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.

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.

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.

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 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.

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.

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.

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.

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.

Volumetric analysis of the initial index computed tomography scan can predict the natural history of acute uncomplicated type B dissections.

OBJECTIVE: Our objective was to characterize the predictive impact of computed tomography (CT) scan volumetric analysis on the natural history of acute uncomplicated type B aortic dissections (ADs). METHODS: We conducted a retrospective review of patients with acute type B ADs from 2009 to 2014. On an iNtuition workstation (TeraRecon, Foster City, Calif), volume measurements were obtained using the true lumen volume (TLV), false lumen volume (FLV), and total aortic volume from the left subclavian artery to the celiac artery. Growth rate was calculated as the change in maximal diameter between first and last available CT scans during the time interval. The primary outcome of the study was delayed aortic intervention. P < .05 was considered statistically significant. RESULTS: During a 5-year period, 164 patients had CT scan evidence of acute type B ADs; 11 patients were excluded for lack of subsequent follow-up imaging; 36 patients who underwent urgent repair (<14 days from presentation) were also excluded. We evaluated a total of 117 patients: 85 patients who did not require intervention and 32 who underwent delayed (>14 days) thoracic endovascular aneurysm repair (29) or open repair (3). Mean age was 66 ± 12 years. Mean TLV/FLV ratio on initial CT scan was significantly higher in patients who did not eventually require an operation (1.55 vs 0.82; P = .02). The mean growth rate was higher in those eventually requiring operation (2.47 vs 0.42 mm/mo; P = .003). Patients were divided into three subgroups on the basis of their initial imaging TLV/FLV ratios (<0.8, 0.8-1.6, and >1.6). There was a significant difference in the growth rates between these three groups (4.6 vs 2.4 vs 0.8 mm/mo; P < .025). Area under the receiver operating characteristic curve analysis revealed that a TLV/FLV ratio <0.8 was highly predictive for requiring an intervention (area = 0.8; sensitivity, 69%; specificity, 84%: positive predictive value, 71%; negative predictive value, 81%), with an odds ratio of 12.2 (confidence interval, 5-26; P < .001). Conversely, a TLV/FLV ratio of >1.6 was highly predictive for freedom from delayed operation (sensitivity, 91%; specificity, 42%; positive predictive value, 61%; negative predictive value, 86%). After Kaplan-Meier analysis, 1-year and 2-year survival free of aortic interventions was 60% and 42% with a TLV/FLV ratio <0.8 and 92% and 82% with a ratio >1.6 (P = .001). CONCLUSIONS: Initial CT scan volumetric analysis in patients presenting with uncomplicated acute type B ADs is a useful tool to predict growth and need for future intervention.

The effect of demographic factors and lesion severity on iliac stent patency.

OBJECTIVE: The aim of our study was to perform a large multivariate analysis to identify demographic, anatomic, or procedural factors that affect iliac artery stent primary patency (PP). METHODS: Patients receiving iliac stents from 2007 to 2013 were retrospectively reviewed. Univariate analysis assessed cohort characteristics and their effect on PP. Variables considered significant (P < .05) were brought forward in the multivariate analysis. RESULTS: A total of 213 patients underwent primary iliac artery stenting, and 307 limbs were analyzed. The average age was 66 years (range, 38-93 years), 54% were male, and 55% were Caucasian. Indications for procedure were claudication in 68%, rest pain in 20%, and tissue loss in 12%. All TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) II classifications were included: 51% TASC II A, 25% TASC II B, 13% TASC II C, and 11% TASC II D. The treated anatomic locations were 27% isolated external iliac artery (EIA), 56% isolated common iliac artery, and 17% combined common iliac artery and EIA. Multivariate analysis found three factors were correlated with decreased PP: non-Caucasian race (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.08-3.13; P = .025), younger age (HR, 1.04; 95% CI, 1.01-1.08; P = .006), and presence of EIA occlusion (HR, 2.02; 95% CI, 1.05-3.89; P = .036). Overall, Kaplan-Meier analysis at 1 and 3 years revealed a PP of 86% and 53%, assisted PP of 98% and 89%, and secondary patency of 99% of 98%. Kaplan-Meier analysis showed PP at 1 year for was 91% Caucasian patients vs 77% for non-Caucasian (P = .001). PP was 75% in patients aged <60 years, 86% in patients aged 60-70 years, and 96% in patients aged >70 years, with a significant difference between all groups (P < .001). PP was significantly different for those with and without EIA occlusion (P = .002), with 1-year PP of 71% and 88%, respectively. CONCLUSIONS: In our experience with a large number of iliac interventions, younger age, non-Caucasian race, and EIA occlusion were strong predictors for loss of PP.

