A case-control comparison of acute-phase peripheral blood gene expression in participants diagnosed with minor ischaemic stroke or stroke mimics.

BACKGROUND: Past studies suggest that there are changes in peripheral blood cell gene expression in response to ischaemic stroke; however, the specific changes which occur during the acute phase are poorly characterised. The current study aimed to identify peripheral blood cell genes specifically associated with the early response to ischaemic stroke using whole blood samples collected from participants diagnosed with ischaemic stroke (n = 29) or stroke mimics (n = 27) following emergency presentation to hospital. Long non-coding RNA (lncRNA), mRNA and micro-RNA (miRNA) abundance was measured by RNA-seq, and the consensusDE package was used to identify genes which were differentially expressed between groups. A sensitivity analysis excluding two participants with metastatic disease was also conducted. RESULTS: The mean time from symptom onset to blood collection was 2.6 h. Most strokes were mild (median NIH stroke scale score 2.0). Ten mRNAs (all down-regulated in samples provided by patients experiencing ischaemic stroke) and 30 miRNAs (14 over-expressed and 16 under-expressed in participants with ischaemic stroke) were significantly different between groups in the whole cohort and sensitivity analyses. No significant over-representation of gene ontology categories by the differentially expressed genes was observed. Random forest analysis suggested a panel of differentially expressed genes (ADGRG7 and miRNAs 96, 532, 6766, 6798 and 6804) as potential ischaemic stroke biomarkers, although modelling analyses demonstrated that these genes had poor diagnostic performance. CONCLUSIONS: This study provides evidence suggesting that the early response to minor ischaemic stroke is predominantly reflected by changes in the expression of miRNAs in peripheral blood cells. Further work in independent cohorts particularly in patients with more severe stroke is needed to validate these findings and investigate their clinical relevance.

Association between aortic peak wall stress and rupture index with abdominal aortic aneurysm-related events.

OBJECTIVE: The aim of this study was to assess whether aortic peak wall stress (PWS) and peak wall rupture index (PWRI) were associated with the risk of abdominal aortic aneurysm (AAA) rupture or repair (defined as AAA events) among participants with small AAAs. METHODS: PWS and PWRI were estimated from computed tomography angiography (CTA) scans of 210 participants with small AAAs (≥ 30 and ≤ 50 mm) prospectively recruited between 2002 and 2016 from two existing databases. Participants were followed for a median of 2.0 (inter-quartile range 1.9, 2.8) years to record the incidence of AAA events. The associations between PWS and PWRI with AAA events were assessed using Cox proportional hazard analyses. The ability of PWS and PWRI to reclassify the risk of AAA events compared to the initial AAA diameter was examined using net reclassification index (NRI) and classification and regression tree (CART) analysis. RESULTS: After adjusting for other risk factors, one standard deviation increase in PWS (hazard ratio, HR, 1.56, 95% confidence intervals, CI 1.19, 2.06; p = 0.001) and PWRI (HR 1.74, 95% CI 1.29, 2.34; p < 0.001) were associated with significantly higher risks of AAA events. In the CART analysis, PWRI was identified as the best single predictor of AAA events at a cut-off value of > 0.562. PWRI, but not PWS, significantly improved the classification of risk of AAA events compared to the initial AAA diameter alone. CONCLUSION: PWS and PWRI predicted the risk of AAA events but only PWRI significantly improved the risk stratification compared to aortic diameter alone. KEY POINTS: • Aortic diameter is an imperfect measure of abdominal aortic aneurysm (AAA) rupture risk. • This observational study of 210 participants found that peak wall stress (PWS) and peak wall rupture index (PWRI) predicted the risk of aortic rupture or AAA repair. • PWRI, but not PWS, significantly improved the risk stratification for AAA events compared to aortic diameter alone.

Risk Factors for Hospital Re-admission for Diabetes Related Foot Disease: A Prospective Cohort Study.

