Abstract Background An animal model commonly used to investigate pathways and potential therapeutic interventions relevant to abdominal aortic aneurysm (AAA) involves subcutaneous infusion of angiotensin II within the apolipoprotein E deficient mouse. The aim of this study was to investigate genes differentially expressed in aneurysms forming within this mouse model in order to assess the relevance of this model to human AAA. Results Using microarrays we identified genes relevant to aneurysm formation within apolipoprotein E deficient mice. Firstly we investigated genes differentially expressed in the aneurysm prone segment of the suprarenal aorta in these mice. Secondly we investigated genes that were differentially expressed in the aortas of mice developing aneurysms relative to those that did not develop aneurysms in response to angiotensin II infusion. Our findings suggest that a host of inflammation and extracellular matrix remodelling pathways are upregulated within the aorta in mice developing aneurysms. Kyoto Encyclopedia of Genes and Genome categories enriched in the aortas of mice with aneurysms included cytokine-cytokine receptor interaction, leukocyte transendothelial migration, natural killer cell mediated cytotoxicity and hematopoietic cell lineage. Genes associated with extracellular matrix remodelling, such as a range of matrix metalloproteinases were also differentially expressed in relation to aneurysm formation. Conclusion This study is the first report describing whole genome expression arrays in the apolipoprotein E deficient mice in relation to aneurysm formation. The findings suggest that the pathways believed to be critical in human AAA are also relevant to aneurysm formation in this mouse model. The findings therefore support the value of this model to investigate interventions and mechanisms of human AAA.
Importance It is unclear how to effectively promote walking in people with peripheral artery disease (PAD). Objective To test whether brief counseling delivered by allied health professionals increases step count in participants with PAD. Design, Setting, and Participants In this randomized clinical trial, participants with symptomatic PAD were recruited from sites in Australia and randomly allocated 1:1 to the counseling intervention or an attention control. Data were collected from January 2015 to July 2021, and data were analyzed from March to November 2022. Interventions Two 1-hour face-to-face and two 15-minute telephone counseling sessions designed to increase walking. Main Outcomes and Measures The primary outcome was the between-group difference in change in daily step count estimated by accelerometer recordings over 7 days at baseline and 4 months, using imputation for missing values. Other outcomes at 4, 12, and 24 months included step count, 6-minute walk distance, and disease-specific and generic measures of health-related quality of life. Risk of major adverse limb events was assessed over 24 months. Results Of 200 included participants, 144 (72.0%) were male, and the mean (SD) age was 69.2 (9.3) years. The planned sample of 200 participants was allocated to the counseling intervention group (n = 102) or attention control group (n = 98). Overall, 198 (99.0%), 175 (87.5%), 160 (80.0%) and 143 (71.5%) had step count assessed at entry and 4, 12, and 24 months, respectively. There was no significant between-group difference in the primary outcome of change in daily step count over 4 months (mean steps, 415; 95% CI, −62 to 893; P = .07). Participants in the counseling group had significantly greater improvement in the secondary outcome of disease-specific Intermittent Claudication Questionnaire score at 4 months (3.2 points; 95% CI, 0.1-6.4; P = .04) and 12 months (4.3 points; 95% CI, 0.5-8.1; P = .03) but not at 24 months (1.2 points; 95% CI, −3.1 to 5.6; P = .57). Findings were similar for mean PAD Quality of Life Questionnaire component assessing symptoms and limitations in physical functioning (4 months: 1.5 points; 95% CI, 0.3-2.8; P = .02; 12 months: 1.8 points; 95% CI, 0.3-3.3; P = .02; 24 months: 1.3 points; 95% CI. −0.5 to 3.1; P = .16). There was no significant effect of the intervention on change in mean 6-minute walking distance (4 months: 9.3 m; 95% CI, −3.7 to 22.3; P = .16; 12 months: 13.8 m; 95% CI, −4.2 to 31.7; P = .13; 24 months: 1.2 m; 95% CI, −20.0 to 22.5; P = .91). The counseling intervention did not affect the rate of major adverse limb events over 24 months (12 [11.8%] in the intervention group vs 14 [14.3%] in the control group; P = .68). Conclusions and Relevance This randomized clinical trial found no significant effect of brief counseling on step count in people with PAD. Alternate interventions are needed to enable walking. Trial Registration Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614000592640
Abstract Background Accurate repeat assessment of the diameter of an abdominal aortic aneurysm (AAA) is important. This study investigated the reproducibility of different methods of measuring AAA diameter from ultrasound images. Methods Fifty AAA patients were assessed by ultrasound. Maximum AAA diameter was measured independently by three trained observers on two separate occasions using a standardised protocol. Five diameters were measured from each scan, three in the anterior–posterior (AP) and two in the transverse (TV) plane, including inner-to-inner (ITI), outer-to-outer (OTO) and leading edge-to-leading edge (LETLE). Intra- and inter-observer reproducibility were reported as reproducibility coefficients. Statistical comparison of methods was performed using linear mixed effects models. Results Intra-observer reproducibility coefficients (AP LETLE 2.2 mm; AP ITI 2.4 mm; AP OTO 2.6 mm) were smaller than inter-observer reproducibility coefficients (AP LETLE 4.6 mm: AP ITI 4.5; and AP OTO 4.8 mm). There was no statistically significant difference in intra-observer reproducibility of three types of measurements performed in the AP plane. Measurements obtained in the TV plane had statistically significant worse intra-observer reproducibility than those performed in the AP plane. Conclusions This study suggests that the comparison of maximum AAA diameter between repeat images is most reproducibly performed by a single trained observer measuring diameters in the AP plane.
