Comparison of three targeted approaches to screening for abdominal aortic aneurysm based on cardiovascular risk.

BACKGROUND: Abdominal aortic aneurysm (AAA) continues to be a significant health burden yet few countries have implemented a comprehensive screening programme. Screening typically places emphasis on men aged over 65 years; however, there is concern that other at-risk groups may be underidentified. The present study examined three potential screening strategies based on cardiovascular risk. METHODS: The prevalence of AAA was determined by abdominal ultrasound imaging in over 50-year-olds of either sex undergoing coronary angiography, vascular laboratory assessment of peripheral arterial disease, or community-based cardiovascular disease (CVD) event risk assessment. A fourth group, consisting of volunteers aged over 60 years who had no symptoms or signs of cardiovascular disease, was used as a comparator group. RESULTS: A total AAA prevalence of 4·4 per cent was detected across all three strategies (137 of 3142 individuals), compared with 1·0 per cent in the CVD-free group. Male sex, age and smoking were all associated with greater AAA prevalence. Although AAA prevalence was lowest using the community-based strategy, those with an AAA detected were on average 7 years younger than those with AAAs detected with the other two strategies (P < 0·001). CONCLUSION: Different strategies, based on CVD risk, resulted in AAA prevalence rates that were significantly greater than that in CVD-free individuals. This may provide opportunities for a targeted approach to community AAA screening in parts of the world where more sophisticated national screening programmes do not exist.

Twenty-eight loci that influence serum urate levels: analysis of association with gout.

OBJECTIVES: Twenty-eight genetic loci are associated with serum urate levels in Europeans. Evidence for association with gout at most loci is absent, equivocal or not replicated. Our aim was to test the loci for association with gout meeting the American College of Rheumatology gout classification criteria in New Zealand European and Polynesian case-control sample sets. METHODS: 648 European cases and 1550 controls, and 888 Polynesian (Ma¯ori and Pacific) cases and 1095 controls were genotyped. Association with gout was tested by logistic regression adjusting for age and sex. Power was adequate (>0.7) to detect effects of OR>1.3. RESULTS: We focused on 24 loci without previous consistent evidence for association with gout. In Europeans, we detected association at seven loci, one of which was the first report of association with gout (IGF1R). In Polynesian, association was detected at three loci. Meta-analysis revealed association at eight loci-two had not previously been associated with gout (PDZK1 and MAF). In participants with higher Polynesian ancestry, there was association in an opposing direction to Europeans at PRKAG2 and HLF (HLF is the first report of association with gout). There was obvious inconsistency of gout association at four loci (GCKR, INHBC, SLC22A11, SLC16A9) that display very similar effects on urate levels. CONCLUSIONS: We provide the first evidence for association with gout at four loci (IGF1R, PDZK1, MAF, HLF). Understanding why there is lack of correlation between urate and gout effect sizes will be important in understanding the aetiology of gout.

Evaluation of the accuracy of aorta scan BVI 9600 in screening for abdominal aortic aneurysm.

OBJECTIVES: Despite a decreasing incidence of abdominal aortic aneurysm (AAA), the cost-effectiveness of AAA ultrasound screening can be improved by reducing the screening costs and increasing the uptake rates. The BVI 9600 (BVI) is a promising tool for this purpose as it is inexpensive and can detect AAA without a trained operator. This study aims to investigate whether the BVI can be used to detect AAA for the purpose of a low-cost outreach screening approach. METHODS: A total of 142 subjects had their abdominal aortae measured by five sonographers using the BVI and a conventional ultrasound machine. The examination included four anterior-posterior measurements at four equally spaced scanning locations from the xiphisternum to the umbilicus. The measurements produced by each machine were compared using Bland-Altman plots, followed by an analysis of the AAA detection performance. RESULTS: The BVI measured the aortic diameter to within 0.88-1.56 cm of the true diameter, exceeding the 0.5 cm "clinically acceptable difference" (CAD). Its accuracy was poorer when measuring the aneurysmal aortae (mean difference -0.56 cm, variability 1.72 cm) than normal aortae (mean difference 0.02 cm, variability 0.76 cm). Nine out of 52 aneurysms were not detected due to undersizing measurement and non-visualization of the aortae. CONCLUSIONS: At present, the BVI is not sufficiently accurate to detect AAA for screening purposes. A number of technical features require improvement.

