NADPH oxidase 1 promotes hepatic steatosis in obese mice and is abrogated by augmented skeletal muscle mass.

Exercise as a lifestyle modification is a frontline therapy for nonalcoholic fatty liver disease (NAFLD), but how components of exercise attenuate steatosis is unclear. To uncouple the effect of increased muscle mass from weight loss in obesity, myostatin knockout mice were bred on a lean and obese db/db background. Myostatin deletion increases gastrocnemius (Gastrocn.) mass and reduces hepatic steatosis and hepatic sterol regulatory element binding protein 1 (Srebp1) expression in obese mice, with no impact on adiposity or body weight. Interestingly, hypermuscularity reduces hepatic NADPH oxidase 1 (Nox1) expression but not NADPH oxidase 4 (Nox4) in db/db mice. To evaluate a deterministic function of Nox1 on steatosis, Nox1 knockout mice were bred on a lean and db/db background. NOX1 deletion significantly attenuates hepatic oxidant stress, steatosis, and Srebp1 programming in obese mice to parallel hypermuscularity, with no improvement in adiposity, glucose control, or hypertriglyceridemia to suggest off-target effects. Directly assessing the role of NOX1 on SREBP1, insulin (Ins)-mediated SREBP1 expression was significantly increased in either NOX1, NADPH oxidase organizer 1 (NOXO1), and NADPH oxidase activator 1 (NOXA1) or NOX5-transfected HepG2 cells versus ?-galactosidase control virus, indicating superoxide is the key mechanistic agent for the actions of NOX1 on SREBP1. Metabolic Nox1 regulators were evaluated using physiological, genetic, and diet-induced animal models that modulated upstream glucose and insulin signaling, identifying hyperinsulinemia as the key metabolic derangement explaining Nox1-induced steatosis in obesity. GEO data revealed that hepatic NOX1 predicts steatosis in obese humans with biopsy-proven NAFLD. Taken together, these data suggest that hypermuscularity attenuates Srebp1 expression in db/db mice through a NOX1-dependent mechanism.NEW & NOTEWORTHY This study documents a novel mechanism by which changes in body composition, notably increased muscle mass, protect against fatty liver disease. This mechanism involves NADPH oxidase 1 (NOX1), an enzyme that increases superoxide and increases insulin signaling, leading to increased fat accumulation in the liver. NOX1 may represent a new early target for preventing fatty liver to stave off later liver diseases such as cirrhosis or liver cancer.

High maternal adiposity during pregnancy programs an imbalance in the lipidome and predisposes to diet-induced hepatosteatosis in the offspring.

BACKGROUND: Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. RESULTS: Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Female wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high-fat/fructose diet (HFFD) compared with Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams and CD or HFFD-fed Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic polyunsaturated FA (PUFA) levels compared with control offspring. Changes to saturated FA (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Δ9 desaturase activity. CONCLUSION: High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

The biological clock enhancer nobiletin ameliorates steatosis in genetically obese mice by restoring aberrant hepatic circadian rhythm.

