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New findings What is the central question of this study? How does resistance exercise affect peripheral haemodynamics in the active and inactive limb? What is the main finding and its importance? Preliminary data indicate that resistance exercise increases flow and shear rate in the active limb transiently. The same exercise has minimal, short-lasting influence on peripheral haemodynamics in the inactive limb, but further research is required to elaborate on resistance exercise-mediated changes in vascular function in active and inactive limbs. Abstract Current evidence indicates that to achieve maximum health benefits, regular resistance exercise should be a key component of structured physical activity. Several studies have revealed that regular resistance exercise may be associated with impaired vascular function, although this finding is inconsistent. Proposed explanations for impairment include substantial increases in blood pressure and increased retrograde blood flow in active limbs promoted by resistance exercise. However, few studies have examined the acute haemodynamics of resistance exercise in active - and even fewer in inactive - limbs. The purpose of this study was to characterise the haemodynamic responses in peripheral arteries in active and inactive limbs in response to resistance exercise using upper and lower limbs. Ten participants (five male, five female) familiar with resistance training performed three sets of 10 isotonic repetitions of right-sided bicep curls or knee extensions on separate days. Blood flow, shear rate and muscle oxygenation in the active and inactive limb, and blood pressure were measured before and for 3 min after each set. Blood flow increased in response to resistance exercise in the active limb (∼8-fold and ∼6-fold for the upper and lower limb respectively), with concurrent significant increases in mean and antegrade shear rate. In the inactive limb, blood flow more than doubled for both upper and lower limb exercise, transiently, with no significant change in retrograde shear rate. These acute blood flow profiles following resistance exercise are not indicative of long-term vessel impairment based on current understanding of blood flow and shear stress patterns.

Objective Past studies have suggested a potential “J shaped” relationship between infrarenal aortic diameter and both cardiovascular disease (CVD) prevalence and all cause mortality. However, screening programmes have focused primarily on large (aneurysmal) aortas. In addition, aortic diameter is rarely adjusted for body size, which is particularly important for women. This study aimed to investigate specifically the relationship between body size adjusted infrarenal aortic diameter and baseline prevalence of CVD. Methods A retrospective analysis was performed on a total of 4882 elderly (>50 years) participants (mean age 69.4 ± 8.9 years) for whom duplex ultrasound to assess infrarenal abdominal aortic diameters had been performed. History of CVDs, including ischaemic heart disease (IHD), and associated risk factors were collected at the time of assessment. A derivation cohort of 1668 participants was used to select cut offs at the lower and upper 12.5% tails of the aortic size distributions (aortic size index of 1.2, respectively), which was then tested in a separate cohort. Results A significantly elevated prevalence of CVD, and specifically IHD, was observed in participants with both small and large aortas. These associations remained significant following adjustment for age, sex, diabetes, hypertension, dyslipidaemia, obesity (body mass index), and smoking. Conclusion The largest and smallest infrarenal aortic sizes were both associated with prevalence of IHD. In addition to identifying those with aneurysmal disease, it is hypothesised that screening programmes examining infrarenal aortic size may also have the potential to improve global CVD risk prediction by identifying those with small aortas.

Background Obesity is a known risk factor for the development of chronic venous disease (CVD). However, some obese patients with lower limb skin changes suggestive of venous disease do not demonstrate venous reflux or obstruction. Popliteal vein compression (PVC) caused by knee hyperextension during standing has been postulated by others to be more common in the obese due to the increased adipose content of the popliteal fossa. This compression may contribute to the development of venous disease. The objective was to examine the prevalence of PVC in obese and nonobese subjects, with and without venous disease. Methods Participants were recruited across the range of Clinical-Etiology-Anatomy-Pathophysiology (CEAP) clinical classifications and body mass. Those referred for venous studies had full venous ultrasound assessments. To assess for PVC, the popliteal vein was assessed via B-mode ultrasound whilst the subject stood and performed two maneuvers: knee hyperextension and a bilateral toe stand. Video clips of each maneuver were analyzed offline. Results There were 309 limbs (158 subjects), of which 131 were nonobese (body mass index [BMI]: 26 ± 3 kg/m2) and 178 obese (BMI: 43 ± 8 kg/m2). PVC with toe stand (PVC(toe stand)) was more common in obese limbs (89% vs 64%, P Conclusions PVC(toe stand) and PVC(lock) are both functional effects and more common in obese limbs. PVC(toe stand) is likely associated with normal functioning of the calf muscle pump. Although PVC(lock) may contribute to CVD in some obese limbs, the demonstration of PVC(lock) alone is insufficient evidence for direct intervention.

Type 2 diabetes is a prominent risk factor for peripheral artery disease (PAD). Yet, the mechanistic link between diabetes and PAD remains unclear. This study proposes that dysregulation of the endogenous hormone ghrelin, a potent modulator of vascular function, underpins the causal link between diabetes and PAD. Moreover, this study aimed to demonstrate the therapeutic potential of exogenous ghrelin in a diabetic mouse model of PAD. Standard ELISA analysis was used to quantify and compare circulating levels of ghrelin between (i) human diabetic patients with or without PAD (clinic) and (ii) db/db diabetic and non-diabetic mice (lab). Db/db mice underwent unilateral hindlimb ischaemia (HLI) for 14 days and treated with or without exogenous ghrelin (150 µg/kg/day.) Subsequently vascular reparation, angiogenesis, hindlimb perfusion, structure and function were assessed using laser Doppler imaging, micro-CT, microangiography, and protein and micro-RNA (miRNA) analysis. We further examined hindlimb perfusion recovery of ghrelin KO mice to determine whether an impaired vascular response to HLI is linked to ghrelin dysregulation in diabetes. Patients with PAD, with or without diabetes, had significantly lower circulating levels of endogenous ghrelin, compared to healthy individuals. Diabetic db/db mice had ghrelin levels that were only 7% of non-diabetic mice. The vascular reparative capacity of diabetic db/db mice in response to HLI was impaired compared to non-diabetic mice and, importantly, comparable to ghrelin KO mice. Daily therapeutic treatment of db/db mice with ghrelin for 14 days post HLI, stimulated angiogenesis, and improved skeletal muscle architecture and cell survival, which was associated with an increase in pro-angiogenic miRNAs-126 and -132. These findings unmask an important role for endogenous ghrelin in vascular repair following limb ischemia, which appears to be downregulated in diabetic patients. Moreover, these results implicate exogenous ghrelin as a potential novel therapy to enhance perfusion in patients with lower limb PAD, especially in diabetics.

Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF

This study investigated whether microvenous reflux can be detected in limbs with chronic venous disease using superb microvascular imaging (SMI) and colour Doppler imaging. Participants with venous disease (limbs, n = 26) and without venous disease (limbs, n = 10) were studied. The skin in the medial gaiter region was imaged using both SMI and colour Doppler to identify reflux in the small vessels in response to distal augmentation. The diameters and depths of responsive vessels were measured. In limbs with venous disease, reflux in response to provocation was visualised with SMI in a greater number of vessels (12/26 versus 4/26) and smaller vessels than with colour Doppler. Reflux in the superficial skin veins was demonstrated in one control participant (1/10) using SMI and in none using colour Doppler (0/10). Our study indicates that microvenous reflux is demonstrable in limbs with venous disease and that SMI is more sensitive than colour Doppler.