Intra-individual changes of active matrix metalloproteinase-9 are associated with clinical in-stent restenosis of bare metal stents.

OBJECTIVES: Increased chronic postprocedural levels of active matrix metalloproteinase-9 (MMP-9) have been associated retrospectively with a history of in-stent restenosis (ISR). This study aimed to determine whether index or post-percutaneous coronary intervention (PCI) plasma levels of active MMP-9 are a predictor of subsequent clinical ISR, in a standard population of patients treated with bare metal coronary stents. METHODS: Four hundred thirty-two patients were prospectively recruited and sampled at index and 3 and 6 months after PCI. Those who developed symptomatic angiographically confirmed ISR were compared to randomly selected, asymptomatic controls, stratified by index presentation in a nested case-control design. Plasma samples were analyzed for the active form of MMP-9. RESULTS: In all, 35 patients (8.1%) developed ISR, and these were compared to 98 controls. The increase in active MMP-9 over 3 months was significantly greater in the ISR group (p = 0.030) and independent of the established risk factors. Index clinical presentation was not associated with acute changes in active MMP-9; however, patients with ST-elevation myocardial infarction had greater increases in active MMP-9 at 3 months. CONCLUSIONS: The change in active MMP-9 over 3 months after bare metal coronary stent placement appears to be independently associated with the development of ISR in a standard PCI population.

Evidence for a genetic role in varicose veins and chronic venous insufficiency.

There is a strong body of circumstantial evidence which implicates genetics in the aetiology and pathology of varicose veins and venous ulcer disease. The aim of this review is to consider the current knowledge of the genetic associations and the ways in which new genetic technologies may be applied to advancing our understanding of the cause and progression of these venous diseases. A number of publications have used a candidate gene approach to identify genes implicated in venous disease. Although these studies have opened up important new insights, there has been a general failure to replicate results in an independent cohort of patients. With our limited knowledge of the biological pathways involved in the pathogenesis of venous disease we are not in a strong position to formulate truly erudite a priori candidate gene hypothesis-directed studies. A genome-wide association study should therefore be considered to help further our understanding of the genetic basis of venous disease. Due to the large sample sizes required for discovery and validation, using the new generations of molecular technologies, it will be necessary to form collaborating groups in order to successfully advance the field of venous disease genetics.

Pro-MMP-9/TIMP-1 ratio correlates poorly with a direct assessment of MMP-9 activity.

OBJECTIVE: To determine if the pro-MMP-9/TIMP-1 ratio is an accurate surrogate for endogenously active MMP-9 levels. METHODS: Plasma active MMP-9, pro-MMP-9 and TIMP-1 were measured in 295 patients. RESULTS: There was a weak negative correlation between the pro-MMP-9/TIMP-1 ratio and active MMP-9. TIMP-1 was more closely correlated with active MMP-9 than pro-MMP-9. CONCLUSION: Pro-MMP-9/TIMP-1 ratio measured with ELISA is not a good surrogate measure for active MMP-9, and direct measurements of active MMP-9 are therefore recommended.

Seasonal variation and stability of matrix metalloproteinase-9 activity and tissue inhibitor of matrix metalloproteinase-1 with storage at -80°C.

OBJECTIVE: To determine whether active matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 displayed seasonal variation and were stable in storage. METHODS: Plasma active MMP-9 and TIMP-1 were measured at three time-points in 163 individuals. RESULT: There was no evidence for seasonal variation or declining levels for up to three years of storage at -80°C. CONCLUSION: Active MMP-9 and TIMP-1 appear to be stable seasonally, and in storage for at least three years.

A meta-analysis of randomized, controlled trials assessing the prophylactic use of ceftriaxone. A study of wound, chest, and urinary infections.

