Three-dimensional growth and biomechanical risk progression of abdominal aortic aneurysms under serial computed tomography assessment.

Growth of abdominal aortic aneurysms (AAAs) is often described as erratic and discontinuous. This study aimed at describing growth patterns of AAAs with respect to maximal aneurysm diameter (Dmax) and aneurysm volume, and to characterize changes in the intraluminal thrombus (ILT) and biomechanical indices as AAAs grow. 384 computed tomography angiographies (CTAs) from 100 patients (mean age 70.0, standard deviation, SD = 8.5 years, 22 women), who had undergone at least three CTAs, were included. The mean follow-up was 5.2 (SD = 2.5) years. Growth of Dmax was 2.64 mm/year (SD = 1.18), volume 13.73 cm3/year (SD = 10.24) and PWS 7.3 kPa/year (SD = 4.95). For Dmax and volume, individual patients exhibited linear growth in 87% and 77% of cases. In the tertile of patients with the slowest Dmax-growth (< 2.1 mm/year), only 67% belonged to the slowest tertile for volume-growth, and 52% and 55% to the lowest tertile of PWS- and PWRI-increase, respectively. The ILT-ratio (ILT-volume/aneurysm volume) increased with time (2.6%/year, p < 0.001), but when adjusted for volume, the ILT-ratio was inversely associated with biomechanical stress. In contrast to the notion that AAAs grow in an erratic fashion most AAAs displayed continuous and linear growth. Considering only change in Dmax, however, fails to capture the biomechanical risk progression, and parameters such as volume and the ILT-ratio need to be considered.

Proteoglycan 4 Modulates Osteogenic Smooth Muscle Cell Differentiation during Vascular Remodeling and Intimal Calcification.

Calcification is a prominent feature of late-stage atherosclerosis, but the mechanisms driving this process are unclear. Using a biobank of carotid endarterectomies, we recently showed that Proteoglycan 4 (PRG4) is a key molecular signature of calcified plaques, expressed in smooth muscle cell (SMC) rich regions. Here, we aimed to unravel the PRG4 role in vascular remodeling and intimal calcification. PRG4 expression in human carotid endarterectomies correlated with calcification assessed by preoperative computed tomographies. PRG4 localized to SMCs in early intimal thickening, while in advanced lesions it was found in the extracellular matrix, surrounding macro-calcifications. In experimental models, Prg4 was upregulated in SMCs from partially ligated ApoE-/- mice and rat carotid intimal hyperplasia, correlating with osteogenic markers and TGFb1. Furthermore, PRG4 was enriched in cells positive for chondrogenic marker SOX9 and around plaque calcifications in ApoE-/- mice on warfarin. In vitro, PRG4 was induced in SMCs by IFNg, TGFb1 and calcifying medium, while SMC markers were repressed under calcifying conditions. Silencing experiments showed that PRG4 expression was driven by transcription factors SMAD3 and SOX9. Functionally, the addition of recombinant human PRG4 increased ectopic SMC calcification, while arresting cell migration and proliferation. Mechanistically, it suppressed endogenous PRG4, SMAD3 and SOX9, and restored SMC markers' expression. PRG4 modulates SMC function and osteogenic phenotype during intimal remodeling and macro-calcification in response to TGFb1 signaling, SMAD3 and SOX9 activation. The effects of PRG4 on SMC phenotype and calcification suggest its role in atherosclerotic plaque stability, warranting further investigations.

Prediction of Rupture Sites in Abdominal Aortic Aneurysms After Finite Element Analysis.

PURPOSE: To associate regions of highest local rupture risk from finite element analysis (FEA) to subsequent rupture sites in abdominal aortic aneurysms (AAA). METHODS: This retrospective multicenter study analyzed computed tomography angiography (CTA) data from 13 asymptomatic AAA patients (mean age 76 years; 8 men) experiencing rupture at a later point in time between 2005 and 2011. All patients had CTA scans before and during the rupture event. FEA was performed to calculate peak wall stress (PWS), peak wall rupture risk (PWRR), rupture risk equivalent diameters (RRED), and the intraluminal thrombus volume (ILTV). PWS and PWRR locations in the prerupture state were compared with subsequent CTA rupture findings. Visible contrast extravasation was considered a definite (n=5) rupture sign, while a periaortic hematoma was an indefinite (n=8) sign. A statistical comparison was performed between the 13-patient asymptomatic AAA group before and during rupture and a 23-patient diameter-matched asymptomatic AAA control group that underwent elective surgery. RESULTS: The asymptomatic AAAs before rupture showed significantly higher PWRR and RRED values compared to the matched asymptomatic AAA control group (median values 0.74 vs 0.52 and 77 vs 59 mm, respectively; p<0.0001 for both). No statistical differences could be found for PWS and ILTV. Ruptured AAAs showed the highest maximum diameters, PWRR, and RRED values. In 7 of the ruptured AAAs (2 definite and 5 indefinite rupture signs), CTA rupture sites correlated with prerupture PWRR locations. CONCLUSION: The location of the PWRR in unruptured AAAs predicted future rupture sites in several cases. Asymptomatic AAA patients with high PWRR and RRED values have an increased rupture risk.