OBJECTIVE: Diabetes related foot disease (DFD) is a common reason for admission to hospital, but the predictive factors for repeat admission are poorly defined. The primary aim of this study was to identify rates and predictive factors for DFD related hospital re-admission. METHODS: Patients admitted to hospital for treatment of DFD at a single regional centre were recruited prospectively between January 2020 and December 2020. Participants were followed for 12 months to evaluate the primary outcome of hospital re-admission. The relationship between predictive factors and re-admission were examined using non-parametric statistical tests and Cox proportional hazard analyses. RESULTS: The median age of the 190 participants was 64.9 (standard deviation 13.3) years and 68.4% were male. Forty-one participants (21.6%) identified themselves as Aboriginal or Torres Strait Islander people. One hundred participants (52.6%) were re-admitted to hospital at least once over 12 months. The commonest reason for re-admission was for treatment of foot infection (84.0% of first re-admission). Absent pedal pulses (unadjusted hazard ratio [HR] 1.90; 95% confidence interval [CI] 1.26 - 2.85), loss of protective sensation (LOPS) (unadjusted HR 1.98; 95% CI 1.08 - 3.62), and male sex (unadjusted HR 1.62; 95% CI 1.03 - 2.54) increased the risk of re-admission. After risk adjustment, only absence of pedal pulses (HR 1.92, 95% CI 1.27 - 2.91) and LOPS (HR 2.02, 95% CI 1.09 - 3.74) significantly increased the risk of re-admission. CONCLUSION: Over 50% of patients admitted to hospital for treatment of DFD are re-admitted within one year. Patients with absent pedal pulses and those with LOPS are twice as likely to be re-admitted.

Cohort Study Examining the Presentation, Distribution, and Outcomes of Peripheral Artery Disease in Aboriginal, Torres Strait Islander, and Non-Indigenous Australians.

OBJECTIVE: This retrospective cohort study investigated the anatomical distribution, severity, and outcome of peripheral artery disease (PAD) in Aboriginal and Torres Strait Islanders compared with non-indigenous Australians. METHODS: The distribution, severity, and outcome of PAD were assessed using a validated angiographic scoring system and review of medical records in a cohort of Aboriginal and Torres Strait Islander and non-indigenous Australians. The relationship between ethnicity and PAD severity, distribution, and outcome were examined using non-parametric statistical tests, Kaplan-Meier and Cox proportional hazard analyses. RESULTS: Seventy-three Aboriginal and Torres Strait Islanders and 242 non-indigenous Australians were included and followed for a median of 6.7 [IQR 2.7, 9.3] years. Aboriginal and Torres Strait Islander patients were more likely to present with symptoms of chronic limb threatening ischaemia (81% vs. 25%; p < .001), had greater median [IQR] angiographic scores for the symptomatic limb (7 [5, 10] vs. 4 [2, 7]) and tibial arteries (5 [2, 6] vs. 2 [0, 4]) and had higher risk of major amputation (HR 6.1, 95% CI 3.6 - 10.5; p < .001) and major adverse cardiovascular events (HR 1.5, 95% CI 1.0 - 2.3; p = .036) but not for revascularisation (HR 0.8, 95% CI 0.5 - 1.3; p = .37) compared with non-indigenous Australians. The associations with major amputation and major adverse cardiovascular events were no longer statistically significant when adjusted for limb angiographic score. CONCLUSION: Compared with non-indigenous patients, Aboriginal and Torres Strait Islander Australians had more severe tibial artery disease and a higher risk of major amputation and major adverse cardiovascular events.

Cerebrovascular Disorders.

Cerebrovascular disorders pose a global health concern. Advances in basic and clinical research, including induced pluripotent stem cell models and multi-omic approaches, have improved our understanding and management of these disorders. However, gaps in our knowledge remain. BMC Cardiovascular Disorders invites authors to submit articles investigating what drives and affects Cerebrovascular disorders to improve patient care.

Effect of Telmisartan on the Peak Wall Stress and Peak Wall Rupture Index of Small Abdominal Aortic Aneurysms: An Exploratory Analysis of the TEDY Trial.