BACKGROUND: Ceftriaxone is an effective prophylactic antibiotic. However, there is no consensus about whether ceftriaxone should be used as a first-line antibiotic for the prevention of incisional surgical site infection (SSI). Its role in preventing urinary tract infection (UTI) and pneumonia also is controversial. METHODS: A meta-analysis of randomized, controlled trials assessing the prophylactic use of ceftriaxone between 1983 and 2005 was performed. Medline, Embase, and Cochrane registers were reviewed. Additional references, review papers, and proceedings from meetings were searched. The Jadad score was used to assess study quality. A meta-analysis with sensitivity analyses was performed for SSI, UTI, and pneumonia. RESULTS: Of 231 reviewed papers, 90 were included. Ceftriaxone prophylaxis was superior to other antibiotics in each category. Sixty-one studies assessed the prevention of SSI (odds ratio (OR), 0.68; 95% confidence interval (CI), 0.53-0.7, p < 0.001; Cochran's Q statistic, p = 0.93). The difference was greatest for abdominal surgery. There was no difference for cardiac surgery. Thirty-five studies assessed the prevention of UTI (OR 0.53; 95% CI 0.43-0.63, p = 0; Cochran's Q statistic, p = 0.97). The difference was greatest in obstetric and gynecological and colorectal surgery. Thirty-seven studies assessed the prevention of pneumonia (OR 0.66; 95% CI 0.54-0.81, p = 0; Cochran's Q statistic, p = 0.65). The difference was greatest in upper abdominal surgery. CONCLUSIONS: The meta-analysis confirms that prophylactic ceftriaxone is more effective than most other prophylactic antibiotics. This reduces SSI, UTI, and pneumonia in procedures where there is an increased risk of these infections. In such procedures, the data support using ceftriaxone as a first-line prophylactic antibiotic.

Active matrix metalloproteinases 3 and 9 are independently associated with coronary artery in-stent restenosis.

OBJECTIVE: This study aimed to determine whether plasma levels of active matrix metalloproteinases (MMP) are predictors of in-stent restenosis (ISR) in New Zealand patients treated with bare-metal coronary stents. METHODS: A group of 152 patients with a history of ISR were compared with 151 symptom free 1-year post-stenting patients (non-ISR). Demographic and angiographic characteristics were collected. Plasma samples were analyzed for the active forms of MMP-1, -2, -3 and -9 as well as tissue inhibitor of metalloproteinases (TIMP-1) using ELISA-based isoform sensitive assays. RESULTS: Both active MMP-9 and active MMP-3 were independently associated with history of ISR. Elevated levels of both active MMP-3 and -9 had an adjusted odds ratio of 11.8 (95% CI: 4-35, p<0.0001) for association with ISR, with 37% of ISR patients having such levels versus 11% on non-ISR. The addition of both of the MMP biomarkers significantly increased the area under the curve (AUC) of a receiver operator characteristic (ROC) analysis incorporating the significant demographic and angiographic variables (AUC 0.85 versus 0.78, p<0.005). CONCLUSION: Measures of plasma active MMP isoforms appear to be independently associated with ISR, and assessment of multiple MMP markers yields cumulative utility.

Possible association between genetic polymorphisms in transforming growth factor beta receptors, serum transforming growth factor beta1 concentration and abdominal aortic aneurysm.

BACKGROUND: Previous studies have suggested a role for transforming growth factor (TGF) beta and its receptor in thoracic aortic aneurysm, but their role in abdominal aortic aneurysm (AAA) is unknown. This study examined the possible association between TGF-beta receptor 1 and 2 (TGFBR-1 and -2) single nucleotide polymorphisms (SNPs) and serum TGF-beta1 with AAA. METHODS: Serum concentrations of TGF-beta1 and 58 SNPs for TGFBR-1 and -2 were examined in 1003 and 1711 men respectively from the Health In Men Study. Validation of SNPs was examined in a second referral cohort of 1043 subjects from New Zealand, of whom 654 had an AAA. RESULTS: Serum TGF-beta1 was not associated with AAA. Only one SNP in TGFBR-2 was weakly associated with AAA; TGFBR2 g.42917C > T, SNP ID rs1078985CC; odds ratio 0.64 (95 per cent confidence interval (c.i.) 0.45 to 0.93); P = 0.020 uncorrected; but this association did not hold after adjusting for multiple testing and was not validated in the New Zealand cohort: odds ratio 0.98 (95 per cent c.i. 0.50 to 1.94); P = 0.960. CONCLUSION: These findings suggest there is no important role of genetic polymorphisms in the main receptors for TGF-beta and circulating TGF-beta1 in AAA in older individuals. (c) 2009 British Journal of Surgery Society Ltd.

Obesity and impaired venous function.