Passive heat induces beneficial perfusion profiles, provides substantive cardiovascular strain, and reduces blood pressure, thereby holding potential for healthy and cardiovascular disease populations. The aim of this study was to assess acute responses to passive heat via lower-limb, hot-water immersion in patients with peripheral arterial disease (PAD) and healthy, elderly controls. Eleven patients with PAD (age 71 ± 6 yr, 7 male, 4 female) and 10 controls (age 72 ± 7 yr, 8 male, 2 female) underwent hot-water immersion (30-min waist-level immersion in 42.1 ± 0.6°C water). Before, during, and following immersion, brachial and popliteal artery diameter, blood flow, and shear stress were assessed using duplex ultrasound. Lower-limb perfusion was measured also using venous occlusion plethysmography and near-infrared spectroscopy. During immersion, shear rate increased ( P < 0.0001) comparably between groups in the popliteal artery (controls: +183 ± 26%; PAD: +258 ± 54%) and brachial artery (controls: +117 ± 24%; PAD: +107 ± 32%). Lower-limb blood flow increased significantly in both groups, as measured from duplex ultrasound (>200%), plethysmography (>100%), and spectroscopy, while central and peripheral pulse-wave velocity decreased in both groups. Mean arterial blood pressure was reduced by 22 ± 9 mmHg (main effect P < 0.0001, interaction P = 0.60) during immersion, and remained 7 ± 7 mmHg lower 3 h afterward. In PAD, popliteal shear profiles and claudication both compared favorably with those measured immediately following symptom-limited walking. A 30-min hot-water immersion is a practical means of delivering heat therapy to PAD patients and healthy, elderly individuals to induce appreciable systemic (chronotropic and blood pressure lowering) and hemodynamic (upper and lower-limb perfusion and shear rate increases) responses.

ObjectivesTo identify the frequency of postoperative complications, including problems identified by patients and complications occurring after discharge from hospital. To identify how these impact on quality of life (QoL) and the patient’s perception of the success of their treatment.DesignData from three prospective sources: surgical audit, a telephone interview (2 weeks after discharge) and a patient-focused questionnaire (2 months after surgery) were retrospectively analysed.SettingDunedin Hospital, Dunedin, New Zealand.ParticipantsOf the 500 patients, 100 undergoing each of the following types of surgeries: anorectal, biliary, colorectal, hernia and skin.Primary and secondary outcome measuresThe primary outcomes were complications and the 36-item Short Form Health Survey (SF-36). Secondary outcomes included the patient’s ratings of their treatment and a questionnaire-derived patient satisfaction score.Results226 patients reported a complication; there were 344 separate complications and 411 reports of complications (16% of complications were reported on more than one occasion). The audit, telephone interview and questionnaire captured 12.6%, 36.3% and 51% of the 411 reports, respectively. Patients with complications had a lower SF-36 Physical Composite Summary (PCS) score (48.5 vs 43.9, p=0.021) and a lower Patient Satisfaction Score (85.6 vs 74.6, pConclusionsFollowing surgery, over 40% of patients experienced complications. The QoL and satisfaction score were significantly less than for those without complications. The majority of complications were diagnosed after discharge from hospital. Taking more notice of the patient perspective helps us to identify problems, to understand what is important to them and may suggest ways to improve perioperative care.

Peripheral arterial disease (PAD) is characterized by lower limb atherosclerosis impairing blood supply and causing walking-induced leg pain or claudication. Adherence to traditional exercise training programs is poor due to these symptoms despite exercise being a mainstay of conservative treatment. Heat therapy improves many cardiovascular health outcomes, so this study tested if this was a viable alternative cardiovascular therapy for PAD patients. Volunteers with PAD were randomized to 12 wk of heat ( n = 11; mean age 76 ± 8 yr, BMI 28.7 ± 3.5 kg/m2, 4 females) or exercise ( n = 11; 74 ± 10 yr, 28.5 ± 6.8 kg/m2, 3 females). Heat involved spa bathing at ∼39°C, 3–5 days/wk for ≤30 min, followed by ≤30 min of callisthenics. Exercise involved ≤90 min of supervised walking and gym-based exercise, 1–2 days/wk. Following the interventions, total walking distance during a 6-min walk test increased (from ∼350 m) by 41 m (95% CI: [13, 69], P = 0.006) regardless of group, and pain-free walking distance increased (from ∼170 m) by 43 m ([22, 63], P < 0.001). Systolic blood pressure was reduced more following heat (−7 mmHg, [−4, −10], P < 0.001) than following exercise (−3 mmHg, [0, −6], P = 0.078), and diastolic and mean arterial pressure decreased by 4 mmHg in both groups ( P = 0.002). There were no significant changes in blood volume, ankle-brachial index, or measures of vascular health. There were no differences in the improvement in functional or blood pressure outcomes between heat and exercise in individuals with PAD. NEW & NOTEWORTHY Heat therapy via hot-water immersion and supervised exercise both improved walking distance and resting blood pressure in peripheral arterial disease (PAD) patients over 12 wk. Adherence to heat therapy was excellent, and the heat intervention was well tolerated. The results of the current study indicate that heat therapy can improve functional ability and has potential as an effective cardiovascular conditioning tool for individuals with PAD. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/heat-therapy-vs-exercise-in-peripheral-arterial-disease/ .

Recent reports have suggested a reproducible association between the rs11121615 SNP, located within an intron of the castor zinc finger 1 (CASZ1) gene, and varicose veins. This study aimed to determine if this variant is also differentially associated with the various clinical classifications of chronic venous disease (CVD). The rs11121615 SNP was genotyped in two independent cohorts from New Zealand (n = 1876 controls /1606 CVD cases) and the Netherlands (n = 1626/2966). Participants were clinically assessed using well-established CVD criteria. The association between the rs11121615 C-allele and varicose veins was validated in both cohorts. This was strongest in those with higher clinical severity classes and was not significant in those with non-varicose vein CVD. Functional analysis of the rs11121615 variant demonstrated that the risk allele was associated with increased enhancer activity. This study demonstrates that the CASZ1 gene associated C-allele of rs11121615 has a significant, reproducible, association with CVD (CEAP C ≥ 2 meta-odds ratio 1.31, 95% CI 1.27–1.34, P = 1 × 10−98, PHet = 0.25), but not with non-varicose vein (CEAP C1, telangiectasia or reticular veins) forms of venous disease. The effect size of this association therefore appears to be susceptible to influence by phenotypic heterogeneity, particularly if a cohort includes a large number of cases with lower severity CVD.

Ankle-brachial index (ABI) and pulse volume recordings (PVR) are non-invasive tests used in diagnosis of peripheral arterial disease (PAD). The Dopplex Ability is an automated ABI/PVR device utilising air plethysmography, offering easy and rapid PAD diagnosis. The accuracy and repeatability of the Dopplex were assessed in comparison to the Doppler/air plethysmography-based Parks Flo-Lab system.Sixty-six patients (n = 129 lower limbs) were assessed with both Dopplex and Parks systems. For Dopplex ABI and PVR to be deemed accurate, it had to be within ±10% of the Parks ABI, and the PVR grade (1-4) had to be equal. The coefficient of variation (CV) was calculated from three repeat ABI/PVR readings to assess repeatability.The Dopplex and Parks devices correlated poorly for ABI (R2 = 0.17) with only 43% of ABIs and 69% of PVRs meeting the accuracy criteria compared to the Parks values. The specificity and sensitivity were 56% and 82%, respectively for ABI, and 91% and 89%, respectively for PVRs. The Dopplex showed a significantly higher CV for both ABIs and PVRs compared to the Parks.We found the Dopplex device to demonstrate suboptimal accuracy and repeatability in assessing ABI/PVR, and it was deemed unsuitable for use in our community.

Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

We investigated the reliability of contrast-enhanced ultrasound (CEUS) in assessing calf muscle microvascular perfusion in health and disease. Response to a post-occlusive reactive hyperaemia test was repeated on two occasions >48 h apart in healthy young (28 ± 7 y) and elderly controls (70 ± 5 y), and in peripheral arterial disease patients (PAD, 69 ± 7 y; n = 10, 9 and 8 respectively). Overall, within-individual reliability was poor (coefficient of variation [CV] range: 15-87%); the most reliable parameter was time to peak (TTP, 15-48% CV). Nevertheless, TTP was twice as long in elderly controls and PAD compared to young (19.3 ± 10.4 and 22.0 ± 8.6 vs. 8.9 ± 6.2 s respectively; p < 0.01), and area under the curve for contrast intensity post-occlusion (a reflection of blood volume) was ∼50% lower in elderly controls (p < 0.01 versus PAD and young). Thus, CEUS assessment of muscle perfusion during reactive hyperaemia demonstrated poor reliability, yet still distinguished differences between PAD patients, elderly and young controls.

A proportion of patients with deep vein thrombosis (DVT) will develop postthrombotic syndrome (PTS). Currently, the only clearly identified risk factors for developing PTS are recurrent ipsilateral DVT and extensive proximal disease. The aim of the study was to assess the natural history of DVT and identify early predictors of poor clinical outcome at 5 years.Patients with suspected acute DVT in the lower limb were assessed prospectively. All patients with a confirmed DVT were asked to participate in this study. Within 7-10 days after diagnosis of DVT, patients underwent a further review, involving clinical, ultrasound, and air plethysmography assessment of both lower limbs. Patients were reassessed at regular intervals for 5 years.One hundred twenty-two limbs in 114 patients were included in this study. Thrombus regression occurred in two phases, with a rapid regression between 10 days and 3 months, and a more gradual regression thereafter. Reflux developed as thrombus regression occurred. Segmental reflux progressed to axial deep reflux and continued to deteriorate in a significant proportion of patients with iliofemoral-popliteal-calf DVT throughout the 5-year study period. Similarly, venous filling index became progressively more abnormal, in this group, over the course of the study. Four risk factors for PTS were identified as best predictors: extensive clot load on presentation;50% clot regression at 6 months; venous filling index2.5 mL/sec; and abnormal outflow rate (0.6). Patients with three or more of these risk factors had a significant risk of developing PTS with sensitivity 100%, specificity 83%, and positive predictive value 67%. Patients scoring 2 or less did not have PTS at 5 years with a negative predictive value of 100%.This is the first study to show that venous assessment at 6 months post-DVT can predict PTS at 5 years. Those who will not develop PTS can be reassured of this at 6 months.

Objective This study aimed to determine the prevalence and relevance of incidental abdominal aortic aneurysm (AAA) on routine abdominal computed tomography (CT) and to audit the performance of radiologists to identify and report AAA. Methods A retrospective audit of all abdominal CT scans performed on men and women ≥50 years at Dunedin Public Hospital between January 2013 and September 2014 was carried out. All CT scans for planning of AAA treatment or follow-up were excluded. The maximal anterior-posterior diameter of the infrarenal abdominal aorta was measured in both the sagittal and transverse planes on the picture archiving and communication system. The radiologist reports were analyzed. All detected AAAs were reviewed for clinical relevance. Results A total of 3332 scans were performed, of which 86 scans were excluded, resulting in a total cohort of 3246. There were 187 incidental AAAs detected with a prevalence of 5.8%. The prevalence was 8.7% in men and 3.1% in women. Whereas the prevalence increased with age, a significant number were detected in those younger than 65 years, with a prevalence of 1.5%. Of the 187 AAAs, 122 (65%) were reported by radiologists: 100% reporting rate in AAAs ≥50 mm, 87% in AAAs ≥40 to 49 mm, and 52% in AAAs ≥30 to 39 mm. Of these, 15% were specifically recommended for referral to a vascular service. Of the incidentally detected AAAs, 72% were considered to be clinically relevant, which is an overall 4.1% prevalence of AAAs with an ability to benefit. In addition, all 3246 subjects avoided the need for further AAA screening. Conclusions There is a high prevalence of AAAs (5.8%) and clinically relevant AAAs (4.1%) detected on routine abdominal CT. As an opportunistic approach, it is a simple and effective way to detect AAAs and to broaden traditional screening criteria to include women and those younger than 65 years in our region. Furthermore, large numbers of subjects with normal aortic diameters are identified who will not need to be screened. Consequently, we consider routine diagnostic abdominal CT to be an important adjunct to national and community AAA screening strategies.

Contains fulltext : 171388.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. METHODS: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Maori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULTS: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 x 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P 0.10). CONCLUSION: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.

Background Inflammation of the aortic wall is recognised as a key pathogenesis of abdominal aortic aneurysm ( AAA ). This study was undertaken to determine whether inflammatory cytokines could be used as biomarkers for the presence of AAA . Methods and Results Tissue profiles of 27 inflammatory cytokine were examined in AAA (n=14) and nonaneurysmal (n=14) aortic tissues. Three cytokines, regulated upon activation normally T‐cell expressed and secreted ( RANTES ), eotaxin, and macrophage inflammatory protein 1 beta ( MIP‐ 1b), had increased expression in AAA , particularly within the adventitial layer of the aortic wall. Basic fibroblast growth factor ( bFGF ) had reduced expression in all layers of the AAA wall. Examination of the circulating plasma profiles of AAA (n=442) and AAA ‐free controls (n=970) suggested a (risk factor adjusted) AAA ‐association with eotaxin, RANTES , and high sensitivity C‐reactive protein (hs CRP ). A plasma inflammatory cytokine score, calculated using these three markers, suggested a strong risk association with AAA (odds ratio, 4.8; 95% CI , 3.5–6.7; P Conclusions Contrary to reports suggesting a distinct T helper 2–associated inflammatory profile in AAA , this current study suggests a more‐generalized pattern of inflammation, albeit with some potentially distinct features, including elevated plasma eotaxin and decreased plasma RANTES . In combination with hs CRP , these markers may have potential utility as AAA biomarkers.

Introduction: Routine measurement of cardiac biomarkers such as troponin T (TnT) is recommended perioperatively, especially in high-risk vascular surgery. Long-term prognosis is worse even in those with nonspecific perioperative myocardial injury. However, a clear understanding of these biomarker profiles and how they should affect patient management is lacking. Methods: We examined the perioperative profile of high-sensitivity TnT (hsTnT) release in 85 patients undergoing elective major vascular surgery. Plasma hsTnT was measured preoperatively, at 6, 12, and 24 hours postoperatively, and then every 24 hours for a maximum of 5 days. Significant elevations in hsTnT with/without clinical indicators of ischemia were used to diagnose myocardial infarction or injury. Results: A high incidence of myocardial injury was evident (46% had elevated hsTnT); only 5% were associated with myocardial infarction, and 41% were due to myocardial injury. Conclusions: This study emphasizes the high incidence of perioperative myocardial injury and stress in vascular surgery as revealed by the use of the robust and very sensitive biomarker of myocardial damage, hsTnT. The high availability and swift development of increasingly sensitive assays allow detection of abnormal elevated hsTnT levels in a higher proportion of the population. Consequent challenges are the reduced specificity to separate acute events as well as to deduce the prognostic value of elevations due to confusing criteria; this is especially the case in a patient group with multiple comorbidities that affect hsTnT levels chronically.