Nonalcoholic fatty liver disease (NAFLD) is associated with disruption of homeostatic lipid metabolism, but underlying processes are poorly understood. One possible mechanism is impairment in hepatic circadian rhythm, which regulates key lipogenic mediators in the liver and whose circadian oscillation is diminished in obesity. Nobiletin enhances biological rhythms by activating RAR-related orphan receptor nuclear receptor, protecting against metabolic syndrome in a clock-dependent manner. The effect of nobiletin in NAFLD is unclear. In this study, we investigate the clock-enhancing effects of nobiletin in genetically obese (db/db) PER2::LUCIFERASE reporter mice with fatty liver. We report microarray expression data suggesting hepatic circadian signaling is impaired in db/db mice with profound hepatic steatosis. Circadian PER2 activity, as assessed by mRNA and luciferase assay, was significantly diminished in liver of db/db PER2::LUCIFERASE reporter mice. Continuous animal monitoring systems and constant dark studies suggest the primary circadian defect in db/db mice lies within peripheral hepatic oscillators and not behavioral rhythms or the master clock. In vitro, nobiletin restored PER2 amplitude in lipid-laden PER2::LUCIFERASE reporter macrophages. In vivo, nobiletin dramatically upregulated core clock gene expression, hepatic PER2 activity, and ameliorated steatosis in db/db PER2::LUCIFERASE reporter mice. Mechanistically, nobiletin reduced serum insulin levels, decreased hepatic Srebp1c, Acaca1, Tnfα, and Fgf21 expression, but did not improve Plin2, Plin5, or Cpt1, suggesting nobiletin attenuates steatosis in db/db mice via downregulation of hepatic lipid accumulation. These data suggest restoring endogenous rhythm with nobiletin resolves steatosis in obesity, proposing that hypothesis that targeting the biological clock may be an attractive therapeutic strategy for NAFLD.NEW & NOTEWORTHY NAFLD is the most common chronic liver disease, but underlying mechanisms are unclear. We show here that genetically obese (db/db) mice with fatty liver have impaired hepatic circadian rhythm. Hepatic Per2 expression and PER2 reporter activity are diminished in db/db PER2::LUCIFERASE mice. The biological clock-enhancer nobiletin restores hepatic PER2 in db/db PER2::LUCIFERASE mice, resolving steatosis via downregulation of Srebp1c. These studies suggest targeting the circadian clock may be beneficial strategy in NAFLD.

Obesity Induces Disruption of Microvascular Endothelial Circadian Rhythm.

Obese individuals are at significantly elevated risk of developing cardiovascular disease (CVD). Additionally, obesity has been associated with disrupted circadian rhythm, manifesting in abnormal sleeping and feeding patterns. To date, the mechanisms linking obesity, circadian disruption, and CVD are incompletely understood, and insight into novel mechanistic pathways is desperately needed to improve therapeutic potential and decrease morbidity and mortality. The objective of this study was to investigate the roles of metabolic and circadian disruptions in obesity and assess their contributions in promoting vascular disease. Lean (db/+) and obese (db/db) mice were subjected to 12 weeks of constant darkness to differentiate diurnal and circadian rhythms, and were assessed for changes in metabolism, gene expression, and vascular function. Expression of endothelial nitric oxide synthase (eNOS), an essential enzyme for vascular health, was blunted in obesity and correlated with the oscillatory loss of the novel regulator cezanne (OTUD7B). Lean mice subjected to constant darkness displayed marked reduction in vasodilatory capacity, while endothelial dysfunction of obese mice was not further compounded by diurnal insult. Endothelial gene expression of essential circadian clock components was altered in obesity, but imperfectly phenocopied in lean mice housed in constant darkness, suggesting overlapping but separate mechanisms driving endothelial dysfunction in obesity and circadian disruption. Taken together, these data provide insight into the nature of endothelial circadian rhythm in obesity and suggest a distinct mechanism by which obesity causes a unique circadian defect in the vasculature.

Accelerated developmental adipogenesis programs adipose tissue dysfunction and cardiometabolic risk in offspring born to dams with metabolic dysfunction.

This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females (P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Hetdb dams (P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.

Bile Reflux Gastropathy and Functional Dyspepsia.

BACKGROUND/AIMS: The pathoetiology of functional dyspepsia remains unclear; one mechanism could be chemical gastropathy from chronic bile reflux. We aim to examine the association of bile reflux gastropathy with functional dyspepsia and identify predisposing factors. METHODS: In a retrospective study, patients with functional dyspepsia (Rome III) who completed symptom assessment, esophagogastroduodenoscopy, and biopsies were categorized into 3 groups; bile gastropathy (BG), non-bile gastropathy (NBG), and no gastropathy (NG). Demographics, symptoms, endoscopy, and motility data were compared between groups. Multivariate analysis identified clinical factors associated with BG. RESULTS: Of 262 patients (77.5% female), 90 had BG, 121 had NBG, and 51 had NG. Baseline demographics were similar, however, patients with BG reported significantly more severe abdominal pain than NBG or NG groups (P = 0.018). Gastric erythema was significantly more common in BG vs NBG groups (P < 0.001). Cholecystectomy was significantly associated (OR, 6.6; P = 0.003) with the presence of gastropathy in BG compared to NBG or NG group. Patients with cholecystectomy had significantly more severe abdominal pain (P < 0.05), gastric erythema (P < 0.03), and gastritis (P < 0.05), and were more likely to be prescribed narcotic medications (P < 0.004) than patients without cholecystectomy. CONCLUSION: s Bile reflux gastropathy is associated with functional dyspepsia and causes more severe symptoms. Cholecystectomy predisposes to BG and abnormal pain, and could contribute to the pathogenesis of functional dyspepsia.