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.
Background Fractional flow reserve (FFR) is the ratio of blood pressure measured distal to a stenosis and pressure proximal to a stenosis. FFR can be estimated noninvasively using computed tomography (CT) although the usefulness of this technique remains controversial. This meta‐analysis evaluated the agreement of FFR estimated by CT (FFR‐CT) with invasively measured FFR. The study also evaluated the diagnostic accuracy of FFR‐CT, defined as the ability of FFR‐CT to classify lesions as hemodynamically significant (invasive FFR ≤0.8) or insignificant (invasive FFR >0.8). Methods and Results Forty‐three studies reporting on 7291 blood vessels from 5236 patients were included. A moderate positive linear relationship between FFR‐CT and invasively measured FFR was observed (Spearman correlation coefficient: 0.67). Agreement between the 2 measures increased as invasively measured FFR values approached 1. The overall diagnostic accuracy, sensitivity and specificity of FFR‐CT were 82.2%, 80.9%, and 83.1%, respectively. Diagnostic accuracy of 90% could be demonstrated for FFR‐CT values >0.90 and <0.49. The diagnostic accuracy of off‐site tools was 79.4% and the diagnostic accuracy of on‐site tools was 84.1%. Conclusions The agreement between FFR‐CT and invasive FFR is moderate although agreement is highest in vessels with FFR‐CT >0.9. Diagnostic accuracy varies widely with FFR‐CT value but is above 90% for FFR‐CT values >0.90 and <0.49. Furthermore, on‐site and off‐site tools have similar performance. Ultimately, FFR‐CT may be a useful adjunct to CT coronary angiography as a gatekeeper for invasive coronary angiogram.
Abstract 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 < 0.001) was achieved consistently in all 48 mice before allocation to a control (n = 24) or quercetin (n = 24) diet. Quercetin did not improve exercise performance (P = 0.785), physical activity (P = 0.151) or relative limb blood supply (P = 0.954) over the 4-week assessment period. Conclusion These data suggest that quercetin does not improve exercise performance, physical activity or limb blood supply in mice with sustained hind-limb ischaemia, and therefore is unlikely be an effective treatment for PAD.
Abstract Background 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. Methods An angiographic scoring system (the ANGIO score) was developed and applied to a sample of patients from a single vascular surgical department who underwent CT angiography of the lower limbs. The reproducibility of the ANGIO score was compared with those of the Bollinger and Trans-Atlantic inter-Society Consensus (TASC) IIb systems in a series of randomly selected patients. Associations between the ANGIO score and lower-limb ischaemia, as measured by the ankle : brachial pressure index (ABPI), and outcome events (major lower-limb amputations and cardiovascular events – myocardial infarction, stroke and cardiovascular death) were assessed. Results Some 256 patients undergoing CT angiography were included. The interobserver reproducibility of the ANGIO score was better than that of the other scoring systems examined (κ = 0·90, P = 0·002). There was a negative correlation between the ANGIO score and ABPI (ρ = −0·33, P = 0·008). A higher ANGIO score was associated with an increased risk of major lower-limb amputation (hazard ratio (HR) for highest versus lowest tertile 9·30, 95 per cent c.i. 1·95 to 44·38; P = 0·005) and cardiovascular events (HR 2·73, 1·31 to 5·70; P = 0·007) following adjustment for established risk factors. Conclusion The ANGIO score provided a reproducible and valid assessment of the severity of lower-limb ischaemia and risk of major amputation and cardiovascular events in these patients with peripheral artery disease.
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