BACKGROUNDSeveral sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.METHODSWe sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.RESULTSWe found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P = 1.0x10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P = 4.0x10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P = 1.8x10(-3)).CONCLUSIONSASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)

Objective Cholesterol crystals have been shown to cause inflammation, and ultimately atherosclerotic lesions through the activation of the NLRP3 inflammasome. As cholesterol crystals have also been found in the walls of patients with abdominal aortic aneurysms (AAA), it is possible that the NLRP3 inflammasome is involved in AAA and genetic variability within this protein complex could alter disease risk. The primary objective of this study was to assess whether there is genetic evidence for a role of the NLRP3 inflammasome in AAA by testing for association of AAA with functional single nucleotide polymorphisms (SNPs) in the CARD8 and NLRP3 genes. Methods AAA patients ( n =1151) and controls ( n =727) were genotyped for CARD8 SNP rs2043211 and NLRP3 SNP rs35829419 using TaqMan SNP assays. IL1-β, C-reactive protein (CRP), and lipoprotein (a) [Lp(a)] were measured in the plasma of a subset of study participants. The Kruskal–Wallis Rank test was conducted to test for differences in mean concentration of IL1-β, CRP and Lp(a). Logistic regression was used to test for interaction between CARD8 and NLRP3. Results Significantly higher mean concentration of plasma IL1-β was observed in study participants who were homozygous for the common C allele of NLRP3 rs35829419 ( p =0.010). Interaction between rs2043211 and rs35829419 was observed in this dataset ( χ 2 =6.22; p =0.044), which strengthened when adjusted for age, gender, smoking, diabetes, hypertension, and dyslipidemia ( χ 2 =14.75; p =0.012); and separately for NOD2 genotype ( χ 2 =14.06; p =0.015). Conclusion Our finding suggests genetic variability within the NLRP3 inflammasome may be important in the pathophysiology of AAA.

Decision making is a key competency of surgeons; however, how best to assess decisions and decision makers is not clearly established. The aim of the present study was to identify criteria that inform judgments about surgical trainees’ decision-making skills. A qualitative free text web-based survey was distributed to recognized international experts in Surgery, Medical Education, and Cognitive Research. Half the participants were asked to identify features of good decisions, characteristics of good decision makers, and essential factors for developing good decision-making skills. The other half were asked to consider these areas in relation to poor decision making. Template analysis of free text responses was performed. Twenty-nine (52%) experts responded to the survey, identifying 13 categories for judging a decision and 14 for judging a decision maker. Twelve features/characteristics overlapped (considered, informed, well timed, aware of limitations, communicated, knowledgeable, collaborative, patient-focused, flexible, able to act on the decision, evidence-based, and coherent). Fifteen categories were generated for essential factors leading to development of decision-making skills that fall into three major themes (personal qualities, training, and culture). The categories compiled from the perspectives of good/poor were predominantly the inverse of each other; however, the weighting given to some categories varied. This study provides criteria described by experts when considering surgical decisions, decision makers, and development of decision-making skills. It proposes a working definition of a good decision maker. Understanding these criteria will enable clinical teachers to better recognize and encourage good decision-making skills and identify poor decision-making skills for remediation.

Background: Abdominal aortic aneurysm (AAA) is an important cause of mortality for the aged, a group that has been denied surgery in the past for fear of peri-operative mortality. Is this attitude still justified? Methods: Analysis of prospectively gathered data from a vascular database. Results: 10.9% of all open AAA operations were in patients older than 79 years with an 8% mortality cate compared to 3% for younger patients. For fit elderly patients with ASA scores less than 3, mortality was just under 4%. Renal failure and wound dehiscence were more common in the elderly. Conclusion: When endovascular repair is not possible in a fit elderly patient, open surgery can be performed with acceptable results.

Background: New Zealand, like Australia, has a widely dispersed population in towns at long distances from the main centres. We set out to estimate the in-hospital mortality rate for ruptured abdominal aortic aneurysms in New Zealand and identify factors associated with mortality. Methods: Data were gathered prospectively as part of the Vascular Society of New Zealand’s continuous audit programme of all member surgeons. Data collection was validated by random record audit. In-hospital mortality of ruptured abdominal aortic aneurysms, defined as death during hospital admission irrespective of cause, was determined for the period 1993–2005. Along with other performance indicators, differences in outcomes were assessed to take into account the trend over the time period, hospital size and number of non-operative admissions. Results: Of the 740 patients admitted with a mean age of 73.9 ± 8.5 years, 78% were men and 17.8% were declined an operation. The in-hospital mortality was 48.3% and the operative mortality was 37.8%. With univariate analysis increasing patient age, American Society of Anesthesiology score, hospital size and female sex were predictors of in-hospital mortality. Only age and American Society of Anesthesiology score were independent predictors of operative mortality. Women were less likely to have surgery. Conclusion: Over the past 13 years in-hospital mortality of ruptured abdominal aortic aneurysms in New Zealand remained unchanged. In provincial hospitals the operative outcomes were satisfactory, but the reported number not offered surgery was higher.

Background— Saphenofemoral junction (SFJ) ligation has been a major component of surgical intervention for varicose veins; however, recurrence occurs in as many as 40%. Neovascularization with reconnection of the venous channels at the transected SFJ has been identified as the major cause of this recurrence. This randomized controlled study sought to evaluate mechanical suppression of neovascularization at the SFJ, with the use of a synthetic patch, to prevent recurrence after ligation surgery. Methods and Results— A total of 389 limbs (from 292 patients) were randomized into either control (SFJ ligation surgery) or patch (SFJ ligation with polytetrafluoroethylene patch of the transected SFJ) groups. All patients underwent clinical assessment, duplex imaging, and air plethysmography studies preoperatively and at 1, 6, 12, and 36 months postoperatively. The patch consistently halved the recurrence rate to 3 years postoperatively in all clinical subgroups. In those patched SFJs that still developed recurrence, evidence of neovascularization circumventing the polytetrafluoroethylene patch was observed by both ultrasound and histology. Conclusions— This study demonstrates that use of a polytetrafluoroethylene patch is an effective mechanical suppressant of neovasculogenesis at the SFJ and can be safely used as a strategy to improve long-term outcome of varicose vein surgery.

Objectives— Although polymorphic variations in genes of the RAS system have previously been associated with susceptibility to AAA, such studies have been significantly limited by small sample sizes. This study was undertaken, using the largest case series yet reported, to determine whether common genetic variants of the RAS are associated with either susceptibility or severity of AAA. Methods and Results— The frequencies of 4 common genetic variants of genes related to the renin-angiotensin system were investigated in 3 geographically distinct, but ethnically similar, case-control cohorts, resulting in comparison of 1226 AAA cases with 1723 controls. In all 3 the AGTR1 1166C allele was significantly more common in AAA patients than controls (overall adjusted OR 1.60, 95% CI 1.32 to 1.93, P =1.1×10 −6 ). Overall, the ACE ID genotype was associated with AAA (OR 1.33, 95% CI 1.06 to 1.67, P AGT 268T allele appeared to have an epistatic effect on large aneurysm size. Conclusion— This study has identified a strong and repeated association between the AGTR1 1166C allele and susceptibility to AAA, and a weaker effect associated with the ACE deletion allele, in 3 geographically distinct, but ethnically similar, case-control cohorts. This study highlights the key role of the RAS in AAA and emphasizes the need for replication and validation of results in suitable independent cohorts.

Contains fulltext : 70663.pdf (Publisher’s version ) (Closed access) Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

Background: Increased lipoprotein(a) [Lp(a)] concentrations are predictive for coronary artery disease (CAD). The risk conferred by Lp(a) for other types of vascular disease compared with CAD has not been investigated within a single population. This study aimed to investigate Lp(a) risk association for 4 different types of vascular disease (including CAD) within a predominantly white population.Methods: We used an Lp(a) ELISA that measures Lp(a) independently of apolipoprotein(a) size to measure plasma Lp(a) in patients [384 CAD, 262 peripheral vascular disease, 184 ischemic stroke (stroke), 425 abdominal aortic aneurysm] and 230 disease-free controls. We then conducted association studies with logistic regression, integrating the potential confounding effects of age, sex, diabetes, plasma lipids, and a history of previous hypertension, hypercholesterolemia, and smoking.Results: Multivariate analyses with Lp(a) concentrations of >45 nmol/L (the 75th percentile value for controls) as the clinical cutoff showed increased Lp(a) concentrations to be a risk factor for all disease groups, with adjusted odds ratios ranging from 1.96 [95% confidence interval (CI) 1.24–3.08] for CAD to 2.33 (95% CI 1.39–3.89) for PVD. The risk conferred by Lp(a) appeared to be independent of other confounders, including exposure to statin/fibrate therapies. Similar odds ratios and CIs between disease groups indicated that increased Lp(a) conferred a similar risk for all groups studied.Conclusions: Lp(a) constitutes a stable risk factor of similar magnitude for 4 major forms of vascular disease. This association was not altered by exposure to standard lipid-lowering therapy.

ObjectiveTo describe the fate of perforator veins after surgical treatment of varicose veins and factors that influence this.MethodsThis prospective study of 104 patients assessed perforator veins by using duplex ultrasound scanning in 145 limbs before superficial vein surgery for varicose veins. Veins were marked preoperatively with ultrasound guidance and ligated with an open procedure; those missed were later treated with sclerotherapy. Duplex ultrasound scans and air plethysmography were used to confirm surgical success within 1 month and to monitor recurrence at 6 months, 1 year, and 3 years.ResultsA total of 850 incompetent perforators were treated, but 5.7% were missed and required further ablation. After 3 years, 75.8% of the limbs had developed further incompetent perforators for a total of 380 incompetent perforators. The number of ultrasound-detectable competent perforators had also increased from 356 to 1047 in that time. The incompetent perforators arose by (1) new vessel formation at the site of previous ligation in 152 (40.4%), (2) changes in pre-existing perforator vessels at other sites in 225 (59.2%), and (3) vessels missed at treatment (

The purpose of this study was to test the hypothesis that cost, as well as frequency of infection, could be used to demonstrate a difference in the performance of prophylactic antibiotics. In a prospective, randomized, double-blind study, 1013 patients undergoing abdominal surgery were given 1 g of intravenous ceftriaxone (R) or cefotaxime (C) at induction of anesthesia, and an additional 500 mg of metronidazole for colorectal surgery. Infection was checked for during the hospital stay and at 30 days postoperatively. The inpatient, outpatient, and community costs of infection were prospectively collected. The frequency of wound infection for appendectomies when additional metronidazole was not administered was greater with cefotaxime (R 6%, C 18%, p0.05), but the cost of infection was the same (average cost R $994 +/- SD $1101, C $878 +/- $1318). For all other procedures, the frequency of wound infection was similar (R 8%, C 10%), but the cost was less with ceftriaxone (R $887 +/- $1743, C $2995 +/- $6592, p0.05). Ceftriaxone decreased the frequency but not the cost of chest and urinary infection (frequency R 6%, C 11%, p0.02, cost R $1273 +/- 2338, C $1615 +/- 4083). Differences in both the frequency and cost of all infection are also presented. Ceftriaxone decreased either the frequency or the cost of different postoperative infections. The cost of infection can increase the discriminatory power of trials comparing antibiotic effectiveness.

Purpose Matrix metalloproteinase-9 (MMP-9) is a potent endopeptidase with activity against both collagens and elastin. Expression of MMP-9 is elevated in vascular disease, and in particular within aneurysm tissues. This study tested the hypothesis that the functionally more active T allele of the MMP9 C-1562T polymorphism may be overrepresented in patients with abdominal aortic aneurysm (AAA) compared with control subjects and patients with atherosclerotic peripheral vascular disease (PVD). Methods Seven hundred eighty-nine unrelated persons (AAA, n=414; control subjects, n=203; PVD, n=172) were genotyped for the common C-1562T functional promoter polymorphism of the MMP9 gene. Results Genotypes containing the T allele of this polymorphism were significantly more common in patients with AAA compared with both control subjects and patients with PVD (adjusted odds ratio, 2.41 and 2.94, respectively). The greatest shift between groups was observed in male patients, with a difference of 20.6% in CT/TT genotypes. and 12.1% in T allele frequency between patients with AAA compared with patients with PVD. Conclusions This study provides further evidence to support the role of MMP-9 in the pathogenesis of AAA, and indicates that the MMP9 C-1562T functional polymorphism may represent a genetic component contributing to susceptibility to this vascular disease.

Objective We observed long-term venous ultrasound and plethysmographic changes after varicose vein surgery, to determine factors that influence recurrence. Methods and materials This observational sequential prospective study was carried out in an institutional referral center with day surgery. Subjects were 92 consecutive patients, ages 20 to 75 years, with symptomatic varicose veins in 127 limbs, who were able to complete regular assessment. Superficial varicose vein surgery included significant perforator vessels only, defined at preoperative duplex ultrasound scanning and air plethysmography. Similar follow-up assessments were performed at 3 weeks, 3 months, and 1, 3, and 5 years. Results At 3 weeks venous reflux but not muscle pump function was consistently improved in all limbs. However, inadequate surgery at the major junctions was clearly identified as contributing to recurrence of disease in 7.2% of limbs. Recurrence of varicose veins occurred in 1 of 100 limbs (1%) at the saphenofemoral junction and in 8 of 33 (25%) limbs at the saphenopopliteal junction. However, after 3 years disease recurrence at these sites had increased to 23% and 52%, respectively. Incompetent perforator vessels increased progressively in number. Clinical recurrence was 47.1%, and consistent with this was gradual deterioration in air plethysmographic measures of reflux, with physiologic recurrence (venous filling index, >2 mL/s) in 66% at 5 years. Late recurrence was predicted in limbs with multiple sites of reflux preoperatively, venous filling index greater than 2 mL/s, and some other persistent abnormality at duplex scanning at 3 weeks. There was no recurrence in 40 limbs in which these factors were normal at at 3 weeks. However, 29 of 53 limbs with normal venous filling index after operative intervention had deteriorated at 3 years. Conclusion Incomplete superficial surgery, in particular at the saphenofemoral and saphenopopliteal junctions, is a less frequent cause of recurrent disease, and neovascular reconnection and persistent abnormal venous function are the major contributors to disease recurrence.

