A validated restriction enzyme ddPCR cg05575921 (AHRR) assay to accurately assess smoking exposure.

BACKGROUND & METHODS: In this study, a novel restriction enzyme (RE) digestion-based droplet digital polymerase chain reaction (ddPCR) assay was designed for cg005575921 within the AHRR gene body and compared with matching results obtained by bisulfite conversion (BIS) ddPCR and Illumina DNA methylation array. RESULTS: The RE ddPCR cg05575921 assay appeared concordant with BIS ddPCR (r2 = 0.94, P < 0.0001) and, when compared with the Illumina array, had significantly better smoking status classification performance for current versus never smoked (AUC 0.96 versus 0.93, P < 0.04) and current versus ex-smoker (AUC 0.88 versus 0.83, P < 0.04) comparisons. CONCLUSIONS: The RE ddPCR cg05575921 assay accurately predicts smoking status and could be a useful component of 'precision-medicine' chronic disease risk screening tools.

Outcomes of patients with early calcific aortic valve disease detected by clinically indicated echocardiography.

AIMS: Previous studies have demonstrated relatively slow rates of progression of early calcific aortic valve disease (CAVD), which encompasses aortic sclerosis (ASc) and mild aortic stenosis (AS). The potential evolution to clinically significant AS is unclear, and we therefore examined the long-term outcomes of patients with ASc and mild AS detected at the time of clinically indicated echocardiography. METHODS AND RESULTS: Data from initial clinically indicated echocardiograms performed between 2010 and 2018 in patients aged ≥18 years were extracted and linked to nationally collected outcome data. Those with impaired right or left systolic ventricular function or other significant left-sided valve disease were excluded. A time to first event analysis was performed with a composite primary outcome of cardiovascular death and aortic valve intervention (AVI). Of the 13 313 patients, 8973 had no CAVD, 3436 had ASc, and 455 had mild AS. The remainder had moderate or worse stenosis. Over a median follow-up period of 4.2 (interquartile range 1.8-6.7) years (and after adjustment for age and sex), those with ASc were at greater risk of the primary outcome [hazard ratio (HR) 2.9, 95% confidence interval (CI) 2.1-4.0] and need for AVI (HR 26.8, 95% CI 9.1-79.1) compared with those with no CAVD. Clinical event rates accelerated after ∼5 years in those with mild AS. CONCLUSION: Patients with ASc are >25 times more likely to require AVI than those with no CAVD, and follow-up echocardiography should be considered within 3-4 years in those with mild AS.

Gaps in current methods to detect polymorphic CpGs from Illumina Infinium human methylation microarrays and exploring their potential impact in multi-EWAS analyses.

DNA methylation (DNAm) epigenome-wide association studies (EWAS) have been performed on diverse ethnicities to discover novel biomarkers associated with various diseases, such as cancers, autoimmune diseases, and neurological disorders. However, genetic polymorphisms can influence DNAm levels resulting in methylation quantitative trait loci (meQTL). These can be either direct effects, by altering the sequence of the methylation (CpG) site itself, or, in the case of array-based measures, indirectly altering the detection probe-binding site interaction. Given that genetic variant frequencies associated with meQTL can differ between population groups, these have the potential to confound EWAS observations, particularly in multi-ethnic populations. In this study, we analysed publicly available DNA methylation profiles (450K array), consisting of 1342 individuals from 6 distinct ancestral groups. We investigate two distinct tools (GapHunter and MethylToSNP) specifically designed to identify CpG sites that may be influenced by genetic variation. Results from this aggregated trans-ancestral epigenome-wide dataset suggest that both tools fail to consistently identify not only rarer (MAF < 0.05) genetic variant effects but also more than half of sites predicted to be associated with variants with much higher allele frequencies (MAF >0.2). In addition, there is a relatively low concordance in the detection of polymorphic CpGs between GapHunter and MethylToSNP. Screening of CpG site associations from EWAS using either of these tools is unlikely to be a robust or comprehensive means of identifying all genetic variant confounding effects.

The Impact of Suprarenal Diameter on Outcomes Following Endovascular Aneurysm Repair: A Retrospective Cohort Study.

