Carotid-femoral pulse wave velocity is negatively correlated with aortic diameter.

Cardiovascular events pose significant morbidity and mortality burden to abdominal aortic aneurysm (AAA) patients. Arterial stiffness as measured by pulse wave velocity (PWV) is an independent predictor of cardiovascular risk. We investigated the relationship between aortic diameter and PWV. Consecutive patients with AAA were invited to participate. Patients completed a health questionnaire, received aortic ultrasound and carotid-femoral PWV (cfPWV) recordings with a Vicorder. Thirty patients were used for reproducibility assessment. A linear regression model was used to identify significant predictors of cfPWV. Observer variation was assessed using Bland and Altman analysis and the intraclass correlation coefficient. Three hundred and nine patients were included-148 with AAA and 161 controls. The mean difference for repeated cfPWV between observers was 0.11 ms(-1). cfPWV was positively correlated with age (r=0.24, P<0.001) and systolic blood pressure (r=0.29, P<0.001) and negatively correlated with aortic diameter (r=-0.15, P=0.008). There was no difference in cfPWV between AAA and control groups (9.75±2.3 ms(-1) vs. 9.55±2.3 ms(-1), P=0.43). Aortic diameter (P=0.003) and systolic blood pressure (P<0.001) were significant predictors of cfPWV independent of age, aspirin usage and a history of myocardial infarction. Patients with large AAA (>5 cm) had decreased cfPWV compared with patients with small AAA (P=0.02) or normal diameter aorta (P=0.02). Vicorder measurements of cfPWV are repeatable. cfPWV is negatively associated with infra-renal aortic diameter and reduced in large AAA. cfPWV is likely invalid for accurate arterial stiffness assessment in patients with AAA owing to the apparent confounding effect of aortic size.

Statins: the holy grail of Abdominal Aortic Aneurysm (AAA) growth attenuation? A systematic review of the literature.

BACKGROUND: In the era of Abdominal Aortic Aneurysm (AAA) screening, pharmacotherapies to attenuate AAA growth are sought. HMG Co-A reductase inhibitors (statins) have pleiotropic actions independent of their lipid lowering effects and have been suggested as potential treatment for small AAAs. We systematically review the clinical evidence for this effect. METHODS: Medline, EMBASE and the Cochrane Central Register of Controlled Trials (1950-2011) were searched for studies reporting data on the role of statin therapy on AAA growth rate. No language restrictions were placed on the search. References of retrieved articles and pertinent journals were hand searched. Included studies were reviewed by 2 independent observers. The search retrieved 164 papers, 100 were irrelevant based on their title, 47 were reviews and 1 was a letter. 8 studies were excluded based on review of their abstract leaving 8 for inclusion in the study. RESULTS: Eight observational clinical studies with a total of 4,466 patients were reviewed. Four studies demonstrated reduced AAA expansion in statin users while 4 studies failed to demonstrate this effect. The method of determining AAA growth rates varied significantly between the studies and the ability of many studies to control for misclassification bias was poor. CONCLUSIONS: The claim that statins attenuate AAA growth remains questionable. Further prospective studies with stringent identification and verification of statin usage and a standardised method of estimating AAA growth rates are required. Statin type and dose also merit consideration.

A variant in LDLR is associated with abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance. METHODS AND RESULTS: A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10(-4) were carried through to in silico replication in 1292 AAA cases and 30,503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70-0.83; P=2.08×10(-10)). CONCLUSIONS: LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.

Exploring smooth muscle phenotype and function in a bioreactor model of abdominal aortic aneurysm.

