Relationship Among Diabetes, Obesity, and Cardiovascular Disease Phenotypes: A UK Biobank Cohort Study.

OBJECTIVE: Obesity and diabetes frequently coexist, yet their individual contributions to cardiovascular risk remain debated. We explored cardiovascular disease biomarkers, events, and mortality in the UK Biobank stratified by BMI and diabetes. RESEARCH DESIGN AND METHODS: A total of 451,355 participants were stratified by ethnicity-specific BMI categories (normal, overweight, obese) and diabetes status. We examined cardiovascular biomarkers including carotid intima-media thickness (CIMT), arterial stiffness, left ventricular ejection fraction (LVEF), and cardiac contractility index (CCI). Poisson regression models estimated adjusted incidence rate ratios (IRRs) for myocardial infarction, ischemic stroke, and cardiovascular death, with normal-weight nondiabetes as comparator. RESULTS: Five percent of participants had diabetes (10% normal weight, 34% overweight, and 55% obese vs. 34%, 43%, and 23%, respectively, without diabetes). In the nondiabetes group, overweight/obesity was associated with higher CIMT, arterial stiffness, and CCI and lower LVEF (P < 0.005); these relationships were diminished in the diabetes group. Within BMI classes, diabetes was associated with adverse cardiovascular biomarker phenotype (P < 0.005), particularly in the normal-weight group. After 5,323,190 person-years follow-up, incident myocardial infarction, ischemic stroke, and cardiovascular mortality rose across increasing BMI categories without diabetes (P < 0.005); this was comparable in the diabetes groups (P-interaction > 0.05). Normal-weight diabetes had comparable adjusted cardiovascular mortality to obese nondiabetes (IRR 1.22 [95% CI 0.96-1.56]; P = 0.1). CONCLUSIONS: Obesity and diabetes are additively associated with adverse cardiovascular biomarkers and mortality risk. While adiposity metrics are more strongly correlated with cardiovascular biomarkers than diabetes-oriented metrics, both correlate weakly, suggesting that other factors underpin the high cardiovascular risk of normal-weight diabetes.

Preservation of Smooth Muscle Cell Integrity and Function: A Target for Limiting Abdominal Aortic Aneurysm Expansion?

(1) Abdominal aortic aneurysm (AAA) is a silent, progressive disease with significant mortality from rupture. Whilst screening programmes are now able to detect this pathology early in its development, no therapeutic intervention has yet been identified to halt or retard aortic expansion. The inability to obtain aortic tissue from humans at early stages has created a necessity for laboratory models, yet it is essential to create a timeline of events from EARLY to END stage AAA progression. (2) We used a previously validated ex vivo porcine bioreactor model pre-treated with protease enzyme to create "aneurysm" tissue. Mechanical properties, histological changes in the intact vessel wall, and phenotype/function of vascular smooth muscle cells (SMC) cultured from the same vessels were investigated. (3) The principal finding was significant hyperproliferation of SMC from EARLY stage vessels, but without obvious histological or SMC aberrancies. END stage tissue exhibited histological loss of α-smooth muscle actin and elastin; mechanical impairment; and, in SMC, multiple indications of senescence. (4) Aortic SMC may offer a therapeutic target for intervention, although detailed studies incorporating intervening time points between EARLY and END stage are required. Such investigations may reveal mechanisms of SMC dysfunction in AAA development and hence a therapeutic window during which SMC differentiation could be preserved or reinstated.

Developing consensus in Histopathology: the role of the Delphi method.

The Delphi method is a well-established research tool, used for consensus building across a number of fields. Despite its widespread use, and popularity in many medical specialities, there is a paucity of literature on the use of the Delphi method in Histopathology. This literature review seeks to critique the Delphi methodology and explore its potential applications to histopathology-based clinical and research questions. We review those published studies that have utilized the Delphi methodology in Histopathology settings and specifically outline the advantages and limitations of this technique, highlighting situations where its application can be most effective.

Transglutaminase 2 moderates the expansion of mouse abdominal aortic aneurysms.

