Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men.

BACKGROUND: The influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria. OBJECTIVE: To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men. DESIGN: Cohort study. SETTING: UK Biobank prospective cohort. PARTICIPANTS: Community-dwelling men aged 40 to 69 years. MEASUREMENTS: Testosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors. RESULTS: Of 210 700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]). LIMITATION: Observational study; single baseline measurement of testosterone and SHBG. CONCLUSION: Men with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined. PRIMARY FUNDING SOURCE: Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

Trends in the incidence, surgical management and outcomes of type B aortic dissections in Australia over the last decade.

OBJECTIVES: This study aims to investigate the incidence and in-hospital outcomes of surgical repair for type B aortic dissection (TBAD) in Australia. METHODS: Data were obtained from the Australasian Vascular Audit (AVA) and the Australian Institute of Health and Welfare (AIHW). The former is a total practice audit mandated for all members of the Australian and New Zealand Society for Vascular Surgery (ANZSVS) while the latter is an independent government agency which records all healthcare data in Australia. All cases of TBAD which underwent surgical intervention (endovascular or open repair) between 2010 and 2019 were identified using prospectively recorded data from the AVA (New Zealand data was excluded). The primary outcomes were temporal trends in procedures and hospital mortality; secondary outcomes were complications and risk factors for mortality. All admissions and procedures for, and hospital deaths from, TBAD in Australia were identified in AIHW datasets using the relevant diagnosis and procedure codes, with age-standardized rates calculated for the period 2000-01 to 2018-19. RESULTS: A total of 567 cases of TBAD underwent vascular surgical intervention (AVA data, Australia). Of these, 96.3% were treated by endovascular repair. There was an increase in the annual procedure number from 45 in 2010 to 88 in 2019. In-hospital mortality was 4.8% for endovascular repair and 19% for open repair (p = 0.021). From 2000-01 to 201819, the age-standardized procedure rates for TBAD (Australia) doubled, the proportion of admitted patients undergoing a procedure rose from 28% to 43%, and in-hospital deaths fell by 25%. CONCLUSION: There has been an increasing incidence of vascular surgical intervention for TBAD in Australia. The majority of patients received endovascular therapy while the mortality from surgically managed TBAD appears to be falling.

Proximal false lumen thrombosis is associated with low false lumen pressure and fewer complications in type B aortic dissection.

BACKGROUND: Improved risk stratification is a key priority for type B aortic dissection (TBAD). Partial false lumen thrombus morphology is an emerging predictor of complications. However, partial thrombosis is poorly defined, and its evaluation in clinical studies has been inconsistent. Thus, we aimed to characterize the hemodynamic pressure in TBAD and determine how the pressure relates to the false lumen thrombus morphology and clinical events. METHODS: The retrospective admission computed tomography angiograms of 69 patients with acute TBAD were used to construct three-dimensional computational models for simulation of cyclical blood flow and calculation of pressure. The patients were categorized by the false lumen thrombus morphology as minimal, extensive, proximal or distal thrombosis. Linear regression analysis was used to compare the luminal pressure difference between the true and false lumen for each morphology group. The effect of morphology classification on the incidence of acute complications within 14 days was studied using logistic regression adjusted for clinical parameters. A survival analysis for adverse aortic events at 1 year was also performed using Cox regression. RESULTS: Of the 69 patients, 44 had experienced acute complications and 45 had had an adverse aortic event at 1 year. The mean ± standard deviation age was 62.6 ± 12.6 years, and 75.4% were men. Compared with the patients with minimal thrombosis, those with proximal thrombosis had a reduced false lumen pressure by 10.1 mm Hg (95% confidence interval [CI], 4.3-15.9 mm Hg; P = .001). The patients who had not experienced an acute complication had had a reduced relative false lumen pressure (-6.35 mm Hg vs -0.62 mm Hg; P = .03). Proximal thrombosis was associated with fewer acute complications (odds ratio, 0.17; 95% CI, 0.04-0.60; P = .01) and 1-year adverse aortic events (hazard ratio, 0.36; 95% CI, 0.16-0.80; P = .01). CONCLUSIONS: We found that proximal false lumen thrombosis was a marker of reduced false lumen pressure. This might explain how proximal false lumen thrombosis appears to be protective of acute complications (eg, refractory hypertension or pain, aortic rupture, visceral or limb malperfusion, acute expansion) and adverse aortic events within the first year.