OBJECTIVES: To determine the association between suprarenal aortic diameters and complications that may be attributed to a dilating phenotype following endovascular abdominal aortic aneurysm repair. DESIGN: This study is a retrospective review. METHODS: We measured the abdominal aortas of 147 consecutive patients with a mean age of 78.5 (range 60-93) years, who had a mean Endovascular aneurysm repair (EVAR) follow-up of 3 years (6 months to 8 years) at a public Hospital. Aortic calibres measured 5 mm above the highest renal artery were recorded, patients were categorised according to suprarenal diameter; Group A: greater than 25 mm, Group B: less than or equal to 25 mm. Stent migration, aneurysmal sac growth, presence of an endoleak and its type, occlusion events, rupture, interventions and mortality, as well as clinical history and demographic data were compared between groups. RESULTS: There was a significantly higher occurrence of stent migration (11% v 0%; P = .01) in patients with larger suprarenal aortas (Group A). The occurrence of any endoleak did not differ between the groups, however, significantly more complications resulting in secondary intervention, excluding occlusions, were noted in Group A (34% vs 17%, P = .04). CONCLUSIONS: The results from this study suggest that patients with above-average suprarenal diameters (categorised as dilators) may have a higher occurrence of specific complications following EVAR. A more detailed study to establish the association of suprarenal calibre with types of complications following EVAR is warranted.

Near Infrared Fluorescence Imaging to Demonstrate Reflux in the Superficial Microvenous Network of the Leg.

OBJECTIVE: Reflux within the superficial microvenous network may play a critical role in the development of skin changes which can be associated with chronic venous insufficiency. This study aimed to determine if near infrared fluorescence (NIRF) imaging could be used to accurately determine superficial venous reflux in the leg. METHODS: A total of nine limbs were examined ex vivo from patients undergoing limb amputation for peripheral arterial disease. Cannulation of the distal great saphenous vein was used to sequentially perform Xray contrast enhanced venography, NIRF imaging, and venous corrosion casts. RESULTS: Fluorescence imaging visualised a range of different microvenous reflux patterns ex vivo, which were generally not evident by Xray venography but were consistent with retrograde resin vascular casts. These included both focal and diffuse regions of fluorescence within the skin and, consistent with previous observations, the vascular casts indicated that regions of venous reflux were typically associated with incompetent valves. CONCLUSION: The findings from this study suggest a potential method for investigating early stage superficial venous disease, prior to the appearance of visible signs of advanced venous disease, such as skin changes. However, further studies are required to confirm the in vivo clinical utility of these observations.

Genetic Predisposition to Diabetes and Abdominal Aortic Aneurysm: A Two Stage Mendelian Randomisation Study.

OBJECTIVE: Observational studies demonstrate an inverse association between type II diabetes and abdominal aortic aneurysm (AAA) for reasons that are unclear. The aim of this study was to clarify the causal association between type II diabetes predisposition and AAA using Mendelian randomisation. METHODS: Effect estimates for single nucleotide polymorphisms (SNPs) associated with diabetes were obtained from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium to construct a genetic instrumental variable. Corresponding effect estimates for associations of these SNPs with AAA were obtained from the International Aneurysm Consortium comprising six separate AAA genomewide association studies (4 972 cases and 99 858 controls). Mendelian randomisation estimates were calculated using inverse variance, weighted median, and MR-Egger methods, and compared against recently published observational estimates. RESULTS: A genetic risk score was constructed from 206 SNPs associated with diabetes. All three Mendelian randomisation models showed no effect of genetic liability to diabetes and risk of AAA (inverse variance: odds ratio 1.04 per unit higher log odds, 95% 0.98 - 1.11, p = .19; MR-Egger slope p = .33; weighted median p = .50). Results were similar after excluding the TCF7L2 locus (inverse variance p = .075). Findings from the Mendelian randomisation analysis differed from previous observational reports of an inverse association (pdif < .001). CONCLUSION: Lifelong genetic predisposition to diabetes does not appear to protect against AAA. These findings differ from traditional epidemiological studies showing an inverse association between diabetes and AAA, for reasons that remain unclear.

Systematic review of genome-wide association studies of abdominal aortic aneurysm.

BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) is an important cause of death worldwide and has an estimated heritability between 70 and 77%. Genome-wide association studies (GWAS) are an established way to discover genetic risk variants. The aim of this study was to systematically review the findings and quality of previous AAA GWAS. METHODS: The Medline, PubMed, Web of Science and relevant genetic databases were searched to identify previous AAA GWAS. A framework was developed to grade the methodological quality of the GWAS. Data from included studies were extracted to assess methods and findings. RESULTS: Eight case-control studies were included. Thirty-three of the 38 total single nucleotide polymorphisms (SNPs) previously reported were associated with AAA diagnosis at genome-wide significance (p < 5.0 × 10-8). The CDKN2B antisense RNA-1 gene had the most significant association with AAA diagnosis (p = 6.94 × 10-29 and p = 1.54 × 10-33 for rs4007642 and rs10757274 respectively). Age, sex and smoking history were not reported for the complete cohort in any of the included studies, although five of the eight studies adjusted or matched for at least two confounding variables. All included studies had important design limitations including lack of sample size estimation, inconsistent case and control ascertainment and limited phenotyping of the AAAs. AAA growth was assessed in one GWAS, however, no significant associations with the reported SNPs were found. CONCLUSIONS: This systematic review identified 33 SNPs associated with AAA diagnosis at genome-wide significance previously validated in multiple cohorts. The association between SNPs and AAA growth was not adequately examined. Previous GWAS have a number of design limitations.

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program.

BACKGROUND: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. METHODS: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. RESULTS: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. CONCLUSIONS: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Both Small and Large Infrarenal Aortic Size is Associated with an Increased Prevalence of Ischaemic Heart Disease.

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 <0.84 and >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.

Upregulation of microRNA-532 enhances cardiomyocyte apoptosis in the diabetic heart.

Type 2 diabetes has a strong association with the development of cardiovascular disease, which is grouped as diabetic heart disease (DHD). DHD is associated with the progressive loss of cardiovascular cells through the alteration of molecular signalling pathways associated with cell death. In this study, we sought to determine whether diabetes induces dysregulation of miR-532 and if this is associated with accentuated apoptosis. RT-PCR analysis showed a significant increase in miR-532 expression in the right atrial appendage tissue of type 2 diabetic patients undergoing coronary artery bypass graft surgery. This was associated with marked downregulation of its anti-apoptotic target protein apoptosis repressor with caspase recruitment domain (ARC) and increased TUNEL positive cardiomyocytes. Further analysis showed a positive correlation between apoptosis and miR-532 levels. Time-course experiments in a mouse model of type 2 diabetes showed that diabetes-induced activation of miR-532 occurs in the later stage of the disease. Importantly, the upregulation of miR-532 preceded the activation of pro-apoptotic caspase-3/7 activity. Finally, inhibition of miR-532 activity in high glucose cultured human cardiomyocytes prevented the downregulation of ARC and attenuated apoptotic cell death. Diabetes induced activation of miR-532 plays a critical role in accelerating cardiomyocytes apoptosis. Therefore, miR-532 may serve as a promising therapeutic agent to overcome the diabetes-induced loss of cardiomyocytes.

Ribose-cysteine protects against the development of atherosclerosis in apoE-deficient mice.

Ribose-cysteine is a synthetic compound designed to increase glutathione (GSH) synthesis. Low levels of GSH and the GSH-dependent enzyme, glutathione peroxidase (GPx), is associated with cardiovascular disease (CVD) in both mice and humans. Here we investigate the effect of ribose-cysteine on GSH, GPx, oxidised lipids and atherosclerosis development in apolipoprotein E-deficient (apoE-/-) mice. Female 12-week old apoE-/- mice (n = 15) were treated with 4-5 mg/day ribose-cysteine in drinking water for 8 weeks or left untreated. Blood and livers were assessed for GSH, GPx activity and 8-isoprostanes. Plasma alanine transferase (ALT) and lipid levels were measured. Aortae were quantified for atherosclerotic lesion area in the aortic sinus and brachiocephalic arch and 8-isoprostanes measured. Ribose-cysteine treatment significantly reduced ALT levels (p<0.0005) in the apoE-/- mice. Treatment promoted a significant increase in GSH concentrations in the liver (p<0.05) and significantly increased GPx activity in the liver and erythrocytes of apoE-/-mice (p<0.005). The level of 8-isoprostanes were significantly reduced in the livers and arteries of apoE-/- mice (p<0.05 and p<0.0005, respectively). Ribose-cysteine treatment showed a significant decrease in total and low density lipoprotein (LDL) cholesterol (p<0.05) with no effect on other plasma lipids with the LDL reduction likely through upregulation of scavenger receptor-B1 (SR-B1). Ribose-cysteine treatment significantly reduced atherosclerotic lesion area by >50% in both the aortic sinus and brachiocephalic branch (p<0.05). Ribose-cysteine promotes a significant GSH-based antioxidant effect in multiple tissues as well as an LDL-lowering response. These effects are accompanied by a marked reduction in atherosclerosis suggesting that ribose-cysteine might increase protection against CVD.

