Intraluminal thrombus: Innocent bystander or factor in abdominal aortic aneurysm pathogenesis?

BACKGROUND: Abdominal aortic aneurysms (AAAs) represent a complex multifactorial hemodynamic, thrombotic, and inflammatory process that can ultimately result in aortic rupture and death. Despite improved screening and surgical management of AAAs, the mortality rates have remained high after rupture, and little progress has occurred in the development of nonoperative treatments. Intraluminal thrombus (ILT) is present in most AAAs and might be involved in AAA pathogenesis. The present review examined the latest clinical and experimental evidence for possible involvement of the ILT in AAA growth and rupture. METHODS: A literature review was performed after a search of the PubMed database from 2012 to June 2020 using the terms "abdominal aortic aneurysm" and "intraluminal thrombus." RESULTS: The structure, composition, and hemodynamics of ILT formation and propagation were reviewed in relation to the hemostatic and proteolytic factors favoring ILT deposition. The potential effects of the ILT on AAA wall degeneration and rupture, including a review of the current controversies regarding the position, thickness, and composition of ILT, are presented. Although initially potentially protective against increased wall stress, increasing evidence has shown that an increased volume and greater age of the ILT have direct detrimental effects on aortic wall integrity, which might predispose to an increased rupture risk. CONCLUSIONS: ILT does not appear to be an innocent bystander in AAA pathophysiology. However, its exact role remains elusive and controversial. Despite computational evidence of a possible protective role of the ILT in reducing wall stress, increasing evidence has shown that the ILT promotes AAA wall degeneration in humans and in animal models. Further research, with large animal models and with more chronic ILT is crucial for a better understanding of the role of the ILT in AAAs and for the potential development of targeted therapies to slow or halt AAA progression.

Hemodynamic Changes in an Actively Rupturing Abdominal Aortic Aneurysm.

Computational fluid dynamics were used to assess hemodynamic changes in an actively rupturing abdominal aortic aneurysm (AAA) over a 9-day period. Active migration of contrast from the lumen into the thickest region of intraluminal thrombus (ILT) was demonstrated until it ultimately breached the adventitial layer. Four days after symptom onset, there was a discrete disruption of adventitial calcium with bleb formation at the site of future rupture. Rupture occurred in a region of low wall shear stress and was associated with a marked increase in AAA diameter from 6.6 to 8.4 cm. The cross-sectional area of the flow lumen increased across all time points from 6.28 to 12.08 cm2. The increase in luminal area preceded the increase in AAA diameter and was characterized by an overall deceleration in recirculation flow velocity with a coinciding increase in flow velocity penetrating the ILT. We show that there are significant hemodynamic and structural changes in the AAA flow lumen in advance of any appreciable increase in aortic diameter or rupture. The significant increase in AAA diameter with rupture suggests that AAA may actually rupture at smaller sizes than those measured on day of rupture. These findings have implications for algorithms the predict AAA rupture risk.

A Canadian multicenter experience describing outcomes after endovascular abdominal aortic aneurysm repair stent graft explantation.

BACKGROUND: Most studies describing the outcomes after endovascular abdominal aortic aneurysm repair (EVAR) explantation have been from single, high-volume, centers. We performed a multicenter cross-Canadian study of outcomes after EVAR stent graft explantation. Our objectives were to describe the outcomes after late open conversion and EVAR graft explantation at various Canadian centers and the techniques and outcomes stratified by the indication for explant. METHODS: The Canadian Vascular Surgery Research Group performed a retrospective multicenter study of all cases of EVAR graft explantation at participating centers from 2003 to 2018. Data were collected using a standardized, secure, online platform (RedCap [Research Electronic Data Capture]). Univariate statistical analysis was used to compare the techniques and outcomes stratified the indication for graft explantation. RESULTS: Patient data from 111 EVAR explants collected from 13 participating centers were analyzed. The mean age at explantation was 74 years, the average aneurysm size was 7.5 cm, and 28% had had at least one instructions for use violation at EVAR. The average time between EVAR and explantation was 42.5 months. The most common indication for explantation was endoleak (n = 66; type Ia, 46; type Ib, 2; type II, 9; type III, 2; type V, 7), followed by infection in 20 patients; rupture in 18 patients (due to type Ia endoleak in 10 patients, type Ib in 1, type II in 1, type III in 2, and type V in 1), and graft thrombosis in 7 patients. The overall 30-day mortality was 11%, and 45% of the patients had experienced at least one major perioperative complication. Mortality was significantly greater for patients with rupture (33.3%) and those with infection (15%) compared with patients undergoing elective explantation for endoleak (4.5%; P = .003). The average center volume during the previous 15 years was 8 cases with a wide range (2-19 cases). A trend was seen toward greater mortality for patients treated at centers with fewer than eight cases compared with those with eight or more cases (19% vs 9%). However, the difference did not reach statistical significance (P = .23). Overall, 41% of patients had undergone at least one attempt at endovascular salvage before explantation, with the highest proportion among patients who had undergone EVAR explantation for endoleak (51%). Only 22% of patients with rupture had undergone an attempt at endovascular salvage before explantation. CONCLUSIONS: The performance of EVAR graft explantation has increasing in Canada. Patients who had undergone elective explantation for endoleak had lower mortality than those treated for either infection or rupture. Thus, patients with an indication for explanation should be offered surgery before symptoms or rupture has occurred. A trend was seen toward greater mortality for patients treated at centers with lower volumes.