Clinical factors associated with hepatitis B screening and vaccination in high-risk adults.

BACKGROUND: Hepatitis B virus is a viral infection that can lead to acute and/or chronic liver disease, and hepatocellular carcinoma (HCC). Hepatitis B vaccination is 95% effective in preventing infection and the development of chronic liver disease and HCC due to hepatitis B. In 2011, the Centers for Disease Control updated their guidelines recommending that adults at high-risk for hepatitis B infection be vaccinated against hepatitis B including those with diabetes mellitus (DM). We hypothesize that adults at high-risk for hepatitis B infection are not being adequately screened and/or vaccinated for hepatitis B in a large urban healthcare system. AIM: To investigate clinical factors associated with Hepatitis B screening and vaccination in patients at high-risk for Hepatitis B infection. METHODS: We conducted a retrospective review of 999 patients presenting at a large urban healthcare system from 2012-2017 at high-risk for hepatitis B infection. Patients were considered high-risk for hepatitis B infection based on hepatitis B practice recommendations from the Center for Disease Control. Medical history including hepatitis B serology, concomitant medical diagnoses, demographics, insurance status and social history were extracted from electronic health records. Multivariate logistic regression was used to identify clinical risk factors independently associated with hepatitis B screening and vaccination. RESULTS: Among the 999 patients, 556 (55.7%) patients were screened for hepatitis B. Of those who were screened, only 242 (43.5%) patients were vaccinated against hepatitis B. Multivariate regression analysis revealed end-stage renal disease [odds ratio (OR): 5.122; 2.766-9.483], alcoholic hepatitis (OR: 3.064; 1.020-9.206), and cirrhosis or end-stage liver disease (OR: 1.909; 1.095-3.329); all P < 0.05 were associated with hepatitis B screening, while age (OR: 0.785; 0.680-0.906), insurance status (0.690; 0.558-0.854), history of DM (OR: 0.518; 0.364-0.737), and human immunodeficiency virus (OR: 0.443; 0.273-0.718); all P < 0.05 were instead not associated with hepatitis B screening. Of the adults vaccinated for hepatitis B, multivariate regression analysis revealed age (OR: 0.755; 0.650-0.878) and DM were not associated with hepatitis B vaccination (OR: 0.620; 0.409-0.941) both P < 0.05. CONCLUSION: Patients at high-risk for hepatitis B are not being adequately screened and/or vaccinated. Improvements in hepatitis B vaccination should be strongly encouraged by all healthcare systems.

Increased Muscle Mass Protects Against Hypertension and Renal Injury in Obesity.

Background Obesity compromises cardiometabolic function and is associated with hypertension and chronic kidney disease. Exercise ameliorates these conditions, even without weight loss. Although the mechanisms of exercise's benefits remain unclear, augmented lean body mass is a suspected mechanism. Myostatin is a potent negative regulator of skeletal muscle mass that is upregulated in obesity and downregulated with exercise. The current study tested the hypothesis that deletion of myostatin would increase muscle mass and reduce blood pressure and kidney injury in obesity. Methods and Results Myostatin knockout mice were crossed to db/db mice, and metabolic and cardiovascular functions were examined. Deletion of myostatin increased skeletal muscle mass by ≈50% to 60% without concomitant weight loss or reduction in fat mass. Increased blood pressure in obesity was prevented by the deletion of myostatin, but did not confer additional benefit against salt loading. Kidney injury was evident because of increased albuminuria, which was abolished in obese mice lacking myostatin. Glycosuria, total urine volume, and whole kidney NOX-4 levels were increased in obesity and prevented by myostatin deletion, arguing that increased muscle mass provides a multipronged defense against renal dysfunction in obese mice. Conclusions These experimental observations suggest that loss of muscle mass is a novel risk factor in obesity-derived cardiovascular dysfunction. Interventions that increase muscle mass, either through exercise or pharmacologically, may help limit cardiovascular disease in obese individuals.

