Dylan R. Morris

Meta-analysis of peak wall stress in ruptured, symptomatic and intact abdominal aortic aneurysms

Abdominal aortic aneurysm (AAA) is an important cause of sudden death; however, there are currently incomplete means to predict the risk of AAA rupture. AAA peak wall stress (PWS) can be estimated using finite element analysis (FEA) methods from computed tomography (CT) scans. The question is whether AAA PWS can predict AAA rupture. The aim of this systematic review was to compare PWS in patients with ruptured and intact AAA.

Meta-analysis of the association between single nucleotide polymorphisms in TGF-β receptor genes and abdominal aortic aneurysm.

OBJECTIVE The role of transforming growth factor (TGF)-beta in abdominal aortic aneurysm (AAA) is controversial. The aim of this study was to assess the association of single nucleotide polymorphisms (SNPs) within TGFBR1 and TGFBR2 with AAA and infrarenal aortic diameter by combining data from previously published studies. METHODS We performed a meta-analysis using individual subject data from three independent case-control groups from Western Australia (n=1675), New Zealand (n=1209), and the Netherlands (n=1636) with 610, 601, and 693 cases of AAA (maximum infrarenal aortic diameter ≥30 mm), respectively. Data were available for two TGFBR1 (rs10819634, rs1571590) and six TGFBR2 (rs304839, rs1346907, rs1036095, rs9831477, rs9843143, rs764522) SNPs. RESULTS There was marked heterogeneity between studies. The G alleles of the TGFBR2 rs764522 and rs1036095 SNPs were associated with AAA under a recessive model (OR=1.69, 95% CI 1.28-2.25, P<0.001 and OR=1.59, 95% CI 1.23-2.07, P<0.001) when a fixed effects model was used. Both associations remained significant after adjustment for multiple testing. CONCLUSION This study suggests that two common genetic polymorphisms in TGFBR2 are associated with the risk of developing AAA although this association was mainly driven by findings in the Netherlands group and marked between study heterogeneity was detected.

The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis

Context Aberrant matrix turnover is believed to play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitor of metalloproteinases; TIMPs) are important enzymes in the control of extracellular matrix remodelling. Objective The aim of this study was to investigate if single nucleotide polymorphisms (SNPs) within MMP and TIMP gene families are associated with the presence of AAA. Data sources We performed a search of MEDLINE and EMBASE databases on the 21st November 2012. Study selection Case-control studies assessing the association of at least one SNP in a MMP or TIMP gene with AAA were included. Data extraction Data were independently extracted by two reviewers. A random effects model was used to calculate combined odds ratios for commonly investigated SNPs according to dominant, recessive and additive inheritance. Results Thirteen studies examining 58 SNPs within 10 different MMP and TIMP genes were identified. Eight SNPs were assessed in at least 3 studies (combined sample size ranging from 141- 2191 AAA cases and 340-2013 controls) and included in a meta-analysis. Results on 1258 cases and 1406 controls for MMP3 rs3025058 showed an association with AAA presence; best described by a dominant pattern of inheritance (OR=1.48 95%CI 1.23 – 1.78, p=3.95×10-5). No associations with AAA were identified for other SNPs assessed in this study including rs1799750 (MMP1), rs3918242 (MMP9), rs486055 (MMP10), rs2276109 (MMP12), rs2252070 (MMP13), rs4898 (TIMP1) or rs9619311 (TIMP3). Conclusion A common SNP within the MMP3 promoter region, previously suggested to increase MMP3 expression, appears to be a moderate risk factor for AAA.

Meta-analysis of the association between transforming growth factor-beta polymorphisms and complications of coronary heart disease.

Objective To investigate the association between common transforming growth factor beta (TGF-β) single nucleotide polymorphisms (SNP) and significant complications of coronary heart disease (CHD). Method We performed a meta-analysis of published case-control studies assessing the association of TGF-β SNPs with a range of CHD complications. A random effects model was used to calculate odds ratios and confidence intervals. Analyses were conducted for additive, dominant and recessive modes of inheritance. Results Six studies involving 5535 cases and 2970 controls examining the association of common SNPs in TGF-β1 with CHD were identified. Applying a dominant model of inheritance, three TGF-β1 SNPs were significantly associated with CHD complications: The T alleles of rs1800469 (OR = 1.125, 95% CI 1.016–1.247, p = 0.031) and rs1800470 (OR = 1.146, 95% CI 1.026–1.279, p = 0.021); and the C allele of rs1800471 (OR = 1.207, 95% CI 1.037–1.406, p = 0.021). Conclusion This meta-analysis suggests that common genetic polymorphisms in TGF-β1 are associated with complications of CHD.

TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial

BackgroundExperimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.Methods/DesignTelmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands.DiscussionCurrently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms.Trial registrationAustralian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976, registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084, registered on 5 September 2012.