Increased matrix metalloproteinase 9 activity correlates with flow-mediated intraluminal thrombus deposition and wall degeneration in human abdominal aortic aneurysm.

OBJECTIVE: We have previously demonstrated that human abdominal aortic aneurysm (AAA) rupture occurs in zones of low wall shear stress where flow recirculation and intraluminal thrombus (ILT) deposition are increased. Matrix metalloproteinase-9 (MMP-9) is involved in the pathogenesis of AAA via its lytic effect on collagen and elastin. We hypothesize that flow-mediated ILT deposition promotes increased local inflammatory and MMP-9 activity that leads to AAA wall degeneration. The purpose of this study was to examine the correlation between predicted pulsatile flow dynamics and regional differences in MMP-9, elastin, collagen, and ILT deposition in human AAA. METHODS: Full-thickness aortic tissue samples were collected from 24 patients undergoing open AAA repair. Control infrarenal aortic tissue was obtained from 6 patients undergoing aortobifemoral bypass. Full-thickness aortic tissue and ILT were assessed for MMP-9 levels using a cytokine array assay. Histologic and immunohistochemical assessment of inflammation, collagen and elastin content, and MMP-9 levels were also measured. Three-dimensional AAA geometry was generated from computed tomography angiogram (CTA) images using Mimics software and computational fluid dynamics was used to predict pulsatile aortic blood flow. RESULTS: The majority of AAA showed eccentric ILT deposition which was correlated with predicted recirculation blood flow (R2 = -0.17; P < .05). The regions of high ILT were associated with significant increases in inflammation and loss of elastin and collagen compared with regions of low ILT, or with control tissue. MMP-9 was significantly higher in areas of high ILT deposition compared with areas devoid of ILT. Tissue MMP-9 was correlated with the thickness of ILT deposition (R2 = 0.46; P < .05), and was also present in high levels in thick compared with thin ILT. CONCLUSIONS: We have shown a correlation between flow-mediated ILT deposition with increased tissue levels of MMP-9 activity, increased inflammatory infiltrate, and decreased elastin and collagen content in stereotactically sampled human AAA, suggesting that ILT deposition is associated with local increases in proteolytic activity that may preferentially weaken and promote rupture at selected regions.

The Relationship Between Pulsatile Flow Impingement and Intraluminal Thrombus Deposition in Abdominal Aortic Aneurysms.

Direct numerical simulations were performed on four patient-specific abdominal aortic aneurysm (AAA) geometries and the resulting pulsatile blood flow dynamics were compared to aneurysm shape and correlated with intraluminal thrombus (ILT) deposition. For three of the cases, turbulent vortex structures impinged/sheared along the anterior wall and along the posterior wall a zone of recirculating blood formed. Within the impingement region the AAA wall was devoid of ILT and remote to this region there was an accumulation of ILT. The high wall shear stress (WSS) caused by the impact of vortexes is thought to prevent the attachment of ILT. WSS from impingement is comparable to peak-systolic WSS in a normal-sized aorta and therefore may not damage the wall. Expansion occurred to a greater extent in the direction of jet impingement and the wall-normal force from the continuous impact of vortexes may contribute to expansion. It was shown that the impingement region has low oscillatory shear index (OSI) and recirculation zones can have either low or high OSI. No correlation could be identified between OSI and ILT deposition since different flow dynamics can have similar OSI values.

Low wall shear stress predominates at sites of abdominal aortic aneurysm rupture.

OBJECTIVE: Aortic diameter as the primary criterion in the decision to repair abdominal aortic aneurysms (AAAs) has drawbacks as some rupture below size thresholds, whereas others reach extreme size without rupture. Predictions of static aortic wall stress have also failed to reliably predict rupture potential. The objective of this study was to computationally assess blood flow characteristics at the site of infrarenal AAA rupture. On the basis of the finite element literature correlating rupture location with high static local wall stress, we hypothesized that a computational fluid dynamics approach would also demonstrate rupture at regions of high pressure and wall shear stress (WSS). METHODS: Three-dimensional AAA geometry was generated from computed tomography angiography images of seven ruptured AAAs. Aortic blood flow velocity, pressure, and WSS were computationally determined. Flow characteristics at the site of rupture were determined and compared across all cases. RESULTS: AAA size at the time of rupture was 8.3 ± 0.9 cm. Only three of the seven AAAs ruptured at the site of maximal diameter. Blood flow velocity in the aneurysmal aorta showed dominant flow channels with zones of recirculation, where low WSS predominated. Regardless of aneurysm size or configuration, rupture occurred in or near these flow recirculation zones in all cases. WSS was significantly lower and thrombus deposition was more abundant at the site of rupture. CONCLUSIONS: This computational study was the first to assess blood flow characteristics at the site of infrarenal AAA rupture in realistic aortic geometries. In contradiction to our initial hypothesis, rupture occurred not at sites of high pressure and WSS but rather at regions of predicted flow recirculation, where low WSS and thrombus deposition predominated. These findings raise the possibility that this flow pattern may lead to thrombus deposition, which may elaborate adventitial degeneration and eventual AAA rupture.