Split- versus single-dose preparation tolerability in a multiethnic population: decreased side effects but greater social barriers.

BACKGROUND: This study was performed to compare patient-reported tolerability and its barriers in single- vs. split-dose 4-L polyethylene glycol (PEG) bowel preparation for colonoscopy in a large multiethnic, safety-net patient population. METHODS: A cross-sectional, dual-center study using a multi-language survey was used to collect patient-reported demographic, medical, socioeconomic, and tolerability data from patients undergoing outpatient colonoscopy. Univariate and multivariate analyses were used to identify demographic and clinical factors significantly associated with patient-reported bowel preparation tolerability. RESULTS: A total of 1023 complete surveys were included, of which 342 (33.4%) completed single-dose and 681 (66.6%) split-dose bowel preparation. Thirty-nine percent of the patients were Hispanic, 50% had Medicaid or no insurance, and 34% had limited English proficiency. Patients who underwent split-dose preparation were significantly more likely to report a tolerable preparation, with less severe symptoms, than were patients who underwent single-dose preparation. Multiple logistic regression revealed that male sex and instructions in the preferred language were associated with tolerability of the single-dose preparation, while male sex and concerns about medications were associated with tolerability of the split-dose preparation. CONCLUSIONS: In a large multiethnic safety-net population, split-dose bowel preparation was significantly more tolerable and associated with less severe gastrointestinal symptoms than single-dose preparation. The tolerability of split-dose bowel preparation was associated with social barriers, including concerns about interfering with other medications.

Does colectomy predispose to small intestinal bacterial (SIBO) and fungal overgrowth (SIFO)?

OBJECTIVES: After subtotal colectomy, 40% of patients report chronic gastrointestinal symptoms and poor quality of life. Its etiology is unknown. We determined whether small intestinal bacterial overgrowth (SIBO) or small intestinal fungal overgrowth (SIFO) cause gastrointestinal symptoms after colectomy. METHODS: Consecutive patients with unexplained abdominal pain, gas, bloating and diarrhea (>1 year), and without colectomy (controls), and with colectomy were evaluated with symptom questionnaires, glucose breath test (GBT) and/or duodenal aspiration/culture. Baseline symptoms, prevalence of SIBO/SIFO, and response to treatment were compared between groups. RESULTS: Fifty patients with colectomy and 50 controls were evaluated. A significantly higher (p = 0.005) proportion of patients with colectomy, 31/50 (62%) had SIBO compared to controls 16/50 (32%). Patients with colectomy had significantly higher (p = 0.017) prevalence of mixed SIBO/SIFO 12/50 (24%) compared to controls 4/50 (8%). SIFO prevalence was higher in colectomy but not significant (p = 0.08). There was higher prevalence of aerobic organisms together with decreased anaerobic and mixed organisms in the colectomy group compared to controls (p = 0.008). Patients with colectomy reported significantly greater severity of diarrhea (p = 0.029), vomiting (p < 0.001), and abdominal pain (p = 0.05) compared to controls, at baseline. After antibiotics, 74% of patients with SIBO/SIFO in the colectomy and 69% in the control group improved (p = 0.69). CONCLUSION: Patients with colectomy demonstrate significantly higher prevalence of SIBO/SIFO and greater severity of gastrointestinal symptoms. Colectomy is a risk factor for SIBO/SIFO.

A Novel Iliac Morphology Score Predicts Procedural Mortality and Major Vascular Complications in Transfemoral Aortic Valve Replacement.

