Risk Factors for Abdominal Aortic Aneurysm and Larger Infrarenal Aortic Diameters in a General Population

Abstract

Abdominal aortic aneurysms (AAAs) comprise an important public health issue, which could be reduced by primary prevention. Identifying AAA risk factors is critical for developing effective preventive strategies. Previous epidemiologic studies have suggested that some risk factors for atherosclerotic cardiovascular disease are also associated with increased risk of incident AAAs, including advanced age, male gender, white race, greater height, smoking, hypertension, dyslipidemia, and some biomarkers related to inflammation and hemostasis. Some observational studies showed an inverse relationship between diabetes and AAA; while others did not show an association. The inverse relationship between diabetes and AAA is considered counterintuitive in the context of diabetes being a risk factor for various cardiovascular diseases. To better understand the etiology of AAA, further investigation on the relation between atherosclerosis and AAA is warranted. Also, the relation between diabetes and AAA needs to be studied further. With the exception of screening studies where AAAs were defined commonly as a maximum infrarenal aortic diameter (IAD) ≥ 3 cm, in most existing epidemiologic studies, AAAs were obtained through medical records and death certificates. This approach ascertains clinical AAAs that were either symptomatic or at least clinically detected. However, large screening studies have suggested that most AAAs are asymptomatic, even though aortic size often expands rapidly and many asymptomatic AAAs may eventually become symptomatic. Furthermore, an increased IAD between 2.3 and 3 cm has been associated with higher risk of future AAA and other cardiovascular events. Thus, examining the determinants of elevated IADs (i.e. IAD ≥ 2.2) among individuals without clinical or asymptomatic AAAs is potentially important to the prevention of AAAs. Manuscript 1 examined the associations of carotid atherosclerosis and stiffness with later AAAs in ARIC. We used carotid intima-media thickness (1987-1992) and atherosclerotic plaque (1987-1989) as indices of carotid atherosclerosis, and used carotid Beta Index (1990-1992) to represent carotid distensibility. We identified 542 incident, clinical AAAs during follow-up through 2011 using hospital discharge codes, Medicare outpatient diagnoses, or death certificates during 22.5 years of follow-up. After multivariable adjustment, the presence of carotid atherosclerotic plaque at baseline was associated with 1.31 (95% CI: 1.10 - 1.57; P: 0.003) times higher risk of clinical AAA. Greater carotid intima-media thickness and Beta Index were also associated with clinical AAA with a dose-response across quartiles (P trend for both: 0.006; hazard ratios [95% CI] for the highest vs. lowest quartiles: 1.55 [1.13 - 2.11] and 1.68 [1.16 - 2.43], respectively). The results suggest that indices of greater carotid atherosclerosis and lower carotid distensibility are markers of increased AAA risk. Manuscript 2 explored risk factors for an elevated IAD (IAD ≥ 2.2 cm) in the absence of AAA in 5620 ARIC participants who attended an abdominal ultrasound screening in 2011-2013. We assessed a variety of risk factors and created derived variables to capture their long-term cumulative effects (over 1987-2013). In the model with adjustment for AAA risk factors, men (vs. women) had 2.50 (95% CI: 1.90, 3.28) times higher odds of having an elevated IAD, and participants with long-term diabetes (vs. non-diabetics) had 0.52 (0.35, 0.77) times lower odds. Height, waist circumference and smoking pack-years were positively associated with elevated IADs [ORs (95% CI) for the highest vs. lowest quintiles of each risk factor: 1.93 (1.36, 2.75), 1.67 (1.28, 2.19) and 1.62 (1.26, 2.08), respectively]. Other factors were not associated with elevated IAD. In summary, male sex, smoking, greater height, larger waist circumference and not having diabetes were associated with elevated IAD among persons without an AAA. The findings highlight the potential for primary prevention of AAA through control of these factors. Manuscript 3 represents a meta-analysis of prospective cohort studies and case-control studies to examine further the relation between diabetes and AAAs. We searched for English literature from online database search (MEDLINE (1966-), EMBASE and Web of Science) plus a manual examination of references in selected articles as of Feb 2018, and included a total of 12 cohorts with 11,410 AAAs in 2,665,121 adult participants and 4 case-control studies with 1,065 AAAs and 12,074 controls who met pre-determined eligibility criteria in the meta-analyses. A DerSimonian and Laird random effects model pooled association estimates and their 95% confidence intervals from studies. Diabetes was inversely associated with the risk of AAA (pooled relative risk: 0.56; 95% confidence interval: 0.50 - 0.63). Results were similar in the subgroup analyses by sex (male/female), setting (population/clinical), and study design (cohort/case-control). In summary, in contrast with diabetes being a risk factor for most cardiovascular diseases, diabetes appears to be strongly and inversely associated with the risk of AAA. In summary, my dissertation studies filled a gap of literature and further assessed AAA etiology by completing the three manuscripts. The three studies have potential to improve understanding of the etiology and early prevention of AAAs at the population level. Findings from my dissertation studies may offer a strategy to clinically identify high-risk individuals.