OBJECTIVE: This study was an unplanned exploratory analysis of a subset of participants from the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. It aimed to assess the efficacy of the angiotensin 1 receptor blocker telmisartan in reducing abdominal aortic aneurysm (AAA) peak wall stress (PWS) and peak wall rupture index (PWRI) among individuals with small AAAs. METHODS: Participants with AAAs measuring 35 - 49 mm in maximum diameter were randomised to receive telmisartan 40 mg or identical placebo in the TEDY trial. Participants who had computed tomography angiography performed at entry and at least one other time point during the trial (12 or 24 months) were included in the current study. Orthogonal AAA diameter, PWS, and PWRI were measured using previously validated methods. The annual change in PWS and PWRI from baseline was compared between participants allocated telmisartan or placebo using linear mixed effects models. These models were either unadjusted or adjusted for risk factors that were different in the groups at entry (p < .100) or systolic blood pressure (SBP) at one year. RESULTS: Of the 207 participants recruited to TEDY, 124 were eligible for inclusion in this study. This study included 65 and 59 participants from the telmisartan and placebo groups, respectively. The PWS and PWRI were not significantly different in the two groups at baseline. Participants allocated telmisartan had a slower annual increase in PWS (-4.19; 95% CI -8.24, -0.14 kPa/year; p = .043) and PWRI (-0.014; 95% CI -0.026, -0.001; p = .032) compared with those allocated placebo after adjusting for risk factors. After adjustment for SBP at one year, telmisartan did not significantly reduce annual increases in PWS or PWRI. CONCLUSION: The findings of this study suggest that telmisartan limits the rate of increase in PWS and PWRI of small AAAs by reducing blood pressure.

Athero-occlusive Disease Appears to be Associated with Slower Abdominal Aortic Aneurysm Growth: An Exploratory Analysis of the TEDY Trial.

OBJECTIVE: The role of atherosclerosis in abdominal aortic aneurysm (AAA) pathogenesis is controversial. The aim of this study was to compare AAA growth in patients who did and did not have concurrent athero-occlusive disease (AOD). METHODS: Patients with an AAA measuring 35 - 49 mm in maximum diameter were recruited as part of the TElmisartan in the management of abdominal aortic aneurysm (TEDY) trial. TEDY participants who had infrarenal aortic volume and orthogonal diameter assessed by computed tomography at entry and at least one other time point during the trial (12 and/or 24 months) were included. AOD was defined by prior diagnoses of coronary heart disease, stroke, or peripheral arterial disease or an ankle brachial pressure index < 0.90. The increase in AAA volume and diameter from entry for participants who did and did not have AOD was assessed using linear mixed effects models; 131 of the 210 participants recruited to TEDY were included. RESULTS: In an unadjusted analysis, the mean (95% confidence interval) annual increases in AAA volume and diameter for participants with AOD were 3.26 (0.82 - 5.70) cm3 and 0.70 (0.19 - 1.22) mm slower than those without AOD, p = .008 and .007 respectively. The association between AOD and significantly slower AAA growth was maintained after adjusting for risk factors and medications, significantly unequally distributed between participants with and without an AOD diagnosis. CONCLUSION: In an exploratory analysis of a selective cohort from the TEDY trial, AOD was associated with slower AAA growth. Validation of these findings in other cohorts is needed.

Serum angiopoietin-1 concentration does not distinguish patients with ischaemic stroke from those presenting to hospital with ischaemic stroke mimics.

BACKGROUND: A previous study found that circulating angiopoietin-1 (angpt-1) concentrations were significantly lower in patients who had a recent ischaemic stroke compared to healthy controls. The primary aim of this study was to assess whether serum angpt-1 could be used as a diagnostic test of ischemic stroke in patients presenting to hospital as an emergency. Exploratory analyses investigated the association of proteins functionally related to angpt-1 (angpt-2, Tie-2, matrix metalloproteinase-9 and vascular endothelial growth factors A, C and D) with ischaemic stroke diagnosis. METHODS: Patients presenting to Townsville University Hospital for emergency assessment of stroke-like symptoms were consecutively recruited and provided a blood sample. After assessment by a consultant neurologist, patients were grouped into those who did, or did not have ischaemic stroke. The potential for serum angpt-1 to diagnose ischaemic stroke was assessed using receiver operator characteristic (ROC) curves. Cross-sectional analyses appraised inter-group differences in the serum concentration of other proteins. RESULTS: One-hundred and twenty-six patients presenting to Townsville University Hospital for emergency assessment of stroke-like symptoms were recruited (median time from symptom onset to hospital presentation: 2.6 (inter-quartile range: 1.2-4.6) hours). Serum angpt-1 had poor ability to diagnose ischaemic stroke in analyses using the whole cohort, or in sensitivity analyses (area under the ROC curve 0.51 (95% CI: 0.41-0.62) and 0.52 (95% CI: 0.39-0.64), respectively). No associations of serum angpt-1 concentration with ischaemic stroke severity, symptom duration or aetiology were observed. Serum concentrations of the other assessed proteins did not differ between patient groups. CONCLUSIONS: Serum angpt-1 concentration is unlikely to be useful for emergency diagnosis of ischaemic stroke.