BACKGROUND: Vascular complications remain a significant technical challenge for transfemoral TAVR (transcatheter aortic valve replacement). The goal of this study is to develop a preoperative tool for prediction of major vascular complications of TAVR. METHODS: A retrospective review was performed of all patients who underwent transfemoral TAVR at a tertiary medical center from 2011 to 2015. Iliofemoral arterial measurements were obtained with computed tomography angiography three-dimensional reconstruction images and an Iliac Morphology Score (IMS) was created from these measurements. Vascular complications were defined by Valve Academic Research Consortium (VARC-2) criteria. Statistical analyses were performed utilizing chi-squared test, Student's t-test, and binomial regression. RESULTS: We analyzed the data of 198 transfemoral TAVR patients. VARC-2 vascular complications were seen in 25 patients (13%). Major and minor vascular complication rates in the entire cohort were 4% (n = 7) and 9% (n = 18), respectively. Thirty-one patients (15.6%) required vascular surgery consultation. A total of 24 patients (12%) required surgical or percutaneous vascular interventions. Univariate analysis identified gender, iliac diameter, iliac calcification, and access type (open versus percutaneous) as predictors of major complications. The IMS was composed of ipsilateral minimum iliac diameter and iliac calcifications based on area under the receiver operator curve (AUROC) analysis (P < 0.05, AUROC = 0.82). Arterial size and calcification were classified with a value of 0-3 based on severity. Multivariate analysis identified gender and IMS as independent predictors of major complications. The mean IMS for the cohort was 3.4 (range 0-6). Patients were divided into high (IMS ≥ 5, n = 55) and low risk (IMS<5, n = 143) groups based on the inflection point for specificity (73%) and sensitivity (83%). The high-risk group had smaller iliac diameters, areas, luminal volumes, and a higher rate of major vascular complications (9% vs. 1%, P = 0.001). The 30-day mortality rate in the high score group was 9% and 1.4% in low score group (P = 0.02, AUROC = 0.72). CONCLUSIONS: An IMS composed of ipsilateral minimum iliac diameter plus iliac calcification is an excellent predictor of major vascular complications and mortality. Alternative access in patients with high IMS may reduce major vascular complications and 30-day mortality.

Effect of myostatin deletion on cardiac and microvascular function.

The objective of this study is to test the hypothesis that increased muscle mass has positive effects on cardiovascular function. Specifically, we tested the hypothesis that increases in lean body mass caused by deletion of myostatin improves cardiac performance and vascular function. Echocardiography was used to quantify left ventricular function at baseline and after acute administration of propranolol and isoproterenol to assess ß-adrenergic reactivity. Additionally, resistance vessels in several beds were removed, cannulated, pressurized to 60 mmHg and reactivity to vasoactive stimuli was assessed. Hemodynamics were measured using in vivo radiotelemetry. Myostatin deletion results in increased fractional shortening at baseline. Additionally, arterioles in the coronary and muscular microcirculations are more sensitive to endothelial-dependent dilation while nonmuscular beds or the aorta were unaffected. ß-adrenergic dilation was increased in both coronary and conduit arteries, suggesting a systemic effect of increased muscle mass on vascular function. Overall hemodynamics and physical characteristics (heart weight and size) remained unchanged. Myostatin deletion mimics in part the effects of exercise on cardiovascular function. It significantly increases lean muscle mass and results in muscle-specific increases in endothelium-dependent vasodilation. This suggests that increases in muscle mass may serve as a buffer against pathological states that specifically target cardiac function (heart failure), the ß-adrenergic system (age), and nitric oxide bio-availability (atherosclerosis). Taken together, pharmacological inhibition of the myostatin pathway could prove an excellent mechanism by which the benefits of exercise can be conferred in patients that are unable to exercise.

Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice With Metabolic Disease.

RATIONALE: Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species accumulation, yet the extent to which excess reactive oxygen species derive from specific NADPH oxidase isoforms remains ill defined. OBJECTIVE: Identify the role of Nox1 in the development of microvascular dysfunction in metabolic disease. METHODS AND RESULTS: Four genotypes were generated by breeding Nox1 knockout mice with db/db mice: lean (HdbWnox1), lean Nox1 knockout (HdbKnox1), obese (KdbWnox1), and obese KK (KdbKnox1). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice was not influenced by Nox1 deletion as determined by nuclear magnetic resonance spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine in pressurized mesenteric arteries were reduced in KW versus HW (P<0.01), whereas deletion of Nox1 in KW mice normalized dilation. Vasodilator responses after inhibition of NO synthase blunted acetylcholine responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Acetylcholine responses were improved (P<0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, whereas Tempol had no impact and reactive oxygen species staining was negligible in KK. Blunted dilatory responses to an NO donor and loss of myogenic tone in KW animals were also rescued with Nox1 deletion. CONCLUSIONS: Nox1 deletion reduces oxidant load and restores microvascular health in db/db mice without influencing the degree of metabolic dysfunction. Therefore, targeted Nox1 inhibition may be effective in the prevention of vascular complications.