PURPOSE: The purpose of this study was to determine the prognostic significance of occult lymph node metastases in colon cancer detected by cytokeratin 20 reverse transcription polymerase chain reaction. METHODS: Two hundred patients undergoing elective colonic resections were enrolled in the study. Lymph nodes from resected specimens were dissected fresh and assessed by both reverse transcription polymerase chain reaction and histopathology. Follow-up was undertaken for up to five years, and the major end point of death was recorded. Univariate survival analysis was performed by the log-rank method and the change-in-estimate method was used to construct multivariate analysis models for the effect of cytokeratin 20 reverse transcription polymerase chain reaction lymph node status on overall survival. RESULTS: A total of 2,317 lymph nodes from 200 patients were assessed by both histopathology and cytokeratin 20 reverse transcription polymerase chain reaction. Forty-eight of 141 (34 percent) histologically lymph node–negative patients had evidence of occult metastases by cytokeratin 20 reverse transcription polymerase chain reaction. An interim analysis was performed at a median of 42 (range, 23–75) months. Cytokeratin 20 reverse transcription polymerase chain reaction lymph node status was a highly significant predictor of overall survival (P < 0.0001) on univariate analysis. In addition, the number of reverse transcription polymerase chain reaction–positive lymph nodes was a significant predictor of survival in the histologically lymph node–negative group (P < 0.0001) on univariate analysis. On multivariate analysis cytokeratin 20 reverse transcription polymerase chain reaction lymph node status had independent prognostic significance for overall survival (P = 0.021; hazard ratio = 2.7) and the number of cytokeratin 20 reverse transcription polymerase chain reaction–positive lymph nodes was a significant predictor of overall survival in the histologically lymph node–negative group (P = 0.005; hazard ratio = 1.1–11.1). CONCLUSION: Cytokeratin 20 reverse transcription polymerase chain reaction has potential as a clinically useful marker for staging colorectal cancer. Further follow-up is required, but if the current trends continue, a study of the effect of adjuvant therapy in patients with occult metastases detected by cytokeratin 20 reverse transcription polymerase chain reaction is indicated.

A trait of vascular fragility, characterized by the formation of abrupt defects within the elastic laminae of the abdominal aorta, has been identified in Brown Norway (BN) rats. These lesions are greatly exacerbated in F1rats from a BN × New Zealand genetically hypertensive (GH) intercross, implying that the genetic background provided by the GH rat influences lesion severity. The F2progeny of the BN × GH intercross were used to identify susceptibility loci for the lesions as well as exacerbating loci. Two major quantitative trait loci (QTLs) for number of internal elastic lamina lesions were identified on rat chromosomes 5 and 10, with the maximum “log of the odds ratio” (LOD) scores at D5Rat119 (LOD 5.0) and at D10Mit2 (LOD 4.5), respectively, together contributing 33.5% to the genetic variance. Further analysis revealed that the chromosome 10 locus exhibits a dominant mode of inheritance, with BN alleles being associated with increased lesion number ( P < 0.0002) compared with GH homozygotes. This locus was in epistasis to a modifier locus on rat chromosome 2 at D2Mit14 (LOD score 2.12). A second major locus was identified on chromosome 5, exhibiting a semidominant mode of inheritance, again with the BN allele being significantly associated with increased lesion number ( P < 0.0001). Furthermore, a locus influencing lesion severity was identified on chromosome 3 wherein GH alleles associated with increased severity. This is the first study to identify susceptibility loci for vascular elastic tissue fragility.

The aim of this study was to compare the lymphatic drainage of colon cancer with the anatomic distribution of histologic and submicroscopic lymph node metastases.Patients attending for colectomy were eligible to enter the study. At the commencement of surgery, 40 MBq of 99mTc colloidal antimony sulfide in 2 ml of Patent Blue dye was injected subserosally around the tumor. Resection was completed in a standard fashion. After resection, specimens were imaged with a gamma camera to determine the site of sentinel lymph nodes, and then dissected, recording the position of the lymph nodes on an anatomic diagram. Recovered lymph nodes were bisected, one-half for routine histology and one-half for assessment by keratin 20 (K20) reverse transcription polymerase chain reaction. The kappa measure of agreement was used to assess concordance between sentinel nodes and histologic and submicroscopic metastases.Four hundred fifty-six lymph nodes were dissected from 26 tumors and evaluated using lymphoscintigraphy and lymph node mapping. Sentinel nodes were evident in 23 tumors (88 percent). The sensitivity of sentinel nodes involvement as a predictor of metastatic disease was 55 percent (95 percent confidence interval, 23-83), with a false negative (nondiagnostic) rate of 45 percent. Sentinel nodes involved the apical group in four tumors, and represented anatomic "skip" lesions in four tumors.Direct lymphatic drainage to the apical group does occur in colon cancer; however, sentinel node mapping of colon cancer by this technique is of little clinical value because of the poor concordance between lymph node metastases and sentinel nodes.

Purpose: A familial component has previously been identified in 11% to 20% of patients with abdominal aortic aneurysms (AAAs). The genetic basis of familial AAA remains elusive, however. Matrix metalloproteinases have been implicated in aneurysm development; and plasmin, a serine protease, activates metalloproteinases. Plasminogen activator inhibitor-1 (PAI-1) regulates plasmin activation through the tissue plasminogen activators. A polymorphism within the promoter area of PAI-1 has been described that modifies PAI-1 expression and consequently plasminogen activation. The 4G homozygous variant is associated with increased PAI-1 expression and consequently reduced plasmin activity and therefore may be selected against in-familial AAA. The purpose of this study was to investigate the incidence of the 4G/5G insertion/deletion polymorphism in the promoter area of the PAI-1 gene in a population with AAA. Methods: Patients seen at a tertiary referral center for repair of abdominal aortic aneurysms were recruited. DNA was extracted from blood. Primers were designed to amplify a 99 (5G)-base pair (bp) and a 98 (4G)-bp fragment bracketing the polymorphism. The 5′ primer was mutated to allow a restriction endonuclease to cleave the 5G polymorphism into a 77-bp and a 22-bp fragment. Samples were run on agarose gels and stained with ethidium bromide. Results: One hundred ninety patients with AAAs, including 39 patients with strong family histories and 163 controls were examined. The frequency of the 4G:5G alleles in the AAA population and in the control population was 0.6:0.4. However, 26% of patients with familial AAA were homozygous 5G compared with 13% of the control population. The 4G-allele frequency was 0.47 in the familial AAAs, compared with 0.62 in the nonfamilial patients ( P =.02) and 0.61 in the control population ( P =.03). Conclusion: The selection against the 4G4G genotype in the familial AAA population may indicate a role for PAI in the development of AAA in this population. (J Vasc Surg 2000;31:1026-32.)