Wound healing with "spray-on" autologous skin grafting (ReCell) compared with standard care in patients with large diabetes-related foot wounds: an open-label randomised controlled trial.

There is an urgent need for interventions that improve healing time, prevent amputations and recurrent ulceration in patients with diabetes-related foot wounds. In this randomised, open-label trial, participants were randomised to receive an application of non-cultured autologous skin cells ("spray-on" skin; ReCell) or standard care interventions for large (>6 cm2 ), adequately vascularised wounds. The primary outcome was complete healing at 6 months, determined by assessors blinded to the intervention. Forty-nine eligible foot wounds in 45 participants were randomised. An evaluable primary outcome was available for all wounds. The median (interquartile range) wound area at baseline was 11.4 (8.8-17.6) cm2 . A total of 32 (65.3%) index wounds were completely healed at 6 months, including 16 of 24 (66.7%) in the spray-on skin group and 16 of 25 (64.0%) in the standard care group (unadjusted OR [95% CI]: 1.13 (0.35-3.65), P = .845). Lower body mass index (P = .002) and non-plantar wounds (P = .009) were the only patient- or wound-related factors associated with complete healing at 6 months. Spray-on skin resulted in high rates of complete healing at 6 months in patients with large diabetes-related foot wounds, but was not significantly better than standard care (Australian New Zealand Clinical Trials Registry: ACTRN12618000511235).

The application of computational modeling for risk prediction in type B aortic dissection.

OBJECTIVE: New tools are urgently needed to help with surgical decision-making in type B aortic dissection (TBAD) that is uncomplicated at the time of initial presentation. This narrative review aims to answer the clinical question, Can computational modeling be used to predict risk in acute and chronic Stanford TBAD? METHODS: The review (PROSPERO 2018 CRD42018104472) focused on risk prediction in TBAD. A comprehensive search of the Ovid MEDLINE database, using terms related to computational modeling and aortic dissection, was conducted to find studies of any form published between 1998 and 2018. Cohort studies, case series, and case reports of adults (older than 18 years) with computed tomography or magnetic resonance imaging diagnosis of TBAD were included. Computational modeling was applied in all selected studies. RESULTS: There were 37 studies about computational modeling of TBAD identified from the search, and the findings were synthesized into a narrative review. Computational modeling can produce numerically calculated values of stresses, pressures, and flow velocities that are difficult to measure in vivo. Hemodynamic parameters-high or low wall shear stress, high pressure gradient between lumens during the cardiac cycle, and high false lumen flow rate-have been linked to the pathogenesis of branch malperfusion and aneurysm formation by numerous studies. Considering the major outcomes of end-organ failure, aortic rupture, and stabilization and remodeling, hypotheses have been generated about inter-relationships of measurable parameters in computational models with observable anatomic and pathologic changes, resulting in specific clinical outcomes. CONCLUSIONS: There is consistency in study findings about computational modeling in TBAD, although a limited number of patients have been analyzed using various techniques. The mechanistic patterns of association found in this narrative review should be investigated in larger cohort prospective studies to further refine our understanding. It highlights the importance of patient-specific computational hemodynamic parameters in clinical decision-making algorithms. The current challenge is to develop and to test a risk assessment method that can be used by clinicians for TBAD.

Morphology and Hemodynamics in Isolated Common Iliac Artery Aneurysms Impacts Proximal Aortic Remodeling.