OBJECTIVES: The clinical severity of venous disease is often worse in obese patients. The objectives of this study were to compare lower limb venous physiology assessed by air plethysmography in a large group of obese and normal-weight patients; to consider the effect of posture on these measures and on foot vein pressure in a smaller cohort. METHODS: Venous function was assessed using air plethysmography and duplex scanning in 934 consecutive patients presenting for assessment of venous disease. These were grouped into obese or non-obese categories. A smaller group of twenty patients with a range of body weights were randomly selected from a database of patients with varicose veins. Foot vein pressures and femoral vein diameter were measured standing, sitting, lying and ambulating. RESULTS: Venous disease was more clinically severe in the obese limbs (CEAP C5&6 non-obese group 20.5%, obese group 35.4%, p<0.001 chi(2)). Venous reflux was worse in the obese but measures of muscle pump function were better. Residual volumes and fractions were better in the obese (mean residual volume, non-obese 60 SD 36, obese 50 SD 42, p<0.001 t test). In the smaller study group weight correlated with the diameter of the superficial femoral vein (r=0.50), ambulatory venous pressure (r=0.45), venous filling index (r=0.49) and the ejection volume (r=0.38, p<0.05). The foot venous pressure was significantly greater in the obese in all positions. CONCLUSION: The CEAP clinical stage of venous disease is more advanced in obese patients than non-obese patients with comparable anatomical patterns of venous incompetence. This may be the result of raised intra-abdominal pressure reported in previous studies, leading to greater reflux, increased vein diameter and venous pressures.

Novel rare mutations and promoter haplotypes in ABCA1 contribute to low-HDL-C levels.

The ATP-binding cassette A1 (ABCA1) protein regulates plasma high-density lipoprotein (HDL) levels. Mutations in ABCA1 can cause HDL deficiency and increase the risk of premature coronary artery disease. Single nucleotide polymorphisms (SNPs) in ABCA1 are associated with variation in plasma HDL levels. We investigated the prevalence of mutations and common SNPs in ABCA1 in 154 low-HDL individuals and 102 high-HDL individuals. Mutations were identified in five of the low-HDL subjects, three having novel variants (I659V, R2004K, and A2028V) and two with a previously identified variant (R1068H). Analysis of four SNPs in the ABCA1 gene promoter (C-564T, G-407C, G-278C, and C-14T) identified the C-14T SNP and the TCCT haplotype to be over-represented in low-HDL individuals. The R1587K SNP was over-represented in low-HDL individuals, and the V825I and I883M SNPs over-represented in high-HDL individuals. We conclude that sequence variation in ABCA1 contributes significantly to variation in HDL levels.

Drug absorption from the small intestine in immediate postoperative patients.

BACKGROUND: The effects of surgery on gastric emptying have been documented for a considerable time, but less is known about the effects in the small intestine. It is thought that there is minimal diminution in the absorptive capacity of the small intestine after operation, although there is no literature on drug absorption in the early period after surgery. This study investigated drug absorption from the small bowel in patients undergoing abdominal surgery. METHODS: A prospective study of patients undergoing major abdominal surgery in which patients acted as their own preoperative controls was carried out. Patients were administered the test substances, acetaminophen and (99m)TcDTPA, before operation and 2 days after operation. Small intestine transit times, plasma concentrations and other pharmacokinetic variables were compared using Student's paired t-test. Two complementary studies were carried out to establish pharmacokinetic parameters. RESULTS: There were no significant differences in the pre- and postoperative values of t(max), area under the curve, and area under the moment curve (AUMC) before and after operation (P>0.05). There were significant differences between the pre- and postoperative values of C(max) [C(max (preop))>C(max (postop)); P<0.05] and the pre- and postoperative values of mean residence time (MRT) [MRT((preop))

Elevated plasma active matrix metalloproteinase-9 level is associated with coronary artery in-stent restenosis.

