Katherine I. Bridge

Cardiovascular risk in patients with small and medium abdominal aortic aneurysms, and no history of cardiovascular disease.

Cardiovascular disease (CVD) is the main cause of death in people with abdominal aortic aneurysm (AAA). There is little evidence that screening for AAA reduces all‐cause or cardiovascular mortality. The aim of the study was to assess whether subjects with a small or medium AAA (3·0–5·4 cm), without previous history of clinical CVD, had raised levels of CVD biomarkers or increased total mortality.

The alpha-2-antiplasmin Arg407Lys polymorphism is associated with abdominal aortic aneurysm.

INTRODUCTION Abdominal Aortic Aneurysm (AAA) involves dilatation of the abdominal aorta, with a natural history of expansion and eventual rupture. We have previously shown that AAA patients form denser clots with smaller pores, which are more resistant to fibrinolysis. The aim of this study was to use functional polymorphisms of the fibrinolytic system to identify how changes to proteins involved in fibrinolysis may play a role in the development of AAA. METHODS Caucasian subjects ≥ 55 years (602 AAA patients and 490 matched controls) were genotyped for four polymorphisms (α-2-antiplasmin α2AP Arg6Trp and Arg407Lys, Thrombin-activatable fibrinolysis inhibitor TAFI Thr325Ile and tissue plasminogen activator tPA 7351C→T). DNA was extracted from blood, and genotype identified using real time PCR. Fibrin clot structure was analysed by permeation and turbidity in a subset of patients and controls. RESULTS Genotypes across the study population were in Hardy-Weinberg Equilibrium. The two α2AP polymorphisms, Arg6Trp and Arg407Lys were in linkage disequilibrium (P<0.0001), and possession of a 407Lys allele negatively associated with AAA (odds ratio 0.833, CI95 0.7-0.991, P=0.040). The TAFI Thr325Ile and the tPA 7351C→T polymorphisms were not associated with AAA. The α2AP 407Lys allele was not associated with in-vitro fibrinolysis times in plasma from patients with AAA. CONCLUSION Possession of the α2AP 407Lys allele was negatively associated with AAA, and thus changes in α2AP may affect aneurysm growth and development. These data indicate that the regulation of plasmin activity (through binding to α2AP), rather than plasmin generation (TAFI, tPA), may play a role in AAA.

Aspirin therapy is associated with less compact fibrin networks and enhanced fibrinolysis in patients with abdominal aortic aneurysm.

Thrombotic changes in fibrin networks contribute to increased cardiovascular risk in patients with abdominal aortic aneurysm (AAA). Given that aspirin modulates the fibrin network, we aimed to determine if aspirin therapy is associated with changes in ex‐vivo fibrin clot characteristics in AAA patients and also conducted an exploratory analysis of 5‐year mortality in these individuals.

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.

External iliac artery endofibrosis in an amateur runner

Panel B A 43-year-old female amateur marathon runner presented with a 3-year history of debilitating left calf pain and paraesthesia, which had gradually progressed to affect the anterior thigh and lumbar region. This was particularly apparent on running and was relieved entirely by rest. She had no relevant past medical history and no identifiable risk factors for vascular disease. A neurological opinion was sought; however, nerve conduction studies and spinal magnetic resonance imaging were unremarkable, so she was referred for a vascular opinion. Upon referral, examination revealed a full complement of peripheral pulses with a resting ankle–brachial pressure

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.

Common FXIII and Fibrinogen Polymorphisms in Abdominal Aortic Aneurysms

Introduction Abdominal aortic aneurysms (AAA) are characterized by a progressive dilatation of the abdominal aorta, and are associated with a high risk of rupture once the dilatation exceeds 55 mm in diameter. A large proportion of AAA develops an intraluminal thrombus, which contributes to hypoxia, inflammation and tissue degradation. We have previously shown that patients with AAA produce clots with altered structure which is more resistant to fibrinolysis. The aim of this study was to investigate genetic polymorphisms of FXIII and fibrinogen in AAA to identify how changes to these proteins may play a role in the development of AAA. Methods Subjects of Western/European descent, ≥55 years of age (520 AAA patients and 449 controls) were genotyped for five polymorphisms (FXIII-A Val34Leu, FXIII-B His95Arg, FXIII-B Splice Variant (intron K nt29576C-G), Fib-A Thr312Ala and Fib-B Arg448Lys) by RT-PCR. Data were analysed by χ2 test and CubeX. Results The FXIII-B Arg95 allele associated with AAA (Relative risk - 1.240, CI 1.093–1.407, P = 0.006). There was no association between FXIII-A Val34Leu, FXIII-B Splice Variant, Fib-A Thr312Ala or Fib-B Arg448Lys and AAA. FXIII-B His95Arg and FXIII-B Splice variant (intron K nt29576C-G) were in negative linkage disequilibrium (D’ = −0.609, p = 0.011). Discussion The FXIII-B Arg95 variant is associated with an increased risk of AAA. These data suggest a possible role for FXIII in AAA pathogenesis.