Objective- Isolated common iliac artery aneurysms (CIAA) are rare. Their prognosis and influence on aortoiliac blood flow and remodeling are unclear. We evaluated the hypotheses that morphology at and distal to the aortic bifurcation, together with the associated hemodynamic changes, influence both the natural history of CIAA and proximal aortic remodeling. Approach and Results- Twenty-five isolated CIAAs (15 intact, 10 ruptured), in 23 patients were reconstructed and analyzed with computational fluid dynamics: all showed abnormal flow. Then we studied a series of 24 hypothetical aortoiliac geometries in silico with varying abdominal aortic deflection and aortic bifurcation angles: key findings were assessed in an independent validation cohort of 162 patients. Wall shear stress in isolated unilateral CIAAs was lower than the contralateral common iliac artery, 0.38±0.33 Pa versus 0.61±0.24 Pa, inversely associated with CIAA diameter ( P<0.001) and morphology (high shear stress in variants distal to a sharp kink). Rupture usually occurred in regions of elevated low and oscillatory shear with a wide aortic bifurcation angle. Abdominal aortas deflected towards the CIAA for most unilateral isolated CIAAs (14/21). In silico, wider bifurcation angles created high focal regions of low and oscillatory shear in the common iliac artery. The associations of unilateral CIAA with aortic deflection and common iliac artery diameter with bifurcation angle were confirmed in the validation cohort. Conclusions- Decreasing wall shear stress is strongly associated with CIAA progression (larger aneurysms and rupture), whereas abnormal blood flow in the CIAA seems to promote proximal aortic remodeling, with adaptive lateral deflection of the abdominal aorta towards the aneurysmal side.

Morphology and Computational Fluid Dynamics Support a Novel Classification of Common Iliac Aneurysms.

OBJECTIVE: Isolated common iliac artery aneurysms (CIAAs) are uncommon, and evidence concerning their development, progression, and management is weak. The objective was to describe the morphology and haemodynamics of isolated CIAAs in a retrospective study. METHODS: Initially, a series of 25 isolated CIAAs (15 intact, 10 ruptured) in 23 patients were gathered from multiple centres, reconstructed from computed tomography, and then morphologically classified and analysed with computational fluid dynamics. The morphological classification was applied in a separate, consecutive cohort of 162 patients assessed for elective aorto-iliac intervention, in which 55 patients had intact CIAAs. RESULTS: In the isolated CIAA cohort, three distinct morphologies were identified: complex (involving a bifurcation); fusiform; and kinked (distal to a sharp bend in the CIA), with mean diameters of 90.3, 48.3, and 31.7 mm, and mean time averaged wall shear stresses of 0.16, 0.31, and 0.71 Pa, respectively (both analysis of variance p values < .001). Kinked cases vs. fusiform cases had less thrombus and favourable haemodynamics similar to the non-aneurysmal contralateral common iliac artery (CIA). Ruptured isolated CIAAs were large (mean diameter 87.5 mm, range 55.5-138.0 mm) and predominantly complex. The mean CIA length for aneurysmal arteries was greatest in kinked cases followed by complex and fusiform (100.8 mm, 91.1 mm, and 80.6 mm, respectively). The morphological classification was readily applicable to a separate elective patient cohort. CONCLUSION: A new morphological categorisation of CIAAs is proposed. Potentially this is associated with both haemodynamics and clinical course. Further research is required to determine whether the kinked CIAA is protected haemodynamically from aneurysm progression and to establish the wider applicability of the categorisation presented.

Surgical Decision Making in Uncomplicated Type B Aortic Dissection: A Survey of Australian/New Zealand and European Surgeons.

OBJECTIVE: There is controversy about the role of pre-emptive thoracic endovascular aortic repair (TEVAR) in uncomplicated type B aortic dissection (TBAD). The aim was to understand expert opinions and the factors influencing decision making. METHODS: In 2018, surgeons from Australia/New Zealand (ANZ) and Europe (EUR) were contacted to participate in an online survey which comprised questions about preferences for pre-emptive TEVAR, followed by five case scenarios, and two ranking questions for anatomical and technical risk factors respectively. Case 1 was designed to favour TEVAR in a hypertensive patient with partial false lumen thrombosis and large diameter (aortic ≥ 40 mm, false lumen ≥ 22 mm). Case 2 had no risk factors mandating TEVAR, according to current evidence. Cases 3, 4, and 5 were designed to test one risk factor respectively, large entry tear on the inner aortic curvature (≥10 mm), partial false lumen thrombosis, and large diameter alone. RESULTS: There were 75 responses, 42 from EUR and 33 from ANZ. Almost half of surgeons (49.3%) endorsed pre-emptive TEVAR with 82.3% preferring to perform TEVAR in the subacute phase. In Case 1 and 5, 58.3% and 52.8% of surgeons respectively chose TEVAR, the highest rates obtained in the survey. Cases 1 and 5 included large diameters ≥40 mm, which were ranked the highest in importance when surgeons considered anatomical risk factors. Surgeons who recommend pre-emptive TEVAR were more likely to choose TEVAR in both Case 1 (83.3% vs. 33.3%, p < .001, 95% CI 27.6%-65.8%) and Case 5 (69.4% vs. 38.2%, p = .008, 95% CI 8.2%-50.0%). CONCLUSION: In this survey about uncomplicated TBAD, about half of surgeons recommended pre-emptive TEVAR in selected cases. The surgeon's predisposition towards intervention and large diameters appear to be the most influential factors in decision making. These findings underline the uncertainty in today's practice and emphasise the need for better predictive tools.

