Ian M. Loftus

Increased Matrix Metalloproteinase-9 Activity in Unstable Carotid Plaques A Potential Role in Acute Plaque Disruption

BACKGROUND AND PURPOSE Acute disruption of atherosclerotic plaques precedes the onset of clinical syndromes, and studies have implicated a role for matrix metalloproteinases (MMPs) in this process. The aim of this study was to establish the character, level, and expression of MMPs in carotid plaques and to correlate this with clinical status, cerebral embolization, and histology. METHODS Plaques were obtained from 75 consecutive patients undergoing carotid endarterectomy and divided into 4 groups according to symptomatology (group 1, asymptomatic; group 2, symptomatic >6 months before surgery; group 3, symptomatic within 1 to 6 months; group 4, symptomatic within 1 month). All patients underwent preoperative and intraoperative transcranial Doppler monitoring. Plaques were subjected to histological examination and quantification of MMPs by zymography and ELISA. RESULTS The level of MMP-9 was significantly higher in group 4 (median 125.7 ng/mL for group 4, median <32 ng/mL for all other groups; P=0.003), with no difference in the levels of MMPs 1, 2, or 3. Furthermore, the MMP-9 concentration was significantly higher in plaques undergoing spontaneous embolization (P=0.019) and those with histological evidence of plaque instability (P<0.03). In situ hybridization demonstrated increased MMP-9 expression in highly symptomatic plaques in areas of intense inflammatory infiltrate. CONCLUSIONS The concentration, production, and expression of MMP-9 is significantly higher in unstable carotid plaques. If this proves to be a causal relationship, MMP-9 may be a strong candidate for pharmacotherapy aimed at stabilizing plaques and preventing stroke.

Angiogenesis and the atherosclerotic carotid plaque: An association between symptomatology and plaque morphology

Purpose: Symptomatic carotid disease resulting from generation of thromboemboli has been associated with plaque instability and intraplaque hemorrhage. These features of the lesion could be influenced by the fragility and position of neovessels within the plaque. The purpose of this study was to determine whether any association exists between neovessel density, position, morphology, and thromboembolic sequelae. Methods: Carotid endarterectomy samples were collected from 15 asymptomatic patients with greater than 80% stenoses and from 13 highly symptomatic patients who had suffered ipsilateral carotid stenotic events within 1 month of surgery. Both groups were matched for gender, age, risk factors, degree of carotid artery stenosis, and plaque size. Samples were stained with hematoxylin/eosin and van Geison. Immunohistochemistry was performed by using an endothelial specific antibody to CD31. Plaques were assessed for histologic characteristics, and neovessels were counted and characterized by size, site, and shape. Results: There were significantly more neovessels in plaques (P < .00001) and fibrous caps (P < .0001) in symptomatic compared with asymptomatic plaques. Neovessels in symptomatic plaques were larger (P < .004) and more irregular. There was a significant increase in plaque necrosis and rupture in symptomatic plaques. Plaque hemorrhage and rupture were associated with more neovessels within the plaque (P < .017, P < .001) and within the fibrous cap (P < .046, P < .004). Patients with preoperative and intraoperative embolization had significantly more plaque and fibrous cap neovessels (P < .025, P < .001). Conclusion: Symptomatic carotid disease is associated with increased neovascularization within the atherosclerotic plaque and fibrous cap. These vessels are larger and more irregular and may contribute to plaque instability and the onset of thromboembolic sequelae. (J Vasc Surg 1999;30:261-8.)

Pathophysiology and epidemiology of abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) are found in up to 8% of men aged >65 years, yet usually remain asymptomatic until they rupture. Rupture of an AAA and its associated catastrophic physiological insult carries overall mortality in excess of 80%, and 2% of all deaths are AAA-related. Pathologically, AAAs are associated with inflammation, smooth muscle cell apoptosis, and matrix degradation. Once thought to be a consequence of advanced atherosclerosis, accruing evidence indicates that AAAs are a focal representation of a systemic disease of the vasculature. Risk factors for AAAs include increasing age, male sex, smoking, and low HDL-cholesterol levels. Familial associations exist and although susceptibility genes have been described on the basis of candidate-gene studies, robust genetic studies have failed to discover causative gene mutations. The surgical management of AAAs has been revolutionized by minimally invasive endovascular repair. Ongoing randomized trials will establish whether endovascular repair confers a survival advantage over open surgery for patients with a ruptured AAA. In many countries, centralization of vascular surgical services has largely been driven by the improved outcomes of elective aneurysm surgery in specialized centers, the widespread adoption of endovascular techniques, and the introduction of screening programs.

Meta‐analysis and systematic review of the relationship between volume and outcome in abdominal aortic aneurysm surgery

This study investigated the volume–outcome relationship for abdominal aortic aneurysm (AAA) surgery and quantified critical volume thresholds.

Lower extremity amputations — a review of global variability in incidence

Diabet. Med. 28, 1144–1153 (2011)

Modern Treatment of Juxtarenal Abdominal Aortic Aneurysms with Fenestrated Endografting and Open Repair ― A Systematic Review

INTRODUCTION Advances in endovascular technology have led to the introduction of fenestrated stents to treat juxtarenal aneurysms (JRAs), previously deemed unsuitable for standard endovascular repair (EVR). This article reviews the outcomes of fenestrated technology and makes a comparison with open repair. METHODS A systematic review of the literature was performed. RESULTS No randomised studies were identified. 8 cohort studies reporting 368 f-EVR cases and 12 cohorts reporting 1164 open repairs of JRAs were identified. Analysis of outcome measures found the f-EVR and open cohorts to be homogeneous. Combining studies identified an increased 30-day mortality after open repair when compared to f-EVR (Relative risk (RR) 1.03, 95% Confidence interval (CI) 1.01-1.04, p=.02), 2% increased absolute mortality. No difference was identified in postoperative permanent dialysis dependence (RR 1.00, CI 0.99-1.01, p=1). Transient renal failure was more common following open repair (RR 1.06, CI 1.01-1.12, p=.03). Early re-interventions were less common following open repair (RR 0.87, CI 0.83-0.91, p=.0001). CONCLUSIONS Selective f-EVR appears to have reduced peri-operative mortality compared with traditional open surgery, yet selectivity within the study groups and lack of a rigorous classification prohibit more robust comparison. Promising short-term results confirm a role for f-EVR in management of complex abdominal aneurysms.

Aortic Morphology Following Endovascular Repair of Acute and Chronic Type B Aortic Dissection: Implications for Management

OBJECTIVE The study aimed to define early clinical outcomes, and medium term morphological changes, following endovascular treatment of acute (AAD) and chronic (CAD) Type B aortic dissections. MAIN OUTCOMES The cohort comprised 78 patients who underwent endovascular repair for AAD (38) and CAD (40). Early and late clinical outcomes were prospectively recorded. All patients underwent serial follow up with CT scanning. False lumen thrombosis rates, true, false and total aortic short axis diameter were recorded at the mid point of the endograft and below this level in the thoracic aorta. The total maximum aortic diameter in the thoracic, abdominal aorta was quantified. RESULTS The 30-d mortality was 2.6% in AAD and 7.5% in CAD. The 30-d stroke and paraplegia rates were 5.3% and 0% in AAD. There were no cases of stroke or paraplegia in patients with CAD. At 30 months follow up, the cumulative survival for the two groups was 93% for AAD and 66.5% for CAD (P=0.015, Kaplan Meier) and the cumulative re-intervention rate was 62% and 55% in AAD and CAD respectively (P=0.961, Kaplan-Meier). False lumen thrombosis rates were equivalent in the two groups and were higher at the level of the endograft than below this level (P<0.05). Aortic remodelling was greater in AAD, whereas the aortic dimensions after treatment of CAD remained relatively static. Up to 20% of patients in both groups demonstrated enlargement of the thoracic aorta. CONCLUSIONS The data support the use of endovascular repair of the thoracic aorta in Type B aortic dissection. 30-d outcomes are acceptable. Patients with AAD demonstrate significant aortic remodelling whereas patients with CAD do not. This has significant implications for practice as patients with CAD must rely on maintenance of false lumen thrombosis to preserve the integrity of the endovascular repair.