Association of Lower Extremity Performance With Cardiovascular and All-Cause Mortality in Patients With Peripheral Artery Disease: A Systematic Review and Meta-Analysis

Background Peripheral artery disease (PAD) is associated with impaired mobility and a high rate of mortality. The aim of this systematic review was to investigate whether reduced lower extremity performance was associated with an increased incidence of cardiovascular and all‐cause mortality in people with PAD. Methods and Results A systematic search of the MEDLINE, EMBASE, SCOPUS, Web of Science, and Cochrane Library databases was conducted. Studies assessing the association between measures of lower extremity performance and cardiovascular or all‐cause mortality in PAD patients were included. A meta‐analysis was conducted combining data from commonly assessed performance tests. The 10 identified studies assessed lower extremity performance by strength tests, treadmill walking performance, 6‐minute walk, walking velocity, and walking impairment questionnaire (WIQ). A meta‐analysis revealed that shorter maximum walking distance was associated with increased 5‐year cardiovascular (unadjusted RR=2.54, 95% CI 1.86 to 3.47, P<10−5, n=1577, fixed effects) and all‐cause mortality (unadjusted RR=2.23 95% CI 1.85 to 2.69, P<10−5, n=1710, fixed effects). Slower 4‐metre walking velocity, a lower WIQ stair‐climbing score, and poor hip extension, knee flexion, and plantar flexion strength were also associated with increased mortality. No significant associations were found for hip flexion strength, WIQ distance score, or WIQ speed score with mortality. Conclusions A number of lower extremity performance measures are prognostic markers for mortality in PAD and may be useful clinical tools for identifying patients at higher risk of death. Further studies are needed to determine whether interventions that improve measures of lower extremity performance reduce mortality.

Proteomic and genomic analyses suggest the association of apolipoprotein C1 with abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is an important cause of mortality in the elderly. Mouse models are widely used to investigate AAA pathogenesis but their suitability for biomarker discovery is unexplored.

A Systematic Review and Meta-Analysis of Circulating Biomarkers Associated with Failure of Arteriovenous Fistulae for Haemodialysis.

Background Arteriovenous fistula (AVF) failure is a significant cause of morbidity and expense in patients on maintenance haemodialysis (HD). Circulating biomarkers could be valuable in detecting patients at risk of AVF failure and may identify targets to improve AVF outcome. Currently there is little consensus on the relationship between circulating biomarkers and AVF failure. The aim of this systematic review was to identify circulating biomarkers associated with AVF failure. Methods Studies evaluating the association between circulating biomarkers and the presence or risk of AVF failure were systematically identified from the MEDLINE, EMBASE and Cochrane Library databases. No restrictions on the type of study were imposed. Concentrations of circulating biomarkers of routine HD patients with and without AVF failure were recorded and meta-analyses were performed on biomarkers that were assessed in three or more studies with a composite population of at least 100 participants. Biomarker concentrations were synthesized into inverse-variance random-effects models to calculate standardized mean differences (SMD) and 95% confidence intervals (CI). Results Thirteen studies comprising a combined population of 1512 participants were included after screening 2835 unique abstracts. These studies collectively investigated 48 biomarkers, predominantly circulating molecules which were assessed as part of routine clinical care. Meta-analysis was performed on twelve eligible biomarkers. No significant association between any of the assessed biomarkers and AVF failure was observed. Conclusion This paper is the first systematic review of biomarkers associated with AVF failure. Our results suggest that blood markers currently assessed do not identify an at-risk AVF. Further, rigorously designed studies assessing biological plausible biomarkers are needed to clarify whether assessment of circulating markers can be of any clinical value. PROSPERO registration number CRD42016033845.

The association between plasma matrix metalloproteinase-9 concentration and endoleak after endovascular aortic aneurysm repair: a meta-analysis.

BACKGROUND The most common complication after endovascular aneurysm repair (EVAR) is continued perfusion of the aneurysmal sac, known as endoleak. Assessment of markers released from the aneurysm wall into the circulation has been suggested as a possible alternative for detecting endoleaks. The aim of this meta-analysis was to examine if circulating concentrations of matrix metalloproteinase (MMP)-9 were higher in patients with endoleak after EVAR. METHODS A systematic search of the MEDLINE, EMBASE, Scopus, Web of Science and Cochrane Library Databases was conducted. Studies reporting circulating MMP-9 concentrations in patients who did and did not have endoleaks after EVAR that met inclusion and exclusion criteria were included. A meta-analysis using a random effects model was performed to assess the association between circulating concentrations of MMP-9 and endoleak. Sensitivity analyses were performed using the one-study remove approach. Study quality was assessed using a quality assessment tool. RESULTS Prior to EVAR, plasma concentrations of MMP-9 were similar in patients that did and did not subsequently develop an endoleak (Standardised mean difference: -0.13; 95% confidence interval, -0.63 to 0.37, p=0.60). 1 month after EVAR, plasma concentrations of MMP-9 were non-significantly higher in patients that had an endoleak (Standardized mean difference: 0.56; 95% CI -0.02 to 1.15, p=0.06). 3 months after EVAR, plasma concentrations of MMP-9 were higher in patients that had an endoleak (Standardised mean difference: 1.42; 95% confidence interval, 0.48-2.36, p<0.003). CONCLUSIONS This meta-analysis suggests that plasma MMP-9 concentrations measured 3 months after EVAR are higher in patients that have an endoleak. It remains to be established whether plasma MMP-9 testing is sufficiently accurate for use as a surveillance test for endoleak after EVAR.

Assessment and validation of a novel angiographic scoring system for peripheral artery disease

Angiography is used routinely in the assessment of lower‐limb arteries, but there are few well validated angiographic scoring systems. The aim of this study was to develop and validate a novel angiographic scoring system for peripheral artery disease.