Biomechanical Assessment Predicts Aneurysm Related Events in Patients with Abdominal Aortic Aneurysm.

OBJECTIVE: To test whether aneurysm biomechanical ratio (ABR; a dimensionless ratio of wall stress and wall strength) can predict aneurysm related events. METHODS: In a prospective multicentre clinical study of 295 patients with an abdominal aortic aneurysm (AAA; diameter ≥ 40 mm), three dimensional reconstruction and computational biomechanical analyses were used to compute ABR at baseline. Participants were followed for at least two years and the primary end point was the composite of aneurysm rupture or repair. RESULTS: The majority were male (87%), current or former smokers (86%), most (72%) had hypertension (mean ± standard deviation [SD] systolic blood pressure 140 ± 22 mmHg), and mean ± SD baseline diameter was 49.0 ± 6.9 mm. Mean ± SD ABR was 0.49 ± 0.27. Participants were followed up for a mean ± SD of 848 ± 379 days and rupture (n = 13) or repair (n = 102) occurred in 115 (39%) cases. The number of repairs increased across tertiles of ABR: low (n = 24), medium (n = 34), and high ABR (n = 44) (p = .010). Rupture or repair occurred more frequently in those with higher ABR (log rank p = .009) and ABR was independently predictive of this outcome after adjusting for diameter and other clinical risk factors, including sex and smoking (hazard ratio 1.41; 95% confidence interval 1.09-1.83 [p = .010]). CONCLUSION: It has been shown that biomechanical ABR is a strong independent predictor of AAA rupture or repair in a model incorporating known risk factors, including diameter. Determining ABR at baseline could help guide the management of patients with AAA.

Cross-sectional associations of sex hormones with leucocyte telomere length, a marker of biological age, in a community-based cohort of older men.

CONTEXT: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and oestradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men. PARTICIPANTS AND METHODS: We used cross-sectional data from 2913 men aged 76.7 ± 3.2 years with morning blood samples assayed for T, DHT, E2 (mass spectrometry), and sex hormone-binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history. RESULTS: Average difference per decade of age was T -0.46 nmol/L, DHT -0.11 nmol/L, E2 -7.5 pmol/L, SHBG +10.2 nmol/L and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r = 0.038, P = 0.039) and SHBG was inversely correlated (r = -0.053, P = 0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, P = 0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, P = 0.014) and SHBG inversely (coefficient -0.013, P = 0.037) associated with T/S ratio. CONCLUSIONS: In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing.

Differential associations of ferritin and 25-hydroxyvitamin D with fasting glucose and diabetes risk in community dwelling older men.

AIMS: We examined associations of ferritin and 25-hydroxyvitamin D with fasting glucose and prevalent diabetes in older men. METHODS: Cross-sectional analysis of 4153 community-dwelling men aged 70 to 89 years in Western Australia. Plasma ferritin, 25-hydroxyvitamin D, and glucose were assayed. Diabetes was ascertained from self-report, medications, and fasting glucose. RESULTS: There were 577 men with diabetes (13.9%). In the whole cohort, ferritin was associated with fasting glucose (0.051 mmol/L per 1 SD increase in ferritin, P = .006) and 25-hydroxyvitamin D was inversely associated (-0.085 mmol/L per 1 SD, P < .001). Ferritin was not associated with prevalent diabetes (highest vs. lowest quartile; >225 vs <66 µg/L: adjusted odds ratio [OR] 0.97, 95% confidence interval [CI], 0.74-1.27, P = .83). Higher vitamin D was associated with decreased odds of prevalent diabetes (highest vs lowest quartile; >82 nmol/L vs <53 nmol/L: OR = 0.57, 95% CI = 0.43-0.75, P < .001). There was no interaction between ferritin and vitamin D on diabetes risk. CONCLUSIONS: In older men, ferritin is associated with fasting glucose but not prevalent diabetes. Higher 25-hydroxyvitamin D concentrations are independently associated with lower fasting glucose and reduced risk of diabetes. Clinical trials are required to determine whether interventions, which raise vitamin D concentrations, would reduce incidence of diabetes in this expanding demographic group.