A novel anatomic severity grading score for acute Type B aortic dissections and correlation to aortic reinterventions after thoracic endovascular aortic repair.

BACKGROUND: We introduce a novel preoperative anatomic severity grading system for acute type B aortic dissections and validate the system in a cohort of patients who underwent thoracic endovascular aortic repair. METHODS: We identified a cohort of patients who received thoracic endovascular aortic repair (TEVAR) for acute type B aortic dissection from 2008 to 2014. We developed an anatomic severity grading score (ASG) to measure attributes of aortic anatomy that we hypothesized may affect difficulty or durability of repair. Measurements were made using computed tomography angiography images and based on hypothesized severity, giving a potential score range of 0-38. RESULTS: We analyzed the computed tomography angiography images on a cohort of 30 patients with acute type B aortic dissection who underwent TEVAR. We created an area under the receiver operating characteristic curve (AUROC) using anatomic severity grading to predict aortic-related reinterventions. The AUROC was 0.72 (95% CI 0.39 to 1.1). Guided by the AUROC, we divided patients into two groups: a low-score group with anatomic severity grading scores <23 (n = 22), and a high-score group with scores ≥23 (n = 8). With this cutoff, anatomic severity grading exhibited 80% sensitivity and 84% specificity in predicting aortic-related reinterventions, with reinterventions in 50% of high-score patients and 4.5% of low-score patients (P = 0.011). The high score group also had significantly greater blood loss (200 vs 100 mL, P = 0.038), fluoroscopy time (36.0 vs 16.6 min; P = 0.022), and a trend for increased procedure time (164 vs 95 min; P = 0.083) than the low-risk group. Kaplan-Meier analysis revealed that the high-score group had a significantly decreased freedom from aortic-related reinterventions than the low-score group (38% vs 100% at 12-month followup; log rank P = 0.001). CONCLUSIONS: A preoperative anatomic severity grading score for acute type B aortic dissections consists of analysis of the proximal landing zone, curvature and tortuosity of the aorta, dissection anatomy, aortic branch vessel anatomy, and supraceliac aorta anatomy. Anatomic severity grading scores ≤23 are an excellent predictor of aortic-related reinterventions.

Left subclavian artery revascularization in zone 2 thoracic endovascular aortic repair is associated with lower stroke risk across all aortic diseases.

BACKGROUND: The best management strategy for the left subclavian artery (LSA) in pathologic processes of the aorta requiring zone 2 thoracic endovascular aortic repair (TEVAR) remains controversial. We compared LSA coverage with or without revascularization as well as the different means of LSA revascularization. METHODS: A retrospective chart review was conducted of patients with any aortic diseases who underwent zone 2 TEVAR deployment from 2007 to 2014. Primary end points included 30-day stroke and 30-day spinal cord injury (SCI). Secondary end points were 30-day procedure-related reintervention, freedom from aorta-related reintervention, aorta-related mortality, and all-cause mortality. RESULTS: We identified 96 patients with zone 2 TEVAR who met our inclusion criteria. The mean age of the patients was 62 years, with 61.5% male. Diseases included acute aortic dissections (n = 25), chronic aortic dissection with aneurysmal degeneration (n = 22), primary aortic aneurysms (n = 21), penetrating aortic ulcers/intramural hematomas (n = 17), and traumatic aortic injuries (n = 11). Strategies for the LSA included coverage with revascularization (n = 54) or without revascularization (n = 42). Methods of LSA revascularization included laser fenestration with stenting (n = 33) and surgical revascularization: transposition (n = 10) or bypass (n = 11). Of the 54 patients with LSA revascularization, 44 (81.5%) underwent LSA intervention at the time of TEVAR and 10 (18.5%) at a mean time of 33 days before TEVAR (range, 4-63 days). For the entire cohort, the overall incidence of 30-day stroke was 7.3%; of 30-day SCI, 2.1%; and of procedure-related reintervention, 5.2%. At a mean follow-up of 24 months (range, 1-79 months), aorta-related reintervention was 15.6%, aorta-related mortality was 12.5%, and all-cause mortality was 29.2%. The 30-day stroke rate was highest for LSA coverage without revascularization (6/42 [14.3%]) compared with any form of LSA revascularization (1/54 [1.9%]; P = .020), with no difference between LSA interventions done synchronously with TEVAR (1/44 [2.3%]) vs metachronously with TEVAR (0/10 [0%]; P = .63). There was no significant difference in 30-day SCI in LSA coverage without revascularization (2/42 [4.8%]) vs with revascularization (0/54 [0%]; P = .11). There was no difference in aorta-related reintervention, aorta-related mortality, or all-cause mortality in coverage without revascularization (5/42 [11.9%], 6/42 [14.3%], and 14/42 [33.3%]) vs with revascularization (10/54 [18.5%; P = .376], 6/54 [11.1%; P = .641], and 14/54 [25.9%; P = .43], respectively). After univariate and multivariable analysis, we identified LSA coverage without revascularization as associated with a higher rate of 30-day stroke (hazard ratio, 17.2; 95% confidence interval, 1.3-220.4; P = .029). CONCLUSIONS: Our study suggests that coverage of the LSA without revascularization increases the risk of stroke and possibly SCI.