OBJECTIVE: This study aimed to determine whether the plasma levels of matrix metalloproteinase-9 (MMP-9) or tissue inhibitor of metalloproteinases-1 (TIMP-1) were altered in patients with a history of symptomatic in-stent restenosis (ISR). METHODS AND RESULTS: A group of 158 patients with a history of ISR were compared with 128 symptom-free patients. Plasma samples and a detailed risk factor history were collected. Plasma samples were analyzed for pro-MMP-9 and latent MMP-9 and active MMP-9, latent MMP-3, and TIMP-1. Several variables were associated with ISR, including index coronary disease extent and severity (number of diseased vessels and American College of Cardiology/American Heart Association lesion classification), number, diameter, and total length of stent(s) inserted, and plasma high-density lipoprotein cholesterol. Plasma active MMP-9 (odds ratio, 1.96; 95% CI, 1.43 to 2.69) showed independent risk association with ISR. Patients with multiple sites of ISR had significantly higher levels of active MMP-9 compared with patients with only a single ISR lesion or no ISR. CONCLUSIONS: Plasma active MMP-9 levels may be a useful independent predictor of bare metal stent ISR.

The methylenetetrahydrofolate reductase C677T polymorphism does not associate with susceptibility to abdominal aortic aneurysm.

OBJECTIVES: To test whether the T variant of the C677T polymorphism in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) would associate with three distinct forms of vascular disease, abdominal aortic aneurysm (AAA), coronary artery disease (CAD) and peripheral vascular disease (PVD). BACKGROUND: Increases in homocysteine induce elastolytic activity in the arterial wall, a condition which may favour vascular pathogenesis including aneurysm formation. Homozygosity of the common T variant of the C677T polymorphism in the gene for MTHFR has been shown to associate with increased levels of homocysteine. Thus, this functional polymorphism may lead to an increased propensity to develop cardiovascular disease and, in particular, AAA. METHODS: An association study was conducted across 1207 subjects; 428 patients with AAA, 271 CAD patients, 226 PVD patients and 282 controls being genotyped for the C667T variants of MTHFR. RESULTS: There were no significant differences in the frequency of the MTHFR C677T variant between any of the groups examined. AAA patients who were homozygotes for the 677T allele did, however, appear to have significantly larger aneurysms than C allele carriers. CONCLUSION: This study provides no evidence that the T variant of MTHFR is associated with susceptibility to AAA, CAD or PVD. It may, however, be a contributory factor in AAA severity as indicated by aneurysm size.

Incidence of deep vein thrombosis after varicose vein surgery.

BACKGROUND: Varicose vein surgery is generally considered to have little risk of postoperative deep vein thrombosis (DVT). This prospective study examined the incidence of DVT in patients undergoing varicose vein surgery. METHODS: Lower leg veins were assessed before operation by duplex ultrasonography in 377 patients, and reassessed 2-4 weeks after surgery, and again at 6 and 12 months. Patients were instructed to contact a physician if symptoms consistent with DVT occurred before the scheduled follow-up appointment. Preoperative prophylaxis (a single dose of subcutaneous heparin) was left to the discretion of the vascular surgeon. RESULTS: DVT was detected in 20 (5.3 per cent) of the 377 patients. Of these, only eight were symptomatic and no patient developed symptoms consistent with pulmonary embolus. Eighteen of the 20 DVTs were confined to the calf veins. Subcutaneous heparin did not alter the outcome. No propagation of thrombus was observed and half of the DVTs had resolved without deep venous reflux at 1 year. CONCLUSION: The incidence of DVT following varicose vein surgery was higher than previously thought, but these DVTs had minimal short- or long-term clinical significance.

Micro-venous valves in the superficial veins of the human lower limb.

It is commonly believed that venous valves are not present in veins smaller than 2 mm in diameter. Venous valves, however, have been identified recently in small veins in several regions of the body. This study was undertaken to determine the size distribution of venous valves in the human lower limb micro-venous circulation. Vascular casts were made from six adult lower limbs and the sampled areas were viewed by scanning electron microscopy. In total, 2,376 valves were identified from 410 cm(3) of subcutaneous tissue. The vast majority (94%) of the valves were in veins less than 300 microm in luminal diameter, with 65% of the valves present in venous channels less than 100 microm in luminal diameter. The smallest valves identified were present in venous channels 18 microm in diameter. All valves were bicuspid and often associated with a tributary. Endothelial cells on the vein wall not associated with a valve were fusiform and arranged parallel to the long axis of the vessel, however, the endothelial cells on the luminal and valve sinus surfaces of the cusp were more polyhedral in shape and showed no obvious pattern of alignment. This study provides direct evidence to show that small superficial veins of the human lower limb do contain abundant venous valves and, for the first time, shows that the majority of these valves are present within venous channels less than 100 microm in luminal diameter.