Modelling the impact of changes to abdominal aortic aneurysm screening and treatment services in England during the COVID-19 pandemic.

BACKGROUND: The National Health Service (NHS) abdominal aortic aneurysm (AAA) screening programme (NAAASP) in England screens 65-year-old men. The programme monitors those with an aneurysm, and early intervention for large aneurysms reduces ruptures and AAA-related mortality. AAA screening services have been disrupted following COVID-19 but it is not known how this may impact AAA-related mortality, or where efforts should be focussed as services resume. METHODS: We repurposed a previously validated discrete event simulation model to investigate the impact of COVID-19-related service disruption on key outcomes. This model was used to explore the impact of delayed invitation and reduced attendance in men invited to screening. Additionally, we investigated the impact of temporarily suspending scans, increasing the threshold for elective surgery to 7cm and increasing drop-out in the AAA cohort under surveillance, using data from NAAASP to inform the population. FINDINGS: Delaying invitation to primary screening up to two years had little impact on key outcomes whereas a 10% reduction in attendance could lead to a 2% lifetime increase in AAA-related deaths. In surveillance patients, a 1-year suspension of surveillance or increase in the elective threshold resulted in a 0.4% increase in excess AAA-related deaths (8% in those 5-5.4cm at the start). Longer suspensions or a doubling of drop-out from surveillance would have a pronounced impact on outcomes. INTERPRETATION: Efforts should be directed towards encouraging men to attend AAA screening service appointments post-COVID-19. Those with AAAs on surveillance should be prioritised as the screening programme resumes, as changes to these services beyond one year are likely to have a larger impact on surgical burden and AAA-related mortality.

Progressive Device Failure at Long Term Follow Up of the Nellix EndoVascular Aneurysm Sealing (EVAS) System.

OBJECTIVE: High rates of midterm failure of the Nellix EndoVascular Aneurysm Sealing (EVAS) System resulted in device withdrawal from the UK market. The study aim was to report long term Nellix EVAS outcomes and management of a failing device. METHODS: A retrospective review of EVAS procedures at a tertiary unit was performed. Device failure was defined as a triad of stent migration, stent separation, and secondary sac expansion, or any intervention for type 1 endoleak, device rupture, or explant. RESULTS: 161 (male n = 140, female n = 21) patients with a median follow up of 6.0 (IQR 5.0-6.6) years were included. Freedom from all cause mortality estimate at six years was 41.5%. There were 70 (43.5%) device failures with a freedom from device failure estimate at six years of 32.3%. Failure was the result of sac expansion (n = 41), caudal stent migration (n = 36), stent separation (n = 26), and secondary AAA rupture (n = 15). A substantial number of type 1 endoleaks was present (1a n = 33, 1b n = 11), but the type 2 endoleak rate was low at 3.7%. Some 36 (22.4%) patients required re-intervention. Twenty-one patients underwent explant with no 30 day deaths. Six patients underwent Nellix-in-Nellix application (NINA) with one early death from bowel ischaemia and one patient who died later from non-aneurysm related cause. Two NINA patients have ongoing sac expansion and two have had thrombosis of a Nellix limb or visceral stent. Proximal embolisation was only successful in one of six cases. CONCLUSION: The long term failure rate of Nellix EVAS is high. All patients with a device must be informed and be enrolled in enhanced surveillance. EVAS explant is an acceptable technique with favourable outcomes. Management by open explant, if the patient is fit, should be considered early and offered to those with device failure.

Long-term Outcomes Following Endovascular Aneurysm Repair for Ruptured Abdominal Aortic Aneurysms.

Purpose: To investigate the long-term outcomes of endovascular aneurysm repair (EVAR) for ruptured abdominal aortic aneurysm (rAAA) from a single center over an 11-year period. Materials and Methods: A retrospective analysis was conducted of 121 patients (median age 78 years; 100 men) with rAAA who underwent emergency EVAR at a single tertiary vascular center from January 2006 to December 2016. The study included only ruptures confirmed by evidence of hematoma on preoperative computed tomography; both iliac and aortic aneurysm ruptures were eligible. The primary outcome measures included mortality and reintervention rates. Kaplan-Meier estimates of survival and freedom from reintervention are reported with the 95% confidence interval (CI). Results: In-hospital and 30-day mortality rates for emergency EVAR were 16.5%; 90-day mortality was 24.0%. The mortality estimates were 27.3% (95% CI 20% to 36%) at 1 year and 61.7% (95% CI 51% to 72%) at 5 years. In the observation period to 2017, 63 reinterventions were performed on 37 patients (30.6%). Median time to the first reintervention was 3.2 years. Freedom from reintervention in surviving patients at 1 year was 86% (95% CI 72% to 94%) and 51% (95% CI 26% to 71%) at 5 years. Four patients (3.3%) had a secondary sac rupture over the study period. Conclusion: Emergency EVAR for ruptured AAA can be performed with acceptable short-term outcomes; however, long-term surveillance is necessary, and reintervention is common.

Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates.

BACKGROUND: The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection. METHODS: Using data from 2863 participants with AAA from 9 prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter, and time to aortic rupture and death. RESULTS: After adjusting for age and sex, baseline aneurysm size was 0.55 mm (95% CI, 0.13-0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was -0.06 mm per year (-0.18 to 0.06) per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival ( P<0.05). CONCLUSIONS: Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

Editor's Choice - Mid-term Migration and Device Failure Following Endovascular Aneurysm Sealing with the Nellix Stent Graft System - a Single Centre Experience.

OBJECTIVE: Endovascular aneurysm sealing (EVAS) with the Nellix stent graft system is a novel concept in the management of abdominal aortic aneurysm (AAA) that aims to reduce the prevalence of all endoleaks following endovascular repair. There are few data describing the longer-term durability of this approach. The aim was to report the longer-term outcomes following EVAS in a single centre. METHODS: This is a retrospective review of all patients that underwent Nellix at Cambridge University Hospitals Foundation Trust. Factors that are described as device failure include secondary sac rupture, graft explantation, further surgical procedures for Type 1 endoleak, or major migration of the stent grafts with pressurisation of the aortic sac. RESULTS: A total of 161 patients have been treated with Nellix. The indications included primary AAA (n = 115), ruptured AAA (n = 4), salvage of other aortic grafts (n = 18), primary iliac aneurysm (n = 6), and chimney EVAS (ChEVAS) for pararenal AAA (n = 18). In total there have been 42 graft failures in patients treated with EVAS for primary AAA. The 4 year freedom from graft failure was 42% in patients treated for primary AAA. Failures mostly occurred more than 2 years post-Nellix implant. There were eight secondary sac ruptures (incidence 2.4 per 100 person years) and there have been 14 graft explants. CONCLUSIONS: Failure of aneurysm sealing following treatment with Nellix has been more common than anticipated and can cause aortic rupture. Post-operative surveillance of Nellix stent grafts is crucial to identify features of failure.

Editor's Choice - Calcification of Thoracic and Abdominal Aneurysms is Associated with Mortality and Morbidity.

INTRODUCTION: Cardiovascular events are common in people with aortic aneurysms. Arterial calcification is a recognised predictor of cardiovascular outcomes in coronary artery disease. Whether calcification within abdominal and thoracic aneurysm walls is correlated with poor cardiovascular outcomes is not known. PATIENTS AND METHODS: Calcium scores were derived from computed tomography (CT) scans of consecutive patients with either infrarenal (AAA) or descending thoracic aneurysms (TAA) using the modified Agatston score. The primary outcome was subsequent all cause mortality during follow-up. Secondary outcomes were cardiovascular mortality and morbidity. RESULTS: A total of 319 patients (123 TAA and 196 AAA; median age 77 [71-84] years, 72% male) were included with a median follow-up of 30 months. The primary outcome occurred in 120 (37.6%) patients. In the abdominal aortic aneurysm group, the calcium score was significantly related to both all cause mortality and cardiac mortality (odds ratios (OR) of 2.246 (95% CI 1.591-9.476; p < 0.001) and 1.321 (1.076-2.762; p = 0.003)) respectively. In the thoracic aneurysm group, calcium score was significantly related to all cause mortality (OR 6.444; 95% CI 2.574-6.137; p < 0.001), cardiac mortality (OR 3.456; 95% CI 1.765-4.654; p = 0.042) and cardiac morbidity (OR 2.128; 95% CI 1.973-4.342; p = 0.002). CONCLUSIONS: Aortic aneurysm calcification, in either the thoracic or the abdominal territory, is significantly associated with both higher overall and cardiovascular mortality. Calcium scoring, rapidly derived from routine CT scans, may help identify high risk patients for treatment to reduce risk.

Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.

Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. Design, Setting, and Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Main Outcomes and Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). Conclusions and Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.

Assessment of Renal Injury in Patients Undergoing Elective EVAR Using Urinary Neutrophil Gelatin-Associated Lipocalin, Interleukin 18, and Retinol-Binding Protein.

Acute kidney injury (AKI) is a recognized complication post-endovascular aneurysm repair (EVAR). Neutrophil gelatin-associated lipocalin (NGAL), interleukin 18 (IL-18), and retinol-binding protein are emerging urinary biomarkers that have shown promise in detecting subclinical and clinical renal impairment. In this study, we assessed changes in these urinary biomarkers as well as serum creatinine (SCr) in patients undergoing EVAR. Urine samples were collected prospectively at 5 time points for each recruited patient: pre-EVAR (baseline) and 6, 12, 24, and 48 hours after the procedure for serial assessment of urinary biomarkers. Serum creatinine was quantified preoperatively and at 24 and 48 hours postoperatively. Serial changes of urinary biomarkers and SCr were assessed. A significant increase in NGAL and IL-18 from baseline was observed ( P < .05), as early as 6 hours for NGAL. A significant rise in levels of NGAL and IL-18 precedes the significant rise in SCr. These findings highlight the potential of emerging urinary biomarkers in detecting early AKI following EVAR.

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.

BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RESULTS: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)). CONCLUSIONS: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.

Impact of Fenestrated Endovascular Abdominal Aortic Aneurysm Repair on Renal Function.

PURPOSE: To investigate the impact of fenestrated endovascular aneurysm repair (fEVAR) on renal function perioperatively and at midterm. METHODS: A case-controlled study was performed involving 58 patients (mean age 75±7 years; 51 men) who underwent elective fEVAR for a juxtarenal or short-necked abdominal aortic aneurysm (AAA) matched on age, sex, smoking, diabetes, and baseline estimated glomerular filtration rate (eGFR) with a contemporaneous group undergoing open aneurysm repair (OAR) for the same indications. Perioperative incidence of acute kidney injury (AKI) and levels of eGFR at 30 days and 1 year were compared. A systematic literature review was performed to identify studies that had used eGFR as renal outcome after fEVAR; the pooled data were meta-analyzed using an eGFR drop >30% at 1 month and the latest follow-up as endpoints. Results are reported as the pooled proportion and 95% confidence interval (CI). RESULTS: The incidence of AKI after fEVAR was 28% compared to 10% after OAR (p=0.03). Following fEVAR, the mean eGFR dropped from 78±8 to 74±9 mL/min/1.73 m(2) at 30 days compared to a change from 79±8 to 80±16 mL/min/1.73 m(2) after OAR (p<0.01). However, the absolute drop in eGFR between fEVAR and OAR at 1 year was similar (7 mL/min/1.73 m(2); p=0.53); 7% of the fEVAR patients had an eGFR drop >30% at that point compared with none for OAR (p=0.12). The systematic literature review identified eGFR outcomes for 193 fEVAR patients. Combining these patients with the 58 from our cohort study, the pooled proportions of eGFR drop >30% were 20% (95% CI 9% to 39%) at 30 days and 8% (95% CI 0.5% to 13%) at the end of follow-up. CONCLUSION: fEVAR has a significant perioperative impact on renal function, but 1-year results are similar to OAR. fEVAR patients may benefit from targeted AKI prevention strategies that need to be assessed in relevant studies.

The potential role of DNA methylation in the pathogenesis of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is characterised by the chronic degradation and gradual, irreversible dilation of the abdominal aorta. Smoking, genetics, male sex and increased age are major factors associated with developing AAA. Rupture contributes to around 2% of deaths in all Caucasians over 65, and there is no pharmaco-therapeutic treatment. Methylation is an epigenetic modification to DNA, where a methyl group is added to a cytosine base 5' to a guanine (CpG dinucleotide). Methylation patterns are long term, inherited signatures that can induce changes in gene transcription, and can be affected by both genetic and environmental factors. Methylation changes are involved in hypertension and atherosclerosis, both of which are risk factors of, and often coexist with AAA. Extra-cellular matrix degradation and inflammation, both important pathological hallmarks of AAA, are also promoted by changes in CpG methylation in other diseases. Additionally, the adverse effects of smoking and ageing take place largely through epigenetic manipulation of the genome. Every factor associated with AAA appears to be associated with DNA methylation, yet no direct evidence confirms this. Future work to identify a link between global methylation and AAA, and differentially methylated regions may reveal valuable insight. The identification of a common epigenetic switching process may also signify a promising future for AAA pharmaco-therapeutic strategies. Epigenetic therapies are being designed to target pathogenic CpG methylation changes in other diseases, and it is feasible that these therapies may also be applicable to AAA in the future.

