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Background Depression is associated with an increased risk of cardiovascular events but its association with abdominal aortic aneurysm (AAA) progression is unknown. This study examined if a diagnosis of depression was association with more rapid AAA growth. Methods Patients with small AAA measuring between 30 and 50 mm were recruited from surveillance programs at 4 Australian centres. Maximum AAA diameter was measured by ultrasound imaging using a standardised and reproducible protocol to monitor AAA growth. Depression was defined from medical records of treatment for depression at recruitment. Linear mixed effects modelling was performed to examine the independent association of depression with AAA growth. A propensity matched sub-analysis was performed. Results A total of 574 participants were included of whom 73 (12.7%) were diagnosed with depression. Participants were followed with a median of 3 (Inter-quartile range (IQR): 2, 5) ultrasound scans for a median of 2.1 (IQR: 1.1, 3.5) years. The unadjusted model suggested that annual AAA growth was non-significantly reduced (mean difference: -0.3 mm/year; 95% confidence interval (CI): -0.7, 0.2; P = 0.26) in participants with a diagnosis of depression compared to other participants. After adjustment for covariates, depression was not significantly associated with AAA growth (mean difference: -0.3 mm/year; 95% CI: -0.8, 0.2; P = 0.27). Findings were similar in the propensity matched sub-analysis. Sensitivity analyses investigating the impact of initial AAA diameter and follow up on the association of depression with AAA growth found no interaction. Conclusions This study suggested that depression was not associated with faster AAA growth.

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 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.

Objective: There are no current effective abdominal aortic aneurysm (AAA) drug therapies. An important limitation of most preclinical studies is that they test the effect of drugs on AAA formation rather than AAA progression. The aim of this study was to systematically review AAA mouse model studies that have tested the effect of interventions in limiting the progression of preestablished AAA. Approach and Results: The literature search identified 35 studies meeting eligibility, and 30 (n=935 mice) contributed to the meta-analyses. AAAs were induced with angiotensin II (n=745 mice), calcium chloride (n=91 mice), or elastase (n=99 mice). Anti-inflammatory drugs (standardized mean difference [SMD], 1.62 [95% CI, 0.93–2.30]), protease inhibitors (SMD, 1.23 [95% CI, 0.52–1.95]), stem cells (SMD, 1.64 [95% CI, 1.05–2.24]), antiplatelet or anticoagulant drugs (SMD, 0.93 [95% CI, 0.63–1.22]), and renin-angiotensin system inhibitors (SMD, 1.45 [95% CI, 0.58–2.33]) reduced AAA diameter. Interventions initiated soon after model induction commenced were more likely to reduce AAA diameter (R 2 , 16%; P =0.007). Funnel plots suggested possible publication bias. Most studies did not report blinding or sample size calculations, and the risk of bias was considered medium or high in 20 (57%) of the 35 studies. Conclusions: There is low-quality evidence that a range of drugs are effective in limiting AAA progression when administered early after AAA induction in mouse models. Some of these drugs, such as antiplatelet and renin-angiotensin system inhibitors, have been reported to be ineffective in clinical trials.

Disease modifying anti-rheumatic drugs (DMARDs) were developed to treat joint inflammation. There is growing evidence that anti-inflammatory drugs prevent major cardiovascular events (MACE). The aim of this systematic review and meta-analysis was to examine whether DMARDs reduce the risk of MACE. A systematic literature search was performed to identify randomized controlled trials (RCTs) testing the effect of DMARDs on cardiovascular events. The primary outcome was MACE defined as the first occurrence of non-fatal myocardial infarction (MI), non-fatal stroke or cardiovascular death. Secondary outcomes were myocardial infarction or stroke alone and all-cause mortality. Safety was assessed by fatal or life threatening infection. Meta-analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Study quality and publication bias were assessed using the Cochrane Collaboration’s tool for assessing risk of bias and funnel plots. Twelve RCTs involving 18,056 participants testing three different DMARDs subclasses (Tumor Necrosis Factor inhibitors—4 trials; Janus Kinase inhibitors—5 trials; Interleukin inhibitors—3 trials) were included. Meta-analysis suggested that none of the DMARD subclasses had any effect on MACE, MI alone, stroke alone, risk of fatal or life threatening infection or death. Risk of bias was high, low and unclear in five, six and one studies respectively. Funnel plots suggested a low possibility of publication bias. This meta-analysis suggests that DMARDs do not affect the incidence of MACE. More trials are needed for firm conclusions.

This study aimed to examine the association of serum microRNAs (miRNAs) with diagnosis and growth of abdominal aortic aneurysm (AAA), and to test their diagnostic and prognostic value.The expression levels of 800 miRNA tags were assessed in 108 AAA patients and 12 age- and sex-matched healthy controls (HC) and 12 patients with peripheral artery disease (PAD) using nanoString Technologies. Findings were assessed in an independent sample of 66 AAA patients and 29 age and sex-matched HC by reverse transcriptase PCR (rtPCR). AAA growth was assessed by a median of 3 (Interquartile range (IQR) 2, 3) repeat ultrasound scans over a median follow up of 1.1 (IQR 1.0, 2.0) years. The association of the miRNA with AAA diagnosis and growth were examined by regression and linear mixed effects analyses. The diagnostic and prognostic potential of the miRNAs were examined using area under the receiver operator characteristic curve (AUC), net reclassification index (NRI) and Cox hazard analyses.In comparison to HC, a model combining clinical risk factors, let-7b-5p and miR-548n had an AUC of 98.0% (95% CI 95.6, 100.0; p=.003) for diagnosing AAA, which was a significant improvement over clinical risk factors alone (NRI: 1.74; 95% CI 1.61, 1.87; p0.001). In comparison to PAD, a model combining clinical risk factors and miR-548n had an AUC of 99.6% (95% CI 98.9, 100.0, p=.037) for diagnosing AAA, which was a significant improvement over clinical risk factors alone (NRI 1.79, 95% CI 1.68, 1.91; p0.001). In the longitudinal cohort, none of the miRNA were able to predict the likelihood of reaching surgical threshold diameter better than clinical risk factors alone.Serum let-7b-5p and miR548n significantly improved ability to diagnose AAA. None of the miRNAs had independent prognosis value in predicting AAA growth.

Background: The aim of this systematic review was to pool evidence from studies testing if pentagalloyl glucose (PGG) limited aortic expansion in animal models of abdominal aortic aneurysm (AAA). Methods: The review was conducted according to the PRISMA guidelines and registered with PROSPERO. The primary outcome was aortic expansion assessed by direct measurement. Secondary outcomes included aortic expansion measured by ultrasound and aortic diameter at study completion. Sub analyses examined the effect of PGG delivery in specific forms (nanoparticles, periadventitial or intraluminal), and at different times (from the start of AAA induction or when AAA was established), and tested in different animals (pigs, rats and mice) and AAA models (calcium chloride, periadventitial, intraluminal elastase or angiotensin II). Meta-analyses were performed using Mantel-Haenszel’s methods with random effect models and reported as mean difference (MD) and 95% confidence intervals (CIs). Risk of bias was assessed with a customized tool. Results: Eleven studies reported in eight publications involving 214 animals were included. PGG significantly reduced aortic expansion measured by direct observation (MD: −66.35%, 95% CI: −108.44, −24.27, p = 0.002) but not ultrasound (MD: −32.91%, 95% CI: −75.16, 9.33, p = 0.127). PGG delivered intravenously within nanoparticles significantly reduced aortic expansion, measured by both direct observation (MD: −116.41%, 95% CI: −132.20, −100.62, p &lt, 0.001) and ultrasound (MD: −98.40%, 95% CI: −113.99, −82.81, 0.001). In studies measuring aortic expansion by direct observation, PGG administered topically to the adventitia of the aorta (MD: −28.41%, 95% CI −46.57, −10.25, p = 0.002), studied in rats (MD: −56.61%, 95% CI: −101.76, −11.46, p = 0.014), within the calcium chloride model (MD: −56.61%, p = 0.014) and tested in established AAAs (MD: −90.36, 95% CI: −135.82, −44.89, 0.001), significantly reduced aortic expansion. The findings of other analyses were not significant. The risk of bias of all studies was high. Conclusion: There is inconsistent low-quality evidence that PGG inhibits aortic expansion in animal models.