The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.

BACKGROUND: People with peripheral artery disease are at a high risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Randomized controlled trials suggest that intensive lowering of low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors is an effective strategy to prevent these events. This study estimated the potential benefit and cost-effectiveness of administrating PCSK9 inhibitors to a cohort of participants with peripheral artery disease. METHODS: A total of 783 participants with intermittent claudication (IC; n = 582) or chronic limb-threatening ischemia (CLTI; n = 201) were prospectively recruited from three hospitals in Australia. Serum LDL-C was measured at recruitment, and the occurrence of MACE and MALE was recorded over a median (interquartile range) follow-up of 2.2 years (0.3-5.7 years). The potential benefit of administering a PCSK9 inhibitor was estimated by calculating the absolute risk reduction and numbers needed to treat (NNT) based on relative risk reductions reported in published randomized trials. The incremental cost-effectiveness ratio per quality-adjusted life year gained was estimated. RESULTS: Intensive LDL-C lowering was estimated to lead to an absolute risk reduction in MACE of 6.1% (95% confidence interval [CI], 2.0-9.3; NNT, 16) and MALE of 13.7% (95% CI, 4.3-21.5; NNT, 7) in people with CLTI compared with 3.2% (95% CI, 1.1-4.8; NNT, 32) and 5.3% (95% CI, 1.7-8.3; NNT, 19) in people with IC. The estimated incremental cost-effectiveness ratios over a 10-year period were $55,270 USD and $32,800 USD for participants with IC and CLTI, respectively. CONCLUSIONS: This analysis suggests that treatment with a PCSK9 inhibitor is likely to be cost-effective in people with CLTI.

Editor's Choice - Association Between Metformin Prescription and Abdominal Aortic Aneurysm Growth and Clinical Events: a Systematic Review and Meta-Analysis.

OBJECTIVE: A meta-analysis of the association between metformin prescription and abdominal aortic aneurysm (AAA) growth and events (rupture or surgical repair) was performed. METHODS: Open source databases were searched for observational studies reporting the association between metformin prescription and AAA growth or events. Meta-analyses were performed using random effects models. The risk of bias of included studies was assessed using a quality assessment tool developed in a previous systematic review. Sensitivity analyses restricted to people with diabetes, leave one out analyses, and an individual patient risk factor adjusted sub-analysis were performed. Funnel plots assessed reporting bias. RESULTS: Eight studies comprising 153 553 patients were included, of whom 35 240 were and 118 313 were not prescribed metformin. Pooled weighted mean (± standard deviation) AAA growth was significantly reduced in patients prescribed metformin (0.9 ± 0.4 mm/year) compared with those not receiving the medication (1.8 ± 0.4 mm/year; weighted mean difference [WMD] 0.8 mm/year, 95% confidence interval [CI] 0.5 - 1.1; p < .001; I2 = 89%). Leave one out analysis suggested that the significance of findings did not change after removal of individual studies. A sub-analysis within people with diabetes suggested that metformin reduced AAA growth (WMD 0.7 mm/year, 95% CI 0.3 - 1.0). Metformin prescription was associated with a reduced risk of AAA events (risk ratio 0.6, 95% CI 0.4 - 0.9, p = .028). Three, four, and one studies had low, moderate, and high risk of bias, respectively. Individual patient data analysis suggested that metformin prescription slowed annual AAA growth by 0.5 mm/year (95% CI 0.2 - 0.7). The GRADE summary suggested that the certainty of evidence that metformin limited AAA growth and prevented AAA events was very low. CONCLUSION: Observational studies suggest that metformin prescription is associated with a clinically important significant reduction in both growth and clinically relevant events in people with AAA. These findings support the need for randomised trials to examine the benefit of metformin.