A non-coding genetic variant associated with abdominal aortic aneurysm alters ERG gene regulation.

Abdominal aortic aneurysm (AAA) is a major cause of sudden death in the elderly. While AAA has some overlapping genetic and environmental risk factors with atherosclerosis, there are substantial differences, and AAA-specific medication is lacking. A recent meta-analysis of genome-wide association studies has identified four novel single-nucleotide polymorphisms (SNPs) specifically associated with AAA. Here, we investigated the gene regulatory function for one of four non-coding SNPs associated with AAA, rs2836411, which is located in an intron of the ERG gene. Rs2836411 resides within a >70 kb super-enhancer that has high levels of H3K27ac and H3K4me1 in vascular endothelial and haematopoietic cell types. Enhancer luciferase assays in cell lines showed that the risk allele significantly alters enhancer activity. The risk allele also correlates with reduced ERG expression in aortic and other vascular tissues. To identify whether rs2836411 directly contacts the promoters of ERG and/or of genes further away, we performed allele-specific circular chromosome conformation capture sequencing. In vascular endothelial cells, which express ERG, the SNP region interacts highly within the super-enhancer, while in vascular smooth muscle cells, which do not express ERG, the interactions are distributed across a wider region that includes neighbouring genes. Furthermore, the risk allele has fewer interactions within the super-enhancer compared to the protective allele. In conclusion, our results indicate that rs2836411 likely affects ERG expression by altering enhancer activity and changing local chromatin interactions. ERG is involved in vascular development, angiogenesis, and inflammation in atherosclerosis; therefore mechanistically, rs2836411 could contribute to AAA by modulating ERG levels.

Correcting for Body Surface Area Identifies the True Prevalence of Abdominal Aortic Aneurysm in Screened Women.

OBJECTIVE: Recently, the prevalence of abdominal aortic aneurysm (AAA) using screening strategies based on elevated cardiovascular disease (CVD) risk was reported. AAA was defined as a diameter ≥30 mm, with prevalence of 6.1% and 1.8% in men and women respectively, consistent with the widely reported AAA predominant prevalence in males. Given the obvious differences in body size between sexes this study aimed to re-evaluate the expanded CVD risk based AAA screening dataset to determine the effect of body size on sex specific AAA prevalence. METHODS: Absolute (26 and 30 mm) and relative (aortic size index [ASI] equals the maximum infrarenal aorta diameter (cm) divided by body surface area (m2), ASI ≥ 1.5) thresholds were used to assess targeted AAA screening groups (n = 4115) and compared with a self reported healthy elderly control group (n = 800). RESULTS: Male AAA prevalence was the same using either the 30 mm or ASI ≥1.5 aneurysm definitions (5.7%). In females, AAA prevalence was significantly different between the 30 mm (2.4%) and ASI ≥ 1.5 (4.5%) or the 26 mm (4.4%) thresholds. CONCLUSION: The results suggest the purported male predominance in AAA prevalence is primarily an artefact of body size differences. When aortic size is adjusted for body surface area there is only a modest sex difference in AAA prevalence. This observation has potential implications in the context of the ongoing discussion regarding AAA screening in women.

Development and Validation of a Predictive Model to Aid in the Management of Intact Abdominal Aortic Aneurysms.