IntroductionGout is a systemic inflammatory disease which has been associated with an increased risk of cardiovascular events but its association with abdominal aortic aneurysm (AAA) progression is unknown. The aim of this study was to investigate the association of gout with growth of small AAA. MethodsPatients with initial AAA diameter measuring 30-54mm were recruited from surveillance programs at four Australian centres. Maximum AAA diameter was measured with a standardised and reproducible protocol to monitor AAA growth. Presence of gout was defined by clinical diagnosis by clinician or prescription of medications used to treat gout. Linear mixed effects modelling was performed to examine the independent association of gout with AAA growth. ResultsA total of 637 participants, including 66 (10.3%) diagnosed with gout, received a median of 4 (Inter-quartile range (IQR): 3, 6) scans over a median follow-up of 1.8 (IQR: 1.0, 3.0) years. In unadjusted analyses, participants with diagnosis of gout had a slower mean annual AAA growth of -0.3 mm/year (95% CI: -0.7, 0.2; p=0.25) than those without gout. After adjusting for potential confounders including initial AAA diameter, body mass index, prior stroke and anti-hypertensive medication prescription, gout was not significantly associated with AAA growth (-0.3 mm/year; 95% CI: -0.7, 0.2; p=0.24). Sensitivity analyses investigating the impact of initial AAA diameter on the association of gout with AAA growth found no interaction. ConclusionThis study suggests diagnosis of gout is not associated with growth of small AAA.

Disease modifying anti-rheumatic drugs (DMARDs) were developed to treat joint inflammation. There is growing evidence that anti-inflammatory drugs prevent major cardiovascular events (MACE). The aim of this systematic review and meta-analysis was to examine whether DMARDs reduce the risk of MACE. A systematic literature search was performed to identify randomized controlled trials (RCTs) testing the effect of DMARDs on cardiovascular events. The primary outcome was MACE defined as the first occurrence of non-fatal myocardial infarction (MI), non-fatal stroke or cardiovascular death. Secondary outcomes were myocardial infarction or stroke alone and all-cause mortality. Safety was assessed by fatal or life threatening infection. Meta-analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Study quality and publication bias were assessed using the Cochrane Collaboration's tool for assessing risk of bias and funnel plots. Twelve RCTs involving 18,056 participants testing three different DMARDs subclasses (Tumor Necrosis Factor inhibitors-4 trials; Janus Kinase inhibitors-5 trials; Interleukin inhibitors-3 trials) were included. Meta-analysis suggested that none of the DMARD subclasses had any effect on MACE, MI alone, stroke alone, risk of fatal or life threatening infection or death. Risk of bias was high, low and unclear in five, six and one studies respectively. Funnel plots suggested a low possibility of publication bias. This meta-analysis suggests that DMARDs do not affect the incidence of MACE. More trials are needed for firm conclusions.

Proteins from parasitic worms have been posed as novel therapies for rheumatoid arthritis (RA) and other auto-inflammatory diseases. However, with so many potential therapeutics, it is important that drug discovery be based on the specific phyla or species which show the most promising effects. Therefore, the aim of this systematic review and meta-analysis was to evaluate the reported effects of helminthic secretory proteins and derivative therapy on RA in an animal model. Medline, Scopus and Web of Science were searched to identify studies evaluating helminthic therapy in the collagen-induced arthritis model of RA. A meta-analysis was undertaken to determine the overall effect of the proteins. Subgroup analyses were also undertaken to investigate individual treatments. Seven articles were included in the analysis. Overall, helminthic therapy significantly reduced arthritis score (SMD −1.193, 95% CI −1.525, −0.860). Subgroup analyses found a significant reduction in arthritis score following treatment with helminth protein ES-62 (SMD −1.186, 95% CI −1.633, −0.738) and phosphorylcholine-based treatment (SMD −0.997, 95% CI −1.423, −0.571). Subgroup analyses found ES-62 treatment significantly decreased IFN-γ levels (SMD −1.611, 95% CI −2.734, −0.487) and significantly increased levels of IL-10 (SMD 0.946, 95% CI 0.127, 1.765). Therapeutics from parasitic worms are a promising avenue for drug discovery, especially with all included studies reporting a significant improvement in arthritis score. Based on pooled data presented in this study, the nematode Acanthocheilonema viteae seems to be of particular interest for therapeutics.