Alcohol Consumption as a Risk Factor for Abdominal Aortic Aneurysm

Introduction: Abdominal aortic aneurysm (AAA) represents a major cause of death in the over 65 age group. Current evidence suggests that AAA development may be due to an immune mediated inflammatory response leading to degradation of the extracellular matrix, increased biomechanical wall stress and resultant aortic dilatation. Modifiable risk factors include hypertension and smoking; however the potential role of alcohol remains unclear. Methodology: The electronic databases EMBASE, Pubmed, Medline and Web of Science were searched using key word search terms in conjunction with Boolean operators based on the PRISMA recommendations (‘Ethanol’ OR ’alcohol‘) AND (“aneurysm” OR ’abdominal aortic aneurysm‘ OR ’AAA’). Articles considering an association between alcohol and patients with and without AAA were included, based on title, keyword and abstract screen. No limitation was imposed by year, methodology or language. Reference lists of included studies and pertinent journal contents were hand searched for additional suitable studies. Results: A total of eight articles were identified for inclusion, the majority of which were retrospective and prospective cohort studies. Five of the studies reported a positive association between alcohol and AAA; however one reported a loss of association following adjustment for confounders, including smoking. Three further studies reported no association, although in two Scandinavian studies, alcohol consumption was considerably lower compared with those reporting a positive association. Conclusion: Existing evidence is limited but may suggest a link between high levels of alcohol consumption and AAA development, whilst moderate consumption may confer some protection. Further epidemiological study is required.

Images in vascular medicine Delayed Horner’s syndrome as a presenting symptom of traumatic internal carotid artery dissection and pseudoaneurysm

Internal carotid artery (ICA) dissection is a rare complication of major trauma,1,2 typically presenting soon after injury with symptoms of major stroke.3 ICA dissections also occur following minor trauma, and may present with more trivial symptoms, typically headache associated with focal neurological signs. The classic triad of Horner’s syndrome and pain, followed by cerebral or retinal ischaemic symptoms, is present in only about 20% of patients with ICA dissection.4 In cases of major trauma, disruption of the ICA is often present on initial trauma CT scanning, or becomes apparent early following the development of symptoms suggestive of cerebral ischaemia or infarction reflecting disruption of the ICA. It appears to be much less common for ICA dissection to present with focal neurological signs late following major trauma, as in the case outlined below. A previously well 36-year-old motorcyclist was thrown from his bike into a passing car, sustaining multiple leftsided long bone and pelvic fractures which required extensive ortho-plastic reconstruction and a prolonged stay on the intensive care unit. Two left neck lacerations were explored surgically at initial presentation; the carotid sheath was intact. As the patient recovered he reported some visual loss in the left eye. Clinical examination revealed a Panel A

Effects of obesity on insulin: insulin-like growth factor 1 hybrid receptor expression and Akt phosphorylation in conduit and resistance arteries

Insulin and insulin-like growth factor-1 stimulate specific responses in arteries, which may be disrupted by diet-induced obesity. We examined (1) temporal effects of high-fat diet compared to low-fat diet in mice on insulin receptor, insulin-like growth factor-1 receptor, insulin receptor/insulin-like growth factor-1 receptor hybrid receptor expression and insulin/insulin-like growth factor-1-mediated Akt phosphorylation in aorta; and (2) effects of high-fat diet on insulin and insulin-like growth factor-1-mediated Akt phosphorylation and vascular tone in resistance arteries. Medium-term high-fat diet (5 weeks) decreased insulin-like growth factor-1 receptor expression and increased hybrid expression (~30%) only. After long-term (16 weeks) high-fat diet, insulin receptor expression was reduced by ~30%, insulin-like growth factor-1 receptor expression decreased a further ~40% and hybrid expression increased a further ~60%. Independent correlates of hybrid receptor expression were high-fat diet, duration of high-fat diet and plasma insulin-like growth factor-1 (all p < 0.05). In aorta, insulin was a more potent activator of Akt than insulin-like growth factor-1, whereas in resistance arteries, insulin-like growth factor-1 was more potent than insulin. High-fat diet blunted insulin-mediated vasorelaxation (p < 0.01) but had no effect on insulin-like growth factor-1-mediated vasorelaxation in resistance arteries. Our findings support the possibility that hybrid receptor level is influenced by nutritional and metabolic cues. Moreover, vessel-dependent effects of insulin and insulin-like growth factor-1 on vascular tone and Akt activation may have implications in treating obesity-related vascular disease.