Exploring Drug Re-Purposing for Treatment of Abdominal Aortic Aneurysms: a Systematic Review and Meta-analysis.

OBJECTIVE: Large abdominal aortic aneurysms (AAAs) present a significant mortality risk. While numerous medical interventions have been proposed, no drugs have convincingly reduced AAA progression, rupture rates, or repair risk. This systematic review and meta-analysis aimed to assess the impact of re-purposed drugs or dietary supplements on slowing expansion rates, reducing the risk of rupture, or minimising the risk of repair for individuals with AAA. METHODS: A systematic search was conducted in five databases. Both observational studies and randomised controlled trials were included. Unpublished data from two screening trials were incorporated. Risk of bias was assessed using the Newcastle-Ottawa scale and revised Cochrane risk of bias tool. Meta-analyses were performed for each identified drug subclass and were stratified by overall risk of bias. Results were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Of 7 484 screened studies, 39 met the inclusion criteria. No studies on dietary supplements were included. A total of 84 cohorts were derived from the included studies, and twelve distinct drug groups underwent meta-analyses. Two drug groups, metformin and statins, were statistically significant in slowing AAA growth. No low risk of bias studies were included for these two drug groups, and the results had very high heterogeneity (I2 > 80%). Both groups had a GRADE certainty of very low. Metformin, excluding high risk of bias studies, presented an estimated mean growth difference of AAA diameter between users and non-users of -0.73 mm/year, whilst statins had an overall estimated mean difference of -0.84 mm/year. CONCLUSION: This systematic review and meta-analysis suggests that metformin and statins may provide some effect in slowing AAA progression. However, no definitive evidence was found for any of the investigated drugs included in this study. Further research is needed to identify effective medical treatments for AAA progression with more robust methodology.

Complex Hybrid Repair of an Aberrant Right Subclavian Artery With Rapidly Developing Kommerell's Diverticulum.

Introduction: An aberrant right subclavian artery (ARSA) is an aortic anomaly that, in some cases, can be complicated with Kommerell's diverticulum (KD) at the origin of the ARSA. Progression and rupture of KD are associated with high mortality. Timely intervention is therefore required; however, there are no clinical guidelines for the most suitable intervention. Report: A 50 year old, previously healthy, male patient developed dysphagia. He was diagnosed with an aberrant right subclavian artery and KD. The KD increased in size from 4 - 7 cm within 2 months. He underwent single stage hybrid aortic repair involving an aortic valve replacement, total aortic arch debranchment, two thoracic endovascular aortic repair stents, and subclavian plugs. He developed a stroke during the post-operative period; however, all neurological symptoms had disappeared at 6 months and computed tomography showed no endoleaks and all supraortic vessels were open. Discussion: Literature on KD is limited; therefore, there is no consensus on KD treatment. Increasing awareness of rapidly developing KD will add to current knowledge of the disease. One stage cardiac and non-cardiac surgery was successfully performed with no long term complications.

Nicotine Administration Augments Abdominal Aortic Aneurysm Progression in Rats.

Inflammation and elastin degradation are key hallmarks in the pathogenesis of abdominal aortic aneurysms (AAAs). It has been acknowledged that activation of alpha7 nicotinic acetylcholine receptors (α7nAChRs) attenuates inflammation, termed the cholinergic anti-inflammatory pathway (CAP). Thus, we hypothesize that low-dose nicotine impairs the progression of elastase-induced AAAs in rats by exerting anti-inflammatory and anti-oxidative stress properties. Male Sprague-Dawley rats underwent surgical AAA induction with intraluminal elastase infusion. We compared vehicle rats with rats treated with nicotine (1.25 mg/kg/day), and aneurysm progression was monitored by weekly ultrasound images for 28 days. Nicotine treatment significantly promoted AAA progression (p = 0.031). Additionally, gelatin zymography demonstrated that nicotine significantly reduced pro-matrix metalloproteinase (pro-MMP) 2 (p = 0.029) and MMP9 (p = 0.030) activity in aneurysmal tissue. No significant difference was found in the elastin content or the score of elastin degradation between the groups. Neither infiltrating neutrophils nor macrophages, nor aneurysmal messenger RNA (mRNA) levels of pro- or anti-inflammatory cytokines, differed between the vehicle and nicotine groups. Finally, no difference in mRNA levels of markers for anti-oxidative stress or the vascular smooth muscle cells' contractile phenotype was observed. However, proteomics analyses of non-aneurysmal abdominal aortas revealed that nicotine decreased myristoylated alanine-rich C-kinase substrate and proteins, in ontology terms, inflammatory response and reactive oxygen species, and in contradiction to augmented AAAs. In conclusion, nicotine at a dose of 1.25 mg/kg/day augments AAA expansion in this elastase AAA model. These results do not support the use of low-dose nicotine administration for the prevention of AAA progression.

The association between diabetes and abdominal aortic aneurysms in men: results of two Danish screening studies, a systematic review, and a meta-analysis of population-based screening studies.

BACKGROUND: A paradoxical protective effect of diabetes on the development and progression of abdominal aortic aneurysms (AAA) has been known for years. This study aimed to investigate whether the protective role of diabetes on AAAs has evolved over the years. METHODS: A cross-sectional study, a systematic review and meta-analysis. This study was based on two large, population-based, randomised screening trials of men aged 65-74; VIVA (2008-2011) and DANCAVAS (2014-2018), including measurement of the abdominal aorta by ultrasound or CT, respectively. Analyses were performed using multiple logistic regressions to estimate the odds ratios (ORs) for AAAs in men with diabetes compared to those not having diabetes. Moreover, a systematic review and meta-analysis of population-based screening studies of AAAs to visualise a potential change of the association between diabetes and AAAs. Studies reporting only on women or Asian populations were excluded. RESULTS: In VIVA, the prevalence of AAA was 3.3%, crude OR for AAA in men with diabetes 1.04 (95% confidence interval, CI, 0.80-1.34), and adjusted OR 0.64 (CI 0.48-0.84). In DANCAVAS, the prevalence of AAA was 4.2%, crude OR 1.44 (CI 1.11-1.87), and adjusted OR 0.78 (CI 0.59-1.04). Twenty-three studies were identified for the meta-analysis (N = 224 766). The overall crude OR was 0.90 (CI 0.77-1.05) before 2000 and 1.16 (CI 1.03-1.30) after 1999. The overall adjusted OR was 0.63 (CI 0.59-0.69) before 2000 and 0.69 (CI 0.57-0.84) after 1999. CONCLUSION: Both the crude and adjusted OR showed a statistically non-significant trend towards an increased risk of AAA by the presence of diabetes. If this represents an actual trend, it could be due to a change in the diabetes population. TRIAL REGISTRATION: DANCAVAS: Current Controlled Trials: ISRCTN12157806. VIVA: ClinicalTrials.gov NCT00662480.