The Potential Benefits and Costs of an Intensified Approach to Low Density Lipoprotein Cholesterol Lowering in People with Abdominal Aortic Aneurysm.

OBJECTIVE: The aims of this study were to assess the incidence of major vascular events (MVE) and peripheral vascular events (PVE) in people with a small asymptomatic abdominal aortic aneurysm (AAA) and model the theoretical benefits and costs of an intensified low density lipoprotein cholesterol (LDL-C) lowering programme. METHODS: A total of 583 participants with AAAs measuring 30 - 54 mm were included in this study. The control of LDL-C and prescription of lipid lowering drugs were assessed by dividing participants into approximately equal tertiles depending on their year of recruitment into the study. The occurrence of MVE (myocardial infarction, stroke, cardiovascular death, and coronary or non-coronary revascularisation) and PVE (non-coronary revascularisation, AAA repair, and major amputation) were recorded prospectively, and the incidence of these events was calculated using Kaplan-Meier analysis. The relative risk reduction reported for these events in a previous randomised control trial (RCT) was then applied to these figures to model the absolute risk reduction and numbers needed to treat (NTT) that could theoretically be achieved with a mean LDL-C lowering of 1 mmol/L. The maximum allowable expense for a cost effective intensive LDL-C lowering programme was estimated using a cost utility analysis. RESULTS: At entry, only 28.5% of participants had an LDL-C of < 1.8 mmol/L and only 18.5% were prescribed a high potency statin (atorvastatin 80 mg or rosuvastatin 40 mg). The five year incidences of MVE and PVE were 38.1% and 44.7%, respectively. It was estimated that if the mean LDL-C of the cohort had been reduced by 1 mmol/L, this could have reduced the absolute risk of MVE and PVE by 6.5% (95% CI 4.4 - 8.7; NNT 15) and 5.3% (95% CI 1.4 - 7.5; NNT 19), respectively. It was estimated that the maximum allowable expense for a cost effective LDL-C lowering programme would be between $1 239 AUD (€768) and $1 582 AUD (€981) per person per annum over a five year period. CONCLUSION: People with a small asymptomatic AAA are at high risk of MVE and PVE. This study provides evidence of the possible benefits and allowable expense for a cost effective intensive LDL-C lowering programme in this population.

Major amputation rates and outcomes for Aboriginal and Torres Strait Islander and non-Indigenous people in North Queensland Australia between 2000 and 2015.

BACKGROUND: This study estimated the incidence of major amputation for people in North Queensland, Australia, examined changes in amputation rates over time and investigated survival after major amputation. METHODS: This was a retrospective study of patients who underwent a major amputation above the ankle between 2000 and 2015. Major amputation rates and incidence rate ratios (IRR) were calculated using census data to define the at-risk population. Associations between risk factors and calendar year with major amputation were assessed using quasipoisson regression. Kaplan-Meier survival and Cox-proportional hazard analyses estimated the incidence of and risk factors for all-cause mortality. RESULTS: The annual incidence of major amputation was estimated to be greater in Aboriginal and Torres Strait Islanders than non-Indigenous people (IRR 2.75, 95 % CI 1.92 to 3.84). After adjusting for population growth, the annual incidence of major amputations did not change significantly over time for either groups. Aboriginal and Torres Strait Islander people were at greater risk of all-cause mortality after major amputation compared to non-Indigenous people, although this association was not significant after adjusting for other risk factors (hazard ratio 1.24, 95 % CI 0.82 to 1.90). CONCLUSIONS: The incidence of major amputation in North Queensland has not reduced over time, indicating the need for better preventative treatments, particularly in Aboriginal and Torres Strait Islander people.

Can I breastfeed my baby with Down syndrome? A scoping review.

AIM: To summarise existing evidence about barriers and enablers to breastfeeding babies with Down syndrome (DS) in peer-reviewed literature. METHODS: Ovid Medline, CINAHL, Scopus and Ovid Emcare were searched. Inclusion and exclusion criteria were used to screen yielded articles and those meeting the criteria were included for data extraction. Two authors extracted data including outcomes, design, definition of DS, barriers and enablers to breastfeeding babies with DS. RESULTS: Sixteen studies met the inclusion and exclusion criteria. Barriers and enablers were categorised into maternal, child and health professional factors. CONCLUSIONS: This review identified a significant literature gap related to breastfeeding babies with DS and more definitive research under current standards is needed. Mothers reported the need for high-quality health professional breastfeeding support and evidence-based effective breastfeeding techniques. A collaborated and concerted approach from both mothers and health professionals is important to optimise breastfeeding for babies with DS.

Outcomes and Costs of Open and Endovascular Revascularisation for Chronic Limb Ischaemia in an Australian Cohort.

OBJECTIVE: The costs of open and endovascular revascularisation to treat peripheral artery disease (PAD) have not been fully established. This study examined the costs of both the index admission and any readmissions to hospital within 30 days of discharge for people having revascularisation at a single centre in Australia. METHODS: This was a retrospective analysis of prospectively collected data. Eligible participants were those presenting with chronic limb ischaemia requiring revascularisation between 2002 and 2017. Generalised linear modelling was used to estimate mean (95% confidence interval [95% CI]) hospital costs for the index and readmission hospital treatments. RESULTS: A total of 302 participants presenting with intermittent claudication (n=219; 72.5%) or chronic limb threatening ischaemia (n=83; 27.5%) treated by open (n=116; 38.4%) or endovascular (n=186; 61.6%) revascularisation were included. Forty-eight (48) (15.9%) participants were readmitted within 30 days of discharge from their index admission. The mean estimated index admission hospital cost was AUD$13,827 (95% CI, $11,935-$15,818) per person. This cost was significantly greater for open as compared to endovascular revascularisation (p<0.001). The mean estimated hospital cost was AUD$15,324 ($10,944-$19,966) per person readmitted. When comparing participants treated before and after 2010, the total hospital costs decreased, mainly due to decreased lengths of hospital stay for open procedures. CONCLUSIONS: In this study the hospital costs were less for endovascular than open revascularisation of chronic limb ischaemia. Costs decreased over time. Readmission is an important contributor to the overall costs of peripheral revascularisation.

Cohort study examining the relationship between remoteness and requirement for surgery to treat peripheral artery disease at a tertiary hospital in North Queensland.

OBJECTIVE: To assess whether outcomes of peripheral artery disease (PAD) were related to remoteness from the treating tertiary vascular centre. SETTING AND PARTICIPANTS: Participants with a variety of types of occlusive and aneurysmal diseases were recruited from a tertiary hospital in North Queensland, Australia. Remoteness was assessed by residence outside Townsville and estimated distance to the vascular centre. Cox proportional hazard analyses were used to examine the association of remoteness with outcome. DESIGN: Cohort study. MAIN OUTCOME MEASURES: The primary outcome was requirement for surgery to treat PAD. Secondary outcomes were major adverse cardiovascular events (MACE) and all-cause mortality. RESULTS: Of 2487 patients recruited, 1274 (51.2%) had at least one PAD surgery, 720 (29.0%) at least one MACE, and 909 (36.6%) died during a median of 4.2 (inter-quartile range 1.3-7.7) years. Compared to Townsville residents (n = 1287), those resident outside Townsville (n = 1200) had higher rates of PAD surgery (hazard ratio, HR 1.55, 95% confidence intervals, CI, 1.39, 1.73) but no increased risk of MACE (HR 1.00, 95% CI 0.86, 1.16) or death (HR 1.03, 95% CI 0.90, 1.17). This association was attenuated when adjusting for distance from the vascular centre (HR 1.31, 95% CI 1.14, 1.51). Patients in the highest quartile of distance presented with lower ankle-brachial pressure index, more severe carotid artery disease and larger aortic diameter. CONCLUSIONS: People with PAD in North Queensland residing furthest from the tertiary hospital presented with more severe artery disease and had greater rates of PAD surgery.

Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model.

Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

A Randomised Controlled Trial Assessing the Effects of Peri-operative Fenofibrate Administration on Abdominal Aortic Aneurysm Pathology: Outcomes From the FAME Trial.

OBJECTIVE: Experimental studies suggest that fenofibrate prevents abdominal aortic aneurysm (AAA) development by lowering aortic osteopontin (OPN) concentration and reducing the number of macrophages infiltrating the aortic wall. The current study examined the effects of a short course of fenofibrate on AAA pathology in people with large AAAs awaiting aortic repair. METHODS: This randomised double blind parallel trial included male and female participants aged ≥ 60 years who had an asymptomatic AAA measuring ≥ 50 mm and were scheduled to undergo open AAA repair. Participants were allocated to fenofibrate (145 mg/day) or matching placebo for at least two weeks before elective AAA repair. Blood samples were collected at recruitment and immediately prior to surgery. AAA biopsies were obtained during aortic surgery. The primary outcomes were (1) AAA OPN concentration; (2) serum OPN concentration; and (3) number of AAA macrophages. Exploratory outcomes included circulating and aortic concentrations of other proteins previously associated with AAA. Outcomes assessed at a single time point were compared using logistic regression. Longitudinal outcomes were compared using linear mixed effects models. RESULTS: Forty-three participants were randomised. After three withdrawals, 40 were followed until the time of surgery (21 allocated fenofibrate and 19 allocated placebo). As expected, serum triglycerides reduced significantly from recruitment to the time of surgery in participants allocated fenofibrate. No differences in any of the primary and exploratory outcomes were observed between groups. CONCLUSION: A short course of 145 mg of fenofibrate/day did not lower concentrations of OPN or aortic macrophage density in people with large AAAs.

A systematic review and meta-analysis of risk factors for and incidence of 30-day readmission after revascularization for peripheral artery disease.

OBJECTIVE: Readmission to the hospital after revascularization for peripheral artery disease (PAD) is frequently reported. No consensus exists as to the exact frequency and risk factors for readmission. This review aimed to determine the incidence of and risk factors for 30-day readmission after revascularization for PAD. METHODS: PubMed/Medline (Ovid), Scopus, Web of Science, the Cochrane Library, and CINAHL were searched systematically from inception until May 20, 2018. Studies were eligible for inclusion if they included patients with diagnosed PAD undergoing revascularization and reported the readmission rate and a statistical evaluation of the association of at least one risk factor with readmission. Studies were excluded if data for other procedures could not be distinguished from revascularization. Two authors undertook study selection independently with the final inclusion decision resolved through consensus. The PRISMA and Meta-analyses of Observational Studies in Epidemiology guidelines were followed regarding data extraction and quality assessment, which was performed by two authors independently. Data were pooled using a random effects model. RESULTS: The primary outcome was readmission within 30 days of revascularization. Fourteen publications reporting the outcomes of 526,008 patients were included. Reported readmission rates ranged from 10.9% to 30.0% with a mean of 16.4% (95% confidence interval [CI], 15.1%-17.9%). Meta-analyses suggested the following risk factors had a significant association with readmission: female sex (odds ratio [OR], 1.13; 95% CI, 1.05-1.21), black race (OR, 1.36; 95% CI, 1.28-1.46), dependent functional status (OR, 1.72; 95% CI, 1.43-2.06), critical limb ischemia (OR, 2.12; 95% CI, 1.72-2.62), emergency admission (OR, 1.75; 95% CI, 1.43-2.15), hypertension (OR, 1.39; 95% CI, 1.26-1.54), heart failure (OR, 1.82; 95% CI, 1.50-2.20), chronic pulmonary disease (OR, 1.19; 95% CI, 1.08-1.32), diabetes (OR, 1.47; 95% CI, 1.32-1.63), chronic kidney disease (OR, 1.93; 95% CI, 1.62-2.31), dialysis dependence (OR, 2.08; 95% CI, 1.75-2.48), smoking (OR, 0.83; 95% CI, 0.78-0.89), postoperative bleeding (OR, 1.70; 95% CI, 1.23-2.35), and postoperative sepsis (OR, 4.13; 95% CI, 2.02-8.47). CONCLUSIONS: Approximately one in six patients undergoing revascularization for PAD are readmitted within 30 days of their procedure. This review identified multiple risk factors predisposing to readmission, which could potentially serve as a way to target interventions to reduce readmissions.