OBJECTIVE/BACKGROUND: Predicting outcomes prior to elective abdominal aortic aneurysm repair (AAA) requires critical decision making, as the treatment offered is a prophylactic procedure to prevent death from a ruptured AAA. The aim of this work was to develop and validate a model that may predict outcomes for patients with an AAA and hence aid in clinical decision making. METHODS: A discrete event simulation model was built to simulate the natural history of a patient with an AAA and to predict the 30 day and 2-5 year survival of patients undergoing treatment and surveillance. The input parameters of AAA behavior and impact of comorbidities on survival were derived from the published literature and the New Zealand national life tables. The model was externally validated using a cohort of patients that underwent AAA repair (n = 320) and a cohort of patients undergoing small AAA surveillance (n = 376). All patients had completed at least 5 years of follow up. RESULTS: The model was run three times for each data set to test. This produced a SD < 1%, indicating excellent reproducibility. The observed 30 day mortality for the patients undergoing AAA repair was 9/320 (2.8%) and the expected (model predicted) mortality was 3.8% (c-statistic 0.87 [95 confidence interval 0.75-1.0]). The c-statistic for the predicted 2-5 year survival ranged from 0.68 to 0.71 for the repaired AAA cohort and 0.69 to 0.73 for patients with a small AAA on surveillance. CONCLUSION: The AAA clinical decision tool has the ability to accurately predict the 5 year survival of patients with an AAA. This tool can be used during clinical decision making to better inform clinicians and patients of long-term outcomes. Further validation studies in a wider AAA population are required to test the broader clinical utility of this AAA clinical decision tool.

Proteomic Analysis of Liver from Human Lipoprotein(a) Transgenic Mice Shows an Oxidative Stress and Lipid Export Response.

BACKGROUND: Mouse models of hypercholesterolaemia have been used to identify arterial proteins involved in atherosclerosis. As the liver is extremely sensitive to dyslipidemia, one might expect major changes in the abundance of liver proteins in these models even before atherosclerosis develops. METHODS: Lipid levels were measured and a proteomic approach was used to quantify proteins in the livers of mice with an elevated low-density lipoprotein (LDL) and the presence of lipoprotein(a) [Lp(a)] but no atherosclerosis. RESULTS: The livers of Lp(a) mice showed an increased triglyceride but reduced phospholipid and oxidised lipid content. Two-dimensional gel electrophoresis and mass spectrometry analysis identified 24 liver proteins with significantly increased abundance in Lp(a) mice (P<0.05). A bioinformatic analysis of the 24 proteins showed the major effect was that of an enhanced antioxidant and lipid efflux response with significant increases in antioxidant (Park7, Gpx1, Prdx6, and Sod1) and lipid metabolism proteins (Fabp4, Acaa2, apoA4, and ApoA1). Interestingly, human liver cells treated with Lp(a) showed significant increases in Gpx1 and Prdx6 but not Sod1 or Park7. CONCLUSIONS: The presence of human LDL and Lp(a) in mice promotes an enhanced flux of lipids into the liver which elicits an antioxidant and lipid export response before the onset of atherosclerosis. The antioxidant response can be reproduced in human liver cells treated with Lp(a).

Survival Disparity Following Abdominal Aortic Aneurysm Repair Highlights Inequality in Ethnic and Socio-economic Status.

OBJECTIVES: Socio-economic status (SES) and ethnicity have been reported as markers influencing the likelihood of increased mortality. The aim of this study was to investigate how SES and ethnicity impacted patient survival after abdominal aortic aneurysm (AAA) repair. METHODS: Consecutive patients undergoing open and endovascular AAA repair during a 14.5 year period were identified. Ethnicity was defined as recorded on health records and SES (a score of 10, where 1 is least deprived and 10 being most deprived) and was linked to census data. Operative outcomes were reported at 30 days and a medium-term survival analysis used the Cox model to report adjusted hazard ratios (HR). RESULTS: A total of 6239 patients with a median age of 75 years and 78.7% males were included. The majority (5,654) were identified as New Zealand (NZ) Europeans, with 421 identified as NZ Maori, 97 identified as belonging to a Pacific ethnic group, and 67 identified as an Asian ethnic group. The median survival follow-up period was 5 years and after adjusting for confounders, those who identified as NZ Maori had the lowest survival compared with all other ethnic groups with a HR of 1.46 (95% CI 1.23-1.72). Living in areas of high social deprivation ≥ 7 was an independent predictor of short and medium-term overall mortality when compared with living in deprivation deciles 1 or 2. CONCLUSIONS: Low SES was identified as a marker of risk for all ethnic groups in relation to both reduced short and medium-term survival. However, regardless of SES, NZ Maori had worse overall medium-term survival following AAA repair than the other ethnic groups. Therefore it appears that both SES and being Maori were markers of increased exposure to risk that negatively impact upon survival after AAA repair. There is a need to ensure systemic processes support initiatives that reduce this inequality.

Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart.

