Protocol for the Metformin Aneurysm Trial (MAT): A placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm

Background: Multiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms. Methods: MAT is an international, multi-centre, prospective, parallel-group, randomised, placebo-controlled trial. Participants must have an asymptomatic AAA measuring at least 35 mm in maximum diameter, no diabetes, no contraindication to metformin and no current plans for surgical repair. The double-blind period is preceded by a 6-week, single-blind, active run-in phase in which all potential participants receive metformin. Only patients tolerating metformin by taking at least 80% of allocated medication will enter the trial and be randomised to 1500 mg of metformin XR or an identical placebo. The primary outcome is the proportion of AAA events defined as rupture-related mortality or need for surgical repair. Secondary outcomes include AAA growth, major adverse cardiovascular events and health-related quality of life. In order to test if metformin reduced the risk of AAA events by at least 25%, 616 primary outcome events will be required (power 90%, alpha 0.05). Discussion: Currently, there is no drug therapy for AAA. Past trials have found no convincing evidence of the benefit of multiple blood pressure lowering, antibiotics, a mast cell inhibitor, an anti-platelet drug and a lipid-lowering medication on AAA growth. MAT is one of a number of trials now ongoing testing metformin for AAA. MAT, unlike these other trials, is designed to test the effect of metformin on AAA events. The international collaboration needed for MAT will be challenging to achieve given the current COVID-19 pandemic. If this challenge can be overcome, MAT will represent a trial unique within the AAA field in its large size and design

Components of carotid atherosclerotic plaque in spectral photon-counting CT with histopathologic comparison

Objectives This study aimed to demonstrate the effectiveness of spectral photon-counting CT (SPCCT) in quantifying fibrous cap (FC) thickness, FC area, and lipid-rich necrotic core (LRNC) area, in excised carotid atherosclerotic plaques by comparing it with histopathological measurements. Methods This is a single-center ex vivo cross-sectional observational study. Excised plaques of 20 patients (71 +/- 6 years; 13 men), obtained from carotid endarterectomy were scanned with SPCCT using standardized acquisition settings (120k Vp/19 mu A; 7-18 keV, 18-30 keV, 30-45 keV, 45-75 keV, and 75-118 keV). FC thickness, FC area, and LRNC area were quantified and compared between high-resolution 3D multi-energy CT images and histopathology using the Wilcoxon signed-ranks test and Bland-Altman analysis. Images were interpreted twice by two radiologists separately, blinded to the histopathology; inter- and intra-rater reliability were assessed with the intra-class correlation coefficients (ICC). Results FC thickness and FC area did not show significant differences between the SPCCT-derived radiological measurements versus the histopathological measurements (p value range 0.15-0.51 for FC thickness and 0.053-0.30 for FC area). For the LRNC area, the p value was statistically non-significant for reader 1 (range 0.36-0.81). The Bland-Altman analysis showed mean difference and 95% confidence interval for FC thickness, FC area, and LRNC area, 0.04 (-0.36 to 0.12) square root mm, -0.18 (-0.34 to -0.02) log(10) mm(2) and 0.10 (-0.088. to 0.009) log(10) mm(2) respectively. Conclusion The result demonstrated a viable technique for quantifying FC thickness, FC area, and LRNC area due to the combined effect of high spatial and energy resolution of SPCCT

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease