Soroush Sohrabi

A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76-0.85, P = 7.2 × 10(-14)). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case-control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.

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.

Clot Architecture Is Altered in Abdominal Aortic Aneurysms and Correlates With Aneurysm Size

Objective—Abdominal aortic aneurysm (AAA) is characterized by widening of the aorta. Once the aneurysm exceeds 5.5 cm, there is a 10% risk of death due to rupture. AAA is also associated with mortality due to other cardiovascular disease. Our aim was to investigate clot structure in AAA and its relationship to aneurysm size. Methods and Results—Plasma was obtained from 49 controls, 40 patients with small AAA, and 42 patients with large AAA. Clot formation was studied by turbidity, fibrin pore structure by permeation, and time to half lysis by turbidity with tissue plasminogen activator. Plasma clot pore size showed a stepwise reduction from controls to small to large AAA. Lag phase for plasma clot formation and time to half lysis were prolonged, with smaller AAA samples showing intermediate response. Clot structure was normal in clots made with fibrinogen purified from patients compared with controls, suggesting a role for other plasma factors. Endogenous thrombin potential and turbidity using tissue factor indicated that the effects were independent of changes in thrombin generation. Conclusion—Patients with AAA form denser, smaller pored plasma clots that are more resistant to fibrinolysis, and these characteristics correlate with aneurysm size. Clot structure may play a role in AAA development and concomitant cardiovascular disease.

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.

Cardiovascular risk in patients with small and medium abdominal aortic aneurysms, and no history of cardiovascular disease.

Cardiovascular disease (CVD) is the main cause of death in people with abdominal aortic aneurysm (AAA). There is little evidence that screening for AAA reduces all‐cause or cardiovascular mortality. The aim of the study was to assess whether subjects with a small or medium AAA (3·0–5·4 cm), without previous history of clinical CVD, had raised levels of CVD biomarkers or increased total mortality.

Calcium channel blockers enhance sac shrinkage after endovascular aneurysm repair

OBJECTIVE Sac shrinkage is a surrogate marker of success after endovascular aneurysm repair (EVAR). We set out to determine if any common cardioprotective medications had a beneficial effect on sac shrinkage. METHODS This retrospective observational study took place at Leeds Vascular Institute, a tertiary vascular unit in the Northern United Kingdom. The cohort comprised 149 patients undergoing EVAR between January 1, 2005, and December 31, 2008. Medication use was recorded at intervention (verified at study completion in 33 patients), and patients were monitored for 2 years. The main outcome measures were the effect of medication on sac shrinkage as determined by percentage change in maximal idealized cross-sectional area of the aneurysm at 1 month, 6 months, 1 year, and 2 years by linear regression model, in addition to 2-year endoleak and death rates determined by a binary logistic regression model. RESULTS After exclusions, 112 patients, who were a median age of 78 years (interquartile range, 78-83 years), remained for analysis. The median Glasgow Aneurysm Score was 85 (interquartile range, 79-92). At 2 years, mortality was 13.4%, endoleak developed in 37.5%, and significant endoleak developed in 14.3%. Patients taking a calcium channel blocker had enhanced sac shrinkage, compared with those not taking a calcium channel blocker, by 6.6% at 6 months (-3.0% to 16.3%, P = .09), 12.3% at 1 year (2.9% to 21.7%, P = .008), and 13.1% at 2 years (0.005% to 26.2%, P = .007) independent of other medication use, graft type, endoleak development, or death. CONCLUSIONS Enhanced sac shrinkage occurred after EVAR in patients taking calcium channel blockers. This warrants further study in other centers and at the molecular level.

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.

Ankle pressures in UK South Asians with diabetes mellitus: a case control study

Objectives To study ethnic differences in ankle pressures in South Asians versus Europeans and in those with and without diabetes mellitus (DM). Design Case control. Setting Primary care. Participants 391(DM=154) South Asian and 252(DM=72) European adults. Intervention None. Main outcome measures Systolic blood pressure of the left (L) and right (R) brachial, posterior tibial (PT) and dorsalis pedis (DP) arteries were measured using a Doppler probe. Results In comparison with Europeans, in young South Asians, DM was diagnosed 12 years earlier but pressures were lower, p≤0.0001 for all (RPT (146 vs 157 mm Hg), LPT (143 vs 154 mm Hg), RDP (138 vs 150 mm Hg) and LDP (137 vs 149 mm Hg)). Pack year was greater in Europeans. Odds ratios of cardiovascular disease in relation to ankle pressure were increased in South Asians with ankle brachial index between 0.9 and 1.3 or >1.3. Linear regression in South Asians identified age was an independent predictor of increased pedal pressures, DM of increased RPT and LDP, and sex of LPT and LDP. In Europeans, age was an independent predictor of increased pedal pressures, and sex and pack years were independent predictors of decreased pedal pressures. In South Asians, all ankle pressure and in Europeans, RPT, LPT and LDP were increased in subjects with DM versus without. Ankle pressures and cardiovascular disease in South Asians with DM were similar to those of 10 years older Europeans with DM. Conclusions South Asians with DM had higher ankle pressures versus without and were similar to 10 years older Europeans with DM. Prospective studies on ankle pressures for development of diabetes or cardiovascular disease are warranted in South Asians.

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.

PHYLOGENETIC ANALYSIS OF THE Y CHROMOSOME IN ABDOMINAL AORTIC ANEURYSMS: A META-ANALYSIS OF THREE BRITISH COHORTS.

Introduction: Coronary artery disease (CAD) and abdominal aortic aneurysms (AAA) are significantly sexually dimorphic; men develop and die of CAD and AAA more commonly than age-matched women. Haplogroup I of the Y chromosome as a strong, independent risk factor of CAD. As both diseases are sexually dimorphic clinical manifestations of cardiovascular disease we hypothesised that haplogroup I of the Y chromosome may underlie the genetic background that drives the male predominance at diagnosis. Methodology: A total of 2917 (mean age 70years, mean aneurysm diameter 6 cm) men recruited into three British cohorts were genotyped for 11 Y chromosome polymorphisms. Using this information and Y chromosome phylogenetic analysis, each man was assigned one common European Y chromosome lineage. Using age-adjusted linear regression and fixed-effect inverse variance meta-analysis we examined the effect of haplogroup I on the risk of AAA. Results: The distribution of haplogroups identified in each of the three cohorts was in keeping with published prevalence (prevalence of haplogroup I ranged from 14% to 20%). There was no statistically significant individual associations between haplogroup I and age-adjusted risk of AAA in either of three cohorts (p=0.643, p=0.815 and p=0.530 in Leicester, Leeds, and Belfast, respectively). The fixed effect meta-analysis of the three cohorts confirmed that haplogroup I had no affect on the age-adjusted risk of AAA (p= 0.693). Conclusions: Haplogroup I of the Y chromosome does not predispose its carriers to AAA. This may suggest that significant differences in the genetic architecture of sexual dimorphism between AAA and CAD.