BACKGROUND: Vascular smooth muscle cells (SMC) are central to arterial structure and function yet their involvement in the progression of abdominal aortic aneurysm (AAA) disease is not well studied. The progressive and silent nature of AAA in man essentially restricts research to the use of "end-stage" tissue recovered during surgical repair. This study aimed to generate an ex vivo model of AAA using protease-treated porcine carotid arteries maintained in a novel bioreactor, and to compare the structural and functional changes in SMC cultured from the recovered vessels with those from human tissue acquired at elective surgical repair. METHODS: Freshly isolated porcine arteries were pretreated with collagenase and/or elastase before culturing under flow in a bioreactor for 12 days. Human end-stage aneurysmal tissue and saphenous veins from age-matched controls were collected from patients undergoing surgery. SMC were cultured and characterised (immunocytochemistry, measurement of spread cell area) and assessed functionally at the level of proliferation (cell-counting) and matrix-metalloproteinase (MMP) secretion (gelatin zymography). Cellular senescence was investigated using ß-galactosidase staining and apoptosis was quantified using a fluorescence-based caspase 3 assay. RESULTS: Co-expression of alpha-smooth muscle actin and smooth muscle myosin heavy chain confirmed all cell populations as SMC. Porcine SMC harvested and cultivated after collagenase/elastase pretreatment displayed a prominent "rhomboid" morphology, increased spread area (32%, P < 0.01), impaired proliferation (47% reduction, P < 0.05), increased senescence (52%, P < 0.001), susceptibility to apoptosis and reduced MMP-2 secretion (60% decrease, P < 0.01) compared with SMC from vehicle, collagenase or elastase pre-treated vessels. Notably, these changes were comparable to those observed in human AAA SMC which were 2.4-fold larger than non-aneurysmal SMC (P < 0.001) and exhibited reduced proliferation (39% reduction, P < 0.001), greater apoptosis (4-fold increase, P < 0.001), and increased senescence (61%, P < 0.05). CONCLUSIONS: Combined collagenase/elastase exposure of porcine artery maintained in a bioreactor under flow conditions induced a SMC phenotype characteristic of those cultured from end-stage AAA specimens. This model has potential and versatility to examine temporal changes in SMC biology and to identify the molecular mechanisms leading to early aberrancies in SMC function. In the longer term this may inform new targets to maintain aortic SMC content and drive cells to a "reparative" phenotype at early stages of the disease.

Plasma thrombin-antithrombin complex, prothrombin fragments 1 and 2, and D-dimer levels are elevated after endovascular but not open repair of infrarenal abdominal aortic aneurysm.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is associated with hypercoagulability, evidenced by increased markers of coagulation activation, including thrombin-antithrombin complex (TAT), prothrombin fragments 1 and 2 (F1+2), and D-dimer. Our aim was to compare the effect of endovascular aneurysm repair (EVAR) and open aneurysm repair (OAR) on changes in coagulation activation markers after intervention. METHODS: Consecutive patients with AAAs reaching their intervention threshold in a tertiary vascular referral unit in the United Kingdom were invited to participate. The coagulation markers TAT, F1+2, and D-dimer were measured in venous blood collected at baseline and at 5 months after intervention. A forward stepwise multiple linear regression model was used to identify whether treatment by OAR or EVAR had an effect on changes in coagulation factors, independent of significant covariates. RESULTS: The study included 47 patients (14 EVAR, 33 OAR; 85% men) who were a median age of 76 years (range, 69.5-80 years). Aortic diameter at intervention was 5.9 cm (range, 5.5-6.8 cm). There were no significant differences in clinical, anthropometric, or hematologic parameters between groups. At baseline, TAT (P = .13), F1+2 (P = .08), and D-dimer (P = .11) were similar in EVAR and OAR patients. Postintervention, there was a significant increase in TAT (3.0 [2.1-6.0] vs 7.2 [6.3-8.4] ng/mL; P = .03), F1+2 (242 [189-323] vs 392 [312-494] ng/mL; P = .003), and D-dimer (457 [336-615] vs 1197 [840-1509] ng/mL; P = .002) in the EVAR group. No significant changes were observed after intervention in the OAR group. CONCLUSIONS: AAA-related hypercoagulability persists after intervention, with increased TAT, F1+2, and D-dimer levels after EVAR. These findings suggest a potential period of increased cardiovascular risk in the postoperative period after EVAR.

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.

Ankle pressures in UK South Asians with diabetes mellitus: a case control study.

OBJECTIVES: To study ethnic differences in ankle pressures in South Asians versus Europeans and in those with and without diabetes mellitus (DM). DESIGN: Case control. SETTING: Primary care. PARTICIPANTS: 391(DM=154) South Asian and 252(DM=72) European adults. INTERVENTION: None. MAIN OUTCOME MEASURES: Systolic blood pressure of the left (L) and right (R) brachial, posterior tibial (PT) and dorsalis pedis (DP) arteries were measured using a Doppler probe. RESULTS: In comparison with Europeans, in young South Asians, DM was diagnosed 12 years earlier but pressures were lower, p ≤ 0.0001 for all (RPT (146 vs 157 mm Hg), LPT (143 vs 154 mm Hg), RDP (138 vs 150 mm Hg) and LDP (137 vs 149 mm Hg)). Pack year was greater in Europeans. Odds ratios of cardiovascular disease in relation to ankle pressure were increased in South Asians with ankle brachial index between 0.9 and 1.3 or >1.3. Linear regression in South Asians identified age was an independent predictor of increased pedal pressures, DM of increased RPT and LDP, and sex of LPT and LDP. In Europeans, age was an independent predictor of increased pedal pressures, and sex and pack years were independent predictors of decreased pedal pressures. In South Asians, all ankle pressure and in Europeans, RPT, LPT and LDP were increased in subjects with DM versus without. Ankle pressures and cardiovascular disease in South Asians with DM were similar to those of 10 years older Europeans with DM. CONCLUSIONS: South Asians with DM had higher ankle pressures versus without and were similar to 10 years older Europeans with DM. Prospective studies on ankle pressures for development of diabetes or cardiovascular disease are warranted in South Asians.

Modeling the Growth of Infrarenal Abdominal Aortic Aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) growth is a complex process that is incompletely understood. Significant heterogeneity in growth trajectories between patients has led to difficulties in accurately modeling aneurysm growth across cohorts of patients. We set out to compare four models of aneurysm growth commonly used in the literature and confirm which best fits the patient data of our AAA cohort. METHODS: Patients with AAA were included in the study if they had two or more abdominal ultrasound scans greater than 3 months apart. Patients were censored from analysis once their AAA exceeded 5.5 cm. Four models were applied using the R environment for statistical computing. Growth estimates and goodness of fit (using the Akaike Information Criterion, AIC) were compared, with p-values based on likelihood ratio testing. RESULTS: Of 510 enrolled patients, 264 met the inclusion criteria, yielding a total of 1861 imaging studies during 932 cumulative years of surveillance. Overall, growth rates were: (1) 0.35 (0.31,0.39) cm/yr in the growth/time calculation, (2) 0.056 (0.042,0.068) cm/yr in the linear regression model, (3) 0.19 (0.17,0.21) cm/yr in the linear multilevel model, and (4) 0.21 (0.18,0.24) cm/yr in the quadratic multilevel model at time 0, slowing to 0.15 (0.12,0.17) cm/yr at 10 years. AIC was lowest in the quadratic multilevel model (1508) compared to other models (P < 0.0001). CONCLUSION: AAA growth was heterogeneous between patients; the nested nature of the data is most appropriately modeled by multilevel modeling techniques.

Implantable versus cuffed external central venous catheters for the management of children and adolescents with acute lymphoblastic leukaemia.

PURPOSE: The aim of this study was to determine if there is a difference between complications for totally implantable central venous catheters (ports) and tunnelled external central venous catheters (external CVCs) that result in early removal of the central venous catheter (CVC) in children and adolescents with acute lymphoblastic leukaemia (ALL). METHODS: All children hospitalised between November 1996 and December 2007 with ALL who had a CVC were included retrospectively. We analysed data regarding the patient's first CVC. RESULTS: We included 322 patients. 254 received a port and 68 received an external CVC. There were 102 CVC complications that required removal of the CVC prior to the completion of chemotherapy (65 in patients with ports, 37 in patients with external CVCs). Overall complications requiring CVC removal were significantly less likely to occur in the patient's with ports (p < 0.001). Ports were significantly less likely to require removal prior to the end of treatment overall (p < 0.001) and for specific complications such as infection (p < 0.001) and dislodgement (p = 0.001). However, when adjusted for disease severity there is no difference in premature CVC removal rates. CONCLUSION: When patients are risk-stratified for disease severity there is no difference in rates of CVC removal prior to completion of treatment.

Calcium channel blockers enhance sac shrinkage after endovascular aneurysm repair.

OBJECTIVE: Sac shrinkage is a surrogate marker of success after endovascular aneurysm repair (EVAR). We set out to determine if any common cardioprotective medications had a beneficial effect on sac shrinkage. METHODS: This retrospective observational study took place at Leeds Vascular Institute, a tertiary vascular unit in the Northern United Kingdom. The cohort comprised 149 patients undergoing EVAR between January 1, 2005, and December 31, 2008. Medication use was recorded at intervention (verified at study completion in 33 patients), and patients were monitored for 2 years. The main outcome measures were the effect of medication on sac shrinkage as determined by percentage change in maximal idealized cross-sectional area of the aneurysm at 1 month, 6 months, 1 year, and 2 years by linear regression model, in addition to 2-year endoleak and death rates determined by a binary logistic regression model. RESULTS: After exclusions, 112 patients, who were a median age of 78 years (interquartile range, 78-83 years), remained for analysis. The median Glasgow Aneurysm Score was 85 (interquartile range, 79-92). At 2 years, mortality was 13.4%, endoleak developed in 37.5%, and significant endoleak developed in 14.3%. Patients taking a calcium channel blocker had enhanced sac shrinkage, compared with those not taking a calcium channel blocker, by 6.6% at 6 months (-3.0% to 16.3%, P = .09), 12.3% at 1 year (2.9% to 21.7%, P = .008), and 13.1% at 2 years (0.005% to 26.2%, P = .007) independent of other medication use, graft type, endoleak development, or death. CONCLUSIONS: Enhanced sac shrinkage occurred after EVAR in patients taking calcium channel blockers. This warrants further study in other centers and at the molecular level.