TEVAR Rescue of an Embolized Edwards SAPIEN XT Valve Following TAVR.

PURPOSE: To report a successful method of managing an embolized Edwards SAPIEN XT aortic valve prosthesis using a thoracic endovascular aortic repair rescue. CASE REPORT: An 84-year-old man underwent transcatheter aortic valve replacement using a 26-mm Edwards SAPIEN XT valve, which immediately embolized into the ascending aorta. Because of the severe tapering of the patient's transverse aortic arch, the embolized valve was unable to be maneuvered further down the aorta. Therefore, a Cook 36×80-mm Zenith Dissection Endovascular System (ZDES) bare metal stent was used on a compassionate basis to append the embolized valve between the patient's coronary artery ostia and the innominate artery takeoff within the ascending aorta, with no neurological or cardiovascular complications at 12-month follow-up. CONCLUSION: A Cook ZDES bare metal stent may be successfully used to append an embolized Edwards SAPIEN XT valve within the ascending aorta.

Overview of the impact of noninvasive prenatal testing on diagnostic procedures.

Noninvasive prenatal testing (NIPT) has had a profound influence in the field of prenatal diagnosis since the 1997 discovery of cell-free fetal DNA in maternal blood. Research has progressed rapidly, with clinical data supporting laboratory studies showing that NIPT is highly sensitive and specific for fetal aneuploidy, resulting in marked uptake in the high-risk patient population. The superior accuracy of NIPT compared with conventional screening methods has led to significant decreases in the number of invasive diagnostic procedures, in addition to a concomitant decrease in the number of procedure-related fetal losses. Yet, NIPT has been described as a 'disruptive innovation' due to the considerable changes the technology has commanded on current prenatal screening and diagnostic practices. This review summarizes both institutional and global experience with NIPT uptake, its effect on reducing diagnostic invasive procedures, and the unique challenges that reduced procedural volume may have on physician and trainee proficiency, cytogenetic laboratories, and neonatal outcome.

Use of the Combined First-Trimester Screen in High- and Low-Risk Patient Populations After Introduction of Noninvasive Prenatal Testing.

OBJECTIVES: To report changes in the use of the combined first-trimester screen (FTS) in patients classified as high and low risk for fetal aneuploidy, including after introduction of noninvasive prenatal testing (NIPT). METHODS: A prospectively collected database was reviewed to investigate changes in FTS use before and after American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 77 (Obstet Gynecol 2007; 109:217-227), which recommended that all patients be offered aneuploidy screening, and after NIPT introduction. High-risk patients were classified as 35 years or older at the estimated time of delivery or those with an abnormal prior screen, abnormal ultrasound findings, or family history of aneuploidy. Data were normalized per 100 morphologic ultrasound examinations to account for changes in patient number over time. Statistical significance was defined as P < .05. RESULTS: A total of 10,125 FTSs were recorded during the 88-month study period, including 2962 in high-risk patients and 7163 in low-risk patients. The total number of FTSs performed per 100 morphologic ultrasound examinations significantly increased after ACOG Practice Bulletin No. 77 and significantly decreased after NIPT introduction. In high-risk patients, the total number of FTSs performed per 100 morphologic ultrasound examinations significantly increased after ACOG Practice Bulletin No. 77 but significantly decreased after NIPT introduction. In contrast, in low-risk patients, the total number of FTSs performed per 100 morphologic ultrasound examinations significantly increased after ACOG Practice Bulletin No.77 but was not statistically different after NIPT introduction. CONCLUSIONS: American College of Obstetricians and Gynecologists Practice Bulletin No. 77 significantly increased patient use of FTS. The introduction of NIPT significantly decreased FTS use in the high-risk population but not in the low-risk population.

Uptake of noninvasive prenatal testing at a large academic referral center.

OBJECTIVE: Noninvasive prenatal testing (NIPT) is a recently developed risk-assessment technique with high sensitivity and specificity for fetal aneuploidy. The effect NIPT has had on traditional screening and diagnostic testing has not been clearly demonstrated. In this study, NIPT uptake and subsequent changes in the utilization of first-trimester screen (FTS), chorionic villus sampling (CVS), and amniocentesis in a single referral center is reported. STUDY DESIGN: Monthly numbers of NIPT (in high-risk patients), FTS, CVS, and amniocentesis were compared between a 35-month baseline period (April 2009 through February 2012) before introduction of NIPT, and the initial 16 months following NIPT introduction divided in 4-month quarters beginning in March 2012 through June 2013. RESULTS: A total of 1265 NIPT, 6637 FTS, 251 CVS, and 1134 amniocentesis were recorded over the 51-month study period in singleton pregnancies of women who desired prenatal screening and diagnostic testing. NIPT became the predominant FTS method by the second quarter following its introduction, increasing by 55.0% over the course of the study period. Total first-trimester risk assessments (NIPT+FTS) were not statistically different following NIPT (P = .312), but average monthly FTS procedures significantly decreased following NIPT introduction, decreasing by 48.7% over the course of the study period. Average monthly CVS and amniocentesis procedures significantly decreased following NIPT introduction, representing a 77.2% and 52.5% decrease in testing, respectively. Screening and testing per 100 morphological ultrasounds followed a similar trend. CONCLUSION: NIPT was quickly adopted by our high-risk patient population, and significantly decreased alternate prenatal screening and diagnostic testing in a short period of time.

Circadian rhythms in acute intermittent porphyria--a pilot study.

BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem synthesis wherein a partial deficiency of porphobilinogen (PBG) deaminase (PBGD) with other factors may give rise to biochemical and clinical manifestations of disease. The biochemical hallmarks of active AIP are relative hepatic haem deficiency and uncontrolled up-regulation of hepatic 5-aminolevulinic acid (ALA) synthase-1 (ALAS1) with over-production of ALA and PBG. The treatment of choice is intravenous haem, which restores the deficient regulatory haem pool of the liver and represses ALAS1. Recently, haem has been shown to influence circadian rhythms by controlling their negative feedback loops. We evaluated whether subjects with AIP exhibited an altered circadian profile. MATERIALS AND METHODS: Over a 21-h period, we measured levels of serum cortisol, melatonin, ALA, PBG and mRNA levels (in peripheral blood mononuclear cells) of selected clock-controlled genes and genes involved in haem synthesis in 10 Caucasian (European-American) women who were either postmenopausal or had been receiving female hormone therapy, six of whom have AIP and four do not and are considered controls. RESULTS: Four AIP subjects with biochemical activity exhibited higher levels of PBG and lower levels and dampened oscillation of serum cortisol, and a trend for lower levels of serum melatonin, than controls or AIP subjects without biochemical activity. Levels of clock-controlled gene mRNAs showed significant increases over baseline in all subjects at 5 a.m. and 11 p.m., whereas mRNA levels of ALAS1, ALAS2 and PBGD were increased only at 11 p.m. in subjects with active AIP. CONCLUSIONS: This pilot study provides evidence for disturbances of circadian markers in women with active AIP that may trigger or sustain some common clinical features of AIP.

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.

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.

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.