A variant in LDLR is associated with abdominal aortic aneurysm.

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<1×10(-4) were carried through to in silico replication in 1292 AAA cases and 30,503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (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.

Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.

BACKGROUND: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. METHODS: In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. FINDINGS: We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0.90 [SD 0.23]) was strongly associated with LDL-C concentration (p=1.4 x 10(-77); R(2)=0.11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0 [SD 0.21]) than did WHII controls (p=4.5 x 10(-16)), as did the mutation-negative Belgian patients (0.99 [0.19]; p=5.2 x 10(-20)). The score was also higher in UK (0.95 [0.20]; p=1.6 x 10(-5)) and Belgian (0.92 [0.20]; p=0.04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. INTERPRETATION: In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. FUNDING: British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.

Interleukin-6 receptor pathways in abdominal aortic aneurysm.

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.

A gene-centric study of common carotid artery remodelling.

BACKGROUND: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. METHODS: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). RESULTS: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 × 10(-8)). A proxy SNP (rs4916251, R(2) = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 × 10(-3), I(2) = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. CONCLUSIONS: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

Genomic research to identify novel pathways in the development of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a common disease with a large heritable component. There is a need to improve our understanding of AAA pathogenesis in order to develop novel treatment paradigms. Genomewide association studies have revolutionized research into the genetic variants that underpin the development of many complex diseases including AAA. This article reviews the progress that has been made to date in this regard, including mechanisms by which loci identified by GWAS may contribute to the development of AAA. It also highlights potential post-GWAS analytical strategies to improve our understanding of the disease further.

Elective sac perfusion to reduce the risk of neurologic events following endovascular repair of thoracoabdominal aneurysms.

Spinal cord ischemia (SCI) is a catastrophic complication of thoracoabdominal aortic aneurysm (TAAA) repair. This article describes our early experience with a technique for maintaining perfusion of segmental vessels (intercostals and lumbars) in the early postoperative period after endovascular repair of a TAAA, with "sac perfusion branches" added to custom-made stent grafts. These are closed 7 to 10 days after the first procedure to complete exclusion of the aneurysm. We have used this technique in 10 patients with type II TAAAs. One developed monoparesis of the right leg during a period of hypotension secondary to a cardiac event and died within 30 days. Two patients developed lower limb weakness after closure of the perfusion branches, both with full recovery. Controlled perfusion of segmental vessels with perfusion branches is feasible and may be a useful adjunct to prevent SCI, providing protection to spinal cord perfusion during the immediate postoperative period when risk of SCI is greatest.

Association of a sequence variant in DAB2IP with coronary heart disease.

AIMS: A sequence variant, rs7025486[A], in DAB2IP on chromosome 9q33 has recently been associated with coronary heart disease (CHD). We sought to replicate this finding and to investigate associations with a panel of inflammatory and haemostatic biomarkers. We also sought to examine whether this variant, in combination with a chromosome 9p21 CHD variant (rs10757278) and the Framingham risk score (FRS), could improve the prediction of events compared with the FRS alone. METHODS AND RESULTS: rs7025486 was genotyped in 1386 CHD cases and 3532 controls and was associated with CHD [odds ratio (OR) of 1.16, 95% confidence interval (CI) 1.05-1.29, P= 0.003]. Meta-analysis, using data from the original report and from genome-wide association studies in both the Wellcome Trust Case Control Consortium and the Cardiovascular Health Study, comprising 9968 cases and 20 048 controls, confirmed the association (OR of 1.10, 95% CI 1.06-1.14, P= 3.2 × 10(-6)). There was no association with a panel of CHD biomarkers, including any lipid, inflammation, or coagulation trait, nor with telomere length. Addition to the FRS of this variant plus rs10757278 on chromosome 9p21 improved the area under the receiver-operating characteristic curve (A(ROC)) from 0.61 to 0.64 (P= 0.03) as well as improving the reclassification (net reclassification index = 11.1%, P= 0.007). CONCLUSION: This study replicates a previous association of a variant in DAB2IP with CHD. Addition of multiple variants improves the performance of predictive models based upon classical cardiovascular risk factors.