Joseph Dawson

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.

Increased angiogenesis at the site of abdominal aortic aneurysm rupture

Abstract:  Abdominal aortic aneurysm (AAA) rupture is associated with elevated levels of matrix metalloproteinase (MMP). Medial neovascularization is a known characteristic of established AAAs and involves proteolytic degradation of extracellular matrix by MMPs to facilitate endothelial cell proliferation and migration. This study evaluated the extent of neovascularization in abdominal aortic aneurysm rupture. Results indicated upregulation of proangiogenic cytokines and increased medial neovascularization at the aneurysm rupture edge compared with paired aneurysm anterior sac. Further investigations into the role of angiogenesis in aneurysm rupture may open novel therapeutic avenues to prevent aneurysm rupture.

Vascular endothelial growth factor enhances angiotensin II-induced aneurysm formation in apolipoprotein E-deficient mice

OBJECTIVE Abdominal aortic aneurysm (AAA) development is associated with increased angiogenesis and overexpression of vascular endothelial growth factor (VEGF). Inhibition of angiogenesis results in attenuation of experimental aneurysms. This study investigated the effects of recombinant human (rh)VEGF on experimental aneurysms. METHODS Apolipoprotein E-deficient (apoE(-/-)) mice were assigned to one of four groups: (1) normal saline infusion (sham), (2) angiotensin-II (AngII) infusion, (3) AngII infusion plus 100 microg daily rhVEGF for 14 days (AngII+14dVEGF), or (4) AngII infusion plus 100 microg daily rhVEGF for 21 days (AngII+21dVEGF). Aortic maximum diameter and cross-sectional area were determined by magnetic resonance imaging and microscopy. All mice were sacrificed at day 28. RESULTS Aneurysms developed in all mice in the AngII+14dVEGF and AngII+21dVEGF groups by day 21 compared with 40% in the AngII group. Treatment with rhVEGF increased maximum aortic diameter (P < .002) and cross-sectional area of aneurysms (P < .005) at day 21. This effect was maintained at day 28 (P < .0005). Decreasing rhVEGF treatment from 21 to 14 days did not attenuate aneurysm formation. Treatment with rhVEGF upregulated matrix metalloproteinase 2 gene expression within the aortic wall (P < .0009). CONCLUSIONS Treatment with rhVEGF intensified the formation of AngII-induced aneurysms. Further studies are needed to investigate if antiangiogenic therapy may be a valid medical therapy against aneurysm expansion or rupture.

Visceral and renal artery complications of suprarenal fixation during endovascular aneurysm repair.

BackgroundThe effect of suprarenal fixation of endovascular grafts on renal and visceral artery function remains undefined. This study aimed to determine renal and visceral artery complications following suprarenal fixation during endovascular aneurysm repair (EVR).MethodsProspectively collected data from 112 patients who received suprarenal fixation (group SF) and 36 patients who received infrarenal fixation (group IF) in a single institution from December 1997 to April 2005 were reviewed retrospectively. Median follow-up was 26 months (range 0.1–101 months).ResultsStent struts extended to or above the level of 106 (94.6%) right renal arteries, 104 (92.9%) left renal arteries, 49 (43.8%) superior mesenteric arteries (SMA), and 7 (6.3%) celiac arteries in group SF. This group had 2 (1.8%) unintentional main renal artery occlusions, of which 1 was successfully treated at the first procedure with a renal stent. There was 1 (0.9%) SMA occlusion which resulted in bowel infarction and death. Group IF had no renal or visceral artery complications. There were no late-onset occlusions or infarcts. There was no significant difference in median serum creatinine between groups SF and IF at 1 month (p = 0.18) and 6 months to 12 months (p = 0.22) follow-up. The change in serum creatinine over time was also not significantly different within each group (SF, p = 0.09; IF, p = 0.38).ConclusionsIn this study, suprarenal fixation was associated with a very small incidence of immediate renal and visceral artery occlusion. There did not appear to be any medium-term sequelae of suprarenal fixation.

Hypoxia at the Site of Abdominal Aortic Aneurysm Rupture Is Not Associated with Increased Lactate

Abstract:  The mechanisms of hypoxia‐mediated aneurysm wall weakening and rupture are unknown. During hypoxia, strategies to maintain cellular ATP levels include increasing glycolysis (glycolytic strategy) or decreasing ATP consumption (metabolic depression). This study demonstrated that compared to anterior aneurysm sac, rupture edge overexpressed hypoxia‐inducible factor‐1‐α (marker of hypoxia) and showed no significant difference in levels of combined ADP and ATP or lactate (glycolytic end product). Further studies are needed to confirm whether hypoxic AAA cells adapt through metabolic depression rather than glycolysis. The downregulation of protein synthesis during such metabolic depression may be a factor in hypoxia‐mediated wall weakening.

Gene expression profile of abdominal aortic aneurysm rupture.

Abstract:  To search for novel transcriptional pathways that are activated in abdominal aortic aneurysm rupture, cDNA microarrays were used to compare global mRNA expression at the aneurysm rupture edge to anterior sac, and selected results were confirmed using quantitative real‐time‐polymerase chain reaction (QRT‐PCR). This study identified apoptosis, angiogenesis, and inflammation as potentially important participants during the process of aneurysm rupture.

Medical and lifestyle management of peripheral arterial disease

OBJECTIVE Peripheral arterial disease (PAD) is a global health issue associated with impaired functional capacity and elevated risk of major adverse cardiovascular events (MACEs). With changing risk factor profiles and an aging population, the burden of disease is expected to increase. This review considers evidence for the noninvasive management of PAD and makes clinical recommendations accordingly. METHODS A comprehensive literature review was performed to examine the evidence for smoking cessation, exercise therapy, antiplatelet therapy, anticoagulant therapy, antihypertensive therapy, lipid-lowering therapy, and glycemic control in diabetes for patients with PAD. RESULTS Nicotine replacement, bupropion, and varenicline are safe and more effective than placebo in achieving smoking abstinence. Wherever it is practical and available, supervised exercise therapy is ideal treatment for intermittent claudication. Alternatively, step-monitored exercise can increase walking performance and the participants compliance with less staff supervision. Clopidogrel is preferable to aspirin alone for all patients. However, small studies support the use of dual antiplatelet therapy after revascularization to improve limb outcomes. More recently, the addition of low-dose rivaroxaban to aspirin alone was proven to be more effective in reducing MACEs without a significant increase in major bleeding. However, the exact role of direct oral anticoagulant therapy in the management of PAD is still being understood. Evidence is emerging for more intensive blood pressure and lipid-lowering therapy than traditional targets. Whereas research in PAD is limited, there is clinical scope for an individualized approach to these risk factors. The management of diabetes remains challenging as glycemic control has not been demonstrated to improve macrovascular outcomes. Any potential impact of glycemic control on microvascular disease needs to be weighed against the risks of hypoglycemia. Sodium-glucose cotransporter 2 inhibitors appear to reduce MACEs, although caution is advised, given the increased incidence of lower limb amputation in clinical trials of canagliflozin. CONCLUSIONS Medical and lifestyle management of PAD should aim to improve functional outcomes and to reduce MACEs. Smoking cessation counseling or pharmacotherapy is recommended, although new strategies are needed. Whereas supervised exercise therapy is ideal, there can be barriers to clinical implementation. Other initiatives are being used as an alternative to walking-based supervised exercise therapy. More studies are required to investigate the role of intensive glycemic, blood pressure, and dyslipidemia control in patients with PAD. Overall, a multifactorial approach is recommended to alter the natural history of this condition.