Background No network meta‐analysis has considered the relative efficacy of cilostazol, home exercise therapy, supervised exercise therapy (SET), endovascular revascularization (ER), and ER plus SET (ER+SET) in improving maximum walking distance (MWD) over short‐ ( Methods and Results A systematic literature search was performed to identify randomized controlled trials testing 1 or more of these 5 treatments according to Preferred Reporting Items for Systematic Review and Meta‐Analysis guidelines. The primary outcome was improvement in MWD assessed by a standardized treadmill test. Secondary outcomes were adverse events and health‐related quality of life. Network meta‐analysis was performed using the gemtc R statistical package. The Cochrane collaborative tool was used to assess risk of bias. Forty‐six trials involving 4256 patients were included. At short‐term follow‐up, home exercise therapy (mean difference [MD], 89.4 m; 95% credible interval [CrI], 20.9–157.7), SET (MD, 186.8 m; 95% CrI, 136.4–237.6), and ER+SET (MD, 326.3 m; 95% CrI, 222.6–430.6), but not ER (MD, 82.5 m; 95% CrI, −2.4 to 168.2) and cilostazol (MD, 71.1 m; 95% CrI, −24.6 to 167.9), significantly improved MWD (in meters) compared with controls. At moderate‐term follow‐up, SET (MD, 201.1; 95% CrI, 89.8–318.3) and ER+SET (MD, 368.5; 95% CrI, 195.3–546.9), but not home exercise therapy (MD, 99.4; 95% CrI, −174.0 to 374.9) or ER (MD, 84.2; 95% CrI, −35.3 to 206.4), significantly improved MWD (in meters) compared to controls. At long‐term follow‐up, none of the tested treatments significantly improved MWD compared to controls. Adverse events and quality of life were reported inconsistently and could not be meta‐analyzed. Risk of bias was low, moderate, and high in 4, 24, and 18 trials respectively. Conclusions This network meta‐analysis suggested that SET and ER+SET are effective at improving MWD over the moderate term (

Background There are currently few effective drugs to treat the leg symptoms of peripheral arterial disease (PAD). Previous studies have suggested that the nutraceutical, quercetin, can improve exercise performance and reduce pain sensitivity in healthy mice and improve blood supply in a rodent model of acute hind-limb ischaemia. These models may not be relevant to people with PAD. The aim of this study was to examine the effect of quercetin on exercise performance, physical activity and blood supply in a novel mouse model of sustained hind-limb ischaemia. Methods Hind-limb ischaemia was induced in 6-month-old male apolipoprotein E-deficient mice using a novel two-stage surgical procedure. Five days after induction of ischaemia, mice were allocated to commence dietary quercetin or a control diet for 4 weeks. The primary outcome was exercise performance evaluated using a treadmill test. Other outcomes included physical activity, estimated by an open field test, and hind-limb blood supply, assessed by laser Doppler monitoring. Results A sustained reduction in relative limb blood supply (P, The dietary flavonoid quercetin has been reported to improve exercise performance in healthy mice and people, and increase limb perfusion in models of acute hind limb ischemia. Acute hind limb ischemia models may not be representative of human peripheral artery disease.We report that quercetin does not improve exercise performance or limb perfusion in a newly developed two stage mouse model of sustained hind limb ischemia. Our findings suggest that quercetin may not be beneficial for patients with sustained limb ischemia due to peripheral artery disease. little evidence of efficacy