Systematic review and meta-analysis of the association between intraluminal thrombus volume and abdominal aortic aneurysm rupture.

BACKGROUND: Intraluminal thrombus (ILT) is present in most abdominal aortic aneurysms (AAAs), although its role in AAA progression is controversial. METHODS: A literature search was performed to identify studies that investigated the association between ILT volume and AAA rupture. A study assessment tool was developed to assess the methodologic quality of included studies. A meta-analysis was conducted using an inverse variance-weighted random-effects model to compare the ILT volume in ruptured and asymptomatic intact AAAs. Leave-one-out sensitivity analyses were conducted to assess the robustness of the findings. A subanalysis was performed including studies in which patients with asymptomatic intact and ruptured AAAs were matched for aortic diameter. Interstudy heterogeneity was assessed using the I2 statistic. RESULTS: Eight studies involving 672 patients were included in this systematic review. Meta-analysis of all studies found a greater ILT volume in patients with ruptured AAAs than in patients with asymptomatic intact AAAs (standardized mean difference, 0.56; 95% confidence interval, 0.17-0.96; P = .005; I2 = 79.8%). Sensitivity analyses suggested that the findings were robust; however, aortic diameter was significantly larger in ruptured than in asymptomatic intact AAAs (mean ± standard deviation, 78 ± 18 and 64 ± 15 mm, respectively; P < .001). In the subanalysis of studies that matched for diameter, no significant difference in ILT volume between groups was found (standardized mean difference, 0.03; 95% confidence interval, -0.27 to 0.33; P = .824; I2 = 0%). CONCLUSIONS: This meta-analysis suggests that ILT volume is greater in patients with ruptured AAAs than in patients with asymptomatic intact AAAs, although this is most likely due to the larger diameter of ruptured AAAs.

Editor's Choice - Metformin Prescription is Associated with a Reduction in the Combined Incidence of Surgical Repair and Rupture Related Mortality in Patients with Abdominal Aortic Aneurysm.

OBJECTIVES: Currently there is no drug therapy for abdominal aortic aneurysm (AAA) and most previous investigations have focused on imaging rather than clinical outcomes. The aim of this study was to assess whether AAA related clinical events were lower in patients prescribed metformin. METHODS: This was a prospective cohort observational study performed in three cities in Australia, which was designed to study risk factors for clinical events not simply to focus on metformin. Patients with an asymptomatic unrepaired AAA of any diameter ≥30 mm were recruited from hospital outpatient clinics and surveillance programs run at four centres. The main outcome was the requirement for AAA repair or AAA related mortality (AAA events). The association between metformin prescription and AAA events was assessed using Kaplan-Meier analysis and Cox proportional hazard analysis. RESULTS: Patients (1,080) with a mean (SD) initial AAA diameter of 46.1 (11.3) mm were followed for a mean (SD) of 2.5 (3.1) years until an AAA event (n = 454), death (n = 176), loss to follow up (n = 128), or completion of current follow up (n = 322). Patients with diabetes who were prescribed metformin (adjusted HR 0.63, 95% CI 0.44-0.93), but not patients with diabetes who were not prescribed metformin (adjusted HR 1.15, 95% CI 0.83-1.59), had a lower incidence of AAA events compared with those without diabetes. Findings were similar in sensitivity analyses restricted to patients with an initial AAA diameter ≤50 mm and patients with a minimum follow up of six months before an AAA event. CONCLUSIONS: These findings suggest that clinically important AAA events may be reduced in patients with diabetes who are prescribed metformin, but not those with diabetes receiving other treatments. A randomised controlled trial is needed to definitively test whether metformin reduces AAA related clinical events in patients with small AAAs who do not have diabetes.