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Background While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin‐II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease. Methods and Results This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1‐(4‐pyridinyl)‐3‐(2‐quinolinyl)‐2‐propen‐1‐one (PFK15)‐mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self‐limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation. Conclusions Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.

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‐ (

Background Prior studies have suggested aortic peak wall stress (PWS) and peak wall rupture index (PWRI) can estimate the rupture risk of an abdominal aortic aneurysm (AAA), but whether these measurements have independent predictive ability over assessing AAA diameter alone is unclear. The aim of this systematic review was to compare PWS and PWRI in participants with ruptured and asymptomatic intact AAAs of similar diameter. Methods and Results Web of Science, Scopus, Medline, and The Cochrane Library were systematically searched to identify studies assessing PWS and PWRI in ruptured and asymptomatic intact AAAs of similar diameter. Random‐effects meta‐analyses were performed using inverse variance‐weighted methods. Leave‐one‐out sensitivity analyses were conducted to assess the robustness of findings. Risk of bias was assessed using a modification of the Newcastle‐Ottawa scale and standard quality assessment criteria for evaluating primary research papers. Seven case‐control studies involving 309 participants were included. Meta‐analyses suggested that PWRI (standardized mean difference, 0.42; 95% CI, 0.14–0.70; P=0.004) but not PWS (standardized mean difference, 0.13; 95% CI, −0.18 to 0.44; P=0.418) was greater in ruptured than intact AAAs. Sensitivity analyses suggested that the findings were not dependent on the inclusion of any single study. The included studies were assessed to have a medium to high risk of bias. Conclusions Based on limited evidence, this study suggested that PWRI, but not PWS, is greater in ruptured than asymptomatic intact AAAs of similar maximum aortic diameter.

Background Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. The kinin B2 receptor agonist, bradykinin, has been implicated in AAA pathogenesis through promoting inflammation. Bradykinin is generated from high‐ and low‐molecular‐weight kininogen by the serine protease kallikrein‐1. The aims of this study were first to examine the effect of neutralizing kallikrein‐1 on AAA development in a mouse model and second to test how blocking kallikrein‐1 affected cyclooxygenase‐2 and prostaglandin E2 in human AAA explants. Methods and Results Neutralization of kallikrein‐1 in apolipoprotein E‐deficient (ApoE−/−) mice via administration of a blocking antibody inhibited suprarenal aorta expansion in response to angiotensin (Ang) II infusion. Kallikrein‐1 neutralization decreased suprarenal aorta concentrations of bradykinin and prostaglandin E2 and reduced cyclooxygenase‐2 activity. Kallikrein‐1 neutralization also decreased protein kinase B and extracellular signal‐regulated kinase 1/2 phosphorylation and reduced levels of active matrix metalloproteinase 2 and matrix metalloproteinase 9. Kallikrein‐1 blocking antibody reduced levels of cyclooxygenase‐2 and secretion of prostaglandin E2 and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils. Conclusions These findings suggest that kallikrein‐1 neutralization could be a treatment target for AAA.

Background The aim of this study was to assess the relationship between serum lipoprotein (a) (Lp[a]) concentration and the requirement for peripheral artery disease (PAD) operations or incidence of major adverse cardiovascular events. Methods and Results A total of 1472 people with PAD presenting with intermittent claudication (n=355), abdominal aortic aneurysm (n=989) or critical limb ischemia (n=128) were prospectively recruited from 4 outpatient clinics in Australia. Lp(a) was measured in serum samples collected at recruitment using an immunoassay. Participants were followed for a median (interquartile range) of 2.4 (0.1–6.1) years to record requirement for any PAD operation, defined to include any open or endovascular PAD intervention (lower limb peripheral revascularization, abdominal aortic aneurysm repair, other aneurysm repair, or carotid artery revascularization). Myocardial infarctions, strokes, and deaths were also recorded. The association of Lp(a) with events was assessed using Cox proportional hazard analysis adjusting for traditional risk factors. Participants with Lp(a) ≥30 mg/dL had a greater requirement for any PAD operation (hazard ratio, 1.20, 95% CI, 1.02–1.41) and lower limb peripheral revascularization alone (hazard ratio 1.33, 95% CI, 1.06–1.66) but no increased risk of major adverse cardiovascular events or all‐cause mortality. Lp(a) ≥50 mg/dL and a 40 mg/dL increase in Lp(a) were also associated with an increased risk of lower limb peripheral revascularization alone but not with other outcomes. Conclusions In participants with PAD referred for hospital management those with high Lp(a) had greater requirement for lower limb peripheral revascularization but Lp(a) was not consistently associated with other clinical events.

Background The Framingham Risk Score estimates the 10‐year risk of cardiovascular events. However, it performs poorly in older adults. We evaluated the incremental benefit of adding high‐sensitivity cardiac troponin I (hs‐cTnI) to the Framingham Risk Score. Methods and Results The HIMS (Health in Men Study) is a cohort study of community‐dwelling men aged 70 to 89 years in Western Australia. Participants were identified from the electoral roll, with a subset undergoing plasma analysis. Hs‐cTnI (Abbott Architect i2000SR) was measured in 1151 men without prior cardiovascular disease. The Western Australia Data Linkage System was used to identify incident cardiovascular events. After 10 years of follow‐up, 252 men (22%) had a cardiovascular event (CVE+) and 899 did not (CVE–). The Framingham Risk Score placed 148 (59%) CVE+ and 415 (46%) CVE– in the high‐risk category. In CVE– men, adding hs‐cTnI affected the risk categories of 244 (27.2%) men, with 64.8% appropriately reclassified to a lower and 35.2% to a higher category, which decreased the number of high‐risk men in the CVE– to 39%. In CVE+ men, adding hs‐cTnI affected the risk categories of 61 (24.2%), with 50.8% appropriately reclassified to a higher and 49.2% to a lower category and 82.5% remaining above the 15% risk treatment threshold. The net reclassification index was 0.305 (P

Background Hypertension is an important risk factor for cardiovascular events in patients with peripheral artery disease; however, optimal blood pressure targets for these patients are poorly defined. This study investigated the association between systolic blood pressure (SBP) and cardiovascular events in a prospectively recruited patient cohort with peripheral artery disease. Methods and Results A total of 2773 patients were included and were grouped according to SBP at recruitment (≤120 mm Hg, n=604; 121–140 mm Hg, n=1065; and >140 mm Hg, n=1104). Adjusted Cox proportional hazards analyses suggested that patients with SBP ≤120 mm Hg were at greater risk of having a major cardiovascular event (myocardial infarction, stroke, or cardiovascular death) than patients with SBP of 121–140 mm Hg (adjusted hazard ratio, 1.36; 95% CI, 1.08–1.72; P=0.009). Patients with SBP >140 mm Hg had an adjusted hazard ratio of 1.23 (95% CI, 1.00–1.51; P=0.051) of major cardiovascular events compared with patients with SBP of 121–140 mm Hg. These findings were similar in sensitivity analyses only including patients receiving antihypertensive medications or focused on patients with a minimum of 3 months of follow‐up. Conclusions This cohort study suggests that patients with peripheral artery disease and SBP ≤120 mm Hg are at increased risk of major cardiovascular events. The findings suggest caution in intensive SBP lowering in this patient group.