The aims of this systematic review were to assess the clinical relevance and quality of previously published animal models of ischemic ulceration and examine the available evidence for interventions improving ulcer healing in these models. Publicly available databases were searched for original studies investigating the effect of limb ischemia on wound healing in animal models. The quality of studies was assessed using two tools based on the Animal research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the clinical relevance of the models. A total of 640 wounds (ischemic=314; non-ischemic=326) were assessed in 252 animals (92 mice, 140 rats, 20 rabbits) from 7 studies. Meta-analyses showed that wound healing was consistently delayed by ischemia at all time-points examined (day-7 standard median difference (SMD) 5.36, 95% CI 3.67 to 7.05; day-14 SMD 4.50, 95% CI 2.90 to 6.10 and day-21 SMD 2.53, 95% CI 1.25 to 3.80). No significant difference in wound healing was observed between 32 diabetic and 32 non-diabetic animals with ischemic wounds. Many studies lacked methods to reduce bias, such as outcome assessors blinded to group allocation and sample size calculations and clinically relevant model characteristics, such as use of older animals and a peripheral location of the wound. Five different interventions were reported to improve wound healing in these models. The impaired wound healing associated with limb ischemia can be modeled in a variety of different animals. Improvements in study design could increase clinical relevance, reduce bias and aid the discovery of translatable therapies.

A volume-pressure sensor and tail-cuff method for monitoring blood pressure is non-invasive and inexpensive. This method requires animals to be restrained or subjected to anesthesia, but comparative effects of these manipulations on hemodynamic parameters have not been documented.Using a volume-pressure sensor and tail-cuff, we serially measured blood pressure and heart rate in normotensive adult male Lewis rats after light isoflurane-induced anesthesia (5% induction, 1% maintenance) and, following untrained restraint. Blood pressure was recorded until the acquisition of three complete measurements without the range of replicate mean arterial pressures exceeding 15 mmHg (steady-state).Averages for the entire series of consecutive measurements indicated that restraint yielded significantly higher systolic and diastolic blood pressure than anesthesia (P .05), but heart rate was not affected. Following stabilization at steady-state, there were no significant differences in intra- or inter-day hemodynamic values between the restraint and isoflurane groups. The inter-day coefficient of variation for systolic pressure was 13-23% for isoflurane and 9-14% for restraint. Bland-Altman analysis showed wide limits of agreement (±59 mmHg systolic; ±49 mmHg diastolic pressure) between restraint and isoflurane measurements.Isoflurane caused more variability but there was agreement in BP evaluation by the isoflurane and restraint methods. Using the VPR system, light isoflurane-induced anesthesia and restraint could effectively be used to screen and quantify overt changes in hemodynamic parameters for cardiovascular research utilizing laboratory rodents.

Background and aims Diets enriched with tree nuts have been demonstrated to reduce the risk of atherosclerosis-related cardiovascular events. Abdominal aortic aneurysm (AAA) shares common risk factors with atherosclerosis and AAA patients commonly have atherosclerosis related cardiovascular events. AAA has some distinct pathological and clinical characteristics to those of atherosclerosis. No previous study has examined the effect of a diet enriched with tree nuts on experimental or clinical AAA. This study investigated the effect of a diet enriched with tree nuts on the development and severity of AAA within an experimental rodent model. Methods Male apolipoprotein E deficient mice were allocated to a diet enriched with tree nuts or control diet for 56 days (n = 17 per group). After 28 days, all mice were infused with angiotensin II whilst being maintained on their respective diets. The primary outcome was AAA severity assessed by the supra-renal aortic diameter, measured by ultrasound and ex vivo morphometric analysis. The severity of atherosclerosis was assessed by computer-aided analysis of Sudan IV stained aortic arches and sections of brachiocephalic arteries prepared with Van Gieson's stain. Results The diet enriched with tree nuts did not influence aortic diameter or aortic rupture incidence. Mice receiving the diet enriched with tree nuts had significantly less atherosclerosis within the brachiocephalic artery (p = 0.033) but not in the aortic arch. Conclusions This experimental study suggests that a diet enriched with tree nuts does not reduce the severity of AAA, but does reduce the severity of atherosclerosis within the brachiocephalic artery. The study was not powered to identify a moderate effect of the diet on the primary outcome and therefore this cannot be excluded.

Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h) only, oxytocin only (20 or 100 ng/Kg/h), or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h) were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01). Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05) or both oxytocin and angiotensin II, compared to controls (P < 0.01). Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension.