Pathogenesis and management of abdominal aortic aneurysm

Abstract

Abdominal aortic aneurysm (AAA) causes ∼170 000 deaths annually worldwide. Most guidelines recommend asymptomatic small AAAs (30 to <50 mm in women; 30 to <55 mm in men) are monitored by imaging and large asymptomatic, symptomatic, and ruptured AAAs are considered for surgical repair. Advances in AAA repair techniques have occurred, but a remaining priority is therapies to limit AAA growth and rupture. This review outlines research on AAA pathogenesis and therapies to limit AAA growth. Genome-wide association studies have identified novel drug targets, e.g. interleukin-6 blockade. Mendelian randomization analyses suggest that treatments to reduce low-density lipoprotein cholesterol such as proprotein convertase subtilisin/kexin type 9 inhibitors and smoking reduction or cessation are also treatment targets. Thirteen placebo-controlled randomized trials have tested whether a range of antibiotics, blood pressure-lowering drugs, a mast cell stabilizer, an anti-platelet drug, or fenofibrate slow AAA growth. None of these trials have shown convincing evidence of drug efficacy and have been limited by small sample sizes, limited drug adherence, poor participant retention, and over-optimistic AAA growth reduction targets. Data from some large observational cohorts suggest that blood pressure reduction, particularly by angiotensin-converting enzyme inhibitors, could limit aneurysm rupture, but this has not been evaluated in randomized trials. Some observational studies suggest metformin may limit AAA growth, and this is currently being tested in randomized trials. In conclusion, no drug therapy has been shown to convincingly limit AAA growth in randomized controlled trials. Further large prospective studies on other targets are needed.

Keywords: AAA rupture; Abdominal aortic aneurysm; IL-6; Metformin; RAS; Single-nucleotide polymorphism.

Graphical Abstract

Potential medical therapies to limit abdominal aortic aneurysm growth or rupture. VSMC, vascular smooth muscle cell; LDL, low density lipoprotein.

Figure 1

Illustration of the interleukin-6 pathway. Shown are both the classical and trans-signalling interleukin-6 pathways. ADAM, a disintegrin and metalloprotease; CCL3, chemokine (C-C motif) ligand 3; eNOS, endothelial nitric oxide synthase; sgp130, soluble glycoprotein 130; ICAM, intracellular adhesion molecule; sIL-6R, soluble interleukin-6 receptor; JAK, Janus kinase; MYC, myelocytomatosis oncogene; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription 3; VCAM, vascular cellular adhesion molecule; ECM, extracellular matrix; P, phosphorylation.

Figure 2

Meta-analysis of observational studies assessing the association between angiotensin-converting enzyme inhibitors and abdominal aortic aneurysm rupture. Included were the unadjusted ORs and 95% CIs from previously reported observational studies.^,

Figure 3

Measuring peak wall stress in an abdominal aortic aneurysm. Finite element analysis using the A4 Clinics software estimated peak wall stress using computed tomograms of an abdominal aortic aneurysm. (A) Axial and (B) sagittal views of an AAA. (C) Three-dimensional segmentation of the aneurysm generated using finite element analysis. The red pixels indicate areas of high aortic wall stress. Reproduced with permission.

Figure 4

Telmisartan limits increase in peak wall stress (left) and peak wall rupture index (right) within data from the telmisartan in the management of the abdominal aortic aneurysm trial. Reproduced with permission.

Figure 5

Metformin prescription is associated with slower annual abdominal aortic aneurysm growth: results of a meta-analysis of observational studies. Mean difference (MD) in annual abdominal aortic aneurysm growth shown in millimetres. Reproduced with permission.

Figure 6

Combined incidence of abdominal aortic aneurysm (AAA) repair or mortality from AAA rupture (AAA events) in patients with diabetes prescribed metformin (purple dotted line), those with diabetes not prescribed metformin (red line), and those without diabetes (blue line). Graphs show cumulative proportion of events over 5 years for the whole cohort (A), patients with initial AAA diameter ≤ 50 mm (B), and patients with ≥6 month follow-up (C). In the whole cohort, the incidence of AAA events was less in patients with diabetes prescribed metformin than in patients who had diabetes but were not prescribed metformin (P = 0.003) or patients who did not have diabetes (P < 0.001). The incidence of AAA events was similar in people who had diabetes but were not prescribed metformin and patients who did not have diabetes (P = 0.839). Numbers at risk during different stages of follow-up are shown below the graphs. Reproduced with permission.

Figure 7

Illustration of maximum infra-renal abdominal aortic diameter in the adventitial elastase and β-aminopropionitrile mouse model. Previously reported by Phie and colleagues.