Duplex ultrasound criteria for in-stent restenosis of mesenteric arteries.

OBJECTIVE: Duplex ultrasound (DUS) criteria are well defined for evaluating high-grade stenosis (≥70%) of the native superior mesenteric artery (SMA) and celiac artery (CA). It has been shown that native vessel criteria overestimate the degree of in-stent restenosis (ISR) and that velocity criteria for SMA and CA ISR are not well established. The objective of this study was to define DUS velocity criteria for high-grade ISR of the SMA and CA. METHODS: A retrospective review of all patients who underwent SMA or CA stenting from a single institution was performed from 2004 to 2013. Patients were excluded if they did not have a DUS examination <4 months before angiography to assess stent patency or adequate angiographic visualization of the ISR. RESULTS: There were 103 paired DUS scans and angiograms analyzed: 66 SMA studies and 37 CA studies. The average peak systolic velocity (PSV) for SMAs was 367 cm/s with <70% ISR and 536 cm/s with ≥70% ISR. The average PSV for CAs was 302 cm/s with <70% ISR and 434 cm/s with ≥70% ISR. For an ISR ≥70% in the SMA, a PSV ≥445 cm/s produced the highest sensitivity (83%) and specificity (83%), with a positive predictive value of 81% and a negative predictive value of 86%. For an ISR ≥70% in the CA, a PSV ≥289 cm/s produced the highest sensitivity (100%) and specificity (57%), with a positive predictive value of 79% and negative predictive value of 100%. CONCLUSIONS: Increasing PSV correlates with an increasing degree of ISR for both the SMA and CA. Stented vessels have increased PSV, and therefore native PSV criteria are unreliable for the determination of ISR. The PSV criteria for ≥70% stenosis are higher for ISR than for native visceral vessel stenosis. The proposed new velocity criteria define ≥70% ISR as ≥445 cm/s in stented SMAs and ≥289 cm/s in stented CAs.

Anatomic severity grading score for primary descending thoracic aneurysms predicts procedural difficulty and aortic-related reinterventions after thoracic endovascular aortic repair.