Quality and readability of online patient information for abdominal aortic aneurysms.

OBJECTIVE: We assessed the quality and readability of patient information for abdominal aortic aneurysms (AAAs) on the World Wide Web, as accessed from the United Kingdom. METHODS: Web sites returned by a simple Web search using the three largest search engines by market share were objectively and subjectively assessed for quality and readability. The Internet search engines Google, Yahoo!, and Bing were interrogated for the term "abdominal aortic aneurysm" and the first 50 hits screened. Organization type and Health on the Net status were recorded. Each unique site containing AAA information was scored for quality using the University of Michigan Consumer Health Web site Evaluation Checklist by two authors, and readability was calculated using the Flesch Reading Ease (FRE) score. Subjective content assessment was also undertaken. RESULTS: Of 150 hits, 112 were relevant, with 55 unique sites for assessment. Overall, the FRE score was 39 (range, 29-47) and the Michigan score was 36 (range, 25-56), with good interobserver agreement (r(s) = 0.83; P = .01). Michigan and FRE scores were poorly correlated (r(s) = 0.064; P = .6). Sites containing discussion on the merits of endovascular/open repair and the concept of an intervention threshold had the highest Michigan scores (58.5 [50-59.75] vs 28 [13-36.5]; P < .001). Search engine ranking, Health on the Net status, country of origin, and organization type did not affect quality or readability. CONCLUSIONS: The current quality and readability of online patient information for AAAs is poor and requires significant improvement. Clinicians treating patients with AAAs should be aware of the limitations of the online "lay literature."

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Clot architecture is altered in abdominal aortic aneurysms and correlates with aneurysm size.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterized by widening of the aorta. Once the aneurysm exceeds 5.5 cm, there is a 10% risk of death due to rupture. AAA is also associated with mortality due to other cardiovascular disease. Our aim was to investigate clot structure in AAA and its relationship to aneurysm size. METHODS AND RESULTS: Plasma was obtained from 49 controls, 40 patients with small AAA, and 42 patients with large AAA. Clot formation was studied by turbidity, fibrin pore structure by permeation, and time to half lysis by turbidity with tissue plasminogen activator. Plasma clot pore size showed a stepwise reduction from controls to small to large AAA. Lag phase for plasma clot formation and time to half lysis were prolonged, with smaller AAA samples showing intermediate response. Clot structure was normal in clots made with fibrinogen purified from patients compared with controls, suggesting a role for other plasma factors. Endogenous thrombin potential and turbidity using tissue factor indicated that the effects were independent of changes in thrombin generation. CONCLUSIONS: Patients with AAA form denser, smaller pored plasma clots that are more resistant to fibrinolysis, and these characteristics correlate with aneurysm size. Clot structure may play a role in AAA development and concomitant cardiovascular disease.

Dual transplantation of marginal kidneys from nonheart beating donors selected using machine perfusion viability criteria.

PURPOSE: Viability testing can be used to avoid the transplantation of nonheart beating donor organs that are likely to have primary nonfunction. Such testing also identifies a second group of kidneys which, although unsuitable for solitary transplantation, may be considered for dual transplantation. In kidneys in this group solitary transplants would be unlikely to produce a sufficient glomerular filtration rate to support the recipient. However, if used together as a dual transplant, they have the potential to produce sufficient renal function in 1 patient. MATERIALS AND METHODS: The group at our unit has performed 23 dual nonheart beating donor renal transplants from 2003 to date. Using 3 and 12-month post-transplantation recipient glomerular filtration rates as primary end points we compared our dual transplant group with our series of 115 single nonheart beating donor transplants from 1998 to 2006. RESULTS: At 3 and 12 months mean glomerular filtration rates in the dual group were 46.2 and 45.5 ml per minute per 1.73 m(2), respectively. These values were not significantly different from the mean glomerular filtration rates of 40.7 and 43.0 ml per minute per 1.73 m(2), respectively, in the single transplant group. CONCLUSIONS: We have observed that a subset of nonheart beating donor kidneys that do not satisfy the viability criteria for single organ transplantation may become successful dual organ grafts, thus, avoiding unnecessary organ nonuse and maximizing organ resources.