OBJECTIVE: Previously published work has indicated that transcripts encoding transglutaminase 2 (TG2) increase markedly in a rat model of abdominal aortic aneurysm. This study determines whether TG2 and the related TG, factor XIII-A (FXIII-A), protect against aortic aneurysm development in mice. METHODS: C57BL/6J wild-type, Tgm2 -/- knockout, F13a1 -/- knockout, and Tgm2 -/- /F13a1 -/- double knockout mice were subjected to laparotomy and periaortic application of CaCl2. RESULTS: Tgm2 -/- mice showed slightly greater aortic dilatation at 6 weeks after treatment when compared with wild type. However, vessels from Tgm2 -/- mice, but not wild-type mice, continued to dilate up to 6 months after injury and by 24 weeks, a greater number of Tgm2 -/- mice had developed aneurysms (16/17 vs 10/19; P = .008). Laparotomy resulted in a high death rate in F13a1 -/- knockout mice, more frequently from cardiac complications than from hemorrhage, but among F13a1 -/- mice that survived for 6 weeks after CaCl2 treatment, abdominal aortic aneurysm diameter was unaltered relative to wild-type mice. Laparotomy resulted in a higher death rate among Tgm2 -/- /F13a1 -/- double knockout mice, owing to an increased frequency of delayed bleeding. Surprisingly, Tgm2 -/- /F13a1 -/- double knockout mice showed a trend toward decreased dilatation of the aorta 6 weeks after injury, and this finding was replicated in Tgm2 -/- /F13a1 -/- mice subjected to carotid artery injury. Levels of transcripts encoding TG2 were not increased in the aortas of injured wild-type or F13a1 -/- knockout mice relative to uninjured mice, although changes in the levels of other transcripts accorded with previous descriptions of the CaCl2 aneurysm model in mice. CONCLUSIONS: Knockout of Tgm2, but not F13a1 exacerbates aortic dilatation, suggesting that TG2 confers protection. However, levels of TG2 messenger RNA are not acutely elevated after injury. FXIII-A plays a role in preventing postoperative damage after laparotomy, confirming previous reports that it prevents distal organ damage after trauma. TG2 promotes wound healing after surgery and, in its absence, the bleeding diathesis associated with FXIII-A deficiency is further exposed.

Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling.

Pericytes regulate vascular development, stability, and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFRß-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited perivenous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in perivenous and periarterial plexi, and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the perivenous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease.

Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis.

Endothelial insulin receptors (Insr) promote sprouting angiogenesis, although the underpinning cellular and molecular mechanisms are unknown. Comparing mice with whole-body insulin receptor haploinsufficiency (Insr+/-) against littermate controls, we found impaired limb perfusion and muscle capillary density after inducing hind-limb ischemia; this was in spite of increased expression of the proangiogenic growth factor Vegfa. Insr+/- neonatal retinas exhibited reduced tip cell number and branching complexity during developmental angiogenesis, which was also found in separate studies of mice with endothelium-restricted Insr haploinsufficiency. Functional responses to vascular endothelial growth factor A (VEGF-A), including in vitro angiogenesis, were also impaired in aortic rings and pulmonary endothelial cells from Insr+/- mice. Human umbilical vein endothelial cells with shRNA-mediated knockdown of Insr also demonstrated impaired functional angiogenic responses to VEGF-A. VEGF-A signaling to Akt and endothelial nitric oxide synthase was intact, but downstream signaling to extracellular signal-reduced kinase 1/2 (ERK1/2) was impaired, as was VEGF receptor-2 (VEGFR-2) internalization, which is required specifically for signaling to ERK1/2. Hence, endothelial insulin receptors facilitate the functional response to VEGF-A during angiogenic sprouting and are required for appropriate signal transduction from VEGFR-2 to ERK1/2.

Autopsy in the time of COVID.

Whilst much literature has been published since the start of the COVID-19 pandemic, there remains limited knowledge of the autopsy findings following death from SARS-CoV-2 infection. The practicalities of triaging and examining bodies with suspected COVID-19 are complex and the need for full post-mortem must be balanced with the potential risks to mortuary staff. This brief case report describes the features of a COVID-19 autopsy performed at the start of the first phase of the pandemic and highlights some important learning points for trainees engaged in autopsy practice.

The role of endocarditis in sudden cardiac death: highlighting the value of the autopsy, pathological features and cardiac complications.

