY study, 2,279 patients used NSAIDs at least once during the trial. Major bleeding was significantly elevated with NSAID use (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.40 to 2.02; p 0.0001). NSAID use did not significantly alter the risk of major bleeding for DE 150 or 110 mg b.i.d. relative to warfarin (pThe use of NSAIDs was associated with increased risk of major bleeding, stroke/SE, and hospitalization. The safety and efficacy of DE 150 and 110 mg b.i.d. relative to warfarin were not altered. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY]; NCT00262600).

The justification for implanting a left atrial appendage (LAA) exclusion device is based on the assumption that the pathogenesis of stroke in every patient with atrial fibrillation (AF) is the embolism of clot from the LAA to the brain. This hypothesis, although true in some patients, is a simplistic view of a more complex disease. What is well established is that AF is often accompanied by hypertension, diabetes mellitus, systolic left ventricular dysfunction, vascular disease, and previous stroke, conditions that are independent risk factors for stroke.1 In an individual patient it is often impossible to determine which among these factors is responsible for a stroke. Of interest, AF may be the underlying cause of an ischemic stroke but may also go undetected, and lead to the erroneous diagnosis of cryptogenic stroke.2,3 The common pathogenesis of ischemic stroke is thrombosis, and anticoagulation is a highly effective preventative measure particularly when AF is present.4–8 Noteworthy, warfarin, against which the novel anticoagulants and Watchman device have been compared, is very effective for stroke prevention in patients with AF, with a reduction of up to 81% against placebo in open-label trials and 79% in the only completed double-blind trial.5,7 The novel anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban) were developed primarily to obviate the difficulties of using warfarin. The expectation was to show noninferiority for both efficacy and safety compared with warfarin.9–12 In definitive clinical trials these agents have either exceeded or met expectations against warfarin. Dabigatran 150 mg twice daily (BID) and apixaban (5 mg BID down-titrated to 2.5 mg BID for age ≥80 years, body weight ≤60 kg, and serum creatinine ≥1.5 mg/dL) were superior in efficacy to well-controlled warfarin.13,14 Rivaroxaban (20 mg down-titrated to 15 mg …

Human coding variants in scavenger receptor class B member 1 (SR-BI; gene name SCARB1) have recently been identified as being associated with plasma levels of HDL cholesterol. However, a link between coding variants and atherosclerosis has not yet been established. In this study we set out to examine the impact of a SR-BI coding variant in vivo. A mouse model with a coding variant in SR-BI (I179N), identified through a mutagenesis screen, was crossed with Ldlr −/− mice, and these mice were maintained on a Western-type diet to promote atherosclerosis. Mice showed 56 and 125 % increased atherosclerosis in female and male Ldlr −/− Scarb1 I179N mice, respectively, when compared to gender-matched Ldlr −/− control mice. As expected, HDL cholesteryl ester uptake was impaired in Ldlr −/− Scarb1 I179N mice compared to Ldlr –/– control mice, with a net effect of increased small and very small LDL cholesterol in Ldlr −/− Scarb1 I179N mice being the most probable cause of the observed increased atherosclerosis. Our data show that non-null coding variants in SR-BI can have a large significant impact on atherosclerosis, even if plasma lipid levels are not dramatically affected, and that human mutations in other candidate lipid genes could significantly impact atherosclerosis.

Scavenger receptor class B member 1 (SR-BI, also known as SCARB1) is the primary receptor for the selective uptake of cholesterol from high-density lipoprotein (HDL). SR-BI is present in several key tissues; however, its presence and function in the liver is deemed the most relevant for protection against atherosclerosis. Cholesterol is transferred from HDL via SR-BI to the liver, which ultimately results in the excretion of cholesterol via bile and feces in what is known as the reverse cholesterol transport pathway. Much of our knowledge of SR-BI hepatic function and regulation is derived from mouse models and in vitro characterization. Multiple independent regulatory mechanisms of SR-BI have been discovered that operate at the transcriptional and post-transcriptional levels. In this review we summarize the critical discoveries relating to hepatic SR-BI cholesterol metabolism, atherosclerosis, and regulation of SR-BI, as well as alternative functions that may indirectly affect atherosclerosis.

Tribbles1 (TRIB1) was recently identified in genome-wide association studies as being strongly linked to plasma levels of VLDL, HDL, LDL, and TG as well as coronary artery disease in humans. Previous experiments in mice using AAV-mediated hepatic overexpression of Trib1 confirmed this association, as mice overexpressing Trib1 exhibited reductions of 45% and 57% in plasma total cholesterol (TC) and TG, respectively ( Burkhardt et al, 2010 ). Here we report a Trib1 liver-specific knockout mouse (Trib1_LSKO) created through AAV-mediated delivery of Cre recombinase into adult mice with a floxed version of Trib1. Four weeks after infection, Trib1_LSKO mice exhibited 21% and 70% increases in TC and TG, respectively ( p =0.01 and 0.02), as compared to floxed Trib1 littermates infected with null virus (Controls). Trib1_LSKO animals also exhibited a 25% increase in liver weight ( p 2-fold increases in the hepatic transcription of genes involved in fatty acid synthesis in Trib1_LSKO mice as compared to Controls. Examination of hepatic lipids revealed a 78% increase in hepatic TG content ( p p p =0.02), diacylglycerol (1.8-fold, p p =0.05). Microarray analysis of Trib1_LSKO livers compared to Controls revealed greater than 1,600 genes that were significantly altered between the two groups (fold change>1.5, FDR