Aim: Myocardial fibrosis is a well-established cause of increased myocardial stiffness and subsequent diastolic dysfunction in the diabetic heart. The molecular regulators that drive the process of fibrotic events in the diabetic heart are still unknown. We determined the role of the microRNA (miR)-15 family in fibrotic remodelling of the diabetic heart.Methods and results: Right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic (ND) patients undergoing coronary artery bypass graft surgery showed significant down-regulation of miR-15a and -15b. This was associated with marked up-regulation of pro-fibrotic transforming growth factor-ß receptor-1 (TGFßR1) and connective tissue growth factor (CTGF), direct targets for miR-15a/b and pro-senescence p53 protein. Interestingly, down-regulation of miR-15a/b preceded the development of diastolic dysfunction and fibrosis in Type 2 diabetic mouse heart. Therapeutic restoration of miR-15a and -15b in HL-1 cardiomyocytes reduced the activation of pro-fibrotic TGFßR1 and CTGF, and the pro-senescence p53 protein expression, confirming a causal regulation of these fibrotic and senescence mediators by miR-15a/b. Moreover, conditioned medium (CM) collected from cardiomyocytes treated with miR-15a/b markedly diminished the differentiation of diabetic human cardiac fibroblasts.Conclusion: Our results provide first evidence that early down-regulation of miR-15a/b activates fibrotic signalling in diabetic heart, and hence could be a potential target for the treatment/prevention of diabetes-induced fibrotic remodelling of the heart.

Down-regulation of proangiogenic microRNA-126 and microRNA-132 are early modulators of diabetic cardiac microangiopathy.

AIM: Microangiopathy due to endothelial dysfunction is a major contributing factor to the development of diabetes-induced cardiovascular disease (CVD). Dysregulation of endothelial-specific microRNAs (miRs) is correlated with impaired angiogenesis and cell survival. We investigated the profile of two angiomiRs, miR-126, and miR-132, in the plasma of type 2 diabetic individuals without any known history of CVD as well as in the cardiac tissues collected from diabetics undergoing cardiac surgery. METHODS AND RESULTS: The presence of diabetes alone significantly decreased both angiomiRs in the plasma and the myocardium. The down-regulation of angiomiRs was also associated with reduced capillaries and arterioles and increased endothelial cell apoptosis, the hallmark of microangiopathy. Importantly, a time course study in a type 2 diabetic mouse model confirmed that the down-regulation of angiomiRs preceded endothelial apoptosis as well as alterations in the density of the microvasculature. Finally, therapeutic overexpression of both angiomiRs in diabetic aortic rings and human umbilical vein endothelial cells exposed to high glucose (HG) abrogated the deleterious effects of diabetes and HG on cell survival and proliferation and restored their angiogenic potential. CONCLUSIONS: These novel findings demonstrate that the down-regulation of angiomiRs is a major underlying mechanism for the development of microangiopathy in diabetic hearts. Therefore, therapeutic restoration of angiomiRs could become a potential approach to combat the cardiovascular complications of diabetes.

The impact of CT colonography on abdominal aortic aneurysm referrals in a tertiary hospital.

INTRODUCTION: Computed tomography colonography (CTC) for the detection of colorectal disease is gaining popularity as an alternative to colonoscopy. This has been associated with an increase in incidental extra-colonic findings such as abdominal aortic aneurysms. However, due to the patient selection process of obtaining a CTC, it was hypothesised that this patient cohort might represent a high-risk group. The primary aim of this study was to determine the impact that CTC had on small aneurysm referrals. Owing to the potential selection bias, the secondary aim was to compare baseline characteristics referred by CTC to the cohort referred by other radiological modalities. METHODS: Consecutive patients attending the small aneurysm clinic at a single tertiary centre were included. Baseline patient comorbidities were collected and recorded on a prospective database. The characteristics of patients who had a CTC-detected aneurysm were compared to patients referred by other radiological modalities. RESULTS: There were 566 patients with small aneurysms included. Of these, 96 (17.0%) had their aneurysm detected from CTC and the remaining aneurysms were detected by other radiological modalities. These patients were on average 2 years older and were less likely to have a smoking history. There was no difference in other patient characteristics. CONCLUSION: Computed tomography colonography contributed to the initial diagnosis of one in five patients with small aneurysms. Despite a potential selection bias for patients undergoing CTC, there were no major baseline differences between the CTC cohort and patients referred by other radiological modalities. Routine assessment of the aorta during a CTC may aid in aneurysm detection.