Editor's Choice - Metformin Prescription is Associated with a Reduction in the Combined Incidence of Surgical Repair and Rupture Related Mortality in Patients with Abdominal Aortic Aneurysm.

OBJECTIVES: Currently there is no drug therapy for abdominal aortic aneurysm (AAA) and most previous investigations have focused on imaging rather than clinical outcomes. The aim of this study was to assess whether AAA related clinical events were lower in patients prescribed metformin. METHODS: This was a prospective cohort observational study performed in three cities in Australia, which was designed to study risk factors for clinical events not simply to focus on metformin. Patients with an asymptomatic unrepaired AAA of any diameter ≥30 mm were recruited from hospital outpatient clinics and surveillance programs run at four centres. The main outcome was the requirement for AAA repair or AAA related mortality (AAA events). The association between metformin prescription and AAA events was assessed using Kaplan-Meier analysis and Cox proportional hazard analysis. RESULTS: Patients (1,080) with a mean (SD) initial AAA diameter of 46.1 (11.3) mm were followed for a mean (SD) of 2.5 (3.1) years until an AAA event (n = 454), death (n = 176), loss to follow up (n = 128), or completion of current follow up (n = 322). Patients with diabetes who were prescribed metformin (adjusted HR 0.63, 95% CI 0.44-0.93), but not patients with diabetes who were not prescribed metformin (adjusted HR 1.15, 95% CI 0.83-1.59), had a lower incidence of AAA events compared with those without diabetes. Findings were similar in sensitivity analyses restricted to patients with an initial AAA diameter ≤50 mm and patients with a minimum follow up of six months before an AAA event. CONCLUSIONS: These findings suggest that clinically important AAA events may be reduced in patients with diabetes who are prescribed metformin, but not those with diabetes receiving other treatments. A randomised controlled trial is needed to definitively test whether metformin reduces AAA related clinical events in patients with small AAAs who do not have diabetes.

Resveratrol Inhibits Growth of Experimental Abdominal Aortic Aneurysm Associated With Upregulation of Angiotensin-Converting Enzyme 2.

OBJECTIVE: Recent evidence suggests an important role for angiotensin-converting enzyme 2 (ACE2) in limiting abdominal aortic aneurysm (AAA). This study examined the effect of ACE2 deficiency on AAA development and the efficacy of resveratrol to upregulate ACE2 in experimental AAA. APPROACH AND RESULTS: Ace2 deletion in apolipoprotein-deficient mice (ApoE-/-Ace2-/y ) resulted in increased aortic diameter and spontaneous aneurysm of the suprarenal aorta associated with increased expression of inflammation and proteolytic enzyme markers. In humans, serum ACE2 activity was negatively associated with AAA diagnosis. ACE2 expression was lower in infrarenal biopsies of patients with AAA than organ donors. AAA was more severe in ApoE-/-Ace2-/y mice compared with controls in 2 experimental models. Resveratrol (0.05/100-g chow) inhibited growth of pre-established AAAs in ApoE-/- mice fed high-fat chow and infused with angiotensin II continuously for 56 days. Reduced suprarenal aorta dilatation in mice receiving resveratrol was associated with elevated serum ACE2 and increased suprarenal aorta tissue levels of ACE2 and sirtuin 1 activity. In addition, the relative phosphorylation of Akt and ERK (extracellular signal-regulated kinase) 1/2 within suprarenal aorta tissue and gene expression for nuclear factor of kappa light polypeptide gene enhancer in B cells 1, angiotensin type-1 receptor, and metallopeptidase 2 and 9 were significantly reduced. Upregulation of ACE2 in human aortic smooth muscle cells by resveratrol in vitro was sirtuin 1-dependent. CONCLUSIONS: This study provides experimental evidence of an important role for ACE2 in limiting AAA development and growth. Resveratrol upregulated ACE2 and inhibited AAA growth in a mouse model.

Challenges and opportunities in limiting abdominal aortic aneurysm growth.

OBJECTIVE: This review describes ongoing efforts to develop a medical therapy to limit abdominal aortic aneurysm (AAA) growth. METHODS: Data from animal model studies, human investigations, and clinical trials are described. RESULTS: Studies in rodent models and human samples have suggested a number of potential targets for slowing or halting AAA growth. A number of clinical trials are now examining the value of medications targeting some of the pathways identified. These trials have a number of challenges, including identifying medications safe to use in older patients with multiple comorbidities, developing accurate outcome assessments, and minimizing the dropout of patients during the trials. Three recent trials have reported no benefit of the antibiotic doxycycline, a mast cell inhibitor, an angiotensin-converting enzyme inhibitor, or a calcium channel blocker in limiting AAA growth. A number of other trials examining angiotensin receptor blockers, cyclosporine, and an antiplatelet agent are currently underway. CONCLUSIONS: Further refinement of drug discovery pathways and testing paradigms are likely needed to develop effective nonsurgical therapies for AAA.

Modulation of Kinin B2 Receptor Signaling Controls Aortic Dilatation and Rupture in the Angiotensin II-Infused Apolipoprotein E-Deficient Mouse.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Activity of the local kallikrein-kinin system may be important in cardiovascular disease. The effect of kinin B2 receptor (B2R) agonist and antagonist peptides on experimental AAA was investigated. APPROACH AND RESULTS: AAA was induced in apolipoprotein E-deficient mice via infusion of angiotensin II (1.0 µg/kg per minute SC). B2R agonists or antagonists were given via injection (2 mg/kg IP) every other day. The B2R agonist (B9772) promoted aortic rupture in response to angiotensin II associated with an increase in neutrophil infiltration of the aorta in comparison to controls. Mice receiving a B2R/kinin B1 receptor antagonist (B9430) were relatively protected from aortic rupture. Neutrophil depletion abrogated the ability of the B2R agonist to promote aortic rupture. Progression of angiotensin II-induced aortic dilatation was inhibited in mice receiving a B2R antagonist (B9330). Secretion of metalloproteinase-2 and -9, osteoprotegerin, and osteopontin by human AAA explant was reduced in the presence of the B2R antagonist (B9330). B2R agonist and antagonist peptides enhanced and inhibited, respectively, angiotensin II-induced neutrophil activation and aortic smooth muscle cell inflammatory phenotype. The B2R antagonist (B9330; 5 µg) delivered directly to the aortic wall 1 week post-AAA induction with calcium phosphate in a rat model reduced aneurysm growth associated with downregulation of aortic metalloproteinase-9. CONCLUSIONS: B2R signaling promotes aortic rupture within a mouse model associated with the ability to stimulate inflammatory phenotypes of neutrophils and vascular smooth muscle cells. B2R antagonism could be a potential therapy for AAA.

A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76-0.85, P = 7.2 × 10(-14)). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case-control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.

Temporal changes in the prevalence and associates of diabetes-related lower extremity amputations in patients with type 2 diabetes: the Fremantle Diabetes Study.

BACKGROUND: To determine temporal changes in the prevalence and associates of lower extremity amputation (LEA) complicating type 2 diabetes. METHODS: Baseline data from the longitudinal observational Fremantle Diabetes Study (FDS) relating to LEA and its risk factors collected from 1296 patients recruited to FDS Phase 1 (FDS1) from 1993 to 1996 and from 1509 patients recruited to FDS Phase 2 (FDS2) from 2008 to 2011 were analysed. Multiple logistic regression was used to determine associates of prevalent LEA in individual and pooled phases. Generalised linear modelling was used to examine whether diabetes related LEA prevalence and its associates had changed between Phases. RESULTS: There were 15 diabetes-related LEAs at baseline in FDS1 (1.2 %) and 15 in FDS2 (1.0 %; P = 0.22 after age, sex and race/ethnicity adjustment). In multivariable analysis, independent associates of a baseline LEA in FDS1 were a history of vascular bypass surgery or revascularisation, urinary albumin:creatinine ratio, peripheral sensory neuropathy and cerebrovascular disease (P ≤ 0.035). In FDS2, prevalent LEA was independently associated with a history of vascular bypass surgery or revascularisation, past hospitalisation for/current foot ulcer and fasting serum glucose (P ≤ 0.001). In pooled analyses, a history of vascular bypass or revascularisation, past hospitalisation for/current foot ulcer at baseline, urinary albumin:creatinine ratio (P < 0.001), as well as FDS Phase as a binary variable [odds ratio (95 % confidence interval): 0.28 (0.09-0.84) for FDS2 vs FDS1, P = 0.023] were associated with a lower risk of LEA at study entry. CONCLUSIONS: The risk of prevalent LEA in two cohorts of patients with type 2 diabetes from the same Australian community fell by 72 % over a 15-year period after adjustment for important between-group differences in diabetes-related and other variables. This improvement reflects primary care foot health-related initiatives introduced between Phases, and should have important individual and societal benefits against a background of a progressively increasing diabetes burden.

Physical activity and vascular disease in a prospective cohort study of older men: The Health In Men Study (HIMS).

BACKGROUND: The dose-response relationship between volume of physical activity and incidence of major vascular events at older age is unclear. We aimed to investigate this association in a cohort of older men. METHODS: For this prospective cohort study, 7564 men aged 65-83 years and without prior vascular disease were recruited in 1996-99 from the general population in Perth, Western Australia. Men were followed up using the Western Australian Data Linkage System to identify deaths and hospitalisations. During mean follow-up of 11 (SD 4) years, there were 1557 first major vascular events: 833 ischaemic heart disease events, 551 stroke events and 173 other vascular events. Cox regression was used to calculate hazard ratios (adjusted for age, education and smoking) for incidence of major vascular events by volume of baseline recreational physical activity (measured in metabolic equivalent [MET] hours per week). RESULTS: Hazard ratios among men who performed 0, 1-14, 15-24, 25-39, ≥40 MET-hours per week of recreational physical activity were 1.00 (95% CI 0.91-1.10; referent), 0.88 (0.79-1.00), 0.81 (0.72-0.91), 0.81 (0.72-0.91) and 0.80 (0.71-0.89), respectively (P(trend) =0.006). The association was slightly attenuated with further adjustment for BMI. There was evidence of stronger associations at older ages and greater intensity of activity, but no evidence of effect modification by smoking, alcohol intake or BMI. There was also no evidence that the association varied by type of vascular event. CONCLUSIONS: Among men aged over 65 years, there was a curvilinear association between recreational physical activity and incidence of major vascular events, with an inverse association up to about 20 MET-hours per week (equivalent to 1 h of non-vigorous, or half an hour of vigorous, physical activity per day) and no evidence of further reductions in risk thereafter.

Plasma angiopoietin-1 is lower after ischemic stroke and associated with major disability but not stroke incidence.

BACKGROUND AND PURPOSE: Studies in rodent models suggest that upregulating angiopoietin-1 (Angpt1) improves stroke outcomes. The aims of this study were to assess the association of plasma Angpt1 with stroke occurrence and outcome. METHODS: Plasma Angpt1 was measured in 336 patients who had experienced a recent stroke and 321 healthy controls with no stroke history. Patients with stroke (n=285) were reassessed at 3 months and plasma Angpt1 concentration on admission compared between those with severe and minor disability as assessed by the modified Rankin scale. In a separate cohort of 4032 community-acquired older men prospectively followed for a minimum of 6 years, the association of plasma Angpt1 with stroke incidence was examined. RESULTS: Median plasma Angpt1 was 3-fold lower in patients who had experienced a recent stroke (6.42, interquartile range, 4.26-9.53 compared with 17.36; interquartile range, 14.01-22.46 ng/mL; P<0.001) and remained associated with stroke after adjustment for other risk factors. Plasma Angpt1 concentrations on admission were lower in patients who had severe disability or died at 3 months (median, 5.52; interquartile range, 3.81-8.75 ng/mL for modified Rankin scale 3-6; n=91) compared with those with minor disability (median, 7.04; interquartile range, 4.75-9.92 ng/mL for modified Rankin scale 0-2; n=194), P=0.012, and remained negatively associated with severe disability or death after adjusting for other risk factors. Plasma Angpt1 was not predictive of stroke incidence in community-dwelling older men. CONCLUSIONS: Plasma Angpt1 concentrations are low after ischemic stroke particularly in patients with poor stroke outcomes at 3 months. Interventions effective at upregulating Angpt1 could potentially improve stroke outcomes.