Background There is no drug therapy for abdominal aortic aneurysm (AAA). FAME‐2 (Fenofibrate in the Management of Abdominal Aortic Aneurysm 2) was a placebo‐controlled randomized trial designed to assess whether administration of 145 mg of fenofibrate/d for 24 weeks favorably modified circulating markers of AAA. Methods and Results Patients with AAAs measuring 35 to 49 mm and no contraindication were randomized to fenofibrate or identical placebo. The primary outcome measures were the differences in serum osteopontin and kallistatin concentrations between groups. Secondary analyses compared changes in the circulating concentration of AAA‐associated proteins, and AAA growth, between groups using multivariable linear mixed‐effects modeling. A total of 140 patients were randomized to receive fenofibrate (n=70) or placebo (n=70). By the end of the study 3 (2.1%) patients were lost to follow‐up and 18 (12.9%) patients had ceased trial medication. A total of 85% of randomized patients took ≥80% of allocated tablets and were deemed to have complied with the medication regimen. Patients’ allocated fenofibrate had expected reductions in serum triglycerides and estimated glomerular filtration rate, and increases in serum homocysteine. No differences in serum osteopontin, kallistatin, or AAA growth were observed between groups. Conclusions Administering 145 mg/d of fenofibrate for 24 weeks did not significantly reduce serum concentrations of osteopontin and kallistatin concentrations, or rates of AAA growth in this trial. The findings do not support the likely benefit of fenofibrate as a treatment for patients with small AAAs. Clinical Trial Registration URL: www.anzctr.org.au. Unique identifier: ACTRN12613001039774.

Background Poor lower extremity physical performance is an independent predictor of unfavorable outcome in patients with peripheral artery disease (PAD); however, few studies have assessed muscle characteristics on imaging directly. Method and Results A novel 3‐dimensional semi‐automated protocol was developed to estimate leg muscle volume and density (mean attenuation) from computed tomography images. Patients with PAD who underwent a lower extremity computed tomography scan at a tertiary vascular surgery center were included, and were followed up using hospital records and linked data as part of a retrospective cohort study. The primary outcomes were lower limb events (major amputation or peripheral revascularization) and cardiovascular events (myocardial infarction, stroke, or cardiovascular death). Two hundred and twenty‐three patients with PAD were included (median age 69.0 years; 73% men) and followed for a median of 4.9 [2.6–7.0] years. During this time there were 99 index lower limb events and 97 cardiovascular events. Low leg muscle density was associated with increased risk of lower limb (rate ratio 1.41 [1.11–1.80] per SD reduction) and cardiovascular events (rate ratio 1.60 [1.29–1.99] per SD reduction). Low muscle density remained an independent predictor of cardiovascular (but not lower limb) events, after adjusting for age, sex, traditional cardiovascular risk factors, and angiographic PAD severity (rate ratio 1.39 [1.09–1.77] per lower SD). In contrast, leg muscle volume was not associated with outcomes after adjusting for risk factors and PAD severity. Conclusions Low leg muscle density, but not volume, is a strong, independent predictor of major cardiovascular events among people with PAD. Further research is needed to understand the mechanisms underlying these associations.

BackgroundUnderstanding the relationship between body mass index (BMI) and vascular disease at older age has become increasingly important in the many countries where both average age and BMI are rising. Methods and ResultsIn this prospective cohort study, 12 203 men (aged ≥65) were recruited in 1996–1999 from the general population in Perth, Australia. To limit reverse causality, analyses excluded those with past vascular disease and the first 4 years of follow‐up. During a further 8 (SD3) years of follow‐up, there were 1136 first‐ever major vascular events (nonfatal myocardial infarction, nonfatal stroke, or death from any vascular cause). Cox regression (adjusted for age, education, and smoking) related BMI at recruitment to incidence of major vascular events. At ages 65 to 94, the lowest risk of major vascular events was at ≈ 22.5 to 25 kg/m2. In the higher BMI range (≥25 kg/m2), 5 kg/m2 higher BMI was associated with 33% higher risk of major vascular events (hazard ratio, 1.33 [95% confidence interval, 1.18–1.49]): 24% higher risk of ischemic heart disease (1.24 [1.06–1.46]); 34% higher risk of stroke (1.34 [1.11–1.63]); and 78% higher risk of other vascular death (1.78 [1.32–2.41]). In the lower BMI range, there were fewer events and no strong evidence of an association (hazard ratio per 5 kg/m2 higher BMI, 0.82 [95% confidence interval, 0.61–1.12]). ConclusionsIn this population of older men, risk of major vascular events was lowest at ≈ 22.5 to 25 kg/m2. Above this range, BMI was strongly related to incidence of major vascular events, with each 5 kg/m2 higher BMI associated with ≈30% higher risk.

BackgroundIntracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and ResultsWe performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). ConclusionsAlthough there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.