OBJECTIVE: Endocarditis is increasing in incidence due to growing numbers of cardiac interventions, valve replacements and immunosuppressants. It can be difficult to diagnose clinically, has high mortality and can present as sudden cardiac death (SCD) with few/subtle preceding symptoms. True incidence of SCD related to endocarditis is unknown. METHODS: Retrospective analysis of UK national database of 6000 cases of SCD, 1994-2020, for "endocarditis" as cause of death. RESULTS: Of 30 cases (0.50%), 19(63%) were male and mean age was 36.2 ± 20.1 years. Postmortem examination showed the aortic valve was solely affected in 13 (43%), mitral in 9 (30%), tricuspid in 2(6.7%) and pulmonary in 1 (3.3%). Three cases (10%) had more than one valve affected and 2 (6.7%) were nonvalvular affecting the ascending aorta. Vegetations ranged from small easily missed irregularities to large fungating masses. Ten (33%) patients developed aortic abscesses, 2 of which had aneurysms, 13 (43%) had coronary artery septic emboli with micro-abscesses and myocardial microinfarction, and 2 (6.7%) were healed endocarditis with perforation and regurgitation with ventricular remodeling. Thirteen (43%) had an identifiable underlying valve abnormality or replacement, most common being a bicuspid aortic valve (7; 54%). CONCLUSIONS: This study highlights that although rare, endocarditis is an important cause of SCD in those with normal valves, valvular disease and valve replacement surgery. Absence of a premortem diagnosis in 70% of our cohort highlights the need for detailed analysis of the heart and cardiac valves at autopsy. Gross appearance of vegetations varies widely and can be missed. Awareness of associated cardiac complications is required for elucidation of the cause of death and will provide valuable lessons for clinicians.

Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction.

Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased ß-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and ß-amyloid (Aß) are linked with vascular disease development and increased BACE1 and Aß accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased Aß, and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular Aß42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and Aß42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or Aß42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma Aß42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher Aß42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and Aß42. Lowering Aß42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes.

Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency.

BACKGROUND AND AIMS: Transglutaminase (TG) 2 and Factor (F) XIII-A have both been implicated in cardiovascular protection and repair. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect. METHODS: Atherosclerosis was assessed in brachiocephalic artery plaques of fat-fed mixed strain apolipoprotein (Apo)e deficient mice that lacked either or both transglutaminases. Cardiac fibrosis was assessed both in the mixed strain mice and also in C57BL/6J Apoe expressing mice lacking either or both transglutaminases. RESULTS: No difference was found in the density of buried fibrous caps within brachiocephalic plaques from mice expressing or lacking these transglutaminases. Cardiac fibrosis developed in both Apoe/F13a1 double knockout and F13a1 single knockout mice, but not in Tgm2 knockout mice. However, concomitant Tgm2 knockout markedly increased fibrosis, as apparent in both Apoe/Tgm2/F13a1 knockout and Tgm2/F13a1 knockout mice. Amongst F13a1 knockout and Tgm2/F13a1 knockout mice, the extent of fibrosis correlated with hemosiderin deposition, suggesting that TG2 limits the extravasation of blood in the myocardium, which in turn reduces the pro-fibrotic stimulus. The resulting fibrosis was interstitial in nature and caused only minor changes in cardiac function. CONCLUSIONS: These studies confirm that FXIII-A and TG2 fulfil different roles in the mouse myocardium. FXIII-A protects against vascular leakage while TG2 contributes to the stability or repair of the vasculature. The protective function of TG2 must be considered when designing clinical anti-fibrotic therapies based upon FXIII-A or TG2 inhibition.

Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance.

Shc homology 2-containing inositol 5' phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin signaling downstream of phosphatidylinositol 3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2Δ/+). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2Δ/+ was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls. ECs from ECSHIP2Δ/+ mice had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase, although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2Δ/+ mice, as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2Δ/+ mice, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2Δ/+ ECs and was suppressed by PI3K and NADPH oxidase 2 inhibitors. These findings were phenocopied in healthy human ECs after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction.

Cre/lox Studies Identify Resident Macrophages as the Major Source of Circulating Coagulation Factor XIII-A.

OBJECTIVE: To establish the cellular source of plasma factor (F)XIII-A. APPROACH AND RESULTS: A novel mouse floxed for the F13a1 gene, FXIII-Aflox/flox (Flox), was crossed with myeloid- and platelet-cre-expressing mice, and cellular FXIII-A mRNA expression and plasma and platelet FXIII-A levels were measured. The platelet factor 4-cre.Flox cross abolished platelet FXIII-A and reduced plasma FXIII-A to 23±3% (P<0.001). However, the effect of platelet factor 4-cre on plasma FXIII-A was exerted outside of the megakaryocyte lineage because plasma FXIII-A was not reduced in the Mpl-/- mouse, despite marked thrombocytopenia. In support of this, platelet factor 4-cre depleted FXIII-A mRNA in brain, aorta, and heart of floxed mice, where FXIII-Apos cells were identified as macrophages as they costained with CD163. In the integrin αM-cre.Flox and the double copy lysozyme 2-cre.cre.Flox crosses, plasma FXIII-A was reduced to, respectively, 75±5% (P=0.003) and 30±7% (P<0.001), with no change in FXIII-A content per platelet, further consistent with a macrophage origin of plasma FXIII-A. The change in plasma FXIII-A levels across the various mouse genotypes mirrored the change in FXIII-A mRNA expression in aorta. Bone marrow transplantation of FXIII-A+/+ bone marrow into FXIII-A-/- mice both restored plasma FXIII-A to normal levels and replaced aortic and cardiac FXIII-A mRNA, while its transplantation into FXIII-A+/+ mice did not increase plasma FXIII-A levels, suggesting that a limited population of niches exists that support FXIII-A-releasing cells. CONCLUSIONS: This work suggests that resident macrophages maintain plasma FXIII-A and exclude the platelet lineage as a major contributor.