BACKGROUND: An anatomic severity grading (ASG) score for primary descending thoracic aortic aneurysms (DTAs) was developed. The objective of this study was to determine if an ASG score cutoff value for DTAs is predictive of procedural complexity, aortic-related reinterventions, and mortality in patients who undergo thoracic endovascular aortic repair (TEVAR). METHODS: A retrospective review from 2008 to 2013 of patient records was conducted of all consecutive patients who underwent TEVAR for a primary DTA. A comprehensive scoring system of preoperative DTA morphology on the basis of computed tomography angiography images was established to identify and classify anatomic features that might influence outcome after TEVAR. ASG score calculations were achieved using preoperative computed tomography angiography images. Primary outcomes included primary technical success, aortic-related reinterventions, aneurysm-related mortality, and all-cause mortality. Secondary outcomes included procedural complexity (unplanned adjunctive procedures, number of endografts implanted, contrast volume, and procedure time), endoleak formation, endoleak requiring reintervention, stroke and paraplegia, and conversion to open repair. RESULTS: Of 469 patients with a diagnosis of a thoracic aortic aneurysm, 62 patients (13%) underwent TEVAR and had adequate preoperative imaging (mean age, 71 years). Applying the ASG score, we identified 39 patients (63%) with a score ≥24 (high-score group) and 23 patients (37%) with a score <24 (low-score group). Mean follow-up was 15.3 months (range, 4 days to 3.7 years; standard deviation, 1 year) for both groups. Freedom from all-cause mortality was significantly different in the high-score (87% at 1 year, 79% at 2 years, and 57% at 3 years) vs the low-score group (100% at 1, 2, and 3-years; log-rank test, P < .021). There was no significant difference between mortality in the high-score (97% at 1 year, 87% at 2 years, and 69% at 3 years) compared with the low-score group (100% at 1, 2, and 3 years; log-rank test, P = .162). Freedom from aortic-related reinterventions was significantly lower in the high-score (82% at 1 year, 68% at 2 years, and 35% at 3 years) compared with the low-score group (100% at 1, 2, and 3 years; log-rank test, P = .002). Operative difficulty in the form of intraoperative adjunct procedures, number of endografts implanted, and procedural time had significant differences between groups (18% vs 0%, P = .038; 79% vs 39%, P = .004; 120 vs 79 minutes, P = .005, respectively). No significant difference in 30-day combined stroke and paraplegia (16%) was present between groups, and no patient had a conversion to open repair during the follow-up period. CONCLUSIONS: Preoperative ASG score for primary DTAs predicted procedure complexity and aortic-related reinterventions after TEVAR.

Abdominal aortic aneurysm anatomic severity grading score predicts implant-related complications, systemic complications, and mortality.

OBJECTIVE: The aim of our study was to examine the predictive value of the anatomic severity grading (ASG) score for abdominal aortic aneurysms (AAAs) on implant-related complications, systemic complications, and mortality at 30-day and midterm, defined as 2 years, follow-up assessments. METHODS: Patients who underwent endovascular aneurysm repair for infrarenal AAAs between 2009 and 2012 were retrospectively reviewed, and ASG scores were calculated from three-dimensonal computed tomography reconstructions. Two independent patient groups were created: those with a low ASG score (score <14) and those with a high ASG score (score ≥14). RESULTS: We identified 190 patients (77% male), with a mean age of 73 years, and 84% Caucasian, with 104 patients in the low-score group and 86 in the high-score group. Within 30 days of the index endovascular aneurysm repair, 10 implant-related complications occurred in six patients (3%) and 25 systemic complications in 18 (9%). The incidence of 30-day implant-related complications was not significantly different between the low-score group (2 [2%]) and the high-score group (4 [5%]; P = .41). The incidence of patients with 30-day systemic complications was significantly different between the low-score group (5 [5%]) and the high score group (13 [15%]; P = .023). A composite end point of combined implant-related and systemic complications at 30 days showed there was a statistically significant difference between the low-score (7 [7%]) and high-score group (17 [20%]; P = .007). At a midterm follow up of 26 months (range, 1-64 months), implant-related complications occurred in 21 patients (11%), and systemic complications occurred in 29 (15%). The incidence of implant-related complications was significantly different between the low-score group (7 [7%]) and the high-score group (14 [16%]; P = .037). The incidence of midterm systemic complications was significantly different between the low-score group (11 [11%]) and the high-score group (18 [21%]; P = .048). A composite end point of combined implant-related and systemic complications at midterm follow-up resulted in a statistically significant difference between the low-score group (16 [15%]) and the high-score group (26 [30%]; P = .014). Kaplan-Meier analysis revealed that the low-score group had fewer overall complications (combined implant-related and systemic) at 1 year (14% vs 34%) and 2 years (15% vs 45%) compared with the high-score group (P < .001). The low-scoring group also had significantly higher survival at 1 year (96% vs 86%) and 2 years (88% vs 84%) compared with the high-score group (P = .047). CONCLUSIONS: The AAA ASG score can be used to predict patients at risk for midterm implant-related complications, 30-day and midterm systemic complications, and all-cause mortality.