We previously reported that plasma lipoprotein(a) [Lp(a)]1 is an independent risk factor for coronary artery disease, abdominal aortic aneurysm, peripheral arterial disease, and ischemic stroke (1). Although the exact pathophysiological role of Lp(a) has not been definitively established, both atherogenic and thrombogenic mechanisms have been proposed. In this study, we measured plasma Lp(a) in ischemic stroke patients who had been subdivided into etiologic subtypes with the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification to determine if stroke subtype is a confounder of the Lp(a) association. Ischemic stroke patients (n = 245) and arterial disease–free and stroke-free controls (n = 435) were recruited from the Otago region of New Zealand as previously reported (1). Stroke patients were placed into TOAST classification subtypes by means of a computer algorithm developed by Goldstein and colleagues(2). The TOAST subgroups were large-artery atherosclerosis (LAA), cardioembolism, small-artery occlusion (SAO), undetermined due to 2 or more causes (multiple etiologies) (ME), or undetermined etiology due to negative or incomplete evaluation. Inclusion criteria for controls were an age >52 years and no history of ischemic heart disease or stroke, including transient ischemic attack [Questionnaire for Verifying Stroke-Free Status (QVSFS) score = 0]. Plasma lipoprotein and demographic risk factors were assessed as previously described(1). The study …

Abstract —Paraoxonase is an enzyme associated with HDL in human serum that hydrolyzes oxidized phospholipids and inhibits LDL oxidation, which is an important step in atherogenesis. In animals, addition of oxidized lipids to the circulation reduces paraoxonase activity, and diets rich in oxidized fat accelerate the development of atherosclerosis. The current randomized, crossover study was designed to compare the effect of a meal rich in oxidized lipids in the form of fat that had been used for deep-frying in a fast food restaurant and a control meal rich in the corresponding unused fat on postprandial serum paraoxonase (arylesterase) activity and peroxide content of LDL and its susceptibility to copper ion catalyzed oxidation in 12 healthy men. Four hours into the postprandial period, serum paraoxonase activity had decreased significantly after the used fat meal (−17%, P =0.005) and had increased significantly after the meal rich in unused fat (14%, P =0.005). These changes were significantly ( P =0.003) different. A time-course study indicated that serum paraoxonase activity remained lower than baseline for up to 8 hours after the used fat meal. Serum apoA1 concentration tended to decrease after the unused fat meal and tended to increase after the used fat meal. These changes were different at a marginal level of significance ( P =0.07). Also, a significantly ( P =0.03) greater decrease in apoA1 content of postprandial HDL was recorded after the unused fat meal. The peroxide content of LDL tended to decrease after the used fat meal and tended to increase after the control meal. These changes were significantly ( P =0.04) different. Susceptibility of isolated LDL to copper ion oxidation and plasma levels of malondialdehyde were unchanged during the study. These data suggest that in the postprandial period after a meal rich in used cooking fat, the enzymatic protection of LDL against accumulation of peroxides and atherogenic oxidative modification may be reduced, possibly due to factors associated with apoA1, without acutely affecting the intrinsic resistance of LDL to in vitro oxidation.

Anti-Müllerian hormone (AMH) is a gonadal hormone present in the blood in men and pre-menopausal women. AMH regulates male sexual differentiation but has no putative function in adulthood. In recent studies, high AMH levels are associated with absence of cardiovascular disease in men and smaller atherosclerotic burden in monkeys. Mechanistically, AMH has downstream convergence with known regulators of the cardiovascular system, while the specific receptor for AMH is present in murine aorta and the human heart. Our primary objective was to examine whether AMH levels in healthy men correlated with the physical characteristics of their aorta. Our secondary aim was to document whether men with distinct vascular disorders expressed different levels of AMH. Serum AMH assayed by ELISA in 153 men (54–93 years) free from vascular disease inversely correlated with the ultrasonographic diameters of the distal- (r=−0.22, P=0.006) and mid-infrarenal aorta (r=−0.26, P=0.008). This association was similar in magnitude but opposite to that of body surface area (largest known determinant of aortic diameter) and independent of known cardiovascular risk factors. This relationship is specific to AMH, as inhibin B, a Sertoli cell hormone-like AMH, did not correlate with aortic diameter (r=−0.04, P=0.66) despite partially correlating with AMH. Among men with known vascular disease, higher AMH levels were associated with varicose vein disease, while men with higher levels of AMH were under-represented in the abdominal aortic aneurysm relative to the healthy cohort. These findings identify AMH as a novel putative regulator of the cardiovascular system.

Cancer following organ transplantation is a growing public health concern. We describe the first 5 years' experience of a dedicated dermatology clinic for renal transplant recipients, the first of its type in New Zealand.Data from patients seen in the clinic were collected on a nephrology/dermatology database.86 of 99 transplant recipients had a baseline dermatology assessment. Seventy-one skin cancers (45 squamous, 25 basal cell carcinomas, 1 melanoma) were found in 17 patients. Eighteen of these were an incidental finding at the baseline post-transplant examination of 7 patients: they had not been noted either by the patient or by their nephrologist. A further 44 cancers were found in 13 patients at follow-up examinations in the dedicated clinic. Squamous and basal cell carcinomas received definitive treatment after 26 and 38 days (median) respectively. A brief analysis showed this to be a cost-effective way of diagnosing and treating skin cancer in this cohort of patients.The clinic is enabling prompt diagnosis and cost-effective treatment of skin cancers developing in renal transplant recipients and is also identifying significant numbers of pre-existing skin cancers in these patients.

To compare the assessment and treatment of leg ulcers seen in the community and subsequently reviewed in an outpatient clinic, to the New Zealand Guidelines.An observational study including consecutive patients presenting to vascular surgery outpatients with at least one leg ulcer. Outcomes included the clinical descriptions of ulcers, use of an Ankle Brachial Index (ABI) test and compression therapy for mixed and venous ulcers.The study included seventy-six patients. Every ulcer had an adequate clinical description. An ABI investigation was carried out in 9.1% and 66.7% of the patients in the community and outpatient clinic, respectively. Among 31 patients with venous or mixed ulcers in the community, 7 (22.6%) were initiated on compression therapy, and 1 (3.2%) on compression bandaging. Following outpatient clinic appointments, 29 (76.3%) of the 38 patients diagnosed with venous or mixed ulcers were on compression therapy with 20 (52.6%) on compression bandaging.There are low rates of ABI measurements and initiation of compression therapy for patients with leg ulcers in the Otago regional community. This may be due to low accessibility to expertise in ABI measurements delaying initiation of compression therapy. Innovations in facilitating ABI investigation in the community and promoting the use of compression therapy are indicated.

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.

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 −4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P 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.

METHODS: We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach. RESULTS: Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I(2) = 70%, P = 1.1 × 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I(2) = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers. CONCLUSIONS: A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.