Pericytes in diabetes-associated vascular disease.

Pericytes are mural cells that support and stabilise the microvasculature, and are present in all vascular beds. Pericyte-endothelial cell crosstalk is essential in both remodelling and quiescent vasculature, and this complex interaction is often disrupted in disease states. Pericyte loss is believed to be an early hallmark of diabetes-associated microvascular disease, including retinopathy and nephropathy. Here we review the current literature defining pericyte biology in the context of diabetes-associated vascular disease, with a particular focus on whether pericytes contribute actively to disease progression. We also speculate regarding the role of pericytes in the recovery from macrovascular complications, such as critical limb ischaemia. It becomes clear that dysfunctional pericytes are likely to actively induce disease progression by causing vasoconstriction and basement membrane thickening, resulting in tissue ischaemia. Moreover, their altered interactions with endothelial cells are likely to cause abnormal and inadequate neovascularisation in diverse vascular beds. Further research is needed to identify mechanisms by which pericyte function is altered by diabetes, with a view to developing therapeutic approaches that normalise vascular function and remodelling.

Clinical assessment of patients with peripheral arterial disease.

Peripheral arterial disease (PAD) describes the clinical manifestations of atherosclerosis affecting the circulation in the legs. The severity of PAD is classified according to symptom severity, time course, and anatomical distribution. The signs and symptoms of PAD reflect the degree of circulatory compromise and whether there has been a gradual reduction in the circulation or an abrupt, uncompensated decrease. Accurate clinical assessment underpins decisions on management strategy and should objectively assess the severity of the ischemia and need for revascularization. Clinical history should discriminate symptoms of PAD from other conditions presenting with leg pain, elucidate cardiovascular risk factors and the effect of symptoms on the patient's quality of life. Clinical examination includes signs of general cardiovascular disease and associated conditions before assessing the circulation and viability of the limb. Palpation of peripheral pulses must be augmented by determination of the ankle brachial pressure index using hand held Doppler. A whole patient approach to management is required and must include modification of cardiovascular risk status as well as dealing with the local circulatory manifestation of PAD.

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

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

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

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

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

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

Target setting for elective infra-renal AAA surgery: A single mortality figure?

OBJECTIVES: One of the key standards set by the UK NAAASP is that centres performing elective abdominal aortic aneurysm (AAA) repair have a mortality rate of <6%. In light of this, and the current aim to reduce elective AAA repair mortality to 3.5% by 2013, we sought to investigate the statistical validity of such targets. METHODS: The National Vascular Database (NVD) was interrogated and the degree of AAA missing data and its geographical variation is described. Utilising published data from 2006 to 2008 a funnel plot was used to illustrate NHS Trust level data for current estimates of mortality rate. A binomial distribution model was applied to calculate variation in observed mortality rates in relation to number of patients treated, based on a "true" mortality rate of 3.5%. Funnel plots were constructed using simulated data-sets for units performing 10, 30, 50, 100 or 150 procedures annually with control-limits calculated using a cumulative probability distribution. Finally the effect of case-mix on mortality was modelled and shown graphically. RESULTS: The NVD AAA data set shows a range of data missingness across variables (median 22%, IQR 10-64%). High levels of missingness typically coincide with non-required, non-preferred variables however this is subject to geographical variation. Funnel plots of simulated data demonstrate that smaller units have greater variability in 3-year mortality (range 0.0-10.0%) than the largest units performing 150 procedures annually (1.3-5.6%). Around 20% of NVD variables are described as "preferred", these typically relate to clinical measurements and patient medications and would inform any risk model of mortality. Data missingness amongst these variables ranges from 5 to 50%. CONCLUSIONS: There are many problems with the use of a single mortality figure to assess performance. These include the natural statistical variability and the means by which "case-mix" is taken into consideration. This article calls for further research into mortality target setting and suggests strategies which may help provide solutions nationally and facilitate international comparison.

Modeling the Growth of Infrarenal Abdominal Aortic Aneurysms.

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