Abdominal Aortic Aneurysm Rupture Is Associated With Increased Medial Neovascularization and Overexpression of Proangiogenic Cytokines

Objective—Matrix metalloproteinase (MMP) activity has been linked to abdominal aortic aneurysm (AAA) rupture. Medial neovascularization (MNV), a histopathologic characteristic of AAAs, involves proteolytic degradation of extracellular matrix by MMPs to facilitate endothelial cell migration. The role of MNV in aneurysm rupture is unknown. This study investigated whether MNV is increased in aneurysm rupture. Methods and Results—Biopsy samples from aneurysm rupture edge were compared with control biopsy samples from aneurysm wall at the level of rupture and from anterior sac in 12 ruptured AAAs. Further controls were obtained from anterior sac of 10 nonruptured AAAs. MNV, microvessel diameter, maturity index, and inflammatory infiltrate were quantified using morphometric analyses following immunohistochemistry. Expression of proangiogenic mediators was quantified using quantitative real-time–polymerase chain reaction. Compared with anterior sac and aneurysm wall at level of rupture, MNV was increased (P<0.001) in rupture edge biopsy samples and consisted of smaller diameter (P<0.001) and more immature microvessels (P<0.001). mRNA expression of &agr;v-integrin, vascular endothelial growth factor, vascular endothelial-cadherin, monocyte chemoattractant protein-1, and vimentin was increased (P<0.05) in rupture edge biopsy samples. Conclusions—This study demonstrated increased medial neovascularization and overexpression of proangiogenic cytokines at aneurysm rupture edge. Further investigations into whether this angiogenic response was a causative factor of aneurysm rupture are needed.

Unstable Carotid Plaques Exhibit Raised Matrix Metalloproteinase-8 Activity

Background—The fibrous cap of atherosclerotic plaques is composed predominantly of type I and III collagen. Unstable carotid plaques are characterized by rupture of their cap, leading to thromboembolism and stroke. The proteolytic mechanisms causing plaque disruption are undefined, but the collagenolytic matrix metalloproteinase (MMP) -1, -8, and -13 may be implicated. The aim of this study was to quantify the concentrations of these collagenases in carotid plaques and to determine their relationship to markers of plaque instability. Methods and Results—Atherosclerotic plaques were collected from 159 patients undergoing carotid endarterectomy. The presence and timing of carotid territory symptoms were ascertained. Preoperative embolization was recorded by transcranial Doppler. Each plaque was assessed for histological features of instability. Plaque MMP concentrations were quantified with ELISA. Significantly higher concentrations of active MMP-8 were observed in the plaques of symptomatic patients (20.5 versus 11.4 ng/g; P =0.0002), in plaques of emboli-positive patients (22.7 versus 13.5 ng/g; P =0.0037), and in those plaques showing histological evidence of rupture (20.8 versus 14.7 ng/g; P =0.0036). No differences were seen in the levels of MMP-1 and MMP-13. Immunohistochemistry, in situ hybridization, and colocalization studies confirmed the presence of MMP-8 protein and mRNA within the plaque, which colocalized with macrophages. Conclusions—These data suggest that the active form of MMP-8 may be partly responsible for degradation of the collagen cap of atherosclerotic plaques. This enzyme represents an attractive target for drug therapy aimed at stabilizing vulnerable plaques.

Epidemiological study of the relationship between volume and outcome after abdominal aortic aneurysm surgery in the UK from 2000 to 2005

The aim was to assess the relationship between hospital volume and outcome after abdominal aortic aneurysm (AAA) surgery in the UK.