BACKGROUND: Various studies have been performed in general surgery patients comparing low molecular weight heparin (LMWH) with standard heparin (SH) for the prevention of postoperative deep vein thrombosis (DVT), revealing contradicting results. Therefore, we have compared the efficacy and safety of a LMWH for the prevention of DVT after major general surgery.PATIENTS AND METHODS: Patients received either 20 mg LMWH (enoxaparin) once daily, or 5,000 IU SH TID, starting preoperatively in a prospective, randomized, double-blind international multicenter trial. DVT was diagnosed using fibrinogen I 125 leg scanning. Major and minor bleeding were assessed clinically.RESULTS: A total of 718 patients were randomized to LMWH, and 709 patients to SH. DVT was detected in 58 LMWH-treated patients (8.1%, 95% confidence interval [CI] 6.2% to 10.3%) and in 45 patients allocated to SH (6.3%, 95% CI 4.7% to 8.4%, P > 0.05). Major bleeding complications occurred in 11 LMWH-treated patients (1.5%, 95% CI 0.8% to 2.7%) and in 18 patients to whom standard heparin was administered (2.5%, 95% CI 1.5% to 3.9%, P > 0.05). Four LMWH-treated patients (0.6%) required reoperation for bleeding as compared to 13 patients in the SH group (1.8%, P = 0.03).CONCLUSION: This LMWH appeared as effective and safe as SH. In view of its more convenient way of administration, this LMWH might be preferred for thromboprophylaxis.

Objective This prospective study sought to track the natural history of duplex ultrasound (DUS) detected varicose vein recurrence in the groin after surgical intervention during a 5-year period. Methods Patients were recruited from a previous prospective trial investigating outcomes after high ligation and stripping with and without patch saphenoplasty. Follow-up examinations of the lower limb venous systems using DUS, air plethysmography, and clinical assessment were carried out at 1, 6, 12, and 36 months. At 60 months, an additional detailed DUS scan of the groin was performed on those with recurrence, including vessel numbers, diameter, and reflux velocity, to characterize the state of this groin recurrence. Results In the 130 limbs at 5 years, ultrasound groin recurrence was detected in 82%, and visible varicose veins occurred in 83% (108 limbs). In contrast, recurrence with severe varices occurred in 47% (61 limbs) as clinical recurrence (Venous Clinical Severity Score less the stocking component >3) in 22% (29 limbs) and functional recurrence (venous filling index >2 mL/s) in 34% (43/125 limbs). The DUS pattern was junctional in 29 limbs (22%), nonjunctional in 37 limbs (29%), and mixed pattern in 40 limbs (31%). Compared with the 24 (19%) with no ultrasound-detected recurrence, severe visible varicose veins were significantly more common with each of these patterns and especially with multiple connecting vessels (odds ratio, 5.4; confidence interval, 1.5-19.5). The diameter and velocity of reflux through recurrent vessels in the groin did not correlate with disease severity, and no DUS feature in the groin was predictive of Venous Clinical Severity Score >3 or a venous filling index >2 mL/s. The appearance of DUS recurrence within the first year and other features, including residual lower leg reflux, body mass index, gender, and previous treatment, were more consistent predictors. Conclusions Early ultrasound recurrence is predominantly evidence of neovascularization and some small-vessel remodeling at the site of treatment. When it occurs, some visible varicose veins are inevitable. However, these appearances alone are not good predictors of severe clinical recurrence.

Anti-Müllerian hormone (AMH) is a gonad-specific hormone, which is extensively used as a marker of gonadal status. The level of serum AMH has a high variance in similar individuals for reasons that are unknown. The AMH gene promoter contains a vitamin D response element that may cause vitamin D status to influence serum AMH levels.The objective of the study was to determine whether serum levels of AMH are related to 25-hydroxyitamin D [25(OH)D)] status.This was a correlative and intervention study.Three cohorts of participants were analyzed; mature men (n = 113), premenopausal women (n = 33), and 5- to 6-yr-old boys (n = 74). Women were given a daily supplement of ergocalciferol, cholecalciferol, or a placebo for 6 months and provided baseline and posttreatment blood samples.Serum AMH and 25(OH)D were measured and analyzed for covariation.Serum AMH positively correlated with 25(OH)D in men (r = 0.22, P = 0.02) but not boys. Both 25(OH)D and AMH levels exhibited seasonal variation in women, with an 18% decrease in AMH levels in winter compared with summer (P = 0.01). Change in AMH level correlated with the initial AMH level and the magnitude of change in vitamin D levels (r = 0.36, P = 0.004). Cholecalciferol supplementation prevented seasonal AMH change.Vitamin D may be a positive regulator of AMH production in adults, and vitamin D deficiency may confound clinical decisions based on AMH. Vitamin D deficiency should be considered when serum AMH levels are obtained for diagnosis.

Contains fulltext : 97601.pdf (Publisher’s version ) (Closed access) 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 x 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 x 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 x 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. 9 p.

This study aimed to investigate whether the endogenous active levels of MMP-9 or tissue inhibitor of metalloproteinases-1 (TIMP-1) were related to indices of diastolic dysfunction (DD) in the setting of contemporary treatment of coronary artery disease (CAD).We prospectively studied 116 patients with CAD and preserved left ventricular LV systolic function (ejection fraction ≥ 45%). All patients were free of heart failure symptoms at recruitment and underwent percutaneous intervention (PCI) of culprit lesions. Demographic and angiographic characteristics were collected. Plasma samples were analysed for the active form of MMP-9 and TIMP-1 using enzyme-linked immunosorbent assay-based isoform sensitive assays. Conventional and tissue Doppler-echocardiographic assessment of diastolic filling was undertaken with measurements of maximal early (E) and late (A) transmitral velocities in diastole, E/A ratio, E-wave deceleration time, isovolumic relaxation time, peak systolic (S), diastolic (D) and atrial reversal velocities of pulmonary venous flow, S/D fraction, time difference between A and duration of atrial reversal flow, early diastolic peak velocities of the lateral mitral annulus (E') and E/E'. Active MMP-9 level was higher in patients with more severe phases of DD (normal [n=22]: median 0.57 ng/ml; mild [n=19] 0.83 ng/ml; mild-moderate [n=41] 0.64 ng/ml; moderate or severe [n=34] 1.63 ng/ml; p0.0001 for trend). Three month post-PCI elevated levels of active MMP-9 had an adjusted odds ratio of 11.2 (2.3-56.0, p0.004) for association with moderate or severe DD.Elevated active MMP-9 level is associated with more severe DD in patients with CAD and preserved systolic function, which may indicate abnormal extracellular matrix metabolism in myocardial ischaemia.

The role of transforming growth factor (TGF)-beta in abdominal aortic aneurysm (AAA) is controversial. The aim of this study was to assess the association of single nucleotide polymorphisms (SNPs) within TGFBR1 and TGFBR2 with AAA and infrarenal aortic diameter by combining data from previously published studies.We performed a meta-analysis using individual subject data from three independent case-control groups from Western Australia (n=1675), New Zealand (n=1209), and the Netherlands (n=1636) with 610, 601, and 693 cases of AAA (maximum infrarenal aortic diameter ≥30 mm), respectively. Data were available for two TGFBR1 (rs10819634, rs1571590) and six TGFBR2 (rs304839, rs1346907, rs1036095, rs9831477, rs9843143, rs764522) SNPs.There was marked heterogeneity between studies. The G alleles of the TGFBR2 rs764522 and rs1036095 SNPs were associated with AAA under a recessive model (OR=1.69, 95% CI 1.28-2.25, P0.001 and OR=1.59, 95% CI 1.23-2.07, P0.001) when a fixed effects model was used. Both associations remained significant after adjustment for multiple testing.This study suggests that two common genetic polymorphisms in TGFBR2 are associated with the risk of developing AAA although this association was mainly driven by findings in the Netherlands group and marked between study heterogeneity was detected.